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OA16765A - Viral replication inhibitors. - Google Patents

Viral replication inhibitors. Download PDF

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Publication number
OA16765A
OA16765A OA1201400135 OA16765A OA 16765 A OA16765 A OA 16765A OA 1201400135 OA1201400135 OA 1201400135 OA 16765 A OA16765 A OA 16765A
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OAPI
Prior art keywords
heterocycle
alkyl
alkynyl
alkenyl
aryl
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OA1201400135
Inventor
Arnaud Marchand
Dorothée BARDIOT
Gunter Carlens
Kai DALLMEIER
Suzanne Kaptein
Michael McNAUGHTON
Johan Neyts
Wim Smets
Mohamed Koukni
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Katholieke Universiteit Leuven
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Abstract

The present invention relates to a series of novel compounds, methods to prevent or treat viral infections in animals by using the novel compounds and to said novel compounds for use as a medicine, more preferably for use as a medicine to treat or prevent viral infections, particularly infections with RNA viruses, more particularly infections with viruses belonging to the family of the Flaviviridae, and yet more particularly infections with the Dengue virus. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of viral infections. The invention also relates to processes for preparation of the compounds.

Description

The présent invention relates to a sériés of novel compounds, methods to prevent or treat viral infections in animais by using the novel compounds and to said novel compounds for use as a medicine, more preferably for use as a medicine to treat or prevent viral infections, particularly infections with RNA viruses, more particularly infections with viruses belonging to the family of the Flaviviridae, and yet more particularly infections with the Dengue virus. The présent invention furthermore relates to pharmaceutical compositions or combination préparations of the novel compounds, to the compositions or préparations for use as a medicine, more preferably for the prévention or treatment of viral infections. The invention also relates to processes for préparation of the compounds.
BACKGROUND OF THE INVENTION
Flaviviruses, which are transmitted by mosquitoes or ticks, cause life-threatening infections in man, such as encephalitis and hémorrhagie fever. Four distinct, but closely related serotypes of the flavivirus dengue are known (DENV-1, -2, -3, and -4). Dengue is endemic in most tropical and sub-tropical régions around the world, predominantly in urban and semi-urban areas, According to the World Health Organization (WHO), 2.5 billion people of which 1 billion children are at risk of DENV infection (WHO, 2002). An estimated 50 to 100 million cases of dengue fever [DF], half a million cases of severe dengue disease (i.e. dengue hémorrhagie fever [DHF] and dengue shock syndrome [DSS]), and more than 20,000 deaths occur worldwide each year. DHF has become a leading cause of hospitalisation and death amongst children in endemic régions. Altogether, dengue represents the most common cause of arboviral disease. Because of recent large outbreaks in countries situated in Latin America, South-East Asia and the Western Pacifie (including Brazil, Puerto Rico, Venezuela, Cambodia, Indonésie, Vietnam, Thailand), numbers of dengue cases hâve risen dramatically over the past years. Not only is the number of dengue cases increasing as the disease is spreading to new areas, but the outbreaks tend to be more severe.
To prevent and/or control dengue disease, the only available methods at présent are mosquito éradication strategies to control the vector. Although progress is being made in the development of vaccines for dengue, many difficulties are encountered. These include the existence of a phenomenon referred to as antibody-dependent enhancement (ADE).
Recovery from an infection by one serotype provides lifelong immunity against that serotype but confers only partial and transient protection against a subséquent infection by one of the other three serotypes. Following infection with another serotype, pre-existing heterologous antibodies form complexes with the newly infecting dengue virus serotype but do not neutralize the pathogen. Instead, virus entry into cells is believed to be facilitated, resulting in uncontrolled virus réplication and higher peak viral titres. In both primary and secondary infections, higher viral titres are associated with more severe dengue disease. Since maternai antibodies can easily pass on to infants by breast feeding, this might be one of the reasons that children are more affected by severe dengue disease than adults.
In locations with two or more serotypes circulating simultaneously, also referred to as hyperendemic régions, the risk of serious dengue disease is significantly higher due to an increased risk of experîencing a secondary, more severe infection. Moreover, in a situation of hyper-endemicity, the probability of the emergence of more virulent strains is increased, which in turn augmente the probability of dengue hémorrhagie fever (DHF) or dengue shock syndrome.
The mosquitoes that carry dengue, including Aedes aegypti and Aedes albopictus (tiger mosquito), are moving north. According to the United States (US) Centers for Disease Control and Prévention (CDC), both mosquitoes are currently omniprésent in southern Texas. The spread north of dengue-carrying mosquitoes is not confined to the US, but has also been observed in Europe.
Despite large efforts over the past 3 décades, there is currently no vaccine available to protect against dengue virus disease. The main problem is to develop a vaccine that offers protection against ail four serotypes (a tetravalent vaccine) to the same extent. Furthermore, today, spécifie antiviral drugs for the treatment or prévention of dengue fever virus infection are not available. Clearly, there is still a great need for therapeutics for the prévention or treatment of viral infections in animais, more in particular in humans and especially for viral infections caused by Flaviviruses, more in particular Dengue virus. Therapeutics with good potency, no or low levels of less side-effects, a broad spectrum activity against multiple Dengue virus serotypes, a low toxîcity and/or good pharmacokinetic or -dynamic properties are very welcome. The présent invention provides novel compounds which show activity against Flaviviruses, including Dengue virus. The prior art does not lead a person skilled in the art to the compounds of the présent invention, nor to their use as antiviral compounds.
SUMMARY OF THE INVENTION
The présent invention is based on the unexpected finding that at least one of the abovementioned problems can be solved by a novel class of compounds.
The présent invention provides new compounds which hâve been shown to possess antiviral activity. The présent invention furthermore demonstrates that these compounds effîciently inhibit prolifération of viruses, especially Flaviviruses, more specifically Dengue virus (DENV) and Yellow Fever virus (YFV). Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and/or prévention of viral infections in animais, mammals and humans, more specifically for the treatment and/or prévention of infections with viruses belonging to the family of the Flaviviruses, and yet more particularly infections with Dengue viruses or yellow fever virus.
The présent invention furthermore relates to the use of such compounds as medicines and to their use for the manufacture of médicaments for treatîng and/or preventing viral infections, in particular with viruses belonging to the family of the Flaviviruses, and yet more particularly infections with Dengue viruses or yellow fever virus, in animais or mammals, more in particular în humans. The invention also relates to methods for the préparation of ail such compounds and to pharmaceutical compositions comprising them in an effective amount.
The présent invention also relates to a method of treatment or prévention of viral infections in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof. Particularly, the présent invention also relates to a method of treatment or prévention of viral infections, especially Fiaviviral infections, in humans by the administration of an effective amount of one or more such compounds or a pharmaceutically acceptable sait thereof, optionally in combination with one or more other medicines, to a patient in need thereof. More particularly, the présent invention also relates to a method of treatment or prévention of infections by the Dengue virus or yellow fever virus in humans by the administration of an effective amount of one or more such compounds or a pharmaceutically acceptable sait thereof, optionally in combination with one or more other medicines, to a patient in need thereof.
One aspect of the invention is the provision of new compounds of formula (A),
wherein,
- cycle A is a heterocycle, which can be unsubstituted or substituted with one or more Z1;
- cycle B is selected from aryl; and heterocycle; wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1a;
- R1 is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-heteroalkyl; heterocycleheteroalkenyl; heterocycle-heteroalkynyl;
and wherein said cycloalkyl; cycloalkenyl; cycloalkynyl; aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycleheteroalkenyl and heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more Z1b;
- R2 is selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, can be unsubstituted or substituted with one or more Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen; hydroxyl; sulfhydryl; -OZz; =O; -SZ2; =S; -S(O)Z2; -S(O)2Z3; -S(O)2NZ4Z5; trifluoromethyl; trifluoromethoxy; nitro; -NZ4Z5; -NZ4S(O)2Z2; -NZ4C(O)Z2; -NZ4C(O)NZ4Z5; cyano; -C(O)Z3; C(O)OZ2; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycleheteroalkyl, heterocycle-heteroalkenyl; or heterocycie-heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, a ryi heteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycie-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2;
- each Z2 is independently selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkeny); or heterocycie-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycie-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NH2;
- each Z3 is independently selected from hydroxyl; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycie-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycie-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NH2;
- each Z4 and Z5 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(0)0H or NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(O)OH or-NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof,
DETAILED DESCRIPTION OF THE FIGURES
Figure 1: Kaplan Meier plot of dengue virus induced mortality/euthanasia in AG129 mice and the effect of treatment with Celgosivir and CPD-242. The red dotted line indicates end of treatment.
DETAILED DESCRIPTION OF THE INVENTION
The présent invention will be described with respect to particular embodiments but the invention is not limited thereto.
A first embodiment of the présent invention relates to a compound according to formula (D).
wherein
- each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7 and Xe is independently selected from CR3; NR4; O; and S;
- each of X4 and X9 is independently selected from C; CH; and N;
- p is 0; 1; or 2;
-q is 0; 1; or2;
- cycle B is selected from aryl; and heterocycle; wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1a; provided that cycle B is not unsubstituted phenyl;
- R1 is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-heteroalkyl; heterocycleheteroalkenyl; heterocycle-heteroalkynyl;
and wherein said cycloalkyl; cycloalkenyl; cycloalkynyl; aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycleheteroalkenyl and heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more Z1b;
- R2 is selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, can be unsubstituted or substituted with one or more Z1c;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen; hydroxyl; sulfhydryl; -S(O)Z2; -S(O)2Z3; S(O)2NZ4Z5; trifluoromethyl; -C(O)Z3; -C(O)OZ2; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl; or heterocycleheteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3l cyano, nitro, -C(O)OH or NH2;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen; hydroxyl; sulfhydryl; -OZ2; =0; -SZ2; =S; -S(O)Z2; -S(O)2Z3; -S(O)2NZ4Z5; trifluoromethyl;
trifluoromethoxy; nitro; -NZ4Z5; -NZ4S(O)zZ2; -NZ4C(O)Z2; -NZ4C(O)NZ4Z5; cyano; -C(O)Z3; C(O)OZ2; -C(O)NZ4Z5; -C(O)H; aikyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycleheteroalkyl, heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
and wherein said aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2;
- each Z2 is independently selected from aikyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from aikyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NHZ;
- each Z3 is independently selected from hydroxyl; aikyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from aikyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NH2;
- each Z4 and Z5 is independently selected from hydrogen; aikyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl;
heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NHZ;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(O)OH or -NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
In a second embodiment, the compounds hâve a structure according to formula (D3),
In a third embodiment, the compounds hâve a structure according to formula (F1)
In a fourth embodiment, the present invention relates to a compound of formula (D) for use as a medicine,
wherein
- each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7 and X8 is independently selected from CR3; NR4; O; and S;
- each of X4 and X9 is independently selected from C; CH; and N;
- p is 0; 1; or 2;
- q is 0; 1; or 2;
- cycle B is selected from aryl; and heterocycle; wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1a;
- R1 is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-heteroalkyl; heterocycleheteroalkenyl; heterocycle-heteroalkynyl;
and wherein said cycloalkyl; cycloalkenyl: cycloalkynyl; aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycleheteroalkenyl and heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more Z1b;
- Rz is selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, can be unsubstituted or substituted with one or more Z1c;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen; hydroxyl; sulfhydryl; -S(O)Zz; -S(O)2Z3; S(O)2NZ4Z5; trifluoromethyl; -C(O)Z3; -C(O)OZz; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl; or heterocycleheteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, aryl heteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen; hydroxyl; sulfhydryl; -OZ2; =0; -SZ2; =S; -S(O)Z2; -S(O)2Z3; -S(O)2NZ4Z5; trifluoromethyl; trifluoromethoxy; nitro; -NZ4Z5; -NZ4S(O)2Z2; -NZ4C(O)Z2; -NZ4C(O)NZ4Z5; cyano; -C(O)Z3; C(O)OZ2; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycleheteroalkyl, heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2;
- each Z2 is independently selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NH2;
- each Z3 is independently selected from hydroxyl; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF31 cyano, nitro, C(O)OH or NH2;
- each Z4 and Z5 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyi; heteroalkenyl; heteroalkynyi; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyi, heteroalkenyl, heteroalkynyi, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)0H or NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(O)OH or -NH2;
and isomers (in partîcular stereo-isomers or tautomers), solvatés, salts (in partîcular pharmaceutically acceptable salts) or prodrugs thereof.
A fifth embodiment relates to a compound of formula (A) for use as a médicament for the prévention or treatment of a viral infection in an animal (including a human)
R’ (A) wherein,
- cycle A is a heterocycle, which can be unsubstituted or substituted with one or more Z1;
- cycle B is selected from aryl; and heterocycle; wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1a;
- R1 is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-heteroalkyl; heterocycleheteroalkenyl; heterocycle-heteroalkynyl;
and wherein said cycloalkyi; cycloalkenyl; cycloalkynyl; aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycleheteroalkenyl and heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more Z1b;
- R2 is selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, can be unsubstituted or substituted with one or more Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen; hydroxyl; sulfhydryl; -OZ2; =0; -SZ2; =S; -S(O)Z2; -S(O)2Z3; -S(O)2NZ4Z5; trifluoromethyl; trifluoromethoxy; nitro; -NZ4Z5; -NZ4S(O)2Z2; -NZ4C(O)Z2; -NZ4C(O)NZ4Z5; cyano; -C(O)Z3; C(O)OZ2; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycleheteroalkyl, heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2;
- each Z2 is independently selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF31 cyano, nitro, C(O)OH or NH2;
- each Z3 is independently selected from hydroxyl; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl;
heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, aryl heteroalkyl, aryl heteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(O)OH or NH2;
- each Z4 and Z5 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF31 cyano, nitro, C(O)OH or NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(O)OH or -NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
A sixth embodiment relates to a compound of formula (B) for use as a médicament for the prévention or treatment of a viral infection in an animal (induding a human)
wherein
- each dotted line représente an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7 and X8 is independently selected from CR3; NR4; O; and S;
- each of X4 and X9 is independently selected from C; CH; and N;
- X10 is selected from C; CH; and N; whereby minimally 5 of X1 to X10 are selected from CR3, C or CH;
- p is 0; 1; or 2;
- q is 0; 1; or 2;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen; hydroxyl; sulfhydryl; -S(O)Z2; -S(O)2Z3; S(O)2NZ4Z5; trifluoromethyl; -C(O)Z3; -C(O)OZ2; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl; or heterocycleheteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2.
In a seventh embodiment, the présent invention relates to a compound of formula (C) for use as a médicament for the prévention or treatment of a viral infection in an animal (including a human),
In an eighth embodiment, the présent invention relates to the compounds and uses thereof according to the previous embodiments, wherein R2 is hydrogen.
In a ninth embodiment, the présent invention relates to the compounds and uses thereof according to the previous embodiments, wherein R1 is selected from aryl and heterocycle, wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1b.
The présent invention further relates to the compounds according to the previous embodiments, for use as a medicine for the prévention or treatment of a viral infection of an animal.
In one embodiment, the viral infection is an infection with Flavivirus.
In a further embodiment, the Flavivirus is Dengue virus.
The présent invention further relates to a pharmaceutical composition comprising the compounds according to the fourth to ninth embodiments in combination with a pharmaceutically acceptable carrier.
The présent invention further relates to a method for the prévention or treatment of a viral infection in an animal comprising administering said animal (including a human) in need for such prévention or treatment an effective dose of the compounds according to any one of the previous embodiments.
The présent invention further relates a method for the préparation of the compounds according to the first three embodiments, comprising the steps of:
- reacting an heterocycle under Friede! Craft conditions to obtain a ketone dérivative having a methylene adjacent to the carbonyl;
- reacting the previously obtained ketone under halogénation conditions to obtain an alphahalogenoketone;
- substitute the previously obtained alpha-halogenoketone with amines to obtain the desired compounds of the invention.
One aspect of the invention is the provision of compounds of formula (A), R! (A) wherein,
- cycle A is a heterocycle optionally substituted with one, two, or three Z1; preferably cycle A is a heterocycle optionally substituted with one or two Z1; more preferably cycle A is a heterocycle selected from
wherein the wavy line (— ) indicates the point of attachment to the carbonyl of the main formula (A), and wherein the depicted heterocycles may be optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z preferably cycle B is selected from
1a.
!
I
I
I r
/
I l/W
I sH-TV I aux, I
AA
I ,
AA
AW i
ΛΛ,
I ,
AA 1 .
JVC v/W vfW
wherein the wavy line (—) indicates the point of attachment to the carbon atom of the main formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from Ci^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2^alkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2. 6alkenyl, heterocycie-C2.ealkynyl, arylheteroC^alkyl, arylheteroC2^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^ alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2. 6alkynyl; preferably R1 is selected from C^alkyl, C3.7cycloalkyl, aryl, heterocycle;
and wherein said C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2-6alkenyl, arylC2.6alkynyl, heterocycle-Ci.6alkyl, heterocycleC2.6alkenyl, heterocycle-C2.6alkynyl, arylheteroC^ealkyl, arylheteroC^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycleheteroC2.6alkynyl, are optionally substituted with one, two, or three Z1b; preferably said Ci. 6alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three Z1b;
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC2.6alkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and C^alkyl;
and wherein said C16alkyl, C2.6alkenyl, C2^alkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC2.6alkynyl, are optionally substituted with one, two, or three Z1c; preferably said Ci_6alkyl is optionally substituted with one, two, or three Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, CV6alkyl, C^alkenyl, C2. 6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylCi.6alkyl, arylC2^alkenyl, arylC^alkynyl, arylheteroCi^alkyl, arylheteroC2.6alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC!. 6alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl; preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)2Z2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZz, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Ci_6alkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =O, S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Zz, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, Ci^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C^alkyl;
and wherein said Ci.6alkyl, C2^alkenyl. C2.6alkynyl, heteroCvealkyl, heteroC2^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCujalkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-Cvgalkyl, heterocycle-C2.6alkenyl, heterocy cle-C2^a I ky n y I, heterocycle-heteroC^alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2^aikenyl, C2. 6alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2-6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -CiOJOCvealkyl, NH2, -NHCH3; -N(CH3)z, -NH-C(=O)O-CMalkyl, morpholinyl, -S(O)2CMalkyl, and -O-Cv 6alkyl; preferably said Ci^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C;. 6alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, C(O)OH, -CiOpCrealkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-ClJ(alkyl, morpholinyl, S(O)2ClJtalkyl, and -O-C^alkyl; more preferably said Ci.6alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(O)Me, cyano, -C(O)OH, -C{O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O·^. 4alkyl, morpholinyl, -S(O)2C1.4alkyl, and -O-C^alkyl;
- each Z2 is independently selected from Ci^alkyl, C^alkenyl, C2^alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC1_6alkyl, arylC2.6alkenyl, arylC2. ealkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C2^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroCi^alkyl, heterocycleheteroC2^alkenyl, and heterocycle-heteroC2Îalkynyl; preferably Z2 is independently selected from Ci.6alkyl, aryl, heterocycle, and heterocycle-C^alkyl; more preferably Z2 is independently selected from C^alkyl, aryl, and heterocycle-C^alkyl;
wherein said C^alkyl, C^alkenyl, C2^alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.0alkynyl, arylheteroCi^alkyl, arylheteroC2^alkenyl, arylheteroC2.6a1kynyl, heterocycle-Cvealkyl, heterocycle-C2^alkenyl, heterocycle-C^aikynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C^alkyl, OCF3, -S(=O)2C^alkyl, cyano, nitro, -C(-O)OH, -C(s=O)O-CMalkyl, -NH2, -Ν(ΟΗ3)2, pyrrolidinyl, piperidinyl, and piperazinyl; preferably said Ci.6alkyl, aryl, heterocycle, and heterocycle-C^alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -Ο-ΟΊ. 6alkyl, -OCF3, -S(=O)2C1.4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C1.4alkyl, -NH2, 16765
N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said Ci^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C^alkyl, -S(=O)2ClJ1alkyl1 -C(=O)OH, -C(=O)O-C1.4alkyl, NH2, -N(CH3)2i pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, Ci^alkyl, C2.6alkenyl, C2.ealkynyl, heteroC-i. 6alkyl, heteroC2.6aîkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.6alkynyl, arylheteroCi^alkyl, arylheteroC2.6alkenyl, arylheteroC2^alkynyl, heterocycle-C,. 6alkyl, heterocycle-C2.6alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCvealkyl, heterocycleheteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl; preferably Z3 is independently selected from hydroxyl, Ci^alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, C^alkyl, and heterocycle;
wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2.ealkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-Cvgalkyl, heterocycle-C2.6alkenyl, heterocycle-C2.aalkynyl, heterocycle-heteroCMalkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2_6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3l cyano, nitro, -C(=O)OH, -NH2, and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from Cv6alkyl and N(CH3)2; more preferably said Ci_6alkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, Ci^alkyl, C2.6alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2.6alkynyl, aryl, C3.7cycloalkyl, heterocycle, arylCv 6alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroCMalkyl, arylheteroC2.6alkenyl, arylheteroC2. 6alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2^alkynyl, heterocycleheteroCvealkyl, heterocycle-heteroC2.ealkenyl, and heterocycle-heteroC2.ealkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, Ci^alkyl, aryl, C3.7cycloalkyl, and heterocycle; more preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
wherein said C^alkyl, C2.6alkenyl, C2^alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2.ealkenyl, arylheteroCMalkynyl, heterocycle-Cvealkyl, heterocycle-C^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^ealkyl, -OCF3) cyano, nitro, -C(=O)OH or -NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with C^alkyl, C2.6alkenyl, C2.6alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, orNH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
One aspect of the invention relates to compounds of formula (A),
(A) wherein,
- cycle A is a heterocycle optionally substituted with one, two, or three Z1; preferably cycle A is a heterocycle optionally substituted with one or two Z1; more preferably cycle A is a heterocycle selected from
wherein the wavy line (— ) indicates the point of attachment to the carbonyl of the main formula (A), and wherein the depicted heterocycles may be optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a; preferably cycle B is selected from
H
wherein the wavy line (— ) indicates the point of attachment to the carbon atom of the main formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from C^alkyl, Cs.rcycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylCi^alkyl, arylCz^alkenyl, arylC2.6alkynyl, heterocycle-Ci^alkyl, heterocycle-Cz. 6alkenyl, heterocycle-C2^alkynyl, arylheteroC^alkyl, arylheteroCz^alkenyl, arylheteroCz. 6alkynyl, heterocycle-heteroC;^ alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC2. ealkynyl; preferably R1 is selected from C^alkyl, C3.7cycloalkyl, aryl, heterocycle;
and wherein said C^alkyl, Cs^cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylCvealkyl, arylCz.ealkenyl, arylCz.6alkynyl, heterocycle-C^alkyl, heterocycleC^alkenyl, heterocycle-CZ-6alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2. ealkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroCz^alkenyl, and heterocycleheteroC2^alkynyl, are optionally substituted with one, two, or three Z1b; preferably said C,. 6alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three Z1b;
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, C2^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC^alkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and Ci_6alkyl;
and wherein said C^alkyl, C2.6alkenyl, C2.ealkynyl, heteroCi.6alkyl, heteroC^alkenyl, and heteroC^alkynyl, are optîonally substituted with one, two, or three Z1c; preferably said O-alkyl is optîonally substituted with one, two, or three Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C2.6alkenyl, C2. 6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC-i-ealkyl, arylC^alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC2.6alkynyl, heterocycle-Ci.6alkyl, heterocycle-C2.6alkenylt heterocycle-C2.6alkynyl, heterocycle-heteroCi. 6alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl; preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =O, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^afkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Ci.6alkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =0, S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-CV6alkyl;
and wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC243alkenyl, arylheteroC2.6alkynyl, heterocycle-Ci^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCV6alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2.6alkynyl, are optîonally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, heteroCi^alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OCi^alkyl, NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl, morpholinyl, -S(O)2CMalkyl, and -O-Cv 6alkyl; preferably said C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Ci. 6alkyl, are optîonally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-C^alkyl, morpholinyl, S(O)2Ci.4alkyl, and -O-C^alkyl; more preferably said C^calkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(O)Me, cyano, -C(O)0H, -C(O)OC1.6alkyl, -NHZ1 -NHCH3; -N(CH3)2, -NH-C(=O)O-CV 4alkyl, morpholinyl, -S(O)2CMalkyl, and -O-C^alkyl;
- each Z2 is independently selected from C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.Galkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylCh-ealkyl, arylC^alkenyl, arylC2. 6alkynyl, arylheteroCvealkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroCvealkyl, heterocycleheteroC2^alkenyl, and heterocycle-heteroC^alkynyl; preferably Z2 is independently selected from C^alkyl, aryl, heterocycle, and heterocycle-C^alkyl; more preferably Z2 is independently selected from C^alkyl, aryl, and heterocycle-C^alkyl;
wherein said C^alkyl, C2.6alkenyl, C2^alkynyl, heteroCi^alkyl, heteroC2^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylCi^alkyl, arylC2.ealkenyl, arylC2.6alkynyl, arylheteroCi.6alkyl, arylheteroC^alkenyl, arylheteroC2^alkynyl, heterocycle-Ci.6alkyl, heterocycle-C^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.Balkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C^alkyl, OCF3, -S(=O)2Ci_4alkyl. cyano, nitro, -C(=O)OH, -C(=O)O-CMalkyl, -NH2, and -N(CH3)21 pyrrolidinyl, piperidinyl, and piperazinyl; preferably said Cvealkyl, aryl, heterocycle, and heterocycle-C^alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -Ο-Ομ 6alkyl, -OCF3, -S(=O)2ClJ]alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C1.4alkyi, -NH2, and N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said Ci^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C^alkyl, -S(=O)2CMalkyl, -C(=O)OH, -C(=O)O-Ci^alkyl, NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, Ci^alkyl, C2.6alkenyl, C2.6alkynyl, heteroCv 6alkyl, heteroC2.6alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCvgalkyl, arylheteroC2.6alkenyl, arylheteroC^alkynyl, heterocycle-Ci_ 6alkyl, heterocycle-C2.calkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycleheteroC245alkenyl, and heterocycle-heteroC2^alkynyl; preferably Z3 is independently selected from hydroxyl, C^alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, C^alkyl, and heterocycle;
wherein said C^alkyl, C2.5alkenyl, C2.ealkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCi.6alkyl, arylheteroC2.6alkenyl, arylheteroC2.Galkynyl, heterocycle-Cvealkyl, heterocycle-C2^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCi.6alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.ealkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, -NH2, and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from Cn.6alkyl and N(CH3)2; more preferably said Ci.6alkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, C^alkyl, C^alkenyl, C2.ealkynyl, heteroCi.6alkyl, heteroC2.ealkenyl, heteroC2.6alkynyl, aryl, C3.7cycloalkyl, heterocycle, arylC;. 6alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCvealkyl, arylheteroC2.6alkenyl, arylheteroC2. ealkynyl, heterocycle-Cvealkyl, heterocycle-C2.6alkenyl, heterocycle-C2.ealkynyl, heterocycleheteroCi.6alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2.6alkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, aryl, C3.7cycloalkyl, and heterocycle; more preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
wherein said C^alkyl, C2.6alkenyl, C2^alkynyl, heteroCi.ealkyl, heteroC^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylCi_6alkyl, arylC2.6alkenyl, arylC2.ealkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC^alkynyl, heterocycle-Ci.6alkyl, heterocycle-C2.ealkenyl, heterocycle-C^alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.ealkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, or -NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with C-t.ealkyl, C2.6alkenyl, C2.6alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof;
with the proviso that compound of formula (A) is not
- N-( 5-(2-( 7-ethyl-1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)-2-methoxyphenyl)methanesulfonamide (CAS nr. 1294288-37-1);
- 3-(2-(1H-îndol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-212)!
- 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-pheny!ethanone (CAS nr. 1090733-87-1);
- 1-(1 H-indol-S-yl^-phenyl^-Îpyridin-S-ylmethylaminoJethanone (CAS nr. 875860-58-5); or
- 2-(benzo[d][1,3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 920816-95-1).
One aspect of the invention relates to the compounds of formula (A) for use as a medicine,
wherein,
- cycle A is a heterocycle optionally substituted with one, two, or three Z1; preferably cycle A is a heterocycle optionally substituted with one or two Z1; more preferably cycle A is a heterocycle selected from
wherein the wavy line (— ) indicates the point of attachment to the carbonyl of the main formula (A), and wherein the depicted heterocycles may be optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally 15 substituted with one, two, or three Z1a; preferably cycle B is selected from
formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2. 6alkenyl, heterocycle-C2^alkynyl, arylheteroCi.6alkyl, arylheteroC2^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^ alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2. 6alkynyl; preferably R1 is selected from C^alkyl, C3.7cycloalkyl, aryl, heterocycle;
and wherein said C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylCvealkyl, arylC2.salkenyl, arylC2.6alkynyl, heterocycle-C^ealkyl, heterocycleC2.6alkenyl, heterocycle-C2.6alkynyl, arylheteroCi.6alkyl, arylheteroC2.6alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2^alkenyl, and heterocycleheteroC2^alkynyl, are optionally substituted with one, two, or three Z1b; preferably said Ci. ealkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three Z1b;
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC2.6alkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and C1.6alkyl;
and wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2^alkenyl, and heteroC2.6alkynyl, are optionally substituted with one, two, or three Z1c; preferably said C^alkyl is optionally substituted with one, two, or three Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C2.6alkenyl, C2. 6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC^alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCi. ealkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl; preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=0)-OZ2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4ZS, -C(=O)H, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C^alkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =0, S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, heteroCv6alkyl, aryl, heterocycle, and heterocycle-C^alkyl;
and wherein said Ci^alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2-6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC2.6alkynyl, heterocycle-Cvealkyl, heterocycle-C2^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from Ci.6alkyl, C2^alkenyl, C2. 6alkynyl, heteroCi^alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(0)0H, -C(O)OC^alkyl, NH2, -NHCH3; -N(CH3)21 -NH-C(=O)O-CMalkyl, morpholinyl, -S(O)2C1Jtalkyl, and -0-0^ 6alkyl; preferably said C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C-i. 6alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -0-C(0)Me, cyano, nitro, C(0)0H, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl, morpholinyl, S(O)2C1^alkyl, and -O-Cvealkyl; more preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(0)Me, cyano, -C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CV 4alkyl, morpholinyl, -S(O)2CMalkyl, and -O-C^alkyl;
- each Z2 is independently selected from C^alkyl, C2.6alkenyl, C^alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC-i_Galkyl, arylC2^alkenyl, arylC2. 6alkynyl, arylheteroCvealkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCvealkyl, heterocycle16765 heteroC2.6alkenyl, and heterocycle-heteroC2^alkynyl; preferably Z2 is independently selected from C^alkyl, aryl, heterocycle, and heterocycle-Ci.6aikyl; more preferably Z2 is independently selected from C^alkyl, aryl, and heterocycle-Cvgalkyl;
wherein said Ci^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2_ealkenyl, heteroCMalkynyl, aryl, heterocycle, arylC^alkyl, arylC2-6alkenyl, arylC2^alkynyl, arylheteroC^alkyl, arylheteroC2^alkenyl, arylheteroC2^alkynyl, heterocycle-Cvealkyl, heterocycle-C2.6aikenyl, heterocycle-C^alkynyl, heterocycle-heteroC-i^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, “S, trifluoromethyl, difluoromethyl, -O-C^alkyi, OCF3, -S(=O)2Ci_4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-CMalkyl, -NH21 and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; preferably said Ci^alkyl, aryl, heterocycle, and heterocycle-C^alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-Ci. 6alkyl, -OCF3, -S(=O)2ClJ(alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-ClJlalkyl, -NH21 and N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said C^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C^alkyl, -S(=O)2ClJtalkyl, -C(=O)OH, -C(=O)O-Ci.4alkyl, NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, Ci^alkyl, C2.6alkenyl, C^alkynyl, heteroC-i. 6alkyl, heteroC2^alkenyl, heteroC2.salkynyl, aryl, heterocycle, arylC^alkyl, arylC2.ealkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC2.6alkynyl, heterocycle-Cv 6alkyl, heterocycle-C2.5alkenyl, heterocycle-C2.Galkynylr heterocycle-heteroCi.calkyl, heterocycleheteroC2.caikenyl, and heterocycle-heteroC26alkynyl; preferably Z3 is independently selected from hydroxyl, Cn.6alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, Cvealkyl, and heterocycle;
wherein said Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, heteroCi^alkyl, heteroC2^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylCi.6alkyl, arylC2.ealkenyl, arylCMalkynyl, arylheteroCi.6alkyl, arylheteroC2.6alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2-6alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, -NH21 and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from C^lkyl and N(CH3)2; more preferably said Ci.ealkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroCj-ealkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, aryl, C3.7cycloalkyl, heterocycle, arylCv 0alkyl, arylC2.6alkenyl, arylC26alkynyl, arylheteroCvealkyl, arylheteroC2^alkenyl, arylheteroC2. 6alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.ealkynyl, heterocycleheteroCi^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2.6alkynyl; preferably each Z4 and Zs is independently selected from hydrogen, C^alkyl, aryl, C3.7cycloalkyl, and heterocycle; more preferably each Z4 and Zs is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC^alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyi, arylheteroC2^alkynyl, heterocycle-Cvealkyl, heterocycle-C2Îalkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, or -NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with Cvealkyl, C2.6alkenyl, C2^alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-Ci.6alkyl, -OCF3, cyano, nitro, -C(=O)OH, or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in partîcular pharmaceutically acceptable salts) or prodrugs thereof,
One aspect of the invention relates to the compounds of formula (A) for use in the prévention or treatment of a flavivirus infection in an animal, mammal or human, preferably an infection with dengue virus or yellow fever virus,
wherein,
- cycle A is a heterocycle optionally substituted with one, two, or three Z1; preferably cycle A is a heterocycle optionally substituted with one or two Z1; more preferably cycle A is a heterocycle selected from
wherein the wavy line (-^ ) indicates the point of attachment to the carbonyl of the main formula (A), and wherein the depicted heterocycles may be optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a; preferably cycle B is selected from
wherein the wavy line (~~) indicates the point of attachment to the carbon atom of the main formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
• R1 is selected from C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2^alkenyl, arylCz.6alkynyl, heterocycle-Ci^alkyl, heterocycle-C2. ealkenyl, heterocycle-C2^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC,^ alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2. 6alkynyl; preferably R1 is selected from C^alkyl, C3.7cycloalkyl, aryl, heterocycle;
and wherein said C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylCi-6alkyl, arylCz.6alkenyl, arylC2.6alkynyl, heterocycle-Cvealkyl, heterocycleCz.6alkenyl, heterocycle-C2.6alkynyl, arylheteroC^alkyl, arylheteroCz^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycleheteroC^alkynyl, are optionally substituted with one, two, or three Z1b; preferably said Ομ 6alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three i
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, Cz^alkenyl, C2.ealkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC2^alkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and C^alkyl;
and wherein said C^ealkyl, C^alkenyl, CMalkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC2.6alkynyl, are optionally substituted with one, two, or three Z1c; preferably said Ci_ealkyl is optionally substituted with one, two, or three Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =O, -SZ2, =S, -S(=O)Z2, -S(=O)zZ3, -S(=O)zNZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C^alkenyl, C2. 6alkynyl, heteroCi.6alkyl, heteroC2.6alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC^alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroCz.6alkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCv 6alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2Îalkynyl; preferably each Z1, Z1a, Z1b, and Z1e is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)zZ3, -S(=O)zNZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)zZ2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, Cvealkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Cvgalkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =O, S(=O)zZ3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^lkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C^alkyl;
and wherein said Ci^alkyl, C2.ealkenyl, Cz^alkynyl, heteroCvealkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylCz.6alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl. heterocycle-C^alkyl, heterocycle-Cz.6alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2.ealkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.ealkenyl, C2. 6alkynyl, heteroCvealkyl, heteroC2^alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OCi^alkyl, NH21 -NHCH3; -N(CH3)2i -NH-C(=O)O-Ci.4alkyl, morpholinyl, -S(O)zCMalkyl, and -O-C,. 6alkyl; preferably said C^alkyl, heteroCi.Balkyl, aryl, heterocycle, and heterocycle-Ci. ealkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, C(O)OH, -C(O)OC^alkyl, -NHZ, -NHCH3; -N(CH3)21 -NH-C(=O)O-CMalkyl, morpholinyl, S(O)zCMalkyl, and -O-Ci.0alkyl; more preferably said Cvealkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(O)Me, cyano, -C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-C,. 4alkyl, morpholinyl, -StOfeC^alkyl, and -O-C^alkyl;
- each Z2 is independently selected from C^alkyl, C2.6alkenyl, C2^alkynyl, heteroCi.6alkyl, heteroC^alkenyl, heteroC2.ealkynyl, aryl, heterocycle, arylC-iæalkyl, arylC^alkenyl, arylC2. ealkynyï, arylheteroCi.6alkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-Ct^alkyl, heterocycle-Cz^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroCvealkyl, heterocycleheteroC2.6alkenyl, and heterocycle-heteroC^alkynyl; preferably Z2 is independently selected from C^alkyl, aryl, heterocycle, and heterocycle-C^alkyl; more preferably Z2 is independently selected from Ci^alkyl, aryl, and heterocycle-Ci^alkyl;
wherein said C^alkyl, C2^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroC-i^alkyl, arylheteroCz^alkenyl, arylheteroC2Îalkynyl, heterocycle-Ci^alkyl, heterocycle-C2^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.8alkynyl, are optionally substituted with one, two, or three substituents selected from Ci^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C^alkyl, OCF3, -S(=O)2Ci.4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C^alkyl, -NHZ, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; preferably said C^ealkyl, aryl, heterocycle, and heterocycle-C^alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-Ci. 6alkyl, -OCF31 -S(=O)zCMalkyl, cyano, nitro, -C(=O)OH, -C(=O)0-CMalkyl, -NH2, and 16765
N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said C^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-Ci_6alkyl, -S(=O)2Ci^alkyl, -C(=O)OH, -C(=O)O-C^alkyl, NH21 and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, C^alkyl, C2.6alkenyl, C^alkynyl, heteroCt. 6alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.ealkenyl, arylC^alkynyl, arylheteroCi.6alkyl, arylheteroC2.6alkenyl, arylheteroC2^alkynyl, heterocycle-Cfo 6alkyl, heterocycle-C2.6alkenyl, heterocycle-C2-6alkynyl, heterocycle-heteroCvealkyl, heterocycleheteroC^alkenyl, and heterocycle-heteroC2.6alkynyl; preferably Z3 is independently selected from hydroxyl, Ci^alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, Cvealkyl, and heterocycle;
wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroCi.6alkyl, heteroC2^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2^alkenyl, arylheteroC2^alkynyl, heterocycle-Ci.6alkyl, heterocycle-C^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, -NH21 and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and N(CH3)2; more preferably said C^alkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, C^alkyl, C2.ealkenyl, C2.0alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2.6alkynyl, aryl, C3.7cycloalkyl, heterocycle, arylCfo 6alkyl, arylCz.6alkenyl, arylC2^alkynyl, arylheteroCfoealkyl, arylheteroC^alkenyl, arylheteroC2. ealkynyl, heterocycle-Ci^alkyl, heterocycle-C2^alkenyl, heterocycle-C2.6alkynyl, heterocycleheteroCvoalkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, Ci^alkyl, aryl, C3.7cycloalkyl, and heterocycle: more preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, and C3-7cycloalkyl;
wherein said Ci^alkyl, C^alkenyl, C2^alkynyl, heteroCi.6alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCt^alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl, heterocycle-C-i.ealkyl, heterocycle-C2.6a Ikenyl, heterocycle-C2Îal kynyl, heterocycle-heteroC, .6al kyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from Ci^alkyl, C2-6alkenyl, C2.
ealkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH or-NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with C^alkyl, C2.6alkenyl, C2.6alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-Ci.6alkyl, -OCF3, cyano, nitro, -C(=O)OH, or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
One aspect of the invention relates to the compounds of formula (A) for use in the prévention or treatment of a flavivirus infection in an animal, mammal or human, preferably an infection with dengue virus or yellow fever virus,
(A) wherein,
- cycle A is a heterocycle optionally substituted with one, two, or three Z1; preferably cycle A is a heterocycle optionally substituted with one or two Z1; more preferably cycle A is a heterocycle selected from
wherein the wavy line (— ) indicates the point of attachment to the carbonyl of the main formula (A), and wherein the depicted heterocycles may be optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a;
preferably cycle B is selected from
H
wherein the wavy line (~~) indicates the point of attachment to the carbon atom of the main formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from C^alkyl, Cg.ycycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2^alkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2, 6alkenyl, heterocycle-C^alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^ alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2. ealkynyl; preferably R1 is selected from Cvcalkyl, C^cycloalkyl, aryl, heterocycle;
and wherein said C^alkyl, Ca^cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylCi.6alkyl, arylC2.ealkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycleC^alkenyl, heterocycle-C2.6alkynyl, arylheteroC^alkyl, arylheteroC2.Galkenyl, arylheteroC2.
Balkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycleheteroC2^alkynyl, are optionally substituted with one, two, or three Z1b; preferably said Ci.
6alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three
Z1b;
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.6alkenyl, and heteroC2.ealkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and C^alkyl;
and wherein said Ci^alkyl, C2.6alkenyl, C2^alkynyl, heteroC^alkyl, heteroC^alkenyl, and heteroC2^alkynyl, are optionally substituted with one, two, or three Z1c; preferably said C^alkyl is optionally substituted with one, two, or three Z1c;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(-O)H, CMalkyl, C2.6alkenyl, C2. 6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylCi_6alkyl, arylC^alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC2^alkynyl, heterocycle-Ci^alkyl, heterocycle-C^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroCv 6alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2-6alkynyl; preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =O, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, heteroCv6alkyl, aryl, heterocycle, and heterocycle-Ci_Balkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =0, S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C^alkyl;
and wherein said C^lkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2J6alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-Cvealkyl, heterocycle-C^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C^alkenyl, C2. 6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -0-C(0)Me, cyano, nitro, -C(0)0H, -CfOJOC^alkyl, NH2, -NHCH3; -N(CH3)2i -NH-C(=0)0-CMalkyl, morpholinyl, -S(O)2CMalkyl, and -O-Ci. 6alkyl; preferably said C^alkyl, heteroC^galkyl, aryl, heterocycle, and heterocycle-Ci. calkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -0-C(0)Me, cyano, nitro, C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl, morpholinyl, S(O)2Ci^alkyl, and -O-C^alkyl; more preferably said Cv6alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(O)Me, cyano, -C(O)OH, -C(O)OCMalkyl, -NHZ, -NHCH3; -N(CH3)2, -NH-C(=O)O-C1. 4alkyl, morpholinyl, -S(O)2CMalkyl, and —O-C^alkyl;
- each Z2 is independently selected from C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^ealkyl, arylC^alkenyl, arylC2. 6alkynyl, arylheteroC^alkyl, arylheteroCi.ealkenyl, aryiheteroC^alkynyl, heterocycle-Cbealkyl, heterocycle-C2.ealkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC^alkyl, heterocycleheteroC2^alkenyl, and heterocycle-heteroC2^alkynyl; preferably Z2 is independently selected from C-i^alkyl, aryl, heterocycle, and heterocycle-CV6alkyl; more preferably Z2 is independently selected from C^ealkyl, aryl, and heterocycle-Ci^alkyl;
wherein said Ci^alkyl, C2^alkenyl, C2^alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylCi.6alkyl, arylC2.6alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl, heterocycle-Cvealkyl, heterocycle-C2.6alkenyl, heterocycle-CMalkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C^alkyl, OCF3, -S(=O)2Ci.4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C1.4alkyl, -NH2l and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; preferably said C^alkyl, aryl, heterocycle, and heterocycle-C-i^alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C,. 6alkyl, -OCF3, -S(=O)2C1.4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C1^alkyl, -NH2, and N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said Ci.6alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C^alkyl, -S(=O)2C1.4alkyl, -C(=O)OH, -C(=O)O-Ci.4alkyl, NH2, and -N(CH3)21 pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, C^alkyl, C2.6alkenyl, C2.ealkynyl, heteroCi. 6alkyl, heteroC2.6alkenyl, heteroC^alkynyl, aryl, heterocycle, arylCv6alkyl, arylC^alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC2^alkynyl, heterocycle-C;. 6alkyl, heterocycle-C2.6alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC^alkyl, heterocycleheteroCAalkenyl, and heterocycle-heteroC2^alkynyl; preferably Z3 is independently selected from hydroxyl, Ci^alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, Ci.ealkyl, and heterocycle;
wherein said C^alkyl, C2.6alkenyl, C^ealkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.ealkenyl, arylC2.salkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC^alkynyl, heterocycle-Ci-ealkyl, heterocycle-C2^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^ealkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, -NH2, and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from Ci.6alkyl and N(CH3)2; more preferably said Ct.6alkyl and heterocycle are optionally substituted with one, two, or three substituents selected from Ci.6alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, C^alkyl, C2.6alkenyl, C2-6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2^alkynyl, aryl, C3.7cycloalkyl, heterocycle, arylCv 6alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2.ealkenyl, arylheteroC2. 6alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycleheteroCi.6alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2.6alkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, aryl, C3.7cycloalkyl, and heterocycle; more preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl, heterocycle-Cvealkyl, heterocycle-C2^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, or -NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with C^alkyl, C2.6alkenyl, C2.6alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
In a particular embodiment of this aspect of the invention, the compounds hâve a structure according to formula (B),
wherein cycle B, R1, R2, Z1, Z2, Z3, Z4, and Z5 are as defined in any one of the embodiments with formula (A), and
- each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7 and Xe is independently selected from CR3; NR4; O; and S;
- each of X4 and X9 is independently selected from C; CH; and N;
- X10 is selected from C; CH; and N; whereby minimally 5 of X1 to X10 are selected from CR3, C or CH;
- p is 0; 1; or 2;
-q isO; 1; or 2;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen; hydroxyl; sulfhydryl; -S(O)Z2; -S(O)2Z3; S(O)2NZ4Z5; trifluoromethyl; -C(O)Z3; -C(O)OZ2; -C(O)NZ4Z5; -C(O)H; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl; or heterocycleheteroalkynyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(O)OH or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
In a particular embodiment of this aspect of the invention, the compounds, for use in the prévention or treatment of a flavivirus infection in an animal, mammal or human; for use as a medicine; or per se; hâve a structure according to formula (B),
wherein
- each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7, and XB is independently selected from CR3, N, NR4, O, and S;
- each of X4 and X9 is independently selected from C, CH, and N;
- X10 is selected from C, CH, and N;
whereby at least five of X1 to X10 are selected from CR3, C, and CH; and at least one of X1 to X10 is a heteroatom;
- p is 0, 1, or 2;
-q is 0,1, or2;
.xl°
line (>~w) indicates the point of attachment to the carbonyl of the main formula (B); wherein said moiety is optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a; preferably cycle B is selected from
wherein the wavy line ( w ) jndicates the point of attachment to the carbon atom of the main formula (B), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycleheteroalkenyl, and heterocycle-heteroalkynyl; preferably R1 is selected from alkyl, cycloalkyl, aryl, heterocycle;
and wherein said alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three Z1b; preferably said alkyl, cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three Zlb;
- R2 is selected from hydrogen, -C(O)Z3, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and alkyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, are optionally substituted with one, two, or three Z1c; preferably said alkyl is optionally substituted with one, two, or three Z1c;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, -S(=O)Z2, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocyclealkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl; preferably R4 is independently selected from hydrogen, -S(=O)2Z3, C(=O)OZ2, alkyl, and heteroalkyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(=O)OH, -C(O)Oalkyl, and -N(CH3)2, -NH2, -NHC(=O)O-Ci^alkyl, -O-alkyl;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Zz, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl; preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4ZS, -NZ4S(=O)2Z2, NZ4C(=O)Z2, -NZ4C(=O)2Z2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C(=0)H, alkyl, heteroalkyl, aryl, heterocycle, and heterocycle-alkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2,
-O-C(=O)Z3, =O, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, NZ4C(=O)Z2, -NZ4C(=O)-OZz, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, alkyl, heteroalkyl, aryl, heterocycle, and heterocycle-alkyl;
and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)Oalkyl, -NH2, -NHCH3; N(CH3)2, -NH-C(=O)O-CMalkyl, morpholinyl, -S(O)2Ci^alkyl, and -O-alkyl; preferably said alkyl, heteroalkyl, aryl, heterocycle, and heterocycle-alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -0-C(O)Me, cyano, nitro, -C(O)OH, -C(O)Oalkyl, -NH2, -NHCH3; N(CH3)2, -NH-C(=O)O-Ci.4alkyl, morpholinyl, -SfO^C^alkyl, and -O-alkyl; more preferably said alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -O-C(O)Me, cyano, -C(O)OH, C(O)Oalkyl, -NH21 -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl, morpholinyl, -SiOfeCv 4alkyl, and -O-alkyl;
- each Z2 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl; preferably Z2 is independently selected from alkyl, aryl, heterocycle, and heterocycle-alkyl; more preferably Z2 is independently selected from alkyl, aryl, and heterocycle-alkyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-alkyl, -OCF3, -S(=O)2CMalkyl. cyano, nitro, -C(=O)OH, -C(=O)O-C1.4alkyl, -NH2, and -N(CH3)2, pyrrolidinyl, plperidinyl, and piperazinyl; preferably said alkyl, aryl, heterocycle, and heterocycle-alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-alkyl, -OCF3, S(=O)2Ci.4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-ClJ|alkyl, -NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-alkyl, -S(=O)2ClJtalkyl, -C(=O)OH, -C(=O)O-Ci-4alkyl, -NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl; preferably Z3 is independently selected from hydroxyl, alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, alkyl, and heterocycle;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF31 cyano, nitro, C(=O)OH, -NH21 and -N(CH3)2; preferably said alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from alkyl and -N(CH3)2; more preferably said alkyl and heterocycle are optionally substituted with one, two, or three substituents selected from alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, alkyl, aryl, cycloalkyl, and heterocycle; more preferably each Z4 and Z5 is independently selected from hydrogen, alkyl, and cycloalkyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF31 cyano, nitro, C(=O)OH or-NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(=O)OH, or -NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof;
with the proviso that the compound per se of formula (B) is not
- N-(5-(2-(7-ethyl-1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)-2-methoxyphenyl)methanesulfonamide (CAS nr. 1294288-37-1);
- 3-(2-(1 H-îndol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-212);
- 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone (CAS nr. 1090733-87-1);
- 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylmethylamino)ethanone (CAS nr. 875860-58-5); or
- 2-(benzo[d][1l3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 920816-95-1).
In a particular embodiment of this aspect of the invention, the compounds, for use in the prévention or treatment of a flavivirus infection ïn an animal, mammal or human; for use as a medicine; or per se; hâve a structure according to formula (B),
wherein
- each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7, and X8 is independently selected from CR3, N, NR4, O, and S;
- each of X4 and X9 is independently selected from C, CH, and N;
- X10 is selected from C, CH, and N;
whereby at least five of X1 to X10 are selected from CR3, C, and CH; and at least one of X1 to X10 is a heteroatom;
-pisO, 1, or 2;
- q is 0, 1, or 2;
Λ
line (-^ν ) indicates the point of attachment to the carbonyl of the main formula (B); wherein 5 said moiety is optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a; preferably cycle B is selected from
wherein the wavy line ) indicates the point of attachment to the carbon atom of the main formula (B), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2^alkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2. 6alkenyl, heterocycle-C2^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroC^ alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2. 6alkynyl; preferably R1 is selected from Ci^alkyl, C3.7cycloalkyl, aryl, heterocycle:
and wherein said C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC^alkenyl, arylC^alkynyl, heterocycle-Ci_6alkyl, heterocycle-C2^alkenyl, heterocycle-C^alkynyl, arylheteroCi.6alkyl, arylheteroC2. 6alkenyl, arylheteroC2,6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2. 6alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three Z1b; preferably said Ci.6alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three Z1b;
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC^alkenyl, and heteroC^alkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and C^alkyl;
and wherein said Ci.6alkyl, C2^alkenyl, C2^alkynyl, heteroC^alkyl, heteroC^alkenyl, and heteroC^alkynyl, are optionally substituted with one, two, or three Z1c; preferably said C-|,6alkyl is optionally substituted with one, two, or three Z1c;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, -S(=O)Zz, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C2. 6alkenyl, C^alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC^alkynyl, aryl, heterocycle, arylCvealkyl, arylC2.6alkenyl, arylC2.6alkynyl, arylheteroC^ealkyl, arylheteroC2.6alkenyl, arylheteroC2.ealkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC2.6alkynyl; preferably R4 is independently selected from hydrogen, -S(=O)2Z3, -C(=O)OZ2, C^alkyl, and heteroCvealkyl;
and wherein said Ci.6alkyl, C^alkenyl, C^alkynyl, heteroCi.6alkyl, heteroC2^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroC-i-ealkyl, arylheteroC2.calkenyl, arylheteroC2^alkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl are optionally substituted with one, two, or three substituents selected from Cvealkyl, C^alkenyl, C2. 6alkynyl, heteroC^ealkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(=O)OH, -CfOJOC^alkyl, and -N(CH3)2, NH2, -NH-C(=O)O-CMalkyl, -O-C^alkyl;
- each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Zs, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C2.calkenyl, C2. ealkynyl, heteroCi-ealkyl, heteroC2.6alkenyl, heteroC^alkynyl, aryl, heterocycle, arylCvealkyl, arylC^alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocyc1e-C2.6alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC,. ealkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2^alkynyl; preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)2Z2, -NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Cvealkyl; more preferably each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =0, S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Ci .6a I ky I ;
and wherein said Cvealkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2_6alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2^alkenyl, arylC2^alkynyl, arylheteroCmalkyl, arylheteroC^alkenyl, arylheteroC2^alkynyl, heterocycle-Cvealkyl, heterocycle-C2.6alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^ealkyl, C2.6alkenyl, C2. 6alkynyl, heteroCvealkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -CtOJOC^alkyl, 16765
NH2i -NHCH3; -N(CH3)21 -NH-C(=O)O-CMalkyl, morpholinyl, -S(O)2C,.4alkyl, and -O-C,. 6alkyl; preferably said Ci^alkyl, heteroCi.6alkyl, aryl, heterocycle, and heterocycle-Cv 6alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-C,.4alkyl, morpholinyl, S(O)2ClJtalkyl, and -O-C^alkyl; more preferably said Ci_6alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(O)Me, cyano, -C(O)OH, -C(O)OCMalkyl, -NHZ, -NHCH3; -N(CH3)2, -NH-C(=O)O-C1. 4alkyl, morpholinyl, -S(O)2CiJlalkyl, and -O-C^alkyl;
- each Z2 is independently selected from C^alkyl, C2.6alkenyl, C^alkynyl, heteroCi^alkyl, heteroC2.ealkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylCi-6alkyl, arylC^alkenyl, arylC2. 6alkynyl, arylheteroCi.ealkyl, arylheteroC^alkenyl, arylheteroC^alkynyl, heterocycle-Ci.6alkyl, heterocycle-C2.6alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCi^alkyl, heterocycleheteroC26alkenyl, and heterocycle-heteroC2^alkynyl; preferably Z2 is independently selected from Ci-ealkyl, aryl, heterocycle, and heterocycle-Ci.6alkyl; more preferably Z2 is independently selected from C^alkyl, aryl, and heterocycle-C^alkyl;
wherein said Ci^alkyl, C^alkenyl, C^alkynyl, heteroC,.6alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl, heterocycle-C,.6alkyl, heterocycle-C^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC^aikenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C^alkyl, OCF3, -S(=O)2C1.4alkyl, cyano, nitro, -C(=O)OH, -0(=0)0-0,^alkyl, -NH21 and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; preferably said Ci^alkyl, aryl, heterocycle, and heterocycle-C,.6alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C,. calkyl, -OCF3, -S(=O)2CiJ)alkyl, cyano, nitro, -C(=O)OH, -Cf-OjO-C^alkyl, -NH2, and N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said C^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C^alkyl, -S(=O)2CMalkyl, -C(=O)OH, -C(=O)O-Cv4alkyl, NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, C,.6alkyl, C2.6alkenyl, C2.salkynyl, heteroC,. 6alkyi, heteroC2^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC,.6alkyl, arylC2.6alkenyl, arylC2-ealkynyl, arylheteroCi.6alkyl, arylheteroC2.ealkenyl, arylheteroC2^alkynyl, heterocycle-Ci. 6alkyl, heterocycle-C^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC,.ealkyl, heterocycleheteroC^alkenyl, and heterocycle-heteroC2.ealkynyl; preferably Z3 is independently selected from hydroxyl, Ci^alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, C^alkyl, and heterocycle;
wherein said Ci^alkyl, C2^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2^alkenyl, heteroC26alkynyl, aryl, heterocycle, arylC16alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroC^alkyl, arylheteroC2^alkenyl, arylheteroC2.0alkynyl, heterocycle-C1.5alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.ealkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from Ci^alkyl, C2.ealkenyl, C2. ealkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, -NH2, and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and N(CH3)Z; more preferably said Cvealkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, aryl, C3.7cycloalkyl, heterocycle, arylCi. 6alkyl, arylC2.6alkenyl, arylC2.6alkynyl, arylheteroCi^alkyl, arylheteroC2.Galkenyl, arylheteroC2. ealkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycleheteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2.6alkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, aryl, C3.7cycloalkyl, and heterocycle; more preferably each Z4 and Zs is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2<alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC^alkenyl, arylC^alkynyl, arylheteroCb6alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl, heterocycle-Cvealkyl, heterocycle-C^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2^alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C^alkenyl, C2. ealkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-Cvealkyl, -OCF31 cyano, nitro, -C(=O)OH or -NH2;
and wherein Z4 and Zs can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with C^alkyl, C^alkenyl, C2^alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof;
with the proviso that the compound per se of formula (B) is not
- N-( 5-(2-( 7-ethyl-1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)-2-methoxyphenyl)16765 methanesulfonamide (CAS nr. 1294288-37-1);
- 3-(2-(1 H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-212);
- 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 1090733-87-1);
- 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylmethylannino)ethanone (CAS nr. 875860-58-5); or
- 2-(benzo[d][1,3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 920816-95-1).
In another particular embodiment, the compounds hâve a structure according to formula (C),
wherein cycle B, R1, R2, the dotted lines, X1, X2, X4, X5, XB, X7, Xe, X9 and X10 are as defined in any one of the embodiments with formula (A) and (B).
In another particular embodiment, the compounds hâve a structure according to formula (D), (D1), (D2), (D3), (D4), or (D5),
(D3) (D4) (D5) wherein cycle B, R1, R2, the dotted lines, X1, X2, X4, X5, X6, X7, X8, X9 and X10 are as defined in any one of the embodiments with formula (A) and (B).
In another particular embodiment, the compounds hâve a structure according to formula (D),
wherein
- each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
- each of X1, X2, X3, X5, X6, X7, and Xe is independently selected from CR3, N, NR4, O, and S;
- each of X4 and X9 is independently selected from C, CH, and N;
whereby at least five of X1 to X9 are selected from CR3, C, and CH; and at least one of X1 to X9 is a heteroatom;
- p is 0, 1, or 2;
- q Is 0, 1, or 2;
optionally substituted with one or two Z1;
- cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a; preferably cycle B is selected from
wherein the wavy line («) îndicates the point of attachment to the carbon atom of the main formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
- R1 is selected from C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2. 6alkenyl, heterocycle-C^alkynyl, arylheteroCi.6alkylr arylheteroC^alkenyl, arylheteroC2. 6alkynyl, heterocycle-heteroCi,6 alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2. 6alkynyl; preferably R1 is selected from C^alkyl, C^cycloalkyl, aryl, heterocycle; more preferably R Ci.6alkyl, or a moiety selected from
and wherein said C^alkyl, C3.7cycloalkyl, C3.7cycloalkenyl, C3.7cycloalkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2^alkynyl, arylheteroC^alkyl, arylheteroC2. 6alkenyl, arylheteroC2.6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2. 6alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three Z1b; preferably said Ci.6alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optionally substituted with one, two, or three Z1b; more preferably said moiety selected from
, are optionally substituted with one, two, or three Z1b;
- Z1b, is selected from the group consisting of halogen, hydroxyl, -OZ2, =0, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, cyano, -C(=O)Z3, C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, aryl, and heterocycle;
and wherein said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -0-C(0)Me, cyano, -C(O)OH„ -NHCH3; -N(CH3)2, -S(O)2Ci^alkyl, and — O~Ci^alkyl;
- R2 is selected from hydrogen, -C(O)Z3, C^alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC2^alkenyl, and heteroC2^alkynyl; preferably R2 is selected from hydrogen, -C(O)Z3, and Ci-6alkyl;
and wherein said C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroCv6alkyl, heteroC^alkenyl, and heteroC2^alkynyl, are optionally substituted with one, two, or three Z1c; preferably said C^alkyl is optionally substituted with one, two, or three Z1c;
- each R3 is independently selected from hydrogen and Z1;
- each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, -S(=O)Z2, -S(=O)2Z3, -
S(=O)2NZ4Z5, trifluoromethyl, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C2. 6alkenyl, C2.6alkynyl, heteroC^alkyl, heteroCz.6alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylCi^alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroCi.6alkyl, arylheteroC2.6alkenyl, arylheteroC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl; preferably R4 is independently selected from hydrogen, -S(=O)2Z3, -C(=O)OZ2, Ci_ealkyl, and heteroC^alkyl;
and wherein said Ci.6alkyl, C^alkenyl, C2.6alkynyl, heteroC^alkyl, heteroC^alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2.6alkynyl, heterocycle-C^alkyl, heterocycle-C2^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroC1.6alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC^alkynyl are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. ealkynyl, heteroCi.6alkyl, heteroC2.6alkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(=O)OH, -CfOJOC^alkyl, and -N(CH3)2, NH2, -NH-C(=O)O-CMalkyl, -O-C^alkyl; preferably said CV6alkyl is optionally substituted with one, two, or three substituents selected from -C(=O)OH, -0(0)00^ 6alkyl, and -N(CH3)2, -NH2, -NH-C(=O)O-CMalkyl, -O-Ci.6alkyl;
- each Z1, Z1a, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S. -S(=0)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl. trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, -NZ4C(=O)NZ4Z5, cyano, -C(=0)Z3, -C(=0)0Z2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, C^alkenyl, C2.ealkynyl, heteroC^alkyl, heteroCz^alkenyl, heteroC2.calkynyl, aryl, heterocycle, arylC^alkyl, arylCz. 6alkenyl, arylCz^alkynyl, arylheteroC^alkyl, arylheteroC2.6alkenyl, arylheteroCMalkynyl. heterocycle-Ci^alkyl, heterocycle-C2.6alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCv 0alkyl, heterocycle-heteroCz.6alkenyl, and heterocycle-heteroC2^alkynyl; preferably each Z1, Z1a, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, OZ2, -O-C(=O)Z3, =0, -SZ2. =S. -S(=O)Z2, -S(=O)2Z3. -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy. nitro. -NZ4Z5, -NZ4S(=O)zZ2, -NZ4C(=O)Z2, -NZ4C(=O)2Z2, -NZ4C(=O)NZ4Z5. cyano, -C(=0)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(-0)H, CMalkyl. heteroC^alkyl. aryl. heterocycle, and heterocycle-Cvealkyl; more preferably each Z1. Z1a, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =0. -S(=O)2Z3, S(=O)zNZ4Z5, trifluoromethyl, trifluoromethoxy. -NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano. C(=O)Z3, -C(=0)0Z2. -C(=O)NZ4Z5, C^alkyl, heteroCV6alkyl, aryl, heterocycle. and heterocycleC^alkyl;
and wherein said Cv6alkyl, C2.6alkenyl, C^alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC2.ealkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2.6alkynyl, arylheteroC^alkyl, arylheteroC2^alkenyl, arylheteroC^alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, heteroCi_ealkyl( heteroC2.ealkenyl, heteroC2.6alkynyl, hydroxyl, =0, halogen, SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OCV6alkyl, NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMa1kyl, morpholinyl, -S(O)2CMalkyl, and -O-C,. 6alkyl; preferably said C^ealkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C;. 6alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)21 -NH-C(=O)O-CMalkyl, morpholinyl, S(O)2CMalkyl, and -O-Cvealkyl; more preferably said C1-6alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -OC(0)Me, cyano, -C(O)OH, -C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C^OJO-C,. 4alkyl, morpholinyl, -S(O)2Cmalkyl, and -O-C^alkyl;
- each Z2 is independently selected from C^alkyl, C^alkenyl, C2^alkynyl, heteroCi.6alkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, heterocycle, arylCi.6alkyl, arylC^alkenyl, arylC2. 6alkynyl, arylheteroCi.6alkyl, arylheteroCi-6alkenyl, arylheteroCi^alkynyl, heterocycle-C^alkyl, heterocycle-C2^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroC^alkyl, heterocycleheteroC^alkenyl, and heterocycle-heteroC24îalkynyl; preferably Z2 is independently selected from C-i-ealkyl, aryl, heterocycle, and heterocycle-Ci.6alkyl; more preferably Z2 is independently selected from C^alkyl, aryl, and heterocycle-C^alkyl;
wherein said C^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCi.6alkyl, arylheteroC2_0alkenyll arylheteroC^alkynyl, heterocycle-C-|.6alkyl, heterocycle-C^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC2.6alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.6alkenyl, C2. 6alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-Ci^alkyl, OCF3, -S(=O)2C1 ^alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-Ci.4alkyl, -NH2, and -N(CH3)2, pyrrolidînyl, piperidinyl, and piperazinyl; preferably said CV6alkyl, aryl, heterocycle, and heterocycle-C^alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-Cv ealkyl, -OCF3, -S(-O)2CV4alkyl, cyano, nitro, -C(=O)OH, -CC^OJO-C^alkyl, -NH2, and N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl; more preferably said C^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-Ci.6alkyl, -S(=O)2CMalkyl, -C(=O)OH, -C(=0)0-Cwalkyl, 16765
NH2, and -N(CH3)21 pyrrolidinyl, piperidinyl, and piperazinyl;
- each Z3 is independently selected from hydroxyl, C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroCi. 6alkyl, heteroC2.6alkenyl, heteroC2.Balkynyl, aryl, heterocycle, arylC^alkyl, arylC2.ealkenyl, arylC2^alkynyl, arylheteroCV6alkyl, arylheteroC2.ealkenyl, arylheteroC2^alkynyl, heterocycle-Ci. ealkyl, heterocycle-C^alkenyl, heterocycle-C2.6alkynyl, heterocycle-heteroCi.6alkyl, heterocycleheteroC2.calkenyl, and heterocycle-heteroC2^alkynyl; preferably Z3 is independently selected from hydroxyl, C^alkyl, aryl, and heterocycle; more preferably Z3 is independently selected from hydroxyl, Cvealkyl, and heterocycle;
wherein said Ci^alkyl, C^alkenyl, C^alkynyl, heteroC^alkyl, heteroC2.6alkenyl, heteroC2^alkynyl, aryl, heterocycle, arylC^alkyl, arylC^alkenyl, arylC2^alkynyl, arylheteroC^alkyl, arylheteroC^alkenyl, arylheteroC2^alkynyl, heterocycle-Ci.salkyl, heterocycle-C^alkenyl, heterocycle-C^alkynyl, heterocycle-heteroCi^alkyl, heterocycle-heteroC2.6alkenyl, and heterocycle-heteroC^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.ealkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-Cmalkyl, -OCF3, cyano, nitro, -C(=O)OH, -NH2, and -N(CH3)2; preferably said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from C1_ealkyl and N(CH3)2; more preferably said C^alkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
- each Z4 and Z5 is independently selected from hydrogen, C^alkyl, C2.6alkenyl, C2.6alkynyl, heteroCvealkyl, heteroC^alkenyl, heteroC2.6alkynyl, aryl, C3.7 cycloalkyl, heterocycle, arylCi. ealkyl, arylC2.6alkenyl, arylC^alkynyl, arylheteroCi.6alkyl, arylheteroC2.6alkenyl, arylheteroC2. 6alkynyl, heterocycle-C^alkyl, heterocycle-C2.6alkenyl, heterocycle-C2.6alkynyl, heterocycleheteroCvsalkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC^alkynyl; preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, aryl, C3.7cycloalkyl, and heterocycle; more preferably each Z4 and Z5 is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
wherein said C^alkyl, C2.ealkenyl, C2^alkynyl, heteroCi^alkyl, heteroC^alkenyl, heteroC^alkynyl, aryl, heterocycle, arylC^alkyl, arylC2.6alkenyl, arylC2^alkynyl, arylheteroCi.6alkyl, arylheteroC2^alkenyl, arylheteroC2^alkynyl, heterocycle-C^alkyl, heterocycle-C^alkenyl, heterocycle-C2^alkynyl, heterocycle-heteroC^alkyl, heterocycle-heteroC^alkenyl, and heterocycle-heteroC2^alkynyl, are optionally substituted with one, two, or three substituents selected from C^alkyl, C2.Balkenyl, C2. 6alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, or -NH2;
and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with C^alkyl, C2.6alkenyl, C2.ealkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-C^alkyl, -OCF3, cyano, nitro, -C(=O)OH, or NH2;
and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof;
with the proviso that compound of formula (D) is not
- N-(5-(2-(7-ethy 1-1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)-2-methoxyphenyl)methanesulfonamide (CAS nr. 1294288-37-1);
- 3-(2-(1 H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-21-
2);
- 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CASnr. 1090733-87-1);
- 1-(1 H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylmethylamino)ethanone (CAS nr. 875860-58-5); or
- 2-(benzo[d][1,3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 920816-95-1).
In one embodiment, the compound per se of the invention is not any one of the following:
- N-(5-(2-( 7-ethy 1-1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)-2-methoxyphenyl)methanesulfonamide (CAS nr. 1294288-37-1);
- 3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-212);
- 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone (CASnr. 1090733-87-1);
- 1-(1 H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylmethylamino)ethanone (CAS nr. 875860-58-5); or
- 2-(benzo[d][1,3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 920816-95-1).
In another embodiment, the compound per se of the invention is not any one of the following:
- 1-(7-ethyl-1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenyl-ethanone (CAS nr. 1296377-78-0);
- N-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-2-methyl-propanamide (CAS nr. 1294813-77-6);
- N-[4-[[2-(7-ethyl-1 H-indol-3-yl)-2-oxo-1 -phenylethyl]amino]-2-methoxyphenyl]-acetamide (CAS nr. 1287503-18-7);
- 1-(7-ethyl-1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]-ethanone (CAS nr. 1287040-60-1);
- 2-((1-acetyl-2,3-dihydro-1 H-indol-5-yl)amino]-1-(7-ethyl-1 H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 1286579-37-0);
- 3,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone (CAS nr. 1277962-26-1);
- 1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone (CAS nr. 1252467-88-1);
- 2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 1241127-58-1);
- 2-[(1-acetyl-4-piperidinyl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 1210169-39-
3);
- 1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenyl-ethanone (CAS nr, 1181884-558);
- 1-(1 H-indol-3-yl)-2-[( 1-methyl-1 H-pyrazol-3-yl)amino]-2-phenyl-ethanone (CAS nr. 113476619-0);
- 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-benzamîde (CAS nr. 1062257-51-5);
- N-[4-[[2-( 1 H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-2,2-dirnethyl-propanamide (CAS nr. 1062132-16-4);
- N-[3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-acetamide (CAS nr. 1030735-637);
- 2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 1030232-46-
2);
- 1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)-ethanone (CAS nr. 1030214-83-5);
- 1-(1H-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenyl-ethanone (CAS nr. 1030212-41-9);
- 2-(3-(difluoromethoxy)-4-rnethoxyphenylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 1015662-06-2);
- 1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]-ethanone (CAS nr. 101453582-0);
- 2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 1014493-63-0);
- 2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 1014422-80-0);
- N-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-acetamide (CAS nr. 1013712-883);
- 1-(7-ethyl-1H-indol-3-yl)-2-[[3-(hydroxymethyl)phenyl]amino]-2-phenyl-ethanone (CAS nr. 1012956-97-6);
- N-[2-chloro-4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-acetamide (CAS nr. 1011120-58-3);
- 1 -[4-[[2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS nr. 1011119-79-1);
- N-cyclopropyl-4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-benzamide (CAS nr. 1011113-94-2);
- 2-[(1-acetyl-2l3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 949443-90-7);
- 1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]-ethanone (CAS nr. 941047-24-
1):
- 2-(cyclopentylamino)-1-(1 H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 931079-25-3);
- 1-(1H-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenyl-ethanone (CAS nr. 931016-79-4);
- 2-(cyclopropylamino)-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr, 931000-99-6);
- 1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-2-pyrrolidinone (CAS nr. 92471383-7);
- 2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 924713-60-0);
- 2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 924712-67-
4);
- 1-[3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-2-pyrrolidinone (CAS nr. 92095263-2);
- 2-ethoxy-5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzenesulfonamide (CAS nr. 920883-17-6);
- 6-[[2-(1Η-ίηάοΙ-3-γΙ)-2-οχο-1-ρΐΊβηγΐ6ΐΚγ1]3Γηΐηο]-2-ΓηβϋΊγΙ-2Η-1,4-ό6ηζοχ3ζίη-3(4Η)-οηβ (CAS nr. 920834-07-7);
- 2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 920819-87-0);
- 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N-methyl-benzamide (CAS nr. 920672-793);
- 4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-benzeneacetonitrile (CAS nr. 920669-36-9);
- 1-(1H-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenyl-ethanone (CAS nr. 920601-77-0);
- 1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamîno)ethanone (CAS nr. 878619-92-2);
- N-cyclopropyl-3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-benzamide (CAS nr. 87857728-7);
- 2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 87516636-2);
- 2-[(2,3-dihydro-1(4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone (CAS nr. 874669-99-5);
- 1 -( 1 H-indol-3-yl)-2-(methyl((tetrahydrofuran-2-yl)methyl)amino)-2-phenylethanone;
- N-(4-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamïno)phenyl)isobutyramide;
- 2-((benzo[d][1,3]dioxol-5-ylmethyl)(methyl)amino)-1-(1H-indol-3-yI)-2-phenylethanone;
- 3-(3-(2-(7-ethyl-1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)propyl)-1,3-diazaspiro[4.4]nonane-
2,4-dione;
- 1 -( 7-ethyl-1 H-indol-3-yl)-2-((2-methoxypyridin-3-yl)methylamino)-2-phenylethanone;
- 3-(3-(2-(1 H-indol-3-yl)-2-oxo-1 -phenylethylamino)propyl)-1,3-diazaspiro[4.4]nonane-2,4dione;
- 1-(1H-indol-3-yl)-2-(methyl(2,3,4-trimethoxybenzyl)amino)-2-phenylethanone;
- 2-(2-(1 H-indol-3-yl)-2-oxo-1-phenylethylamino)-N-(3,4-difluorophenyl)acetamide;
- 1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone;
- 2-(4-(dimethylamino)benzylamlno)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-(2-(furan-2-yl)ethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 3-(2-(1 H-indol-3-yl)-2-oxo-1-phenylethylamïno)-1-(pyrrolidin-1-yl)propan-1-one;
- 2-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamlno)-1-(1H-indol-3-yl)-2-phenyIethanone;
- 2-((2-(1 H-indol-3-yl)-2-oxo-1 -phenylethyl)(methyl)amino)-N-(4-methoxyphenyl)acetamide;
- 2-(2-(2-fluorophenoxy)ethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((2,3-dimethoxybenzyl)(methyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((3,4-dimethoxybenzyl)(methyl)annino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-phenyl-2-(2-(thiophen-2-yl)ethylamino)ethanone;
- 2-(1-(furan-2-yl)ethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-(2-methoxybenzylamino)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-(methyl(thiophen-2-ylmethyl)amino)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-phenyl-2-((tetrahydrofuran-2-yl)methylamino)ethanone;
- 2-(benzo[d][1,3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-(3-methoxybenzylamino)-2-phenylethanone;
- 2-(2-(dimethylamino)-1-phenylethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-(methyl(thiophen-3-ylmethyl)amino)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-phenyl-2-(1-(thiophen-2-yl)ethylamino)ethanone;
- 2-(3,4-dimethoxyphenethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-(1-(2-methoxyphenyl)ethylamino)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-(4-methoxybenzylamino)-2-phenylethanone;
- 1-(1H-Îndol-3-yl)-2-phenyl-2-(pyridin-2-ylmethylamino)ethanone;
- 2-(benzylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-(furan-2-ylmethylamino )-1-(1 H-indol-3-yl)-2-phenylethanone;
- 2-(2-( 1H-indol-3-yl)-2-oxo-1-phenylethylamino)-N-(2,6-dimethylphenyl)acetamide;
- 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylmethylamino)ethanone;
- 2-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methylamino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 1-(1 H-indol-3-yl)-2-phenyl-2-(thiophen-2-ylmethylamino)ethanone; or
- 2-(furan-2-ylmethylamino)-1-(1H“indol-3-yl)-2-phenylethanone.
In another particular embodiment, the compounds hâve a structure according to formula (E), (E1), or (E2),
(E) (E1)
(E2) wherein cycle B, R1, R2, the dotted lines, X1, X2, X4, X5, X6, X7, X8, X9 and X10 are as defined in any one of the embodiments with formula (A) and (B).
In another particular embodiment, the compounds hâve a structure according to formula (F)or(F1),
(F) (F1) wherein cycle B, R1, R2, the dotted lines, X1, X4, X5, X6, X7, X8, X9 and Z4 are as defined in any one of the embodiments with formula (A) and (B).
In another particular embodiment, the compounds hâve a structure according to formula (G),
(G) wherein cycle B, R1, R2 *, X1, Z1, and R4 are as defined in any one of the embodiments with formula (A) and (B) and wherein n is selected from 0; 1 ; 2 and 3.
In another particular embodiment, the compounds hâve a structure according to formula (H),
wherein
- cycle B, each Z1 independently, and each Z1b independently, are as described in any one of the embodiments with formula (A); preferably Z1b is located in meta or para; preferably cycle
B is not an unsubstituted phenyl;
- m is selected from 0, 1, 2, and 3;
- n is selected from 0,1,2, and 3; and
- X1 and X2, are as described in any one of the embodiments with formula (B).
In another particular embodiment, the compounds hâve a structure according to formula (I),
(l) wherein cycle B, each Z1 independently, and each Z1b independently, are as described in any one of the embodiments with formula (A);
- preferably cycle B is selected from aryl and heteroaryl; more preferably cycle B is selected
; wherein said aryl, heteroaryl, and the depicted cycles may optionally be substituted with halogen, C^alkyl, or C^alkoxy; more preferably said aryl is substituted with halogen, C^alkyl, or CMalkoxy;
- preferably Z1 is hydrogen, halogen, or C^alkyl;
preferably Z1b is C^alkoxy, -OCH2CH2OH, hydrogen, -CH2-OH;
- m is selected from 0, 1, 2, and 3; preferably m is selected from 1 and 2;
n is selected from 0, 1,2, and 3; preferably n is selected from 0 and 1.
In another particular embodiment, the compounds hâve a structure according to formula (J),
(J) wherein
- Z1 is hydrogen, halogen, or C^alkyl;
n is selected from 0 and 1 ;
cycle B is aryl and heteroaryl; more preferably cycle B is selected from
; wherein said aryl, heteroaryl, and the depicted cycles may optionally be substituted with halogen, Ci^alkyl, or Ci^alkoxy; more preferably said aryl is substituted with halogen, C^alkyl, or CMalkoxy;
- Z1b is Cwalkoxy, -OCH2CH2OH, -CH2-OH;
- m is selected from 0 and 1 ; and
- Z2 is CMalkyl.
The compounds of the présent invention présent at least one asymmetric center at the carbon atom substituted with cycle B, as shown below with an asterisk on formula (A). This asymmetric center can occur in its R or S configuration. In one preferred embodiment, said asymmetric center is in the R configuration. In another preferred embodiment, said asymmetric center is in the S configuration.
In a particular embodiment, cycle A is a heteroaryl which can be unsubstituted or substituted with one or more Z1. In another particular embodiment, cycle A is selected from unsubstituted or substituted with one or more Z1 indolyl, benzothienyl, pyrrolopyridinyl, pyridinimidazolyl, indazolyl, tetrahydropyridinthienyl, pyrazolepyridinyl and indolinyl. In a more particular embodiment, cycle A is selected from unsubstituted or substituted with one or more Z1 indolyl and indolinyl. Yet more in particular, cycle A is selected from unsubstituted or substituted with one or more Z1 indol-3-yl and indolin-1 -yl.
In a particular embodiment of the invention, cycle A is not selected from indolin-1-yl.
In another particular embodiment, cycle B is selected from unsubstituted or substituted with one or more Z1a phenyl; pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyridinimidazolyl, pyridinpyrolyl, pyrazolepyridinyl, benzpyrolyl, triazinyl, purinyl, quinoxalinyl, quinazolinyl, dihydroimîdazooxazinyl and pteridinyl. In yet another particular embodiment, cycle B is selected from unsubstituted or substituted with one or more Z1a phenyl; and pyridyl.
In another particular embodiment, cycle B is a heterocycle which can be unsubstituted or substituted with one or more Z1a. In another particular embodiment, cycle B is selected from unsubstituted or substituted with one or more Z1a aryl and heteroaryl. In a more particular embodiment cycle B is a heteroaryl which can be unsubstituted or substituted with one or more Z1a.
In a yet more particular embodiment, cycle B is selected from unsubstituted or substituted with one or more Z1a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyridinimidazolyl, pyridinpyrolyl, pyrazolepyridinyl, benzpyrolyl, triazinyl, purinyl, quinoxalinyl, quinazolinyl, and pteridinyl.
In a still more particular embodiment, cycle B is selected from unsubstituted or substituted with one or more Z1a pyridyl, pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, thienyl, isoquinolinyl, benzimidazolyl, pyridinimidazolyl, benzopyrolyl, pyrazolepyridinyl and quinoxalinyl.
In a particular embodiment, cycle B is not an unsubstituted phenyl.
In another particular embodiment, R2 is selected from hydrogen and unsubstituted or substituted with one or more Z1c aikyl. In another particular embodiment, R2 is selected from hydrogen and aikyl (more in particular Ci.3alkyl) . In yet another particular embodiment, R2 is selected from hydrogen, methyl, ethyl, and propyl.
In another embodiment, R1 is selected from aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; heterocycle-heteroalkynyl; and wherein said aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl and heterocycleheteroalkynyl can be unsubstituted or substituted with one or more Z1b.
In another embodiment, R1 is selected from aryl; heterocycle; W-aryl; and Wheterocycle; wherein said aryl, heterocycle, W-aryl, and W-heterocycle can be unsubstituted or substituted with one or more Z1b; and wherein W is selected from C^alkyl, Ci.3alkenyl, Ci. 3alkynyl, C^a heteroalkyl, C1.3 heteroalkenyl and C,.3 heteroalkynyl.
In another particular embodiment, R1 is selected from aryl; heterocycle; W-aryl; and Wheterocycle; wherein said aryl, heterocycle, W-aryl, and W-heterocycle can be unsubstituted or substituted with one or more Z1b; and wherein W is selected from Ci.3alkyl.
In yet another particular embodiment, R1 is selected from aryl; heterocycle; -CH2-aryl; and -CHî-heterocycle; wherein said aryl, heterocycle, -CH2-aryl and -CH2-heterocycle can be unsubstituted or substituted with one or more Z1b, In another embodiment, R1 is selected from aryl; and heterocycle; wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1b. In yet a more particular embodiment, R1 is selected from phenyl and pyridine, unsubstituted or substituted with one or more Z1b. In still a more particular embodiment, R1 is selected from phenyl and , unsubstituted or substituted with one or more Z1b
A very particular embodiment of the invention relates to the compounds selected from: 2-((3-ethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((4-chloro-3-methoxyphenyl)amïno)-1-(1/7-indol-3-yl)-2-phenylethanone; 1-(1H-lndol-3-yl)-2-phenyl-2-((3-(trifluoromethoxy)phenyl)amino)ethanone;
- 2-((3-chlorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((3,4-difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((3-fluorophenyl)amino)-1-(1/-/-indol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((3,5-difluorophenyl)amino)-1-(1/7-indol-3-yi)-2-phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(2-methyl-1H-indol-3-yl)-2-phenylethanone;
1-(6-chloro-1H-indol-3-yl )-2-((3,5-dimethoxyphenyl)amino)-2-phenylethanone;
1- (1H-indol-3-yl)-2-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-2-phenylethanone;
2- ((3-fluoro-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylamino)ethanone;
-(1 H-indol-3-yl)-2-phenyl-2-(pyridin-4-ylamino)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)(methyl)amîno)-2-phenylethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone;
1-(1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-4-yl)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(methylsulfonyl)phenyl)ethanone;
1- (1/-/-indol-3-yl)-2-((5-methylisoxazol-3-yl)amino)-2-phenylethanone;
2- (furan-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-2-yl)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol-3-yl)ethanone;
1-(1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl-1/-/-imidazol-2-yl)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)arnino)-2-(thiophen-3-yl)ethanone;
2- (1H-imidazol-2-yl)-1-(1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrimidin-5-yl)ethanone;
2- (imidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
2-((2-hydroxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
1-(1H-indol-3-yl)-2-phenyl-2-((pyridin-2-ylmethyl)amino)ethanone;
1- (1H-indol-3-yl)-2-phenyl-2-((thiophen-2-ylmethyl)amino)ethanone;
2- ((furan-2-ylmethyl)amino)-1 -( 1 H-indol-3-yl)-2-phenylethanone;
3- ((2-( 1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzonitrile;
4- (2-(1 H-indol-3-yl)-1-((3-methoxyphenyl)arnino)-2-oxoethyl)benzonitrile;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(quinoxalin-6-yl)ethanone;
1- (1H-indol-3-yl)-2-((2-methoxyphenyl)amino)-2-phenylethanone;
2- ((2,5-dîmethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
2- ((2,3-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
3- (2-(1/7-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1 -methyl-1 H-pyrazol-4-yl)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-7-yl)ethanone;
1-(1H-indol-3-yl)-2-((3-(methylsulfonyl)phenyl)amino)-2-phenylethanone;
1- (1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone;
2- ((3-ethylphenyl)amino)-1-(1/7-indol-3-yl)-2-phenylethanone;
1-(1 H-indol-3-yl)-2-(isoquinolin-5-yl)-2-((3-methoxyphenyl)amino)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(pyrimidin-5-yl)phenyl)ethanone;
2- ((3-methoxyphenyl)amino)-1-(1-methyl-1 H-indol-3-yl)-2-phenylethanone;
1-(1/7-indol-3-yl)-2-phenyl-2-(quinoxalin-6-ylamino)ethanone;
3- ((2-(1/7-indol-3-yl)-2-oxo-1-phenylethyl)amino)-N,N-dimethyl benzamide;
3- ((2-( 1H-indol-3-yl)-2-oxo-1-phenylethyl)arnino)-/V-methylbenzenesulfonamide;
1-(4-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amîno)-2-phenylethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-(pyrimidin-5-yl)phenyl)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone;
6-((2-( 1/7-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzo[d]oxazol-2(3/7)-one;
2- ((3-(1/7-1,2,4-triazol-l -yl)phenyl)amino)-1 -(1 /7-indol-3-yl)-2-phenylethanone;
1-(1/7-indol-3-yl)-2-((3-(oxazol-5-yl)phenyl)amino)-2-phenylethanone;
5-(2-( 1/7-indol-3-yl)-1-((3-methoxyphenyl )amino)-2-oxoethyl)-1,3-dimethyl-1/7benzo[c()imidazol-2(3/7)-one;
4- (2-( 1H-indol-3-yl)-1-((2-methoxypyridin-4-yl)amino)-2-oxoethyl)benzonitrile;
1- (1Η-ΙηύοΙ-3-ν1)-2-((4-ηΊβ1ΐΊθχγ-6-ΐΌβΑΊνΙρνΐΊΠΊΐΰίη-2-νΙ)3ΐτ>ιηο)-2-ρΐΊβηνΙβ1ΐΊ3ηοηβ;
2- (6-hydroxypyridin-3-yl)-1-(1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
2- (imidazo[1,2-a]pyridin-2-yl)-1-(1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone;
3- ((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzamide;
1-(1/7-indol-3-yl)-2-((4-methoxypyridin-2-yl)amino)-2-phenylethanone;
1-(1/7-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone;
ethyl 3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoate;
-(6-chloro-1 H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4yl)amino)ethanone;
-(1 /7-indol-3-yl)-2-((5-methoxy-1,2,4-thiadiazol-3-yl)amino)-2-phenylethanone;
3-((2-(1 /7-indol-3-yl)-2-oxo-1 -phenylethyl)amino)benzoic acid;
1-(1/7-indol-3-yl)-2-((6-methoxypyrimidin-4-yl)amino)-2-phenylethanone;
1-(6-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone;
1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(pyridin-3-yl)ethanone;
1-(6-fiuoro-1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone;
1-(6-methoxy-1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone;
1-(6-methoxy-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1- (5-methoxy-1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone;
methyl 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-177-indole-6-carboxylate;
2- (6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl )-2-((3methoxyphenyl)amino)ethanone;
- 2-(5-fluoroimidazo[1,2-a]pyridin-2-yl)-1 -(1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone;
1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(thiazol-4-yl)ethanone;
-(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone; 1-(7-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate;
1- (5-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((2l6-dimethoxypyrimidin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-((3“methoxyphenyl)amino)-2-(8-methylimidazo[1,2-a]pyridin-2yl)ethanone;
1- (1H-indol-3-yl)-2-((4-methoxypyrimidin-2-yl)amino)-2-phenylethanone;
2- (4-fluorophenyl)-1 -( 1 H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone;
2- (3-fluorophenyl)-1-(1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone;
1- (5-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
3- (2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-1H-indole-6-carbonitrile;
3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1/7-indole-6-carbonitrile;
2- (618-dihydro-5H-imidazo[2,1 -c][1,4]oxazin-2-yl)-1 -(1 H-indol-3-yl)-2-((2-methoxypyridin-4yl)amïno)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(7-methylimidazo[1,2-a]pyridin-2yl)ethanone;
1-(1H-indol-3-yl)-2-(1H-indol-5-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone; 1-(1/7“indol“3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylimidazo[1,2-a]pyridin-2yl)ethanone;
1- (5-chloro-1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone;
2- ((2-methoxypyridin-4-yl)amino)-1-(1 -methyl-1 H-indol-3-yl)-2-phenylethanone;
1-(7-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone; 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-methylisoxazol-5-yl)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1 -methyl-1 H-imidazol-4-yl)ethanone; 1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1- (1-(2-amînoethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- (3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetic acid;
2-(1-ethyl-1H-pyrazol-5-yl)-1-(1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
1- (1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(5-methylisoxazol-3-yl)ethanone;
2- (5-fluoroimidazo[1,2-a]pyridin-2-yl)-1 -( 1 H-indol-3-yl )-2-((3methoxyphenyl)amino)ethanone;
- 2-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone;
2-((3-methoxyphenyl)amino)-1-(1-(methylsulfonyl)-1/-/-indol-3-yl)-2-phenylethanone;
- 2-(4-(2-(dimethylamino)ethoxy)phenyl)-1 -(17-/-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone;
- ethyl 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 H-indoI-1 -yl)acetate; 1-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- /7-(2-( 1H-indol-3-yl)-2-oxo-1-phenylethyl)-2-(dimethylamino)-/V-(3methoxyphenyl)acetamide;
1- (6-chloro-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol-3-yl)ethanone;
2- ((3-methoxyphenyl)amino)-1-(1 -methyl-1 H-indol-3-yl)-2-(5-methylisoxazol-3-yl)ethanone;
1-(6-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1- (5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
4-(2-(7-chloro-1/7-indol-3-yl)-1-((3-methoxyphenyl)amîno)-2-oxoethyl)benzonitrile;
2- ((2-methoxypyridin-4-yl)amino)-1-(1-(methylsulfonyl)-1H-indol-3-yl)-2-phenylethanone;
2-((3-methoxyphenyl)amino)-1-(6-methyl-1H-indol-3-yl)-2-phenylethanone;
1- (6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- (4-((dimethylamino)methyl)phenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone;
1- (1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-methyl-1/7-imidazol-5-yl)ethanone;
- 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carbonitrile;
2- (4-(hydroxymethyl)phenyl)-1-(1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
- 1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-A/,N-dimethyl-1/7-indole-5-sulfonamide;
- 2-((3-methoxyphenyl)amîno)-1 -(5-methyl-1 H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(5-fluoro-1 H-indol-3-yl)-2-phenylethanone;
- 4-(2-(1 H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-2-fluorobenzonitrile;
- 4-(2-( 1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-3,5-difluorobenzonitrile;
1-(6-hydroxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 H-indole-6-carboxylic acid;
- 1 -(1 -(2-methoxyethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1-(5-fluoro-1-methyl-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(m-tolyl)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(p-tolyl)ethanone;
-(6-(hydroxymethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 1 -(6-(2-hydroxyethoxy)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 H-indole-5-carboxylate;
- 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 W-indole-5-carboxylic acid;
- 2-(2-fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
-(5-f I uo ro-1 -(2-(methoxymethoxy)ethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone;
-(5-flu oro-1 -(2-hydroxyethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)arnino)-2-phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(1-(2-(methoxymethoxy)ethyl)-1/7-indol-3-yl)-2phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(1-(2-hydroxyethyl)-1/7-indol-3-yl)-2-phenylethanone;
2-(4-fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
-(6-chloro-1 A7-indol-3-yl)-2-(imidazo[1,2-a] pyrid in-2-yl )-2-(( 3methoxyphenyl)amino)ethanone;
1-(5-fluoro-1/-/-ïndol-3-yi)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone;
1-(6-fluoro-1H-indol-3-yl)-2-((3-rnethoxyphenyl)amino)-2-(pyridin-3-yl)ethanone;
1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone;
1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone;
1- (7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone;
2- ((3,5-dimethoxyphenyl)amino)-1 -(5-fluoro-1 -(3-hydroxypropyl)-1 H-\ndol-3-yl)-2phenylethanone;
1-(6-fluoro-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone;
1-(1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone;
4-(2-(1 H-lndol-3-yl)-1-((5-methoxypyridin-3-yl)amino)-2-oxoethyl)benzonitrile;
1- (benzo[b]thiophen-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone;
2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone;
1- (imidazo[1,2-a]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((3-methoxyphenyl)amino)-2-phenyl-1-(pyrazolo[1,5-a]pyridin-3-yl)ethanone;
1-(1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1- (benzo[b]thiophen-3-yl)-2-(irnidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4yl)amino)ethanone;
2- ((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone;
2-((3-methoxyphenyl)amino)-2-phenyl-1-(1/7-pyrrolo[3,2-c]pyridin-3-yl)ethanone;
2-((3-methoxyphenyl)amino)-1-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-2phenylethanone;
2-((3-methoxyphenyl)amino)-1-(1 -methyl-1 H-indazol-3-yl)-2-phenylethanone;
1-(indolin-1-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
tert-butyl (2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 H-indol-1 -yl)ethyl)carbamate;
1- (7-fluoro-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3yl)ethanone;
- 2-((2-fluoropyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-((tetrahydrofuran-3-yl)sulfonyl)-1H-indol-3yl)ethanone;
- 2-((3-methoxyphenyl)amino)-1-(1-((1-methyl-1 H-imidazol-4-yl)sulfonyl)-1H-indol-3-yl)-2phenylethanone;
- 2-((3,5-dimethoxyphenyl)amÎno)-1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone;
-( 1 -( ethy Isulfony I )-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 1 -(5-fluoro-1 -(methylsulfonyl)-l H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
-(6-fluo ro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone;
- 2-(6-fluoropyridin-3-yl)-1-(1/-/-indol-3-yl)-2-((3-methoxyphenyl)amîno)ethanone:
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyridin-3-yl)ethanone;
- 2-((3-methoxyphenyl)amino)-1-(1-(2-morpholinoethyl)-1H-indol-3-yl)-2-phenylethanone;
- 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-(piperidîn-4-ylsulfonyl)-1H-indol-3-yl)ethanone;
4-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amïno)-2-methoxybenzonitrile;
- 1 -(5-(hydroxymethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
tert-butyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-6,7-dihydro-1Hpyrazolo[4,3-c]pyridine-5(4H)-carboxylate;
- 2-((3-methoxyphenyl)amino)-1-(1-methyl-4,5,6l7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-
2- phenylethanone hydrochloride;
1- (7-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 1-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-ç/pyridin-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone;
- 2-((3-methoxyphenyl)amino)-1-(7-methyl-1/-/-indol-3-yl)-2-phenylethanone;
2- ((3-methoxyphenyl)amino)-1 -(6-methyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylpyridin-3-yl)ethanone;
- 1 -(5-fluoro-1 /-/-pyrrolo[2,3-b]pyridin-3-yl)-2-((3-methoxypheny1)amino)-2-phenylethanone; 1-(5-((dimethylamino)methyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 2-((3-methoxyphenyl)amino)-1 -(5-( methylsuffonyl )-1 H-indol-3-yl)-2-phenylethanone;
-(4-fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1- (4-methoxy-1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2phenylethanone;
- 4-(1-((3,5-dimethoxyphenyl)amino)-2-(1H-indol-3-yl)-2-oxoethyl)benzonitrile;
- 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-pyrrolo[2l3-b]pyridin-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone;
2- ((3,5-dimethoxyphenyl)amîno)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone;
- 2-((3-methoxyphenyl)amino)-1 -(6-morpholino-1 /7-indol-3-yl)-2-phenylethanone;
2-(imidazo[1,2-d]pyridazin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
- 2-(6-(dimethylamino)pyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
- 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypynmidin-5-yl)ethanone;
- 1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
1- (6-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
- 2-((3-(2-(dimethylamino)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone;
- 1-(1-(2-(tert-butoxy)ethyl)-6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone;
-(6 -flu oro-1 -(2-hydroxyethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((5-ethoxypyridin-3-yl)amino )-1-(1 /7-indol-3-yl)-2-phenylethanone;
1- (1H-indol-3-yl)-2-((5-isopropoxypyridin-3-yl)amino)-2-phenylethanone;
2- ((5-ethylpyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazÎn-2-yl)ethanone;
2- (6-ethoxypyridin-3-yl)-1-(1H-indol-3-yî)-2-((3-methoxyphenyl)amino)ethanone; 2-((3-methoxyphenyl)amino)-1-(4-methyl-1H-indol-3-yl)-2-phenylethanone;
1- (1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone;
2- ((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
2-((3-ethoxy-5-methoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-phenylethanone;
2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone; 2-((516^ϊ™θί1Ίθχγργπάΐη-3-γΙ)3ΓΤΉηο)-1-(1Η-ΪΓ^οΙ-3-γ1)-2-ρΐΊβηνΙβΙΐΊ3ηοηβ;
2-((6-(dimethylamino)-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
2-((6-ethoxy-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
2-((5-methoxypyridin-3-yl)amino)-1 -(1 -methyl-1 H-indazol-3-yl)-2-phenylethanone;
4-(1-((3-methoxyphenyl)amino)-2-(1-methyl-1H-indazol-3-yl)-2-oxoethyl)benzonitrile;
1- (1H-indol-3-yl)-2-((5-methoxy-6-(methylamino)pyridin-3-yl)amino)-2-phenylethanone;
2- ((3-(hydroxymethyl)-5-methoxyphenyl)amino )-1-(1/-/-indol-3-yl)-2-phenylethanone;
2-((3-((dirnethylamino)methyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone; 2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1-(1-methyl-1H-indazol-3yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone; 1-(6-methoxy-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 2-(1,5-dimethyl-1H-pyrazo!-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)arnino)ethanone;
- 1-(1H-indol-3-yl)-2-(6-isopropoxypyridin-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
- 2-((5-(difluoromethoxy)pyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
-(5-flu oro-1 -methyl-1 H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(methylamino)pyridin-3-yl)ethanone;
- 2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)-1-(1 -methyl-1 H-indazol-3yl)ethanone;
- 2-((3-methoxyphenyl)amïno)-1-(1-methyl-1 H-indazol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2yl)ethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazin-2-yl)ethanone;
- 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-1H-indazole-5-carbonitrile;
- 2-((6-methoxypyrazin-2-yl)amino)-1-(1 -methyl-1 H-indazol-3-yl)-2-phenylethanone;
- 1-(1H-indol-3-yl)-2-((6-methoxypyridin-2-yl)amino)-2-phenylethanone;
- 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1 -methyl-1 H-indazol-3-yl)-2phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1 H-indazol-3-yl)-2-(pyridin-3-yl)ethanone;
-(1 H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyridin-3-yl)ethanone;
- 1 -(6-fluoro-1 -methyl-1 /7-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
- 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-lndol-3-yl)-2-(pyridin-3-yl)ethanone;
- 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridin-3yl)ethanone;
- 1 -( 1 H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(6-methoxypyridin-3-yl)ethanone;
-(6-fluoro-1 /7-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-phenylethanone;
- 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 -methyl-1 H-indazole-6-carbonitrile;
-(6-fluoro-1 /7-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone;
- 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5-methoxypyrazin-2yl)ethanone;
- 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2yl)ethanone;
- 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone;
- 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridln-3yl)ethanone;
- 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1/7-indol-3-yl)-2-(5-methoxypyrazin-2yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1/7-indol-3-yl)-2-(5-methoxypyrazin-2-yl)ethanone;
-(5-fluo ro-1 H-indol-3-yl)-2“((3-methoxyphenyl)amïno)-2-(5-methoxypyrazin-2-yl)ethanone;
- 1 -(5-fluoro-1 H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-phenylethanone;
- 1 -(6-fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone;
- 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1 H-indazol-3-yl)-2phenylethanone;
(-)-1-(1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone;
(+)-1-(1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone;
1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-2-yl)ethanone;
1-(1H-îndol-4-y!)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
1- (1-(2-hydroxyethyl)-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2- ((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1 H-indol-3-yl)-2phenylethanone;
2- ((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1 -(1 -methyl-1 H-indol-3-yl)-2phenylethanone;
3- methoxy-5-((2-( 1 -methyl-1 /7-indol-3-yl)-2-oxo-1 -phenylethyl)amino)benzyl acetate;
2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1-methyl-1 H-indol-3-yl)-2phenylethanone;
1-(isoquinolin-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone; 1-(1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylpyridin-3-yl)ethanone;
1- (1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-2-yl)ethanone;
2- (6,7-dihydro-4H-pyrazolo[5,1 -c][ 1,4]oxazin-2-yl)-1 -(1 /7-i ndol-3-yl )-2-((3methoxyphenyl)amino)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)arnino)-2-(5-rnethoxypyridin-3-yl)ethanone;
2- (4-fluorophenyl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3yl)ethanone;
5-(2-(1 H-indol-3-yl)-1-((3-methoxyphenyl)arnino)-2-oxoethyl)picolinonitrile;
1-(1H-îndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanone;
1-(6-fluoro-1H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)arnino)-2phenylethanone;
1- (1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridazin-3-yl)ethanone;
2- ((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2phenylethanone;
2-((2,6-dimethoxypyridin-4-yl)amino)-1-(1/7-indol-3-yl)-2-phenylethanone; 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methylpyridin-3yl)ethanone;
2-(5-fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
(-)-1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
- (+)-1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
- (-)-1 -( 1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone;
- (+)-1-(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone;
- (-)-2-((3,5-dimethoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-phenylethanone;
- (+)-2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-(benzo[d]oxazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone;
- 2-((3-methoxyphenyl)amino)-1 -(7-methyl-1 H-indol-3-yl)-2-(pyrazolo[1,5-a] pyridi n-2yl)ethanone;
- 1-(benzo[d]isoxazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;
2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1 -(7-methyl-1 H-tndol-3-y l)-2phenylethanone;
- 2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1 -(7-methyl-1 /-/-indol-3-yl)ethanone; 2-(6-fluoropyridin-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indoi-3yl)ethanone;
-(5-fluo ro-1 H-îndol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-(pyridin-3yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-(6-methoxypyridîn-3-yl)ethanone;
- 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1/7-indol-3-yl)-2-(pyrazolo[1,5-a]pyridîn2-yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(7-methyl-1/7-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(7-(2-hydroxyethyl)-1 H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1-methyl-1/7-indazol-3-yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(7-methyl-1 H-indol-3-yl)ethanone;
- 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3yl)ethanone;
2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone;
-(6-fluoro-1 H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amîno)-2-(pyridin-3yl)ethanone;
- 2-((2-fluoro-3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone;
- 2-((4,6-dimethoxypyrimidin-2-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
-(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(o-tolyl)ethanone;
2-((3-(2-(/ert-butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1/7-indol-3yljethanone;
- 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1 -( 1 H-indol-3yljethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(5-(hydroxymethyl)-1 H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(4-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone;
- 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1 -(5-fluoro-1 H-indol-3-yl)-2phenylethanone;
-(5-fluoro-1 H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-2phenylethanone;
- 2-((4-fluoro-3-methoxyphenyl)arnino)-1-(1H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(4-(3-hydroxypropyl)-1 H-indol-3-yl)-2-phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1-methyl-1/-/-indol-3-yl)-2phenylethanone;
2-((3-hydroxy-5-methoxyphenyl)amino )-1-(1 H-indol-3-yl)-2-phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-(pyridin-3-yl)ethanone;
2-((3-(3-hydroxypropoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(7-(hydroxymethyl)-1/7-indol-3-yl)-2-phenylethanone;
2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1/-Aindol-7-yl)ethyl acetate;
1- (7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyrîdin-3-yl)amino)-2-phenylethanone;
2- ((3,5-dimethoxyphenyl)amino)-1-(7-(2-(dimethylamino)ethyl)-1/7-indol-3-yl)-2phenylethanone;
2-((3-hydroxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone;
ethyl 4-(3-((2-(1 H-îndol-3-yl)-2-oxo-1 -phenylethyl)amino)-5-methoxyphenoxy)butanoate;
2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(p-tolyl)ethanone;
2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(p-tolyl)ethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone;
2- ((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1/7-indol-3yl)ethanone;
3- (3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1 H-indol-5-yl)propyl acetate;
- 1-(5-(3-hydroxypropyl)-1/7-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone;
- 2-(3-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3yl)ethanone;
- 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1/-/-indol-7-yl)ethyl acetate;
-(7-(2-hydroxyethyl)-1 /-/-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
- 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyrid in-2-yl)acetyl )-1 H-indol-7yl)ethyl acetate;
-(7-(2-hydroxyethyl)-1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone;
- 2-(3-(2-(5-fluoropyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1 H-indol-7-yl)ethyl acetate;
- 2-( 5-fl uoropyrîd în-3-yl )-1 -(7-(2-hydroxyethyl)-1 /-/-indol-3-yl)-2-((5-methoxypyridin-3yl)amîno)ethanone;
- 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1 H-indol-5-yl)ethyl acetate;
-(5-(2-hydroxyethyl)-1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone;
- 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)ethyl acetate;
-(5-( 2-hyd roxyethyl )-1 H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
2- (3-(2-((5-methoxypyrïdin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1 H-indol-5yl)ethyl acetate;
1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone;
- 2-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate;
- 2-(4-fluorophenyl)-1 -(7-(2-hydroxyethyl)-1 /7-indol-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
- 4-(3-((2-( 1 H-indol-3-yl)-2-oxo-1 -phenylethyl)amino)-5-methoxyphenoxy)butanoic acid;
- 2-(3-(2-((3,5-dimethoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyrid i n-2-yl)acetyl )-1 H-indol-5yl)ethyl acetate;
- 2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1/7-indol-3-yl)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone;
- 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1 H-îndol-5yl)propyl acetate;
-(5-(3-hydroxypropyl)-1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone;
3- (3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1/-/-indol-5-yl)propyl acetate;
- 1 -(5-(3-hydroxypropyl)-1 /7-indol-3-yi)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridÎn-3“ yl)amino)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(7-(2-(methylsulfonyl)ethyl)-1 H-indo l-3-y I )-2phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(5-(3-hydroxypropyl)-1 H-indol-3yl)ethanone;
3-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridÎn-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate;
- 2-(4-fluorophen y I)-1 -(5-(3-hydroxypropyl)-1 H-indol-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(5-( 2-h yd roxyethy I )-1 H-îndol-3yl)ethanone;
- 4-(3-(( 1-(4l6-dimethylpyridin-3-yl)-2-(1H-indol-3-yl)-2-oxoethyl)amino)-5methoxyphenyl)butanoic acid;
- 2-(6-(hydroxymethyl)pyrïdin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxy-5-(2(methylsulfonyl)ethyl)phenyl)amino)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(5-fluoro-7-(2-hydroxyethyl)-1 H-indol-3-yl)-2(tetrahydrofuran-3-yl)ethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-((methylsulfonyl)methyl)-1/-/-indol-3-yl)-2-(tetrahydro2H-pyran-4-yl)ethanone;
- 2-((3,5-dÎmethoxyphenyl)amino)-1-(5-(3-(dimethylamino)propyl)-1H-indol-3-yl)-2-(3,5dimethylisoxazol-4-yl)ethanone;
- 2-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-(7-(3-aminopropyl)-1H-indol-3-yl)-2-((3,5dimethoxyphenyl)amino)ethanone;
2- (benzo[d]isoxazol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-1 -(7-(3-hydroxypropyl)-1 H-indol-
3- yl)ethanone;
3-(3-(2-((3,5-dimethoxyphenyl)amino)-2-(5-phenylisoxazol-3-yl)acetyl)-1H-indol-5yl)propanoic acid;
- 1 -(5-(2-aminoethyl)-1 H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(5-methyl-1 -phenyl-1 Hpyrazol-3-yl)ethanone;
-methyl-4-((2-(5-(2-(methylsulfonyl)ethyl)-1 H-indol-3-yl)-2-oxo-1 phenylethyl)amino)pyrrolidin-2-one;
1- (1H-îndol-3-yl)-2-((3-methoxy-5-((methylamino)methyl)phenyl)amino)-2-(3-methyl-3Himidazo[4,5-b]pyridin-2-yl)ethanone;
- 2-(6,7-dihydro-4/7-pyrano[3,4-c/]thiazol-2-yl)-2-((3-(2-hydroxyethyl)-5-methoxyphenyl)amino)1 -(1 /-/-indol-3-yl)ethanone;
2- ((3-(2-amÎnoethoxy)-5-methoxypheny[)amino)-1-(1H-indol-3-yl)-2-(1-methyl-1/-/benzo[c/]imidazol-2-yl)ethanone;
- 2-(benzo[djthiazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxy-5-(2-(pyrrolidin-1yl)ethoxy)phenyl)amino)ethanone;
- 2-((3-(difluoromethoxy)phenyl)amino)-1-(1H-indol-3-yl)-2-(thiazolo[4,5-b]pyrazin-2yl)ethanone;
- 2-(3-((1-(benzo[b]thiophen-2-yl)-2-(1H-indol-3-yl)-2-oxoethyl)amino)-5-methoxyphenyl)acetic acid;
- 2-((3-(3-aminopropoxy)-5-methoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-(thieno[2,3-b]pyridin-2yl)ethanone;
- 1-(5-(aminomethyl)-1H-indol-3-yl)-2-((3l5-dimethoxyphenyl)amino)’2-(thiazolo[5l4’C]pyridin2-yl)ethanone;
1- (7-(aminomethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[4,5-c]pyridin-
2- yl)ethanone;
1- (5-(2-aminoethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[4,5-b]pyridin-
2- yl)ethanone;
1- (1H-indol-3-yl)-2-((3-methoxy-5-(2-(methylsulfonyl)ethoxy)phenyl)amino)-2-(5-methyl4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethanone;
2- ((3,5-dimethoxyphenyl)amino)-1-(1H-ïndol-3-yl)-2-(5-methyl-415l6,7-tetrahydrothiazolo[4,5c]pyridin-2-yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(7-(2-hydroxyethyl)-1 H-indol-3-yl)-2-(p-tolyl)ethanone;
- 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-
H-indol-3-yl)ethanone;
- 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1 -(5-(2-hydroxyethyl)-1 H-indol-3-yl)-2phenylethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(5-(2-(dimethylamino)ethyl)-1 H-indol-3-yl)-2-(4fluorophenyl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(2-hydroxyethyl)-1-methyl-1Hindazol-3-yl)ethanone;
- 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-
3- yl)ethanone;
- 2-((3,5-dimethoxyphenyl)amino)-1 -(5-(2-hydroxyethyl)-1 -methyl-1 H-indazol-3-yl)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone;
- 2-(4-fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxy-5((methylsulfonyl)methyl)phenyl)amino)ethanone;
- 2-((3l5-dîmethoxyphenyl)amino)-2-(3-methylpyridin-2-yl)-1 -(7-((methylsulfonyl)methyl)-1 Hindol-3-yl)ethanone; and
- 3-(3-(2-(6-cyanopyridin-2-yl)-2-((3,5-dimethoxyphenyl)amino)acetyl)-1H-indol-5-yl)propanoic acid.
Another aspect of the invention relates to the compounds described in the first aspect with the formulas (A), (B), (C), (D), (D1 ), (D2), (D3), (D4), (D5), (E), (E1 ), (E2), (F), (F1) and (G) and ail embodiments thereof, for use as a medicine.
Another aspect of the invention relates to the compounds described in the first aspect with the formulas (A), (B), (C), (D), (D1 ), (D2), (D3), (D4), (D5), (E), (E1), (E2), (F), (F1), (G), (H), (I), (J), and ail embodiments thereof, for use as a medicine.
Yet another aspect of the invention relates to the compounds described herein for use as a medicine for the prévention or treatment of a flavivirus infection in an animal, mammal or human. In a particular embodiment, flavivirus infection is an infection with dengue virus. The présent invention also relates to the use of the compounds herein described for the manufacture of a médicament, in a particular embodiment said médicament is for the prévention or treatment of a flavivirus infection in an animal, mammal or human.
Another aspect of the présent invention relates to a pharmaceutical composition comprising the compounds described herein above and ail embodiments thereof in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition comprises compounds selected from the formulas (A), (B), (C), (D), (D1), (D2), (D3), (D4), (D5), (E), (E1 ), (E2), (F), (F1) and (G)and ail embodiments thereof.
Another aspect of the présent invention relates to a pharmaceutical composition comprising an effective amount of the compounds described herein above and ail embodiments thereof in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition comprises compounds selected from the formulas (A), (B), (C), (D), (D1), (D2), (D3), (D4), (D5), (E), (E1), (E2), (F), (F1), (G), (H), (I), (J), and ali embodiments thereof.
Yet another aspect of the présent invention relates to a method for the prévention or treatment of a flavivirus infection in an animal, mammal or human comprising administering to an animal, mammal or human in need for such prévention or treatment an effective dose of the compounds of the first aspect described herein and the embodiments thereof.
Still another aspect relates to a method for the préparation of the compounds of the invention, comprising the step of reacting an imine with an aldéhyde under umpolung conditions in the presence of a thiazolium catalyst to obtain the desired compounds of the invention.
In another embodiment, the invention relates to a method for the préparation of the compounds of the invention, comprising the steps of
- reacting an heterocycle under Friedel Craft conditions to obtain a ketone dérivative having a methylene adjacent to the carbonyl,
- reacting the previously obtained ketone under halogénation conditions to obtain an alphahalogenoketone,
- substitute the previously obtained alpha-halogenoketone with amines to obtain the desired compounds of the invention.
In another embodiment, the invention relates to a method for the préparation of the compounds of the invention, comprising the steps of
- reacting a heterocyclicamine with 2-halogeno-acetic acid halide to obtain an alphahalogenoamide dérivative,
- substitute the previously obtained alpha-halogenoamide with amines to obtain the desired compounds of the invention.
In another embodiment, the invention relates to a method for the préparation of the compounds of the invention, comprising the steps of
- reacting an aldéhyde with an imine in the presence of a catalyst to obtain a beta-aminoketone dérivative as desired compound.
One embodiment of the invention relates to a method for the préparation of the compounds of the invention, comprising the step of
- reacting compound of formula (X1) with the amine R1R2NH in a suitable solvent, wherein cycle A, cycle B, R1, and R2 hâve the meaning according to any one of the embodiments presented herein, and LG is a leaving group as known by the skilled in the art, preferably selected from chlorine, bromîne, and iodine; or
reacting the imine of formula (X2) with an aldéhyde of formula (X3) in the presence of a catalyst and a suitable solvent to obtain compound of formula (A1), wherein cycle A, cycle B, and R1, hâve the meaning according to any one of the embodiments presented herein, and provided that in cycle A of formulae (X3) and (A1), a carbon atom is binding to the carbonyl.
to
refer to administration of a compound or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through inhibition of a viral infection. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through the inhibition of the viral infection. The term “subject” refers to an animal or mammalian patient in need of such treatment, such as a human.
It is to be noticed that the term comprising, used in the daims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other éléments or steps.
Reference throughout this spécification to one embodiment or an embodiment means
The term “treat” or treating” as used herein is intended that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the présent invention. Thus, appearances of the phrases in one embodiment or in an embodiment in various places throughout this spécification are not necessarily ail referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill în the art from this disclosure, in one or more embodiments. Where an indefinite or definite article is used when referring to a sîngular noun e.g. a or an, the, this includes a plural of that noun unless something else is specifïcally stated.
Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.
In each of the following définitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally présent in the substituent or linker; it is understood that where otherwise indicated in the présent application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
The term “leaving group or LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).
The term protecting group refers to a moiety of a compound that masks or allers the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: Protectîve Groups in Organic Chemistry, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashton. Protection of functional groups of a compound allers other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.
Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and résistance to enzymatic dégradation or séquestration. In this rôle, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more désirable if the products are pharmacologically innocuous.
The term “hydrocarbyl”, “C^a hydrocarbyl, “hydrocarbyl group or Cmb hydrocarbyl group as used herein refers to CrC18 normal, secondary, tertiary, unsaturated or saturated, non-aromatic, acyclic or cyclic, hydrocarbons and combinations thereof, This term therefore comprises alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl.
The terminology “heterohydrocarbyl”, “hetero Cvie hydrocarbyl, “heterohydrocarbyl group, “hetero C^a hydrocarbyl group or “hydrocarbyl group which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” as used herein, refers to a hydrocarbyl group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom(s) and thus includes heteroalkyl, heteroalkenyl, heteroalkynyl and non-aromatic heterocycle. This term therefore comprises as an example alkoxy, alkenyloxy, Cwalkyl-O-C^-walkyl, Cwalkenyl-O-alkyl, Cwalkyl-NH-C18.walkenyl, among others, wherein w is selected from any number between 1 and 18.
The term alkyl or “C,.^ alkyl” as used herein means CrC18 normal, secondary, or tertiary, linear or cyclic (or a combination of linear and cyclic), branched or straight hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyi-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2methyl-3-pentyl, cyclopropylethylene, methylcyclopropylene, 2,3-dimethyl-2-butyl, cyclopentylmethylene, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, ndodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, nnonadecyl, n-icosyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a particular embodiment, the term alkyl refers to ΟΊ_ι2 hydrocarbons, yet more in particular to Ci^ hydrocarbons, yet more in particular to Ο;.3 hydrocarbons as further defined herein above. A preferred alkyl is Ci^alkyl. Another preferred alkyl is Ci^alkyl.
The term “acyclic alkyl or “linear alkyl” as used herein means CrC18 non-cyclic normal, secondary, or tertiary, linear, branched or straight, hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1-propyl, 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (sBu), 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl16765
2-butyl, 3-methyl-1-butyl, 2-methyl-1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl n-heptyl, n-octyl, n-nonyl, π-decyl, n-undecyl, n-dodecyl, n-tridecyl, ntetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl and n-îcosyl.
The term cycloalkyl or C3.18 cycloalkyl as used herein and unless otherwise stated means a saturated hydrocarbon monovalent radical having from 3 to 18 carbon atoms consisting of or comprising a C3.10 monocyclic or C7.i8 polycyclic saturated hydrocarbon, such as for instance cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclopentylmethylene, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, isopropoylcyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like. For the avoidance of doubt and as an example, cyclopentylmethylene refers to whereby the methyl group on the cyclopentyl is coupled to another group. Furthermore, for the avoidance of doubt and as an example, methylcyclopropylene refers to whereby the cyclopropyl of the methylcyclopropyl is coupled to another group.
A preferred cycloalkyl is C3.7cycloalkyl.
The term “alkenyl” or “C2.18alkenyr as used herein is C2-C18 normal, secondary or tertiary, linear or cyclic, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), cyclohexenyl (-C6H9), cyclopentenylpropylene, methylcyclohexenylene and 5-hexenyl (CH2CH2CH2CH2CH=CH2). The double bond may be in the cis or trans configuration. In a particular embodiment, the term alkenyl refers to Ci.12 hydrocarbons, yet more in particular to Cv6 hydrocarbons as further defined herein above. A preferred alkenyl is Cz.6alkenyl.
The term acyclic alkenyl or “linear alkenyl” as used herein refers to C2-C18 non-cyclic normal, secondary or tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2) and
5-hexenyl (-CH2CH2CH2CH2CH=CH2). The double bond may be in the cis or trans configuration.
The term “cycloalkenyl as used herein refers to a non-aromatic hydrocarbon radical having from 3 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond and consisting of or comprising a C3·^ monocyclic or C7.18 polycyclic hydrocarbon. Examples include, but are not limited to: cyclopentenyl (-C5H7), cyclopentenylpropylene, methylcyclohexenylene and cyclohexenyl (CeHe). The double bond may be in the cis or trans configuration.
The term alkynyl or “C2.i8alkynyl·' as used herein refers to C2-C18 normal, secondary, tertîary, linear or cyclic, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (-C^CH), 3-ethyl-cyclohept-1-ynylene, 4-cyclohept-1-yn-methylene and 1propynyl (propargyl, -CH2CsCH). In a particular embodiment, the term alkenyl refers to Cm2 hydrocarbons, yet more in particular to Ci_6 hydrocarbons as further defined herein above. A preferred alkynyl is C2.6alkynyl.
The term “acyclic alkynyl” or “linear alkynyl as used herein refers to C2-C18 non-cyclic normal, secondary, tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (-C=CH) and 1-propynyl (propargyl, -CHZC=CH).
The term “cycloalkynyl” as used herein refers to a non-aromatic hydrocarbon radical having from 3 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond and consisting of or comprising a C3.10 monocyclic or C7.18 polycyclic hydrocarbon. Examples include, but are not limited to: cyclohept1-yne, 3-ethyl-cyclohept-1-ynylene, 4-cyclohept-1-yn-methylene and ethylene-cyclohept-1-yne.
The term alkylene as used herein each refer to a saturated, branched or straight chain hydrocarbon radical of 1-18 carbon atoms (more in particular Ci.12or Ομ6 carbon atoms), and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH2-), 1,2-ethyl (-CHZCH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (CH2CHZCHZCH2-), and the like.
The term alkenylene as used herein each refer to a branched or straight chain hydrocarbon radical of 2-18 carbon atoms (more ïn particular Cz.izor Cz^ carbon atoms) with at least one site (usually 1 to 3, preferably 1 ) of unsaturation, namely a carbon-carbon, sp2 double bond, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
The term alkynylene as used herein each refer to a branched or straight chain hydrocarbon radical of 2-18 carbon atoms (more in particular Cz.12or Cz.8 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
The term “heteroalkyl” as used herein refers to an acyclic alkyl wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said acyclic alkyl can be replaced by -NH2 and/or that one or more -CH2- of said acyclic alkyl can be replaced by -NH-, -O- or -S-. The S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfoxîdes and sulfones, respectively.
Furthermore, the heteroalkyl groups in the compounds of the présent invention can contain an oxo or thio group at any carbon or heteroatom that will resuit in a stable compound. Exemplary heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers, primary, secondary, and tertiary alkyl amines, amides, ketones, esters, alkyl sulfides, and alkyl sulfones.
The term “heteroalkenyl” as used herein refers to an acyclic alkenyl wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said acyclic alkenyl can be replaced by -NH2, that one or more -CH2- of said acyclic alkenyl can be replaced by -NH-, -O- or -S- and/or that one or more -CH= of said acyclic alkynyl can be replaced by -N=. The S atoms in said chaîne may be optionally oxidîzed with one or two oxygen atoms, to afford sulfoxides and sulfones, respectively. Furthermore, the heteroalkyl groups in the compounds of the présent invention can contain an oxo or thio group at any carbon or heteroatom that will resuit in a stable compound. The term heteroalkenyl thus comprises imines, -O-alkenyl, -NH-alkenyl, -N(alkenyl)z, -N(alkyl)(alkenyl), and -S-alkenyl.
The term “heteroalkynyl” as used herein refers to an acyclic alkynyl wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said acyclic alkynyl can be replaced by -NHZ) that one or more -CH2- of said acyclic alkynyl can be replaced by -NH-, -O- or -S-, that one or more -CH= of said acyclic alkynyl can be replaced by -N= and/or that one or more =CH of said acyclic alkynyl can be replaced by -N. The S atoms in said chains may be optionally oxidîzed with one or two oxygen atoms, to afford sulfoxides and sulfones, respectively. Furthermore, the heteroalkynyl groups in the compounds of the présent invention can contain an oxo or thio group at any carbon or heteroatom that will resuit in a stable compound. The term heteroalkynyl thus comprises -O-alkynyl, -NH-alkynyl, -N(alkynyl)2, -N(alkyl)(alkynyl), -N(alkenyl)(alkynyl), and -Salkynyl.
The term “heteroalkylene as used herein refers to an alkylene wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said alkylene can be replaced by -NH2 and/or that one or more -CHZ- of said alkylene can be replaced by -NH-, -O- or -S-. The S atoms in said chains may be optionally oxidîzed with one or two oxygen atoms, to afford sulfoxides and sulfones, respectively. Furthermore, the heteroalkylene groups in the compounds of the présent invention can contain an oxo or thîo group at any carbon or heteroatom that will resuit in a stable compound.
The term “heteroalkenylene as used herein refers to an alkenylene wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said alkenylene can be replaced by -NH2, that one or more -CH2- of said alkenylene can be replaced by -NH-, -O- or -S- and/or that one or more -CH= of said alkynylene can be replaced by -N=. The S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfoxides and sulfones, respectively. Furthermore, the heteroalkenylene groups in the compounds of the présent invention can contain an oxo or thio group at any carbon or heteroatom that will resuit in a stable compound.
The term “heteroalkynylene” as used herein refers to an alkynylene wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said alkynylene can be replaced by -NH2( that one or more -CH2- of said alkynylene can be replaced by -NH-, -O- or -S-, that one or more -CH= of said alkynylene can be replaced by -N= and/or that one or more =CH of said alkynylene can ve replaced by N. The S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfoxides and sulfones, respectively. Furthermore, the heteroalkynylene groups in the compounds of the présent invention can contain an oxo or thio group at any carbon or heteroatom that will resuit in a stable compound. .
The term aryl as used herein means an aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The term “parent aromatic ring system means a monocyclic aromatic ring System or a bi- or tricyclic ring system of which at least one ring is aromatic. Therefore, in this embodiment, typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, 2,3-dihydro-1H-indenyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,6,7,8,8a-hexahydroacenaphthylenyl, 1,2-dihydroacenaphthylenyl, and the like. Particular aryl groups are phenyl and naphthyl, especially phenyl.
The term arylalkyl or arylalkyl- as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, îs replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
The term arylalkenyl or arylalkenyl- as used herein refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl radical.
The arylalkenyl group comprises 6 to 20 carbon atoms, e.g. the alkenyl moiety of the arylalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
The term arylalkynyl or “arylalkynyl- as used herein refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl radical. The arylalkynyl group comprises 6 to 20 carbon atoms, e.g. the alkynyl moiety of the arylalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
The term arylheteroalkyl or “arylheteroalkyl- as used herein refers to a heteroalkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. The arylheteroalkyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkyl moiety of the arylheteroalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
The term arylheteroalkenyl or arylheteroalkenyl- as used herein refers to a heteroalkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl radical. The arylheteroalkenyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkenyl moiety of the arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
The term arylheteroalkynyl or arylheteroalkynyl- as used herein refers to a heteroalkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl radical. The arylheteroalkynyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkynyl moiety of the arylheteroalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
The term heterocycle as used herein means a saturated, unsaturated or aromatic ring system of 3 to 18 atoms including at least one N, O, S, or P. Heterocycle thus include heteroaryl groups. Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Léo A. Principles of Modem Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A sériés of Monographs (John Wiley & Sons, New York, 1950 to présent), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. Comprehensive Heterocyclic Chemistry (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566. In a particular embodiment, the term means pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidîzed tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperîdinyl, 4piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H.6H1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyi, 3H-indolyl, 1Hindazoly, purinyl, 4H-quinolizinyl, phthalazînyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, B-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothlenyl, benzothiazolyl and isatlnoyl.
The term “heteroaryl means an aromatic ring system of 5 to 18 atoms including at least one N, O, S, or P and thus refers to aromatic heterocycles. Examples of heteroaryl include but are not limited to pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyî, isoxazolyl, pyrazolyl, isothiazolyl, furyl, thienyl, and pyrrolyl.
The term “non-aromatic heterocycle” as used herein means a saturated or unsaturated non-aromatic ring system of 3 to 18 atoms including at least one N, O, S, or P.
The term heterocycle-alkyl or “heterocycle-alkyl- as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocycle radical. An example of a heterocycle-alkyl group is 2-pyridyl-methylene. The heterocycle-alkyl group comprises 6 to 20 atoms, e.g. the alkyl moiety of the heterocycle-alkyl group is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.
The term heterocycle-alkenyl or heterocycle-alkenyl-1* as used herein refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, Is replaced with an heterocycle radical. The heterocycle-alkenyl group comprises 6 to 20 atoms, e.g. the alkenyl moiety of the heterocycle-alkenyl group is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.
The term heterocycle-alkynyl or “heterocycle-alkynyl- as used herein refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocycle radical. The heterocycle-alkynyl group comprises 6 to 20 atoms, e.g. the alkynyl moiety of the heterocycle-alkynyl group is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.
The term heterocycle-heteroalkyl or “heterocycle-heteroalkyl- as used herein refers to a heteroalkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocycle radical. The heterocycle-heteroalkyl group comprises 6 to 20 atoms, e.g. the heteroalkyl moiety of the heterocycle-heteroalkyl group is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.
The term heterocycle-heteroalkenyl or “heterocycle-heteroalkenyl- as used herein refers to a heteroalkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heterocycle radical. The heterocycle-heteroalkenyl group comprises 6 to 20 atoms, e.g. the heteroalkenyl moiety of the heterocycle-heteroalkenyl group is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.
The term heterocycle-heteroalkynyl or “heterocycle-heteroalkynyl- as used herein refers to a heteroalkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocycle radical. The heterocycle-heteroalkynyl group comprises 6 to 20 atoms, e.g. the heteroalkynyl moiety of the heterocycle-heteroalkynyl group is 1 to 6 carbon atoms and the heterocycle moiety is 3 to 14 atoms.
The term “heteroaryl-alkyl or uheteroaryl-alkyl-“ as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteraryl radical. An example of a heteroaryl-alkyl group is 2pyridyl-methylene. The heteroaryl-alkyl group comprises 6 to 20 atoms, e.g. the alkyl moiety of the heteroaryl-alkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
The term heteroaryl-alkenyl or “heteroaryl-alkenyl- as used herein refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl radical. The heteroaryl-alkenyl group comprises 6 to 20 atoms, e.g. the alkenyl moiety of the heteroaryl-alkenyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
The term heteroaryl-alkynyl or “heteroaryl-alkynyl- as used herein refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, îs replaced with a heteroaryl radical. The heteroaryl-alkynyl group comprises 6 to 20 atoms, e.g. the alkynyl moiety of the heteroaryl-alkynyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
The term heteroaryl-heteroalkyl or heteroaryl-heteroalkyl- as used herein refers to a heteroalkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocycle radical. The heteroaryl-heteroalkyl group comprises 6 to 20 atoms, e.g. the heteroalkyl moiety of the heteroaryl-heteroalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
The term heteroaryl-heteroalkenyl or “heteroaryl-heteroalkenyl- as used herein refers to a heteroalkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl radical. The heteroaryl-heteroalkenyl group comprises 6 to 20 atoms, e.g. the heteroalkenyl moiety of the heteroaryl-heteroalkenyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
The term heteroaryl-heteroalkynyl or “heteroaryl-heteroalkynyl- as used herein refers to a heteroalkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl radical. The heteroaryl-heteroalkynyl group comprises 6 to 20 atoms, e.g. the heteroalkynyl moiety of the heteroaryl-heteroalkynyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
The term “non-aromatic heterocycle-alkyl or “non-aromatic heterocycle-alkyl-“ as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a non-aromatic heterocycle radical. The non-aromatic heterocycle-alkyl group comprises 6 to 20 atoms, e.g. the alkyl moiety of the non-aromatic heterocycle-alkyl group is 1 to 6 carbon atoms and the non-aromatic heterocycle moiety is 3 to 14 atoms.
The term non-aromatic heterocycle-alkenyl or “non-aromatic heterocycle-alkenyl- as used herein refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an non-aromatic heterocycle radical. The non-aromatic heterocycle-alkenyl group comprises 6 to 20 atoms, e.g. the alkenyl moiety of the non-aromatic heterocycle-alkenyl group is 1 to 6 carbon atoms and the non-aromatic heterocycle moiety is 3 to 14 atoms.
The term non-aromatic heterocycle-alkynyl or “non-aromatic heterocycle-alkynyl-“ as used herein refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a non-aromatic heterocycle radical. The non-aromatic heterocycle-alkynyl group comprises 6 to 20 atoms, e.g. the alkynyl moiety of the non-aromatic heterocycle-alkynyl group is 1 to 6 carbon atoms and the non-aromatic heterocycle moiety is 3 to 14 atoms.
The term non-aromatic heterocycle-heteroalkyl or “non-aromatic heterocycleheteroalkyl-“ as used herein refers to a heteroalkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocycle radical. The non-aromatic heterocycle-heteroalkyl group comprises 6 to 20 atoms, e.g. the heteroalkyl moiety of the non-aromatic heterocycle-heteroalkyl group is 1 to 6 carbon atoms and the non-aromatic heterocycle moiety is 3 to 14 atoms.
The term non-aromatic heterocycle-heteroalkenyl or “non-aromatic heterocycleheteroalkenyl- as used herein refers to a heteroalkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an non-aromatic heterocycle radical. The nonaromatic heterocycle-heteroalkenyl group comprises 6 to 20 atoms, e.g. the heteroalkenyl moiety of the non-aromatic heterocycle-heteroalkenyl group is 1 to 6 carbon atoms and the nonaromatic heterocycle moiety is 3 to 14 atoms.
The term non-aromatic heterocycle-heteroalkynyl or “non-aromatic heterocycleheteroalkynyl-“ as used herein refers to a heteroalkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a non-aromatic heterocycle radical. The nonaromatic heterocycle-heteroalkynyl group comprises 6 to 20 atoms, e.g. the heteroalkynyl moiety of the non-aromatic heterocycle-heteroalkynyl group is 1 to 6 carbon atoms and the nonaromatic heterocycle moiety is 3 to 14 atoms.
By way of example, carbon bonded heterocyclic rings are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrîmidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thîophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1 -aziridyl, 1azetedyl, 1 -pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
As used herein and unless otherwise stated, the terms “alkoxy, “cyclo-alkoxy”, aryloxy, “arylalkyloxy, “heterocycleoxy, “alkylthio, “cycloalkylthio”, “arylthio”, arylalkylthio and “heterocyclethio refer to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl or heterocycle (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyioxy, mercaptobenzyl and the like. The same définitions will apply for alkenyl and alkynyl radicals in stead of alkyl. A preferred alkoxy is ΟΊ. 6alkoxy; another preferred alkoxy is CMalkoxy.
As used herein and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
As used herein with respect to a substituting group, and unless otherwise stated, the terms substituted such as in “substituted alkyl”, substituted alkenyi, substituted alkynyl·', “substituted aryl, “substituted heterocycle, substituted arylalkyl, “substituted heterocyclealkyl” and the like refer to the chemical structures defined herein, and wherein the said hydrocarbyl, heterohydrocarbyl group and/or the said aryl or heterocycle may be optionally substituted with one or more substituents (préférable 1, 2, 3, 4, 5 or 6), meaning that one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include, but are not limited to and in a particular embodiment said substituents are being independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl and heterocycle-alkynyl, -X, -Z, -0‘, -OZ, =O, -SZ, -S', =S, -NZ2, -N+Z3, =NZ, =N-OZ, -CX3 (e.g. trifluoromethyl), -CN, -OCN, -SCN, -N=C=O, -N=C=S, -NO, -NO2, =N21 -N31 -NZC(O)Z, -NZC(S)Z, -NZC(O)O‘, -NZC(O)OZ, -NZC(S)OZ, -NZC(O)NZZ, NZC(NZ)Z, NZC(NZ)NZZ, -C(O)NZZ, -C(NZ)Z, -S(O)2O’, -S(O)20Z, -S(O)2Z, -OS(O)2OZ, 16765
OS(O)2Z, -OS(O)2O-, -S(O)2NZ, -S(O)Z, -OP(O)(OZ)2, -P(O)(OZ)2, -P(O)(O‘)2, -P(O)(OZ)(O ), P(O)(OH)21 -C(O)Z, -C(O)X, -C(S)Z, -C(O)OZ, -C(O)O“, -C(S)OZ, -C(O)SZ, -C(S)SZ, -C(O)NZZ, -C(S)NZZ, -C(NZ)NZZ, -OC(O)Z, -OC(S)Z, -OC(O)O; -OC(O)OZ, -OC(S)OZ, wherein each X is independently a halogen selected from F, Cl, Br, or I; and each Z is independently -H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, protecting group or prodrug moiety, while two Z bonded to a nitrogen atom can be taken together with the nitrogen atom to which they are bonded to form a heterocycle, Alkyl(ene), alkenyl(ene), and alkynyl(ene) groups may also be similarly substituted.
Any substituent désignation that is found in more than one site in a compound of this invention shall be independently selected.
Substituents optîonally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and ail possible orientations of the substituent are intended.
As used herein and unless otherwise stated, the term “solvaté includes any combination which may be formed by a dérivative of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.
The term heteroatom(s)” as used herein means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
The term hydroxy as used herein means -OH.
The term “carbonyl” as used herein means carbon atom bonded to oxygen with a double bond, i.e., C=O.
The term “amino as used herein means the -NH2 group.
The compounds of the invention are employed for the treatment or prophylaxis of viral infections, more particularly Flaviviral infections.
Flavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis. Flaviviruses share a common size (40-65 nm), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single stranded RNA approximately 10,000-11,000 bases), and appearance in the électron microscope. These viruses are transmitted by the bite from an infected arthropod (mosquito or tick).
The compounds of the invention are particularly active against dengue virus réplication.
For dengue virus, four distinct, but closely related serotypes are known (DENV-1, -2, -3, and -4).
Dengue is endemic in most tropical and sub-tropical régions around the world, predominantly in urban and semi-urban areas. According to the World Health Organization (WHO), 2.5 billion people of which 1 billion children are at risk of DENV infection (WHO, 2002). An estimated 50 to
100 million cases of dengue fever [DF], half a million cases of severe dengue disease (i.e. dengue hémorrhagie fever [DHF] and dengue shock syndrome [DSS]), and more than 20,000 deaths occur worldwide each year. DHF has become a leading cause of hospitalisation and death amongst children in endemic régions. Altogether, dengue represents the most common cause of arboviral disease. Because of recent large outbreaks in countries situated in Latin America, South-East Asia and the Western Pacifie (including Brazil, Puerto Rico, Venezuela, Cambodia, Indonesia, Vietnam, Thailand), numbers of dengue cases have risen dramatically over the past years. Not only is the number of dengue cases increasing as the disease îs spreading to new areas, but the outbreaks tend to be more severe.
To prevent and/or control dengue disease, the only available methods at présent are mosquito éradication strategies to control the vector. Although progress is being made in the development of vaccines for dengue, many difficulties are encountered. These include the existence of a phenomenon referred to as antibody-dependent enhancement (ADE). Recovery from an infection by one serotype provides lifelong immunity against that serotype but confers only partial and transient protection against a subséquent infection by one of the other three serotypes. Following infection with another serotype, pre-existing heterologous antibodies form complexes with the newly infecting dengue virus serotype but do not neutralize the pathogen. Instead, virus entry into cells is believed to be facilitated, resulting in uncontrolled virus réplication and higher peak viral titres. In both primary and secondary infections, higher viral titres are associated with more severe dengue disease. Since maternai antibodies can easily pass on to infants by breast feeding, this might be one of the reasons that children are more affected by severe dengue disease than adults.
In locations with two or more serotypes circulating simultaneously, also referred to as hyperendemic régions, the risk of serious dengue disease is significantly higher due to an increased risk of experiencing a secondary, more severe infection. Moreover, in a situation of hyper-endemicity, the probability of the emergence of more virulent strains is increased, which in turn augments the probability of dengue hémorrhagie fever (DHF) or dengue shock syndrome.
When using one or more compounds of the invention and of the formulae as defined herein:
- the compound(s) may be administered to the animal or mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
- the therapeutically effective amount of the préparation of the compound(s), especially for the treatment of viral infections in humans and other mammals, preferably is a flaviviral réplication inhibiting amount of the formulae as defined herein and corresponds to an amount which ensures a plasma level of between 1pg/ml and 100 mg/ml, optionally of 10 mg/ml.
The présent invention further relates to a method for preventing or treating viral infections in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of the compounds of the présent invention. The therapeutically effective amount of the compound(s), especially for the treatment of viral infections in humans and other mammals, preferably is a flaviviral réplication inhibiting amount. The suitable dosage is usually in the range of 0.001 mg to 60 mg, optionally 0.01 mg to 10 mg, optionally 0.1 mg to 1 mg per day per kg bodyweight for humans. Depending upon the pathologie condition to be treated and the patient’s condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
As is conventional in the art, the évaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the médian effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as Cl) defined by the following équation:
wherein EDX is the dose of the first or respectively second drug used alone (1a, 2a), or in combination with the second or respectively first drug (1c, 2c), which is needed to produce a given effect. The said first and second drug hâve synergistic or additive or antagonistic effects depending upon Cl < 1, Cl = 1, or Cl > 1, respectively.
Synergistic activity of the pharmaceutical compositions or combined préparations of this invention against viral infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using ECa, for calculating the fractional inhibitory concentration (hereinafter referred as FIC). When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FICX + FICy) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as subsynergistic, and when it is lower than 0.5, the combination is by defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as subantagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
This principle may be applied to a combination of different antiviral drugs of the invention or to a combination of the antiviral drugs of the invention with other drugs that exhibit anti-viral activity or that stimulate the immune response.
The invention thus relates to a pharmaceutical composition or combined préparation having synergistic effects against a viral infection and containing:
Either:
A) (a) a combination of two or more of the compounds of the présent invention, and (b) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prévention of a flaviviral infection or
B) (c) one or more anti-viral agents and/or immune stimulating agents, and (d) at least one of the compounds of the présent invention, and (e) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prévention of a flaviviral infection.
Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined préparations of this invention include ribavirin,
Suitable immune stimulating agents for inclusion into the synergistic antiviral compositions or combined préparations of this invention include interferon.
The pharmaceutical composition or combined préparation with synergistic activity against viral infection according to this invention may contain the compounds of the présent invention over a broad content range depending on the contemplated use and the expected effect of the préparation. Generally, the content of the compound of the invention for inclusion into the synergistic antiviral compositions of the présent invention of the combined préparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
According to a particular embodiment of the invention, the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of Flaviviral infections, more preferably Dengue viral infections. The invention therefore relates to the use of a composition comprising:
(a) one or more compounds of the formulae described herein, and (b) one or more Picornaviral enzyme inhibitors as biologically active agents in respective proportions such as to provide a synergistic effect against a Flaviviral infection, particularly an Dengueviral infection in a mammal, for instance in the form of a combined préparation for simultaneous, separate or sequential use in viral infection therapy.
More generally, the invention relates to the compounds of formula (A), (B), (C), (D-1 ), (D2), (E), (F), and (G) and ail embodiments thereof being useful as agents having biological activity (particularly antiviral activity) or as diagnostic agents. Any of the uses mentioned with respect to the présent invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use reiated to cells remote from an animal.
More generally, the invention relates to the compounds of formula (A), (B), (G), (D-1), (D2), (E), (F), (G), (H), (I), (J), and ail embodiments thereof being useful as agents having biological activity (particularly antiviral activity) or as diagnostic agents. Any of the uses mentioned with respect to the présent invention may be restricted to a non-medical use, a nontherapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use reiated to cells remote from an animal.
Those of skill in the art will also recognize that the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state - any and ail protonated forms of the compounds are intended to fall within the scope of the invention.
The term pharmaceutically acceptable salts as used herein means the therapeutically active non-toxic sait forms which the compounds of formulae herein are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, NH4+, Ca2+ and Mg2+. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth métal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the invention may bear multiple positive or négative charges. The net charge of the compounds of the invention may be either positive or négative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Métal salts typically are prepared by reacting the métal hydroxide with a compound of this invention. Examples of métal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble métal sait can be precipitated from the solution of a more soluble sait by addition of the suitable métal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e, butanedioic acid), maleic, fumaric, malic, tartane, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvatés which the compounds of formulae herein as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, Isoleucine, or leucine.
The compounds of the invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali métal (for example, sodium), an alkaline earth (for example, magnésium), ammonium and NX/ (wherein X is CrC4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartane, maleic, malonic, malic, isethîonïc, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na* and NX/ (wherein X typically is independently selected from H or a CrC4 alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the préparation or purification of a physiologically acceptable compound. Ail salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the présent invention.
Préférable anions to form pharmaceutically acceptable acid addition salts are acetate, benzenesulfonate , benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate,
100 napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stéarate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and the like.
Préférable cations to form pharmaceutically acceptable basic salts are benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procalne, and the like; and those formed with metallic cations such as aluminum, calcium, lithium, magnésium, potassium, sodium, zinc, and the like.
As used herein and unless otherwise stated, the term enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
The term isomers as used herein means ail possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomère. Typically, the structures shown herein exemplify only one tautomeric or résonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical désignation of compounds dénotés the mixture of ail possible stereochemically isomeric forms, said mixtures containing ail diastereomers and enantiomers (since the compounds of formulae herein may hâve at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenîc centers may hâve either the R- or
S-configuration, and multiple bonds may hâve either cis- or trans-configuration.
Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In partîcular, the term stereoisomerically pure or chirally pure relates to compounds having a stereoisomeric excess of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms enantiomerically pure and diastereomerically pure should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.
Séparation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill;
Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Séparation of isomère in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and séparation by fractional crystallization or other methods, (2)
101 formation of diastereomeric compounds with chiral derivatizing reagents, séparation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphétamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For séparation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can resuit in formation of the diastereomeric salts. Altematively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl dérivatives, followed by séparation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for séparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose dérivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as éthanol, isopropanol and the like. (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase, J. of Chromatogr. 513:375378).
The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety. The absolute stereochemical configuration of the compounds of formula (1) may easily be determined by those skilled in the art while using well-known methods such as, for example, Xray diffraction.
102
The compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accordance with standard practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in stérile form, and when intended for delivery by other than oral administration generally will be isotonie. Formulations optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients'1 (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
Subsequently, the term pharmaceutically acceptable carrier as used herein means any material or substance with which the active ingrédient is formulated in order to facilitate its application or dissémination to the locus to be treated, for instance by dissolving, dispersing or diffusîng the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrâtes, émulsions, solutions, granulates, dusts, sprays, aérosols, suspensions, ointments, creams, tablets, pellets or powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their sélection within the présent invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phénol, sorbic acid, chlorobutanol), isotonie agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the présent invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingrédients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents, may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingrédients.
Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the présent invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents.
Suitable soaps are alkaline or alkaline-earth métal salts, unsubstituted or substituted ammonium salts of higher fatty acids (Ci0-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable from coconut oil or tallow oil. Synthetic surfactants
103 include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole dérivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth métal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium sait of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metai salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole dérivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutylnaphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphoshatidyl -choline and their mixtures.
Suitable non-ionic surfactants include polyethoxylated and polypropoxylated dérivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molécule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether dérivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said dérivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Représentative examples of non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycérol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further
104 substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals.
A more detailed description of surface-active agents suitable for this purpose may be found for instance in McCutcheon’s Détergents and Emulsifiers Annual (MC Publishing Crop., Ridgewood, New Jersey, 1981), Tensid-Taschenbucw', 2 d ed. (Hanser Verlag, Vîenna, 1981) and Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981).
Compounds of the invention and their physiologically acceptable salts (hereafter collectively referred to as the active ingrédients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parentéral (including subcutaneous, intramuscular, Intravenous, intradermal, intrathecal and épidural). The preferred route of administration may vary with for example the condition of the récipient.
While it is possible for the active ingrédients to be administered alone, it is préférable to présent them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the présent invention comprise at Ieast one active ingrédient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other. therapeutic ingrédients. The carrier(s) optimally are acceptable in the sense of being compatible with the other ingrédients of the formulation and not deleterious to the récipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parentéral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and épidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingrédient with the carrier which constitutes one or more accessory ingrédients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingrédient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules, cachets or tablets each containing a predetermined amount of the active ingrédient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid émulsion or a water-in-oil liquid émulsion. The active ingrédient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingrédients. Compressed tablets may be prepared by compressing in a suitable machine the active ingrédient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound
105 moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingrédient therein. For infections of the eye or other external tîssues e.g. mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in incréments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingrédients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingrédients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or pénétration of the active ingrédient through the skin or other affected areas. Examples of such dermal pénétration enhancers include dimethylsulfoxide and related analogs.
The oily phase of the émulsions of this invention may be constituted from known ingrédients in a known manner. While the phase may comprise merely an emulsifier (otherwîse known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilie emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical émulsion formulations is very low. Thus the cream should optionally be a nongreasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stéarate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stéarate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other minerai oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingrédient is dissolved or suspended in a suitable carrier, especially an
106 aqueous solvent for the active ingrédient. The active ingrédient is optionally présent in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingrédient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingrédient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingrédient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in incréments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingrédient. Formulations suitable for aérosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingrédient such carriers as are known in the art to be appropriate.
Formulations suitable for parentéral administration include aqueous and non-aqueous stérile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutés which render the formulation isotonie with the blood of the intended récipient; and aqueous and non-aqueous stérile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the stérile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from stérile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit daily subdose, as herein above recited, or an appropriate fraction thereof, of an active ingrédient.
It should be understood that in addition to the ingrédients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Compounds of the invention can be used to provide controlled release pharmaceutical
107 formulations containing as active ingrédient one or more compounds of the invention (controlled release formulations) in which the release of the active ingrédient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrète units comprising one or more compounds of the invention can be prepared according to conventional methods.
Additional ingrédients may be included in order to control the duration of action of the active ingrédient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvînyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulphatesulphate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingrédient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl méthacrylate and the other above-described polymers. Such methods include colloid drug delivery Systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectionable use include stérile aqueous solutions or dispersions and stérile powders for the extemporaneous préparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, éthanol, glycérol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
In view of the fact that, when several active ingrédients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingrédients in separate but adjacent repositories or compartments. In the latter context, each active ingrédient may therefore be formulated in a way suitable for an administration route different from that of the other ingrédient, e.g. one of them may be in the form of an oral or parentéral formulation whereas the other is in the form of an ampoule for intravenous injection or an aérosol.
Another embodiment of this invention relates to various precursor or prodrug forms of the compounds of the présent invention. It may be désirable to formulate the compounds of the présent invention in the form of a chemical species which itself is not significantly biologicallyactive, but which when delivered to the animal will undergo a chemical reaction catalyzed by the normal fonction of the body of the animal, inter alia, enzymes présent in the stomach or in blood sérum, said chemical reaction having the effect of releasing a compound as defined herein. The term “pro-drug” thus relates to these species which are converted in vivo into the active pharmaceutical ingrédient.
108
The prodrugs of the présent invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms. In the présent case, however, the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme présent at the target locus. For example, a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used. The counterpart of the active pharmaceutical ingrédient in the pro-drug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.
For the purpose of the présent invention the term “therapeutically suitable prodrug is defined herein as “a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal, mammal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergie response, and achieving the intended therapeutic outcome”.
More specifically the term prodrug, as used herein, relates to an inactive or significantly less active derivative of a compound of the invention, which undergoes spontaneous or enzymatic transformation within the body in order to release the pharmacologically active form of the compound. For a comprehensive review, référencé is made to Rautio J. et al. (“Prodrugs: design and clinical applications” Nature Reviews Drug Discovery, 2008, doi: 10.1038/nrd2468).
The compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity chromatography (séparations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl are useful in hydrophobie affinity séparations.
The compounds of the invention can be prepared while using a senes of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the présent invention.
The compounds of the présent invention may be prepared according to the general procedure outlined in the following schemes.
Scheme 1:
LG r1r2nh
109
Scheme 1: ail B, R1, R2, X1, X2, X3, X4, X5, Xe, X7, X8, X9, X10, p, q and LG are as described for the compounds of the présent invention and its embodiments and formuiae.
Dérivatives of general formula 1 (commercially available or synthesized by procedures known to the skilled in the art) may be reacted with intermediates of formula 2 (commercially available or synthesized by procedures known to the skilled in the art) wherein LG is independently selected from chlorine, bromine and iodine (more preferably chlorine) in an aprotic solvent (e.g. toluene, dichloromethane, dichloroethane and the like) at a température raising from 0 to 100°C to provide intermediates of formula 3. In case of X10 = C or CH, a catalyst (e.g. AICI3, Et2AICI, ZrCI4 and the like) or a base (e.g. pyridine, DBN, DMAP and the like) might be required. More information can be found in the following references: Tetrahedron 29, 971-976, 1973; Org. Lett., Vol. 12, No. 24, 2010; J. Org. Chem. 2011, 76, 4753-4758. In case of X10 = N, compounds of formula 1 can be converted in compounds of formula 3 by réaction with intermediates of formula 2 following standard amide bond conditions. The leaving group (LG) from intermediates of formula 3 may then be displaced by amines of formula R1R2NH (commercially available or synthesized) following procedures known to the skilled in the art or as set forth in the examples below to provide the desired compounds of formula 4.
Alternatively, the compounds of the présent invention may also be prepared according to the general procedure depicted in the following scheme.
Scheme 2:
Scheme 2: ail B, R1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, p and q are as described for the compounds of the présent invention and its embodiments and formulae
Aldéhydes of general formula 5 may be reacted with amines of formula R1NH2 to provide îmines of general formula 6 which may be reacted with intermediates of formula 7 (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below), wherein X10 is a carbon atom, in the presence of a catalyst such as 3-benzyl-
5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride to provide the desired compounds of formula 8. More detailed information can be found in Chem. Commun., 2007, 852-854.
In another embodiment, compounds of the présent invention may also be synthesized according to the general procedure outlined in the following scheme.
Scheme 3:
110
R1, R2, X1, X2, X3, X4, X5, X6, X7, Xe, X9, X10, p, q and
LG are as described for the
Scheme 3 ail B, compounds of the présent invention and its embodiments and formulae.
Dérivatives of general formula 1, wherein X10 is only
T©
Oxidation
selected from C or CH (commercially available or synthesized by procedures known to the skilled in the art) may be reacted with intermediates of formula 11 (commercially available or synthesized by procedures known to the skilled in the art) wherein LG is a leaving group such as chlorine, bromine and iodine, under Friedel Crafts conditions to provide intermediates of formula 10. Alternatively, intermediates of formula 10 may also be prepared by condenstation of grignard or organolithium dérivatives with an amide dérivatives (preferably Weinreb amide dérivatives) as known to the skilled in the art. These intermediates of formula 10 may be converted into intermediates of formula 3 wherein LG is an halogen such as chlorine, bromine or iodine following reactions known to the skilled in the art or as set forth in the examples below. Intermediates of formula 10, wherein B is only selected from aryl or heteroaryl, may be prepared by α-arylation of ketone of 15 formula 12 with halogenoaryl or halogenoheteroaryl in the presence of a catalyst (e.g. Pd2dba3,
Pd(OAc)2, Pd(dba)and the like), a ligand (e.g. BINAP, Xantphos, PfBu3 and the like) and a base (e.g. NaO/Bu, K3PO4 and the like). More information can be found in the following references: J.
111 Am. Chem. Soc. 1997, 11108-11109 and J. Am. Chem. Soc. 1999, 1473-1478. Alternatively, intermediates of formula 9 may also be obtained from aldéhydes of formula 7, wherein X10 is only selected from C or CH, and reagents of general formula 8, wherein M is Li or MgCI or MgBr, followed by an oxidation reaction known to the skilled in the art. Compounds of interest having a general formula 4 may be obtained from intermediates 3 as described in Scheme 1.
Abbreviations used in the description, particularly in the schemes and examples, are as follows:
BOC fert-Butyloxycarbonyl
DBU 1,8-Diazabicyclo[5,4,0]undec-7-ene
DBN 1,5-Diazabicyclo[4.3.0]non-5-ene
DIPEA Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMF N,A/-Dimethylformamide
DMSO Dimethylsulfoxide
ee Enantiomeric excess
eq h Equivalent Hour
HATU 0-(7-Azabenzotriazol-1-yl)-N,A/,/\/',/\f-tetramethyluronium hexafluorophosphate
HPLC High performance liquid chromatography
min Minute
NMP A/-Methyl-2-pyrrolidone
TBDMSCI tert-Butyldimethylchlorosilane
THF Tetrahydrofuran
TLC Thin layer chromatography
tr rétention time
Examples
The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.
Part A represents the préparation of the compounds (intermediates and final compounds) whereas Part B represents the pharmacological examples.
Table 1: Structures of example compounds of the invention and their respective codes.
112
Coda Structura Coda Structura Coda Structura
O O F 7*o
0 W 0 -PA ό
CPD-001 CPD-011 fn ^A bM CPD-021 OK. vQ OMe
OMe F oJ A
/TA J OMô JS
\-=/ OMe
0 JA o J A 0
CPD-002 nAj CPD-012 Æ CPD-022 «AA.
H 'ûMe prt- PO
^B H A
O N—7 ÛM» Vo
0 -Z VZ A B'Q^
CPD-003 Pn> b<4 OE1 CPD-013 Pt ÎB-M J OM· CPD-023 Pn>
^b B ^A
O O CP. Js
| CPD-004 0 ver CPD-014 o VO CPD-024 0 A H OM»
prs OM* PrS OM· H 4 >
I ^B ^A ^A
p JA, \ A F Z'O
CPD-005 A OCFj CPD-015 Prs bO OM· CPD-025 0 γυ4 «A.
^A
O O - O
CPD-006 I 0 rvS VQ. CPD-016 0 [Î]v vo CPD-026 0 Cn
A
æ-y o ç
I CPD-007 o «Ό' CPD-017 0 B-O CPD-027 A AL
I O? F ors H
I O
I CPD-008 0 aO CPD-018 0 n-Q CPD-028 «A.
jA F PA ' OM·
A \Ah H A
O f N
VJ/ Vji
CPD-009 0 -Cq H CF> CPD-019 O bO OM· CPD-029 0 bO H OM»
Pd Po PtS
1 A ^A
1 i CPD OIO O Po O nOw > OM* CPD-020 0 0^ Îq OM» CPD-030 o An 9 AL
A
113
Cod· Structure Cod* Structure Cod* Structure
O p-CN O
CPD-031 0 «V CPD-041 0 OrS «Ό» CPD-051 0 (TT$ RO >
^R ^R O
P)
V^J V--/
CPD-032 0 fHrS CPD-042 a (ΓίΓζ rQ OM· CPD· 052 0 rrÇ RQ
^R w ^R o' NH
P) P)
\ss/ N’ N f
CPDO33 q5 A CPD-043 O PO M. CPD-053 a y (M «Ά.
o O D
N-J.
CPD-034 O cq A CPD-044 0 Co »A.« ox CPD-054 0 ?a
PrA OMe
C^r
O □Mo
CPD-035 0 Ov rO CN CPD-045 0 PD CPD-055 O ?Q
^R Cd OM·
CN o P)
r$
CPD-036 0 Po OM· CPD-046 0 aj r<L CPD-056 V co ίτΌ OM·
JO Mes P^ Λ
Çp 0 -O 0 Y3’
CPD-037 o Co rO^ CPD-047 Prt ^R DAi □Me CPD-057 aj fl-w
O O
0 H-O V 0 rO
CPD-038 Qo M J— MeO CPD-048 CPD-058 Co
-Gp> N^N
I «H,
I II J / ^R
I <P) OM. o O
CPD-039 I 0 frS ^'R rV MeO CPD-049 0 iPrS A^'-N k pQ OM* CPD-058 0 Co VQ N
O O 0 ώ
O o P=\'N
I CPD-040 PO A (U “M· CPD-050 o? R-Vtj CPD-060 c cH O hnO
R OMe
114
Coda Structura Coda Structura Coda Structura
CN P? F*
zS N-/
CPD-061 Π 0 7 pc< □Me CPD-071 0 o? H —V°H o CPO-081 0 îîXtA U «Ό H OM·
X^ w
O o ù
CPO-062 Pi 0 Ά K Ni=\ nA-L OM· CPD-072 0 rri J Nî=X «X. CPD-082 0 ΓΥ> h-Q H OM·
'H ^îl \AnZ H
OH O N^y
Pn Xs=/
CPD-003 P 0 Ά X CPD-073 Pi >va OM· Ή CPD-083 0 Γτ4 M
Ή uy
Q O O
CPD-064 Ÿ-Q CPD-074 pp va OM· CPD-084 pra νλ.
c 7 OM·
a
O O O
CPD-065 0 O -Λ «Q.», CPD-075 Ztva H 1 OM* CPD-085 II vva J X> OM·
fi a H O
O O o
CPO-068 O va CPD-076 CPD-086 CJ-. Λ. H-Q
i OM· II XX OM· T Ί OM·
H 'fi
1T\ O O ™·
CPD-067 P 0 VS CPD-077 CPD-087 0 / ν=Λ a Λα
OM· II T XX OM· η ΤΛ OM·
lisv fi Ux H
O O CK
CPD-068 0 y H 0 CPD-078 ΜβΟ^Λ Y Pva ητ a om· >1 CPD-088 0 [PyS jj tO. OM·
p Pv X> OM· o O
CPO-069 i CPD-079 1*10 Jn-Q XÂ ^ ^OM. ^ΊΙ CPD-089 0 a} OM·
cX 'fi O
i CPD-070 c 0 5 fi o -( ?'8 ΗΖΖομ· CPD-OBO o li^T^ C «-Q > OMe CPD-090 0 iPn X
W
115
Code Structure Code Structure Code Structure
S-v O Q
CPD-091 KQ cpd-101 Jrw ίΤΛ H “** CPD-111 p
0 i n X* ’L»? O'V 0
i
0
UK3. >Ç-€? jkq ζ
CPD-092 CQ CPD-102 1 HL ? CPD-112 z-*, J$Q
c IJ H
0 O
CPD-093 CPD-103 Jp-CJ CPD-113
i ΤΛ °°· r y ou.
«J
CPD-094 J CPD-1M Jn-Q γιΓ / H θ”* CPD-114
NC^ s S
I OH H-. /
I ν-/ o y rîr? M s /£a~
I CPO-095 if’’ J >- n CPD-105 CPD-115 c rVo
HH,
€< O ο_ζ* <JT
cPD-œe i? v^'-q CPD-106 JJ-P F j| OU· CPD.116 a* JrVQ ί Ίν °m«
C ΪΛ OU« ’S H
OH
/T*HH v<2 0^_Z ΝϋΓ
CPD47B7 O ou/% JT r-Va 0M« CPD-107 CPD-117
X r 9 p
CPD-0D8 LJ CPD-108 XsN °γ-Λ ί*^' N H'Aa CPD-118
ί T? “· O-H a' .My
i TA om·
λβ
o O
CPD-099 ccp^- CPD-109 Çl JrW CPD-119 oF°~
flX °“·
F L CH
Q < i r$
I VT JpN .JP HAA °Lr
1 CPD-100 CPD-110 o r —v CPD-120 1
^*N t
1 l 7ΓΛ °·
;
116
Coda Structure Coda Structura Coda Structura
CPD-12» o\u CP0-131 .Qr CPD-141 «xz-oV·/
CPD-122 AVQ ΓιΓ? o** CPD-132 CN &’ ΟΓ°“ CFD-142 ΛΟτ^“·
CPD-123 AW ΓίΓ? Μ θ*1* CPO-133 CN 3¾ L ΐΓζ H CPO-143
CPD-124 ι r.Æ> ί 1? ομ· CPD-134 YÇ?-Q Il T? ow* CPO-144 Y&L 11 l 7 O-f|
CPD-125 -φκ CQ CPD-135 <^CrQ CPD-145 FvJrvQ YYj> H ^OM. ? 0 i ✓
CPD-126 CPD-136 L CPD-148 v4?Q Il iS OMe Οή t
CPD-127 ΗΟ α^λ. CPD-137 'Ό^“ CPD-147 0M1 r,rÇÙ i ZL/ <*·· ë < 0 /
CPD-128 J CPD-138 ί ηΓ^ ou* CPO-148 ? OH
( | CPD429 >ζΥΤτθ Η CP0-139 i 17 OM· CPO-149 F [ÎT? OM.
I | CPD-130 Ύ ΤΛ 0Μ* CPD-140 CPD-150 Q
117
Cod· Structure Cod· Structure Cod· Structur»
O O Q
CPD-151 MQ CPD-161 0 CPO-171 A- V°
I |y H 0 Q --0
O O O
CPD-152 Jrt-q CPD-162 0 S'Vx CPD-172 0 vo-
i YR> dm· r> p
F-** ^B 3 La
M»0
O
CPD-153 HQ om. CPD-163 0 Ta CPO-173 0 Ri Uc
L· F « « nw-\7 b
OM* O O
CPD-154 F et* M-Q OM. M CPD-164 A** 0 O B ço~ CPD-174 A 0 rS B rQ 4 ba>
OM· /=\ O
CPD-1S5 HQ CPD-165 0 O vo? CPD-175 C A VO
I c* ΤΛ) M ou. a B
! *«
O /A O
\ —/ OM· y7 V
F, O VO--
CPD-156 l HA OM. Xii+'N CPD-166 A* O K P OM· CPD-176 A*· F$ B
1 HO
i | CPD-157 CPD-167 Γ M CPD-177 Γ £
Si OM· J* h M
OM· V CN mh O
CPD-158 MO CPD-168 f#* 0 O CPD-178 0 HQ? l
1 c Γ A ou· a **B
1
î CN ό P 0 O VQ, HO
CPD-159 r xVM CPD-169 c i no CPD-179 L- s
I I
P p-\ MM #A
CPO-160 CPD-170 0 -A H'Mto CPD-1S0 0
i_______________________________ lA Aa X Il > λβ
118
Cod· Structura Code Structura Code Structura
CPD-181 CPD-191 fe CPD-201
CPD-182 CPD-192 CPD-202 .cfa-
CPD-183 <0 CPD-193 O0 CPD-203 00Q OC*N
CPD-184 kJLjf CPD-194 CPD-2M 00- ? Ύ
CPD-185 00^’· CPO-195 rVO-Q- J T / o*·*· CPD-205 An-Q rïy H ™*
CPD-186 CPD*1M CPD-206 ou· 0Æ
CPD-187 CPD-197 0Y\ H ûm· CPD-207 o0
CPD-188 ο0Λ CPD-19B ί[ | SH ou· CPD-208 α^°~ °'S
CPD-189 kAjf »0 CPD-199 p CPD-209 00- °s
CPD-190 oAo CPD-200 0^°” CPD *210 f) ou· Arw rii? 0141 J
119
Code Structure Code Structure Code Structure
CPD-211 CPD-221 ΎνΟ ΧΧΉ ' HQ CPD-231 *A
CPD-212 0'»·° CPD-222 A OMa CPO-232 A
CPD-213 ÛM· ,<A CPD-223 ,-à?Q f ||*n OM· xAn V CPD-233 CN Ci OU· zàvi AjA H ou»
CPD-214 CPD-224 Ai-Q fiTS °“· Υή CPD-234 A
CPD-215 zTrQ ^ah CPD-225 CPD-235 À
CPD-216 oA 0 CPD.226 A CPD-236 G *
CPD-217 oJ^“· •ç CPD-227 J* CPD-237 ,Α-
CPD-218 A CPO-223 CPD-238 Q
CPD-219 =xxAQ~ CPD-229 CPD-239 NM·,
CPD-220 xA H CPD-230 A CPD-240 ou· A A-va Ι1Γ? °“* A
120
Coda Structure Code Structure Ccd· Structura
OM· J Λ p
CPD-241 F CPD-251 VCL CPD-201 oi VCr~
<Ύ\ H <*·
DM· J r\
Avi h om· i O rw
CPD-242 CPD-252 0? Wu CPD-262 w»
F** H
O 0-^.NM^ ?rC7- P /-”·
V A J”S
CPD-243 r CPD-253 [TYS CPD-263 ÛD
Λϋ
p OM·
/ OEt VQ H OM·
CPD-244 J CPD-254 0 Γ ιΓΛ w H OM· CPD-284 0
fs ? Cvh
Ύ
O i P n-“ ? 7 OM·
AÇq OM· yr Çô 0 VÔ
CPD-245 CPO-255 rrS CPD-265
L XAn \
o D
CPD-246 f CPD-256 A vcc CPD-266 rt-Q r\ ou.
ï? ULjj' MtO·'^ \
0 < D
CPD-247 i /-A CPD-257 oT CPD-287 A VV
uç
0 □ OiPr
CPD-24B e rP-^ CPD-258 qT ÎA“ CPD-269 o f'H VQ M OM·
^B iTo l*tZv'N H
QM·
CPD-249 v“ CPD-259 0 CTï7N w M OM· CPD-269 ri
O-Jj
Z** N
H
OEI CN jT\
CPD-250 jXq VS M °“* CPD-260 0 VQ M CM· CPD-270 < Xa n-Q % H ou.
r r\ N
ab '^Z^N'
121
Code Structur* Cod· Structure Cod· Structure
U OM· i
CPO-271 An CPD-281 t 3^ h-Q % H <** CPD-291 Cj 0-V.OH /Ατά
ΑϊΛ r'' N So “·
OM· O A ou·
An An
N % AA> N J °Ά-0Η
CPD-272 0 ÇQ H OM· CPD-282 C 0 h^om. CPD-292 oS<
1 11 n fl
VS t
OM·
i7 H l t* <-0M
VpH V r Χ,Η ί**
CPD-273 0 PiPn S-Q H OM· CPD-283 0 TP ji'Ca M OM· CPD-293 fïV^ L II ? ou·
R ^R
N ? OM· 0M« An
CPD-274 At CPD-284 0 i PN r-M CPD-294
Γ M OM·
R ^R
TS ô A OM· ïS
CPD-275 TJ no. CPD-285 £ 3 SA. CPD-295 Ά*Α·
‘N A •R
0
CPD-276 Û vCl CPD-286 CPD-296
Γ [Λ OM· Γ Pn Υπ °“·
NCX ^•N
P- OM*
fe. Ah
CPD-277 CPD-287 i 3 sa. CPO-297 +.3 xrvA-
^R P R
fAAjj
OM·
7 r0H Atl Ο 0-Ά-0Η
CPD-278 0 fipj Ç'Ca H OM» CPD-288 Λ H i r-OH A- CPD-298 „U'Vu ApN
VS p ïri VS
\ A S
1 « Ail x a W- O
0 vP M OU· 0 r ^oi rA ArW ΓιΓ? M
CPD-279 C o CPD-289 r-Va . M OM· CPD-299
%ζ*·Η V
ar enantiomer 1 tra 6.7 min
pN /P)
CPD-280 CPD-290 0 ip «A. CPD-300 Arvû pTS m om·
R enanuomer2 lf » 121 min
122
Coda Structura Coda Structura Coda Structura
CPD-301 0^- CPD-311 oA- CPD-321 cP-
CPD-302 Λχ. co CPD-312 kW O op0· CPD-322 ou· enaotlomer 1 t 0 7 min
CPD-303 ίΊτ« “· H i. CPD*3I3 oÀ CPD-323 OMd enantomer 2 1,« 125 mn
CPO'304 oP-y X CPD-314 CH op0- CPD-324 fil? w· enanUomer 1 L · 03 mm
CPD-306 Q P-X-™ oP4- CPD-315 op- CPD-325 ΓιΓ? °** enanuonw2 U· 120 min
CPD-303 Pi X CPO313 Q P-X-OH ,op - CPD-320 enanliomer 1 L«ûi min
CPD-307 oM X CPD-317 r*« oP^ CPD-327 enanUomerî l,· 170 min
cpû-μθ œ CPD-318 CPD-320 P >-
CPD-3OT CPD-3W oP- CPD-320 À v»
CPD-31Û CM· 0^°“ CPD-320 CPO-330
123
Cod« Structure Code Structure Code Structure
Q P\-OH F ξ ) 7·
% Tr S OM· j M
CPD-331 ΓΊΤΛ «A X. CPD-341 0 flA i CPD-351 HO ΥΊ rV «H,
AA γΒ *θΜβ M
OM· 1O) OM· -$
f*N VJ rn HO 0^ ΛJ
CPD-332 Pt Λ-Q CPD-342 m ba OM* CPD-352 v=p\ OKto
Ç'M OM* A
F A, N \k ÿ P\-OH 0 ?“·
G ^-OH Ύ Γ/Λ o< J rS
CPD-333 jy R-C CPD-343 m R-X H *OMe CPD-353 ho'
(DMt A
^B
r\ —OH p -OH O
AJ A c A 0
CPD-334 Ç r M CPD-344 r«- Ά CPD-354 ’ y
Tï OM· Ar ^Ï5M· 'ï OM·
B ,ΧΑ B Ά
OM* O
/*Ή OM· P“\_0H
OM· 0 $ 0 0 OM·
CPD-335 cr V i CPD-345 An ΌΜ· CPD-355 F. in
ÎD ou* ^A ^A
î
CPD-336 Û \s>N B-C .0-X-OH i CPD-340 0 /*H V OM· A CPD-356 0 n B ζ-cr H OM·
Γ |ΓΛ OM· i. 1] ?
A
OM· 0 OM· HOS P ) CM·
O F Γ 0 7^ n' k 0 A
CPD-337 flTS ΛΑ OM· CPD-347 ΓιΓΛ Λα Ah CPD-357 ί*ιΓ p DM·
γ*Β ^B AA a”
Q jT\
OM· OM·
Λ-< i t> A-Q 0 U i
CPD-338 œ \ CM· CPD-349 An ^A OM· CPO-358 CH <1*N/ OM·
o F β
OM* J (5 _/ r- ( P OH J
0 i 0 y J i
CPD-339 An OM· CPD-349 bA CPD-359 A n OM·
yr Ad (OM· A- A
OH
F F ό OM·
OM· P'X.oh ΟΛ J s
CPD-340 0 4 i CPD-350 0 Λα i CPD-300 (3M·
f’T'S OM· m OM· ^H
%Ζ**Ν’ ^*Α
124
Code Sirvictur· Code Structure Code Structure
CPD’381 CPD‘370 CPDJ79 Y
CPD-382 HCT CPD-371 F om* CH CPD-3S0 OH
CPD-363 0^0 CPD-372 Λ°'~Χ·Ρ“ζ'ί“ CPD-M1
CPD -384 Ç5- CPD-373 CPD-382
CPD-3&5 NM», CPD-374 oA CPD-M3 OM· γ-χς^»
CPD-388 CPD-376 OM· Y CFD-3&4 OM·
CPD-3Ô7 CPD-370 Ou· Γ^Η cpo-aes
CPD-36fl cA? CPD-377 rïXA. Y CPD-386
CPO-360 Ο θ'Χ,ΟΗ CPD-370 Y~tl CPD-387 °γ°
125
Cod· Structure Cod· Structure Cod· Structure
F F h Λ>„
rS \ c**· 4.M
va, ÿ OM·
CPD-3S8 0 HrS Xta CPD-397 HO-^^ 0 yyÇ ^OM. CPD-406 0 [TYS V-A
γΊΙ Xn
OH ''HH
r% F
y W, ^coot A- fi 0 Ar-
CPD-389 of CPD-398 0 Ao- 0Qc CPD-407 Γχί y«
^OH
F
cb
Cri ÇM. G? j5· yyOY
CPD-390 Y- o Ό7 W OM· CPD-399 H0'^X 0 vxi Of| M. CPD-408 HOOC^
^fi
'N ,N iï F A J OM· k-0 y «*
0. / r\
CPD-39Î 11 CPCMOO ©rf OMe CPD-409 fi-^ 1 Tv OM.
<A H
CPD-392 0 Λο^ 0 Ύρ e, ï OM· CPD-401 O cf H-Cj 'X-COOH OM· CP0-410
£0) HO o
p-N -, H] _~HHM·
\sN „ Y*N J
CPD-393 0 X CPD-402 o n-0 SOjM· » CPD-411 0 «Ό H ^^OM·
^fi ^fi
OM· z-o
N 7 ( yp OM· £C
CPD-394 K CPD-403 O ρΛ H 4 OM· CPD-412 O m y»N jj c*t H A-4 ^OM·
OH
OM· r°
/0« \ J ÇM· p
H J O ^^□M. \sN ^Χ_.ΝΗ2
CPD-395 HO''''''' of CPD-4(M of CPD-413 0 Ct? «Ό OM·
O <* °'N (O
4» -G -!L °Μ· O
0 0 ΛΌ 0 y ο-χ.Ηςΐ
CPD-390 rM> χη DM· CPD-405 H 1 ΊΟ? > OM· CPD-414 rvf Λ-Q M ^OM·
SOjM·
126
Code Structura Coda Structure Code Structure
ύ F ό
O y» h P'X-SOA’· %X f
CPD-415 AA. CPD-421 V X> A CPD-427 HOk 4
i ' OCHFj Γ jA ηΆ X T*»* OM·
A \
Π F
--COOW OMt C/ p-V-OH
0 Τ’ rttf» οΛ / rsl\
CPD-416 hA_ CPD-422 AA. CPD-428 h Αχ OM·
c Tj H OM. c A OM* O?n \
n O A
OM* OM·
o _ 0
O -A J °V C F*
CPD-417 AA. i CPD-423 U tS nA A OM· CPD-429 ηο^λ
II OM* A [ 1 k OM·
Ύ
OH
F F
9 V J. om· (A “VOH O rS'V·'·
O. O -A Λ A o A /=A
CPD-41B HjN n w OM· CPD-424 |T ***!*? hA Au. CPD-430 aA
OH A
β xX P'X-OH ÎT\ y* JJ
οΛ 8 T J /** OM» s HOk O -w o ttAx
CPD-419 hA. x CPD-425 An OM· CPD-431 An oku
|T ' τΆ OM· W
A
F o \sN -CH
Vn LS OM. OM*
B T y»N OM* / ά
û o J /A HOOC K4
CPD-4 20 HjN A a CPD-420 t ,N CPD-432 T jA OM*
OM· iAn
Part A
Ail the préparative HPLC purifications mentioned in this experimental part have been carried out with the following system: a Waters 2489 UV/Visible Detector, a Waters 2545 Binary Gradient Module, a Waters Fraction Collector III and a Waters Dual Flex Injector.
The séparations were performed with a XBridge Prep C18 column (19x100 mm; 5 pm) equipped with a XBridge C18 guard column (19x10 mm; 5 pm) or with a SunFire Prep C18 ODB column (19x100 mm; 5 pm) equipped with a SunFire C18 guard column (19x10 mm; 5 pM).
Elutions were carried out with the methods described in the following tables, and détection wavelengths were fixed at 210 and 254 nm.
Method 1
Time Flow Rate Solvent A Solvent B
(min) (mL/min) (%) (%)
127
0 20 50 50
2.00 20 50 50
9.00 20 10 90
11.00 20 10 90
11.20 20 50 50
16.00 20 50 50
Solvent A: Formic Acid LC-MS grade 0.1% in milliQ water
Solvent B: Acetonitrile HPLC grade.
Method 2
Time Flow Rate Solvent A Solvent B
(min) (mL/min) (%) (%)
0 20 80 20
2.00 20 80 20
8.00 20 10 90
10.80 20 10 90
11.00 20 80 20
16.00 20 80 20
Solvent A: Formic Acid LC-MS grade 0.1% in milliQ water
Solvent B: Acetonitrile HPLC grade.
Method 3
Time Flow Rate Solvent A Solvent B
(min) (mL/min) (%) (%)
0 20 95 5
2.00 20 95 5
8.00 20 50 50
9.00 20 10 90
11.80 20 10 90
12.00 20 95 5
16.00 20 95 5
Solvent A: Formic Acid LC-MS grade 0.1% in milliQ water
Solvent B: Acetonitrile HPLC grade.
Method 4
Time Flow Rate Solvent A Solvent B
(min) (mL/min) (%) (%)
0 20 50 50
2.00 20 50 50
9.00 20 10 90
11.00 20 10 90
11.20 20 50 50
16.00 20 50 50
128
Solvent A: Ammonium Acetate puriss p.a. for HPLC 10mM in millîQ water, adjusted at pH10 with Ammonium Hydroxyde puriss p.a. for HPLC
Solvent B: Acetonitrile HPLC grade.
Method 5
Time Flow Rate Solvent A Solvent B
(min) (mL/min) (%) (%)
0 20 80 20
2.00 20 80 20
8.00 20 10 90
10.80 20 10 90
11.00 20 80 20
16.00 20 80 20
Solvent A: Ammonium Acetate puriss p.a. for HPLC 10mM in milliQ water, adjusted at pH10 with Ammonium Hydroxyde puriss p.a. for HPLC Solvent B: Acetonitrile HPLC grade.
Ail the enantiomer séparations mentioned in this experimental part hâve been carried out with the following system: a Waters 2489 UV/Visible Detector, a Waters 2545 Binary Gradient Module, a Waters Fraction Collecter III and a Waters Dual Flex Injecter. The séparations were performed with a ChiralPak IC column (20x250 mm; 5 pm) equipped with a ChiralPak IC guard column (10x20 mm; 5 pM). Elutions were carried out with the isocratic methods described below, and détection wavelengths were fixed at 210 and 254 nm.
Method 6:
Eluant: Acetonitrile/diethylamine: 100/0.1 Flow rate: 20 mL/min
Method 7:
Eluant: n-heptane/dichloromethane/ethanol/diethylamine: 50/50/1/0.1 Flow rate: 20 mL/min
General procedures used in the synthesis of compounds of the invention: General procedure A:
To a solution of an appropriate indole and pyridine in toluene heated at 55 °C was added dropwise α-chlorophenylacetyl chloride. The reaction mixture was heated at 55 °C for 2 h. After cooling to room température, water and methanol were added. After 1 h at room température, the precipitate was filtered, washed with water and dried to afford the desired compound. In case of no précipitation, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel or by précipitation to give the desired compound.
General Procedure B:
129
A mixture of 2-chloro-1-(1H-indol’3’yl)-2-phenylethanone, an amine and triethylamine in DMF was heated at 100 °C overnight in a sealed tube. The solvent was evaporated under vacuum. The residue was partitioned between ethyl acetate and a 5% hydrochloric acid solution. The phases were separated. The organic phase was washed with water, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel followed by recrystallization.
General Procedure C:
A mixture of an α-halogenoketone, an amine and a base (DIPEA or triethylamine) in a solvent (e.g. DMF, éthanol, acetonitrile, dioxane or THF) was irradiated in a microwave oven at 100°C to 200°C (more in particular at 120 to 200 °C) for 5 to 180 min. (more in particular for 15 to 120 min). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel.
General procedure D:
A mixture of an α-halogenoketone, an amine and PS-DIPEA in acetonitrile was irradiated in a microwave oven at 200 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel. Further purification by préparative HPLC was undertaken to furnish the product.
General procedure E:
A mixture of an α-halogenoketone and an aniline in acetonitrile was irradiated in a microwave oven at 100 to 200 C (more in particular at 130 to 150 °C) for 5 to 120 min (more in particular for 15 to 30 min). The reaction mixture was then concentrated. The residue was partitioned between ethyl acetate and a 1N hydrochloric acid solution. The phases were separated. The organic phase was washed with a saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel.
General procedure F:
To a solution of an appropriate indole, azaindole or alternative heterocycles (1.0 eq) and di-tert-butyl dicarbonate (1eq. to 2 eq., more in particular 1.2 eq) in acetonitrile was added DMAP (0.1 to 0.5 eq. more in particular 0.1 eq). The reaction mixture was stirred overnight at room température. The reaction mixture was concentrated under reduced pressure. The residue was dissolved în dichloromethane and washed with a saturated sodium bicarbonate solution. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with a saturated ammonium chloride solution, water and brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The BOC-protected compound was used in the next step without further purification.
General procedure G:
130
To a mixture of an aldéhyde (1.0 eq) and magnésium sulfate (1.3 eq) in éthanol was added an amine (1.0 eq). The reaction mixture was stirred ovemight at room température and filtered. The filtrate was concentrated under reduced pressure to give quantitatively the imine which was used without further purification in the next step.
General procedure H:
To a mixture of an aldéhyde (1.0 eq) and magnésium sulfate (1.3 eq) in éthanol was added an amine (1.0 eq). The mixture was heated ovemight at 80 °C and filtered. The filtrate was concentrated under reduced pressure to give quantitatively the imine which was used without further purification in the next step.
General procedure I:
A mixture of an aldéhyde (1.0 eq) and an amine (1.0 eq) was heated in a sealed tube at 60 °C for 6 h. The crude material was dried under vacuum over phosphorus(V) oxide to give quantitatively the imine which was used in the next step without further purification.
General Procedure J:
A mixture of an aldéhyde (1.0 eq), magnésium sulfate (100 mg) and an amine (1.0 eq) in éthanol was heated at 80 eC ovemight. The reaction mixture was filtered. The formation of the imine was quantitative and the filtrate containing the imine was used in the next step without purification.
General procedure K:
To a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride in éthanol was added triethylamine and the mixture was stirred at 70 °C for 5 min. To the resulting yellow solution were added an aldéhyde and a solution of an imine in éthanol. The reaction mixture was stirred in a sealed tube at 50 - 70 °C for 18 - 170 h, after which the réaction mixture was irradiated in a microwave oven at 160 °C for 4 min. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel or précipitation.
General procedure L:
To a solution of 3-benzyl'5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride in éthanol was added triethylamine and the mixture was stirred at 70 °C for 5 min. To the resulting yellow solution were added an aldéhyde and a solution of an imine in éthanol. The reaction mixture was stirred in a sealed tube at 50 - 70 °C for 18 - 120 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel or précipitation.
General procedure M:
To a solution of an appropriate indole in DMF were added an alkyl halide and potassium carbonate. The reaction mixture was stirred at room température for 1-20 hours. Water was added. The resulting precipitate was filtered, dried and recrystallized to afford the desired
131 compound. In case of no précipitation, the reaction mixture was extracted with ethyl acetate.
The organic layer was dried over magnésium sulfate, evaporated under reduced pressure and purified by flash chromatography.
General procedure N:
To a solution of an alcohol (1.0 eq) in THF (e.g. 3.5 mL/mmol) were added DBU (1 eq. to 2 eq., more in particular 1.0 eq) and TBDMSCI (1 eq. to 2 eq., more in particular 2.0 eq). After 4 h at room température, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel.
General procedure O:
To a solution of an indole in dichloromethane cooled to 0 °C was added dropwise a 1M diethylaluminium chloride solution in hexane. After 30 min at 0 °C, a solution of an acyl chloride in dichloromethane was added. The réaction mixture was stirred at 0 °C for 2 to 3 h and poured into a mixture ice/buffer (pH 7) solution. Altematively, a saturated sodium bicarbonate solution or a 1M Rochelle sait solution was added to the reaction mixture. The phases were separated. The organic phase was washed with a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel or by précipitation.
General procedure P:
To a solution of a α-methylketone in THF cooled to 0 °C was added a solution of phenyltrimethylammonîum tribromide in THF. The reaction mixture was stirred at 0 °C for 1 h and at room température for 2 to 20 h. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel or by précipitation.
General procedure Q:
To a solution of an alcohol in dichloromethane were added DMAP and acetic anhydride. The reaction was stirred at room température for 15 to 60 min. The reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel. General procedure R:
To a solution of oxalyl chloride in anhydrous dichloromethane cooled to 0 °C was added DMF. After 30 min at 0 °C, an indole was added and the réaction mixture was stirred at room
132 température for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in THF and a 20% ammonium acetate solution. The mixture was refluxed for 30 min. After cooling to room température, the reaction mixture was diluted with ethyl acetate. The phases were separated and the organic phase was washed with a sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure The residue was purified by flash chromatography on silica gel.
General procedure S:
To a solution of an ester in a mixture of THF and methanol was added potassium carbonate. The reaction mixture was stirred at 20 - 45 °C for 3 to 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel.
EXAMPLE 1: PREPARATION OF 2-((3,4-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
Step 1: 2-Chloro-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure A from indole (1.000 g; 8.536 mmol), pyridine (0.690 mL; 8.531 mmol) and achlorophenylacetyl chloride (1.610 g; 8.565 mmol) in toluene (22 mL). Purification by précipitation furnished 1.294 g (56%) of the desired compound as a white solid. ESl/APCI(+): 270, 272 (M+H); 292, 294 (M+Na). ESf/APCI(-): 268, 270 (M-H).
Step 2: 2-((3,4-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure B from 2-chloro-1-(1/7-indol-3-yl)-2-phenylethanone (0.125 g; 0.463 mmol), 4-aminoveratrole (0.142 g; 0.927 mmol) and triethylamine (0.200 mL; 1.443 mmol) in DMF (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by recrystallization from éthanol furnished 0.014 g (8%) of the desired compound as a beige solid. ESI/APCI(+): 387 (M+H); 409 (M+Na). ESI/APCI(-); 385 (M-H). 1H NMR (DMSO-cfe) δ 8.87 (1H, br s); 8.15 (1H, m); 7.61-7.64 (2H, m);
7,45 (1H, d); 7.13-7.30 (4H, m); 6.60-6.65 (2H, m); 6.24 (1H, m); 5.97-6.07 (2H, m); 3.65 (3H, s); 3.57 (3H, s).
EXAMPLE 2: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure B from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.054 g; 0.200 mmol),
3,5-dimethoxyaniline (0.068 g; 0.444 mmol) and triethylamine (0.100 mL; 0.717 mmol) in DMF (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by recrystallization from éthanol furnished 0.005 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H). 1H NMR (DMSO-de) δ 12.12 (1H, brs); 8.88 (1 H, s); 8.16 (1 H, m); 7.61-7.64 (2H, m); 7.45 (1H, m); 7.14-
7.31 (5H, m); 6.35 (1 H, m); 6.03-6.08 (3H, m); 5.70 (1H. s); 3.61 (6H, s).
/----16765
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EXAMPLE 3: PREPARATION OF 2-((3-ethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2- ((3-Ethoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0.050 g; 0.185 mmol),
3- ethoxyaniline (0.100 mL; 0.751 mmol) and DIPEA (0.100 mL; 0.574 mmol) in DMF (2 mL), irradiated in a microwave oven at 180 ’C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.010 g (15%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H); 393 (M+Na). ESI/APCI(-): 369 (M-H). 1H NMR (CDCI3) δ 8.56 (1H, br s); 8.41 (1H, m); 8.01 (1 H, d); 7.53-7.55 (2H, m); 7.40 (1H, m); 7.20-7.32 (5H, m); 7.01 (1 H, m); 6.29 (1H, d); 6.20-6.24 (2H, m); 5.72 (1 H, m); 5.52 (1H, m); 3.94 (2H, q); 1.35 (3H, t).
EXAMPLE 4: PREPARATION OF 2-((4-chloro-3-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2-((4-Chloro-3-methoxyphenyl)amino)-1 -(1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.104 g; 0.386 mmol), 3-methoxy-4-chloroaniline (0.105 g; 0.666 mmol) and DIPEA (0.200 mL; 1.148 mmol) in DMF (2 mL), irradiated in a microwave oven at 180 ’C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) tn heptane furnished 0.027g (18%) of the desired compound as a white solid. ESI/APCI(+): 391, 393 (M+H); 413, 415 (M+Na). ESI/APCI(-): 389, 391 (M-H). 1H NMR (CDCI3) δ 8.65 (1 H, br s); 8.40 (1H, m); 7.95-8.11 (2H, m); 7.50-7.53 (2H, m); 7.24-7.53 (5H, m); 7.05 (1H, d); 6.18-6.28 (2H, m); 5.70(1 H, s); 3.79 (3H, s).
EXAMPLE 5: PREPARATION OF 1-(1H-indol-3-yl)-2-phenyl-2-((3(trifluoromethoxy)phenyl)amino)ethanone
1- (1H-lndol-3-yl)-2-phenyl-2-((3-(trifluoromethoxy)phenyl)amino)ethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.050 g; 0.185 mmol), 3-(trifluoromethoxy)aniline (0.100 mL; 0.751 mmol) and DIPEA (0,100 mL; 0.574 mmol) in DMF (2 mL), irradiated in a microwave oven at 180 ’C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.009 g (12%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H); 393 (M+Na). ESI/APCI(-): 369 (M-H). 1H NMR (CDCI3) δ 8.56 (1H, br s); 8.41 (1H. m); 8.01 (1H, d); 7.53-7.55 (2H, m); 7.40 (1H, m); 7.20-7.32 (5H, m); 7.01 (1 H, m); 6.29 (1H, d); 6.20-6.24 (2H, m); 5.72 (1H, m); 5.52 (1H, m); 3.94 (2H, q); 1.35 (3H, t).
EXAMPLE 6: PREPARATION OF 2-((3-chlorophenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2- ((3-Chlorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0,105 g; 0,389 mmol),
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3-chloroaniline (0.200 mL; 1.890 mmoL) and DIPEA (0.200 mL; 1.148 mmoL) in DMF (2 mL), irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by recrystallization from methanol furnished 0.005 g (4%) of the desired compound as a white solid. ESI/APCI(+): 361, 363 (M+H); 383, 385 (M+Na). ESI/APCI(-): 359, 361 (M-H). 1H NMR (CDCI3) δ 8.59 (1H, br s); 8.40 (1H, m); 8.02 (1H, d); 7.51-7.53 (2H, m); 7.21-7.38 (6H, m); 7.02 (1H. m); 6.54-6.65 (3H, m); 5.70(1 H, s).
EXAMPLE 7: PREPARATION OF 2-((3,4-difluorophenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2-((3,4-Difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.105 g; 0.389 mmol), 3,4-difluoroaniline (0.200 mL; 2.017 mmol) and DIPEA (0.200 mL; 1.148 mmol) in DMF (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by purification by préparative HPLC (XBridge column, method 1) furnished 0.025 g (18%) of the desired compound as an amorphous solid. ESI/APCI(+): 363 (M+H); 385 (M+Na). ESIZAPCI(-): 361 (ΜΗ). 1H NMR (CDCI3) δ 8.59 (1H, br s); 8.40 (1H, m); 8.00 (1H. d); 7.49-7.52 (2H, m); 7.23-7.41 (6H, m); 6.71 (1H, m); 6.32-6.46 (2H, m); 5.30-5.64 (2H, m).
EXAMPLE 8: PREPARATION OF 2-((3-fluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone
2- ((3-Fluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.103 g; 0.382 mmol),
3- fluoroaniline (0.200 mL; 2.081 mmoL) and DIPEA (0.200 mL; 1.148 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 eC for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.030 g (23%) of the desired compound as a beige solid. ESI/APCI(+): 345 (M+H); 367 (M+Na). ESI/APCI(-): 343 (M-H). 1H NMR (CDCI3) 6 8.59 (1H, br s); 8.40 (1 H. m); 8.01 (1H, d); 7.51-7.54 (2H, m); 7.227.41 (6H, m); 7.04 (1 H, m); 6.46 (1H, d); 6.31-6.37 (2H, m); 5.69 (1H, s); 5.30 (1H, s).
EXAMPLE 9: PREPARATION OF 1-(1H-indol-3-yl)-2-phenyl-2-((3(trifluoromethyl)phenyl)amino)ethanone 1-(1H-lndol-3-yl)-2-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.104 g; 0.386 mmol), 3-(trifluoromethyl)aniline (0.100 mL; 0.801 mmol) and DIPEA (0.200 mL; 1.148 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.028 g (18%) of the desired compound as a beige solid. ESI/APCI(+): 395 (M+H). ESI/APCI(-): 393 (M-H). 1H NMR (CDCI3) δ 8.59 (1H, br s); 8.41 (1H, m); 8.01 (1H, d); 7.51-7.54 (2H, m); 7.17-7.41 (7H, m); 6.80-6.90 (3H, m); 5.83 (1H, br s); 5,73 (1H, s).
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EXAMPLE 10: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone has been prepared according to 2 different procedures described hereunder as method A and method B.
Method A: 1-(1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.103 g; 0.382 mmol), 3-methoxyaniline (0.100 mL; 0.894 mmol) and DIPEA (0.100 mL; 0.574 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.050 g (37%) of the desired compound as a white solid. ESI/APCI(+): 357 (M+H); 379 (M+Na). ESI/APCI(-): 355 (M-H). 1H NMR (CDCl3) δ 8.67 (1H, br s); 8.41 (1H, m); 7.98 (1H, d); 7.50-7.53 (2H, m); 7.20-7.39 (6H, m); 7.01 (1H, m); 6.23-6.25 (2H, m); 5.70 (1H, s); 5.52 (1H. br s); 3.72 (3H, s).
Method B:
Step 1: 1-(1H-lndol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of 1H-indole (2.500 g; 21.34 mmol) in dichloromethane (80 mL), a 1M diethylaluminium chloride solution in hexane (32.00 mL; 32.00 mmol) and a solution of phenylacetyl chloride (4.300 mL; 32.27 mmol) in dichloromethane (80 mL). Purification by précipitation from ethyl acetate furnished 3.240 g (65%) of the desired compound as a white solid. ESI/APCI(+): 236 (M+H). ESI/APCI(-): 234 (M-H).
Step 2: 2-Bromo-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2-phenylethanone (3.240 g: 13.77 mmol) in THF (140 mL) and a solution of phenyltrimethylammonium tribromide (5.700 g; 15.16 mmol) in THF (70 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 4 h. Purification by précipitation from ethyl acetate yielded 3.690 g (85%) of the desired product as a white solid. ESl/APCI(+): 314, 316 (M+H); 336, 338 (M+Na). ESI/APCI(-): 312, 314 (M-H). 1H NMR (DMSO-de) δ 12.21 (1H, br s); 8.67 (1H, s); 8.20 (1H, m); 7.68 (1H, d); 7.0-7.4 (7H, m);
6.84 (1H, s).
Step 3: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.032 g; 0.102 mmol) and m-anisidine (0.063 mL; 0.563 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 60%) in heptane furnished 0.030 g (83%) of the desired product as a white powder.
EXAMPLE 11: PREPARATION OF 2-((3,5-difluorophenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
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2-((3,5-Difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.103 g; 0.382 mmol),
3,5-difluoroaniline (0.117 g; 0.906 mmol) and DIPEA (0.100 mL; 0.574 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 eC for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.008 g (6%) of the desired compound as a beige solid. ESI/APCl(+): 363 (M+H); 385 (M+Na). ESIZAPCI(-): 361 (M-H). ’H NMR (CDCI3) δ 8.63 (1H, br s); 8.38 (1H, m); 7.99 (1H, d); 7.51-7.54 (2H, m); 7.237.41 (7H. m); 6.08-6.18 (2H, m); 5.88 (1H, brs); 5.65 (1 H, m).
EXAMPLE 12: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(2-methyl-1H-indol-3-yl)2-phenylethanone
Step 1: To a solution of 2-methylindole (0.098 g; 0.747 mmol) and pyridine (0.070 mL; 0.865 mmol) in toluene (2 mL) heated at 55 °C was added dropwise α-chlorophenylacetyl chloride (0.120 mL; 0.762 mmol). A brownish oil separated after the addition. The mixture was heated for 4 h at 55 °C and then water was added. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane to provide 0.068 g (32%) of 2-chloro-1-(2-methyl-1H-indol-3-yl)-2-phenylethanone as a beige foam. ESI/APCI(+) 284 (M+H); 306 (M+Na). ESI/APCI(-): 282 (M-H).
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1 -(2-methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(2-methyl-1H-indol-3-yl)-2phenylethanone (0.068 g; 0.240 mmol), 3,5-dimethoxyaniline (0.173 g; 1.129 mmol) and DIPEA (0,250 mL; 1,435 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.029 g (30%) of the desired compound as a beige solid. ESI/APCI(+): 401 (M+H); 423 (M+Na). ESI/APCI(-): 399 (M-H). 1H NMR (CDCI3) δ 8.40 (1H, br s); 8.10 (1H, d); 7.46-7.47 (2H, m); 7.20-7.32 (6H, m); 6.04 (1 H. d); 5.85-5.89 (3H, m); 5.43 (1 H, br s); 3.73 (6H, s); 2.68 (3H, s).
EXAMPLE 13: PREPARATION OF 1-(6-chloro-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)2-phenylethanone
Step 1: To a solution of 6-chloroindole (0.103 g; 0.679 mmol) and pyridine (0.060 mL; 0.742 mmol) in toluene (2 mL) heated at 55 °C was added dropwise α-chlorophenylacetyl chloride (0.100 mL; 0.635 mmol). A brownish oil separated after the addition. The mixture was stirred for 18 hours at 55 °C and then water was added. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 60%) in heptane to provide 0.073 g (35%) of
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2-chloro-1-(6-chloro-1H-indol-3-yl)-2-phenylethanone as a brown solid. ESI/APCI(+): 304, 306 (M+H); 326, 328 (M+Na). ESI/APCI(-): 302, 304 (M-H).
Step 2: 1 -(6-Chloro-1 H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(6-chloro-1H-indol-3-yl)-2phenylethanone (0.073 g; 0.240 mmol), 3,5-dimethoxyaniline (0.100 g; 0.653 mmol) and DIPEA (0.200 mL; 1,148 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.010 g (10%) of the desired compound as a white solid. ESI/APCI(+): 421, 423 (M+H). ESIZAPCI(-): 419, 421 (M-H). 1H NMR (CDCI3) δ 8.63 (1H, brs); 8.30 (1H, d); 7.95 (1H, d); 7.48-
7.51 (2H, m); 7.21-7.37 (6H, m); 5.84-5.87 (3H, m); 5.66 (1H, s); 5.49 (1H, brs); 3.70 (6H, s).
EXAMPLE 14: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxy-5(trifluoromethyl)phenyl)amîno)-2-phenylethanone
-(1 H-lndol-3-yl)-2-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.109 g; 0.404 mmol), 3-methoxy-5-(trifluoromethyl)aniline (0.108 g; 0.565 mmol) and DIPEA (0.100 mL; 0.574 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.024 g (14%) of the desired compound as a white solid. ESI/APCI(+): 425 (M+H); 447 (M+Na). ESI/APCI(-): 423 (M-H). 1H NMR (CDCI3) δ 8.63 (1H, br s); 8.41 (1H, m); 7.99 (1H, d); 7.50-7.52 (2H, m); 7.21-7.38 (6H, m); 6.54 (1H, s); 6.42 (1H, s); 6.33 (1H, s); 5.84 (1H, brs); 5.70 (1H, m);
3,74 (3H, s).
EXAMPLE 15: PREPARATION OF 2-((3-fluoro-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2-((3-Fluoro-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0.105 g; 0.389 mmol), 3-methoxy-5-fluoroaniline (0.100 mL; 0.849 mmol) and DIPEA (0,100 mL; 0.574 mmol) in éthanol (2 mL), irradiated in a microwave oven at 180 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.047 g (32%) of the desired compound as a white solid. ESI/APCI(+): 375 (M+H); 397 (M+Na). ESI/APCI(-): 373 (M-H). 1H NMR (CDCI3) δ 8.61 (1H, br s); 8.41 (1H, m); 8.00 (1H, d); 7.50-7.52 (2H, m); 7.25-7.33 (6H, m); 5.95-6.02 (3H, m); 5.68 (2H, m); 3.70 (3H, s).
EXAMPLE 16: PREPARATION OF 1-(1/-/-indol-3-yl)-2-phenyl-2-(pyridin-3-ylamino)ethanone 1-(1H-lndol-3-yl)-2-phenyl-2-(pyridin-3-ylamino)ethanone was prepared according to general procedure D from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.107 g; 0.397 mmol), 316765
138 aminopyridine (0.099 g; 1.052 mmol) and PS-DIPEA (solid support 3.56 mmol/g; 0.300 g; 1.068 mmoL) in acetonitrile (2 mL). Purification by flash chromatography on silica gel using a gradient of methanol (0% to 20%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.004 g (3%) of the desired compound as a beige amorphous solid. ESI/APCI(+): 328 (M+H). ESI/APCI(-): 326 (M-H). 1H NMR (CDCI3) δ 8.70 (1H, br s); 8.37 (1H, m); 8.11 (1H, d); 7.99 (1H, d); 7.89 (1H, d); 7.48-7.51 (2H, m); 7.35 (1H, m); 7.19-7.29 (5H, m); 6.93-6.99 (2H, m); 5.67-5.72 (2H, m).
EXAMPLE 17: PREPARATION OF 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-4-ylamino)ethanone 1-(1H-lndol-3-yl)-2-phenyl-2-(pyridin-4-ylamino)ethanone was prepared according to general procedure D from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.103 g; 0.382 mmol), 4aminopyridine (0.098 g; 1.041 mmol) and PS-DIPEA (solid support 3.56 mmol/g; 0.295 g; 1.050 mmol) in acetonitrile (2 mL). Purification by flash chromatography on silica gel using a gradient of methanol (0% to 20%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.022 g (18%) of the desired compound as a beige solid. ESI/APCI(+): 328 (M+H). ESI/APCI(-): 326 (M-H). H NMR (CDCI3) δ 8.32 (1H, m); 8.22 (1 H, m); 8.05 (1H, d); 7.3-7.55 (11 H, m); 6.80 (1H, d).
EXAMPLE 18: PREPARATION OF 1-(1/7-indol-3-yl)-2-((3-methoxyphenyl)(methyl)amino)-2phenylethanone 1-(1/-/-lndol-3-yl)-2-((3-methoxyphenyl)(methyl)amino)-2-phenylethanone was prepared according to general procedure D from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.101 g; 0.374 mmol), N-methyl-3-methoxyaniline (0.100 mL; 0.752 mmoL) and PS-DIPEA (solid support
3.56 mmol/g; 0.292 g; 1.040 mmol) in acetonitrile (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.011 g (8%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H); 393 (M+Na). ESI/APCI(-): 369 (M-H). 1H NMR (CDCI3) ô 8.41 (1H, m); 7.73 (1H, s); 7.13-7.41 (7H, m); 6.26-6.50 (4H, m); 3.77 (3H, s);
2.93 (3H, s).
EXAMPLE 19: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3yl)ethanone
Step 1 : tert-Butyl 3-formyl-1/7-indole-1-carboxylate was prepared according to general procedure F from 1H-indole-3-carbaldehyde (3.770 g; 25.97 mmol), di-iert-butyl dicarbonate (6.800 g; 31.16 mmol) and DMAP (0.317 g; 2.595 mmol) in acetonitrile (70 mL) to afford 6.100 g (96%) of the desired compound as a yellow solid. 1H NMR (DMSO-cfe) δ 10,09 (1H, s); 8.66 (1H, s); 8.15 (2H, dd); 7.32-7.53 (2H, m); 1.68 (9H, s).
Step 2: 3-Methoxy-A/-(pyridin-3-ylmethylene)aniline was prepared quantitatively according to general procedure G from 3-pyridinyl carboxaldehyde (0.179 mL; 1.867 mmol), magnésium sulfate (0.300 g; 2.492 mmol) and 3-methoxyaniline (0.230 g; 1.867 mmol) in éthanol (1 mL).
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Step 3: 1-(1H-lndol-3-yl)-2-((3-rnethoxyphenyl)arnino)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.101 g; 0.373 mmol) and triethylamine (0.052 mL; 0.373 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.549 g; 2.239 mmol) and a solution 3methoxy-N-(pyridin-3-ylmethylene)aniline (1.867 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by précipitation from acetonitrile furnished 0.050 g (8%) of the desired compound as a white solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 20: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-4yl)ethanone
Step 1: 3-Methoxy-A/-(pyridin-4-ylmethylene)aniline was prepared quantitatively according to general procedure G from 4-pyridinyl carboxaldehyde (0.179 mL; 1.867 mmol), magnésium sulfate (0.300 g; 2.492 mmol) and 3-methoxyaniline (0.230 g; 1.867 mmol) in éthanol (1 mL).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-4-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.101 g; 0.373 mmol) and triethylamine (0.052 mL; 0.373 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.549 g; 2.239 mmol) and a solution of 3methoxy-/V-(pyridin-4-ylmethylene)aniline (1.867 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by précipitation from dichloromethane furnished 0.074 g (11%) of the desired compound as a white solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 21: PREPARATION OF 1-(1H-indo!-3-yl)-2-((3-methoxyphenyl)amino)-2-(4(methylsulfonyl)phenyl)ethanone
Step 1: 3-Methoxy-/V-(4-(methylsulfonyl)benzylidene)aniline was prepared quantitatively according to general procedure G from 4-(methylsulfonyl)benzaldehyde (0.748 g; 4.061 mmol), magnésium sulfate (0.600 g; 4.985 mmol) and 3-methoxyaniline (0.500 g; 4.060 mmol) in éthanol (5 mL). ESI/APCI(+): 290 (M+H).
Step 2: 1 -(1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(methylsulfonyl)phenyl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methyithiazol-3-ium chloride (0.056 g; 0.207 mmol) and triethylamine (0.029 mL; 0.207 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.305 g; 1.244 mmol) and a solution of 3-methoxy-N-(4-(methylsulfonyl)benzylidene)aniline (1.037 mmol) in éthanol (1 mL) heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by précipitation from dichloromethane furnished 0.048 g (10%) of the desired compound as a white solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H).
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EXAMPLE 22: PREPARATION OF 1-(1H-indo1-3-yl)-2-((5-methylisoxazol-3-yl)amino)-2phenylethanone
Step 1: N-Benzylidene-5-methylisoxazol-3-amine was prepared according to general procedure G from benzaldehyde (0.193 mL: 2.039 mmol), magnésium sulfate (0.300 g; 2.492 mmol) and
3-amino-5-methylisoxazole (0.200 g; 2.039 mmol) in éthanol (2 mL).
Step 2: 1-(1H-lndol-3-yl)-2-((5-methylisoxazol-3-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.056 g; 0.207 mmol) and triethylamine (0.029 mL; 0.207 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.308 g; 1.257 mmol) and a solution of Nbenzylidene-5-methylisoxazol-3-amine (1.047 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by purification by préparative HPLC (XBridge column, method 2) furnished 0.060 g (16%) of the desired compound as a white powder. ESI/APCI(+): 332 (M+H). ESI/APCI(-): 330 (M-H).
EXAMPLE 23: PREPARATION OF 2-(furan-2-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: /V-(Furan-2-ylmethylene)-3-methoxyaniline was prepared quantitatively according to general procedure G from 2-furaldehyde (0.390 g; 4.059 mmol), magnésium sulfate (0.733 g; 6.090 mmol) and 3-methoxyaniline (0.500 g; 4.060 mmol) in éthanol (5 mL). 1H NMR (DMSOde) δ 8.45 (1H, s); 7.95 (1H, s); 7.24-7.41 (1H, m); 7.16 (1H, d); 6.77-6.87 (3H, m); 6.72 (1H, dd); 3.79 (3H, s).
Step 2: 2-(Furan-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.046 g; 0.170 mmol) and triethylamine (0.024 mL; 0.170 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.250 g; 1.019 mmol) and a solution of /V(furan-2-ylmethylene)-3-methoxyaniline (0.849 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.058 g (19%) of the desired compound as a white solid. ESI/APCI(+): 347 (M+H). ESI/APCl(-): 345 (M-H).
EXAMPLE 24: PREPARATION OF 1-(1H-indol-3-yl)-2-{(3-methoxyphenyl)amino)-2-(thiophen-2yl)ethanone
Step 1: 3-Methoxy-A/-(thiophen-2-ylmethylene)aniline was prepared quantitatively according to general procedure G from 2-thiophenecarboxaldehyde (0.455 g; 4.057 mmol), magnésium sulfate (0.733 g; 6.090 mmol) and 3-methoxyaniline (0.500 g; 4.060 mmol) in éthanol (5 mL).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol16765
141
3- ium chloride (0.046 g; 0.170 mmol) and triethylamine (0.024 mL; 0.170 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.250 g; 1.019 mmol) and a solution of 3methoxy-N-(thiophen-2-ylmethylene)aniline (0,185 g; 0.849 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.058 g (7%) of the desired compound as an oil. ESI/APCI(+): 363 (M+H). ESI/APCK-): 361 (M-H).
EXAMPLE 25: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5methylisoxazol-3-yl)ethanone
Step 1: 3-Methoxy-A/-((5-methylisoxazol-3-yl)methylene)aniline was prepared quantitatively according to general procedure I from 5-methylisoxazole-3-carbaldehyde (0.151 g; 1.359 mmol) and 3-methoxyaniline (0.152 mL; 1.353 mmol). 1H NMR (DMSO-ct6) δ 8.69 (1H, s); 7.35 (1H, t); 6.85-6.97 (3H, m); 6.69 (1H, s); 3.81 (3H, s); 2.50 (3H, s).
Step 2; 1-(1H-lndol-3-vn-2-((3-methoxvphenvl)amino)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.180 g; 0.667 mmol) and triethylamine (0,095 mL; 0.676 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.400 g; 1.631 mmol) and a solution of 3-methoxy-/V-((5-methylisoxazol-3-yl)methylene)aniline (1.353 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.142 g (29%) of the desired compound as a white powder . ESI/APCI(+): 362 (M+H). ESIZAPCI(-): 360 (M-H).
EXAMPLE 26: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl1 H-imidazol-2-yl)ethanone
Step 1: 3-Methoxy-N-((1-methyl-1 H-imidazo1-2-yl)methylene)anilïne was prepared quantitatively according to general procedure I from 1-methyl-1 H-imtdazole-2-carbaldehyde (0.098 g; 0.890 mmol) and 3-methoxyaniline (0.100 mL; 0.890 mmol).
Step 2: 1 -( 1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1 -methyl-1 H-imidazol-2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0.120 g; 0.445 mmol) and triethylamine (0.065 mL; 0.462 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.265 g; 1.080 mmol) and a solution of 3-methoxy-/V-((1 -methyl-1 H-imidazol-2-yl)methylene)aniline (0.890 mmol) in éthanol (0.5 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.065 g (22%) of the desired compound as a white powder. ESI/APCI(+): 361 (M+H). ESI/APCI(-): 359 (M-H).
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EXAMPLE 27: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-3yl)ethanone
Step 1: 3-Methoxy-/V-(thiophen-3-ylmethylene)aniline was prepared quantitatively according to general procedure I from thiophene-3-carbaldehyde (0.120 mL; 1.370 mmol) and 3methoxyaniline (0.152 mL; 1.353 mmol).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amlno)-2-(thiophen-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.180 g; 0.667 mmol) and triethylamine (0.095 mL; 0.676 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.400 g; 1.631 mmol) and 3-methoxy-/V(thiophen-3-ylmethylene)aniline (1.353 mmol) in éthanol (1 mL), heated at 70 ’C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by précipitation from diethyl ether furnished 0.076 g (15%) of the desired compound as a pale yellow powder. ESI/APCI(+): 363 (M+H). ESI/APCI(-): 361 (M-H).
EXAMPLE 28: PREPARATION OF 2-(1H-imidazol-2-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1 : /V-((1H-lmidazol-2-yl)methylene)-3-methoxyaniline was prepared quantitatively according to general procedure I from 1H-imidazole-2-carbaldehyde (0.086 g; 0.895 mmol) and
3-methoxyaniline (0.100 mL; 0.890 mmol).
Step 2: 2-(1 /7-lmidazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.120 g; 0.445 mmol) and triethylamine (0.065 mL; 0.462 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.265 g; 1.080 mmol) and A/-((1Hlmidazol-2-yl)methylene)-3-methoxyaniline (0.890 mmol) in éthanol (0.5 mL), heated at 70 °C for 3 days. Purification by précipitation from methanol furnished 0.046 g (15%) of the desired compound as a pale brown solid. ESI/APCI(+): 347 (M+H). ESIZAPCI(-): 345 (M-H).
EXAMPLE 29: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrlmidin-
5-yl)ethanone
Step 1: 3-Methoxy-/V-(pyrimidin-5-ylmethylene)aniline was prepared quantitatively according to general procedure I from pyrimidine-5-carboxaldehyde (0.115 g; 1.064 mmol) and 3methoxyaniline (0.120 mL; 1.068 mmol).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrimidin-5-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.144 g; 0.534 mmol) and triethylamine (0.100 mL; 0.712 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1/-/-indole-1-carboxylate (0.295 g; 1.203 mmol) and a solution of 3methoxy-A/-(pyrimidin-5-ylmethylene)aniline (1.064 mmol) in éthanol (0.5 mL), heated at 70 °C for 24 h, Purification by flash chromatography on silica gel using a gradient of ethyl acetate
143 (50% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.065 g (17%) of the desired compound as a beige powder. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H). EXAMPLE 30: PREPARATION OF 2-(imidazo[1,2-a]pyridin-2-yl)-1-( 1 H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A/-(lmidazo[1,2-a]pyridin-2-ylmethylene)-3-methoxyaniline was prepared quantîtatîvely according to general procedure I from imidazo[1,2-a]pyridine-2-carbaldehyde (0.156 g; 1.067 mmol) and 3-methoxyaniline (0.120 mL; 1.068 mmol).
Step 2: 2-(lmidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.144 g; 0.534 mmol) and triethylamine (0.100 mL; 0.712 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1/-/-indole-1 -carboxylate (0.295 g; 1.203 mmol) and a solution of N-(imidazo[1,2-a]pyridin-2-ylmethylene)-3-methoxyaniline (1.067 mmol) in éthanol (0.5 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.111 g (28%) of the desired compound as a beige powder. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).
EXAMPLE 31: PREPARATION OF 2-((2-hydroxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone
A mixture of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.104 g; 0.386 mmol), 2methoxypyridin-4-amine (0.100 g; 0.806 mmol) and DIPEA (0.100 mL; 0.574 mmol) in acetonitrile (2 mL) was irradiated in a microwave oven at 120 C for 60 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of methanol (2% to 20%) in dichloromethane. Further purification by recrystallization from dichloromethane furnished 0.017 g (13%) of 2-((2hydroxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 344 (M+H); 366 (M+Na). ESIZAPCI(-): 342 (M-H). ’H NMR (DMSO-c/6) δ 11.99 (1 H, s); 8.27 (1 H, s); 8.18 (1 H, m); 7.2-7.5 (7H, m); 6.89 (1H, d); 6.09 (2H, s); 5.64 (1H, d); 5.29 (1H, s).
EXAMPLE 32: PREPARATION OF 1-(1H-indol-3-yl)-2-phenyl-2-((pyridin-2ylmethyl)amino)ethanone
1-(1H-lndol-3-yl)-2-phenyl-2-((pyridin-2-ylmethyl)amino)ethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.108 g; 0.400 mmol), pyridin-2-ylmethanamine (0.100 mL; 0.970 mmol) and DIPEA (0.100 mL; 0.574 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by recrystallization from dichloromethane furnished 0.003 g (2%) of the desired compound as a solid. ESI/APCI(+): 342 (M+H). ESIZAPCI(-): 340 (M-H). 1H NMR (MeOD) δ 8.46 (1 H, m); 8.37 (1 H, m); 7.91 (1H, s); 7.69 (1 H. m); 7.20-7.46 (10H. m); 5.16 (1H, s); 3.90 (2H, m).
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EXAMPLE 33: PREPARATION OF 1-(1H-indol-3-yl)-2-phenyl-2-((thiophen-2ylmethyl)amino)ethanone
1- (1M-lndol-3-yl)-2-phenyl-2-((thiophen-2-ylmethyl)amino)ethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.111 g; 0.412 mmol), thiophen-2-ylmethanamine (0.100 mL; 0.972 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of methanol (2% to 20%) in dichloromethane followed by recrystallization from dichloromethane furnished 0.021 g (15%) of the desired compound as a solid. ESI/APCI(+): 347 (M+H); 369 (M+Na). ESI/APCI(-): 345 (M-H). 1H NMR (DMSO-d6) δ 12.01 (1H, br s); 8.50 (1H, s); 8.18 (1H, m); 7.14-7.58 (9H, m); 6.38 (1 H, s); 6.24 (1H, s); 5.25(1 H, s); 3.67 (2H, s).
EXAMPLE 34: PREPARATION OF 2-((furan-2-ylmethyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2- ((Furan-2-ylmethyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.103 g; 0.382 mmol), furan-2-ylmethanamïne (0.100 mL; 0.382 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of methanol (2% to 20%) in dichloromethane followed by recrystallization from dichloromethane furnished 0.040 g (32%) of the desired compound as a solid. ESI/APCI(+): 331 (M+H); 353 (M+Na). ESI/APCI(-): 329 (M-H). 1H NMR (DMSO-d6) δ 12.01 (1H, br s); 8.49 (1H, s); 8.20 (1H, m); 7.16-7.53 (9H, m); 6.89-6.93 (2H, m); 5.27(1 H, s); 3.80 (2H, s).
EXAMPLÈ 35: PREPARATION OF 3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzonitrile
3- ((2-( 1H-lndol-3-yl)-2-oxo-1-phenylethyl)amino)benzonitrile was prepared according to general procedure C from 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0.100 g; 0.371 mmol), 3aminobenzonitrile (0.098 g; 0.830 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 40%) in heptane followed by recrystallization from dichloromethane furnished 0.007 g (5%) of the desired compound as a solid. ESI/APCI(+): 352 (M+H). ESI/APCI(-): 350 (M-H). 1H NMR (CDCI3) δ 8.59 (1H, br s); 8.40 (1H, m); 8.01 (1H, s); 7.51 (2H, d); 7.17-7.41 (7H, m); 6.84-6.91 (3H, m); 5.70 (1H, s).
EXAMPLE 36: PREPARATION OF 4-(2-( 1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2oxoethyl)benzonitrile
Step 1: 4-(((3-Methoxyphenyl)imino)methyl)benzonitrile was prepared quantitatively according to general procedure I from 4-formyl-benzonitrile (0.135 g; 1.030 mmol) and 3-methoxyaniline (0.116 mL; 1.030 mmol).
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Step 2: 4-(2-(1 /7-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.144 g; 0.534 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.252 g; 1.028 mmol) and a solution of 4-(((3-methoxyphenyl)imino)methyl)benzonitrile (1.030 mmol) in éthanol (0.5 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 60%) in heptane followed by précipitation from diethyl ether furnished 0.203 g (52%) of the desired compound as a pale yellow solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-); 380 (M-H).
EXAMPLE 37: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(quinoxalin-
6-yl)ethanone
Step 1: 3-Methoxy-/V-(quinoxalin-6-ylmethylene)aniline was prepared quantitatively according to general procedure I from quinoxaline-6-carbaldehyde (0.100 g; 0.632 mmol) and 3methoxyaniline (0.071 mL; 0.632 mmol).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(quinoxalin-6-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.135 g; 0.491 mmol) and triethylamine (0.055 mL; 0.397 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxyîate (0.155 g; 0.630 mmol) and a solution of 3methoxy-/V-(quinoxalin-6-ylmethylene)aniline (0.632 mmol) in éthanol (0.7 mL), heated at 70 °C for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from methanol furnished 0.069 g (27%) of the desired compound as a yellow solid. ESI/APCI(+): 409 (M+H). ESI/APCI(-): 408 (M-H). EXAMPLE 38: PREPARATION OF 1-(1H-indol-3-yl)-2-((2-methoxyphenyl)amino)-2phenylethanone
1- (1H-lndol-3-yl)-2-((2-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.109 g; 0.404 mmol),
2- methoxyaniline (0.100 mL; 0.893 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by recrystallization from dichloromethane furnished 0.013 g (9%) of the desired compound as white crystals. ESI/APCI(+): 357 (M+H); 379 (M+Na). ESI/APCI(-): 355 (M-H). 1H NMR (CDCI3) δ 8.55 (1H, br s); 8.42 (1H, m); 8.05 (1 H, s); 7.54 (2H, d); 7.20-7.38 (6H, m); 6.57-6.78 (4H, m); 5.72 (1H,s); 3.88 (3H, s).
EXAMPLE 39: PREPARATION OF 2-((2,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2-((2,5-Dimethoxyphenyl)amîno)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.110 g; 0.408 mmol),
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2,5-dimethoxyanïline (0.102 g; 0.666 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 ’C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by recrystallization from dichloromethane furnished 0.009 g (6%) of the desired compound as a white solid. ESI/APCI(+): 387 (M+H); 409 (M+Na). ESI/APCI(-): 385 (M-H). 1H NMR (CDCI3) δ 8.62 (1H, br s); 8.41 (1H, m); 7.98 (1H, s); 7.52 (2H, d); 7.19-7.37 (5H, m); 6.66 (1 H, d); 6.10-
6.18 (2H, m); 5.67(1 H, s); 5.30(1 H, s); 3.84 (3H, s); 3.66 (3H, s).
EXAMPLE 40: PREPARATION OF 2-((2,3-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
2- ((2,3-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.044 g; 0.163 mmol), 2,3-dimethoxyaniline (0.050 mL; 0.326 mmol) and DIPEA (0.100 mL; 0.574 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by recrystallization from dichloromethane furnished 0.008 g (13%) of the desired compound as white crystals. ESI/APCI(+): 387 (M+H); 409 (M+Na). ESI/APCI(-): 385 (M-H). 1H NMR (CDCI3) δ 8.54 (1H, br s); 8.42 (1H, m); 8.03 (1 H, s); 7.52 (2H. d); 7.20-7.38 (6H, m); 6.81 (1H, m); 6.29 (2H, m); 5.75 (1H, s); 3.89 (3H, s); 3.82 (3H, s).
EXAMPLE 41: PREPARATION OF 3-(2-( 1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2oxoethyl)benzonitrile
Step 1: 3-(((3-Methoxyphenyl)imino)methyl)benzonitrile was prepared quantitatively according to general procedure I from 3-formylbenzonitrile (0.135 g; 1.030 mmol) and 3-methoxyaniline (0.116 mL; 1.032 mmol).
Step 2: 3-(2-(1 H-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.144 g; 0.534 mmol) and triethylamine (0.100 mL; 0.712 mmol) in éthanol (1 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.252 g; 1.028 mmol) and a solution of 3-(((3methoxyphenyl)imino)methyl)benzonitrile (1.030 mmol) in éthanol (0.5 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by précipitation from diethyl ether furnished 0.077 g (20%) of the desired compound as a solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).
EXAMPLE 42: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl1 H-pyrazol-4-yl)ethanone
Step 1: 3-Methoxy-/\/-((1-methyl-1/7-pyrazol-4-yl)methylene)aniline was prepared quantitatively according to general procedure I from 1-methyl-1H-pyrazole-4-carbaldehyde (0.110 g; 0.999 mmol) and 3-methoxyanïline (0.112 mL; 0.999 mmol).
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Step 2: 3-(2-(1 H-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- rum chloride (0.135 g; 0.500 mmol) and triethylamine (0.100 mL; 0.712 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3methoxy-W-((1-methyl-1H-pyrazol-4-yl)methylene)aniline (0.999 mmol) in éthanol (0.5 mL), heated at 70 °C for 24 h. After concentration of the reaction mixture under reduced pressure, purification by précipitation from dichloromethane furnished 0.219 g (61%) of the desired compound as a white solid. ESI/APCI(+): 361 (M+H). ESI/APCI(-): 359 (M-H).
EXAMPLE 43: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-7-yl)ethanone
Step 1: 3-Methoxy-N-(pyrazolo[1,5-a]pyridin-7-ylmethylene)aniline was prepared quantitatively according to general procedure I from pyrazolo[1,5-a]pyrtdine-7-carbaldehyde (0.100 g; 0.684 mmol) and 3-methoxyaniline (0.077 mL; 0.685 mmol), ESI/APCI (+): 252 (M+H).
Step 2: 1 -(1 /-/-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-7-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0.095 g; 0.352 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.168 g; 0.684 mmol) and a solution of 3-methoxy-/V-(pyrazolo[1,5-a]pyridin-7-ylmethylene)aniline (0.684 mmol) in éthanol (0.5 mL) .heated at 50 °C for 3 days. After concentration of the reaction mixture under reduced pressure, methanol was added. The resulting precipitate was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by précipitation from diethyl ether furnished 0.095 g (35%) of the desired compound as a yellow solid. ESI/APCI(+): 397 (M+H). ESl/APCI(-): 395 (M-H).
EXAMPLE 44: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-(methylsulfonyl)phenyl)amino)-2phenylethanone 1-(1H-lndol-3-yl)-2-((3-(methylsulfonyl)phenyl)amino)-2-phenylethanone was prepared according general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.100 g; 0.371 mmol), 3-(methylsulfonyl)aniline hydrochloride (0.112 g; 0.539 mmol) and DIPEA (0.300 mL; 1.722 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.017 g (11%) of the desired compound as an amorphous crystals. ESI/APCI(+): 405 (M+H); 427 (M+Na); ESI/APCI(-): 403 (M-H).
EXAMPLE 45: PREPARATION OF 1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2phenylethanone /Ci
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Step 1: N-Benzylldene-2-methoxypyridin-4-amine was prepared quantitatively according to general procedure l from benzaldehyde (2.027 mL; 20.01 mmol) and 2-methoxypyridln-4-amine (2.483 g; 20.01 mmol).
Step 2: 1-(1H-lndol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.125 g; 0.463 mmol) and triethylamine (0.100 mL; 0,717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.197 g; 0.803 mmol) and a solution of Nbenzylidene-2-methoxypyridin-4-amine (0.803 mmol) in éthanol (2 mL), heated at 70 ’C for 65 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by recrystallization from dichloromethane furnished 0.015 g (5%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H); 380 (M+Na). ESI/APCI(-): 356 (ΜΗ). 1H NMR (CDCIg) δ 9.39 (1 H, br s); 8.42 (1 H, d); 7.87 (2H, s); 7.48 (2H, d); 7.20-7.35 (4H, m);
6.40 (1H, d); 6.20 (1H, m); 6.01 (1H, s); 5.87 (1H, d); 5.29 (1H, s); 3.76 (3H, s).
EXAMPLE 46: PREPARATION OF 2-((3-ethylphenyl)amino)-1-(1 H-indol-3-yl)-2phenylethanone
2- ((3-Ethylphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.106 g; 0.393 mmol),
3- ethylaniline (0.100 mL; 0.805 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL) Irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 40%) in heptane followed by recrystallization from dichloromethane furnished 0.028 g (20%) of the desired compound as a solid. ESI/APCI(+): 355 (M+H); 377 (M+Na). ES1/APCI(-): 353 (M-H). 1H NMR (CDCI3) δ 8.55 (1H, br s); 8.40 (1H, m); 8.02 (1H, s); 7.54 (2H, d); 7.20-7.40 (6H, m); 7.04 (1H, m); 6.51-6.55 (3H, m); 5,72 (1H, s); 5.46 (1H, br s); 2.57 (2H, q); 1.17 (3H, t).
EXAMPLE 47: PREPARATION OF 1 -(1 H-indol-3-yl)-2-(isoquinolin-5-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: N-(lsoquinolin-5-ylmethylene)-3-methoxyaniline was prepared quantitatively according to general procedure I from isoquinoline-5-carbaldehyde (0.119 g; 0.757 mmol) and 3methoxyaniline (0.087 mL; 0.774 mmol).
Step 2: 1-(1/7-lndol-3-yl)-2-(isoquinolin-5-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.100 g; 0.371 mmol) and triethylamine (0.080 mL; 0.574 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.186 g; 0.759 mmol) and a solution of A/-(isoquinolin-5-ylmethylene)-3-methoxyaniline (0.757 mmol) in éthanol (0.5 mL), heated at 60 °C for 2 days. After concentration of the reaction mixture under reduced pressure, purification by précipitation from methanol furnished 0.093 g (30%) of the desired compound as a white powder. ESI/APCI (+): 408 (M+H). ESI/APCI (-): 406 (M-H).
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EXAMPLE 48: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4(pyrimidin-5-yl)phenyl)ethanone
Step 1: 3-Methoxy-A/-(4-(pyrimidin-5-yl)benzylldene)aniline was prepared quantitatively according to general procedure I from 5-(4-formylphenyl)pyrimidine (0.125 g; 0.679 mmol) and
3-methoxyaniline (0.076 mL; 0.679 mmol). ESI/APCI (+): 290 (M+H).
Step 2: 1-(1 F/-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(pyrimidin-5-yl)phenyl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.090 g; 0.334 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.166 g; 0.677 mmol) and a solution of 3-methoxy-/V-(4-(pyrimidin-5-yl)benzylidene)aniline (0.679 mmol) in éthanol (0.5 mL), heated at 75 °C for 3.5 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether and dichlorométhane furnished 0.061 g (21%) of the desired compound as a pale yellow solid. ESI/APCI (+): 435 (M+H). ESI/APCI (-): 433 (M-H).
EXAMPLE 49: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2phenylethanone
This compound has been prepared according to 2 different procedures described hereunder as method A and method B.
Method A:
Step 1: A/-Benzylidene-3-methoxyaniline was prepared quantitatively according to general procedure G from benzaldehyde (3.030 mL; 29.98 mmol), 3-methoxyaniline (3.690 mL; 32.84 mmol) and magnésium sulfate (3.610 g; 29.99 mmol) in éthanol (15 mL). ’H NMR (DMSO-d6) δ
8.63 (1H, s); 7.95 (2H, dd); 7.47-7.63 (3H, m); 7.32 (1H, t); 6.75-6.93 (3H, m); 3.80 (3H, s).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(1 -methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.169 g; 0.628 mmol) and triethylamine (0.088 mL; 0.628 mmol) in éthanol (2 mL), 1-methyl-1H-indole-3-carbaldehyde (0.200 g; 1.256 mmol) and a solution of Nbenzylidene-3-methoxyaniline (1.256 mmoi) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.028 g (6%) of the desired compound as a white foam. ESI/APCI(+): 371 (M+H).
Method B:
Step 1: 2-Chloro-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general method M from 2-chloro-1-(1/7-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol), methyliodide (0.166 mL; 2.573 mmol) and potassium carbonate (0.205 g; 1,476 mmol) in DMF (5 mL) The reaction mixture was stirred at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished
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0.140 g (66%) of the desired compound as a beige solid. ESI/APCI(+): 284, 286 (M+H); 306, 308 (M+Na).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(1-methyl-1/-/-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1-methyl-1/-/-indol-3-yl)-2-phenylethanone (0.140 g; 0.493 mmol), 3-methoxyaniline (0.110 mL; 0.987 mmol) and DIPEA (0.169 mL; 0.987 mmol) in acetonitrile (1.5 mL), irradiated in a microwave oven at 200eC for 1.5 h. After standing at room température for 24 h, the formed precipitate was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane as eluent. Further purification by préparative TLC using dichloromethane as eluent furnished 0.011 g (6%) of the desired compound as a beige solid. ESI/APCl(+): 371 (M+H).
EXAMPLE 50: PREPARATION OF 1-(1/-/-indol-3-yl)-2-phenyl-2-(quinoxalin-6-ylamino)ethanone 1-(1/7-lndol-3-yl)-2-phenyl-2-(quinoxalin-6-ylamino)ethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.101 g; 0.374 mmol), quinoxalin-6-amîne (0.094 g; 0.648 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane, followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.008 g (6%) of the desired compound as an orange solid. ESI/APCI(+): 379 (M+H). ESI/APCI(-): 377 (M-H).
EXAMPLE 51: PREPARATION OF 3-((2-( 1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-A/,/Vdimethylbenzamide
3-((2-(1 H-lndol-3-yl)-2-oxo-1-phenylethyl)amino)-N,/\/-dimethylbenzamide was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.099 g; 0.367 mmol), 3-amino-A/,/\/-dimethylbenzamide (0.095 g; 0.579 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane, followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.028 g (19%) of the desired compound as a pink solid. ESI/APCI(+): 398 (M+H). ESIZAPCI(-): 396 (M-H).
EXAMPLE 52: PREPARATION OF 3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-Nmethylbenzenesulfonamide
3-((2-(1 H-lndol-3-yl)-2-oxo-1-phenylethyl)amino)-A/-methylbenzenesulfonamide was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.096 g;
0.356 mmol), 3-amino-A/-methylbenzenesulfonamide hydrochloride (0.101 g; 0.454 mmol) and
DIPEA (0.300 mL; 1.722 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by purification by préparative HPLC (XBridge column;
151 method 2) furnished 0.006 g (4%) of the desired compound as an orange solid. ESl/APCI(+): 420 (M+H). ESI/APCI(-): 418 (M-H).
EXAMPLE 53: PREPARATION OF 1-(4-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1: tert-Butyl 4-chloro-3-formyl-1/-/-indole-1-carboxylate was prepared according to general procedure F from 4-chloro-1H-indole-3-carbaldehyde (0.310 g; 1.726 mmol), di-tert-butyl dicarbonate (0.451 g; 2.066 mmol) and DMAP (0.021 g; 0.172 mmol) in acetonitrile (4 mL) to afford 0.431 g (89%) of the desired compound.
Step 2: 1-(4-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.232 g; 0.860 mmol) and triethylamine (0.120 mL; 0.860 mmol) in éthanol (3 mL), tert-butyl 4-chloro-3-formyl-1H-indole-1-carboxylate (0.481 g; 1.720 mmol) and a solution of M-benzylidene-3-methoxyaniline (1.718 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.009 g (1%) of the desired compound as a white powder. ESI/APCI(+): 391, 393 (M+H). ESI/APCI(-): 389, 391 (M-H).
EXAMPLE 54: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3(pyrimidin-5-yl)phenyl)ethanone
Step 1: 3-Methoxy-N-(3-(pyrimidin-5-yl)benzylidene)aniline was prepared quantitatively according to general procedure I from 3-pyrimidin-5-ylbenzaldehyde (0.125 g; 0.679 mmol) and
3-methoxyaniline (0.076 mL; 0.679 mmol). ESI/APCI (+): 290 (M+H).
Step 2: 1-(1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-(pyrimidin-5-yl)phenyl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthïazol-3-ium chloride (0.091 g; 0.337 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1 -carboxylate (0.166 g; 0.677 mmol) and a solution of 3-methoxy-N-(3-(pyrimidin-5-yl)benzylidene)aniline (0.679 mmol) in éthanol (0.5 mL), heated at 65 °C for 5 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.066 g (22%) of the desired compound as a yellow solid. ESI/APCI (+): 435 (M+H). ESI/APCI (-): 433 (M-H).
EXAMPLE 55: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino )-2-(6methoxypyridin-3-yl)ethanone
Step 1: 3-Methoxy-/V-((6-methoxypyridin-3-yl)methylene)aniline was prepared quantitatively according to general procedure I from 6-methoxynicotinaldehyde (0.140 g; 1.021 mmol) and 3methoxyaniline (0.115 mL; 1.021 mmol). ESI/APCI (+): 243 (M+H).
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Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.143 g; 0.530 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.251 g; 1.020 mmol) and a solution of 3-methoxy-A/-((6-methoxypyridin-3-yl)methylene)aniline (1.021 mmol) in éthanol (0.5 mL), heated at 65 °C for 5 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by précipitation from diethyl ether furnished 0.097 g (25%) of the desired compound as a pale yellow solid. ESI/APCI (+): 388 (M+H). ESI/APCI (-): 386 (M-H).
EXAMPLE 56: PREPARATION OF 6-((2-( 1 H-indol-3-yl)-2-oxo-1phenylethyl)amino)benzo[rt]oxazol-2(3H)-one
6-((2-(1 H-lndol-3-yl)-2-oxo-1-phenylethyl)amino)benzo[d]oxazol-2(3H)-one was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.102 g; 0.378 mmol), 6-aminobenzo[d]oxazol-2(3H)-one (0.104 g; 0.693 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200’C for 30 minutes. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.023 g (16%) of the desired compound as an amorphous solid. ESI/APCI(+): 384 (M+H); 406 (M+Na). ESI/APCI(-): 382 (M-H).
EXAMPLE 57: PREPARATION OF 2-((3-( 1H-1,2,4-triazol-1-yl)phenyl)amino)-1-(1H-indol-3-yl)2-phenylethanone
2- ((3-(1H-1,2,4-Triazol-1-yl)phenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.104 g; 0.386 mmol), 3-(1 H-1,2,4-triazol-1 -yl)aniline (0.093 g; 0.581 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane, followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.009 g (6%) of the desired compound as an amorphous solid. ESI/APCI(+): 394 (M+H); 416 (M+Na). ESI/APCI(-): 392 (M-H).
EXAMPLE 58: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-(oxazol-5-yl)phenyl)amino)-2phenylethanone
1-(1H-lndol-3-yl)-2-((3-(oxazol-5-yl)phenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0,101 g; 0.374 mmol),
3- (oxazol-5-yl)aniline (0.086 g; 0.537 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane, followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.008 g
153 (5%) of the desired compound as an amorphous solid. ESI/APCI(+): 394 (M+H); 416 (M+Na). ESI/APCI(-): 392 (M-H).
EXAMPLE 59: PREPARATION OF 5-(2-(1 H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2oxoethyl)-1,3-dimethyl-1 H-benzo[d]imidazol-2(3H)-one
Step 1: 5-(((3-Methoxyphenyl)imino)methyl)-1,3-dimethyl-1/-/-benzo[cf|imidazol-2(3H)-one was prepared quantitatively according to general procedure I from 1,3-dimethyl-2-oxo-2,3-dihydro1H-benzo[c/Jimidazole-5-carbaldehyde (0.109 g; 0.573 mmol) and 3-methoxyaniline (0.065 mL; 0.578 mmol). ESI/APCI (+): 296 (M+H).
Step 2: 5-(2-(1 H-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-1,3-dimethyl-1Hbenzo[d]imidazol-2(3H)-one was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.077 g; 0.285 mmol) and triethylamîne (0.060 mL; 0.430 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1carboxylate (0.140 g; 0.572 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)-1,3dimethyl-1H-benzo[d]imidazol-2(3H)-one (0.573 mmol) in éthanol (0.5 mL), heated at 65 °C for 3 days. After concentration of the reaction mixture under reduced pressure, précipitation from acetone and diethyl ether furnished 0.049 g (19%) of the desired compound as a pale yellow solid. ESI/APCI (+): 441 (M+H). ESI/APCI (-): 439 (M-H).
EXAMPLE 60: PREPARATION OF 4-(2-( 1 H-indol-3-yl)- 1-((2-methoxypyridin-4-yl)amino)-2oxoethyl)benzonitrile
Step 1: 4-(((2-Methoxypyridin-4-yl)imino)methyl)benzonitrile was prepared quantitatively according to general procedure J from 4-formylbenzonitrile (0.131 g; 0.998 mmol), 2methoxypyridin-4-amine (0.124 g; 0.999 mmol) and magnésium sulfate (0.100 g; 0.831 mmol) in éthanol (1 mL).
Step 2: 4-(2-(1 H-lndol-3-yl)-1-((2-methoxypyridin-4-yl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamîne (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 4-(((2-methoxypyridin-4-yl)imino)methyl)benzonitrile (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane furnished 0.125 g (31%) of the desired compound as a white powder. ESl/APCl(+): 383 (M+H). ESIZAPCI(-): 381 (M-H).
EXAMPLE 61: PREPARATION OF 1-(1H-indol-3-yl)-2-((4-methoxy-6-methylpyrimidin-2yl)amino)-2-phenylethanone
Step 1: A/-Benzylidene-4-methoxy-6-methylpyrimidin-2-amine was prepared quantitatively according to general procedure J from benzaldehyde (0.100 mL; 0.987 mmol), 4-methoxy-6methylpyrimidin-2-amine (0.132 g; 0.949 mmol) and magnésium sulfate (0.100 g; 0.831 mmol) in éthanol (1 mL). ESI/APCI(+): 228 (M+H).
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Step 2: 1-(1H-lndol-3-yl)-2-((4-methoxy-6-methylpyrimidin-2-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.124 g; 0.460 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1 H-indole-1 -carboxylate (0.204 g; 0.832 mmol) and a solution of N-benzylidene-4-methoxy-6-methylpyrimidin-2-amine (0.949 mmol) in éthanol (2 mL), heated at 70 °C for 65 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by recrystallization from dichloromethane furnished 0.001 g (1%) of the desired compound as a powder. ESI/APCI(+): 373 (M+H); 395 (M+Na). ESI/APCI(-): 371 (M-H).
EXAMPLE 62: PREPARATION OF 2-(6-hydroxypyridin-3-yl)-1-(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: 5-(((3-Methoxyphenyl)imino)methyl)pyridin-2-ol was prepared quantitatively according to general procedure I from 6-hydroxynicotinaldehyde (0.125 g; 1.015 mmol) and 3-methoxyaniline (0.115 mL; 1.023 mmol). ESI/APCI (+): 229 (M+H). ESI/APCI (-): 227 (M-H)
Step 2: 2-(6-Hydroxypyridin-3-yl)-1-(1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.249 g; 1.016 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)pyridin-2-ol (1.015 mmol) in éthanol (1 mL), heated at 65 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane followed purification by préparative HPLC (XBridge column; method 2) furnished 0.078 g (21%) of the desired compound as a yellow solid. ESI/APCI (+): 374 (M+H). ESI/APCI (-): 372 (M-H).
EXAMPLE 63: PREPARATION OF 2-(imidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((2methoxypyridin-4-yl)amino)ethanone
Step 1: /V-(lmidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine has been prepared according to 2 different procedures described hereunder as method A and method B.
Method A: A/-(lmidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine was prepared quantitatively according to general procedure H from imidazo[1,2-a]pyridine-2-carbaldehyde (0.150 g; 1.026 mmol), magnésium sulfate (0.200 g; 1.662 mmol) and 4-amino-2methoxypyridine (0.129 g; 1.039 mmol) in éthanol (1 mL). ESI/APCI (+): 253 (M+H).
Method B: A mixture of imidazo[1,2-a]pyridine-2-carbaldehyde (0.250 g; 1,711 mmol) and 4amino-2-methoxypyridine (0.215 g; 1.732 mmol) in 2-methyltetrahydrofuran (5 mL) was heated at reflux with a Dean-Stark apparatus. The solvent was evaporated under reduced pressure to give quantitatively /V-(imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine which was used in the next step without further purification. ESI/APCI (+): 253 (M+H).
155
Step__________2: 2-(lmidazo[1,2-a]pyridin-2-yl)-1-(1/-/-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-
5-(2-hydroxyethyl)-4-methylthiazolium chloride (0,140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.252 g; 1.027 mmol) and a solution of /V-(imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridine-4-amine (1.026 mmol) in éthanol (1 mL), heated at 65 °C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 3) furnished 0.031 g (7%) of the desired compound as a yellow solid. ESI/APCI (+): 398 (M+H). ESI/APCI (-): 396 (M-H).
EXAMPLE 64: PREPARATION OF 3-((2-( 1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzamide 3-((2-( 1/7-lndol-3-yl)-2-oxo-1-phenylethyl)amino)benzamide was prepared according to general procedure C from 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0.105 g; 0.389 mmol), 3aminobenzamide (0.099 g; 0.727 mmol) and DIPEA (0.200 mL; 1.148 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.003 g (2%) of the desired compound as a solid. ESI/APCI(+): 370 (M+H); 392 (M+Na). ESIZAPCI(-): 368 (M-H).
EXAMPLE 65: PREPARATION OF 1-(1H-indol-3-yl)-2-((4-methoxypyridin-2-yl)amino)-2phenylethanone
Step 1: N-Benzylidene-4-methoxypyridin-2-amine was prepared quantitatively according to general procedure J from benzaldehyde (0.100 mL; 0.987 mmol), 4-methoxypyridin-2-amine (0.124 g; 0.999 mmol) and magnésium sulfate (0.100 g; 0.831 mmol) in éthanol (1 mL). ESI/APCI(+): 213 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((4-methoxypyridin-2-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.128 g; 0.474 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.202 g; 0.824 mmol) and a solution of Nbenzylidene-4-methoxypyridin-2-amine (0.999 mmol) in éthanol (2 mL), heated at 70 °C for 65 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by purification by préparative HPLC (SunFire column; method 2) furnished 0.032 g (11%) of the desired compound as an amorphous solid. ESI/APC1(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 66: PREPARATION OF 1-(1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2phenylethanone
Step 1: N-Benzylidene-5-methoxypyridin-3-amine was prepared quantitatively according to general procedure J from benzaldehyde (0.100 mL; 0.987 mmol), 5-methoxypyridin-3-amine
156 (0.130 g; 1.047 mmol) and magnésium sulfate (0.100 g; 0.831 mmol) in éthanol (1 mL). ESI/APCI(+): 213 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.124 g; 0.460 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.203 g; 0.828 mmol) and a solution of Nbenzylidene-5-methoxypyridin-3-amine (0.987 mmol) in éthanol (2 mL), heated at 70 °C for 65 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.033 g (11%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H); 380 (M+Na). ESI/APCI(-): 356 (M-H). 1H NMR (DMSO-de): δ 12.19 (1H, br s); 8.91 (1H, m); 8.15 (1H, m); 7.83 (1H, m); 7.65 (2H, m); 7.48 (2H, m); 7.19-7.32 (4H, m); 6.68-6.81 (2H, m); 6.16 (1H, m); 3.70 (3H, s).
EXAMPLE 67: PREPARATION OF ethyl 3-((2-(1 H-indol-3-yl)-2-oxo-1phenylethyl)amino)benzoate
Ethyl 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoate was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.292 g; 1.083 mmol), ethyl 3-aminobenzoate (0.322 g; 1.949 mmol) and DIPEA (0.400 mL; 2.296 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane followed by précipitation from diethyl ether furnished 0.123 g (29%) of the desired compound as a solid. ESI/APCI(+): 399 (M+H); 421 (M+Na). ESI/APCI(-): 397 (M-H). 1H NMR (COCI3) δ 8.58 (1H, br s); 8.40 (1 H. m); 8,02 (1H, m); 7.54 (2H, m); 7.18-7.38 (9H, m); 6.87 (1H, m); 5.77 (1H, s); 4.32 (2H, q); 1.36 (3H, t).
EXAMPLE 68: PREPARATION OF 1-(6-chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2((2-methoxypyridin-4-yl)amino)ethanone
Step 1 : tert-Butyl 6-chloro-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 6-chloro-1H-indole-3-carbaldehyde (0.500 g; 2.784 mmol), dï-tert-butyl dicarbonate (0.740 g; 3.391 mmol) and DMAP (0.050 g; 0.409 mmol) in acetonitrile (9 mL) to afford 0.760 g (98%) of the desired compound as a brown solid. 1H NMR (DMSO-de) δ 10.07 (1H, s); 8.70 (1H, s); 8.13 (2H, m); 7.45 (1H, d); 1.67 (9H, s).
Step 2: 1 -(6-Chloro-1 H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.141 g; 0.476 mmol) and triethylamine (0.085 mL; 0.611 mmol) in éthanol (1 mL), fert-butyl 6-chloro-3-formyl-1H-indole-1-carboxylate (0.240 g; 0.856 mmol) and a solution of /V-(imidazo[1,2-a]pyridin-2-ylmethylene)-2methoxypyridine-4-amine (0.856 mmol) in éthanol (2 mL), heated at 65 °C for 5 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate
157 (25% to 100%) in heptane, Further purification by préparative HPLC (XBridge column; method 3) followed by précipitation from acetone and heptane furnished 0.015 g (4%) of the desired compound as a beige solid. ESI/APCI (+): 432, 434 (M+H).
EXAMPLE 69: PREPARATION OF 1-(1H-indol-3-yl)-2-((5-methoxy-1,2,4-thiadiazol-3-yl)amino)2-phenylethanone
Step 1 : A/-Benzylidene-5-methoxy-1,2,4-thiadiazol-3-amine was prepared quantitatively according to general procedure J from benzaldehyde (0.100 mL; 0.987 mmol), 5-methoxy-1,2,4thiadiazol-3-amine (0.157 g; 1.197 mmol) and magnésium sulfate (0.100 g; 0.831 mmol) in éthanol (1 mL). ESI/APCI(+): 220 (M+H).
Step 2: 1 -(1 H-lndol-3-yl)-2-((5-methoxy-1,2,4-thiadiazol-3-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.130 g; 0.482 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.210 g; 0.856 mmol) and a solution of A/-benzylidene-5-methoxy-1,2,4-thiadiazol-3-amine (0.987 mmol) in éthanol (2 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 80%) in heptane followed by recrystailization from diethyl ether furnished 0.002 g (1%) of the desired compound as a solid. ESI/APCI(+): 365 (M+H); 387 (M+Na). ESI/APCI(-): 363 (M-H).
EXAMPLE 70: PREPARATION OF 3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoic acid
A mixture of ethyl 3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoate (0.067 g; 0.168 mmol) and lithium hydroxide (0.065 g; 2.714 mmol) in éthanol (2.5 mL) and water (2.5 mL) was stirred at room température for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The aqueous phase was acidified with a 1N hydrochloric acid solution and extracted with ethyl acetate. The phases were separated. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by recrystailization from diethyl ether furnished 0.010 g (16%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).
EXAMPLE 71: PREPARATION OF 1-(1H-indol-3-yl)-2-((6-methoxypyrimidin-4-yl)amino)-2phenylethanone
Step 1: A solution of N-benzylidene-6-methoxypyrimidin-4-amine in methanol was prepared by heating a solution of benzaldehyde (0.100 mL; 0.987 mmol) and 6-methoxypyrimidln-4-amine (0.165 g; 1.319 mmol) în methanol (1 mL) at 70 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 214 (M+H).
Step 2: To a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.147 g;
0.545 mmol) in éthanol (1 mL) was added triethylamine (0.100 mL; 0.717 mmol) and the mixture
158 was stirred at 70 °C for 5 min. To the resulting yellow solution were added tert-butyl 3-formyl1H-indole-1-carboxylate (0.208 g; 0.848 mmol) and a solution of N-benzylidene-6methoxypyrimidin-4-amine (0.987 mmol) in methanol (1 mL). The reaction mixture was stirred in a sealed tube at 70 °C for 65 h. The reaction mixture was concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.015 g (5%) of 1-(1/7-indol-3-yl)-2-((6-methoxypyrimidin-4-yl)amino)-2phenylethanone as a white solid. ESl/APCI(+): 359 (M+H); 381 (M+Na). ESI/APCI(-): 357 (ΜΗ).
EXAMPLE 72: PREPARATION OF 1-(6-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-
2- phenylethanone
1- (6-Chloro-1 H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 6-chloro-3-formyl-1/7-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of A/-benzylidene-2-methoxypyridin-4-amine (1.000 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gei using a gradient of ethyl acetate (10% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.094 g (23%) of the desired compound as a solid. ESI/APCI(+): 392, 394 (M+H). ESI/APCI(-): 390, 392 (M-H).
EXAMPLE 73: PREPARATION OF 1-(1/7-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2(pyridin-3-yl)ethanone
Step 1: 2-Methoxy-A/-(pyridin-3-ylmethylene)pyridin-4-amine was prepared quantitatively according to general procedure H from nicotinaldehyde (0.094 mL; 0.999 mmol), 2methoxypyridin-4-amine (0.124 g; 0.999 mmol) and magnésium sulfate (0.100 g; 0.831 mmol) in éthanol (1 mL).
Step 2: 1 -(1 /7-lndol-3-yl)-2-((2-rnethoxypyridin-4-yl)amino)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.555 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 2-methoxy-/V-(pyridin-3-ylmethylene)pyridin-4-amine (0,999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane furnished 0.069 g (19%) of the desired compound. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H).
EXAMPLE 74: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-
2- phenylethanone
Step 1: tert-Butyl 6-fluoro-3-formyl-1H-indole-1 -carboxylate was prepared according to general procedure F from 6-fluoro-1H-indole-3-carbaldehyde (0.653 g; 4.003 mmol), di-tert-butyl dicarbonate (1.048 g; 4.802 mmol) and DMAP (0.049 g; 0.401 mmol) in acetonitrile (10 mL) to
159 afford 0.924 g (88%) of the desired compound as a white solid. ESI/APCI(+): 264 (M+H). 1H NMR (DMSO-d6) ÔD10.06 (1H, s); 8.67 (1 H, s); 8.14 (1H, t); 7.83 (1H, d); 7.28 (1H, t); 1.67 (9H, s).
Step 2: 1-(6-Fluoro-1 H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), ferf-butyl 6-fluoro-3-formyl-1H-indole-1 -carboxylate (0.263 g; 0.999 mmol) and a solution of A/-benzylidene-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane furnished 0.107 g (28%) of 1-(6-fluoro-1H-indol-3-yl)-2-((2methoxypyridin-4-yl)amino)-2-phenylethanone. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (ΜΗ).
EXAMPLE 75: PREPARATION OF 1-(6-methoxy-1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)-2-phenylethanone
Step 1 : fert-Butyl 3-formyl-6-methoxy-1/-/-indole-1-carboxylate was prepared according to general procedure F from 6-methoxy-1 H-indole-3-carbaldehyde (0.466 g; 2.660 mmol), di-fertbutyl dicarbonate (0.697 g; 3.134 mmol) and DMAP (0.032 g; 0.266 mmol) in acetonitrile (4 mL) to afford 0.648 g (88%) of the desired compound as a white solid.
Step 2: 1-(6-Methoxy-1 H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), fert-butyl 3-formyl-6-methoxy-1 H-indole-1 -carboxylate (0.275 g; 0.999 mmol) and a solution of A/-benzylidene-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.070 g (18%) ofthe desired compound as a solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).
EXAMPLE 76: PREPARATION OF 1-(6-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
-(6-Methoxy-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 3-formyl-6-methoxy-1H-indole-1 -carboxylate (0.275 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.053 g (13%) of the desired compound as a solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).
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EXAMPLE 77: PREPARATION OF 1-(5-methoxy-1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)-2-phenylethanone
Step 1 : tert-Butyl 3-formyl-5-methoxy-1H-indole-1-carboxylate was prepared according to general procedure F from 5-methoxy-1H-indole-3-carbaldehyde (0.701 g; 4.001 mmol), di-tertbutyl dicarbonate (1.048 g; 4.712 mmol) and DMAP (0.049 g; 0.4007 mmol) in acetonitrile (10 mL) to afford 0.934 g (85%) of the desired compound as a white solid. ESI/APCI(+): 276 (M+H).
Step 2: 1 -(5-Methoxy-1 /-/-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 3-formyl-5-methoxy-1H-indole-1-carboxylate (0.275 g; 0.999 mmol) and a solution of /V-benzylidene-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.085 g (21%) of the desired compound as a solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).
EXAMPLE 78: PREPARATION OF methyl 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)1 H-indole-6-carboxylate
Step 1: 1-tert-Butyl 6-methyl 3-formyl-1H-indole-1,6-dicarboxylate was prepared according to general procedure F from methyl 3-formyl-1H-indole-6-carboxylate (0.813 g; 4.001 mmol), ditert-butyl dicarbonate (1.048 g; 4.712 mmol) and DMAP (0.049 g; 0.4007 mmol) în acetonitrile (10 mL) to afford 1.139 g (94%) of the desired compound as a white solid,
Step 2: Methyl 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), 1 -tert-butyl 6-methyl 3-formyl-1H-indole-1,6-dicarboxylate (0.303 g; 0.999 mmol) and a solution of N-benzylidene-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.055 g (13%) of the desired compound as a solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).
EXAMPLE 79: PREPARATION OF 2-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1Hindol-3-yl)-2-((3-methoxyphenyl)amino)ethanone
Step 1 : A/-((6,8-Dihydro-5/-/-imidazo[2,1 -c]oxazïn-2-yl)methylene)-3-methoxyaniline was prepared quantitatively according to general procedure I from 6,8-dihydro-5H-imidazo[2,1c][1,4]oxazine-2-carbaldehyde (0.125 g; 0.999 mmol) and 3-methoxyaniline (0.115 mL; 1.023 mmol).
161
Step 2: 2-(6,8-Dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1H-îndol-3-yl)-2-((3-methoxyphenyl) amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of /V-((6,8-dihydro-5H-imidazo[2,1-c]oxazin-2-yl)methylene)-3methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 65 °C for 3 days and at 80°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from dichloromethane and diethyl ether furnished 0.036 g (9%) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H).
EXAMPLE 80: PREPARATION OF 2-(5-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1 H-indol-3-yl)-2-((2methoxypyridin-4-yl)amino)ethanone
Step 1 : A solution of A/-((5-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-2-methoxypyridin-4amine in éthanol was prepared by heating a solution of 5-fluoroimidazo[1,2-a]pyridine-2carbaldehyde (0.100 g; 0.609 mmol) and 6-methoxypyrimidin-4-amine (0.076 g; 0.609 mmol) in éthanol (1 mL) at 65 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 271 (M+H).
Step 2: 2-(5-Fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-
5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.080 g; 0.297 mmol) and triethylamine (0.065 mL; 0,466 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.215 g; 0.611 mmol) and a solution of A/-((5-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-2methoxypyridin-4-amine (0.609 mmol) in éthanol (1 mL), heated at 65 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane and then methanol (25%) in dichloromethane as eluent. Further purification by préparative HPLC (XBridge column; method 3) furnished 0.063 g (25%) of the desired compound as a white solid. ESI/APCI(+): 416 (M+H). ESI/APCl(-): 414 (M-H).
EXAMPLE 81: PREPARATION OF 1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2(thiazol-4-yl)ethanone
Step 1 : A mixture of thîazole-4-carbaldehyde (0.115 g; 1.016 mmol) and 4-amtno-2methoxypyridine (0.126 g; 1.016 mmol) in éthanol (1 mL) was stirred at 65°C for 16 h. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively 2-methoxy-/V-(thiazol-4-ylmethylene)pyridin-4-amine which was used without further purification. ESI/APCI (+): 220 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(thiazol-4-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0,140 g; 0.519 mmol) and triethylamine (0.100 mL; 0,717 mmol) in
162 éthanol (1 mL), fert-butyl 3-formyl-1/-/-indole-1-carboxylate (0.249 g; 1.017 mmol) and a solution of 2-methoxy-A/-(thiazol“4-ylmethylene)pyridin-4-amine (1.016 mmol) in éthanol (1 mL), heated at 65 °C for 6 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.044 g (12%) of the desired compound as a white solid. ESI/APCI(+): 365 (M+H). ESI/APCt(-)r 363 (ΜΗ).
EXAMPLE 82: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone
Step 1: To a solution of pyrazolo[1,5-a]pyridine-2-carboxylic acid (0.202 g; 1.246 mmol) in dichloromethane (2 mL) were added HATU (0.472 g; 1.241 mmol) and DIPEA (0.450 mL; 2.577 mmol). After stirring for 5 min at room température, Λ/,Ο-dimethylhydroxylamine hydrochloride (0.128 g; 1.312 mmol) was added and the reaction mixture was stirred at room température overnight. The reaction mixture was diluted with dichloromethane and washed with water. The phases were separated. The organic phase was washed with a 1N hydrochloric acid solution, a 1N sodium bicarbonate solution and brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to give A/-methoxy-/V-methylpyrazolo[1,5-a]pyridine-2carboxamide which was used in the next step without further purification. ESI/APCI (+): 206 (M+H).
Step 2: To a solution of A/-methoxy-A/-methylpyrazolo[1,5-a]pyridine-2-carboxamide (1.246 mmol) in dry THF (3 mL) cooled at -15 °C (acetone/glace) was added lithium aluminum hydride (0.048 g; 1.257 mmol) and the solution was stirred for 3 h. A 1N Rochelle sait solution was added and the reaction mixture was stirred at room température for 10 min. The phases were separated. The aqueous phase was extracted with ether. The organic phases were combined, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica using a gradient of ethyl acetate (0% to 30%) in heptane furnished 0.088 g (48% over 2 steps) of pyrazolo[1,5-a]pyridine-2-carbaldehyde as a white solid. ESI/APCI (+): 147 (M+H).
Step 3: 3-Methoxy-A/-(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline was prepared quantitatively according to general procedure I from pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.087 g; 0.595 mmol) and 3-methoxyaniline (0.070 mL; 0.623 mmol).
Step 4: 1 -( 1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)4-methylthiazol-3-ium chloride (0.082 g; 0.304 mmol) and triethylamine (0.060 mL; 0.430 mmol) in éthanol (0.7 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.151 g; 0.616 mmol) and a solution of 3-methoxy-N-(pyrazolo[1l5-a]pyridin-2-ylmethylene)aniline (0.623 mmol) in éthanol (0.7 mL), heated at 65 ’C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane followed by précipitation from
163 dichloromethane furnished 0.055 g (23%) of the desired compound as a yellow solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).
EXAMPLE 83: PREPARATION OF 1-(7-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1: tert-Butyl 7-chloro-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 7-chloro-1H-indole-3-carbaldehyde (0.718 g; 3.998 mmol), di-tert-butyl dicarbonate (1.048 g; 4.712 mmol) and DMAP (0.049 g; 0.401 mmol) in acetonitrile (10 mL) to afford 0.687 g (61%) of the desired compound as a white solid.
Step 2: 1-(7-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 7-chloro-3-formyl-1/-/-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of /V-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 ’C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from acetonitrile furnished 0.058 g (14%) of the desired compound as a solid. ESI/APCI(+): 391 (M+H). ESI/APCI(-): 389 (M-H).
EXAMPLE 84: PREPARATION OF methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1Hindole-6-carboxylate
Methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), 1-tert-butyl 6-methyl 3-formyl-1H-indole-1,6-dicarboxylate (0.303 g; 0.999 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 ’C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.038 g (9%) of the desired compound as a solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).
EXAMPLE 85: PREPARATION OF 1-(5-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1: tert-Butyl 5-chloro-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 5-chloro-1W-indole-3-carbaldehyde (0.718 g; 3.998 mmol), di-tert-butyl dicarbonate (1.048 g; 4.712 mmol) and DMAP (0.049 g; 0.401 mmol) in acetonitrile (10 mL) to afford 1.001 g (89%) of the desired compound as a white solid.
Step 2: 1-(5-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 5-chloro-3-formyl-1H-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 ’C for 2 days.
164
Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.011 g (3%) of the desired compound as a solid. ESI/APCI(+): 391 (M+H). ESI/APCI(-): 389 (M-H).
EXAMPLE 86: PREPARATION OF 2-((2,6-dimethoxypyrimidin-4-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone
Step 1: A solution of A/-benzylidene-2)6-dimethoxypyrimidin-4-amine in methanol was prepared by heating a solution of benzaldehyde (0.100 mL; 0.987 mmol) and 2,6-dimethoxypyrimidin-4amîne (0.136 g; 0.877 mmol) in methanol (1 mL) at 70°C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 244 (M+H). Step 2: To a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0,132 g; 0.489 mmol) in éthanol (1 mL) was added triethylamine (0.100 mL; 0.717 mmol) and the mixture was stirred at 70 °C for 5 min. To the resulting yellow solution were added a solution of Nbenzylidene-2,6-dimethoxypyrimidin-4-amine (0.877 mmol) in methanol (1 mL) and fert-butyl 3formyî-1/-/-indole-1-carboxylate (0.208 g; 0.848 mmol). The reaction mixture was stirred in a sealed tube at 70 °C for 24 h. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane. Further purification by préparative HPLC (XBridge column; method 2) furnished 0.005 g (2%) of the desired compound as a white solid. ESI/APCI(+): 389 (M+H); 411 (M+Na). ESI/APCI(-): 387 (M-H).
EXAMPLE 87: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(8methylimidazo[1,2-a]pyridîn-2-yl)ethanone
Step 1 : A solution of 3-methoxy-A/-((8-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline in éthanol was prepared by heating a solution of 8-methylimidazo[1,2-a]pyridine-2-carbaldehyde (0.162 g; 1.011 mmol) and 3-methoxyaniline (0.115 mL; 1.023 mmol) in éthanol (0.5 mL) at 65 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 266 (M+H); 288 (M+Na); 531 (2M+H); 553 (2M+Na).
Step 2: 1 -( 1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(8-methylimidazo[1,2-a]pyridin-2yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), fert-butyl 3-formyl-1/-/-indole-1-carboxylate (0.270 g; 1.101 mmol) and a solution of 3-methoxy-A/-((8-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline (1.011 mmol) in éthanol (1 mL), heated at65 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane followed by précipitation from diethyl ether and dichloromethane furnished 0.022 g (5%) of the desired compound as a pale yellow solid. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).
EXAMPLE 88: PREPARATION OF 1-(1H-indol-3-yl)-2-((4-methoxypyrimidin-2-yl)amino)-2phenylethanone
165
Step 1: A solution of N-benzylidene-4-methoxypyrimidin-4-amine in methanol was prepared by heating a solution of benzaldehyde (0.100 mL; 0.987 mmol) and 4-methoxypyrimidin-2-amine (0.163 g; 1.303 mmol) in methanol (1 mL) at 70 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 214 (M+H).
Step 2: 1-(1FMndol-3-yl)-2-((4-methoxypyrimidin-2-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.163 g; 0.604 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.195 g; 0.795 mmol) and a solution of Nbenzylidene-4-methoxypyrimidin-4-amine (0.987 mmol) in methanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 20%) in ethyl acetate followed by recrystallization from methanol furnished 0.020 g (7%) of the desired compound as a white solid. ESI/APCI(+): 359 (M+H); 381 (M+Na). ESI/APCI(-): 357 (M+H).
EXAMPLE 89: PREPARATION OF 2-(4-fluorophenyl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone
Step 1 : N-(4-Fluorobenzylidene)-2-methoxypyridin-4-amine was quantitatively prepared according to general procedure H from 4-fluorobenzaldehyde (0.106 mL; 1.004 mmol), magnésium sulfate (0.100 g; 0.831 mmol) and 2-methoxypyridin-4-amine (0.124 g; 0.999 mmol) in éthanol (1 mL).
Step 2: 2-(4-Fluorophenyl)-1-(1 H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0,245 g; 0.999 mmol) and a solution of W-(4-fluorobenzylidene)-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.068 g (17%) of the desired compound. ESI/APCI(+): 376 (M+H). ESIZAPCI(-): 374 (M-H).
EXAMPLE 90: PREPARATION OF 2-(3-fluorophenyl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone
Step 1 : N-(3-Fluorobenzylidene)-2-methoxypyridin-4-amine was quantitatively prepared according to general procedure H from 3-fluorobenzaldehyde (0.106 mL; 1.003 mmol), magnésium sulfate (0.100 g; 0.831 mmol) and 2-methoxypyridin-4-amine (0.124 g; 0.999 mmol) in éthanol (1 mL).
Step 2: 2-(3-Fluorophenyl)-1-(1/-/-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0,500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in
166 éthanol (1 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of A/-(3-fluorobenzylidene)-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.093 g (24%) of the desired compound. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).
EXAMPLE 91: PREPARATION OF 1-(5-methoxy-1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
-(5-Methoxy-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), fert-butyl 3-formyl-5-methoxy-1H-indole-1 -carboxylate (0.275 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane furnished 0.085 g (22%) of the desired compound. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).
EXAMPLE 92: PREPARATION OF 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-1Hindole-6-carbonitrile
Step 1: fert-Butyl 6-cyano-3-formyl-1/-/-indole-1-carboxylate was prepared according to general procedure F from 3-formyl-1H-indole-6-carbonitrile (0.511 g; 3.003 mmol), di-fert-butyl dicarbonate (0.786 g; 3.601 mmol) and DMAP (0.037 g; 0.303 mmol) in acetonitrile (7 mL) to afford 0.697 g (76%) of the desired compound as a white solid.
Step 2: 3-(2-((2-Methoxypyridin-4-yl)amino)-2-phenylacetyl)-1 /-/-indole-6-carbonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), fert-butyl 6-cyano-3-formyl-1H-indole-1 -carboxylate (0.270 g; 0.999 mmol) and a solution of A/-benzylidene-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane furnished 0.058 g (15%) of the desired compound. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (M-H).
EXAMPLE 93: PREPARATION OF 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1/-/-indole-6carbonitrile
3-(2-((3-Methoxyphenyl)amîno)-2-phenylacetyl)-1 H-indole-6-carbonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), fert-butyl 6-cyano-3-formyl-1/-/-indole-1-carboxylate (0.270 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h.
167
Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane furnished 0.038 g (9%) of the desired compound. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).
EXAMPLE 94: PREPARATION OF 2-(6,8-dihydro-5/-/-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1Hindol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone
Step 1: A mixture of 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (0.156 g; 1.025 mmol) and 4-amino-2-methoxypyridine (0.130 g; 1.047 mmol) in éthanol (1 mL) was stirred at 65°C for 2.5 days. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively W-((6l8-dihydro-5H-imidazo[2)1-c][1,4]oxaz!n-2-yl)methylene)-2methoxypyridin-4-amine which was used without further purification.
Step 2: 2-(6t8-Dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1/7-indol-3-yl)-2-((2-methoxypyridin-
4-yl)amino)ethanone was prepared according to general procedure K from a mixture of 3benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.133 g; 0.493 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1W-indole-1carboxylate (0.252 g; 1.026 mmol) and a solution of A/-((6,8-dihydro-5H-imidazo[2,1c][1,4]oxazin-2-yl)methylene)-2-methoxypyridin-4-amine (1.025 mmol) in éthanol (1 mL), heated at 65 °C for 7 days. The residue was purified by flash chromatography on silica gel eluted first with ethyl acetate and then with methanol (30%) in dichloromethane. Further purification by préparative HPLC (XBridge column; .method 2) furnished 0.131 g (32%) of the desired compound as a yellow oil. ESI/APCI(+): 404 (M+H). ESI/APCI(-): 402 (M-H).
EXAMPLE 95: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(7methylimidazo[1,2-a]pyridin-2-yl)ethanone
Step 1: A solution of 3-methoxy-A/-((7-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline in éthanol was prepared by heating a solution of 7-methylimldazo[1,2-a]pyridine-2-carbaldehyde (0.160 g; 0.999 mmol) and 3-methoxyaniline (0.113 mL; 1.009 mmol) in éthanol (0.5 mL) at 65 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 266 (M+H)
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(7-methylimidazo[1,2-a]pyridin-2yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.102 mmol) and a solution of 3-methoxy-/V-((7-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 65 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) în heptane followed by précipitation from acetone furnished 0.050 g (12%) of the desired compound as a pale yellow solid. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).
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EXAMPLE 96: PREPARATION OF 1-(1H-indol-3-yl)-2-(1H-indol-5-yl)-2-((2-methoxypyridin-4yl)amino)ethanone
Step 1: A solution of A/-((1/V-indol-5-yl)methylene)-2-methoxypyridin-4-amine in éthanol was prepared by heating a solution of 1H-indole-5-carbaldehyde (0.098 g; 0.675 mmol) and 2methoxypyridin-4-amine (0.144 g; 1.160 mmol) in éthanol (1 mL) at 70 °C for 65 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 252 (M+H). ESI/APCI(-): 250 (M-H).
Step 2: 1-(1 F/-lndol-3-yl)-2-(1/-/-indol-5-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methyithiazol-3-ium chloride (0.156 g; 0.578 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.214 g; 0.872 mmol) and a solution of A/-((1H-indol-5-yl)methylene)-2-methoxypyridin-4-amine (0.675 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.011 g (3%) of the desired compound as a white solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).
EXAMPLE 97: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6methylimidazo[1,2-a]pyridin-2-yl)ethanone
Step 1: A solution of 3-methoxy-/V-((6-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline in éthanol was prepared by heating a solution of 6-methylimidazo[1,2-a]pyridine-2-carbaldehyde (0.160 g; 0.999 mmol) and 3-methoxyaniline (0.113 mL; 1.009 mmol) In éthanol (0.5 mL) at 65 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 266 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylimidazo[1,2-a]pyridin-2yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.102 mmol) and a solution of 3-methoxy-N-((6-methylÎmidazo[1,2-a]pyridin-2-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated overnight at 65 °C. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by précipitation from acetone furnished 0.084 g (21%) of the desired compound as a white solid. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).
EXAMPLE 98: PREPARATION OF 1-(5-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-
2- phenylethanone
-(5-Chloro-1 /-/-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1
169 mL), tert-butyl 5-chloro-3-formyl-1/-/-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of /V-benzylidene-2-methoxypyridin-4-amine (0.999 mmol) in éthanol (1 mL), heating at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.089 g (22%) of the desired compound. ESI/APCI(+): 392, 394 (M+H). ESI/APCI(-): 390, 392 (M-H).
EXAMPLE 99: PREPARATION OF 2-((2-methoxypyridin-4-yl)amino)-1-(1-methyl-1F/-indol-3-yl)2-phenylethanone
2- ((2-Methoxypyridin-4-yl)amino)-1-(1-methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.169 g; 0.628 mmol) and triethylamine (0.088 mL; 0.628 mmol) in éthanol (2 mL), l-methyMH-indole-S-carbaldehyde (0.200 g; 1.256 mmol) and a solution of Nbenzylidene-2-methoxypyridin-4-amine (1.256 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by préparative HPLC (XBridge column; method 5) furnished 0.034 g (7%) of the desired compound. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).
EXAMPLE 100: PREPARATION OF 1-(7-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)-2-phenylethanone
1-(7-Chloro-1 H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 7-chloro-3-formyl-1H-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of A/-benzylidene-2-methoxypyridin-4-amine (0.212 g; 0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.083 g (21%) of the desired compound. ESI/APCI(+): 392, 394 (M+H). ESI/APCI(-): 390, 392 (M-H).
EXAMPLE 101: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino )-2-(3methylisoxazol-5-yl)ethanone
Step 1: 3-Methoxy-/V-((3-methylisoxazol-5-yl)methylene)aniline was prepared quantitatively according to general procedure I from 3-methylisoxazole-5-carbaldehyde (0.111 g; 1.000 mmol) and 3-methoxyaniline (0.113 mL; 1.000 mmol). ESI/APCI(+): 217 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-methylisoxazol-5-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.069 mL; 0.497 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.294 g; 1.199 mmol) and a solution of 3-methoxy-M-((3-methylisoxazol-5-yl)methylene)aniline (1.000 mmol) in éthanol (0.7 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a ό
170 gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate furnished 0.051 g (14%) of the desired compound as a white solid. ESI/APCI(+): 362 (M+H); 384 (M+Na); 745 (2M+Na). ESI/APCI(-): 360 (M-H).
EXAMPLE 102: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl1 /7-îmidazol-4-yl)ethanone
Step 1: 3-Methoxy-N-((1-methyl-1 H-imidazol-4-yl)methylene)aniline was prepared quantitatively according to general procedure I from 1-methyl-1 H-imidazole-4-carbaldehyde (0.110 g; 0.999 mmol) and 3-methoxyaniline (0.113 mL; 1.000 mmol). ESI/APCI(+): 216 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1 -methyl-1 H-imidazol-4-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.069 mL; 0.497 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.294 g; 1.199 mmol) and a solution of 3-methoxy-/V-((1 -methyl-1 H-imidazol-4-yl)methylene)aniline (0.999 mmol) in éthanol (0.7 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0 % to 10%) in dichloromethane followed by précipitation from dichloromethane furnished 0.045 g (12%) of the desired compound as a beige powder. ESI/APCI(+): 361 (M+H); 383 (M+Na); 743 (2M+Na). ESI/APCI(): 359 (M-H).
EXAMPLE 103: PREPARATION OF 1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amïno)-2-phenylethanone
Step 1: 2-Chloro-1-(1-(2-hydroxyethyl)-1/-/-indol-3-yl)-2-phenylethanone was prepared according to general method M from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0,150 g; 0.556 mmol), 2-bromoethanol (0.079 mL; 1.113 mmol) and potassium carbonate (0.115 g; 0.834 mmol) in DMF (3 mL). The réaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.020 g (11%) of the desired compound as a white solid. ESI/APCI(+): 314 (M+H); 336 (M+Na). ESI/APCI(-): 312 (M-H).
Step 2: 1-(1-(2-Hydroxyethyl)-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2phenylethanone (0.020 g; 0.064 mmol), 3-methoxyaniline (0.014 mL; 0.127 mmol) and DIPEA (0.021 mL; 0.127 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 20%) in dichloromethane furnished 0.006 g (25%) of the desired compound as a beige solid. ESI/APCI(+): 401 (M+H).
171
EXAMPLE 104: PREPARATION OF 1-(1-(2-aminoethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone and tert-butyl (2-(3-(2-((3-methoxyphenyl)amino)-2phenylacetyl)-1 H-indol-1 -yl)ethyl)carbamate
Step 1: fert-Butyl (2-(3-(2-chloro-2-phenylacetyl)-1H-indol-1-yl)ethyl)carbamate was prepared according to general method M from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.150 g; 0.556 mmol), tert-butyl (2-bromoethyl)carbamate (0.249 g; 1.111 mmol) and potassium carbonate (0.154 g; 1,114 mmol) in DMF (3 mL). The réaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.120 g (52%) of the desired compound as a pink solid. ESI/APCI(+): 413 (M+H); 435 (M+Na).
Step 2: tert-Butyl (2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 H-indol-1 yl)ethyl)carbamate was prepared according to general procedure C from tert-butyl (2-(3-(2chloro-2-phenylacetyl)-1H-indol-1-yl)ethyl)carbamate (0.120 g; 0.291 mmol), 3-methoxyaniline (0,065 mL; 0.581 mmol) and DIPEA (0.099 mL; 0.581 mmol) in acetonitrile (3 mL), irradiated in a microwave oven at 200°C for 1.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1% to 10%) in dichloromethane furnished 0.066 g (45%) of the desired compound as an orange solid. ESI/APCI(+): 500 (M+H), 522 (M+Na).
Step 3: To a solution of tert-butyl (2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1yl)ethyl)carbamate (0.066 g; 0.132 mmol) in dichloromethane (6 mL) was added trifluoroacetic acîd (3 mL) and the mixture was stirred at room température for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnésium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of methanol (1% to 15%) in dichloromethane. Further purification by préparative TLC using 10% methanol in dichloromethane as eluent furnished 0.033 g (62%) of 1-(1-(2-aminoethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone as a beige solid. ESI/APCI(+): 400 (M+H); 422 (M+Na).
EXAMPLE 105: PREPARATION OF ethyl 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)1H-indol-1-yl)acetate
Step 1: Ethyl 2-(3-(2-chloro-2-phenylacetyl)-1H-indol-1-yl)acetate was prepared according to general procedure M from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.400 g; 1.483 mmol), ethyl bromoacetate (0.329 mL; 2.974 mmol) and potassium carbonate (0.410 g; 2.967 mmol) in
DMF (10 mL). The reaction mixture was stirred at room température for 1 h. Purification by précipitation followed by recrystallization from éthanol furnished 0.475 g (90%) of the desired compound as a beige solid. ESI/APCI(+): 356, 358 (M+H). ESl/APCI(-): 354, 356 (M-H).
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Step 2: Ethyl 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetate was prepared according to general procedure C from ethyl 2-(3-(2-chloro-2-phenylacetyl)-1H-indol-
1- yl)acetate (0.250 g; 0.703 mmol), 3-methoxyaniline (0.157 mL; 1.402 mmol) and DIPEA (0.240 mL; 1.402 mmol) in acetonitrile (3 mL), irradiated in a microwave oven at 200°C for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane, Further purification by flash chromatography on silica gel eluting with dichloromethane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.058 g (19%) of the desired compound as a beige solid. ESI/APCI(+): 443 (M+H). ESI/APCI(-): 441 (M-H).
EXAMPLE 106: PREPARATION OF 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1/-/indol-1-yl)acetic acid
To a solution of ethyl 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetate (0.040 g; 0.090 mmol) in éthanol (2 mL) was added a 1N sodium hydroxide solution (0.108 mL; 0.108 mmol) and the reaction mixture was stirred at room température for 3 h. Ethanol was evaporated under reduced pressure. The residue was diluted with water and extracted with dichloromethane. The phases were separated. The aqueous phase was acidified with a 1N hydrochloric acid solution to pH 2-3 and extracted with ethyl acetate. The organic phase was dried over magnésium sulfate and evaporated under reduced pressure to give 0.021 g (55%) of
2- (3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetic acid as a white solid. ESI/APCI(+): 415 (M+H). ESIZAPCI(-): 413 (M-H).
EXAMPLE 107: PREPARATION OF 2-(1 -ethyl-1 H-pyrazol-5-yl)-1 -(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: N-((1-Ethyl-1/-/-pyrazol-5-yl)methylene)-3-methoxyaniline was prepared quantitatively according to general procedure I from 1-ethyl-1/-/-pyrazole-5-carbaldehyde (0.254 g; 2.046 mmol) and 3-methoxyaniline (0.229 mL; 2.045 mmol). ESI/APCI(+): 230 (M+H).
Step 2: To a solution of 1/-/-indole-3-carbaldehyde (5.000 g; 34.45 mmol) in DMSO (35 mL) was added sodium hydride (60% dispersion in minerai oil; 1.520 g; 37.89 mmol) and the mixture was stirred at room température for 30 min. Ethyl chloroformate (3.520 mL; 37.89 mmol) was and the reaction mixture was stirred for 30 min. The reaction mixture was poured into a mixture icewater. The resulting precipitate was filtered and dissolved in ethyl acetate. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 6.79 g (91%) of ethyl 3-formyl-1/-/-indole-1 -carboxylate as a beige solid. ESI/APCI(+): 218 (M+H).
Step 3: 2-(1 -Ethyl-1 H-pyrazol-5-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.124 g; 0.460 mmol) and triethylamine (0.064 mL; 0.462 mmol) in
173 éthanol (2 mL), ethyl 3-formyl-1H-indole-1-carboxylate (0.200 g; 0.921 mmol) and a solution of N-((1-ethyl-1H-pyrazol-5-yl)methylene)-3-methoxyaniline (0.921 mmol) in éthanol (1 mL), heated ovemight at 70 °C. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from dichloromethane and diethyl ether furnished 0.008 g (2%) of the desired compound as a beige solid. ESI/APCI(+): 375 (M+H). ESIZAPCI(-): 373 (M-H).
EXAMPLE 108: PREPARATION OF 1-(1H-îndol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(5methylisoxazol-3-yl)ethanone
Step 1: 2-Methoxy-A/-((5-methylisoxazol-3-yl)methylene)pyridin-4-amine was quantitatively prepared according to general procedure H from 5-methylisoxazole-3-carbaldehyde (0.111 g; 0.999 mmol), magnésium sulfate (0.100 g; 0.831 mmol) and 2-methoxypyridin-4-amine (0.124 g; 0.999 mmol) in éthanol (1 mL).
Step 2: 1-(1H-lndol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 2-methoxy-A/-((5-methylisoxazol-3-yl)methylene)pyridin-4-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane. Further purification by préparative HPLC (XBridge column; method 5) followed by purification by préparative TLC using 65% ethyl acetate in heptane as eluent furnished 0.021 g (6%) of the desired compound. ESI/APCi(+): 363 (M+H). ESI/APCI(-): 361 (M-H).
EXAMPLE 109: PREPARATION OF 2-(5-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2((3-methoxyphenyl)amino)ethanone
Step 1: A solution of 5-fluoroimidazo[1,2-a]pyridine-2-carbaldehyde (0.151 g; 0.920 mmol) and
3-methoxyaniline (0.105 mL; 0.934 mmol) in éthanol (1 mL) was stirred ovemight at 60°C. The reaction mixture was evaporated and dried under reduced pressure to give quantitatively N-((5fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-3-methoxyaniline which was used without further purification. ESI/APCI (+): 270 (M+H)
Step 2: 2-(5-Fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-îum chloride (0.125 g; 0.463 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.102 mmol) and a solution of N-((5-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-3-methoxyaniline (0.920 mmol) in éthanol (1 mL), heated at 60 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane followed
174 by purification by préparative HPLC (XBridge column; method 5) furnished 0.072 g (19%) of the desired compound. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).
EXAMPLE 110: PREPARATION OF 2-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2((3-methoxyphenyl)amino)ethanone
Step 1 : A solution of A/-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-3-methoxyaniline in éthanol was prepared by heating a solution of 6-fluoroimidazo[1,2-a]pyridine-2-carbaldehyde (0.150 g; 0.914 mmol) and 3-methoxyaniline (0.113 mL; 1.009 mmol) in éthanol (0.5 mL) at 65 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 270 (M+H); 292 (M+Na).
Step 2: 2-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.130 g; 0.482 mmol) and triethylamîne (0.090 mL; 0.646 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.275 g; 1.121 mmol) and a solution of N-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-3-methoxyaniline (0.914 mmol) in éthanol (1 mL), heated at 65 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane furnished 0.078 g (21%) of the desired compound as a brown solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).
EXAMPLE 111: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(1-(methylsulfonyl)-1Hindol-3-yl)-2-phenylethanone
Step 1: To a suspension of 1 H-indole-3-carbaldehyde (0.214 g; 1.447 mmol) in dichloromethane (3 mL) were added methanesulfonyl chloride (0.200 mL; 2.578 mmol) and DIPEA (0.300 mL; 1.722 mmol), The reaction mixture was stirred at room température for 18 h. Water was added and the solution was stirred for 1 h. The phases were separated. The organic phase was washed with a saturated bicarbonate solution and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 40%) in heptane furnished 0.189 g (57%) of 1(methylsulfonyl)-1/7-indole-3-carbaldehyde as a beige solid. ESI/APCI(+): 224 (M+H).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(1-(methylsulfonyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.157 g; 0,582 mmol) and triethylamîne (0.100 ml; 0,717 mmol) in éthanol (1 mL), 1-(methylsulfonyl)-1H-indole-3-carbaldehyde (0.144 g; 0.645 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.914 mmol) in éthanol (2 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.041 g (15%) of the desired compound. ESI/APCI(+): 435 (M+H); 457 (M+Na). ESI/APCI(-): 433 (M-H).
175
EXAMPLE 112: PREPARATION OF 2-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(1H-indol-3-yl)-2((3-methoxyphenyl)amino)ethanone
Step 1: A/-(4-(2-(Dimethylamino)ethoxy)benzylidene)-3-methoxyaniline was prepared according to general procedure I from 4-(2-(dimethylamino)ethoxy)benzaldehyde (0.185 g; 0.943 mmol) and 3-methoxyaniline (0.108 mL; 0.965 mmol). ESI/APCI(+): 299 (M+H).
Step______________2: 2-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.129 g; 0.478 mmol) and triethylamine (0.066 mL; 0.496 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1carboxylate (0.281 g; 1.146 mmol) and a solution of W-(4-(2(dimethylamino)ethoxy)benzylidene)-3-methoxyaniline (0.943 mmol) in éthanol (0.7 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 30%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.087 g (20%) of the desired compound as a yellow solid. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H).
EXAMPLE 113: PREPARATION OF 1-(1-(2-(dimethylamino)ethyl)-1H-îndol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
To a solution of 1-(1-(2-aminoethyl)-1F/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone (0.020 g; 0.056 mmol) in a mixture of THF (1 mL) and acetonitrile (1 mL) was added a 37% formaldéhyde solution in water (0.020 mL; 0.250 mmol) and sodium cyanoborohydride (0.004 g; 0.080 mmol). The reaction mixture was stirred at room température for 2 h. The reaction mixture was then diluted with dichloromethane and washed with a saturated sodium bicarbonate solution. The phases were separated, The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by préparative TLC using 5% methanol in dichloromethane as eluent furnished 0.006 g (30%) of 1(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone as a beige solid. ESI/APCI(+): 428 (M+H). ESI/APCI(-): 426 (M-H).
EXAMPLE 114: PREPARATION OF N-(2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)-2(dimethylamino)-/\/-(3-methoxyphenyl)acetamide
Step 1: To a solution of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.050 g; 0.140 mmol) in dichloromethane (3 mL) cooled at 0 °C were added triethylamine (0.059 mL; 0.421 mmol) and chloroacetyl chloride (0.034 mL; 0.421 mmol). The reaction mixture was allowed to warm to room température over 15 min. The reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution. The phases were separated. The organic layer was dried over magnésium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.027 g (44%) of A/-(2-(1/7-indol-3-yl)-2-oxo-116765
176 phenylethyl)-2-chloro-/V-(3-methoxyphenyl)acetamide as a beige solid. ESI/APCI(+): 433, 435 (M+H). ESI/APCI(-): 431, 433 (M-H).
Step 2: To a solution of A/-(2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)-2-chloro-/\/-(3methoxyphenyl)acetamide (0.027 g; 0.062 mmol) in dry THF (2 mL) cooled at 0 °C was added a 2M dimethylamine solution in THF (0.156 mL; 0.312 mmol). The reaction mixture was stirred at room température for 2 h and was then heated at 55 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by préparative TLC using 10% methanol in dichloromethane as eluent furnished 0.015 g (57%) of A/-(2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)-
2-(dimethylamino)-/V-(3-methoxyphenyl)acetamide as a beige solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H).
EXAMPLE 115: PREPARATION OF 1-(6-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(5-methylisoxazol-3-yl)ethanone
1- (6-Chloro-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0,070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 6-chloro-3-formyl-1/7-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of 3-methoxy-A/-((5-methylisoxazol-3-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.060 g (14%) of the desired compound. ESI/APCI (+): 396, 398 (M+H). ESI/APCI (-): 394, 396 (M-H).
EXAMPLE 116: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(1 -methyl-1 H-indol-3-yl)-2(5-methylisoxazol-3-yl)ethanone
2- ((3-Methoxyphenyl)amîno)-1-(1 -methyl-1 H-indol-3-yl)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), 1 -methyl-1 H-indole-3-carbaldehyde (0.159 g; 0.999 mmol) and a solution of 3methoxy-/\/-((5-methylisoxazol-3-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 eC for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.005 g (1%) ofthe desired compound. ESI/APCI (+): 376 (M+H).
EXAMPLE 117: PREPARATION OF 1-(6-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amîno)-2phenylethanone
-(6-Chloro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 6-chloro-3-formyl-1/-/-indole-1-carboxylate (0.280 g; 0.999 mmol) and
177 a solution of A/-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate furnished 0.047 g (12%) of the desired compound as a solid. ESI/APCI (+): 391, 393 (M+H). ESI/APCI (-): 389, 391 (M-H).
EXAMPLE 118: PREPARATION OF 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1: tert-Butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 5-fiuoro-1H-indole-3-carbaldehyde (0.454 g; 2.783 mmol), di-fert-butyl dicarbonate (0.728 g; 3.336 mmol) and DMAP (0.034 g; 0,278 mmol) in acetonitrile (7 mL) to afford 0,473 g (65%) of the desired compound as a solid. 1H NMR (DMSO-cQ δ 10.07 (1H, s);
8.74 (1H, s); 8.12 (1H, dd); 7.82 (1H, dd); 7.33 (1 H, dt); 1.66 (9H, s).
Step 2: 1-(5-Fluoro-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0,135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.263 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.043 g (11%) of the desired compound as a solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).
EXAMPLE 119: PREPARATION OF 4-(2-(7-chloro-1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-
2- oxoethyl)benzonitrile
4- (2-(7-Chloro-1 H-indol-3-yl)-1 -((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 7-chloro-3-formyl-1H-indole-1-carboxylate (0.280 g; 1.001 mmol) and a solution of 4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate furnished 0.050 g (12%) of the desired compound as a solid . ESI/APCI(+): 416 (M+H), ESIZAPCI(-): 414 (M-H). EXAMPLE 120: PREPARATION OF 2-((2-methoxypyridin-4-yl)amino)-1-(1-(methylsulfonyl)-1/-/indol-3-yl)-2-phenylethanone
2-((2-Methoxypyridin-4-yl)amino)-1 -( 1 -(methylsulfonyl)-l /-/-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.166 g; 0.615 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), 1-(methylsulfonyl)-1H-indole-3-carbaldehyde (0.189 g; 0.847 mmol) and a solution of A/-benzy1idene-2-methoxypyridin-4-amine (0.909 mmol) in éthanol (2 mL), heated at
178 °C for 24 h. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in ethyl acetate followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.008 g (2%) of the desired compound. ESI/APCI(+): 436 (M+H). ESI/APCI(-): 434 (M-H).
EXAMPLE 121: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(6-methyl-1H-indol-3-yl)-2phenylethanone
Step 1: 2-Chloro-1-(6-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure A from 6-methyl-1H-indole (0.200 g; 1.525 mmol), pyridine (0.100 mL; 1.270 mmol) and a-chlorophenylacetyl chloride (0.240 mL; 1.530 mmol) in toluene (2.5 mL). Purification by précipitation furnished 0.200 g (46%) of the desired compound as a beige solid. ESI/APCI(+): 284, 286. ESI/APCI(-): 282, 284 (M-H).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(6-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(6-methyl-1/7-indol-3-yl)-2-phenylethanone (0.110 g; 0.388 mmol), 3-methoxypiridine (0.087 mL; 0.388 mmol), DIPEA (0.133 g; 0.775 mmol) and a catalytic amount of sodium iodide in acetonitrile (1.5 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel eluting with dichloromethane followed by purification by préparative HPLC (XBridge column, method 5) furnished 0.006 g (4%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).
EXAMPLE 122: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1: 2-Chloro-1-(6-fluoro-1F/-indol-3-yl)-2-phenylethanone was prepared according to general procedure A from 6-fluoro-1 H-indole (0.250 g; 1.850 mmol), pyridine (0.120 mL; 1.518 mmol) and α-chlorophenylacetyl chloride (0.292 mL; 1.861 mmol) in toluene (3 mL). Purification by précipitation furnished 0.150 g (28%) of the desired compound as a beige solid. ESI/APCI(+): 288, 290 (M+H). ESI/APCI(-): 286, 288 (M-H).
Step 2: 1-(6-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(6-fluoro-1H-indol-3-yl)-2-phenylethanone (0.100 g; 0.348 mmol), 3-methoxyaniline (0.078 mL; 0.695 mmol), DIPEA (0.119 mL; 0.695 mmol) and a catalytic amount of sodium iodide in a mixture of dioxane (1 mL) and DMF (0.5 mL), irradiated in a microwave oven at 160°C for 30 min. Purification by flash chromatography on silica gel eluting with dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.012 g (9%) of the desired compound as a beige solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).
EXAMPLE 123: PREPARATION OF 2-(4-((dimethylamino)methyl)phenyl)-1-(1H-indol-3-yl)-2((3-methoxyphenyl)amino)ethanone
179
Step 1 : A solution of W-(4-((dimethylamino)methyl)benzylidene)-3-methoxyaniline in éthanol was prepared by heating a solution of p-dimethylaminomethylbenzaldehyde (0.161 g; 0.986 mmol) and 3-methoxyaniline (0.113 mL; 1.000 mmol) in éthanol (0.5 mL) at 65 °C for 18 h. The formation of the tmine was quantitative and the solution was used without further purification. ESI/APCI (+): 269 (M+H)
Step 2: 2-(4-((Dimethylamino)methyl)phenyl)-1-(1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.101 mmol) and a solution of A/-(4-((dimethylamino)methyl)benzylidene)-3-methoxyanillne (0.986 mmol) in éthanol (1.5 mL), heated overnight at 65 °C. Purification by préparative HPLC (XBridge column; method 2) furnished 0.135 g (33%) of the desired compound as a brown solid. ESI/APCI(+): 414 (M+H). ESI/APCI(-): 412 (M-H).
EXAMPLE 124: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-methyl1H-imidazol-5-yl)ethanone
Step 1: A solution of 3-methoxy-A/-((4-methyl-1H-imidazol-5-yl)methylene)aniline in éthanol was prepared by heating a solution of 4-methyl-1/-/-imidazole-5-carbaldehyde (0.110 g; 0.999 mmol) and 3-methoxyaniline (0,115 mL; 1.023 mmol) in éthanol (0,7 mL) at 65°C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 216 (M+H). ESI/APCI (-): 214 (M-H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-methyl-1/-/-imidazol-5-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyi-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0.134 g; 0.496 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.7 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.101 mmol) and a solution of 3-methoxy-/V-((4-methyl-1H-imidazol-5-yi)methylene)aniline (0.999 mmol) in éthanol (1.5 mL), heated overnight at 65 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by préparative HPLC (XBridge column, method 3). Further purification by préparative HPLC (SunFire column; method 3) furnished 0.043 g (12%) of the desired compound. ESI/APCI(+): 361 (M+H).
EXAMPLE 125: PREPARATION OF 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1/7-indole-
5- carbonitrile
Step 1: tert-Butyl 5-cyano-3-formyl-1/-/-indole-1-carboxylate was prepared according to general procedure F from 3-formyl-1H-indole-5-carbonitrile (0.340 g; 1.999 mmol), di-terî-butyl dicarbonate (0.524 g; 2.401 mmol) and DMAP (0.024 g; 0.197 mmol) in acetonitrile (7 mL) to afford 0.379 g (73%) of the desired compound as a solid. 1H NMR (DMSO-d6) δ 10.11 (1H, s);
8.85 (1 H, s); 8.50 (1H, s); 8.27 (1H, d); 7.87 (1H, dd); 1.68 (9H, s).
Step 2: 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carbonitrile was prepared
180 according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), tert-butyl 5-cyano-3-formyl-1H-indole-1-carboxylate (0.270 g; 1.000 mmol) and a solution of /\/-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate furnished 0.034 g (9%) of the desired compound as a white solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).
EXAMPLE 126: PREPARATION OF 2-(4-(hydroxymethyl)phenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1 : ((4-Bromobenzyl)oxy)(tert-butyl)dîmethylsilane was prepared according to general procedure N from 4-bromobenzyl alcohol (0.500 g; 2.673 mmol), DBU (0.408 mL; 2.734 mmol) and TBDMSCI (0.816 g; 5.414 mmol) in THF (10 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished 0.749 g (93%) of the desired compound as a colourless liquid.
Step 2: To a solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (0.500 g; 1.660 mmol) in THF (6 mL) cooled at -70 °C, was added dropwise a 2.5 M n-butyllithium solution in hexane (0.800 mL; 2.000 mmol). After 30 min at -70 °C, DMF (0.300 mL; 3.875 mmol) was added and the reaction mixture was allowed to warm to -5 ’C over 4 h. The reaction was quenched by addition of a saturated ammonium chloride solution. After warming to room température, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of dichloromethane (10% to 80%) in heptane to afford 0.382 g (92%) of 4-(((tertbutyldimethylsilyl)oxy)methyl)benzaldehyde as a colourless liquid. 1H NMR (DMSO-d6) δ 9.89 (1H, s); 7.79 (2H, d); 7.44 (2H, d); 4.72 (2H, s); 0.82 (9H, s); 0.00 (6H, s).
Step 3: N-(4-(((iert-Butyldimethylsilyl)oxy)methyl)benzylidene)-3-methoxyaniline was prepared quantitatively according to general procedure I from 4-(((fertbutyldimethylsilyl)oxy)methyl)benzaldehyde (0.250 g; 0.998 mmol) and m-anisidine (0.113 mL; 1.000 mmol). ESl/APCI(+): 356 (M+H).
Step_________4: 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-1-(1/7-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0,069 mL; 0.498 mmol) in éthanol (0.7 mL), fert-butyl 3-formyl-1H-indole-1carboxylate (0.294 g; 1.199 mmol) and a solution of A/-(4-(((tertbutyldimethylsilyl)oxy)methyl)benzylidene)-3-methoxyaniline (0.998 mmol) in éthanol (0.7 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane. Further purification by flash
181 chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished 0.148 g (30%) of the desired compound as a yellow oil. ESI/APCI(+): 501 (M+H); 523 (M+Na). ESI/APCI(-): 499 (M-H).
Step 5: To a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone (0.148 g; 0.296 mmol) in DMF (2.5 mL) was added césium fluoride (0.221 g; 1.455 mmol). After 3 h at room température, the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and a 1N hydrochloric acid solution. The phases were separated. The organic phase was washed with a saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 8%) in dichlorométhane followed by recrystallization from ethyl acetate to give 0.027 g (24%) of 2-(4-(hydroxymethyl)phenyl)-1 -(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone as a white powder. ESI/APCI(+): 387 (M+H); 409 (M+Na). ESIZAPCI(-): 385 (M-H).
EXAMPLE 127: PREPARATION OF 1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: 2-Chloro-1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general method M from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol), 3-bromopropan-1-ol (0.206 g; 1.482 mmol) and potassium carbonate (0.205 g; 1.483 mmol) in DMF (3 mL). The réaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.215 g (84%) of the desired compound as a red oil. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H).
Step 2: 1-(1-(3-Hydroxypropyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(1-(3-hydroxypropyl)-1H-indol3-yl)-2-phenylethanone (0.070 g; 0.213 mmol), 3-methoxyaniline (0.478 mL; 4.270 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane followed by purification by préparative TLC using 10% ethyl acetate in dichlorométhane as eluent furnished 0.027 g (30%) of the desired compound as a beige solid. ESI/APCI(+): 415 (M+H).
EXAMPLE 128: PREPARATION OF 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-A/,Wdimethyl-1H-indole-5-sulfonamide
Step 1 : tert-Butyl 5-(/V,N-dimethylsulfamoyl)-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 3-formyl-/V,N-dimethyl-1H-indole-5-sulfonamide (0.505 g;
2.003 mmol), di-tert-butyl dicarbonate (0.524 g; 2.401 mmol) and DMAP (0.024 g; 0.197 mmol) in acetonitrile (5 mL) to afford of 0.602 g (85%) of the desired compound as a solid. 1H NMR (DMSO-cf6) δ 10.13 (1H, s); 8.87 (1H, s); 8.50 (1H, s); 8.36 (1H, d); 7.84 (1H, d); 2.62 (6H, s);
182
1.68 (9H, s).
Step 2: 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-N,/V-dimethyl-1H-indole-5-sulfonamide was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), fert-butyl 5-(A/,A/-dimethylsulfamoyl)-3-formyl-1H-indole-1-carboxylate (0.352 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.047 g (9%) of the desired compound as a solid. ESI/APCI(+): 464 (M+H). ESI/APCI(-): 462 (M-H).
EXAMPLE 129: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(5-methyl-1H-indol-3-yl)-2phenylethanone
Step 1: fert-Butyl 3-formyl-5-methyl-1/-/-indole-1-carboxylate was prepared according to general procedure F from 5-methyl-1/-/-indole-3-carbaldehyde (0.478 g; 3.003 mmol), di-fert-butyl dicarbonate (0.524 g; 3.602 mmol) and DMAP (0.036 g; 0.295 mmol) in acetonitrile (8 mL) to afford 0.710 g (91%) of the desired compound as a solid. 1H NMR (DMSO-c/6) δ 10.06 (1H, s); 8.61 (1H, s); 7.91-8.03 (2H, m); 7.27 (1H, d); 2.43 (3H, s); 1.66 (9H, s).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(5-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.498 mmol) in éthanol (1 mL), fert-butyl 3-formyl-5-methyl-1H-îndole-1-carboxylate (0.259 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from methyl fert-butyl ether furnished 0.053 g (14%) of the desired compound as a solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).
EXAMPLE 130: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)2-phenylethanone
Step 1: 2-Chloro-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure A from 5-fluoro-1H-indole (1.000 g; 7.400 mmol), pyridine (0.120 mL; 7.419 mmol) and α-chlorophenylacetyl chloride (1.100 mL; 7.390 mmol) in toluene (19 mL). Purification by précipitation furnished 0.978 g (46%) of the desired compound as a light yellow solid. ESI/APCI(+): 288, 290 (M+H); 310, 312 (M+Na). ESI/APCI(-): 286, 288 (M-H).
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1 -(5-fluoro-1 H-indol-3-yl)-2-phenylethanone was prepared according to general method E from 2-chloro-1-(5-fluoro-1H-indol-3-yl)-2phenylethanone (0.100 g; 0.348 mmol) and 3,5-dimethoxyaniline (0.484 g; 3.160 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150qC for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished
183
0.045 g (32%) of the desired compound as a beige solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).
EXAMPLE 131: PREPARATION OF 4-(2-( 1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2oxoethyl)-2-fluorobenzonitrile
Step 1: A solution of 2-fluoro-4-(((3-methoxyphenyl)-imino)methyl)benzonitrile in éthanol was prepared by heating a solution of 2-fluoro-4-formylbenzonitrile (0.137 g; 0.919 mmol) and 3methoxyaniline (0.107 mL; 0.952 mmol) in éthanol (1 mL) at 60 °Cfor 18 h. The formation ofthe imine was quantitative and the solution was used without further purification. ESI/APCI (+): 255 (M+H).
Step 2: 4-(2-(1 H-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-2-fluorobenzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.124 g; 0.460 mmol) and triethylamine (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.260 g; 1.060 mmol) and a solution of 2-fluoro-4-(((3-methoxyphenyl)-imino)methyl)benzonitrile (0.919 mmol) in éthanol (1.5 mL), heated at 60 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane furnished 0.154 g (42%) of the desired compound as a yellow foam. ESI/APCI(+): 400 (M+H). ESI/APCI(-): 398 (M-H).
EXAMPLE 132: PREPARATION OF 4-(2-( 1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2oxoethyl)-3,5-difluorobenzonitrile
Step 1: A solution of 3,5-difluoro-4-(((3-methoxyphenyl)-imino)methyl)benzonitrile in éthanol was prepared by heating a solution of 3,5-difluoro-4-formylbenzonitrile (0.151 g; 0.904 mmol) and 3-methoxyaniline (0.105 mL; 0.934 mmol) in éthanol (1 mL) at 60 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 273 (M+H).
Step 2: 4-(2-(1 H-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-3,5-difluorobenzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.124 g; 0.460 mmol) and triethylamine (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1/-/-indole-1-carboxylate (0.260 g; 1.060 mmol) and a solution of 3,5-difluoro-4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.904 mmol) in éthanol (1.5 mL), heated at 60 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane furnished 0.214 g (58%) of the desired compound as a yellow oil. ESI/APCI(+): 418 (M+H).
EXAMPLE 133: PREPARATION OF 1-(6-hydroxy-1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1 :
6-((tert-Butyldimethylsilyl)oxy)-1H-indole was prepared according to general procedure N from
6-hydroxyindole (0.500 g; 3.755 mmol), DBU (0.573 mL; 3.839 mmol) and TBDMSCI (1.150 g;
184
7,630 mmol) in THF (13 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished 0.888 g (96%) of the desired compound as a white solid. ESI/APCI(+): 248 (M+H). ESI/APCI(-): 246 (M-H).
Step 2:
1-(6-((tert-Butyldimethylsilyl)oxy)-1 H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to general procedure A from 6-((tert-butyldimethylsilyl)oxy)-1 H-indole (0.785 g; 3.173 mmol), pyridine (0.275 mL; 3.276 mmol) and α-chlorophenylacetyl chloride (0.547 mL; 3.461 mmol) in toluene (8 mL). The residue obtained after extraction was purified by précipitation from ethyl acetate to give 0.669 g (53%) of the desired compound as a white solid. ESI/APCI(+): 400, 402 (M+H); 422, 424 (M+Na). ESI/APCI(-): 398, 400 (M-H).
Step 3: 1-(6-((fert-Butyldimethylsilyl)oxy)-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 1-(6-((fert-butyldimethylsilyl)oxy)-1H-indol3-yl)-2-chloro-2-phenylethanone (0.300 g; 0.750 mmol) and 3-methoxyaniline (1.680 mL; 15.02 mmol) in acetonitrile (3 mL), irradiated in a microwave oven at 150 'C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 50%) in heptane furnished 0.200 g (55%) of the desired compound as a beige powder. ESI/APCI(+): 487 (M+H); 509 (M+Na). ESI/APCI(-): 485 (M-H).
Step 4:
To a solution of 1-(6-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone (0.200 g; 0.411 mmol) in DMF (3.5 mL) was added césium fluoride (0.312 g; 2.054 mmol). After 2.5 h at room température, the réaction mixture was concentrated. The residue was partitioned between ethyl acetate and a 1N hydrochloric acid solution. The phases were separated. The organic phase was washed with a saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane followed by recrystallization from ethyl acetate and heptane furnished 0.020 g (13%) of 1-(6-hydroxy-1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone as a grey powder. ESI/APCI(+): 373 (M+H); 395 (M+Na). ES1/APCI(-): 371 (M-H).
EXAMPLE 134: PREPARATION OF 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-rndole-
6-carboxylic acid
To a solution of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate (0.100 g; 0.241 mmol) in a mixture of THF (3 mL) and methanol (3 mL) was added a 6N sodium hydroxide solution (1.500 mL; 9.000 mmol) and the mixture was refluxed for 3 h. The reaction mixture was partially concentrated under reduced pressure. The remaining aqueous solution was acidified with a 1N hydrochloric acid solution to pH 2-3. The precipitate was filtered, washed with water and dried. Further purification of the precipitate by préparative HPLC
185 (XBridge column; method 2) furnished 0.020 g (21%) of 3-(2-((3-methoxyphenyl)amino)-2phenylacetyl)-1H-indole-6-carboxylic acid as a white solid. ESI/APCI(+): 401 (M+H). ESI/APCI(): 399 (M-H).
EXAMPLE 135: PREPARATION OF 1-(1-(2-methoxyethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: 2-Chloro-1-(1-(2-methoxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general method M from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol), 1-bromo-2-methoxyethane (0.206 g; 1.482 mmol) and potassium carbonate (0.205 g; 0.183 mmol) in DMF (3 mL). The reaction mixture was stirred at room température ovemight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.115 g (47%) of the desired compound as a beige solid. ESi/APCI(+): 350, 352 (M+Na). ESI/APCI(-): 326, 328 (M-H).
Step 2: 1-(1-(2-Methoxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(1-(3-hydroxypropyl)-1H-indol3-yl)-2-phenylethanone (0.050 g; 0.153 mmol), 3-methoxyaniline (0.354 mL; 3.150 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 15 min. Purification by flash chromatography on silica gel using 5% ethyl acetate in dichloromethane as eluent followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.025 g (39%) of the desired compound as a white solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H). 1H NMR (DMSO-dç) δ 8.95 (1H, s); 8.17 (1H, d); 7.57-7.68 (3H, m); 7.11-7.33 (5H, m); 6.92 (1 H, t); 6.34-
6.46 (3H, m); 6.11 (1H, d); 6.05 (1 H, d); 4.45 (2H, br s); 3.73 (2H, m); 3.62 (3H, s); 3.23 (3H, s).
EXAMPLE 136: PREPARATION OF 1-(5-fluoro-1-methyl-1 H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: 2-Chloro-1-(5-fluoro-1-methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general method M from 2-chloro-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.695 mmol), iodomethane (0.216 mL; 3.470 mmol) and potassium carbonate (0.192 g; 1.389 mmol) in DMF (3 mL). The reaction mixture was stirred at room température ovemight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 50%) in heptane furnished 0.076 g (36%) of the desired compound as a beige solid. ESI/APCI(+): 302, 304 (M+H); 324, 326 (M+Na). ESI/APCI(-): 300, 302 (M-H).
Step 2: 1 -(5-Fluoro-1 -methyl-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(5-fluoro-1-methyl-1 H-indol-3-yl)-2phenylethanone (0.070 g; 0.232 mmol), 3-methoxyaniline (0.519 mL; 4.619 mmol) in acetonitrile (1 mL), irradiated at 150 °C for 30 min. Purification by two flash chromatography on silica gel using first a gradient of ethyl acetate (5% to 50%) in heptane and then a gradient of dichloromethane (15% to 70%) in heptane followed by précipitation from tert-butyl methyl ether furnished 0.020 g (22%) of the desired compound as a beige solid. ESI/APCI(+): 389 (M+H).
186
ESIZAPCI(-): 387 (M-H). 1H NMR (DMSO-dg) δ 8.99 (1H, s); 7.79-7.88 (1H, dd); 7.63 (2H, d); 7.54-7.61 (1H, m); 7.25-7.35 (2H, m); 7.10-7.24 (2H, m); 6.92 (1H, t); 6.33-6.44 (3H, m); 6.11 (1H, d); 5.99 (1 H. d); 3.91 (3H, s); 3.62 (3H, s).
EXAMPLE 137: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(mtolyljethanone
Step 1: A solution of 3-methoxy-/V-(3-methylbenzylidene)aniline in éthanol was prepared by heating a solution of 3-methylbenzaldehyde (0.120 mL; 1.019 mmol) and 3-methoxyanîline (0.120 mL; 1.068 mmol) in éthanol (1 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 226 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-rnethoxyphenyl)amino)-2-(m-tolyl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-lum chloride (0.140 g; 0.519 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.101 mmol) and a solution of 3methoxy-/V-(3-methylbenzylidene)aniline (1.019 mmol) in éthanol (1.5 mL), heated 60 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 30%) in heptane followed by préparative HPLC (XBridge column; method 1 ) furnished 0.085 g (23%) of the desired compound. ESI/APCI(+): 371 (M+H). ESIZAPCl(-): 369 (M-H).
EXAMPLE 138: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(ptolyl)ethanone
Step 1: A solution of 3-methoxy-A/-(4-methylbenzylidene)aniline in éthanol was prepared by heating a solution of 4-methylbenzaldehyde (0.120 mL; 1.014 mmol) and 3-methoxyaniline (0.120 mL; 1.068 mmol) in éthanol (1 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 226 (M+H).
Step 2: 1-(1/7-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(p-tolyl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.138 g; 0.512 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.274 g; 1.117 mmol) and a solution of 3methoxy-/V-(4-methylbenzylidene)aniline (1.014 mmol) in éthanol (1.5 mL), heated at 60 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane followed by précipitation from acetone and heptane furnished 0.085 g (23%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H). ESIZAPCI(-): 369 (M-H).
EXAMPLE 139: PREPARATION OF 1-(6-(hydroxymethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1 : To a suspension of lithium aluminium hydride (0.866 g; 22.82 mmol) in dry THF (30 mL) cooled at 0 °C was added a solution of methyl 1H-indole-6-carboxylate (2.000 g; 11.42 mmol) in
THF (30 mL) under nitrogen atmosphère. The reaction mixture was stirred at room température overnight. The reaction was quenched by careful addition of a 1N Rochelle sait solution. The
187 reaction mixture was stirred at room température for 2 h and was then extracted with dichloromethane. The phases were separated. The organic phase was dried over magnésium sulfate and evaporated under reduced pressure to afford 2.050 g of (1H-indolyl-6-yl)methanol as a yellow oil which was used in the next step without further purification. ESI/APCI(-): 146 (ΜΗ).
Step 2: To a solution of (1H-indol-6-yl)methanol (0.500 g; 3.397 mmol) in dry THF (20 mL) cooled at 0 °C was added portionwise sodium hydride (60% in minerai oil; 0.271 g; 6.775 mmol). After stirring for 5 min, TBDMSCI (0.512 g; 3.397 mmol) was added. The resulting solution was stirred at room température for 1 h. The reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, dried over magnésium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 20%) in heptane furnished 0.482 g (46% over 2 steps) of 6-(((tertbutyldimethylsilyl)oxy)methyl)-1H-indole as a white solid. ESI/APCI(+): 262 (M+H). ESI/APCI(-): 260 (M-H).
Step 3: 2-Chloro-1-(6-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure A from 6-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole (0.265 g; 1.014 mmol), pyridine (0.082 mL; 1.014 mmol) and α-chlorophenylacetyl chloride (0.151 mL; 1,014 mmol) in toluene (2.6 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 100%) in heptane furnished 0.064 g (21%) of the desired compound. ESI/APCI(+): 300, 302 (M+H); 322, 324 (M+Na). ESI/APCI(-): 298, 300 (M-H). 1H NMR (DMSOd6) δ 12.15 (1H, br s); 8.61 (1H, d); 8.09 (1H, d); 7.63 (2H, d); 7.25-7.48 (5H, m); 7.16 (1H, d);
6.73 (1H, s); 5.20 (1H, t); 4.58 (2H, d).
Step 4: 1-(6-(Hydroxymethyl)-1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(6-(hydroxymethyl)-1H-indol-3-yl)-2phenylethanone (0,060 g; 0.200 mmol) and 3-methoxyaniline (0,448 mL; 3.987 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 130 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane and followed by another purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.021 g (27%) of the desired compound as a beige solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).
EXAMPLE 140; PREPARATION OF 1-(6-(2-hydroxyethoxy)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: To a solution of 6-hydroxyindole (0.645 g; 4.844 mmol) in acetone (25 mL) were added potassium carbonate (1.350 g; 9.768 mmol) and ethyl bromoacetate (1.000 mL; 9.018 mmol). The reaction mixture was refluxed overnight. After cooling to room température, the reaction
188 mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished ethyl 2-((1 H-indol-6-yl)oxy)acetate contaminated with the dialkylated product as a pink oil. This mixture was used in the next step without further purification. ESI/APCI(+): 220 (M+H); 242 (M+Na). ESI/APCI(-): 218 (M-H).
Step 2: To a suspension of lithium alumininîum hydride (0.406 g; 10.97 mmol) in THF cooled at 0 °C was added dropwise a solution of ethyl 2-((1/7-indol-6-yl)oxy)acetate (crude, 4.844 mmol) in THF (15 mL) over 25 min. After one night at room température, the reaction mixture was diluted with diethyl ether and cooled to 0 °C. A 1M Rochelle sait solution was added and the reaction mixture was stirred at room température for 2 h. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 90%) in heptane furnished 0.586 g (68% over 2 steps) of 2-((1 H-indol-6-yl)oxy)ethanol as a pink powder. ESI/APCI(+): 178 (M+H); 200 (M+Na). ESI/APCI(-): 176 (M-H). ’H NMR (DMSO-d6) δ
10.84 (1H, s); 7.39 (1 H, d); 7.18 (1H, s); 6.89 (1H, s); 6.66 (1H, d); 6.32 (1H, s), 4.85 (1H, m), 3.98 (2H, m); 3.73 (2H, m).
Step 3: 6-(2-((fert-Butyldimethylsilyl)oxy)ethoxy)-1H-indole was prepared according to general procedure N from 2-((1 H-indol-6-yl)oxy)ethanol (0.581 g; 3.279 mmol), DBU (0.500 mL; 3.350 mmol) and TBDMSCI (1.000 g; 6.635 mmol) in THF (12 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished 0.757 g (79%) of the desired compound as a pink solid. ES1/APCI(+); 292 (M+H); 314 (M+Na). ESI/APCI(-): 290 (M-H).
Step 4: 1-(6-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1H-îndol-3-yl)-2-chloro-2-phenylethanone was prepared according to general procedure A from 6-(2-((tert-butyldimethylsiiyl)oxy)ethoxy)1H-indole (0.400 g; 1.372 mmol), pyridine (0.115 mL; 1.422 mmol) and a-chlorophenylacetyl chloride (0.240 mL; 1.536 mmol) in toluene (3.5 mL). The residue obtained after extraction was purified by précipitation from ethyl acetate and heptane. Further purification by recrystallization from ethyl acetate furnished 0.060 g (10%) of the desired compound as a beige powder. The filtrate of the recrystallization was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 80%) in heptane to give 0.066 g of the desired compound (11%) as a pink powder. ESI/APCI(+): 444, 446 (M+H); 466, 468 (M+Na). ESI/APCl(-): 442, 444 (M-H).
Step 5: 1 -(6-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone was prepared according to general procedure E from 1-(6-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-1H-indoi-3-yl)-2-chloro-2-phenylethanone (0.242 g; 0.545 mmol) and 3-methoxyaniline (1.157 mL; 10.344 mmol) in acetonitrile (2.6 mL), irradiated in a microwave oven at 150 °C for 30 min. Purification by flash chromatography on silica gel using a
189 gradient of ethyl acetate (20% to 50%) in heptane furnished 0.099 g (34%) of the desired compound as a beige powder. ESI/APCI(+): 487 (M+H); 509 (M+Na). ESI/APCI(-): 485 (M-H). Step 6: To a solution of 1-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone (0.099 g; 0.186 mmol) in dichloromethane (2.75 mL) cooled to 0 °C was added a 4N hydrogen chloride solution in dioxane (0.645 mL; 2.580 mmol). After 2.5 h at room température, the reaction mixture was diluted with dichloromethane and basified with a 2N sodium hydroxide solution. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 95%) in heptane furnished 0.043 g (55%) of 1-(6-(2-hydroxyethoxy)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone as a yellow oil. ESI/APCI(+): 417 (M+H); 439 (M+Na); 855 (2M+Na). ESIZAPCi(-): 415 (M-H). 1H NMR (DMSO-de) δ 11.92 (1H, s); 8.75 (1 H. s); 8.00 (1H, d); 7.63 (1H, d); 7.28 (2H, m); 7.19 (1 H, m); 6.92 (3H, m); 6.08 (2H, m); 4.86 (1H, t); 3.98 (2H,t); 3.72 (2H,q); 3.62 (3H, s).
EXAMPLE 141: PREPARATION OF methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1Hindole-5-carboxylate
Step 1: Methyl 3-(2-chloro-2-phenylacetyl)-1F/-indole-5-carboxylate was prepared according to general procedure A from methyl 1H-indole-5-carboxylate (2.000 g; 11.42 mmol), pyridine (0.923 mL; 11.42 mmol) and α-chlorophenylacetyl chloride (1.676 mL; 11.42 mmol) in toluene (30 mL). Précipitation by précipitation furnished 0.324 g (9%) of the desired compound as a pink solid. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H). 1H NMR (DMSO-d6) δ 12.53 (1H, br. s); 8.87 (1H, s); 8.76 (1H, d); 7.87 (1H, dd); 7.54-7.69 (3H, m); 7.29-7.45 (3H, m); 6.79 (1H,s); 3.88 (3H, s).
Step 2: Methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-îndole-5-carboxylate was prepared according to general procedure E from methyl 3-(2-chloro-2-phenylacetyl)-1H-indole-
5-carboxylate (0.100 g; 0.305 mmol) and 3-methoxyaniline (0.683 mL; 6,101 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0% to 100%) in heptane followed by précipitation from ethyl acetate furnished 0.040 g (32%) of the desired compound as a white solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H)
EXAMPLE 142: PREPARATION OF methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1Hindole-5-carboxylate
To a solution of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carboxylate (0,028 g; 0.068 mmol) in a mixture of methanol (0.5 mL) and THF (0.5 mL) was added a 6N sodium hydroxide solution (0.250 mL; 1.500 mmol). The mixture was refluxed for 3 h and was concentrated under reduced pressure. The residue was dissolved in water and acidified with a 1N hydrochloric acid solution. The resulting precipitate was filtered and washed with water.
190
Further purification by préparative HPLC (XBridge column; method 2) furnished 0.007 g (22%) of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carboxylic acid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H).
EXAMPLE 143: PREPARATION OF 2-(2-fluorophenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A solution of /V-(2-fluorobenzylidene)-3-methoxyaniline was prepared by heating a solution of 2-fluorobenzaldehyde (0.105 mL; 0.998 mmol) and 3-methoxyaniline (0.120 mL; 1.068 mmol) in éthanol (1 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 230 (M+H)
Step 2: 2-(2-Fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.139 g; 0.515 mmol) and triethylamine (0.100 mL; 0.717 mmol), in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.272 g; 1.109 mmol) and a solution of N-(2-fluorobenzylidene)-3-methoxyaniline (0.998 mmol) in éthanol (1.5 mL), heated at 60 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 35%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.037 g (10%) ofthe desired compound as a beige solid. ESI/APCI (+): 375 (M+H). ESI/APCI (-): 373 (M-H)
EXAMPLE 144: PREPARATION OF 1-(5-fluoro-1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2((3-methoxyphenyl)amino)-2-phenylethanone
Step 1: 2-Chloro-1 -(5-fluoro-1 -(2-(methoxymethoxy)ethyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure M from 2-chloro-1-(5-fluoro-1W-indol-3-yl)-2phenylethanone (0.200 g; 0.695 mmol), 1-bromo-2-(methoxymethoxy)ethane (0.235 g; 1.390 mmol) and potassium carbonate (0.288 g; 2.084 mmol) in DMF (5 mL). The reaction mixture was stirred at room température for 4 h and was heated at 60 °C for 2 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.070 g (27%) of the desired compound as an oil. ESI/APCI(+): 376, 378 (M+H); 398, 400 (M+Na). ESI/APCI(-): 374, 376 (M-H).
Step 2: 1-(5-Fluoro-1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to general procedure E from 2-chloro-1-(5-fluoro-1-(2(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.070 g; 0.186 mmol), 3methoxyanlline (0.417 mL; 3.711 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.036 g (42%) of the desired compound as a red solid. ESI/APCI(+): 463 (M+H); 485 (M+H). ESI/APCI(-): 461 (M-H).
EXAMPLE 145: PREPARATION OF 1-(5-fluoro-1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
191
-(5-FI uoro-1 -(2-(methoxymethoxy)ethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone (0.036 g; 0.078 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3 mL; 12.00 mmol). The reaction mixture was stirred at room température for 4 h. The reaction mixture was neutralized with potassium carbonate, diluted with ethyl acetate and washed with water. The phases were separated. The organic layer was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.015 g (45%) of 1 -(5fluoro-1-(2-hydroxyethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone as a white solid. ESl/APCI(+): 419 (M+H); 441 (M+Na). ESIZAPCI(-): 417 (M-H).
EXAMPLE 146: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1 -(1-(2(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-phenylethanone
Step 1: 2-Chloro-1-(1-(2-(methoxymethoxy)ethyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure M from 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.300 g; 1,112 mmol), 1-bromo-2-(methoxymethoxy)ethane (0.375 g; 2.218 mmol) and potassium carbonate (0.461 g; 3.336 mmol) in DMF (5 mL). The reaction mixture was stirred at room température for 4 h and was heated at 60 °C for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.144 g (36%) of the desired compound as an oil. ESI/APCI(+): 358, 360 (M+H); 380, 382 (M+Na). ESI/APCI(): 356, 358 (M-H).
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1-(1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2phenylethanone was prepared according to general procedure E from 2-chloro-1-(1-(2(methoxymethoxy)ethyl)-1H-îndol-3-yl)-2-phenylethanone (0.070 g; 0.196 mmol), 3,5dimethoxyaniline (0.300 g; 1.958 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 130 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.038 g (41%) of the desired compound as a beige solid. ESI/APCI(+): 463 (M+H); 485 (M+H). ESI/APCI(-): 461 (M-H).
EXAMPLE 147: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1-(2-hydroxyethyl)-1Hindol-3-yl)-2-phenylethanone
2-((3,5-Dimethoxyphenyl)amino)-1-(1-(2-(methoxymethoxy)ethyi)-1/7-indol-3-yl)-2phenylethanone (0.036 g; 0.079 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3 mL; 12.00 mmol). The reaction mixture was stirred at room température for 4 h. The reaction mixture was neutralized with potassium carbonate, diluted with ethyl acetate and washed with water. The phases were separated. The organic layer was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.005 g (15%) of 2
192 ((3l5-dimethoxyphenyl)amino)-1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 431 (M+H).
EXAMPLE 148: PREPARATION OF 2-(4-fluorophenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A solution of N-(4-fluorobenzylidene)-3-methoxyaniline in éthanol was prepared by heating a solution of 4-fluorobenzaldehyde (0.156 g; 1.257 mmol) and 3-methoxyaniline (0.140 mL; 1.253 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 230 (M+H). Step 2: 2-(4-Fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.170 g; 0.630 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.350 g; 1.136 mmol) and a solution of A/-(4-fluorobenzylidene)-3-methoxyaniline (1.253 mmol) in éthanol (1.5 mL), heated at 60 °C for 4 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane furnished 0.120 g (26%) of the desired compound as a yellow solid. ESI/APCI(+): 375 (M+H).
EXAMPLE 149: PREPARATION OF 1-(6-chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2((3-methoxyphenyl)amino)ethanone
1-(6-Chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.156 g; 0.542 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 6-chloro-3-formyl-1H-indole-1-carboxylate (0.319 g; 1.140 mmol) and a solution of /V-(imidazo[1,2-a]pyridin-2-ylmethylene)-3-methoxyaniline (1.068 mmol) in éthanol (1.5 mL), heated at 60 °C for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 70%) in heptane followed by précipitation from ethyl acetate and heptane furnished 0.052 g (11%) of the desired compound as a white solid. ESI/APCI(+): 431, 433 (M+H). ESI/APCI(-): 429, 431 (M-H).
EXAMPLE 150: PREPARATION OF 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyridin-3-yl)ethanone
1-(5-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.067 g; 0.248 mmol) and triethylamine (0.035 mL; 0.252 mmol) in éthanol (0.37 mL), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.158 g; 0.600 mmol) and a solution of 3-methoxy-N-(pyridin-3-ylmethylene)aniline (0.499 mmol) in éthanol (0.75 mL), heated at 70 °C for 20 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.036 g (19%) of the desired compound as a white solid. ESI/APCI(+): 376 (M+H); 398 (M+Na).
193
ESl/APCI(-): 374 (M-H).
EXAMPLE 151: PREPARATION OF 1-(6-fluoro-1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyridin-3-yl)ethanone
1-(6-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.067 g: 0.248 mmol) and triethylamine (0.035 mL; 0.252 mmol) in éthanol (0.37 mL), tert-butyl 6-fluoro-3-formyl-1/7-indole-1-carboxylate (0.158 g; 0.600 mmol) and a solution of 3-methoxy-/V-(pyridin-3-ylmethylene)aniline (0.499 mmol) in éthanol (0.75 mL), heated at 70 °C for 20 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.045 g (24%) of the desired compound as a yellow solid. ESI/APCI(+): 376 (M+H); 398 (M+Na). ESI/APCI(-): 374 (M-H).
EXAMPLE 152: PREPARATION OF 1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyridin-3-yl)ethanone
Step 1: The synthesis was performed as described in W02009/015067. To a solution of DMF (0,600 mL; 7.749 mmol) in dichloromethane (2 mL) cooled at -15 °C was added dropwise phosphorus oxychloride (0.350 mL; 3.748 mmol). After 15 min at -15 °C, 7-fluoroindole (0.497 g; 3.678 mmol) was added portionwise. The réaction mixture was then allowed to warm to room température and was stirred at room température ovemight. The réaction mixture was basified with a 1N sodium hydroxide solution to pH 8 and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate and with a mixture of methanol in dichloromethane. The organic phases were combined, washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to yield 0.078 g of a yellow solid. After 24 h, the precipitate in the aqueous phase was filtered to yield 0.264 g of a white solid. The filtrate was basified with a 1N sodium hydroxide solution to pH 12 and was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to yield 0.290 g of a yellow solid. The three solids were mixed, adsorbed on silica gel and purified by flash chromatography on silica gel using 40% ethyl acetate in heptane as eluent to give 0.485 g (81%) of 7-fluoro-1H-indole-3-carbaldehyde as a pink solid. ESI/APCI(+): 164 (M+H). ESI/APCI(-): 162 (M-H).
Step 2: tert-Butyl 7-fluoro-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 7-fluoro-1H-îndole-3-carbaldehyde (0.485 g; 2.973 mmol), di-tert-butyl dicarbonate (0.780 g; 3.574 mmol) and DMAP (0.046 g; 0.377 mmol) in acetonitrile (9 mL) to afford 0.687 g (88%) of the desired compound as a beige solid. 1H NMR (DMSO-d6) δ 10.08 (1H, s); 8.77 (1H, s); 8.01 (1H, d); 7.25-7.43 (2H, m); 1.64 (9H, s).
Step 3: 1 -(7-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-416765
194 methylthiazol-3-ium chloride (0.067 g; 0.248 mmol) and triethylamine (0.035 mL; 0.252 mmol) in éthanol (0.37 mL). fert-butyl 7-fluoro-3-formyl-1H-indole-1-carboxylate (0.158 g; 0.600 mmol) and a solution of 3-methoxy-A/-(pyridin-3-ylmethylene)aniline (0.499 mmol) in éthanol (0.75 mL), heated at 70 QC for 20 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.033 g (18%) of the desired compound as a white powder. ESI/APCI(+): 376 (M+H); 398 (M+Na). ESI/APCI(-): 374 (M-H).
EXAMPLE 153: PREPARATION OF 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(6-methoxypyridin-3-yl)ethanone
-(5-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.034 g; 0.125 mmol) and triethylamine (0.013 mL; 0.093 mmol) in éthanol (0.25 mL), fert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.066 g; 0.251 mmol) and a solution of 3-methoxy-/V-((6-methoxypyridin-3-yl)methylene)aniline (0.248 mmol) in éthanol (0.25 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.004 g (4%) of the desired compound as a beige solid. ESI/APCI(+): 406 (M+H). ESI/APC!(-): 404 (M-H).
EXAMPLE 154: PREPARATION OF 1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(6-methoxypyridin-3-yl)ethanone
-(7-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.034 g; 0.125 mmol) and triethylamine (0.013 mL; 0.093 mmol) in éthanol (0.25 mL), fert-butyl 7-fiuoro-3-formyl-1H-indole-1-carboxylate (0.066 g; 0.251 mmol) and a solution of 3-methoxy-A/-((6-methoxypyridin-3-yl)methylene)aniline (0.248 mmol) in éthanol (0.25 mL), heated at 70 ’C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.005 g (5%) of the desired compound as a beige solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).
EXAMPLE 155: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1-(3hydroxypropyl)-1W-indol-3-yl)-2-phenylethanone
Step 1: 2-Chloro-1-(5-fluoro-1-(3-hydroxypropyl)-1F/-indol-3-yl)-2-phenylethanone was prepared according to general method M from 2-chloro-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.695 mmol), 3-bromopropan-1-ol (0.193 g; 1.389 mmoi) and potassium carbonate (0.192 g; 1.389 mmol) in DMF (5 mL). The reaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in dichloromethane furnished 0.219 g (91%) of the desired compound as a brown
195 oil. ESI/APCI(+): 346. 348 (M+H); 368, 370 (M+Na).
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1 -(5-fluoro-1 -(3-hydroxypropyl)-1 /-/-indol-3-yl)-2phenylethanone was prepared according to general procedure E from 2-chloro-1-(5-fluoro-1-(3hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.125 g; 0.361 mmol), 3,5-dimethoxyaniline (0.554 g; 3.617 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 130 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in dichloromethane followed by a second purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.032 g (19%) of the desired product as a white solid. ESI/APCl(+): 463 (M+H).
EXAMPLE 156: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-
2- phenylethanone
-(6-Fluoro-1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.067 g; 250 mmol) and triethylamine (0.035 mL; 0.250 mmol) in éthanol (1 mL), tert-butyl 6-fluoro-3-formyl-1/-/-indole-1 -carboxylate (0.132 g; 0.500 mmol) and a solution of Nbenzylidene-5-methoxypyridin-3-amine (0.500 mmol) in éthanol (1 mL), heated at 70 °C for 18 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by précipitation from dichloromethane furnished 0.017 g (9%) of the desired compound as a beige solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).
EXAMPLE 157: PREPARATION OF 1-(1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5methoxypyridin-3-yl)amino)ethanone
Step 1: A mixture of 6-methoxynicotinaldehyde (0.137 g; 0.999 mmol) and 5-methoxypyridin-3amine (0.124 mg; 0.999 mmol) in éthanol (1.5 mL) was heated at 60 °C for 6 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum over phosphorus(V) oxide to give quantîtatively 5-methoxy-A/-((6-methoxypyridin-3-yl)methylene)pyridine-3-amine which was used without further purification in the next step. ESI/APCI (+): 244 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0.134 g; 0.500 mmol) and triethylamine (0.069 mL; 0.496 mmol) in éthanol (2 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 5-methoxy-/V-((6-methoxypyridin-3-yl)methylene)pyridine-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 ’C for 18 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 15%) in dichloromethane followed by précipitations from diethyl ether and dichloromethane furnished 0.025 g (6%) of the desired compound as a beige solid. ESI/APCK+): 389 (M+H). ESI/APCI(-): 387 (M-H).
EXAMPLE 158: PREPARATION OF 4-(2-( 1H-indol-3-yl)-1-((5-methoxypyridin-3-yl)amino)-2oxoethyl)benzonitrile
196
Step 1: A mixture of 4-formylbenzonitrile (0.131 g; 0.999 mmol) and 5-methoxypyridin-3-amine (0.124 mg; 0.999 mmol) in éthanol (1.5 mL) was heated at 60 °C for 6 h. The reaction mixture was concentrated under reduced pressure and was dried under vacuum over phosphorus(V) oxide to give quantitatively 4-(((5-methoxypyridin-3-yl)imino)methyl)benzonitrile which was used without further purification in the next step. ESI/APCI (+): 238 (M+H).
Step 2: 4-(2-(1 H-lndol-3-yl)-1-((5-methoxypyridin-3-yl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.134 g; 0.500 mmol) and triethylamine (0.069 mL; 0.496 mmol) in éthanol (2 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 4-(((5-methoxypyridin-3-yl)imino)methyl)benzonitrile (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 18 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 7%) in dichloromethane followed by précipitation from diethyl ether furnished 0.132 g (34%) of the desired compound as a white solid. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (ΜΗ).
EXAMPLE 159: PREPARATION OF 1-(benzo[b]thiophen-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1: To a solution of thianaphthene (0.300 g; 2.235 mmol) and phenylacetyl chloride (0.300 mL; 2.266 mmol) in dichloroethane (5 mL) cooled at 0 ’C was added portionwise aluminum trichloride (0.894 g; 6.705 mmol) over 2 h. The reaction mixture was then stirred at room température overnight. A 1M Rochelle sait solution was added and the reaction mixture was stirred at room température for 1 h. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (30% to 90%) in heptane furnished 0.239 g (42%) of 1-(benzo[b]thiophen-3yl)-2-phenylethanone as a white solid. ESI/APCI(+): 253 (M+H); 275 (M+Na). ESI/APCI(-): 251 (M-H). 1H NMR (CDCI3)Ô 8.78 (1H, d); 8.37 (1H, s); 7.85 (1H, d); 7.5-7.2 (7H, m); 4.30 (2H, s).
Step 2:1-(Benzo[b]thiophen-3-yl)-2-bromo-2-phenylethanone has been prepared according to 2 different procedures described hereunder as method A and method B.
Method A.
To a solution of 1-(benzo[b]thiophen-3-yl)-2-phenylethanone (0.100 g; 0.396 mmol) in THF (4 mL) cooled to 0 °C was added dropwise a solution of phenyltrimethylammonîum tribromide (0.171 g; 0.455 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 15 min and at room température for 1 h. The reaction mixture was filtered and the solid was washed with diethyl ether. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was washed with water. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of
197 dichloromethane (20% to 80%) in heptane furnished 0,114 g of a mixture containing 1(benzo[b]thiophen-3-yl)-2-bromo-2-phenylethanone as a brown oil. ESI/APCI(+): 331,333 (M+H). 1H NMR (DMSO-de) δ 9.27 (1H, s); 8.61 (1 H, d); 8.11 (1H, d); 7.7-7.1 (7H, m); 7.17 (1 H,
s) (80% purity).
Method B.
To a solution of 1-(benzo[b]thiophen-3-yl)-2-phenylethanone (0.108 g; 0.428 mmol) in ethyl acetate (2 mL) was added copper(ll) bromide (0.162 g; 0.725 mmol). The reaction mixture was refluxed for 2.5 h. After cooling to room température, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (30% to 80%) in heptane furnished 0.102 g of a mixture containing 1-(benzo[b]thiophen-3-yl)-2-bromo-2phenylethanone (same purity as in method A) as a brown oil.
Step 3: 1-(Benzo[b]thiophen-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure C from 1-(benzo[b]thiophen-3-yl)-2-bromo-2-phenylethanone (0.050 g; 0.151 mmol), DIPEA (0.052 mL; 0.298 mmol) and 3-methoxyaniline (0.034 mL; 0.303 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 200 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 50%) in heptane followed by a second purification by flash chromatography on silica gel using a gradient of dichloromethane (20% to 90%) in heptane furnished 0.029 g (44% over two steps) of the desired product as a yellow oil. ESI/APCI(+): 374 (M+H); 396 (M+Na). ESI/APCI(-): 372 (M-H). 1H NMR (DMSO-de) δ 9.51 (1 H, s); 8.53 (1H. d); 8.07 (1 H, d); 7.6-7.2 (7H. m); 6.94 (1H, t); 6.42 (4H, m); 6.14 (1H, dd); 3.63 (3H, s).
EXAMPLE 160: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3b]pyridin-3-yl)ethanone
Step 1: tert-Butyl 3-formyl-1/-/-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared according to general procedure F from 7-azaindole-3-carboxaldehyde (0.500 g; 3.421 mmol), di-fert-butyl dicarbonate (0.896 g; 4.105 mmol) and DMAP (0.042 g; 0.342 mmol) in acetonitrile (8 mL) to afford 0.779 g (92%) of the desired compound as a white solid. ESI/APCI(+): 269 (M+Na).
Step 2: 2-((3-Methoxyphenyl)amïno)-2-phenyl-1-(1H-pyrrolo[2I3-b]pyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.114 g; 0.423 mmol) and triethylamine (0.059 mL; 0.423 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1/7-pyrrolo[2,3-b]pyridine-1-carboxylate (0.250 g; 1.015 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.846 mmol) in éthanol (0.5 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by a second purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane
198 furnished 0.028 g (9%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 161: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2b]pyridin-3-yl)ethanone
Step 1: A mixture of 4-azaindole (0.500 g; 4.223 mmol), hexamethylenetetramine (0.890 g; 6.348 mmol) and acetic acid (3.630 mL; 63.45 mmol) in water (9 mL) was refluxed for 4 h. The reaction mixture was cooled to room température and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (2% to 4%) in dichloromethane furnished 0.550 g (89%) of 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H).
Step 2: tert-Butyl 3-formyl-1H-pyrrolo[3,2-b]pyrîdine-1-carboxylate was prepared according to general procedure F from 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (0.550 g; 3.763 mmol), ditert-butyl dicarbonate (0.986 g; 4.518 mmol) and DMAP (0.048 g; 0.376 mmol) in acetonitrile (8 mL) to afford 0.802 g (87%) of the desired compound as a white solid. ESI/APCI(+): 269 (M+Na).
Step 3: 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1/-/-pyrrolo[3,2-b]pyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.137 g; 0.508 mmol) and triethylamine (0.071 mL; 0.508 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (0.300 g; 1.218 mmol) and a solution of A/-benzylidene-3-methoxyaniline (1.015 mmol) in éthanol (0.5 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethylacetate (20% to 100%) in heptane followed by précipitation from dichloromethane furnished 0.019 g (5%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 162: PREPARATION OF 1-(imidazo[1,2-a]pyridin-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone
1-(lmidazo[1,2-a]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), imidazo[1,2-a]pyridine-3-carbaldehyde (0.146 g; 0.999 mmol) and a solution of N-benzylîdene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.112 g (31%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 163: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(pyrazolo[1,5a]pyridin-3-yl)ethanone
199
Step 1: To a solution of ethyl pyrazolo[1,5-a]pyridine-3-carboxylate (0.400 g; 2.103 mmol) in dry dichloromethane (8 mL) cooled at -78 °C under a nitrogen atmosphère was added dropwise a 1M diisobutylaluminium hydride solution in dichloromethane (4.630 mL; 4.630 mmol). The reaction was stirred for 1.5 h at -78 °C after which it was allowed to warm to -15 °C for 30 min.
The reaction was quenched by addition of a 1N Rochelle sait solution and the reaction mixture was vigorously stirred for 1h. The phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, dried over magnésium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (20% to 100%) in heptane furnished 0.128 g (41%) of pyrazolo[1,5-a]pyridin-3-ylmethanol as a colourless oil. ESI/APCI(+): 149 (M+H).
Step 2: To a solution of pyrazolo[1,5-a]pyridin-3-ylmethanol (0.128 g; 0.864 mmol) in dichloromethane (10 mL) was added molecular sieves (4A) and pyridinium dichromate (0.488 g;
1.296 mmol). The reaction was stirred at room température overnight. Celite ® was added and the reaction mixture was stirred for 30 min. The red suspension was filtered. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (2% to 20%) in heptane furnished 0.064 g (51%) of pyrazolo[1,5a]pyridine-3-carbaldehyde as a white solid. ESI/APCI(+): 147 (M+H).
Step 3: 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(pyrazolo[1,5-a]pyridin-3-yl)ethanone was 20 prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.059 g; 0.219 mmol) and triethylamine (0.031 mL; 0.219 mmol) in éthanol (0.5 mL), pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.093 g; 0.438 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.438 mmol) in éthanol (0.5 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0% to 100%) 25 in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.020 g (13%) of the desired compound. ESI/APCI(+): 358 (M+H).
EXAMPLE 164: PREPARATION OF 1-(1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1 : tert-Butyl 3-formyl-1H-indazole-1-carboxylate was prepared according to general 30 procedure F from 1H-indazole-3-carboxaldehyde (0.500 g; 3.421 mmol), di-tert-butyl dicarbonate (0.896 g; 4.105 mmol) and DMAP (0.042 g; 0.342 mmol) in acetonitrile (8 mL). Purification by flash chromatography on silica gel using a gradient of ethylacetate (5% to 40%) in heptane furnished 0.318 g (38%) of the desired compound. ESI/APCI(+): 269 (M+Na).
Step 2: 1-(1H-lndazol-3-yl)-2-((3-methoxyphenyl)amîno)-2-phenylethanone was prepared 35 according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.174 g; 0.646 mmol) and triethylamine (0,091 mL; 0.646 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indazole-1-carboxylate (0.318 g; 1.291 mmol) and a
200 solution of A/-benzylidene-3-methoxyaniline (1.291 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.004 g (1%) of the desired compound. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (ΜΗ).
EXAMPLE 165: PREPARATION OF 1-(benzo[b]thiophen-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2((2-methoxypyridin-4-yl)amino)ethanone
1-(Benzo[jb]thiophen-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-
5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.110 g; 0.408 mmol) and triethylamine (0.080 mL; 0.574 mmol) in éthanol (0.5 mL), benzo[b]thiophene-3-carbaldehyde (0.140 g; 0.863 mmol) and a mixture of /V-(imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine (0.856 mmol) in éthanol (1 mL), heated at 65 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethylacetate (50% to 100%) in heptane followed by précipitation from éthanol and heptane furnished 0.022 g (6%) of the desired compound as a pink solid. ESI/APCI(+): 415 (M+H).
EXAMPLE 166: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3c]pyridin-3-yl)ethanone
Step 1: To a solution of 1/7-pyrrolo[2,3-c]pyridine (0.400 g; 3.386 mmol) in a mixture of 1,2dichloroethane (10 mL) and nitromethane (10 mL) cooled at 0 °C under an argon atmosphère were added dichloro(methoxy)methane (1.544 mL; 16,92 mmol) and aluminum trichloride (1.500 g; 11.25 mmol) over 1 h. After the addition, the reaction was quenched by addition of water and of a saturated sodium bicarbonate solution. The reaction mixture was extracted with a solution of dichloromethane and éthanol (9/1, 6x100 mL). The combined organic layers were washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to yield 0.295 g (60%) of 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde which was used without further purification. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H). ’H NMR (DMSOde) δ 10.01 (1 H, s); 8.88 (1H, s); 8.50 <1 H, s); 8.33 (1H, d); 8.00 (1H, d).
Step 2: fert-Butyl 3-formyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate was prepared according to general procedure F from 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (0.295 g; 2.019 mmol), ditert-butyl dicarbonate (0.529 g; 2.019 mmol) and DMAP (0.025 g; 0.202 mmol) in acetonitrile (5 mL) to afford 0.411 g (83%) of the desired compound as a solid. ’H NMR (DMSO-d6) δ 10.13 (1H, s); 9.32 (1H, s); 8.86 (1H, s); 8.51 (1H, d); 8.07 (1 H, d), 1.69 (9H, s).
Step 3: 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1 H-pyrrolo[2,3-c]pyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), fert-butyl 3-formyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.246 g; 0.999 mmol)
201 and a solution of M-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0% to 100%) in heptane followed by a second purification by flash chromatography on silica gel using gradient of methanol (0% to 10%) in dichloromethane and a précipitation from diethyl ether furnished 0.055 g (14%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 167: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2c]pyridin-3-yl)ethanone
Step 1: To a solution of 1H-pyrrolo[3,2-c]pyridine (0.400 g; 3.386 mmol) in a mixture of 1,2dichloroethane (10 mL) and nitromethane (10 mL) cooled at 0 °C under an argon atmosphère were added dichloro(methoxy)methane (1.544 mL; 16.92 mmol) and aluminum trichloride (1.500 g; 11.25 mmol) over 1 h. After the addition, the reaction was quenched by addition of water and of a saturated sodium bicarbonate solution. The reaction mixture was extracted with a solution of dichloromethane and éthanol (9/1, 6x100 mL). The combined organic layers were washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to yield 0.333 g (67%) of 1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde which was used without further purification. ESI/APCI(+): 147 (M+H). ESI/APCi(-): 145 (M-H). 1H NMR (DMSOd6) δ 10.00 (1H, s); 9.29 (1 H. s); 8.42 (1H, s); 8.35 (1 H. d); 7.53 (1 H. d).
Step 2: tert-Butyl 3-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylate was prepared according to general procedure F from 1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (0.330 g; 2.258 mmol), ditert-butyl dicarbonate (0.591 g; 2.708 mmol) and DMAP (0.027 g; 0.226 mmol) in acetonitrile (5 mL) to afford 0.374 g (67%) of the desired compound as a brown solid. 1H NMR (DMSO-de) δ
10.12 (1H, s); 9.33 (1H, s); 8.77 (1H, s); 8.57 (1H, d); 8.02 (1H, d); 1.63-1.74 (9H, m).
Step 3: 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.246 g; 0.999 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0% to 100%) in heptane followed by a second purification by flash chromatography on silica gel using gradient of methanol (0% to 10%) in dichloromethane and a précipitation from diethyl ether furnished 0.056 g (14%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 168: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(6-methyl-4,5,6,7tetrahydrothieno[2,3-c]pyridin-3-yl)-2-phenylethanone
Step 1: To a suspension of ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno-[2l3-c]pyridine-3carboxylate (1.000 g; 4.161 mmol) in dioxane (5 mL) was added a concentrated hydrochloric
202 acid solution (3.200 mL; 38.40 mmol). After cooling to -5 °C, a solution of sodium nitrite (0.316 g; 4.580 mmol) in water (0.5 mL) was added. The resulting black reaction mixture was stirred at -5 °C for 40 min and was then added portionwise to a mixture of a 50% orthophosphoric acid solution (9 mL) and diethyl ether (9 mL) cooled at 0 eC. The reaction mixture was allowed to warm to room température and was stirred at room température overnight. The reaction mixture was carefully poured into a mixture ice/1N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (5% to 10%) in dichloromethane furnished 0.431 g (46%) of ethyl e-methyl-A.S.ej-tetrahydrothienoRA-cjpyrïdine-S-carboxylate as a brown oil. ESI/APCI(+): 226 (M+H). 1H NMR (DMSO-d6) δ 8.12 (1H, s); 4.23 (2H, q); 3.53 (2H, s); 2.85 (2H, t); 2.61 (2H, t); 2.35 (3H, s); 1.28 (3H, s).
Step 2: A suspension of lithium aluminium hydride (0.110 g; 2.899 mmol) în diethyl ether (20 mL) was refluxed for 30 min. After cooling to room température, a solution of ethyl 6-methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (0.580 g; 2.574 mmol) in diethyl ether (6 mL) was added. The reaction mixture was refluxed for 5.5 h. After cooling to room température, the reaction mixture was diluted with ethyl acetate and washed with a 1N sodium hydroxide solution. The phases were separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.415 g of (6-methyl-4,5,6,7tetrahydrothieno[2,3-c]pyridin-3-yl)methanol which was used in the next step without further purification. ESI/APCI(+): 184 (M+H).
To a solution of (6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)methanol (crude; 2.264 mmol) in dichloromethane (18 mL) was added a 15% Dess-Martin periodinane solution in dichloromethane (5.700 mL; 2.750 mmol). After 5 h at room température, a 15% Dess-Martin periodinane solution in dichloromethane (1.000 mL; 0.480 mmol) was added again and the reaction mixture was stirred at room température overnight. The reaction mixture was diluted with diethyl ether and a 1N sodium hydroxide solution was added. After 15 min at room température, the phases were separated. The organic phase was washed with a 1N sodium hydroxide solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (5% to 10%) in dichloromethane furnished 0.235 g (50% over two steps) of 6-methyl-4,5,6,7tetrahydrothieno[2,3-c]pyridine-3-carbaldehyde as a brown solid. ESI/APCI(+): 182 (M+H). 1H NMR (DMSO-de) δ 9.87 (1H, s); 8.41 (1H, s); 3.55 (2H, s); 2.86 (2H. m); 2.51 (2H, t); 2.36 (3H, s).
Step 3: 2-((3-Methoxyphenyl)amino)-1-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-2phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-516765
203 (2-hydroxyethyl)-4-methylthiazolium chloride (0.117 g; 0.554 mmol) and triethylamine (0.039 mL; 0.281 mmol) in éthanol (1 mL), e-methyl^.S^.y-tetrahydrothieno^.S-cjpyridine-Scarbaldehyde (0.100 g; 0.552 mmol) and a mixture of /V-benzylidene-3-methoxyaniline (0.117 g; 0.554 mmol) in éthanol (1 mL,) heated at 70 °C for 24 h. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in methanol and by préparative TLC using 10 % methanol in dichlorométhane as eluent and by préparative HPLC (XBridge column; method 4) furnished 0.023 g (11%) of the desired compound as a yellow solid. ESI/APCI(+): 393 (M+H); 415 (M+Na). ESIZAPCI(-): 391 (M-H).
EXAMPLE 169; PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(1 -methyl-1 H-indazol-3-yl)-
2-phenylethanone
2-((3-Methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (1.000 mmol) in éthanol (1 mL), heated at 70 ’C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.139 g (37%) of the desired compound as a white solid. ESI/APCI(+): 372 (M+H).
EXAMPLE 170: PREPARATION OF 1-(indolin-1-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1 : To a solution of indoline (0.050 mL; 0.444 mmol) in dichlorométhane (5 mL) were added potassium carbonate (0.262 g; 1.896 mmol) and α-chlorophenylacetyl chloride (0.150 mL; 0.952 mmol). The reaction mixture was stirred at room température for 2 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 2-chloro-1 -(indolin-1 -yl)-2phenylethanone which was used in the next step without further purification. ESI/APCI(+): 272 (M+H); 294 (M+Na).
Step 2: A mixture of 2-chloro-1-(indolin-1-yl)-2-phenylethanone (crude; 0.444 mmol), 3methoxyaniline (0.100 mL, 0.893 mmol) and DIPEA (0.100 mL, 0.514 mmol) In acetonitrile (2 mL) was irradiated in a microwave oven at 120 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography using a gradient of ethyl acetate (10% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.043 g (27% over two steps) of the desired product as a white solid. ESI/APCI(+): 359 (M+H); 381 (M+Na). 1H NMR (CDCI3): δ 8.26 (1H, m); 7.50 (1H, m); 7.17-7.36 (8H, m); 7.03 (1H, m); 6.21-6.27 (2H, m); 5.21 (1H, s); 4.26 (1H, m); 3.92 (1H, m);
3.73 (3H, s); 3.08-3.30 (2H, m).
EXAMPLE 171: PREPARATION OF 1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
204
-(7-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.163 g; 0.604 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol, tertbutyl 7-fluoro-3-formyl-1H-indole-1-carboxylate (0.277 g; 1.052 mmol) and a solution of Nbenzylidene-3-methoxyaniline (1.046 mmol) in éthanol (1.5 mL), heated at 60 °C for 48 h. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane. Further purification by précipitation from diisopropyl ether and ethyl acetate furnished 0.042 g (11%) of the desired compound as a yellow solid. ESI/APCI(+): 375 (M+H). ESl/APCI(-): 373 (M-H).
EXAMPLE 172: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-lndol-3-yl)-
2- (6-methoxypyridin-3-yl)ethanone
Step 1: A solution of 3,5-dimethoxy-/\/-((6-methoxypyridin-3-yl)methylene)aniline in éthanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.139 g; 1.014 mmol) and 3,5dimethoxyaniline (0.158 g; 1.031 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 273 (M+H).
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1 -(5 -f I uoro-1 /-/-indol-3-yl)-2-(6-methoxypyridin-3yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.160 g; 0.593 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.290 g; 1.102 mmol) and a solution of S.S-dimethoxy-N-Ke-methoxypyridin-S-yOmethyleneJaniline (1.014 mmol) in éthanol (2 mL), heated at 60 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 70%) in heptane followed by précipitation from dichloromethane furnished 0.043 g (9%) of the desired compound as a white solid. ESI/APCI(+): 436 (M+H). ESI/APCl(-): 434 (M-H).
EXAMPLE 173: PREPARATION OF 2-((2-fluoropyridin-4-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone
Step 1: A solution of A/-benzylidene-2-fluoropyridin-4-amine in éthanol was prepared by heating a solution of benzaldehyde (0.115 mL; 1.138 mmol) and 4-amino-2-fluoropyridine (0.130 g; 1.160 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 201 (M+H).
Step 2: 2-((2-Fluoropyridin-4-yl)amino)-1-(1/7-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.158 g; 0.586 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.311 g; 1.268 mmol) and a solution of Nbenzylidene-2-fluoropyridin-4-amine (1.138 mmol) in éthanol (1.5 mL), heated at 60 °C for 96 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%)
205 în heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.035 g (9%) of the desired compound as a white solid. ESI/APCI(+): 346 (M+H). ESI/APCI(~): 344 (M-H).
EXAMPLE 174: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1((tetrahydrofuran-3-yl)sulfonyl)-1H-indol-3-yl)ethanone
Step 1: To a solution of 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol) in DMF (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.053 g;
1.333 mmol). The reaction mixture was stirred at room température for 0.5 h. Tetrahydrofuran-3sulfonyl chloride (0.253 g; 1.483 mmol) and DMAP (0.005 g; 0.037 mmol) were added and the reaction mixture was stirred at room température for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.299 g (100%) of 2-chloro-2-phenyl-1-(1-((tetrahydrofuran-3-yl)sulfonyl)-1H-indol-3-yl)ethanone as a solid. ESI/APCI(+): 404 (M+H). ESI/APCI(-): 402 (M-H).
Step 2: 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1-((tetrahydrofuran-3-yl)sulfonyl)-1H-indol-3yl)ethanone was prepared according to general procedure E from 2-chloro-2-phenyl-1-(1((tetrahydrofuran-3-yl)sulfonyl)-1H-indol-3-yl)ethanone (0.100 g; 0.248 mmol) and m-anisîdine (0.277 mL; 2.474 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 100 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.058 g (48%) of the desired compound a beige solid. ESI/APCI(+): 491 (M+H). ESI/APCI(-): 489 (M-H).
EXAMPLE 175: PREPARATION OF 2-((3-methoxyphenyl)amino)-1 -(1-((1 -methyl-1 H-imidazol-
4-yl)sulfonyl)-1H-indol-3-yl)-2-phenylethanone
Step 1: To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol) in DMF (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.053 g;
1.333 mmol). The reaction mixture was stirred at room température for 0.5 h. 1 -Methyl-1 Himidazole-4-sulfonyl chloride (0.268 g; 1.484 mmol) and DMAP (0.005 g; 0.037 mmol) were added and the reaction mixture was stirred at room température for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.301 g (98%) of 2-chloro-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1F/-indol3-yl)-2-phenylethanone as a solid. ESI/APCI(+): 414 (M+H); 436 (M+Na). ESI/APCI(-): 412 (ΜΗ).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(1-((1-methyl-1 H-imidazol-4-yl)sulfonyl)-1/-/-indol-3-yl)-216765
206 phenylethanone was prepared according to general procedure E from 2-chloro-1-(1-((1-methyl1H-imldazol-4-yl)sulfonyl)-1H-indol-3-yl)-2-phenylethanone (0.166 g; 0.402 mmol) and manisidine (0.449 mL; 4.011 mmol) in acetonitrile (1.5 mL), irradiated in a microwave oven at 100 °C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.058 g (29%) of the desired compound a beige solid. ESI/APCI(+): 501 (M+H). ESI/APCI(-): 499 (M-H).
EXAMPLE 176: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1-(3-hydroxypropyl)1 H-indol-3-yl)-2-phenylethanone
2-((3,5-Dimethoxyphenyl)amino)-1 -(1 -(3-hydroxypropyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(1-(3-hydroxypropyl)-1/-/-indol-3-yl)2-phenylethanone (0,125 g; 0.381 mmol) and 3,5-dimethoxyaniline (0.584 g; 3.813 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 130 °C for 15 min. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 20%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) ΐη heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.022 g (13%) of the desired compound as a white solid. ESI/APCI(+): 445 (M+H).
EXAMPLE 177: PREPARATION OF 1-(1-(ethylsulfonyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol) in DMF (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.053 g;
1.333 mmol). The reaction mixture was stirred at room température for 0.5 h. Ethane sulfonyl chloride (0.141 mL; 1.480 mmol) and DMAP (0.005 g; 0.037 mmol) were added and the reaction mixture was stirred at room température for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 0.247 g (92%) of 2-chloro-1-(1-(ethylsulfonyl)-1/-/-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 362 (M+H). ESI/APCI(-): 360 (M-H).
Step 2: 1-(1-(Ethylsulfonyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(1-(ethylsulfonyl)-1H-indol-3-yl)-2phenylethanone (0.130 g; 0.359 mmol) and m-anisidine (0.402 mL; 3.591 mmol) in acetonitrile (1.5 mL), irradiated in a microwave oven at 100 °C for 45 min. Purification by flash chromatography on silica gel using a gradient of dichloromethane (15% to 70%) in heptane furnished 0.039 g (25%) of the desired compound as a beige solid. ESI/APCI(+): 449 (M+H).
ESI/APCI(-): 447 (M-H). ’H NMR (DMSO-ο^ ÔD 9.15 (1H, s); 8.23 (1H, d); 7.87 (1 H, d); 7.62
207 (2H, d); 7.43 (2H, m); 7.25-7.35 (2H, m); 7.14-7.24 (1H, m); 6.89-6.98 (1H. m); 6.39-6.53 (3H, m); 6.28-6.38 (1 H, m): 6.12 (1 H, d); 3.68-3.87 (2H, m); 3.63 (3H, s); 1.03 (3H, t).
EXAMPLE 178: PREPARATION OF 1-(5-fluoro-1-(methylsulfonyl)-1H-indol-3-yl)-2-((3methoxyphenyl)arïiino)-2-phenylethanone
Step 1: To a solution of 2-chloro-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.695 mmol) in DMF (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.053 g; 1.333 mmol). The reaction mixture was stirred at room température for 0.5 h, Mesyl chloride (0.108 mL; 1.395 mmol) and DM AP (0.005 g; 0.037 mmol) were added and the reaction mixture was stirred at room température for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 0.219 g (86%) of 2-chloro-1-(5-fluoro-1-(methylsulfonyl)-1F/-indol-3-yl)-2-phenylethanone as a solid. ESI/APCI(+): 366 (M+H). ESI/APCI(-): 364 (M-H).
Step_______2: 1 -(5-Fluoro-1 -(methylsulfonyl)-l /-/-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to general procedure E from 2-chloro-1-(5-fluoro-1(methylsulfonyl)-1/7-indol-3-yl)-2-phenylethanone (0.130 g; 0.355 mmol) and m-anisidine (0.398 mL; 3.555 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 100 °C for 45 min. The residue was purified by flash chromatography on silica gel using a gradient of dichloromethane (15% to 70%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 0.030 g (18%) of the desired compound as a beige solid. ESI/APCI(+): 453 (M+H). ESI/APCI(-): 451 (M-H). 1H NMR (DMSOde) 609.22 (1 H, s); 7.85-7.96 (2H, m); 7.62 (2H, d); 7.32 (3H, m); 7.15-7.26 (1H, m); 6.93 (1H, t); 6.39-6.50 (3H, m); 6.27-6.35 (1H, m); 6.13 (1 H, d); 3.69 (3H, s); 3.63 (3H, s),
EXAMPLE 179: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(6-methoxypyridin-3-yl)ethanone
-(6-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.067 g; 0.248 mmol) and triethylamine (0.035 mL; 0.248 mmol) in éthanol (0.4 mL), tert-butyl 6-fluoro-3-formyl-1H-indole-1-carboxylate (0.158 g; 0.600 mmol) and a solution of 3-methoxy-/\/-((6-methoxypyridin-3-yl)methylene)aniline (0.503 mmol) in éthanol (0.735 mL), heated at 70 °C for 113 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative TLC using methanol (5%) in dichloromethane as eluent furnished 0.032 g (16%) of the desired compound as a yellow solid. ESI/APCI(+): 406 (M+H); 428 (M+Na). ESI/APCI(-): 404 (M-H).
EXAMPLE 180: PREPARATION OF 2-(6-fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
208
Step 1: A solution of /V-((6-fluoropyridin-3-yl)methylene)-3-methoxyaniline in éthanol was prepared by heating a solution of 6-fluoronicotinaldehyde (0.131 g; 1.047 mmol) and 3methoxyaniline (0.120 mL; 1.074 mmol) în éthanol (0.5 mL) at 60 °C for 4 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 231 (M+H).
Step 2: 2-(6-Fluoropyridin-3-yl)-1-(1/-/-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.160 g; 0.593 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1 H-indole-1 -carboxylate (0.281 g; 1.146 mmol) and a solution of N-((6-fluoropyridin-3-yl)methylene)-3-methoxyaniline (1.047 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.123 g (31%) of the desired compound as a yellow solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).
EXAMPLE 181: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino )-2-(2methoxypyridin-3-yl)ethanone
Step 1: A solution of 3-methoxy-N-((2-methoxypyridin-3-yl)methylene)aniline in éthanol was prepared by heating a solution of 2-methoxynicotinaldehyde (0.141 g; 1.028 mmol) and 3methoxyaniline (0.122 g; 1.088 mmol) in éthanol (0.5 mL) at 60 eC for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H).
Step 2:1-(1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.156 g; 0.578 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0,5 mL), tert-butyl 3-formyl-1A7-indole-1-carboxylate (0.294 g; 1.199 mmol) and a solution of 3-methoxy-/V-((2-methoxypyridin-3-yl)methylene)aniline (1.028 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by purification by solid phase extraction on C18-reversed phase column using a gradient of acetonitrile (30% to 100%) in water furnished 0.105 g (26%) of the desired compound as a yellow foam. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).
EXAMPLE 182: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(1-(2-morpholinoethyl)-1Hindol-3-yl)-2-phenylethanone
Step 1: To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol) in
DMF (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.053 g;
1.333 mmol). The reaction mixture was stirred at room température for 0.5 h. 4-(2bromoethyl)morpholine (0.287 g; 1.479 mmol) and DMAP (0.005 g; 0.037 mmol) were added
209 and the reaction mixture was stirred at room température ovemight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 5%) in dichloromethane furnished 0.198 g (70%) of 2-chloro-1-(1-(2-morpholinoethyl)-1H-indol-3-yl)-2-phenylethanone as an oil. ESI/APCI(+): 383 (M+H); 405 (M+Na). ESI/APCI(-): 381 (M-H).
Step 2: 2-f(3-Methoxvphenvl)amino)-1-f1-(2-morDholinoethvl)-1H-indol-3-vl)-2-phenvlethanone was prepared according to general procedure E from 2-chloro-1-(1-(2-morpholinoethyl)-1Hindol-3-yl)-2-phenylethanone (0.130 g; 0.261 mmol) and m-anisidine (0.402 mL; 3.591 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 15 min. The residue was purified by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 4) furnished 0.019 g (15%) of the desired product as a beige solid. ESI/APCI(+): 470 (M+H). ESI/APCl(-): 468 (M-H). 1H NMR (DMSO-c/6) ÔD8.95 (1H, s); 8.17 (1H, d); 7.57 (3H, m); 7.15-7.35 (5H, m); 6.92 (1H, t); 6.32 (3H, m); 6.11 (1H, d); 6.02 (1 H. d); 4.40 (2H, m); 3.62 (3H, s); 3.52 (4H, m); 3.37 (2H, m); 2.74 (2H, m); 2.40 (3H, m).
EXAMPLE 183: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-(piperidin-4ylsulfonyl)-1H-indol-3-yl)ethanone
Step 1: To a solution of 2-chloro-1-(1/-/-indol-3-yl)-2-phenylethanone (0.200 g; 0.741 mmol) in DMF (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.053 g;
1.333 mmol). The reaction mixture was stirred at room température for 0.5 h. Benzyl 4(chlorosulfonyl)piperidine-l-carboxylate (0.471 g; 1.482 mmol) and DMAP (0.005 g; 0.037 mmol) were added and the reaction mixture was stirred at room température for 3 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.320 g (78%) of benzyl 4-((3-(2-chloro-2-phenylacetyl)-1H-indol-1yl)sulfonyl)piperidine-1-carboxylate as a white solid. ESI/APCI(+): 551 (M+H); 573 (M+Na). ESI/APCI(-): 549 (M-H).
Step 2: Benzyl 4-((3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1 H-indol-1 yl)sulfonyl)piperidine-1-carboxylate was prepared according to general procedure E from benzyl
4-((3-(2-chloro-2-phenylacetyl)-1 H-indoM -yl)sulfonyl)piperidine-1 -carboxylate (0.150 g; 0.272 mmol) and m-anisidine (0.304 mL; 2.724 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 0.068 g (39%) of the desired compound as a beige solid. ESl/APCI(+): 638 (M+H); 660 (M+Na). ESI/APCI(-): 636 (M-H).
210
Step 3: A mixture of benzyl 4-((3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1yl)sulfonyl)piperidine-1-carboxylate (0.135 g; 0.212 mmol), ammonium formate (0.047 g; 0.741 mmol) and palladium hydroxide (0.003 g; 0.021 mmol) in a mixture of methanol (1 mL) and THF (0,5 mL) was irradiated in a microwave oven at 100 °C for 10 min. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 4) furnished 0.009 g (8%) of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-(piperidin-4-ylsulfonyl)-1Hindol-3-yl)ethanone as a beige solid. ESI/APCI(+): 504 (M+H). ESI/APCI(-): 502 (M-H).
EXAMPLE 184: PREPARATION OF 4-((2-( 1 H-indol-3-yl )-2-oxo-1-phenylethyl)amino)-2methoxybenzonitrile
Step 1: 4-(Benzylideneamino)-2-methoxybenzonitrile was prepared quantitatively according to general procedure I from benzaldehyde (0.102 mL; 1.004 mmol) and 4-amîno-2methoxybenzonitrile (0.148 g; 0.999 mmol).
Step 2: 4-((2-(1 H-lndol-3-yl)-2-oxo-1-phenylethyl)amino)-2-methoxybenzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (2 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 1.000 mmol) and a solution of 4-(benzylideneamino)-2-methoxybenzonitrile (0.999 mmol) in éthanol (1 mL), heated at 70 °C ovemight The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane. Further purification by flash chromatography on silica gel using a gradient of dichloromethane (30% to 100%) in heptane followed by purification by flash chromatography on silica gel using a gradient of ethyl acetate (1% to 10%) in dichloromethane furnished 0.100 g (26%) of the desired compound as a beige solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H). 1H NMR (DMSO-de) δ 12.25 (1H, brs); 8.89 (1H, s); 8.17 (1 H, d); 7.65 (2H, d); 7.46 (2H, t); 7.12-7.38 (6H, m); 6.63 (1H, br s); 6.49 (1H, d); 6.24(1 H, d); 3.76(3 H, s).
EXAMPLE 185: PREPARATION OF 1-(5-(hydroxymethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: To a solution of (1H-indol-5-yl)methanol (0.253 g; 1.719 mmol), triethylamine (0.479 mL; 3.437 mmol) and DMAP (0.021 g; 0.172 mmol) in dichloromethane (4 mL) was added TBDMSCI (0.285 g; 1.891 mmol) and the reaction mixture was stirred at room température for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, washed with a 0.5N hydrochloric acid solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to furnish 0.370 g (82%) of 5-(((tert16765
211 butyldimethylsilyl)oxy)methyl)-1 H-indole. 1H NMR (DMSO-de) δ 10.95 (1H, br s); 7,39 (1H, s); 7.20-7.31 (2H, m); 6.96 (1 H. d); 6.32 (1 H, s); 4.67 (2H, s); 3.27 (6H, s); 0.83 (9H, s).
Step 2: 1 -(5-(((tert-Butyldimethylsilyl)oxy)methyl)-1 /-/-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to general procedure A from α-chlorophenylacetyl chloride (0.208 mL; 1.415 mmol), 5-(((tert-butyldimethylsilyl)oxy)methyl)-1 H-indole (0.370 g; 1.415 mmol) and pyridine (0.114 mL; 1.415 mmol) in toluene (4 mL) at 55 °C. The solid obtained after précipitation was recrystallized from acetonitrile to afford 0.183 g (31%) of the desired compound as a pink solid. ESI/APCI(-): 412, 414 (M-H).
Step 3:1-(5-(Hydroxymethyl)-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 1 -(5-(((tert-butyldimethylsilyl)oxy)methyl)-1 Hindol-3-yl)-2-chloro-2-phenylethanone (0.100 g; 0.242 mmol) and 3-methoxyaniline (0.541 mL; 4.832 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 30 min.
Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.002 g (2%) of the desired product. ESI/APCI(+): 387 (M+H). ESIZAPCI(-): 385 (M-H).
EXAMPLE 186: PREPARATION OF tert-butyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)1-methyl-6,7-dihydro-1/7-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate tert-Butyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3c]pyridine-5(4H)-carboxylate was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.117 g; 0.433 mmol) and triethylamine (0.061 mL; 0.433 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1-methyl-6,7-dihydro1/-/-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.230 g; 0.867 mmol) and a solution of Nbenzylidene-3-methoxyaniline (0.867 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane furnished 0.235 g (57%) of the desired compound. ESI/APCI(+): 477 (M+H).
EXAMPLE 187: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(1-methyl-4,5,6,7tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-phenylethanone hydrochloride
To a solution of tert-butyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-6,7-dihydro1/-/-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.235 g; 0.493 mmol) in dioxane (2 mL) cooled to 0 °C was added dropwise a 4N hydrogen chloride solution in dioxane (5.000 mL; 20.00 mmol). The reaction mixture was allowed to warm to room température and was stirred at room température for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethylether and the resulting solid was filtered and dried under reduced pressure over phosphorus(V) oxide to afford 0.104 (48%) of 2-((3methoxyphenyl)amino)-1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2phenylethanone hydrochloride as a green solid. ESI/APCI(+): 377 (M+H). ESI/APCI(-): 375 (ΜΗ).
212
EXAMPLE 188: PREPARATION OF 1-(7-methoxy-1/7-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone
Step 1: To a solution of DMF (0.600 mL; 7.749 mmol) in dichloromethane (2 mL) cooled to -15 °C was added dropwise phosphorus oxychloride (0.350 mL; 3.755 mmoi). After 15 min at -15 °C, a solution of 7-methoxy-1H-indole (0.498 g; 3.384 mmol) in dichloromethane (1.5 mL) was added. The reaction mixture was allowed to warm to room température and was stirred at room température overnight. The reaction mixture was basified with a 1M sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (50%) in heptane as eluent furnished 0,346 g (58%) of 7-methoxy1H-indole-3-carbaldehyde as a green solid. ’H NMR (DMSO-d6) δ 12.31 (1H, br s); 9.92 (1H, s); 8.17 (1H, s); 7.65 (1 H, d); 7.14 (1H, t); 6.84 (1H, d); 3.94 (3H, s).
tert-Butyl 3-formyl-7-methoxy-1H-lndole-1-carboxylate was prepared according to general procedure F from 7-methoxy-1H-indole-3-carbaldehyde (0.346 g; 1.975 mmol), di-tert-butyl dicarboxylate (0.552 g; 2.529 mmol) and DMAP (0.032 g; 0.262 mmol) in acetonitrile (6 mL) to furnish 0.505 g (93%) of the desired product as an orange solid. ESI/APCI(+): 276 (M+H). ’H NMR (DMSO-d6) δ 10.03 (1H, s); 8.59 (1H, s); 7.74 (1H, d); 7.73 (1 H, t); 7.05 (1H, d); 3.92 (3H, s); 1.61 (9H, s).
Step 3: 1-(7-Methoxy-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.161 g; 0.597 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol, tert-butyl 3-formyl-7-methoxy-1/-/-indole-1-carboxylate (0,297 g; 1.079 mmol) and a solution of N-benzylidene-3-methoxyaniline (1.037 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.018 g (4%) of the desired compound as a yellow solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).
EXAMPLE 189: PREPARATION OF 1-(1,5-dimethyl-4,5,6l7-tetrahydro-1/-/-pyrazolo[4,3c]pyridîn-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone
To a stirred solution of 2-((3-methoxyphenyl)amino)-1-(1-methyl-4,5,6,7-tetrahydro-1Hpyrazolo[4,3-c]pyridin-3-yl)-2-phenylethanone hydrochloride (0.086 g; 0.208 mmol) in THF (2 mL) were added triethylamine (0.087 mL; 0.625 mmol), formaldéhyde (0.047 mL; 0.625 mmol), sodium triacetoxyborohydride (0.132 g; 0.625 mmol) and a drop of acetic acid. The reaction mixture was stirred at room température for 16 h and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and a mixture of methanol and a 25% ammonium hydroxide solution (9/1 ) was added. The precipitate was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure. Purification by flash
213 chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1 ) (0% to 10%) in dichloromethane furnished 0.030 g (35%) of 1-(1,5-dimethyl-4,5,6,7-tetrahydro-1/7pyrazolo[4,3-c]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone. ESI/APCI(+): 391 (M+H). 1H NMR (DMSCLde) δ 7.51 (2H, d); 7.27-7.36 (2H, m); 7.18-7.26 (1H, m); 6.92 (1H, t); 6.33-6.44(1 H, m); 6.18-6.32 (3H, m); 6.12 (1H, d); 3.84 (3H, s); 3.61 (3H, s); 3.37-3.51 (2H, m); 2.53-2.75 (4H, m); 2.32 (3H, s).
EXAMPLE 190: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2phenylethanone
Step 1: tert-Butyl 3-formyl-7-methyl-1/7-indole-1-carboxylate was prepared according to general procedure F from 7-methyl-1/7-indole-3-carbaldehyde (0.500 g; 3.141 mmol), di-tert-butyl dicarboxylate (0.910 g; 4.170 mmol) and DMAP (0.057 g; 0.467 mmol) in acetonitrile (10 mL) to furnish 0.790 g (97%) of the desired product as a beige solid. ESI/APCl(+): 260 (M+H). 1H NMR (DMSO-d6)Ô 10.05(1 H, s); 8.65(1 H, s); 8.03 (1 H, d); 7.28 (2H, m); 2.54 (3H, s); 1.64 (9H, s).
Step 2: 2-((3-Methoxyphenyl)amino)-1 -(7-methyl-1 /7-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.145 g; 0.537 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-7-methyl-1/7-indole-1carboxylate (0.280 g; 1.080 mmol) and a solution of /V-benzylidene-3-methoxyaniline (0.989 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane followed by précipitation from diethyl ether furnished 0.019 g (5%) of the desired compound as a yellow solid. ESI/APCI(+): 371 (M+H). ESIZAPCI(-): 369 (M-H).
EXAMPLE 191: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(6-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)-2-phenylethanone
Step 1 : tert-Butyl 3-formyl-6-methyl“1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared according to general procedure F from 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.481 g; 3.003 mmol), di-tert-butyl dicarbonate (0.786 g; 3.601 mmol) and DMAP (0.037 g; 0.300 mmol) in acetonitrile (7.5 mL) to afford 0.753 g (96%) of the desired compound.
Step 2: 2-((3-Methoxyphenyl)amino)-1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5(2-hydroxyethyl)-4-methylthîazol-3-ium chloride (0.135 g; 0.556 mmol) and triethylamine (0.075 mL; 0.541 mmol) in éthanol (1 mL), tert-butyl 3-formyl-6-methyl-1H-pyrrolo[2,3-b]pyridine-1carboxylate (0.260 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (55%) in heptane as eluent
214 furnished 0,058 g (15%) of the desired compound as a white solid. ESI/APCI(+): 372 (M+H), ESI/APCI(-): 370 (M-H).
EXAMPLE 192: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino )-2-(6methylpyridin-3-yl)ethanone
Step 1: A solution of 3-methoxy-N-((6-methylpyridin-3-yl)methylene)aniline in éthanol was prepared by heating a solution of 6-methylnicotinaldehyde (0.126 g; 1.023 mmol) and 3methoxyaniline (0.125 g; 1.131 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 227 (M+H). ESIZAPCI(-): 225 (M-H).
Step 2: 1-(1/-Mndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylpyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.400 mL; 2.886 mmol) in éthanol (0.5 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.270 g; 1.101 mmol) and a solution of 3-methoxy-/V-((6-methylpyridin-3-yl)methylene)aniline (1.023 mmol) in éthanol (1.5 mL), heated at 60 °C for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane followed by précipitation from methanol furnished 0.021 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).
EXAMPLE 193: PREPARATION OF 1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: To a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.545 g; 4.004 mmol) in a mixture of 1,2-dichloroethane (10 mL) and nitromethane (10 ml) cooled to 0 °C were added under an argon atmosphère dichloro(methoxy)methane (1.825 mL; 20.00 mmol) and aluminum trichloride (1.600 g; 12.00 mmol). The reaction mixture was stirred for 1 h. The reaction was quenched by the addition of water and a saturated sodium bicarbonate solution. The reaction mixture was extracted with a mixture of dichloromethane and éthanol (9/1 ). The organic layer was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to afford 0.503 g (77%) of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a brown solid. ESIZAPCi(-): 163 (M-H). 1H NMR (DMSO-ds) δ 12.88 (1H, br s); 9.94 (1H, s); 8.57 (1 H, d); 8.378.42(1 H, m); 8.40(1 H, brs); 8.18(1 H, dd).
Step 2: fert-Butyl 5-fluoro-3-formyl-1A7-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared according to general procedure F from 5-fluoro-1/-/-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.497 g; 3.028 mmol), di-fert-butyl dicarbonate (0.793 g; 3.633 mmol) and DMAP (0.037 g; 0.303 mmol) in acetonitrile (7.5 mL) to afford 0.687 g (86%) of the desired compound as a brown solid. 1H NMR (DMSO-cfe) δΠ 10.06 (1H, s); 8.89 (1H, s); 8.54 (1H, d); 8.25 (1H, dd); 1.66 (9 H, s).
Step________3: 1-(5-Fluoro-1H-pyrro!o[2,3-b]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-216765
215 phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.556 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 5-fluoro-3-formyl-1H-pyrrolo[2,3-b]pyridine-1carboxylate (0.264 g; 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.998 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane followed by précipitation from diethyl ether furnished 0.034 g (9%) of the desired compound as a white solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M+H).
EXAMPLE 194; PREPARATION OF 1-(5-((dimethylamino)methyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: A solution of 1H-indole-5-carbaldehyde (1.000 g; 6.889 mmol), a 2M dimethylamine solution in THF (5.170 mL; 10.34 mmol), acetic acid (2.370 mL; 41.40 mmol) and sodium triacetoxyborohydride (3.650 g; 17.22 mmol) in THF (20 mL) was heated to 75 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (0% to 12%) in dichloromethane furnished 0.657 g (55%) of 1 -(1 H-indol-5-yl)Λ/,/V-dimethylmethanamine. ESI/APCI(+): 175 (M+H).
Step 2: To DMF (2 mL) cooled to 0 °C was added dropwise phosphorus oxychloride (0.520 mL; 5.579 mmol) and the reaction mixture was stirred at 0 °C for 30 min. A solution of 1-(1H-indol-5yl)-N,A/-dimethylmethanamine (0,486 g; 2.789 mmol) in DMF (5 mL) was added dropwise to the cold Vilsmeier reagent and the reaction mixture was stirred at room température for 3 h. The suspension was poured into an ice/water mixture and neutralized with a 1N sodium hydroxide solution. The aqueous layer was extracted with a mixture of dichloromethane and éthanol (9/1) and with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.365 g (65%) of 5-((dimethylamino)methyl)-1H-indole-3carbaldehyde. ESI/APCI(+): 203 (M+H).
Step 3: fert-Butyl 5-((dimethylamino)methyl)-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 5-((dimethylamino)methyl)-1H-indole-3-carbaldehyde (0.365 g; 1.805 mmol), di-tert-butyl dicarbonate (0.473 g; 2.166 mmol) and DMAP (0.022 g; 0.180 mmol) in acetonitrile (5 mL) to afford 0.112 g (21%) of the desired compound. ESI/APCI(+): 303 (M+H).
Step 5: 1-(5-((Dimethylamino)methyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.050 g; 0.185 mmol) and triethylamine (0.026 mL; 0.188 mmol) in éthanol (0.5 mL), tert-butyl 5-((dimethylamino)methyl)-3-formyl-1H-indole-1carboxylate (0.112 g; 0.370 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.369
216 mmol) in éthanol (0.5 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1)(0% to 10%) in dichloromethane followed by purification by préparative TLC using methanol (10%) in dichloromethane as eluent. Further purification by préparative HPLC (XBridge column; method 5) followed by purification by préparative TLC using methanol/25% ammonium hydroxide (9/1 ) (10%) in dichloromethane as eluent furnished 0.001 g (1%) of the desired compound. ESI/APCI(+): 414 (M+H). ESI/APCI(-): 412 (M-H).
EXAMPLE 195: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(5-(methylsulfonyl)-1Hindol-3-yl)-2-phenylethanone
Step 1: To a solution of 5-(methylsulfonyl)indoline (0.450 g; 2.281 mmol) in dioxane (10 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.777 g; 3.423 mmol). The reaction mixture was heated at 80 °C for 2 h. After cooling to room température, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.210 g (47%) of 5-methylsulfonyl-1H-indole as a white solid. ESI/APCI(+): 196 (M+H); 218 (M+Na). ESI/APCI(-): 194 (M-H).
Step 2: 5-(Methylsulfonyl)-1H-indole-3-carbaldehyde was prepared according to general procedure R from a solution of oxalyl chloride (0.107 mL; 1.231 mmol) in dichloromethane (8 mL), DMF (0.095 mL; 1.228 mmol) and 5-(methylsulfonyl)-1H-indole (0.200 g; 1.024 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane furnished 0.155 g (84%) of the desired compound as a white solid. ESI/APCI(+): 224 (M+H); 246 (M+Na). ESI/APCI(-): 222 (M-H).
Step 3: To a solution of 5-(methylsulfonyl)-1H-indole-3-carbaldehyde (0.155 g; 0.694 mmol) in dichloromethane (10 mL) were added di-tert-butyl dicarbonate (0.182 g; 0.831 mmol), DMAP (0.017 g; 0.139 mmol) and triethylamine (0.116 mL; 0.833 mmol). After stirring for 15 min, the reaction mixture was diluted with a saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 100%) in heptane furnished 0.198 g (88%) of tert-butyl 3-formyl-5-(methylsulfonyl)-1H-indole-1-carboxylate as a white solid. ESI/APCI(+): 324 (M+H); 346 (M+Na).
Step 4: 2-((3-Methoxyphenyl)amino)-1 -(5-(methylsulfonyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general method K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.093 g; 0.345 mmol) and triethylamine (0.042 mL; 0.313 mmol) in éthanol (2 mL), tert-butyl 3-formyl-5-(methylsulfonyl)-1H-indole-1-carboxylate (0.198 g; 0.612 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.610 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of
217 ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from dichloromethane furnished 0.070 g (26%) of the desired compound as a yellowish solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H). 1H NMR (DMSO-de) 509.11 (1H, s); 8.73 (1H, s); 7.70-7.81 (2H, m); 7.67 (2H, d); 7.27-7.38 (2H, m); 7.23 (1H, m); 6.95 (1H, t); 6,35-6,49 (3H, m); 6.16 (2H, m); 3.65 (3H,s); 3.17 (3H, s).
EXAMPLE 196: PREPARATION OF 1-(4-fluoro-1H-indol-3-yl)-2-((3-methoxy-phenyl)amino)-2phenylethanone
Step 1: To a solution DMF (0.670 mL; 8.653 mmol) in dichloromethane (2.5 mL) cooled to -15 °C was added dropwise phosphorus oxychloride (0.400 mL; 4.291 mmol). After 15 min at -15 °C, a solution of 4-fluoro-1H-indole (0.500 g; 3.700 mmol) in dichloromethane (2 mL) was added. The reaction mixture was allowed to warm to room température and was stirred at room température overnight. A saturated sodium bicarbonate solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (50%) in heptane as eluent furnished 0.144 g (24%) of 4-fluoro1H-indole-3-carbaldehyde as a beige solid. ESI/APCI(+): 164. ESI/APCI(-): 162 (M-H).
Step 2: tert-Butyl 4-fluoro-3-formyl-1H-îndole-1-carboxylate was prepared according to general procedure F from 4-fluoro-1H-indole-3-carbaldehyde (0,164 g; 1.005 mmol), di-tert-butyl dicarboxylate (0.301 g; 1.379 mmol) and DMAP (0.032 g; 0.261 mmol) in acetonitrile (3 mL) to furnish 0.230 g (87%) of the desired product as a beige solid, 1H NMR (DMSO-d6) 5 10.08 (1H, s); 8,59(1 H, s); 8.00(1 H, d); 7.46(1 H, dt); 7.22(1 H, t); 1.66 (9H, s).
Step 3: 1 -(4-Fluoro-1 /7-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.110 g; 0.408 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 4-fluoro-3-formyl-1/7-indole-1carboxylate (0.230 g; 0.874 mmol) and a solution of /V-benzylîdene-3-methoxyaniline (0.809 mmol) in éthanol (1.5 mL), heated at 60 °C for 72 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.021 g (7%) of the desired compound as a beige solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).
EXAMPLE 197: PREPARATION OF 1-(4-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone
Step 1 : tert-Butyl 3-formyl-4-methoxy-1/-/-indole-1-carboxylate was prepared according to general procedure F from 4-methoxy-1H-indole-3-carbaldehyde (0.400 g; 2.283 mmol), di-tertbutyl dicarboxylate (0.600 g; 2.749 mmol) and DMAP (0.030 g; 0.246 mmol) in acetonitrile (7
218 mL) to furnish 0.537 g (85%) of the desired product as a beige solid. APCI/ESCI(+): 276 (M+H). 1H NMR (DMSO-d6) δ 10.43 (1H, s); 8.19 (1H, s); 7.77 (1 H, d); 7.40 (1H, t); 7.00 (1H, d); 3.98 (3H, s); 1.66 (9H, s).
Step 2: 1-(4-Methoxy-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.115 g; 0.426 mmol) and triethylamine (0.085 mL; 0.610 mmol) in éthanol (0.5 mL), fert-butyl 3-formyl-4-methoxy-1H-indole-1-carboxylate (0.252 g; 0.915 mmol) and a solution of /V-benzylidene-3-methoxyaniline (0.800 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.031 g (10%) of the desired compound as a yellow foam. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).
EXAMPLE 198: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(6-methyl-1 Hpyrrolo[2,3-b]pyridin-3-yl)-2-phenylethanone
Step 1: /V-Benzylidene-3,5-dimethoxyaniline was prepared quantitatively according to general procedure l from benzaldehyde (0.101 mL; 0.999 mmol) and 3,5-dimethoxyaniline (0.153 g; 0.999 mmol).
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1 -(6-methyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-2phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0,070 mL; 0.504 mmol) in éthanol (1 mL), fert-butyl 3-formyl-6-methyl-1H-pyrrolo[2,3-b]pyridine-1carboxylate (0.260 g; 0.999 mmol) and a solution of A/-benzylidene-3,5-dimethoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (60%) in heptane as eluent followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.016 g (4%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (ΜΗ).
EXAMPLE 199: PREPARATION OF 4-(1-((3,5-dimethoxyphenyl)amino)-2-(1H-indol-3-yl)-2oxoethyl)benzonitrile
Step 1 : A solution of 4-(((3,5-dimethoxyphenyl)imino)methyl)benzonitrile in éthanol was prepared by heating a solution of 4-formylbenzonitrile (0.132 g; 1.007 mmol) and 3,5dimethoxyaniline (0.166 g; 1.084 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+):
267 (M+H). ESI/APCI(-): 265 (M-H).
Step 2: 4-(1-((3,5-Dimethoxyphenyl)amino)-2-(1H-indol-3-yl)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-416765
219 methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1 H-indole-1 -carboxylate (0.270 g; 1.101 mmol) and a solution of 4-(((3,5-dïmethoxyphenyl)imino)methyl)benzonitrile (1.007 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane followed by précipitation from methanol and water furnished 0.102 g (25%) of the desired compound as a yellow powder. ESI/APCI(+): 412 (M+H). ESIZAPCI(-): 410 (M-H).
EXAMPLE 200: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-pyrrolo[2,3b]pyridin-3-yl)-2-phenylethanone
2-((3,5-Dimethoxyphenyl)amino)-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 5-fluoro-3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.264 g; 0.999 mmol) and a solution of /V-benzylidene-3,5-dimethoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (55%) in heptane as eluent followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.003 g (1%) of the desired compound as a white solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).
EXAMPLE 201: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1Hindol-3-yl)ethanone
Step 1: A solution of 4-fluorobenzaldehyde (0.124 g; 0.999 mmol) and 3,5-dimethoxyaniline (0.153 g; 0.999 mmol) in éthanol (1 mL) was heated at 60 °C overnight. The reaction mixture was concentrated under reduced pressure to give quantitatively A/-(4-fluorobenzylidene)-3,5dimethoxyaniline which was used in the next step without further purification.
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.069 mL; 0.498 mmol) in éthanol (2 mL), tert-butyl 3-formyl-1 H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of A/-(4-fluorobenzylidene)-3,5-dimethoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.008 g (2%) of the desired compound as a beige solid. ESI/APCi(+): 405 (M+H). ESI/APCI(-): 403 (M-H).
EXAMPLE 202: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2(pyridin-3-yl)ethanone
220
2-((3,5-Dimethoxyphenyl)amino)-1 -( 1/-/-indol-3-yl)-2-(pyridin-3-yl)ethanone has been prepared according to 2 different procedures described hereunder as method A and method B.
Method A:
Step 1: A solution of 3,5-dimethoxy-A/-(pyrrdin-3-ylmethylene)aniline in éthanol was prepared by heating a solution of nicotinaldehyde (0.107 g; 0.999 mmol) and 3,5-dimethoxyaniline (0,153 g; 0.999 mmol) in éthanol (1.5 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1-(1/-/-indoi-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolîum chloride (0.135 g; 0.500 mmol) and triethylamine (0.069 mL; 0.498 mmol) in éthanol (1.5 mL), fert-butyl 3-formyl-1H-indole-1 -carboxylate (0.245 g; 0.999 mmol) and a solution of 3,5-dimethoxy-N-(pyridin-3-ylmethylene)aniline (0.999 mmol) in a mixture of éthanol (1.5 mL) and dichloromethane (1.5 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane followed by purification by préparative HPLC (XBrîdge column; method 5) furnished 0.010 g (3%) of the desired compound as a white solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). 1H NMR (DMSO-cfe) 5D12.21 (1H, br s); 8.94 (1H, d); 8.88 (1H, s); 8.40 (1H, d); 8.16 (1H, d); 7.96 (1H, d); 7.48 (1 H, d); 7.32 (1H, dd); 7.12-7.27 (2H, m); 6.48 (1H, d); 6.17 (1H, d); 6.06 (2H, s); 5,74(1H, s); 3.62 (6H, s).
Method B:
Step 1: A mixture of (pyrïdin-3-yl)acetic acid (1.850 g; 10.67 mmol) in acetic anhydride (1 mL) was heated in a seaied tube at 85 °C for 1 h and indole (1.250 g; 10.67 mmol) was added. The reaction mixture was heated at 85 °C for 20 min and at 105 °C for 30 min. After cooling to room température, the reaction mixture was basified (pH 8) with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.674 g (27%) of 1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone as a beige solid. ESI/APCI(+): 237 (M+H). ESI/APCI(-): 235 (M-H).
Step 2: 2-Bromo-1-(1/-/-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.570 g; 2.412 mmol) in THF (17 mL) and a solution of phenyltrimethylammonium tribromide (0.997 g; 2.652 mmol) in THF (22 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10 %) in dichloromethane furnished 0.275 g (36%) of the desired compound as a brown solid. ESI/APCI(+): 315, 317 (M+H).
Step 3: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.050 g; 0,159 mmol) and 3,5-dimethoxyaniline (0.121 g; 0.793 mmol) in acetonitrile (1 mL) was irradiated in a
221 microwave oven at 100 °C for 5 min. A saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate, The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of methanol (1% to 7%) in dichlorométhane. Further purification by préparative HPLC (XBridge column; method 5) followed by précipitation from ethyl acetate furnished 0.019 g (31%) of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone as a white solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).
EXAMPLE 203: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(6-morpholino-1H-indol-3yl)-2-phenylethanone
Step 1: To a solution of 6-nitroindole (0.800 g; 4.934 mmol) in pyridine (8 mL) cooled to 0 °C was added acetic anhydride (2.000 mL; 21,16 mmol). The reaction mixture was stirred at room température for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The phases were separated. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (40 mL) and THF (40 mL). 10% Palladium on carbon (0.080 g; 0.752 mmol) and ammonium formate (2.000 g; 31.72 mmol) were added. The reaction mixture was stirred at 60 °C for 2 h. After cooling to room température, the réaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The phases were separated. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichlorométhane furnished 0.266 g (31%) of 1-(6-amino-1H-indol-1-yl)ethanone as a brown solid.
Step 2: A mixture of 1-(6-amino-1H-indol-1-yl)ethanone (0.260 g; 1.493 mmol), 1-bromo-2-(2bromoethoxy)ethane (0.415 g; 1.789 mmol) and DIPEA (0.766 mL; 4.475 mmol) in DMF (8 mL) was stirred at 90 °C overnight. After cooling to room température, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.242 g (80%) of 4-(1H-indol-6yl)morpholine as a white solid. ESI/APCl(+): 203 (M+H). ESI/APCI(-): 201 (M-H).
Step 3: 6-Morpholino-1F/-indole-3-carbaldehyde was prepared according to general procedure R from a solution of oxalyl chloride (0.125 mL; 1.438 mmol) in dichlorométhane (8 mL), DMF (0,111 mL; 1.435 mmol) and 4-(1H-indol-6-yl)morpholine (0.242 g; 1.197 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichlorométhane furnished 0.228 g (83%) of the desired compound as a white solid. ESI/APCI(+): 231 (M+H). ESI/APCI(-): 229 (M-H).
Step 4: To a solution of 6-morpholino-1H-indole-3-carbaldehyde (0.228 g; 0.990 mmol) in dichlorométhane (15 mL) were added di-ferî-butyl dicarbonate (0.259 g; 1.188 mmol), DMAP
222 (0.024 g; 0.198 mmol) and triethylamine (0.165 mL; 1.190 mmol). After stirring for 30 min, the reaction mixture was washed with a saturated bicarbonate solution. The organic phase was washed with a saturated ammonium chloride solution, dried over magnésium sulfate, filtered and concentrated under reduced pressure to give 0.308 g (94%) of tert-butyl 3-formyl-6morpholino-1H-indole-1-carboxylate as a white solid. ESI/APCI(+): 331 (M+H).
Step 5: 2-((3-Methoxyphenyl)amîno)-1 -(6-morpholino-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.082 g; 0.304 mmol) and triethylamine (0.042 mL; 0.303 mmol) in éthanol (2 mL), tert-butyl 3-formyl-6-morpholino-1H-indole-1-carboxylate (0.200 g; 0.605 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.605 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from diethyl ether furnished 0.059 g (22%) of the desired compound as a yellow solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H). 1H NMR (DMSO-d6) 5Π11.84 (1H, br s); 8.71 (1 H, br s); 7.97 (1H, d); 7.62 (2H, d); 7.22 (2H, m); 7.19 (1H, d); 6.90 (2H, m); 6.86 (1 H. br s); 6.35 (2H, m); 6.31 (1H, d); 6.10 (1H, d); 6.04 (1H, d); 3.75 (4H, br s); 3.62 (3H, s); 3.07 (4H, br s).
EXAMPLE 204: PREPARATION OF 2-(imidazo[1,2-b]pyridazin-2-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: To a solution of imidazo[1,2-b]pyridazine-2-carboxylic acid (0.390 g; 2.391 mmol) in dichloromethane (7 mL) were added DIPEA (1.500 mL; 8.589 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (0.505 g; 2.634 mmol) and hydroxybenzotriazole (0.406 g; 2.651 mmol). The solution was stirred at room température for 10 min and Λ/,Ο-dimethylhydroxylamine hydrochloride (0.266 g; 2.727 mmol) was added. The reaction mixture was stirred at room température for 4 h. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution and brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to furnîsh 0.360 g (73%) of Nmethoxy-N-methylimidazo[1,2-b]pyridazine-2-carboxamide as a yellow oil. ESl/APCI(+): 207 (M+H).
Step 2: To a solution of /V-methoxy-A/-methylimidazo[1,2-b]pyridazine-2-carboxamide (0.360 g;
1.746 mmol) in THF (10 mL) cooled to 0 °C was added lithium aluminium hydride (0.075 g;
1.976 mmol). The reaction mixture was stirred at room température for 1.5 h. A citric acid buffer (pH 5) solution was added and the reaction mixture was stirred at room température for 20 min.
The reaction mixture was filtered through celite and the solid was washed with ethyl acetate.
The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over magnésium sulfate, filtered and
223 concentrated under reduced pressure to furnish 0.190 g (74 %) of imidazo[1,2-ib]pyridazine-2carbaldehyde as a yellow solid. ESI/APCI(+): 148 (M+H). 1H NMR (DMSO-cQ δ 10.09 (1H, s);
9.02(1 H, s); 8.69(1 H, s); 8.28 (1 H, d); 7.39 (1 H, d).
Step 3: A solution of /V-(imidazo[1,2-b]pyridazin-2-ylmethylene)-3-methoxyaniline in éthanol was prepared by heating a solution of imidazo[1,2-b]pyridazine-2-carbaldehyde (0.124 g; 0.843 mmol) and 3-methoxyaniline (0.101 mL; 0.901 mmol) in éthanol (2 mL) at 60 ’C for 20 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 253 (M+H).
Step 4: 2-(lmidazo[1,2-b]pyridazin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.120 g; 0.445 mmol) and triethylamine (0.080 mL; 0.574 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.250 g; 1.019 mmol) and a solution of A/-(imidazo[1,2-b]pyridazin-2-ylmethylene)-3-methoxyaniline (0.843 mmol) in éthanol (2.5 mL), heated at 60 °C for 72 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by crystallization from ethyl acetate furnished 0.055 g (16%) of the desired compound as a white solid. ESI/APCI(+): 398 (M+H). ESI/APCI(-): 396 (M-H).
EXAMPLE 205: PREPARATION OF 2-(6-(dimethylamino)pyridin-3-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: 5-(((3-Methoxyphenyl)imino)methyl)-A/,/V-dimethylpyridin-2-amlne was prepared quantitatively according to general procedure I from 6-(dimethylamlno)nicotinaldehyde (0.150 g; 0.999 mmol) and 3-methoxyaniline (0,112 mL; 1.001 mmol).
Step 2: 2-(6-(Dimethylamino)pyridin-3-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1carboxylate (0.245 g; 0.999 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)-A/,/Vdimethylpyridin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by précipitation from ethyl acetate furnished 0.026 g (6%) of the desired compound as a white solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M+H).
EXAMPLE 206: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2methoxypyrimidin-5-yl)ethanone
Step 1: 3-Methoxy-/V-((2-methoxypyrimidin-5-yl)methylene)aniline was prepared quantitatively according to general procedure I from 2-methoxypyrimidine-5-carbaldehyde (0.138 g; 0.999 mmol) and 3-methoxyanlline (0.112 mL; 1.001 mmol).
Step 2: 1-(1 H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyrimidin-5-yl)ethanone was
224 prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3-methoxy-/\/-((2-methoxypyrimidin-5-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by précipitation from ethyl acetate furnished 0.093 g (24%) of the desired compound as a white solid. ESI/APCI(+): 389 (M+H). ESIZAPCI(-): 387 (M-H).
EXAMPLE 207: PREPARATION OF 1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5methoxypyridin-3-yl)amino)ethanone
Step 1: A solution of 5-methoxy-A/-((6-methoxypyridin-3-yl)methylene)pyridin-3-amine in éthanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.137 g; 0.999 mmol) and 5methoxypyridin-3-amine (0.124 g; 0.999 mmol) in éthanol (0.25 mL) at 45 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ES!/APCI(+): 244 (M+H); 487 (2M+H).
Step_______2: 1-(5-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-
5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.263 g; 0.999 mmol) and a solution of 5-methoxy-/V-((6-methoxypyridin-3-yl)methylene)pyridin3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane followed by précipitation from diethyl ether furnished 0.095 g (23%) of the desired compound as a white solid. ESI/APCI(+): 407 (M+H). ESIZAPCI(-): 405 (M-H).
EXAMPLE 208: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5methoxypyridin-3-yl)amino)ethanone
1-(6-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 6-fluoro-3-formyl-1H-indole-1 -carboxylate (0.263 g; 0.999 mmol) and a solution of 5-methoxy-/V-((6-methoxypyridin-3-yl)methylene)pyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane followed by précipitation from diethyl ether furnished 0.053 g (13%) of the desired compound as a white solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M+H).
EXAMPLE 209: PREPARATION OF 2-((3-(2-(dimethylamino)ethoxy)-5-methoxyphenyl)amino)1 -(1 H-indol-3-yl)-2-phenylethanone
225
Step 1: To a solution of /V,A/-dimethylethanolamine (2.000 g; 22,44 mmol) in diethyl ether (100 mL) cooled to 0 °C was added dropwise methanesulfonyl chloride (1,910 mL; 24,68 mmol). The reaction mixture was stirred at room température for 65 h. The resulting white solid was filtered, washed with diethyl ether and dried under vacuum to give 4.460 g (97%) of 2(dimethylamino)ethyl methanesulfonate hydrochloride.
Step 2: To a solution of 3,5-dimethoxyaniline (2.500 g; 16.32 mmol) in NMP (12 mL) was added sodium methanethiolate (2.290 g; 32.64 mmol) and the reaction mixture was heated to 140 °C ovemight. After cooling to room température, the reaction mixture was poured into a saturated sodium phosphate monobasic solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 1.400 g (62%) of 3-amino-5methoxyphenol as an orange oil. ESI/APCI(+): 140 (M+H).
Step 3: To a solution of 3-amino-5-methoxyphenol (0.500 g; 3.593 mmol) in DMF (25 mL) cooled to 0 °C was added portionwise sodium hydride (60% dispersion in minerai oil; 0.316 g; 7.925 mmol) followed by 2-(dimethylamino)ethyl methanesulfonate hydrochloride (0.731 g; 3.593 mmol). The reaction mixture was stirred at room température for 60 h. A saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2% to 20%) in dichloromethane furnished 0.264 g (35%) of 3-(2-(dimethylamino)ethoxy)-5-methoxyaniline as a brown oil. ESI/APCI(+): 211 (M+H).
Step 4: A mixture of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0,150 g; 0.556 mmol) and 3(2-(dimethylamino)ethoxy)-5-methoxyaniline (0.117 g; 0.556 mmol) in acetonitrile (1 mL) was irradiated in a microwave oven at 150 °C for 30 min. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2% to 20%) in dichloromethane followed by purification by préparative TLC using methanol (10%) in dichloromethane as eluent furnished 0.005 g (18%) of 2-((3-(2-(dimethylamino)ethoxy)-5-methoxyphenyl)amino)-1-(1/7-indol-3-yl)-2phenylethanone as a beige solid. ESI/APCI(+): 444 (M+H). ESIZAPCI(-): 442 (M-H). 1H NMR (DMSO-d6) 5012.14 (1 H. br s); 8.90 (1 H, br s); 8.16 (1 H, d); 7.63 (2H, d); 7.46 (1H, d); 7.27 (2H, m); 7.19 (3H, m); 6,33 (1H, d); 5.97-6.17 (3H, m); 5.71 (1H, br s); 3.89 (2H, m); 3.61 (3H, s); 2.55 (2H, m); 2.18 (6H, s).
EXAMPLE 210: PREPARATION OF 1 -(1-(2-(tert-butoxy)ethyl)-6-fluoro-1 H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: To a solution of 2-(tert-butoxy)ethanol (2.220 mL; 16.92 mmol) in dichloromethane (50 mL) cooled to 0 °C were added triethylamine (2.820 mL; 20.31 mmol), tosyl chloride (3.870 g,
20.31 mmol) and DMAP (0.413 g; 3.381 mmol). The reaction mixture was allowed to warm to
226 room température and was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with a saturated ammonium chloride solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 3.930 g (85%) of 2-(tertbutoxy)ethyl 4-methylbenzenesulfonate as a colorless oil. ESI/APCI(+): 295 (M+Na).
Step 2: To a solution of 2-chloro-1-(6-fluoro-1H-indol-3-yl)-2-phenylethanone (0.139 g; 0.483 mmol) in THF (4 mL) cooled to 0 °C was added sodium hydride (60% dispersion in minerai oil; 0.035 g; 0.870 mmol). The mixture was stirred at room température for 30 min. 2-(tertButoxy)ethyl 4-methylbenzenesulfonate (0.263 g; 0.966 mmol) was added and the reaction mixture was stirred at room température for 60 h. The reaction mixture was partitioned between ethyl acetate and a saturated ammonium chloride solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.085 g (45%) of 1-(1-(2-(tertbutoxy)ethyl)-6-fluoro-1H-indol-3-yl)-2-chloro-2-phenylethanone as an orange oil. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).
Step 3: 1 -(1-(2-( tert-Butoxy)ethyl)-6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to general procedure E from 1-(1-(2-(tertbutoxy)ethyl)-6-fluoro-1H-indol-3-yl)-2-chloro-2-phenylethanone (0.085 g; 0.219 mmol) and manisidine (0.245 mL; 2,188 mmol) In acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.066 g (64%) of 1-(1-(2-(fert-butoxy)ethyl)-6-fluoro1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone as an orange solid. ESI/APCI(+): 475 (M+H); 497 (M+Na). ESI/APCI(-): 473 (M-H).
EXAMPLE 211: PREPARATION OF 1-(6-fluoro-1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
1-(1-(2-(tert-Butoxy)ethyl)-6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone (0.066 g; 0.139 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3.000 mL; 12.00 mmol). The reaction mixture was stirred at room température overnight. The solution was neutralîzed with potassium carbonate and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.007 g (11%) of 1-(6-fluoro-1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone as a white solid. ESI/APCI(+): 419 (M+H). ESI/APCI(-): 417 (M-H). ’H NMR (DMSO-de) δΠ8.95 (1H, br s); 8.14 (1H, m); 7.63 (2H, d); 7.51 (1 H, d); 7.23-7.35 (2H, m); 7.19 (1 H, m); 7.07 (1H, t); 6.91 (1H, t); 6.31-6.46 (3H, m); 6.11 (1H, d); 6.04 (1H, d); 4.99 (1H, br s);
4.30 (2H, m); 3.78 (2H, m); 3.62 (3H, s).
227
EXAMPLE 212: PREPARATION OF 2-((5-ethoxypyridin-3-yl)amino)-1-(1 H-indol-3-yl)-2phenylethanone
Step 1 : To a suspension of sodium hydride (60% dispersion in minerai oil; 1.690 g; 42.21 mmol) in DMF (15 mL) cooled to 0 °C was added dropwise éthanol (2.460 mL; 42.21 mmol). The mixture was stirred at 0 °C for 30 min and 3,5-dibromopyridine (5.000 g; 21.11 mmol) was added. The reaction mixture was allowed to warm to room température and stirred at room température for 60 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (30% to 100%) in heptane furnished 1.920 g (45%) of 3-bromo-5-ethoxypyridine as an oil. ESI/APCI(+): 202, 204 (M+H).
Step 2: A mixture of 3-bromo-5-ethoxypyridine (1.000 g; 4.949 mmol), copper(ll) sulfate pentahydride (0.238 g; 0,990 mmol) and a 25% ammonium hydroxide solution (7.620 mL; 49.49 mmol) was placed in a sealed vessel and heated at 140 °C overnight. After cooling to room température, a 1N sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane furnished 0.357 g (52%) of 5-ethoxypyridin-3-amine as an orange oil. ESI/APCI(+): 139 (M+H). ESIZAPCI(-): 137 (M-H).
Step 3: /\/-Benzylidene-5-ethoxypyridin-3-amine was prepared quantitatively according to general procedure I from benzaldehyde (0.102 mL; 1.004 mmol) and 5-ethoxypyridin-3-amine (0.138 g; 0.999 mmol).
Step 4: 2-((5-Ethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of A/-benzylidene-5-ethoxypyridin-3-amine (0.999 mmol) in éthanol (1.5 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane followed by précipitation from ethyl acetate furnished 0.090 g (24%) of the desired compound as a green solid. ESI/APCI(+): 372 (M+H). ESIZAPCI(-): 370 (M-H).
EXAMPLE 213: PREPARATION OF 1-(1H-indol-3-yl)-2-((5-isopropoxypyridin-3-yl)amino)-2phenylethanone
Step 1: To a suspension of sodium hydride (60% dispersion in minerai oil; 1.690 g; 42.21 mmol) in DMF (15 mL) cooled to 0 °C was added dropwise isopropanol (3.230 mL; 42.21 mmol). After min at 0 °C, 3,5-dibromopyridine (5.000 g; 21.11 mmol) was added. The reaction mixture was allowed to warm to room température and stirred at room température for 16 h. The
228 reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (15% to 70%) in heptane furnished 1.210 g (26%) of 3bromo-5-isopropoxypyridine as an oil. ESI/APCI(+): 216, 218 (M+H).
Step 2: A mixture of 3-bromo-5-isopropoxypyridine (1.000 g; 4.628 mmol), copper(ll) sulfate pentahydride (0.223 g; 0.926 mmol) and a 25% ammonium hydroxide solution (7.130 mL; 46.28 mmol) was placed in a sealed vessel and heated at 140 °C overnight. After cooling to room température, a 1N sodium hydroxide solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane furnished 0.243 g (34%) of 5-isopropoxypyridin-3-amine as an orange oil. ESI/APCK+); 153 (M+H).
Step 3: A/-Benzylidene-5-isopropoxypyridin-3-amine was prepared quantitatively according to general procedure I from benzaldehyde (0,102 mL; 1.004 mmol) and 5-isopropoxypyridin-3amine (0.152 g; 0.999 mmol).
Step 4: 1-(1H-lndol-3-yl)-2-((5-isopropoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of A/-benzylidene-5-isopropoxypyridin-3-amine (0.999 mmol) in éthanol (1.5 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane followed by précipitation from ethyl acetate and heptane furnished 0.045 g (12%) of the desired compound as a beige solid. ESI/APCI(+): 386 (M+H). ESI/APCI(-): 384 (M-H).
EXAMPLE 214: PREPARATION OF 2-((5-ethylpyridin-3-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone
Step 1: A solution of A/-benzylidene-5-ethylpyridin-3-amine in éthanol was prepared by heating a solution of benzaldehyde (0.102 mL; 1.008 mmol) and 3-amino-5-ethylpyridine (0.117 g; 0.958 mmol) in éthanol (0.5 mL) at 60 °C for 16 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 211 (M+H).
Step 2: 2-((5-Ethylpyridin-3-yl)amino)-1-(1 A7-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.126 g; 0.467 mmol) and triethylamine (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.250 g; 1.019 mmol) and a solution of Nbenzylidene-5-ethylpyridin-3-amine (0.958 mmol) in éthanol (1.5 mL), heated at 60 °C for 16 h.
Purification by solid phase extraction on C18-reversed phase column using a gradient of acetonitrile (0% to 100%) in water furnished 0.051 g (15%) of the desired compound as a yellow
229 solid, ESl/APC!(+): 356 (M+H). ESI/APCI(-): 354 (M-H).
EXAMPLE 215: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5methoxypyrazin-2-yl)ethanone
Step 1: 3-Methoxy-A/-((5-methoxypyrazin-2-yl)methylene)aniline was prepared quantitatively according to general procedure I from 5-methoxypyrazine-2-carbaldehyde (0.138 g; 0.999 mmol) and 3-methoxyaniline (0.112 mL; 1.001 mmol).
Step 2: 1-(1/7-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3-methoxy-A/-((5-methoxypyrazin-2-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from dichloromethane furnished 0.142 g (36%) of the desired compound as a white solid. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H).
EXAMPLE 216: PREPARATION OF 2-(6-ethoxypyridin-3-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A solution of /V-((6-ethoxypyridin-3-yl)methylene)-3-methoxyaniline in éthanol was prepared by heating a solution of 6-ethoxynicotinaldehyde (0.153 g; 1.012 mmol) and 3methoxyaniline (0.114 mL; 1.012 mmol) in éthanol (0.5 mL) at 60 °C for 16 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 257 (M+H).
Step 2: 2-(6-Ethoxypyridin-3-yl)-1-(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.143 g; 0.530 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.273 g; 1.113 mmol) and a solution of A/-((6-ethoxypyridin-3-yl)methylene)-3-methoxyaniline (1.012 mmol) in éthanol (1.5 mL), heated at 60 °C for 72 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 45%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.058 g (14%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H). ESIZAPCI(-): 400 (M-H).
EXAMPLE 217: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(4-methyl-1H-indol-3-yl)-2phenylethanone
Step 1 : tert-Butyl 3-formyl-4-methyl-1/7-indole-1-carboxylate was prepared according to according to general procedure F from 4-methyl-1H-indole-3-carbaldehyde (0.250 g; 1.571 mmol), di-tert-butyl dicarboxylate (0.445 g; 2.039 mmol) and DMAP (0.030 g; 0.246 mmol) in acetonitrile (4 mL) to yield 0.392 g (96%) of the desired compound as a yellow solid. 1H NMR
230 (DMSO-cfe) δ 10.06 (1H, s); 8.59 (1 H, s); 8.01 (1H, d); 7.33 (1H, t); 7.17 (1H, s); 2.76 (3H, s);
1,66 (9H, s).
Step 2: 2-((3-Methoxyphenyl)amino)-1-(4-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.137 g; 0.508 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-4-methyl-1/7-indole-1-carboxylate (0.277 g; 1.068 mmol) and a solution of /V-benzylidene-3-methoxyaniline (0.989 mmol) in éthanol (1.5 mL), heated at 60 °C for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.046 g (13%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).
EXAMPLE 218: PREPARATION OF 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2phenylethanone
Step 1: A/-Benzylidene-6-methoxypyrazin-2-amine was prepared quantitatively according to general procedure I from benzaldehyde (0.102 mL; 1.004 mmol) and 6-methoxypyrazin-2-amine (0.125 g; 0.999 mmol).
Step 2: 1-(1H-lndol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1/7-indoîe-1-carboxylate (0.245 g; 0.999 mmol) and a solution of A/-benzylidene-6-methoxypyrazin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C ovemight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from diethyl ether furnished 0.048 g (13%) of the desired compound as a beige solid. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H). 1H NMR (DMSO-cf6j) δθ 12.02 (1H, brs); 8.72 (1H, s); 8.17 (1H, d); 7.78 (1H, d); 7.76 (1 H, s); 7.67 (2H, d); 7.45 (1H, d); 7.31-7.38 (2H, m); 7.30 (1H, s); 7.13-7.28 (3H, m); 6.39 (1H, d); 3.60 (3H, s).
EXAMPLE 219: PREPARATION OF 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1(1H-indol-3-yl)-2-phenylethanone AND 2-((3-ethoxy-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-
2-phenylethanone
Step 1: To a solution of 3-amino-5-methoxyphenol (0.447 g; 3.214 mmol) in DMF (20 mL) cooled to 0 °C was added portionwise sodium hydride (60% dispersion in minerai oil; 0.282 g;
7.050 mmol). After addition of a solution of 2-(tert-butoxy)ethyl 4-methylbenzenesulfonate (0.875 g; 3.213 mmol) in DMF (3 mL), the reaction mixture was stirred at room température for
h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.241 g of 3-(2-(tert16765
231 butoxy)ethoxy)-5-methoxyaniline (contaminated with 3-ethoxy-5-methoxyaniline) as a brown oil. ESI/APCI(+): 240 (M+H).
Step________2: 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3yl)-2-phenylethanone (0.120 g; 0.445 mmol), 3-(2-(tert-butoxy)ethoxy)-5-methoxyaniline (0.106 g; 0.445 mmol) and triethylamine (0.124 mL; 0.890 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 150 °C for 30 min. Purification by flash chromatography on silica gel using dichloromethane as eluent furnished 0.054 g (26%) of 2-((3-(2-(tert-butoxy)ethoxy)-5methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 473 (M+H); 495 (M+Na). ESI/APCI(-): 471 (M-H).
2-((3-Ethoxy-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was also isolated after the purification by flash column on silica gel described above. Further purification by préparative HPLC (XBridge column; method 5) furnished 0.008 g of pure compound as a white solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H). 1H NMR (DMSO-d6) 5Π12.14 (1H, br s);
8.90 (1H, s); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.25-7.35 (2H, m); 7.11-7.24 (3H, m); 6.32 (1H, d); 5.97-6.13 (3H, m); 5.69 (1H, s); 3.87 (2H, q); 3.60 (3H, s); 1.24 (4H. t).
EXAMPLE 220: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-phenylethanone
2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone (0.054 g; 0.114 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3.000 mL; 12.00 mmol). The reaction mixture was stirred at room température for 6 h. The reaction mixture was poured into a mixture ice/water, neutralized with potassium carbonate and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from diethyl ether furnished 0.009 g (19%) of 2-((3-(2hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 417 (M+H). ESI/APCI(-): 415 (M-H). Ή NMR (DMSO-de) ÔC12.13 (1H, br s); 8.89 (1H, s); 8.17 (1H, d); 7.63 (2H, d); 7.47 (1H, d); 7,25-7.33 (2H, m); 7.14-7.25 (3H, m); 6.32 (1H, d); 6.07 (1H, d); 6.05 (2H, br s); 5.72 (1H, s); 4.77 (1H, t); 3.78-3.90 (2H, m); 3.63-3.69 (2H, m); 3.62 (3H, s).
EXAMPLE 221: PREPARATION OF 2-((5,6-dimethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone
Step 1: To a solution of sodium methoxide (0.215 g; 3.980 mmol) in methanol (13 mL) was added 2-chloro-3-methoxy-5-nitropyridine (0.500 g; 2.652 mmol). After 5.5 h at room température, sodium methoxide (0.215 g; 3.980 mmol) was added and the reaction mixture was stirred at room température overnight. Sodium methoxide (0.215 g; 3.980 mmol) was added again. After 4,5 h at room température, the reaction mixture was concentrated under reduced
232 pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished 0.467 g (96%) of 2,3-dimethoxy-5nitropyridine as a yellow powder. ESI/APCI(+): 185 (M+H). 1H NMR (DMSO-d6) δ 8.69 (1H, s);
7.94 (1H, s); 4.02 (3H, s); 3.93 (3H, s).
Step 2: To a suspension of 2,3-dimethoxy-5-nitropyridine (0.463 g; 2.514 mmol) in water (9 mL) was added acetic acid (0.500 mL; 8.734 mmol). After portionwise addition of sodium dithionite (1.670 g; 9.562 mmol), the suspension was stirred at room température for 4 h. The reaction mixture was poured into a mixture ice/1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichlorométhane furnished 0.111 g (29%) of 5,6-dimethoxypyridin-3amine as a pink solid. ESI/APCI(+): 155 (M+H). 1H NMR (DMSO-cfe) δ 7.03 (1 H, s); 6.65 (1H, s); 4.72 (2H, br s); 3.70 (6H, m).
Step 3: A solution of N-benzylidene-5,6-dimethoxypyridin-3-amine in éthanol was prepared by heating a solution of benzaldehyde (0.067 mL; 0.661 mmol) and 5,6-dimethoxypyridin-3-amine (0.101 g; 0.655 mmol) in éthanol (1.3 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H).
Step 4: 2-((5l6-Dimethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3-ium chloride (0.090 g; 0.334 mmol) and triethylamine (0.045 mL; 0.325 mmol) in éthanol (0.5 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.193 g; 0.787 mmol) and a solution of Nbenzylidene-5,6-dimethoxypyridin-3-amine (0.655 mmol) in éthanol (1.3 mL), heated at 70 °C for 65 h. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichlorométhane. Further purification by préparative HPLC (XBridge column; method 5) followed by recrystallization from ethyl acetate and heptane furnished 0.006 g (2%) of the desired product as a pink powder. ESI/APCI(+): 388 (M+H); 410 (M+Na). ESI/APCI(-): 386 (M-H). 1H NMR (DMSO-de) δ 12.16 (1 H. br s); 8.87 (1H, s); 8.16 (1H, d); 7.63 (2H, m); 7.30 (1H, d); 7.17-7.26 (6H, m); 7.05 (1H, s); 6.11 (2H, m); 3.67 (6H, d).
EXAMPLE 222: PREPARATION OF 2-((6-(dimethylamino)-5-methoxypyridin-3-yl)amino)-1-(1Hindol-3-yl)-2-phenylethanone
Step 1: To a 2M dimethylamine solution in THF (6.250 mL; 12.50 mmol) was added 2-chloro-3methoxy-5-nitropyridine (0.471 g; 2.500 mmol). The reaction mixture was stirred at 80 °C for 16 h and was concentrated under reduced pressure. The crude bright yellow residue was dissolved in methanol (20 mL). Palladium on carbon (0.030 g, 0.282 mmol) was added and the reaction mixture was stirred at room température for 16 h under hydrogen atmosphère. The reaction
233 mixture was filtered over diatomaceous earth and the filter cake was washed with éthanol. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.337 g (81%) of 3methoxy-A^A-dimethylpyridine^^-diamine. ESI/APCI(+): 168 (M+H).
Step 2: A mixture of benzaldehyde (0.102 mL; 1.004 mmol) and S-methoxy-Af.A/2dimethylpyridine-2,5-diamine (0.167 g; 0.999 mmol) in methanol (0.25 mL) was stirred at 45° C for 24 h. The solvent was evaporated and the residue was dried under reduced pressure to give N5-benzylidene-3-methoxy-/\/2,N2-dimethylpyridine-215-diannine quantitatively which was used without further purification. ESI/APCI (+): 256 (M+H).
Step 3: 2-((6-(Dimethylamino)-5-methoxypyridin-3-yl)annino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) In éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of N&-benzylidene-3-methoxy-A/2,A/2-dimethylpyridine-2,5-diamine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by crystallization from acetonitrile furnished 0.046 g (12%) of the desired compound as a light brown solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M+H).
EXAMPLE 223: PREPARATION OF 2-((6-ethoxy-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3yl)-2-phenylethanone
Step 1: To a 21% sodium ethoxide solution in éthanol (2.000 mL; 5.357 mmol) was added 2chloro-3-methoxy-5-nitropyridine (0.500 g; 2.652 mmol). The reaction mixture was stirred at room température overnight and was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 0.476 g of 2-ethoxy-3-methoxy-5-nitropyridine as a brown foam which was used in the next step without further purification. ESI/APCI(+): 199 (M+H).
Step 2: To a suspension of 2-ethoxy-3-methoxy-5-nitropyridine (0.250 g; 1.261 mmol) in éthanol (8.5 mL) cooled to 0 °C was added a 2N hydrochloric acid solution (6.600 mL; 13.20 mmol). After addition of zinc (1.800 g; 27.53 mmol), the reaction mixture was stirred at room température for 3 h. The reaction mixture was poured into a mixture ice/1N sodium hydroxide solution and was filtered through celite. The filtrate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.168 g (72% over two steps) of 6-ethoxy-
5- methoxypyridin-3-amine as a brown solid. ESI/APCI(+): 169 (M+H); 191 (M+Na). ’H NMR (DMSO-d6) δ 7.02 (1H, s); 6.65 (1H, s); 4.68 (2H, br s); 4.15 (2H, q); 3.69 (3H, s); 1.25 (3H, t).
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Step 3: A solution of N-benzylidene-6-ethoxy-5-methoxypyridin-3-amine in éthanol was prepared by heating a solution of benzaldehyde (0.100 mL; 0.942 mmol) and 6-ethoxy-5methoxypyridin-3-amine (0.164 g; 0.975 mmol) in éthanol (2 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 257 (M+H).
Step 4: 2-((6-Ethoxy-5-methoxypyridln-3-yl)amino )-1-(1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.134 g; 0.497 mmol) and triethylamine (0.067 mL; 0.483 mmol) in éthanol (0.7 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.287 g; 1.170 mmol) and a solution of N-benzylidene-6-ethoxy-5-methoxypyridin-3-amine (0.942 mmol) in éthanol (2 mL), heated at 70 °C for 65 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.018 g (5%) of the desired product as a pink powder. ESI/APCi(+): 402 (M+H); 424 (M+Na). ESI/APCI(-): 400 (M-H). 1H NMR (DMSO-de) δ 12.16 (1H, br s); 8.87 (1H, s); 8.15 (1H, d); 7.63 (2H, m); 7.46 (1H, d); 7.20-7.29 (6H, m); 7.04 (1H, s); 6.10 (2H, s); 4.09 (2H, q); 3.69 (3H, s); 1.22 (3H, t).
EXAMPLE 224: PREPARATION OF 2-((5-methoxypyridin-3-yl)amino)-1-(1 -methyl-1 H-indazol3-yl)-2-phenylethanone
2- ((5-Methoxypyridin-3-yl)amino)-1-(1-methyl-1 F/-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of Nbenzylidene-5-methoxypyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from éthanol and diethyl ether furnished 0.092 g (24%) of the desired compound as a white solid. ESI/APCI(+): 373 (M+H). ESI/APCI(-): 371 (ΜΗ).
EXAMPLE 225: PREPARATION OF 4-(1-((3-methoxyphenyl)amino)-2-(1-methyl-1H-indazol-3yl)-2-oxoethyl)benzonitrile
4- (1 -((3-Methoxyphenyl)amino)-2-(1 -methyl-1 H-indazol-3-yl)-2-oxoethyl)benzonitrile was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of
4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by précipitation from éthanol furnished 0.176 g (43%) of the desired compound as a white solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).
235
EXAMPLE 226: PREPARATION OF 1-(1H-indol-3-yl)-2-((5-methoxy-6-(methylamino)pyridin-3yl)amino)-2-phenylethanone
Step 1:
To a 2M methylamine solution in THF (6.250 mL; 12.500 mmol) was added 2-chloro-3-methoxy-
5-nitropyridine (0.471 g; 2.500 mmol). The reaction mixture was stirred at 80 °C for 16 h and was concentrated under reduced pressure. The crude bright yellow residue was dissolved in methanol (20 mL) and palladium on carbon (0.030 g, 0.282 mmol) was added. The reaction mixture was stirred at room température for 16 h under hydrogen atmosphère. The reaction mixture was filtered over diatomaceous earth and the filter cake was washed with éthanol. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.172 g (45%) of 3methoxy-W2-methylpyridine-2,5-diamine. ESI/APCI(+): 154 (M+H).
Step 2: A mixture of benzaldehyde (0.114 mL; 1.123 mmol) and 3-methoxy-A/2-methylpyridine-
2,5-diamine (0.172 g; 1.123 mmol) in methanol (0.25 mL) was stirred at 45° C for 24 h. The reaction mixture was concentrated under reduced pressure to give quantitatively Λ/5benzylidene-3-methoxy-N2-methylpyridine-2,5-diamine which was used without further purification. ESI/APCI (+): 242 (M+H).
Step 3: 1-(1H-lndol-3-yl)-2-((5-methoxy-6-(methylamino)pyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.151 g; 0.562 mmol) and triethylamine (0.079 mL; 0.562 mmol) in éthanol (1 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.275 g; 1.121 mmol) and a solution of A/5-benzylidene-3-methoxy-W2-methylpyridine-2,5-diamine (1.123 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by crystallization from acetonitrile furnished 0.008 g (2%) of the desired compound as a white solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).
EXAMPLE 227: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1/-/indol-3-yl)-2-phenylethanone
Step 1: To a solution of the 3-amino-5-methoxybenzoic acid (2.500 g; 14.96 mmol) in éthanol (30 mL) cooled to 0 °C, was added dropwise thionyl chloride (1.500 mL; 20.68 mmol) over 15 min. The resulting suspension was stirred at room température for 1 h and refluxed for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure to yield crude ethyl 5-amino-2-chlorobenzoate as brown oil. To a suspension of lithium aluminium hydride (2.200 g; 57.99 mmol) in THF (15 mL) cooled to 0 °C was slowly added a solution of ethyl 5-amino-2-chlorobenzoate (14.50 mmol) in THF (30 mL).
236
The reaction mixture was stirred at 0°C for 30 min and at room température for 2 h. After cooling to 0 °C, the reaction was quenched by slow addition of a 1N Rochelle sait solution. The reaction mixture was stirred for 2 h and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane furnished 1.670 g (75%) of (3-amino-
5-methoxyphenyl)methanol as a white solid. ESI/APCI(+): 154 (M+H).
Step 2: A solution of 3-(benzylideneamino)-5-methoxyphenyl)methanol in éthanol was prepared by heatîng a solution of benzaldehyde (0.102 mL; 1.004 mmol) and (3-amino-5methoxyphenyl)methano! (0.153 g; 0.999 mmol) in éthanol (1 mL) at 60°C overnight. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 342 (M+H).
Step 3: 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from dichloromethane furnished 0.060 g (15%) of the desired compound as a white solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H). 1H NMR (DMSO-d6) 0012.10 (1 H, brs); 8.87 (1H, s); 8.17 (1 H. d); 7.64 (2H, d); 7.47 (1H, d); 7.29 (2H, t); 7.12-7.25 (3H, m); 6.41 (1H, s); 6.22-6.32 (2H, m); 6.12 (1H, s); 6.09 (1H, d); 4.97 (1H, br s); 4.30 (2H, d); 3.63 (3H. s).
EXAMPLE 228: PREPARATION OF 2-((3-((dimethylamino)methyl)-5-methoxyphenyl)amino)-1(1H-indol-3-yl)-2-phenylethanone
Step 1: To a solution of (3-amino-5-methoxyphenyl)methanol (0.500 g; 3.264 mmol) in dichloromethane (30 mL) was added triethylamine (0.635 mL; 4.581 mmol) followed by mesyl chloride (0.278 mL, 3.592 mmol). The mixture was stirred at room température for 2 h. A 2M dimethylamine solution in THF (2.000 mL; 4.000 mmol) was added and the mixture was stirred at room température overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2% to 15%) in dichloromethane furnished 0.192 g (32%) of 3-((dimethylamino)methyl)-5methoxyanîline as an oil. ESI/APCI(+): 180 (M+H).
Step 2: A mixture of 2-ch!oro-1-(1H-indol-3-yl)-2-phenylethanone (0.170 g; 0.630 mmol) and 3((dimethylamino)methyl)-5-methoxyaniline (0.102 g; 0.567 mmol) in acetonitrile (1 mL) was irradiated in a microwave oven at 150 °C for 15 min. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of
237 methanol/25% ammonium hydroxide (9/1) (2% to 20%) in dichloromethane furnished 0.032 g (13%) of 2-((3-((dimethylamino)methyl)-5-rnethoxyphenyl)amino)-1 -( 1 /-/-indol-3-yl)-2phenylethanone as a white solid. ESI/APCI(+): 414 (M+H). ESI/APCI(-): 412 (M-H). 1H NMR (DMSO-c/6) ÔC12.14 (1 H, br s); 8.89 (1H, d); 8.16 (1 H. d); 7.64 (2H, d); 7.46 (1 H. d); 7.24-7.24 (5H, m); 6.39 (1H, s); 6.24-6.34 (2H, m); 6.03-6.13 (2H, m); 3.61 (3H, s); 3.21 (2H, s); 2.09 (6H, s).
EXAMPLE 229: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1(1 -methyl-1 H-îndazol-3-yl)ethanone
2- ((3-Methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1-(1-methyl-1 H-indazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of
3- methoxy-N-((6-methoxypyridin-3-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. The precipitate was filtered, washed with éthanol and dried under reduced pressure to furnish 0.249 g (61%) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H).
EXAMPLE 230: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1 H-indazol-3yl)-2-phenylethanone
2- ((3,5-Dimethoxyphenyl)amino)-1 -(1 -methyl-1 H-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of Nbenzylidene-3,5-dimethoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane followed by purification by solid phase extraction on C18-reversed phase column using a gradient of acetonitrile (30% to 100%) in water. Further purification by crystallization from acetonitrile furnished 0.008 g (2%) of the desired compound as clear crystals. ESI/APCl(+): 402 (M+H).
EXAMPLE 231: PREPARATION OF 1-(6-methoxy-1 -methyl-1 /7-indazol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: To a solution of 6-methoxy-1/-/-indazole-3-carbaldehyde (0.088 g; 0.500 mmol) and césium carbonate (0.652 g; 2.000 mmol) in DMSO (2.5 mL) was added iodomethane (0.062 mL; 1.000 mmol) and the reaction mixture was stirred at room température for 3 h. The reaction mixture was diluted with water until a precipitate formed. The solid was filtered, washed with water and dried under reduced pressure over phosphorus(V) oxide to furnish 0.063 g (66%) of
6-methoxy-1-methyl-1 H-indazole-3-carbaldehyde as a grey solid. ESI/APCI(+): 191 (M+H). 1H
NMR (DMSO-dg) δ 10,07 (1 H, s); 7.97 (1H, d); 7.29 (1H, s); 7.01 (1H, d); 4.17 (3H, s); 3.89 (3H,
238
s).
Step 2: 1 -(6-Methoxy-1 -methyl-1 A7-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.042 g; 0.158 mmol) and triethylamine (0.022 mL; 0.158 mmol) in éthanol (0.35 mL), 6-methoxy-1 -methyl-1 H-indazole-3-carbaldehyde (0.060 g; 0.315 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.315 mmol) in éthanol (0.35 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane followed by précipitation from diethyl ether furnished 0.042 g (32%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H).
EXAMPLE 232: PREPARATION OF 2-(1,5-dimethyl-l H-pyrazol-3-yl)-1 -(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A solution of N-((1,5-dimethyl-1H-pyrazol-3-yl)methylene)-3-methoxyaniline in éthanol was prepared by heating a solution of 1,5-dimethyl-1H-pyrazole-3-carbaldehyde (0.127 g; 1.023 mmol) and 3-methoxyaniline (0.119 mL; 1.056 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 230 (M+H); 252 (M+Na); 481 (2M+Na).
Step 2: 2-(1,5-Dimethyl-1 H-pyrazol-3-yl)-1 -( 1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.141 g; 0.523 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.263 g; 1.072 mmol) and a solution of A/-((1,5-dimethyl-1H-pyrazol-3-yl)methylene)-3-methoxyaniline (1.023 mmol) in éthanol (1.5 mL), heated at 60 °C for 24 h. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane. Further purification by précipitation from ethyl acetate followed by précipitation from a mixture of acetonitrile, water and DMF furnished 0.085 g (22%) of the desired compound as a white solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).
EXAMPLE 233: PREPARATION OF 1-(1H-indol-3-yl)-2-(6-isopropoxypyridin-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A solution of N-((6-isopropoxypyridin-3-yl)methylene)-3-methoxyaniline in éthanol was prepared by heating a solution of 6-isopropoxynicotinaldehyde (0.156 g; 0.944 mmol) and 3methoxyaniline (0.109 mL; 0.966 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 1-(1/-/-lndol-3-yl)-2-(6-isopropoxypyridin-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general protocol K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.136 g; 0.504 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.267 g; 1.089 mmol) and a solution of /V-((6-isopropoxypyridin-3-yl)methylene)-3-methoxyaniline (0.944 mmol) in éthanol
239 (1.5 mL), heated at 60 qC for 120 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.084 g (21%) of the desired compound as a yellow solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).
EXAMPLE 234 : PREPARATION OF 2-((5-(difluoromethoxy)pyridin-3-yl)amino)-1-(1H-indol-3yl)-2-phenylethanone
Step 1: A mixture of 6-bromopyridinol (2.000 g; 11.49 mmol), sodium chlorodifluoroacetate (2.630 g; 17.24 mmol) and potassium carbonate (3.180 g; 22.99 mmol) in acetonitrile (50 mL) was placed in a sealed tube and heated at 110 °C overnight. After cooling to room température, the reaction mixture was diluted with diethyl ether and washed with a saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using dichloromethane as eluent furnished 0.393 g (15%) of 3-bromo-5-(difluoromethoxy)pyridine as a yellow oil. ESI/APCI(+): 224,226 (M+H).
Step 2: A mixture of 3-bromo-5-(difluoromethoxy)pyridine (0.500 g; 2.232 mmol), copper(ll) sulfate pentahydride (0.107 g; 0.446 mmol) and a 25% ammonium hydroxide solution (3.440 mL; 22.32 mmol) was placed in sealed tube and heated at 150 °C overnight After cooling to room température, a 1N sodium hydroxide solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane furnished 0.291 g (81%) of 5-(difluoromethoxy)pyridin-3-amine as a brown solid. ESI/APCI(+): 161 (M+H). ESI/APCI(-): 159 (M-H).
Step 3: A solution of /V-benzylidene-5-(difluoromethoxy)pyridin-3-amîne in éthanol was prepared by heating a solution of benzaldehyde (0.102 mL; 1.004 mmol) and 5-(difluoromethoxy)pyridin3-amine (0.160 g; 0.999 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 4: 2-((5-(Difluoromethoxy)pyridin-3-yl)amino)-1 -( 1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of A/-benzylidene-5-(difluoromethoxy)pyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of methanol (1% to 7%) in dichloromethane followed by précipitation from dichloromethane furnished 0,018 g (6%) of the desired compound as a white solid. ESI/APCI(+): 394 (M+H). ESI/APCI(-): 392 (M-H). 1H NMR (DMSO-cf6j 6Π12.20 (1H, brs); 8.89 (1H, s); 8.17 (1H, d); 8.11 (1H, d); 7.65 (3H, d); 7.48 (1H, d); 7.41 (1H. t); 7.267.37 (2H, m); 7.17-7.26 (3H, m); 7.08 (1H, d); 7.02 (1H, s); 6.21 (1H, d).
240
EXAMPLE 235: PREPARATION OF 1-(5-fluoro-1 -methyl-1 H-indazol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Step 1: A mixture of 5-fluoro-1H-indazole-3-carbaldehyde (0.050 g; 0.305 mmol), césium carbonate (0.397 g; 1.218 mmol) and methyl iodide (0.038 mL; 0.609 mmol) in DMSO (2.5 mL) was stirred at room température for 2 h. Water was added. The resulting precipitate was filtered, washed with water and dried to give 0.027 g (50%) of 5-fluoro-1-methyl-1 H-indazole-3carbaldehyde as a beige solid. ESI/APCI(+): 179 (M+H).
Step 2: 1-(5-Fluoro-1-methyl-1 H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.020 g; 0.076 mmol) and triethylamine (0.011 mL; 0.076 mmol) in éthanol (0.5 mL), 5-fluoro-1-methyl-1 H-indazole-3-carbaldehyde (0.027 g; 0.152 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.152 mmol) in éthanol (0.5 mL), heated at 70 °C for 60 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane followed by précipitation from acetonitrile furnished 0.010 g (17%) of the desired compound as a yellow solid. ÈSI/APCI(+): 390 (M+H). 1H NMR (DMSO-d6) 5D7.92 (1H, dd); 7.80 (1H, d); 7.61 (2H, d); 7.42-7.52 (1H, m); 7.29-7.39 (2H, m); 7.18-7.29 (1H, m); 6.95 (1H, t); 6.52-6.60 (1H, m); 6.39-6.48 (1H, m); 6.34 (2H, br s); 6.15 (1H, d); 4.29 (3H, s); 3.56 (3H, s).
EXAMPLE 236: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6(methylamino)pyridin-3-yl)ethanone
Step 1: 5-(((3-Methoxyphenyl)imino)methyl)-/V-methylpyridin-2-amine was prepared quantitatively according to general procedure I from 6-(methylamino)nicotinaldehyde (0.136 g; 0.999 mmol) and 3-methoxyaniline (0.112 mL; 1.001 mmol).
Step 2:1-(1/-/-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(rnethylamino)pyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)-A/-methylpyridin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 12%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of methanol (0% to 12%) in dichloromethane followed by précipitation from éthanol furnished 0.006 g (2%) of the desired compound. ESI/APCI(+): 387 (M+H). ESIZAPCt(-): 385 (M-H).
EXAMPLE 237: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)-1(1 -methyl-1 H-indazol-3-yl)ethanone 2-((3-Methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)-1-(1 -methyl-1 /7-indazol-3-yl)ethanone
241 was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of 3-methoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. The precipitate was filtered, washed with éthanol and dried to furnish 0.312 g (76%) of the desired compound as a white solid. ESI/APCI(+): 404 (M+H). 1H NMR (DMSO-cfe) δ 8.55 (1H, s); 8.21 (1H, s); 8,15 (1H, d); 7.81 (1H, d); 7.53 (1H, t); 7.33-7.43 (1H, m); 6.96 (1H, t); 6.62 (1H, d); 6.46 (1H, d); 6.33-6.42 (2H, m); 6.14-6.22 (1H, m); 4.22 (3H, s); 3.87 (3H, s);
3.63 (3 H, s).
EXAMPLE 238: PREPARATION OF 2-((3-methoxyphenyl)amîno)-1-(1-methyl-1H-indazol-3-yl)2-(pyrazolo(1,5-a]pyridin-2-yl)ethanone
2- ((3-Methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.118 g; 0.438 mmol) and triethylamine (0.062 mL; 0.438 mmol) in éthanol (1 mL), 1-methyl-1H-indazole-3-carbaldehyde (0.140 g; 0.874 mmol) and a solution of 3-methoxy-/V-(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline (0.876 mmol) in éthanol (1 mL) heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane followed by précipitation from diethyl ether furnished 0.209 g (56%) of the desired compound as a white solid. ESI/APCI(+): 412 (M+H).
EXAMPLE 239: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazin-2yl)ethanone
Step 1: 3-Methoxy-A/-(pyrazin-2-ylmethylene)aniline was prepared quantitatively according to general procedure I from pyrazine-2-carbaldehyde (0.108 g; 0.999 mmol) and 3-methoxyaniline (0.112 mL; 1.001 mmol). ESI/APCI(+): 214 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0,245 g; 0.999 mmol) and a solution of 3methoxy-N-(pyrazin-2-ylmethylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane followed by précipitation from diethyl ether furnished 0.046 g (13%) of the desired compound as a white solid. ESI/APCI(+): 359 (M+H). ESIZAPCI(-): 357 (M-H).
EXAMPLE 240: PREPARATION OF 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl1 H-indazole-5-carbonitrile
Step 1: To a solution of 3-formyl-1H-imidazole-5-carbonitrile (0.100 g; 0.584 mmol) in DMSO (3 mL) were added potassium carbonate (0.330 g; 2.388 mmol) and methyl iodide (0.073 mL;
242
1.167 mmol). The reaction mixture was stirred at room température for 18 h. Water was added and the precipitate was filtered. The pink solid was dissolved in dichloromethane and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to furnish 0.083 g (77%) of 3-formyl-1-methyl-1 H-indazole-5-carbonitrile as an orange solid. ESI/APCI(+): 186 (M+H).
Step 2: 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1 -methyl-1 H-indazole-5-carbonitrile was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.133 g; 0.493 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.7 mL), 3-formyl-1 -methyl-1 H-indazole-5-carbonitrile (0.179 g; 0.987 mmol) and a solution of /V-benzylidene-3-methoxyaniline (0.985 mmol) in éthanol (1 mL), heated at 60 °C for 24 h. The precipitate formed during the reaction was filtered. The solid was recrystallized from diethyl ether and washed with methanol to furnish 0.230 g (59%) of the desired compound as a bright yellow solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).
EXAMPLE 241: PREPARATION OF 2-((6-methoxypyrazin-2-yl)amino)-1-(1 -methyl-1 H-indazol3-yl)-2-phenylethanone
2- ((6-Methoxypyrazin-2-yl)amino)-1-(1 -methyl-1 H-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of Nbenzylidene-6-methoxypyrazin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane followed by précipitation from diethyl ether furnished 0.049 g (13%) of the desired compound as a white solid. ESI/APCI(+): 374 (M+H).
EXAMPLE 242: PREPARATION OF 1-(1H-indol-3-yl)-2-((6-methoxypyridin-2-yl)amino)-2phenylethanone
1- (1H-lndoi-3-yl)-2-((6-methoxypyridin-2-yl)amino)-2-phenylethanone was prepared according to general procedure E from 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.045 g; 0.143 mmol) and 2-amino-6-methoxypyridine (0.089 g; 0.717 mmol) in acetonitrile (0.6 mL), irradiated in a microwave oven at 120 °C for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 60%) in heptane followed by recrystallization from ethyl acetate and heptane furnished 0.020 g (39%) of the desired product as a white powder. ESI/APCI(+): 358 (M+H); 380 (M+Na). ESI/APCI(-): 356 (M-H). ’H NMR (DMSO-cfe) δ 11.99 (1H, br s); 8.71 (1H, s); 8.17 (1 H, d); 7.65 (2H, m); 7.44 (1H, d); 7,1-7.35 (7H, m); 6.41 (1 H, d);
6.30 (1H, d); 5.86 (1H, d); 3.54 (3H, s).
EXAMPLE 243: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1methyl-1H-indazol-3-yl)-2-phenylethanone
2- ((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1-methyl-1 H-indazol-3-yl)-2-phenylethanone
243 was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.187 g (45%) of the desired compound as a light yellow solid. ESI/APCI(+): 402 (M+H).
EXAMPLE 244: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1 -methyl-1 /-/-indazol-3yl)-2-(pyridin-3-yl)ethanone
2-((3,5-Dimethoxyphenyl)amino)-1 -(1 -methyl-1 H-indazol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of
3,5-dimethoxy-/\/-(pyridin-3-ylmethylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.077 g (18%) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H). ’H NMR (DMSO-de) δ 8.83 (1H, d); 8.38-8.50 (1H, m); 8.14 (1H, d); 7.96 (1H, d); 7.82 (1H, d); 7.53 (1H, t); 7.30-7.44 (2H, m); 6.68 (1H, d); 6.49 (1H, d); 5.97 (2H, d); 5.77 (1H, s); 4.26 (3H, s); 3.60 (6H, s).
EXAMPLE 245: PREPARATION OF 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2(pyridin-3-yl)ethanone
Step 1: A solution of 6-methoxy-A/-(pyridin-3-ylmethylene)pyrazin-2-amine in éthanol was prepared by heating a solution of nicotinaldehyde (0.107 g; 0.999 mmol) and 6-methoxypyrazin2-amine (0.125 g; 0.999 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 1-(1H-lndol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0,070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxy!ate (0.245 g; 0.999 mmol) and a solution of 6-methoxy-/V-(pyridin-3-ylmethylene)pyrazin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C ovemight. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.005 g (1%) of the desired compound as a yellow solid. ESI/APCI(+): 360 (M+H). ESI/APCI(-): 358 (M-H).
EXAMPLE 246: PREPARATION OF 1-(6-fluoro-1-methyl-1H-indazol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
244
Step 1: To a suspension of lithium aluminum hydride (0.210 g; 5.553 mmol) in THF (20 mL) cooled to 0 °C was added dropwise a solution of 6-fluoro-1/-/-indazole-3-carboxylic acid (0.500 g; 2.776 mmol) in THF (5 mL). The reaction mixture was stirred at room température for 2 h. After cooling to 0 °C, a saturated Rochelle sait solution was added. The reaction mixture was vigorously stirred and was extracted with ethyl acetate. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure to furnish crude (6-fluoro1H-indazol-3-yl)methanol as a white solid. ESI/APCI(+): 167 (M+H).
To a solution of (6-fluoro-1H-indazol-3-yl)methanol (0.207 g; 1,25 mmol) in dichloromethane (15 mL) was manganese(IV) oxide (1.080 g; 12.46 mmol). The resulting suspension was stirred at room température for 3 h and filtered through a pad of celite. The solid was washed with dichloromethane. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.153 g (34% over the two steps) of 6-fluoro-1H-indazole-3-carbaldehyde as a white solid. ESI/APCI(+): 165 (M+H). ESI/APCI(-): 163 (M-H).
Step 2: A mixture of 6-fluoro-1H-indazole-3-carbaldehyde (0.150 g; 0.914 mmol), césium carbonate (1.190 g; 3.652 mmol) and methyl iodide (0.114 mL; 1.831 mmol) in DMSO (7.5 mL) was stirred at room température for 2 h. Water was added and the precipitate was filtered, washed with water and dried to afford 0.105 g (65%) of 6-fluoro-1-methyl-1 H-indazole-3carbaldehyde as a beige solid. ESI/APCI(+): 179 (M+H).
Step 3: 1-(6-Fluoro-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.079 g; 0.295 mmol) and triethylamine (0.041 mL; 0.295 mmol) in éthanol (1 mL), 6-fluoro-1-methyl-1 H-indazole-3-carbaldehyde (0.105 g; 0.589 mmol) and a solution of A/-benzylidene-3-methoxyaniline (0.589 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane followed by précipitation from acetonitrile furnished 0,054 g (23%) of the desired compound as a yellow solid. ESI/APCI(+): 390 (M+H). ESI/APCI(-): 388 (M-H). Ή NMR (DMSO-d6) ÔD8.13 (1H, dd); 7.74 (1H, d); 7.59 (2H. d); 7.18-7.40 (4H, m); 6.93 (1H, t); 6.496.60 (1H, m); 6.42 (1H, d); 6.26-6.37 (2H, m); 6.14 (1H, d); 4.22 (3H, s); 3.61 (3H, s).
EXAMPLE 247: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(pyrîdin-3-yl)ethanone
Step 1: A solution of (3-methoxy-5-((pyridin-3-ylmethylene)amino)phenyl)methanol in éthanol was prepared by heating a solution of nicotinaldehyde (0.107 g; 0.999 mmol) and (3-amino-5methoxyphenyl)methanol (0.153 g; 0.999 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(216765
245 hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-îndole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of (3-methoxy-5-((pyridin-3-ylmethylene)amino)phenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by précipitation from diethyl ether and dichloromethane furnished 0.150 g (39%) of the desired compound as a yellow solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). ’H NMR (DMSO-cU ÔD 12.23 (1 H. br s); 8.85-8.98 (2H, m); 8.41 (1H, d); 8.18 (1H. d); 7.98 (1H, d); 7.50 (1H, d); 7.34 (1H, dd); 7.15-7.29 (2H, m); 6.38-6.50 (2H, m); 6.31 (1H. br s); 6.20 (1H, d); 6.16 (1H, s); 5.02 (1 H, t); 4.32 (2H, d); 3.65 (3H, s).
EXAMPLE 248: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(6-methoxypyridin-3-yl)ethanone
Step 1: A solution of (3-methoxy-5-(((6-methoxypyridin-3-yl)methylene)amino)phenyl)-methanol in éthanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.137 g; 0.999 mmol) and (3-amino-5-methoxyphenyl)methanol (0.153 g; 0.999 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridin-3yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1 -carboxylate (0.245 g; 0.999 mmol) and a solution of (3-methoxy-5-(((6-methoxypyridin-3yl)methylene)amino)phenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient methanol (1% to 7%) in dichloromethane followed by précipitation from diethyl ether furnished 0.081 g (19%) of the desired compound as a yellow solid. ESI/APCI(+): 418 (M+H). ESI/APCI(-): 416 (M-H). ’H NMR (DMSO-ds) 5012.17 (1H, brs); 8.88 (1H, s); 8.47 (1H, s); 8.16 (1H, d); 7.85 (1H, dd); 7.48 (1H, d); 7.20 (2H, m); 6.74 (1H, d); 6.41 (1H, s); 6.23-6.37 (2H, m); 6.05-6.18 (2H, m); 5.00 (1H, t); 4.31 (2H, d); 3.77 (3H, s); 3.63 (3H, s).
EXAMPLE 249: PREPARATION OF 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(6methoxypyridin-3-yl)ethanone
Step 1 : A solution of 6-methoxy-A/-((6-methoxypyridin-3-yl)methylene)pyrazin-2-amine in éthanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.137 g; 0.999 mmol) and 6-methoxypyrazin-2-amine (0.125 g; 0.999 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
ESI/APCI(+): 245 (M+H).
Step 1: 1 -(1 /-/-lndol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(6-methoxypyridin’3-yl)ethanone
246 was prepared according to general procedure K from a mixture of 3-benzy1-5-(2-hydroxyethyl)-
4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1 -carboxylate (0.245 g; 0.999 mmol) and a solution of 6-methoxy-N-((6-methoxypyridin-3-yl)methylene)pyrazin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane followed by précipitation from dichloromethane furnished 0.137 g (30%) of the desired compound as a white solid. ESI/APCI(+): 390 (M+H). 1H NMR (DMSO-d6) 6012.08 (1H, br s); 8.76 (1H, s); 8.50 (1H, d); 8.17 (1 H, d); 7.80-7.94 (2H, m); 7.73 (1H, s); 7.46 (1H, d); 7.32 (1H, s); 7.12-7.26 (2H, m); 6.80 (1H, d); 6.39 (1H, d); 3.79 (3H, s); 3.60 (3H, s).
EXAMPLE 250: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5methoxyphenyl)amino)-2-phenylethanone
1-(6-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazol-3-ium chloride (0.132 g; 0.489 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 6-fluoro-3-formyl-1H-indole-1-carboxylate (0.262 g; 0.995 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.974 mmol) in éthanol (1 mL), heated at 60 ’C for 16 h. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (40% to 80%) in heptane followed by purification by solid phase extraction on C18-reversed phase column using a gradient of acetonitrile (0% to 90%) in water furnished 0.032 g (8%) of the desired compound as a yellow solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).
EXAMPLE 251: PREPARATION OF 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl1 H-indazole-6-carbonitrile
Step 1: To a solution of 3-formyl-1H-imidazole-6-carbonitrile (0.250 g; 1.461 mmol) in DMSO (7 mL) were added potassium carbonate (0.817 g; 5.911 mmol) and methyl iodide (0.185 mL; 2.958 mmol). The reaction mixture was stirred at room température for 18 h. Water was added and the precipitate was filtered. The pink solid was dissolved in dichloromethane and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to furnish 0.247 g of crude 3-formyl-1-methyl-1 H-indazole-6-carbonitrile (contaminated with 3-formyl-2-methyl-2H-indazole-6-carbonitrile). ESI/APCI(+): 186 (M+H).
Step 2: 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1 -methyl-1 H-indazole-6-carbonitrile was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.070 g; 0.259 mmol) and triethylamine (0.050 mL; 0.359 mmol) rn éthanol (0.3 mL), 3-formyl-1-methyl-1 H-indazole-6-carbonitrile (0.095 g; crude) and a solution of
N-benzylidene-3-methoxyaniline (0.488 mmol) in éthanol (0.5 mL), heated at 60 °C for 16 h.
247
The precipitate formed during the reaction was filtered, washed with éthanol and water and dried. The solid was purified by préparative HPLC (XBridge column; method 2) to furnish 0.064 g (11% over the two steps) of the desired compound as a yellow solid. ESI/APCI(+): 397 (M+H). ESIZAPCI(-): 395 (M-H).
EXAMPLE 252: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((6-methoxypyrazin-2yl)amino)-2-phenylethanone
-(6-Fluoro-1 H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (1 mL), tert-butyl 6-fluoro-3-formyl-1H-indole-1-carboxylate (0.268 g; 1.018 mmol) and a solution of /V-benzylidene-6-methoxypyrazin-2-amine (0.999 mmol) in éthanol (1 mL), heated at 60 ’C for 72 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 80%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.056 g (15%) of the desired compound as a pink solid. ESI/APCI(+): 377 (M+H), ESI/APCI(-): 375 (M-H).
EXAMPLE 253: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(5-methoxypyrazin-2-yl)ethanone
Step 1: A solution of (3-methoxy-5-(((5-methoxypyrazin-2-yl)methylene)amino)phenyl)methanol in éthanol was prepared by heating a solution of 5-methoxypyrazine-2-carbaldehyde (0.138 g; 0.999 mmol) and (3-amino-5-methoxyphenyl)methanol (0.153 g; 0.999 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5-methoxypyrazin-
2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of (3-methoxy-5-(((5-methoxypyrazin-2yl)methylene)amino)phenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. The residue was purified by flash chromatography on silica gel using a gradient of methanol (1% to 7%) in dichlorométhane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichlorométhane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.089 g (21%) of the desired compound as a white solid. ESI/APCI(+): 419 (M+H). ESI/APCI(-): 417 (M-H). 1H NMR (DMSOd6) 5Π12.14 (1H, br s); 8.75 (1H, s); 8.49 (1H, s); 8.23 (1H, s); 8.15 (1 H. d); 7.47 (1H, d); 7.12-
7.28 (2H, m); 6.40 (1H, s); 6.26-6.36 (2H, m); 6.18-6.25 (1H, m); 6.15 (1H, s); 5.01 (1H, t); 4.31 (2H, d); 3.84 (3H, s); 3.64 (3H, s).
EXAMPLE 254: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H16765
248 indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone Step 1: A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.066 g; 0.452 mmol) and (3amino-5-methoxyphenyl)methanol (0.069 g; 0.451 mmol) in éthanol (0.4 mL) was heated at 60 °C ovemight. The reaction mixture was concentrated under reduced pressure and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 3-methoxy-5((pyrazolo[1,5-a]pyridin-2-ylmethylene)amino)phenyl)methanol which was used without further purification.
Step 2: 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1 -(1 H-indol-3-yl)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.061 g; 0.226 mmol) and triethylamine (0.032 mL; 0.231 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1carboxylate (0.111 g; 0.453 mmol) and a solution of (3-methoxy-5-((pyrazolo[1,5-a]pyridin-2ylmethylene)amino)phenyl)methanol (0.451 mmol) in éthanol (0.5 mL), heated at 70 °C for 4 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by a gradient of methanol (0% to 10%) in dichloromethane furnished 0.019 g (10%) of the desired compound as a white solid. ESI/APCI(+): 427 (M+H). ESI/APCI(-): 425 (M-H).
EXAMPLE 255: PREPARATION OF 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2(pyrazolo[1,5-a]pyrid i n-2-yl )etha none
Step 1: A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.066 g; 0.452 mmol) and 6methoxypyrazin-2-amine (0.057 g; 0.456 mmol) in éthanol (0.4 mL) was heated at 60 °C ovemight. The reaction mixture was concentrated under reduced pressure and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 6-methoxy-/V(pyrazolo[1,5-a]pyridin-2-ylmethylene)pyrazîn-2-amîne which was used without further purification.
Step 2: 1 -(1 H-lndol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.061 g; 0.226 mmol) and triethylamine (0.032 mL; 0.231 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0,111 g; 0.453 mmol) and a solution of 6-methoxy-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)pyrazin-2-amine (0.452 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by a gradient of methanol (0% to 12%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane furnished 0.004 g (2%) of the desired compound as a white solid. ESI/APCI(+): 399 (M+H). ESI/APCI(-): 397 (M-H).
EXAMPLE 256: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H16765
249 indol-3-yl)-2-(6-methoxypyridin-3-yl)ethanone
Step 1 : A mixture of 3-amino-5-methoxyphenol (1.860 g; 13.37 mmol), césium carbonate (8.710 g; 26.73 mmol) and 2-bromoethanol (1.040 mL; 14.70 mmol) in DMF (40 mL) was stirred at 60 °C for 3 days. After cooling to room température, the reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 100%) in dichloromethane furnished 0.749 g (30%) of 2-(3amino-5-methoxyphenoxy)ethanol as a brown solid. ESI/APCI(+): 184 (M+H).
Steo 2: 2-(3-Methoxy-5-(((6-methoxypyridin-3-yl)methylene)amino)phenoxy)ethanol was prepared quantitatively according to general procedure I from 6-methoxynicotinaldehyde (0.069 g; 0.503 mmol) and 2-(3-amino-5-methoxyphenoxy)ethanol (0.092 g; 0.502 mmol).
Step 3: 2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridin-
3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride (0.067 g; 0.248 mmol) and triethylamîne (0.035 mL; 0.252 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.123 g; 0.501 mmol) and a solution of 2-(3-methoxy-5-(((6-methoxypyridin-3yl)methylene)amino)phenoxy)ethanol (0.502 mmol) in éthanol (1mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.011 g (5%) the desired compound as a white solid. ESI/APCI(+): 448 (M+H). ESI/APCI(-): 446 (M-H). 1H NMR (DMSO-dJ ô 12.17 (1H, br s); 8.90 (1H. s); 8.46 (1 H, s); 8.16 (1H. d); 7.84 (1H, d); 7.47 (1H, d); 7.13-7.28 (2H, m); 6.75 (1H, d); 6.37 (1H, d); 6.09 (1H, d); 6.05 (2H, br s); 5.73 (1H, s); 4.79 (1H, t); 3.84 (2H, br s); 3.77 (3H, s); 3.65 (2H, br s); 3.62 (3H, s).
EXAMPLE 257: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(5-methoxypyrazin-2-yl)ethanone
Step 1: 2-(3-Methoxy-5-(((5-methoxypyrazin-2-yl)methylene)amino)phenoxy)ethanol was prepared quantitatively according to general procedure I from 5-methoxypyrazine-2carbaldehyde (0.069 g; 0.500 mmol) and 2-(3-amino-5-methoxyphenoxy)ethanol (0.092 g; 0.502 mmol).
Step________2: 2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5methoxypyrazin-2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.067 g; 0.248 mmol) and triethylamîne (0.035 mL; 0.252 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1carboxylate (0.123 g; 0.501 mmol) and a solution of 2-(3-methoxy-5-(((5-methoxypyrazin-2yl)methylene)amrno)phenoxy)ethanol (0.500 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of
250 methanol (1% to 7%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.008 g (3%) of the desired compound as a beige solid. ESI/APCI(+): 449 (M+H). ESItAPCI(-); 447 (M-H). 1H NMR (DMSOde) ÔD12.14 (1 H, br s); 8.76 (1 H, s); 8.48 (1H, s); 8.23 (1 H, s); 8.15 (1 H, d); 7.47 (1 H, d); 7.20 (2H, br s); 6.36 (1H, d); 6.21 (1H, d); 6.05 (2H, br s); 5.75 (1H, s); 4.79 (1H, t); 3.84 (5H, m); 3.55-3.71 (5H, m).
EXAMPLE 258: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino )-1-(1 H-indol-3-yl)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone
Step 1: A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.066 g; 0.452 mmol) and 3,5dimethoxyaniline (0.069 g; 0.450 mmol) in éthanol (0.4 mL) was heated at 60 °C overnight. The reaction mixture was concentrated under reduced pressure and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 3,5-dimethoxy-A/(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline which was used without further purification.
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2yljethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.061 g; 0.226 mmol) and triethylamine (0.032 mL; 0.231 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.111 g; 0.453 mmol) and a solution of 3,5-dimethoxy-A/-(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline (0.450 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 4) furnished 0.003 g (1%) of the desired compound. ESI/APCI(+): 427 (M+H). ESI/APCI(-): 425 (M-H).
EXAMPLE 259: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5methoxypyrazin-2-yl)ethanone
Step 1: A mixture of 5-methoxypyrazine-2-carbaldehyde (0.138 g; 0.999 mmol) and 3,5dimethoxyaniline (0.153 g; 0.999 mmol) in éthanol (1 mL) was heated at 60 °C overnight. The reaction mixture was concentrated under reduced pressure and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 3,5-dimethoxy-/V-((5methoxypyrazin-2-yl)methylene)aniline which was used without further purification.
Step 2: 2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3,5-dimethoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL),
251 heated at 70 °C for 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (25% to 100%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate/dichloromethane/heptane (3/3/4) as eluent followed by purification by préparative HPLC (XBridge column; method 4) furnished 0.009 g (2%) ofthe desired compound. ESI/APCI(+): 419 (M+H). ESI/APCI(-): 417 (M-H).
EXAMPLE 260: PREPARATION OF 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(5-methoxypyrazin-2-yl)ethanone
-(5-Fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.101 g; 0.374 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (0.5 mL), fert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.194 g; 0.737 mmol) and a solution of 3-methoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.724 mmol) in éthanol (1 mL), heated at 60 °C for 96 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.120 g (41%) of the desired compound as a yellow solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M-H).
EXAMPLE 261: PREPARATION OF 1-(5-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5methoxyphenyl)amino)-2-phenylethanone
1-(5-Fluoro-1/-/-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.084 g; 0.311 mmol) and triethylamine (0.065 mL; 0.466 mmol) in éthanol (0.5 mL), fert-butyl 5-fluoro-3-formyl-1H-îndole-1 -carboxylate (0.177 g; 0.672 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.655 mmol) in éthanol (1 mL), heated at 60 °C for 96 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) In heptane followed by purification by solid phase extraction on C18reversed phase column using a gradient of acetonitrile (20% to 80%) in water furnished 0.053 g (20%) of the desired compound as a brown solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H). 1H NMR (DMSO-de) δ 12.25 (1H, br s); 8.93 (1H, s); 7.82 (1H, dd); 7.63 (1H, d); 7.48 (1H, dd); 7.29 (1 H. t); 7.16 (1 H. t); 7.05 (1H, dt); 6.40 (1H, s); 6.29 (1H. d); 6.26 (1 H, s); 6.11 (1H, s); 6.07 (1 H, d); 4.98 (1 H, t); 4.29 (2H, d); 3.62 (3H, s).
EXAMPLE 262: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(5-methoxypyrazin-2-yl)ethanone
1-(6-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.133 g; 0.493 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), fert-butyl 6-fluoro-3-formyl-1H-indole-1 -carboxylate (0.253 g; 0.961 mmol) and a solution of 3-methoxy-/V-((5-methoxypyrazin-2-yl)methylene)aniline (0.933 mmol) in éthanol (1
252 mL), heated at 60 °C for 96 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane followed by précipitation from diethyl ether furnished 0.146 g (39%) of the desired compound as a white solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M-H).
EXAMPLE 263: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1methyl-1H-indazol-3-yl)-2-phenylethanone
Step 1: 2-(3-(Benzylideneamrno)-5-methoxyphenoxy)ethanol was prepared quantitatively according to general procedure I from benzaldehyde (0.102 mL; 1.004 mmol) and 2-(3-amino-5methoxyphenoxy)ethanol (0.183 g; 0.999 mmol).
Step 2: 2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), 1-methyl-1/7-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of 2-(3-(benzylideneamino)-5-methoxyphenoxy)ethanol (0.999 mmol) in éthanol (1.5 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.031 g (7%) of the desired compound as a beige solid. ESI/APCI(+): 432 (M+H). 1H NMR (DMSO-cU ÔC 8.14 (1H, d); 7.82 (1H. d); 7.59 (2H, d); 7.46-7.56 (1H, m); 7.16-7.43 (5H, m); 6.54 (1H, d); 6.44 (1H, d); 5.95 (2H, br s);
5.74 (1 H, s); 4.78 (1 H, br s); 4.27 (3H, s); 3.81 (2H, m); 3.53-3.70 (5H, m).
EXAMPLE 264 : Enantiomers séparation of 1-(1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-
2- phenylethanone leading to (-)-1 -(1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2phenylethanone and (+)-1-(1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone.
1-(1H-lndol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone (0.054 g) was separated into its enantiomers and purified by préparative HPLC (ChiralPak column; method 6). Under these conditions, 0.021 g of the faster eluting enantiomer (tr = 6.7 min; ee > 98%) and 0.020 g of the slower eluting enantiomer (tr = 12.1 min; ee = 96%) were obtained.
EXAMPLE 265: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-2yl)ethanone
Step 1: 3-Methoxy-N-(pyridin-2-ylmethylene)aniline was prepared quantitatively according to general procedure I from picolinaldehyde (0.107 g; 0.999 mmol) and 3-methoxyaniline (0.112 mL; 1.001 mmol).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-2-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-
3- ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1/-/-indole-1-carboxylate (0.245 g; 0,999 mmol) and a solution of 3methoxy-/\/-(pyridin-2-ylmethylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3
253 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by çrystallization from acetonitrile furnished 0.013 g (4%) of the desired compound as a white solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).
EXAMPLE 266: PREPARATION OF 1-(1H-indol-4-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
Step 1 : tert-butyl 4-Formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 1H-indole-4-carbaldehyde (0.435 g; 2.997 mmol), di-tert-butyl dicarbonate (0.786 g; 3.601 mmol) and DMAP (0.037 g; 0.303 mmol) in acetonitrile (7.5 mL) to afford 0.654 g (89%) of the desired compound as a brown oil. 1H NMR (DMSO-d6) 10.26 (1H, s); 8.41 (1H, d); 7.92 (1 H, d); 7.88 (1 H, d); 7.57 (1 H, t); 7.34 (1 H, d); 1.65 (9H, s).
Step 2: 1-(1/7-lndol-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 4-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of Nbenzylidene-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 4) furnished 0.051 g (14%)ofthe desired compound. ESI/APCI(+): 357 (M+H). ESI/APCI(-): 355 (M-H).
EXAMPLE 267: PREPARATION OF 1-(1-(2-hydroxyethyl)-1H-indazol-3-yl)-2-((3methoxyphenyl)amino)-2-phenylethanone
Stepl: To a solution of 1H-indazole-3-carbaldehyde (0.201 g; 1.375 mmol), potassium carbonate (0.218 g; 1.577 mmol) and lithium iodide (0.095 g; 0.710 mmol) in NMP (3 mL) was added 2-(2-chloroethoxy)tetrahydro-2/7-pyran (0.210 mL; 1,422 mmol). The reaction mixture was stirred at 80 °C for 20 h. After cooling to room température, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 35%) in heptane furnished 0.145 g (38%) of 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indazole-3carbaldehyde as a pale yellow oil.
Step 2: 2-((3-Methoxyphenyl)amîno)-2-phenyl-1-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1/7indazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.067 g; 0.248 mmol) and triethylamine (0,050 mL; 0.359 mmol) in éthanol (0.7 mL), 1-(2-((tetrahydro-2H-pyran-2yl)oxy)ethyl)-1H-indazole-3-carbaldehyde (0.145 g; 0.529 mmol) and a solution of Nbenzylidene-3-methoxyaniline (0.483 mmol) In éthanol (1.2 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 30%) in heptane furnished 0.138 g (59%) of the desired product as a yellow oil (80% purity).
254
ESI/APCI(+): 486 (M+H).
Step 2: To a solution of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-(2-((tetrahydro-2H-pyran-2yl)oxy)ethyl)-1H-indazol-3-yl)ethanone (0.138 g; 0.284 mmol) in acetonitrile (3 mL) was added a 1N hydrochloric acid solution (0.150 mL; 0.150 mmol). The reaction mixture was stirred at room température for 24 h. The reaction mixture was concentrated under reduced pressure. Purification by préparative HPLC (XBridge column; method 2) furnished 0.022 g (36%) of the desired compound as a yellow oil. ESI/APCI(+): 402 (M+H).
EXAMPLE 268: PREPARATION OF 2-((3-(2-( tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1methyl-1H-indol-3-yl)-2-phenylethanone
2- ((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1 -methyl-1 H-indol-3-yl)-2phenylethanone was prepared according to general procedure C from 2-chloro-1-(1-methyl-1Hindol-3-yl)-2-phenylethanone (0.100 g; 0.352 mmol), triethylamine (0.057 mL; 0.423 mmol) and
3- (2-(tert-butoxy)ethoxy)-5-methoxyaniline (0.107 g; 0.423 mmol) In acetonitrile (1 mL), irradiated in a microwave oven at 130 °C for 15 min and at 150 °C for 1h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.151 g (88%) of the desired compound as an oil. ESI/APCI(+): 487 (M+H), 509 (M+Na). ESI/APCI(-): 485 (M-H).
EXAMPLE 269: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1methyl-1H-indol-3-yl)-2-phenylethanone
2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino )-1-(1 -methyl-1 H-indol-3-yl)-2phenylethanone (0.150 g; 0.308 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (10.00 mL; 40.00 mmol). The reaction mixture was stirred at room température for 6 h and was concentrated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in dichloromethane furnished 0.032 g (24%) of 2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)-1-(1-methyl-1 H-indol-3-yl)-2-phenylethanone as a white solid.
ESI/APCI(+): 431 (M+H). 1H NMR (DMSO-d6) 5D8.94 (1H, br s); 8.17 (1H, d); 7.63 (2H, d); 7.55 (1H, d); 7.11-7.37 (5H, m); 6.35 (1H, d); 5.91-6.08 (3H, m); 5.72 (1H, brs); 4.79 (1H, br s); 3.90 (3H, s); 3.83 (2H, m); 3.61 (5H, m).
EXAMPLE 270: PREPARATION OF 3-methoxy-5-((2-(1 -methyl-1 H-indol-3-yl)-2-oxo-1phenylethyl)amino)benzyl acetate
Step 1 : To a solution of (3-amino-5-methoxyphenyl)methanol (0.300 g; 1.958 mmol), triethylamine (0.817 mL: 5.894 mmol) and DMAP (0.024 g; 0.196 mmol) in dichloromethane (10 ml) was added dropwise acetic anhydride (0.184 mL; 1.965 mmol). The reaction mixture was
255 stirred at room température for 1.5 h and the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.314 g (82%) of 3-amino-5-methoxybenzyl acetate as an oil. ESI/APCI(+): 196 (M+H).
Step 2: 3-Methoxy-5-((2-(1-methyl-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzyl acetate was prepared according to general procedure C from 2-chloro-1-(1-methyl-1 H-indol-3-yl)-2phenylethanone (0,080 g; 0.282 mmol), triethylamine (0.078 mL; 0,564 mmol) and 3-amino-5methoxybenzyl acetate (0.110 g; 0,564 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 150 °C for 1 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.057 g (46%) of the desired compound as an orange solid. ESI/APCI(+): 443 (M+H); 465 (M+Na).
EXAMPLE 271: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1methyl-1H-indol-3-yl)-2-phenylethanone
To a solution of 3-methoxy-5-((2-(1 -methyl-1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzyl acetate (0,057 g; 0.129 mmol) in a mixture of THF (1.5 mL) and methanol (1.5 mL) was added potassium carbonate (0.036 g; 0.258 mmol). After stirring at room température for 3 h, the reaction mixture was diluted with dichloromethane and filtered through a plug of celite. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.020 g (38%) of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1methyl-1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H). ’H NMR (DMSO-cf6) δΠ8.92 (1 H, s); 8.17 (1H, d); 7.63 (2H, d); 7.54 (1 H, d); 7.11-
7.35 (5H, m); 6.39 (1H, s); 6.29 (1H, d); 6.24 (1H, s); 6.12 (1H, s); 5.99 (1H, d); 4.99 (1 H, t);
4.29 (2H, d); 3.90 (3H, s); 3,62 (3H. s).
EXAMPLE 272: PREPARATION OF 1-(isoquinolin-4-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
1-(lsoquinolin-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), isoquinoline-4-carbaldehyde (0.157 g, 0.999 mmol) and a solution of /V-benzylidene-3methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.002 g (1%) of the desired compound as a white solid. ESI/APCI(+): 369 (M+H). ESI/APCI(-): 367 (M-H).
EXAMPLE 273: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5methylpyridin-3-yl)ethanone
256
Step 1: A solution of 3-methoxy-N-((5-methylpyridin-3-yl)methylene)aniline in éthanol was prepared by heating a solution of 5-methylnicotinaldehyde (0.105 g; 0.867 mmol) and 3methoxyaniline (0.111 mL; 0.983 mmol) in éthanol (0.5 mL) at 60 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)arnino)-2-(5-methylpyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.130 g; 0.482 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.230 g; 0.938 mmol) and a solution of 3-methoxy-/V-((5-methylpyridin-3-yl)methylene)aniline (0.867 mmol) in éthanol (1 mL), heated at 60 °C for 96 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.029 g (9%) of the desired compound as a white solid. ESI/APCI(+): 372 (M+H). ESI/APCI(~): 370 (M-H).
EXAMPLE 274: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5methoxypyridin-2-yl)ethanone
Step 1: A solution of 3-methoxy-A/-((5-methoxypyridin-2-yl)methylene)aniline in éthanol was prepared by heating a solution of 5-methoxypicolinaldehyde (0.137 g; 0.999 mmol) and manisidine (0.112 mL; 1.000 mmol) in éthanol (1 mL) at 60 °C overnight The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H); 265 (M+Na).
Step 2: 1-(1/-/-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in ethanoi (1.5 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3-methoxy-/V-((5-methoxypyridin-2-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by précipitation from diethyl ether and heptane furnished 0.139 g (36%) of the desired compound as a beige solid. ESi/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). 1H NMR (DMSOde) ÔD12.07 (1H, br s); 8.71 (1H, d); 8.22 (1H, d); 8.15 (1H, d); 7.53 (1H, d); 7.46 (1H, d); 7.33 (1H, dd); 7.12-7.25 (2H, m); 6.92 (1H, t); 6.28-6.45 (3H, m); 6.01-6.17 (2H, m); 3.75 (3H, s);
3.63 (3H, s).
EXAMPLE 275: PREPARATION OF 2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1-(1Hindol-3-yl)-2-((3-methoxyphenyl)amino)ethanone
Step 1: To a solution of morpholine-3-carboxylic acid hydrochloride (1.000 g; 5.967 mmol) in water (3 mL) cooled to 0 °C was added portionwise sodium nitrite (0.553 g; 8.015 mmol). The
257 reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in acetone. The solid was filtered. The filtrate was concentrated under reduced pressure. The residue was coevaporated with THF to furnish 4nitrosomorpholine-3-carboxylic acid as a pale yellow foam which was used in the next step without further purification. ESI/APCI(-): 159 (M-H).
Step 2: To solution of 4-nitrosomorpholine-3-carboxylîc acid (5.967 mmol) in THF (25 mL) cooled to 0 °C was added dropwise a solution of trifluoroacetic anhydride (0.850 mL; 6.018 mmol) in THF (2 mL). The reaction mixture was stirred at 0 °C for 5 h and at room température overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and stirred with potassium carbonate. The solid was filtered through cellite. The filtrate was concentrated under reduced pressure to furnish 6,7-dihydro-4H[1I2,3]oxadiazolo[4,3-c][1,4]oxazin-8-ium-3-olate as a pale brown wax which was used in the next step without purification. ESI/APCI (+): 143 (M+H).
Step 3: To a solution of 6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazin-8-ium-3-olate (5.967 mmol) in xylene (20 mL) was added ethyl propiolate (0.650 mL; 6.414 mmol). The reaction mixture was heated at 140 °C for 5 h. Ethyl propiolate (0.500 mL, 4.934 mmol) was added again and the reaction mixture was heated at 140 °C for 16 h. After cooling to room température, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (50%) in heptane as eluent furnished 0.638 g (55% over 3 steps) of ethyl 6,7-dihydro-4/-/-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate as a yellow solid. ESI/APCI (+): 197 (M+H). 1H NMR (DMSO-de) δ 6.55 (1H, s); 4.80 (1H, s), 4.28 (2H, q); 4.18 (1H, t); 4.08 (2H, t); 1.27 (3H, t).
Step 4: To a solution of ethyl 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (0.327 g; 1.667 mmol) in THF (5 mL) cooled to -78 °C was added lithium aluminium hydride (0.100 g; 2.635 mmol). The reaction mixture was allowed to warm to room température and was stirred at room température overnight. Water was added and the reaction mixture was stirred for 10 min. After addition of magnésium sulfate, stirring was continued for 5 min. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to furnish 0.245 g (95%) of (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2yljmethanol as a yellow oil. ESI/APCI (+): 155 (M+H). 1H NMR (DMSO-d6) δ 5.97 (1H, s); 4.99 (1H, t); 4.75 (2H, s); 4,36 (1 H, d); 4.02 (4H, s).
Step 5: To a solution of (6,7-dihydro-4/7-pyrazolo[5,1-c][1,4]oxazine-2-yl)methanol (0.237 g;
1.537 mmol) in dichloroethane (12 mL) was added manganèse dioxide (1.210 g; 13.92 mmol).
The reaction mixture was stirred at 60 °C for 1 h and at room température for 18 h. The reaction mixture was filtered through celite. The solid was washed with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure to furnish 0.201 g (86%) of 6,7dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carbaldehyde as an orange solid. ESI/APCI (+): 153
258 (M+H).
Step 6: A solution of A/-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene)-3methoxyaniline in éthanol was prepared by heating a solution of 6,7-dihydro-4H-pyrazolo[5,1c][1,4]oxazine-2-carbaldehyde (0.102 g; 0.670 mmol) and 3-methoxyaniline (0.078 mL; 0.690 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification.
Step_________7: 2-(6,7-Dihydro-4H-pyrazolo[5,1 -c][1,4]oxazin-2-yl)-1 -( 1 /7-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.089 g; 0.330 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1carboxylate (0.193 g; 0,787 mmol) and a solution of /V-((6,7-dihydro-4H-pyrazolo[5,1c][1,4]oxazin-2-yl)methylene)-3-methoxyaniline (0.670 mmol) in éthanol (1 mL), heated at 60 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane followed by précipitation from diethyl ether furnished 0.087 g (32%) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H).
EXAMPLE 276: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino )-2-(5methoxypyridin-3-yl)ethanone
Step 1: A solution of 3-methoxy-A/-((5-methoxypyridin-3-yl)methylene)aniline in éthanol was prepared by heating a solution of 5-methoxynicotinaldehyde (0.137 g; 0.999 mmol) and 3methoxyaniline (0.119 mL; 1.056 mmol) in éthanol (1 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 243 (M+H).
Step 2: 1-(1/7-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.138 g; 0.512 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.260 g; 1.060 mmol) and a solution of 3-methoxy-/V-((5-methoxypyridin-3-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 60 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from methanol furnished 0.065 g (17%) of the desired compound as a white solid. ESI/APCI(+): 388 (M+H). ESIZAPCI(-): 386 (M-H).
EXAMPLE 277: PREPARATION OF 2-(4-fluorophenyl)-2-((3-(hydroxymethyl)-5methoxyphenyl)amino)-1-(1H-indol-3-yl)ethanone
Step 1: A solution of (3-((4-fluorobenzylidene)amino)-5-methoxyphenyl)methanol in éthanol was prepared by heating a solution of 4-fluorobenzaldehyde (0.114 g; 0.919 mmol) and (3-amino-5methoxyphenyl)methanol (0.130 g; 0.849 mmol) in éthanol (0.5 mL) at 60 °C for 18 h. The formation of the imine was quantitative and the solution was used without further purification,
259
ESI/APCI (+): 260 (M+H).
Step 2: 2-(4-Fluorophenyl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.130 g; 0.482 mmol) and triethylamine (0.085 mL; 0.610 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1 H-indole-1 -carboxylate (0.220 g; 0.897 mmol) and a solution of (3-((4-fluorobenzylidene)amino)-5-methoxyphenyl)methanol (0.849 mmol) in éthanol (1 mL), heated at 60 °C for 24 h. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (40% to 100%) in heptane. Further purification by flash chromatography on silica gel using isopropanol (2.5%) in dichloromethane as eluent furnished 0.051 g (15%) of the desired compound as a yellow foam. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).
EXAMPLE 278: PREPARATION OF 5-(2-( 1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2oxoethyl)picolinonitrile
Step 1: To a solution of 6-bromonicotinaldehyde (0.500 g; 2.688 mmol) in DMF (5 mL) was added copper(l) cyanide (0.361 g; 4.031 mmol) and the mixture was heated to 120 °C. After cooling to room température, the reaction mixture was diluted with ethyl acetate and filtered over a pad of celite. The organic phase was washed with water and brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 80%) in heptane to yield 0.161 g (45%) of 5-formylpicolinonitrile as a pink solid. 1H NMR (CDCI3) δ 10.21 (1H, s);
9.19 (1H, s); 8.33 (1H, dd); 7.90 (1H, d); 7.27 (1H, s).
Step 2: 5-(((3-Methoxyphenyl)imino)methyl)picolinonitrile was prepared quantitatively according to general procedure I from 5-formylpicolinonitrile (0.132 g; 0.999 mmol) and 3-methoxyaniline (0.112 mL; 1.001 mmol).
Step 3: 5-(2-(1 H-lndol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)picolinonitrile was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 5-(((3methoxyphenyl)imino)methyl)picolinonitrile (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 3 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (42%) in heptane as eluent furnished 0.049 g (12%) of the desired compound as a yellow solid. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (M-H).
EXAMPLE 279: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6(trifluoromethyl)pyridin-3-yl)ethanone
Step 1: A solution of 3-methoxy-/V-((6-(trifluoromethyl)pyridin-3-yl)methylene)aniline in éthanol was prepared by heating a solution of 6-(trifluoromethyl)nicotinaldehyde (0.175 g; 0.999 mmol)
260 and m-anisidine (0.112 mL; 1.000 mmol) in éthanol (1 mL) at 60 °C overnight. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+):281 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzy 1-5-(2-hydroxyethyl)-
4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1/7-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3-methoxy-A/-((6-(trifluoromethyl)pyridin-3-yl)methylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane followed by précipitation from dichloromethane and heptane furnished 0.125 g (29%) of the desired compound as a beige solid. ESI/APCI(+): 426 (M+H). ESI/APCI(-): 424 (M-H). 1H NMR (DMSO-cfe) 0Π12.28 (1H, br s); 9.07 (1H, s); 8.96 (1H, s); 8.27 (1H, d); 8.17 (1 H, d); 7.89 (1H, d); 7.50 (1H, d); 7.16-7.29 (2H, m); 6.96 (1H, t); 6.67 (1H, d); 6.41-6.52 (2H, m); 6.36 (1H, d); 6.16 (1H, d); 3.65 (3H, s).
EXAMPLE 280: PREPARATION OF 1-(6-fluoro-1H-lndol-3-yl)-2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)-2-phenylethanone
1-(6-Fluoro-1H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 6-fluoro-3-formyl-1H-indole-1-carboxylate (0.263 g; 0.999 mmol) and a solution of 2-(3-(benzylideneamino)-5-methoxyphenoxy)ethanol (0.999 mmol) ïn éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from diethyl ether furnished 0.025 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H). nH NMR (DMSO-c^ 6D12.19 (1H, br s); 8.90 (1H, s); 8.13 (1H, dd); 7.62 (2H, d); 7.12-7.35 (5H, m); 7.05 (1H, t); 6.34 (1H, d); 5.96-6.11 (3H, m); 5.71 (1H, s); 4.78 (1H, t); 3.83 (2H, m); 3.64 (2H, m); 3.60 (3H, s).
EXAMPLE 281: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridazin3-yl)ethanone
Step 1: A mixture of 3-methylpyridazine (1.830 mL; 20.03 mmol), benzaldehyde (4.080 mL; 40.08 mmol)) and zinc chloride (0.546 g; 4.006 mmol) was heated at 150 C for 2.5 h in a sealed tube. After cooling to room température, the reaction mixture was diluted with dichloromethane and was washed with a 1N sodium hydroxide solution. The organic phase concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane furnished 2.820 g (77%) of 3styrylpyridazine as a pale brown solid. ESI/APCI(+): 183 (M+H).
Step 2: A mixture of 3-styrylpyridazine (0.600 g; 3.293 mmol), sodium periodate (1,410 g; 6.592
261 mmol) and a 2.5% osmium tetraoxide solution in tert-butanol (4.500 mL; 0.494 mmol) in a mixture of acetone (6 mL), tert-butanol (6 mL) and water (6 mL) was stirred at room température for 2 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane furnished 0.264 g (74%) of pyridazîne-3-carbaldehyde as a light brown solid. ESI/APCI(+): 109 (M+H).
Step 3: A solution of 3-methoxy-/V-(pyridazin-3-ylmethylene)aniline in éthanol was prepared by heating a solution of pyridazine-3-carbaldehyde (0.108 g; 0.999 mmol) and m-anisidine (0.112 mL; 1.000 mmol) in éthanol (1 mL) at 60 °C overnight. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+):214 (M+H).
Step 4: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridazin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3-methoxy-/V-(pyridazin-3-ylmethylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane followed by précipitation from ethyl acetate furnished 0.080 g (22%) of the desired compound as a beige solid. ESI/APCI(+): 359 (M+H). 1H NMR (DMSO-de) ÔO12.22 (1H, br s); 9.11 (1H, d); 8.83 (1H, s); 8.12 (1 H. m); 7.78 (1H, m); 7.66 (1H, dd); 7.50 (1H, d); 7.16-7.30 (2H, m); 6.96 (1 H, t); 6.68 (1H, d); 6.39 (3H, m); 6.17 (1H, d); 3.65 (3H, s).
EXAMPLE 282: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(7methyl-1H-indol-3-yl)-2-phenylethanone
2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-7-methyl-1H-indole-1-carboxylate (0.259 g; 0.999 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by précipitation from ethyl acetate furnished 0.080 g (20%) of the desired compound as a beige solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H). ’H NMR (DMSO-d6) 5D12.08 (1H, br s); 8.87 (1H, d); 7.98 (1H, d); 7.63 (2H, d); 7.22-7.33 (2H, m); 7.12-7.22 (1H, m); 7.03-7.11 (1H, m); 6.96-7.03 (1H, m);
6.41 (1H, s); 6.22-6.32 (2H, m); 6.07-6.17 (2H, m); 4.97 (1H, t); 4.30 (2H, d); 3.62 (3H, s); 2.47 (3H, s).
EXAMPLE 283: PREPARATION OF 2-((2,6-dimethoxypyridin-4-yl)amino)-1-( 1H-indol-3-yl)-2phenylethanone
262
2-((2,6-Dimethoxypyridin-4-yl)amino)-1-( 1/-/-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.042 g; 0.134 mmol) and 2,6-dimethoxy-4-pyridinamine (0.103 g; 0.668 mmol) in acetonitrile (0.6 mL), irradiated in a microwave oven at 100 °C for 30 min, at 120 °C for 15 min and at 130 °C for 35 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 60%) in heptane furnished 0.021 g (41%) of the desired product as a white powder. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). 1H NMR (DMSO-d6) δ 12.16 (1H, br s); 8.88 (1H, d); 8.15 (1H, d); 7.61 (2H, m); 7.45 (1H, d); 7.1-7.35 (7H, m); 6.13 (1H, d); 5.85 (2H, s);
3.69 (6H, s).
EXAMPLE 284: PREPARATION OF 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(6-methylpyridin-3-yl)ethanone
Step 1: A solution of (3-methoxy-5-(((6-methylpyridin-3-yl)methylene)amino)phenyl)methanol in éthanol was prepared by heating a solution of 6-fluoronicotinaldehyde (0.098 g; 0.809 mmol) and (3-amino-5-methoxyphenyl)methanol (0.124 g; 0.810 mmol) in éthanol (0.7 mL) at 60 °C for 24 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 257 (M+H).
Step 2: 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methylpyridin-3yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.110 g; 0.408 mmol) and triethylamine (0.080 mL; 0.574 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.210 g; 0.856 mmol) and a solution of (3-methoxy-5-(((6-methylpyridin-3-yl)methylene)amino)phenyl)methanol (0.809 mmol) in éthanol (1 mL), heated at 60 °C for 96 h. The residue was purified by flash chromatography on silica gel using a gradient of methanol (1% to 15%) in ethyl acetate. Further purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in ethyl acetate furnished 0.056 g (17%) of the desired compound. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).
EXAMPLE 285: PREPARATION OF 2-(5-fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1: A solution of A/-((5-fluoropyridin-3-yl)methylene)-3-methoxyaniline in éthanol was prepared by heating a solution of 5-fluoronicotinaldehyde (0.125 g; 0.999 mmol) and manisidine (0.112 mL; 1,000 mmol) in éthanol (1 mL) at 60 °C overnight. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+):231 (M+H).
Step 2: 2-(5-Fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a
263 solution of N-((5-fluoropyridin-3-yl)methylene)-3-methoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichlorométhane followed by précipitation from diethyl ether furnished 0.161 g (43%) of the desired compound as a beige solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H). 1H NMR (DMSO-d0Jl 5Π12.26 (1H, brs); 8.95 (1H, d); 8.78 (1H, s); 8.43 (1H, d); 8.17 (1H. d); 7.91 (1H, d); 7.50 (1H, d); 7.15-7.29 (2H, m); 6.96 (1H, t); 6.58 (1H, d); 6.40-6.50 (2H, m); 6.27 (1H, d); 6.16 (1H, d); 3.65 (3H, s).
EXAMPLE 286 : Enantiomers séparation of 1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)2-((5-methoxypyridin-3-yl)amino)ethanone leading to (-)-1-(5-fluoro-1F/-indol-3-yl)-2-(6methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone and (+)-1-(5-fluoro-1H-Îndol-3yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone 1-(5-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone (0.064 g) was separated into its enantiomers and purified by préparative HPLC (ChiralPak column; method 6). Under these conditions, 0.015 g of the faster eluting enantiomer (tr = 9.7 min; ee = 90%) and 0.013 g of the slower eluting enantiomer (tr = 12.5 min; ee = 96%) were obtained.
EXAMPLE 287: Enantiomers séparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone leading to (-)-1-(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone and (+)-1-(1 H-indol-3-yl)-2-((3methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone
1- (1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone (0.029 g) was separated into its enantiomers and purified by préparative HPLC (ChiralPak column; method 7). Under these conditions, 0.008 g of the faster eluting enantiomer (L = 9.3 min; ee = 98%) and 0.008 g of the slower eluting enantiomer (tr = 12.9 min; ee = 94%) were obtained.
EXAMPLE 288: Enantiomers séparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone leading to (-)-2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone and (+)-2-((3,5-dlmethoxyphenyl)amino)-1-(1F/-indol-3-yl)-2-phenylethanone
2- ((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone (0.050 g) was separated into its enantiomers and purified by préparative HPLC (ChiralPak column; method 7). Under these conditions, 0.016 g of the faster eluting enantiomer (tr = 8.1 min; ee = 96%) and 0.012 g of the slower eluting enantiomer (tr = 17.9 min; ee = 96%) were obtained.
EXAMPLE 289: PREPARATION OF 2-(benzo[cf]oxazol-2-yl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone
Step 1 : A solution of 2-methylbenzo[c(]oxazole (1.020 g; 7.661 mmol) and Λ/,Νdimethylformamide dimethyl acetal (1.230 g; 10.32 mmol) in DMF (8 mL) was heated at 140 °C for 18 h. The reaction mixture was concentrated under reduced pressure to furnish 1.170 g (81%) of 2-(benzo[cQoxazol-2-yl)-A/,N-dimethylethenamine as a brown solid. ESI/APCI (+): 189
264 (M+H). ’H NMR (DMSO-c/6) δ 7.64 (1H, d); 7.42 (1H, d); 7.38 (1H, d); 7.19 (1H, t); 7.09 (1H, t); 5.00(1 H, d); 2.95 (6H, s).
Step 2: To a solution of 2-(benzo[d]oxazol-2-yl)-A/,A/-dimethylethenamine (0.233 g; 1.238 mmol) in THF (3.8 mL) heated at 45°C was added a 1M sodium periodate solution in water (3.800 mL; 3.800 mmol). The reaction mixture was stirred at 45 °C for 1 h. After cooling to room température, the precipitate was filtered and was washed with ethyl acetate. The filtrate was washed with a 1M sodium bicarbonate solution. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 25%) in heptane furnished 0.079 g (43%) of benzo[d]oxazole-2-carbaldehyde as a yellow oil ESI/APCI (+): 148 (M+H). 1H NMR (DMSO-d6) δ
9.92 (1H, s); 8.02 (1H, d); 7.93 (1H, d); 7.67 (1H, t); 7.56 (1 H, t).
Step 3: A solution of N-(benzo[djoxazol-2-ylmethylene)-3-methoxyaniline in éthanol was prepared by heating a solution of benzo[d]oxazole'2-carbaldehyde (0.100 g; 0.680 mmol) and
3- methoxyaniline (0.078 mL; 0.698 mmol) in éthanol (0.5 mL) at 60 °C for 5 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 253 (M+H).
Step 4: 2-(Benzo[d]oxazol-2-yl)-1 -(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.095 g; 0.352 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.189 g; 0.771 mmol) and a solution of A/-(benzo[d]oxazoi-2-ylmethylene)-3-methoxyaniline (0.680 mmol) in éthanol (1 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane followed by précipitation from methanol furnished 0.028 g (10%) of the desired compound as a yellow solid. ESI/APCI(+): 398 (M+H). ESI/APCI(-): 396 (M-H).
EXAMPLE 290: PREPARATION OF 2-((3-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone 2-((3-Methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0.095 g; 0.352 mmol) and triethylamine (0.070 mL; 0.502 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-7-methyl-1H-indole-1-carboxylate (0.195 g; 0.752 mmol) and a solution of 3-methoxy-/V-(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline (0.704 mmol) in éthanol (1 mL), heated at 60 °C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane furnished 0.034 g (12%) of the desired compound as a yellow oil. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).
EXAMPLE 291: PREPARATION OF 1-(benzo[d]isoxazol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone
265
Step 1: To a solution of benzo[cf]isoxazole-3-carboxylic acid (0.500 g; 3.065 mmol) in THF (20 mL) was added Λ/,Ο-dimethylhydroxylamine hydrochloride (0.359 g; 3.680 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.180 g; 6.155 mmol) and pyridine (0.500 mL; 6.195 mmol). The reaction mixture was stirred at room température overnight. And was concentrated under reduced pressure. The residue was partitioned between ethyl acetate. The phases were separated. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.225 g (36%) of A/-methoxy-A/-methylbenzo[d]!soxazole-3-carboxamÎde as a white solid. ESI/APCI(+): 207 (M+H).
Step 2: To a solution of N-methoxy-N-methylbenzo[d]isoxazole-3-carboxamide (0.100 g; 0.485 mmol) in THF (5 mL) cooled to 0 °C was added a 1M benzylmagnesium chloride solution in THF (1.450 mL; 1.450 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room température overnight. After cooling to 0 °C, the reaction was quenched by addition of water. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 20%) in heptane furnished 0.052 g (45%) of 1-(benzo[c/]isoxazol-3-yl)-2phenylethanone as a beige solid. ESI/APCI(+): 238 (M+H). ESI/APCI(+): 236 (M-H).
Step 3: 1-(Benzo[c/]isoxazol-3-yl)-2-bromo-2-phenylethanone was prepared according to general procedure P from a solution of 1-(benzo[d]isoxazol-3-yl)-2-phenylethanone (0.080 g; 0.337 mmol) in THF (3.5 mL) and a solution of phenyltrimethylammonium tribromide (0.140 g; 0.371 mmol) in THF (4.5 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 20%) in heptane furnished 0.092 g (86%) of 1-(benzo[d]isoxazol-3-yl)-2bromo-2-phenylethanone as a yellow solid.
Step 4: 1-(Benzo[d]isoxazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure E from 1-(benzo[cf]isoxazol-3-yl)-2-bromo-2-phenylethanone (0.044 g; 0.114 mmol) and m-anisidine (0.127 mL; 1.134 mmol) in acetonitrile (0.5 mL), irradiated in a mïcrowave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.004 g (9%) of the desired compound as a yellow solid. ESI/APCI(+): 359 (M+H).
EXAMPLE 292: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7methyl-1H-indol-3-yl)-2-phenylethanone
2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyi-5-(2-hydroxyethyl)4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 3-formyl-7-methyl-1/-/-indole-1-carboxylate (0.259 g; 0.999 mmol)
266 and a solution of 2-(3-(benzylideneamino)-5-methoxyphenoxy)ethanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane followed by purification by préparative HPLC (XBridge column; method 1) furnished 0.012 g (3%) of the desired compound as a white solid. ESI/APCI(+): 431 (M+H). ESI/APCI(-): 429 (ΜΗ). 1H NMR (DMSO-de) SD12.09 (1H, br s); 8.89 (1H, d); 7.98 (1H, d); 7.62 (2H, d); 7.22-7.36 (2H, m); 7.13-7.22 (1H, m); 7.03-7.11 (1H, m); 6.95-7.03 (1H, m); 6.32 (1H, d); 6.10 (1H, d); 6.05 (2H, br s); 5.71 (1H, s); 4.78 (1H, t); 3.83 (2H, m); 3.62-3.71 (2H, m); 3.61 (3H, s); 2.48 (3H. s).
EXAMPLE 293: PREPARATION OF 2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1(7-methyl-1H-indol-3-yl)ethanone
2-((3-Methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1 -(7-methyl-1 H-indol-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.126 g; 0.467 mmol) and triethylamîne (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-7-methyl-1H-indole-1-carboxylate (0.241 g; 0.929 mmol) and a solution of 3-methoxy-/\/-((6-methoxypyridin-3-yl)methylene)aniline (0.875 mmol) in éthanol (1 mL), heated at 60 °C for 98 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane furnished 0.055 g (16%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).
EXAMPLE 294: PREPARATION OF 2-(6-fluoropyridin-3-yl)-2-((3-(hydroxymethyl)-5methoxyphenyl)amino)-1-(1H-indol-3-yl)ethanone
Step 1: A solution of (3-(((6-fluoropyridin-3-yl)methylene)amino)-5-methoxyphenyl)methanol in éthanol was prepared by heating a solution of 6-fluoronicotinaldehyde (0.110 g; 0.879 mmol) and (3-amino-5-methoxyphenyl)methanol (0.140 g; 0.914 mmol) in éthanol (0.5 mL) at 60 °C for 5 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI (+): 261 (M+H).
Step 2: 2-(6-Fluoropyridin-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3yljethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.121 g; 0.448 mmol) and triethylamîne (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.235 g; 0.958 mmol) and a solution of (3-(((6-fluoropyridin-3-yl)methylene)amino)-5-methoxyphenyl)methanol (0.879 mmol) in éthanol (1 mL), heated at 60 °C for 16 h. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0% to 4%) in dichloromethane furnished 0.038 g (11%) of the desired compound as a yellow oil. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).
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EXAMPLE 295: PREPARATION OF 1-(5-fluoro-1 H-indol-3-yl )-2-(( 3-(hydroxymethyl )-5methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone
1- (5-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-(pyridin-3yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.126 g; 0.467 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.259 g; 0.984 mmol) and a solution of (3-methoxy-5-((pyridin-3-ylmethylene)amino)phenyl)methanol (0.953 mmol) in éthanol (1 mL), heated at 60 °C for 96 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane followed by précipitation from dichloromethane furnished 0.100 g (26%) of the desired compound as a white solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).
EXAMPLE 296: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6methoxypyridin-3-yl)ethanone
2- ((3,5-Dimethoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.125 g; 0.463 mmol) and triethylamine (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), tert-butyl 3-formyl-1/-/-indole-1-carboxylate (0.260 g; 1.060 mmol) and a solution of 3,5-dimethoxy-N-((6-methoxypyridin-3-yl)methylene)aniline (0.912 mmol) in éthanol (1 mL), heated at 60 °C for 16 h. tert-Butyl 3-formyl-1 H-indole-1 -carboxylate (0.127 g; 0.518 mmol) was added and the reaction mixture was heated at 60 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.008 g (2%) of the desired compound as a brown solid. ESI/APCI(+): 418 (M+H). ESI/APCI(-): 416 (M-H).
EXAMPLE 297: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone
Step_______T A solution of 2-(3-methoxy-5-((pyrazolo[1,5-a]pyridin-2ylmethylene)amino)phenoxy)ethanol in éthanol was prepared by heating a solution of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.073 g; 0.499 mmol) and 2-(3-amino-5methoxyphenoxy)ethanol (0.092 g; 0.502 mmol) in éthanol (1 mL) at 60 °C for 6 h. The formation of the Imine was quantitative and the solution was used without further purification. ESI/APCI(+):312 (M+H).
Step 2: 2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1 /-/-indol-3-yl)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone was prepared according to general procedure K from a mixture of 3benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.067 g; 0.248 mmol) and triethylamine (0.035 mL; 0.252 mmol) in éthanol (1 mL), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.123 g;
0.501 mmol) and a solution of 2-(3-methoxy-5-((pyrazolo[1,5-a]pyrîdin-2ylmethylene)amino)phenoxy)ethanol (0.499 mmol) in éthanol (0.5 mL), heated at 70 °C
268 overnight. The residue was purified by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane. Further purification by préparative HPLC (XBridge column; method 5) followed by précipitation from diethyl ether furnished 0.010 g (4%) of the desired compound as a light brown solid. ESI/APCI(+): 457 (M+H). ESI/APCI(-): 455 (M-H). 1H NMR (DMSO-de) ÔC12.10 (1 H, br s); 8.80 (1 H, br s); 8.61 (1H, d); 8.19 (1H, d); 7.61 (1H, d); 7.48 (1H, d); 7.08-7.29 (3H, m); 6.82 (1 H, t); 6.65 (1H, s); 6.29 (2H, s); 6.10 (2H, s); 5.75 (1H, s); 4.81 (1H, t); 3.85 (2H, m); 3.67 (2H,m); 3.63 (3H, s).
EXAMPLE 298: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(7-methyl-1H-indol-3yl)-2-phenylethanone
Step 1: 1-(7-Methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of 7-methylindole (0.500 g; 3.811 mmol) in dichloromethane (16 mL), a 1M diethylaluminium chloride solution in hexane (5.790 mL; 5.790 mmol) and a solution of phenylacetyl chloride (0.762 mL; 5.718 mmol) in dichloromethane (16 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.320 g (34%) of the desired compound as a beige solid. ESI/APCI(+): 250 (M+H). ESI/APCI(-): 248 (M-H).
Step 2: 2-Bromo-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(7-methyl-1H-indol-3-yl)-2-phenylethanone (0.200 g; 0.802 mmol) in THF (5.5 mL) and a solution of phenyltrimethylammonium tribromide (0.332 g; 0.882 mmol) in THF (7 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0,314 g (99%) of the desired compound as a brown solid. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H).
Step 3: 2-((3,5-Dimethoxyphenyl)amino)-1 -(7-methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 2-bromo-1-(7-methyl-1H-indol-3-yl)-2phenylethanone (0.120 g; 0.366 mmol) and 3,5-dimethoxyaniline (0.280 g; 1.828 mmol) in acetonitrile (1.5 mL), irradiated in a microwave oven at 100 °C for 5 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.042 g (29%) of 2-((3,5-dimethoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 401 (M+Na). ESI/APCI(-): 399 (M-H). 1H NMR (DMSO-d6) SD12.08 (1H, br s); 8.88 (1H, d); 7.98 (1H, d); 7.63 (2H, d); 7.23-7.34 (2H, m); 7.18 (1H, d); 7.03-7.12 (1H, m); 6.96-7.03 (1 H. m); 6.34 (1H, d); 6.10 (1H, d); 6.06 (2H, d); 5.71 (1H, m); 3.61 (6H, s); 2.48 (3H. s).
EXAMPLE 299: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1 -methyl-1 H-indol-3yl)-2-phenylethanone
Step 1: To a solution of phenylacetic acid (0.500 g; 3.672 mmol) in dichloromethane (7 mL) was added a solution of 1 H-benzotriazole (1.360 g; 11.42 mmol) and thionyl chloride (0.294 mL;
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4.053 mmol) in dichloromethane (7 mL). The reaction mixture was stirred at room température for 1 h. The white precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium carbonate solution. The phases were separated. The organic phase was washed with a saturated sodium carbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 0.812 g (93%) of l-OH-benzoIdHI^.Sltriazol-lyl)-2-phenylethanone as a yellow solid. 1H NMR (CDCI3) δ 8.27 (1H, d); 8.12 (1H, d); 7.65 (1H, t); 7.25-7.5 (6H, m); 4.74 (2H, s).
Step 2: 1-(1 -Methyl-1 H-indol-3-yl)-2-phenylethanone has been prepared according to 2 different procedures described hereunder as method A and method B.
Method A: To a solution of /V-methylindole (0,300 g; 2.287 mmol) and 1-(1 Hbenzo[c/][1,2r3]triazol-1-yl)-2-phenylethanone (0.434 g; 1.829 mmol) in dichloromethane (19 mL) cooled to 0 °C was added portionwise aluminum trichloride (0.381 g; 2.857 mmol). The reaction mixture was stirred at room température for 3 h. Methanol was added and the réaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium carbonate solution. The phases were separated. The organic phase was washed with a saturated sodium carbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of by fiash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane furnished 0.266 g (58%) of 1-(1-methyl-1 H-indol-3-yl)-2-phenylethanone as a pink oil. ESI/APCI(+): 250 (M+H); 272 (M+Na). Ή NMR (DMSO-d6) δ 8.56 (1H, s); 8.18 (1H, d); 7.54 (1H, d); 7.2-7.4 (7H, m); 4.11 (2H. s); 3.89 (3H, s).
Method B: 1-(1 -Methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of N-methylindole (0.300 g; 2.287 mmol) in dichloromethane (11.5 mL), a 1M diethylalumînium chloride solution in hexane (3.960 mL; 3.960 mmol) and a solution of phenylacetyl chloride (0.518 mL; 3.887 mmol) in dichloromethane (11,5 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 60%) in heptane furnished 0.350 g (76%) of the desired product as pink powder.
Step 3: 2-Bromo-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(1-methyl-1 H-indol-3-yl)-2-phenylethanone (0.256 g; 1.027 mmol) in THF (11 mL) and a solution of phenyltrimethylammonium tribromide (0.448 g; 1.192 mmol) in THF (13.5 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 2 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 50%) in heptane furnished 0.302 g (90%) of the desired product as a pink solid. ESI/APCI(+): 328, 330 (M+H). 1H NMR (DMSO-d6) δ 8.69 (1H, s); 8.20 (1H, d); 7.67 (2H, m);
7.57 (1H, d); 7.0-7.4 (5H, m); 6.73 (1 H, s); 3.88 (3H, s).
Step 4: 2-((3,5-Dimethoxyphenyl)amino)-1-(1-methyl-1 H-indol-3-yl)-2-phenylethanone was
270 prepared according to general procedure E from 2-bromo-1-(1-methyl-1H-indol-3-yl)-2phenylethanone (0.050 g; 0.152 mmol) and 3,5-dimethoxyaniline (0.116 g; 0.757 mmol) in acetonitrile (0.7 mL), irradiated in a microwave oven at 100 °C for 10 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 60%) in heptane furnished 0.051 g (84%) of the desired product as a white powder. ESI/APCI(+): 401 (M+H); 423 (M+Na). ESI/APCI(-): 399 (M-H). 1H NMR (DMSO-d6) δ 8.93 (1H, s); 8.17 (1H, d); 7.61 (2H, m); 7.55 (1H, d); 7.1-7.3 (4H, m); 6.36 (1H, d); 3.88 (3H, s).
EXAMPLE 300: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1Hindol-3-yl)-2-phenylethanone
Step 1 : To a suspension of 1H-indole-7-carboxaldehyde (1,000 g; 6.889 mmol) and methyltriphenylphosphonium bromide (2.960 g; 8.286 mmol) in THF (40 mL) cooled to 0 °C was added dropwise a solution of potassium tert-butoxide (1.170 g; 10.43 mmol) in THF (10 mL). The reaction mixture was stirred overnight at room température. The reaction mixture was poured into a mixture ice/water and was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 50%) in heptane furnished 0.914 g of 7-vinyl-1 H-indole as a pink oil. ESI/APCI(+): 144 (M+H).
Step 2: To a solution of 7-vinyl-1H-indole (0.914 g; 6.383 mmol) in THF (37 mL) cooled to 0 °C was added dropwise a 1M borane-tetrahydrofuran complex solution in THF (6.400 mL ; 6.400 mmol). The reaction mixture was stirred at room température for 2.5 h. A 10% sodium hydroxide solution (3.100 mL; 7.750 mmol) was added dropwise followed by the addition of a 30% hydrogen peroxide solution in water (0.869 mL; 9.837 mmol). The reaction mixture was stirred at room température for 4 h. A saturated ammonium chloride solution was added. After 5 min at room température, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 70%) in heptane furnished 0.490 g (44% over two steps) of 2-(1H-lndol-7yl)ethanol as a brown oil. ESI/APCI(+): 162 (M+H). ESI/APCI(-): 160 (M-H). 1H NMR (DMSO-c/6) δ 11.00 (1H, br s); 7.35 (1 H, m); 7.28 (1 H, t); 6.90 (2H, m); 6.40 (1H, m); 4.67 (1H, t); 3.70 (2H, q); 2.98 (2H, t).
Step 3: 7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indole was prepared according to general procedure N from 2-(1H-indol-7-yl)ethanol (0.200 g; 1.241 mmol), DBU (0.280 mL; 1.876 mmol) and TBDMSCI (0.412 g; 2.734 mmol) in THF (4.6 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 80%) in heptane furnished 0.288 g (84%) of the desired product as an orange oil. ESI/APCI(+): 276 (M+H). ’H NMR (DMSO-d6) δ 11.12 (1H, br s); 7.48 (1H, m); 7.39 (1H, t); 7.00 (2H, m); 6.51 (1H, m); 3.97 (2H, t); 3.14 (2H, t); 0.91 (9H,
s); 0.00 (6H, s).
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Step 3:1-(7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of 7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1Hindole (0,193 g; 0.701 mmol) in dichloromethane (3.5 mL), a 1M diethylaluminium chloride solution in hexane (1.200 mL; 1.200 mmol) and a solution of phenylacetyl chloride (0.156 mL; 1.171 mmol) in dichloromethane (3.5 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 70%) in heptane furnished 0,179 g (65%) of the desired product as pink powder. ESI/APCI(+): 394 (M+H); 416 (M+Na). ESI/APCI(-): 392 (M-H). 1H NMR (DMSO-d6) δ 12.11 (1H, br s); 8.64 (1H, s); 8.17 (1H, d); 7.3-7.5 (5H, m); 7.17-7.26 (2H, m); 4.30 (2H, s); 4,01 (2H, t); 3.21 (2H, t); 0.93 (9H, s); 0.00 (6H, s).
Step 4: 2-Bromo-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)1/-/-indol-3-yl)-2-phenylethanone (0.064 g; 0.163 mmol) in THF (2 mL) and a solution of phenyltrimethylammonium tribromide (0.074 g; 0.197 mmol) in THF (2.4 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.045 g (77%) of the desired product as a beige solid. ESI/APCI(+): 358, 360 (M+H). ESI/APCI(-): 356, 358 (M-H).
Step 5: 2-((3,5-Dimethoxyphenyl)amino)-1 -(7-(2-hydroxyethyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 2-bromo-1-(7-(2-hydroxyethyl)-1H-indol-3yl)-2-phenylethanone (0.045 g; 0.126 mmol) and 3,5-dimethoxyaniline (0.194 g; 1.266 mmol) in acetonitrile (0.8 mL), irradiated in a microwave oven at 100 °C for 5 min. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.033 g (61%) of the desired product as a green powder. ESI/APCI(+): 431 (M+H); 453 (M+Na). ESI/APCI(-): 429 (M-H). 1H NMR (DMSO-d6) 8 12.06 (1H, br s); 8.86 (1H, s); 8.01 (1H, d); 7.63 (2H, m); 7.28 (2H, m); 7.0-7.2 (3H, m); 6.33 (1H, d); 6.10 (1H, d); 6.05 (2H, d); 5.71 (1H, s); 4.69 (1H, br s); 3.69 (2H, t); 3.61 (6H, s); 3.00 (2H, t).
EXAMPLE 301: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1methyl-1 H-indazol-3-yl)ethanone
2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1 -methyl-1 H-indazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1 mL), 1-methyl-1 H-indazole-3-carbaldehyde (0.160 g; 0.999 mmol) and a solution of /V-(4-fluorobenzylidene)-3,5-dimethoxyaniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane followed by crystallization from dichloromethane furnished 0.062 g (15%) of the desired compound as a white solid. ESI/APCI(+): 420 (M+H). ESI/APCI(-): 418 (M-H). 1H NMR (DMSO-d6) δ 8.14 (1H, d); 7.82 (1H, d); 7.63 (2H, dd); 7.53 (1H, t); 7.33-7.44 (1H, m); 7,16
272 (2H, t); 6.57 (1 H. d); 6.43 (1H, d); 5.95 (2H, br s); 5.75 (1 H, s); 4.26 (3H, s); 3.60 (6H, s).
EXAMPLE 302: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(7methyl-1 H-indol-3-yl)ethanone
Step 1: To a solution of 2-(4-fluorophenyl)acetic acid (0.500 g; 3.244 mmol) in dichloromethane (5 mL) were added oxalylchloride (0.550 mL; 6.282 mmol) and DMF (1 drop). The reaction mixture was stirred at room température for 2 h and was concentrated under reduced pressure. The residue was coevaporated with toluene to give quantitatively 2-(4-fluorophenyl)acetyl chloride which was used in the next step without further purification.
Step 2: 2-(4-Fluorophenyl)-1-(7-methyl-1H-indol-3-yl)ethanone was prepared according to general procedure O from a solution of 7-methyl-1 H-indole (0.280 g; 2,135 mmol) in dichloromethane (8.5 mL), a 1M diethylaluminium chloride solution in hexane (4.300 mL; 4.300 mmol) and a solution of 4-(2-fluorophenyl)acetyl chloride (3.244 mmol) in dichloromethane (8.5 mL). Purification by précipitation from diethyl ether furnished 0.188 g (33%) of the desired compound as a beige solid. ESI/APCI(+): 268 (M+H). ESI/APCI(-): 266 (M-H).
Step 3: 2-Bromo-2-(4-fluorophenyl)-1-(7-methyl-1H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(4-fluorophenyl)-1-(7-methyl-1-H-indol-3yl)ethanone (0.186 g; 0.696 mmol) in THF (5 mL) and a solution of phenyltrimethylammonium tribromide (0.296 g; 0.787 mmol) in THF (6 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 30%) in heptane furnished 0.225 g (93%) of the desired compound as a brown solid. ESI/APCI (+): 346, 348 (M+H). ESI/APCI (-): 344, 346 (M-H).
Step 4: A mixture of 2-bromo-2-(4-fluorophenyl)-1-(7-methyl-1/7-indol-3-yl)ethanone (0.050 g; 0.144 mmol) and 3,5-dimethoxyaniline (0.047 g; 0.307 mmol) in acetonitrile (1 mL) was stirred at room température for 72 h. The reaction mixture was diluted with ethyl acetate and washed with a 1M sodium bicarbonate solution. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0 % to 40%) in heptane furnished 0.054 g (89%) of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(7-methyl-1 H-indol-3-yl)ethanone as a white solid. ESI/APCI (+): 419 (M+H). ESI/APCI (-): 417 (M-H).
EXAMPLE 303: PREPARATION OF 2-((3-(2-( tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone
Step 1: A mixture of (pyridin-3-yl)acetic acid hydrochloride (1.850 g; 10.67 mmol) and acetic anhydride (1.000 mL; 10.68 mmol) was heated in a sealed tube at 85 °C for 1 hour. Indole (1.250 g; 10.7 mmol) was added. The reaction mixture was heated at 85 °C for 20 min and at
105 °C for 30 min. After cooling to room température, the reaction mixture was basified with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a
273 gradient of methanol (1% to 10%) in dichloromethane furnished 0.674 g (27%) of 1-(1H-indol-3yl)-2-(pyridin-3-yl)ethanone as a beige solid. ÊSI/APCI(+): 237 (M+H). ESI/APCI(-): 235 (M-H). Step 2: 2-Bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.570 g; 2.412 mmol) in THF (17 mL) and a solution of phenyltrimethylammonium tribromide (0.997 g; 2.652 mmol) in THF (22 mL). The reaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10 %) in dichloromethane furnished 0.275 g (36%) of the desired compound as a brown solid. ESI/APCI(+): 315, 317 (M+H).
Step 3: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.060 g; 0.190 mmol) and 3-(2-(ferf-butoxy)ethoxy)-5-methoxyaniline (0.091 g; 0.381 mmol) in acetonitrile (1mL) was stirred at room température for 24 h. The reaction mixture was diluted with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.041 g of 2-((3-(2-(fert-butoxy)ethoxy)-5methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone as a beige solid. ESI/APCI(+): 474 (M+H), 496 (M+Na). ESI/APCI(-): 472 (M-H).
EXAMPLE 304: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(pyridin-3-yl)ethanone 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.040 g; 0.084 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3.000 mL; 12.00 mmol). The reaction mixture was stirred at room température for 6 h and was partially concentrated under reduced pressure. The residue was partitioned dichloromethane and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 15%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.015 g (42%) of 2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone as a beige solid. ESI/APCI(+): 418 (M+H). ESI/APCI(~): 416 (M-H). 1H NMR (DMSO-d6) 5D12.22 (1 H, br s); 8.94 (1 H. s); 8.87 (1H, s); 8.40 (1H, d); 8.16 (1H. d); 7.95 (1H, d); 7.48 (1H, d); 7.32 (1H. dd); 7.14-7.27 (2H, m);
6.47 (1H, d); 6.17 (1H, d); 6.06 (2H, s); 5.70-5.79 (1H, m); 4.79 (1 H, t); 3.76-3.93 (2H, m); 3.623.71 (2H, m); 3.61 (3H, s).
EXAMPLE 305: PREPARATION OF 1-(6-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5methoxyphenyl)amÎno)-2-(pyridin-3-yl)ethanone
1-(6-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-(pyridin-3yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070
274 mL; 0.505 mmol) ίη éthanol (1 mL), fert-butyl 6-fluoro-3-formyl-1H-indole-1-carboxylate (0.263 g; 0.999 mmol) and a solution of (3-methoxy-5-((pyridin-3-ylmethylene)amino)phenyl)methanol (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 12%) in dichloromethane followed by purification by préparative TLC using methanol (10%) in dichloromethane as eluent furnished 0.029 g (7%) ofthe desired compound. ESI/APCI(+): 406 (M+H). ESIZAPCI(-): 404 (ΜΗ).
EXAMPLE 306: PREPARATION OF 2-((2-fluoro-3,5-dimethoxyphenyl)amino)-1-(1/7-indol-3-yl)2-phenylethanone
Step 1: To a solution of 3,5-dimethoxyaniline (0.200 g; 1.306 mmol) in dichloromethane (5 mL) was added N-fluoro-2,4,6-trimethylpyridinium triflate (0.377 g; 1.303 mmol) and the reaction mixture was heated at 100 °C overnight. After cooling to room température, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.068 g (30%) of 2-fluoro-3,5-dimethoxyaniline as a white solid. ESI/APCI(+): 172 (M+Na). 1H NMR (DMSO-cfe) ÔD5.94 (1H, dd); 5.89 (1 H, dd);
3.73 (3H, s); 3.63 (3H, s).
Step 2: 2-((2-Fluoro-3,5-dimethoxyphenyl)amino)-1-(1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-bromo-1-(1/7-indol-3-yl)-2-phenylethanone (0.120 g; 0.382 mmol), 2-fluoro-3,5-dimethoxyaniline (0.065 g; 0.382 mmol) and triethylamine (0.106 mL; 0,764 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 100 °C for 15 min and at 120 °C for 10 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70 %) in heptane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.058 g (37%) of the desired compound as a white solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H). 1H NMR (DMSO-de) ÔD12.20 (1 H, br s); 8.87 (1H, s); 8.15 (1H, d); 7.62 (2H, d); 7.47 (1H, d); 7.24-7.34 (2H, m); 7,13-7.23 (3H. m); 6.21 (1 H, d); 6.13 <1 H, dd); 5.98 (1H, dd); 5.72-5.81 (1 H, m); 3.75 (3H, s); 3.63 (3H, s).
EXAMPLE 307: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6methylpyridin-3-yl)ethanone
Step 1: A mixture of 2-(6-methylpyridin-3-yl)acetic acid (0.150 g; 0.992 mmol) in acetic anhydride (0.094 mL; 0.996 mmol) was irradiated at 85 °C for 1 h in a microwave oven. 1/7Indole (0.116 g; 0.990 mmol) was added and the reaction mixture was irradiated at 85 °C for 60 min in a microwave oven. The reaction mixture was diluted with ethyl acetate and washed with a 1M sodium bicarbonate solution. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane furnished 0.057 g (23%) of 1-(1/7-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone as a beige solid.
275
ESI/APCI(+): 251 (M+H). ESI/APCI (-): 249 (M-H).
Step 2: 2-Bromo-1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone (0.084 g; 0.336 mmol) in THF (5 mL) and a solution of phenyltrimethylammonium tribromide (0.145 g; 0.386 mmol) in THF (2 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 4 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane furnished 0.039 g (35%) of the desired compound. ESI/APCI(+): 329, 331 (M+H). ESI/APCI(-): 327, 329 (M-H).
Step 3: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone (0.038 g; 0.115 mmol) and 3,5-dimethoxyaniline (0.036 g; 0.235 mmol) in acetonitrile (0.8 mL) was stirred at room température for 96 h. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.020 g (43%) of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methylpyridin3-yl)ethanone as a yellow solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).
EXAMPLE 308: PREPARATION OF 2-((4,6-dimethoxypyrirnidin-2-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone
To a solution of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.050 g; 0.159 mmol) in acetonitrile (0.5 mL) was added 4,6-dimethoxypyrimidin-2-amine (0,123 g; 0.793 mmol) and the mixture was irradiated to 130 °C for 20 min in a microwave oven. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 70%) in heptane. Further purification by solid phase extraction on C18-reversed phase column using a gradient of acetonitrile (30% to 100%) in water furnished 0.010 g (16%) of 2-((4,6-dimethoxypyrimidin-2-yl)amino)-1-(1 H-indol-3-yl)-2phenylethanone. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H).
EXAMPLE 309: PREPARATION OF 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(otolyl)ethanone
Step 1: 3-Methoxy-A/-(2-methylbenzylidene)aniline was prepared quantitatively according to general procedure I from 2-methylbenzaldehyde (0.116 mL; 1.003 mmol) and 3-methoxyaniline (0.112 mL; 1.001 mmol). ESI/APCI(+): 226 (M+H).
Step 2: 1-(1H-lndol-3-yl)-2-((3-methoxyphenyl)amino)-2-(o-tolyl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL: 0.505 mmol) in éthanol (1 mL), fert-butyl 3-formyl-1H-indole-1-carboxylate (0.245 g; 0.999 mmol) and a solution of 3methoxy-A/-(2-methylbenzylidene)aniline (1.001 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to
100%) in heptane followed by précipitation from diethyl ether furnished 0.056 g (15%) of the
276 desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).
EXAMPLE 310: PREPARATION OF 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4fluorophenyl)-1 -( 1 H-indol-3-yl)ethanone
Step 1: 2-(4-Fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to general procedure O from a solution of 1 H-indole (0.234 g; 1.997 mmol) in dichloromethane (10 mL), a 1M diethylaluminum chloride solution in hexane (3.000 mL; 3.000 mmol) and a solution of 2-(4fluorophenyl)acetyl chloride (0.411 mL; 3.001 mmol) in dichloromethane (1 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 80%) in heptane furnished 0.324 g (64%) of the desired product. ESI/APCI(+): 254 (M+H). ESI/APCI(-): 252 (ΜΗ).
Step 2: 2-Bromo-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(4-fluorophenyl)-1-(1/-/-îndol-3-yl)ethanone (0.320 g; 1.263 mmol) in THF (8.5 mL) and a solution of phenyltrimethylammonium tribromide (0.522 g; 1.389 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température overnight. Purification by flash chromatography on silica gel ustng a gradient of ethyl acetate (0% to 80%) in heptane furnished quantitatively the desired product as a crude brown solid. ESI/APCI(-): 330, 332 (M-H).
Step 3: 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3yl)ethanone was prepared according to general procedure C from 2-bromo-2-(4-fluorophenyl)-1(1H-ïndol-3-yl)ethanone (0.200 g; 0.602 mmol), 3-(2-(tert-butoxy)ethoxy)-5-methoxyaniline (0.200 g; 0.836 mmol) and triethylamine (0.168 mL; 1.212 mmol) in acetonitrile (1 mL), irradiated in a microwave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane furnished 0.153 g (52%) of the desired compound as a brown solid. ESI/APCI(+): 491 (M+H). ESI/APCI(-): 489 (M-H).
EXAMPLE 311: PREPARATION OF 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)-1-(1H-îndol-3-yl)ethanone
2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3yl)ethanone (0.150 g; 0.306 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3.000 mL; 12.00 mmol) was stirred at room température for 16 h. The reaction was quenched by addition of a saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.052 g (39%) of 2-(4fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)ethanone. ESI/APCI(+): 435 (M+H). ESl/APCI(-): 433 (M-H).
EXAMPLE 312: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-(hydroxymethyl)-1Hindol-3-yl)-2-phenylethanone
277
Step 1: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-1 H-indole was prepared according to general procedure N from (1/7-indol-5-yl)methanol (1.000 g; 6.785 mmol), DBU (1.520 mL; 10.18 mmol) and TBDMSCI (2.250 g; 14.93 mmol) in THF (25 mL). Purification by flash chromatography on silica gel using a gradient of dichloromethane (5% to 50%) in heptane furnished 1.540 g (86%) of the desired compound as a beige solid.
Step 2: 1 -(5-(((tert-Butyldimethylsilyl)oxyJmethyl)-1 /7-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to general procedure A from 5-(((tert-butyldimethylsilyl)oxy)methyl)-1Hindole (0.700 g; 2.675 mmol), pyridine (0.210 mL; 2.602 mmol) and a-chlorophenylacetyl chloride (0.386 mL; 2.678 mmol) in toluene (2 mL). The residue obtained after extraction was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 100%) in heptane to give 0.550 g (50%) of the desired compound as a white solid.
Step 3; 2-((3,5-Dimethoxyphenyl)amino)-1 -(5-(hydroxymethyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 1-(5-(((tert-butyldimethylsilyl)oxy)methyl)1 W-indo!-3-yl)-2-chloro-2-phenylethanone (0.300 g; 0.724 mmol) and 3,5-dimethoxyaniline (1.110 g; 7.246 mmol) in acetonitrile (3 mL), irradiated in a microwave oven at 130 °C for 30 min. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.019 g (5%) of the desired compound as a white solid. ESI/APCI(+): 417 (M+H). ESIZAPCI(-): 415 (M-H). 1H NMR (DMSO-de) 5012.08 (1H, br s); 8.87 (1H, s); 8.15 (1H, s); 7.64 (2H, d); 7.41 (1H, d); 7.25-7.35 (2H, m); 7.12-7.24 (2H, m); 6.33 (1H, d); 5.98-6.15 (3H, m); 5.73 (1H, s); 5.11 (1H, t); 4.56 (2H, d); 3.63 (6H, s).
EXAMPLE 313: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(4-(hydroxymethyl)-1/7indol-3-yl)-2-phenylethanone
Step 1: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-indole was prepared according to general procedure N from (1H-indol-4-yl)methanol (1.000 g; 6.785 mmol), DBU (1.520 mL; 10.18 mmol) and TBDMSCI (2.250 g; 14.93 mmol) in THF (25 mL). Purification by flash chromatography on silica gel using a gradient of dichloromethane (15% to 70%) in heptane furnished 1.650 g (93%) of the desired compound as a white solid.
Step 2: To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1 H-indole (1.000 g; 3.825 mmol) and pyridine (0.300 mL; 3.717 mmol) in toluene (10 mL) heated at 55 °C was added dropwise achlorophenylacetyl chloride (0.552 mL; 3.825 mmol). The réaction mixture was heated at 55 °C for 1 h. After cooling to room température, water and methanol were added. The reaction mixture was stirred at room température for 1 h. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.648 g (41%) of 1-(4-(((tert16765
278 butyldimethylsilyl)oxy)methyl)-1 H-indol-3-yl)-2-chloro-2-phenylethanone as a brown oil and
0.317 g (28%) of 2-chloro-1-(4-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone.
Step 3: 2-((3,5-Dimethoxyphenyl)amino)-1-(4-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 2-chloro-1-(4-(hydroxymethyl)-1H-indol-3yl)-2-phenylethanone (0.150 g; 0.500 mmol) and 3,5-dimethoxyaniline (0.767 g; 5.007 mmol) in acetonitrile (3 mL), irradiated in a microwave oven at 130 °C for 15 min. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane. Further purification by préparative HPLC (XBridge column; method 2) followed by précipitation from dichloromethane furnished 0.028 g (14%) of the desired compound as a white solid. ESI/APCI(+): 417 (M+H). ESIZAPCI(-): 415 (M-H). 1H NMR (DMSO-d6) ÔD12.24 (1H, br s);
8.96 (1H, s); 7.60 (3H, d); 7.25-7.43 (4H, m); 7.20 (2H, m); 6.36 (1 H, d); 6.17 (1H, d); 6.08 (2H, s); 4.94-5,15 (2H, m); 4.65 (1 H, dd); 3.64 (6H, s).
EXAMPLE 314: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-(3-hydroxypropyl)1 H-indol-3-yl)-2-phenylethanone
Step 1: To a mixture of 1H-indole-5-carboxaldehyde (4.790 g; 33.00 mmol) and potassium carbonate (11.40 g; 82.48 mmol) in THF (90 mL) was added methyl diethylphosphonoacetate (8.700 mL; 47.40 mmol). The reaction mixture was heated under reflux for 24 h and concentrated under reduced pressure. The residue was taken up in water, a 1N hydrochloric acid solution and diethyl ether .The orange precipitate was filtered. The phases of the filtrate were separated. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane furnished 2.350 g (35%) of methyl 3-(1 H-indol-
5-yl)acrylate as a white solid. ESI/APCI(-): 200 (M-H). 1HNMR (DMSO-cfe) δ 8.32 (1H, br s); 7.85 (1H, d); 7.81 (1H, s); 7.43 (1H, dd); 7.38 (1H, d); 7.24 (1H, t); 6.59 (1H, brs); 6.42 (1H, d); 3.81 (3H, s).
Step 2: To a solution of methyl 3-(1 H-indol-5-yl)acrylate (2.000 g; 9.939 mmol) in methanol (20 mL) was added 10% palladium on carbon (0.530 g; 0.489 mmol). The suspension was stirred at room température under hydrogen atmosphère for 24 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 1.820 g (90%) of methyl 3-(1H-indol-5-yl)propanoate as a white solid. ESI/APCI(+): 204 (M+H).
Step 3: To a solution of methyl 3-(1H-indol-5-yl)propanoate (1.820 g; 8.955 mmol) in a mixture of THF (30 mL) and éthanol (7.5 mL) was added a 4M lithium borohydride solution in THF (5.000 mL; 20.00 mmol). The reaction mixture was stirred at room température overnight. After cooling to 0 °C, the reaction was quenched by addition of a saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over magnésium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane furnished
279
1.400 g (89%) of 3-(1/7-indol-5-yl)propan-1-ol as a colorless oil. ESI/APCI(+): 176 (M+H).
Step 4: 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1 H-indole was prepared according to general procedure N from 3-(1H-indol-5-yl)propan-1-ol (0.200 g; 1.141 mmol), DBU (0.255 mL; 1.708 mmol) and TBDMSCI (0.378 g; 2.508 mmol) in THF (4 mL). Purification by flash chromatography on silica gel using a gradient of dichloromethane (15% to 70%) tn heptane furnished 0,313 g (95%) of the desired compound as an oil, ESI/APCI(+): 290 (M+H).
Step 5: To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-1 H-indole (0.310 g; 1.071 mmol) in dichloromethane (4 mL) cooled to 0 °C was added a 1M diethylaluminium chloride solution in THF (1.630 mL; 1.630 mmol). The mixture was stirred at 0°C for 30 min and a solution of phenylacetyl chloride (0.214 mL; 1.606 mmol) in dichloromethane (4 mL) was added dropwise. The resulting solution was stirred at 0 ’C for 2 h. The reaction was quenched by addition of a mixture of water and a saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 100%) in heptane furnished 0.071 g (23%) of 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 294 (M+H); 316 (M+Na). ESI/APCI(-): 292 (M-H).
Step 6: 2-Bromo-1-(5-(3-hydroxypropyl)-1/7-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2phenylethanone (0.088 g; 0.300 mmol) in THF (2.5 mL) and a solution of phenyltrimethylammonium tribromide (0.124 g; 0.330 mmol) in THF (2.5 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température overnight. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane furnished 0.096 g (86%) of the desired compound as a beige solid. ESI/APCI(+): 372, 374 (M+H); 394, 396 (M+Na). ESI/APCI(-): 370, 372 (M-H).
Step 7: A mixture of 2-bromo-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.100 g; 0.269 mmol), 3,5-dimethoxyaniline (0.205 g; 1.345 mmol) and triethylamine (0.075 mL; 0.541 mmol) in acetonitrile (2 mL) was stirred at room température for 2 days. A 1N hydrochloric acid solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane furnished 0.071g (59%) of 2-((3l5-dimethoxyphenyl)amino)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 445 (M+Na). ESI/APCl(-): 443 (M-H). 1H NMR (DMSO-d6) δΠ 12.06 (1H, br s); 8.86 (1H, br s); 8.01 (1H, s); 7.65 (2H, d); 7.38 (1H, d); 7.31 (2H, t); 7.16-7.25 (1 H, m); 7.08 (1H, d); 6.32 (1 H. br s); 6.06 (3H, br s); 5.74 (1H, br s); 4.45 (1 H, br s); 3.63 (6H, s); 3.43 (2H, m); 2.69 (2H, t); 1.65-1.85 (2H, m).
EXAMPLE 315: PREPARATION OF 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(516765
280 fluoro-1H-indol-3-yl)-2-phenylethanone Step 1: 1-(5-Fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of 5-fluoro-1 /7-indole (0.680 g; 5.032 mmol) in dichloromethane (20 mL), a 1M diethylaluminium chloride solution in hexane (7.600 mL; 7.600 mmol) and a solution of phenylacetyl chloride (1.000 mL; 7.504 mmol) in dichloromethane (20 mL). Purification by précipitation from ethyl acetate furnished 0.820 g (64%) of the desired compound as a white solid. ESI/APCI(+): 254 (M+H). ESI/APCI(-): 252 (M-H).
Step 2: 2-Bromo-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.800 g; 3.159 mmol) in THF (22 mL) and a solution of phenyltrimethylammonium tribromide (1.310 g; 3.485 mmol) in THF (25 mL). The reaction mixture was stirred at 0 ’C for 1 h and at room température for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 70%) in heptane furnished 1.040 g (99%) of the desired compound as a white solid. ESI/APCI(+): 332, 334 (M+H). ESI/APCI (-): 330, 332 (M-H).
Step 3: A solution of 2-bromo-1-(5-fluoro-1H-indol-3-y[)-2-phenylethanone (0.100 g; 0.301 mmol), 3-(2-(fert-butoxy)ethoxy)-5-methoxyaniline (0.075 g; 0.313 mmol) and triethylamine (0.085 mL; 0.610 mmol) in acetonitrile (0.45 mL) was stirred at room température for 7 days. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane furnished 0.101 g (68%) of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(5-fluoro-1H-indol-3yl)-2-phenylethanone as an oil. ESI/APCI(+): 491 (M+H). ESI/APCI(-): 489 (M-H).
EXAMPLE 316; PREPARATION OF 1-(5-fluoro-1 W-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)-2-phenylethanone
2-((3-(2-fert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)-2phenylethanone (0.101 g; 0.206 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (2.000 mL; 8,000 mmol). The reaction mixture was stirred at room température for 16 h and was concentrated under reduced pressure, The residue was partitioned between ethyl acetate and a 1 M sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) in heptane furnished 0.060 g (67%) of 1-(5-fluoro-1H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-
5-methoxyphenyl)amino)-2-phenylethanone as a solid. ESI/APCI(+): 435 (M+H). ESI/APCI (-): 433 (M-H).
EXAMPLE 317; PREPARATION OF 2-((4-fluoro-3-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
A solution of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.048 g; 0.153 mmol), 4-fluoro-3methoxyaniline (0.026 g; 0.184 mmol) and triethylamine (0.030 mL; 0.215 mmol) in acetonitrile
281 (0.5 mL) was stirred at 50 °C for 16 h and at room température for 96 h. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 40%) in heptane furnished 0.054 g (94%) of 2-((4fluoro-3-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a beige foam. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).
EXAMPLE 318: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(4-(3-hydroxypropyl)1 H-indol-3-yl)-2-phenylethanone
Step 1: To a solution of 1/-/-indole-4-carbaldehyde (1.000 g; 6.889 mmol) and methyl 2(diethoxyphosphoryl)acetate (1.511 mL; 8.268 mmol) in THF (15 mL) was added potassium carbonate (2.380 g; 17.22 mmol). The reaction mixture was heated under reflux for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The phases were separated. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 60%) in heptane furnished 1.059 g (76%) of methyl 3-(1H-indol-4-yl)acrylate as an oil. ESI/APCI(-): 200 (M-H).
Step 2: To a solution of methyl 3-(1H-indol-4-yl)acrylate (1.059 g; 5.263 mmol) in methanol was added 10% palladium on carbon (0.560 g; 5.262 mmol). The suspension was stirred under a hydrogen atmosphère at room température for 16 h. The reaction mixture was filtered over a plug of celite. The solid was washed with éthanol and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 60%) in heptane furnished 0.936 g (88%) of methyl 3-(1H-indol-4-yl)propanoate. ESI/APCI(+): 204 (M+H).
Step 3: To a solution of methyl 3-(1H-indol-4-yl)propanoate (0.935 g; 4.601 mmol) in a mixture of THF (15 mL) and éthanol (4 mL) was added lithium borohydride (0.230 g; 10.58 mmol). The reaction mixture was stirred at room température for 16 h. The reaction was quenched by addition of a saturated ammonium chloride solution and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure to furnish 0,730 g (91%) of 3-(1H-indol-4-yl)propan1-01 as a milky oil. ESI/APCI(+): 176 (M+H). ESI/APCI(-): 174 (M-H),
Step 4: 4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1H-indole was prepared according to general procedure N from 3-(1 H-indol-4-yl)propan-1 -ol (0,300 g; 1.712 mmol), TBDMSCI (0.568 g; 3.769 mmol) and DBU (0.387 mL; 2.568 mmol) in THF (6 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 60%) in heptane furnished 0,388 g (78%) of the desired compound. ESI/APCI(+): 290 (M+H). ESI/APCI(-): 288 (M-H).
Step 5: 1 -(4-( 3-(( tert-B utyld im ethylsilyl )oxy)propyl )-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of 4-(3-((tert16765
282 butyldimethylsilyl)oxy)propyl)-1 H-indole (0.385 g; 1.330 mmol) in dichloromethane (7 mL), a 1M diethylaluminum chloride solution in hexane (1.995 mL; 1.995 mmol) and phenylacetyl chloride (0.266 mL; 1.996 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 60%) in heptane furnished 0.090 g (17%) of the desired product as a white solid. ESI/APCI(+): 408 (M+H); 430 (M+Na). ESIZAPCI(-): 406 (M-H).
Step 6: 2-Bromo-1-(4-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)1H-indol-3-yl)-2-phenylethanone (0.090 g; 0.221 mmol) in THF (2 mL) and a solution of phenyltrimethylammonium tribromide (0.091 g; 0.243 mmol) in THF (2 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 100%) in heptane furnished 0.040 g (49%) the desired product. ESI/APCI(+): 372, 374 (M+H). ESIZAPCl(-): 370, 372 (M-H).
Step 7: To a solution of 2-bromo-1-(4-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.040 g; 0.107 mmol) in acetonitrile (0.5 mL) was added 3,5-dimethoxyaniline (0.049 g; 0.322 mmol) and the mixture was stirred at room température for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 80%) in heptane. Further purification by préparative HPLC (XBridge column; method 2) furnished 0.009 g (18%) of 2-((3,5dimethoxyphenyl)amino)-1-(4-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone as a white amorphous solid, ESI/APCI(+): 445 (M+H). ESIZAPCl(-): 443 (M-H).
EXAMPLE 319; PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1methyl-1H-indol-3-yl)-2-phenylethanone
Step 1: 2-(1H-lndol-7-yl)ethyl acetate was prepared according to general procedure Q from 2(1H-indol-7-yl)ethanol (0.200 g; 1.241 mmol), DMAP (0.310 g; 2.537 mmol) and acetic anhydride (0.310 mL; 3.285 mmol) in dichloromethane (30 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 80%) in heptane furnished 0.218 g (86%) of the desired product as a colourless oil. ESI/APCI(+): 204 (M+H); 226 (M+Na). 1H NMR (DMSO-de) δ 11.11 (1 H, br s); 7.41 (1H, m); 7.33(1 H, t); 6.93 (2H, m); 6.43 (1H, m); 4.29 (2H, t); 3.16 (2H, t); 1.97 (3H, s).
Step 2: To a solution of 2-(1H-indol-7-yl)ethyl acetate (0.118 g; 0,581 mmol) in DMF (4 mL) were added césium carbonate (0.483 g; 2.965 mmol) and methyl iodide (0.055 mL; 1.767 mmol). After 7 h at room température, césium carbonate (0.483 g; 2.965 mmol) and methyl iodide (0.055 mL; 1.767 mmol) were added again. The reaction mixture was stirred overnight at room température. Water was added and the reaction mixture was extracted with ethyl acetate.
The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a
283 gradient of ethyl acetate (20% to 60%) in heptane furnished 0.094 g (75%) of 2-( 1 -methyl-1 Hindol-7-yl)ethyl acetate as a yellow oil. ESI/APCI(+): 218 (M+H); 240 (M+Na). 1H NMR (DMSOcfe) 5 7.44 (1 H, m); 7.24 (1H, t); 6.95 (2H, m); 6.40 (1 H, m); 4.30 (2H, t); 4.04 (3H, s); 3.38 (2H,
t); 2.02 (3H, s).
Step 3: 2-(1-Methyl-3-(2-phenylacetyl)-1H-indol-7-yl)ethyl acetate was prepared according to general procedure O from a solution of 2-(1-methyl-1 H-indol-7-yl)ethyl acetate (0.094 g; 0.433 mmol) in dichloromethane (2.2 mL), a 1M diethylaluminium chloride solution in hexane (0,750 mL; 0.750 mmol) and a solution of phenylacetyl chloride (0.098 mL; 0.735 mmol) in dichloromethane (2.2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 80%) in heptane furnished 0.071 g (49%) of the desired product as purple powder. ESI/APCI(+): 336 (M+H); 358 (M+Na). 1H NMR (DMSO-d6) δ 8.53 (1H, m); 8.15 (1H, d); 7.1-7.4 (7H, m); 4.31 (2H, t); 4.15 (3H, s); 4.11 (2H, s); 3.40 (2H, t); 2.00 (3H, s).
Step 4: To a suspension of 2-(1-methyl-3-(2-phenylacetyl)-1H-indol-7-yl)ethyl acetate (0.090 g; 0.268 mmol) in a mixture of dioxane (1.4 mL) and water (1.4 mL) was added a 1N lithium oxide solution. The reaction mixture was stirred at room température for 2 h. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with a 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.069 g (88%) of 1-(7-(2-hydroxyethyl)-1-methyl-1 H-indol-3yl)-2-phenylethanone as a white foam. ESI/APCI(+): 294 (M+H); 316 (M+Na).
Step 4: 2-Bromo-1-(7-(2-hydroxyethyl)-1-methyl-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(7-(2-hydroxyethyl)-1-methyl-1 H-indol-3yl)-2-phenylethanone (0.069 g; 0.235 mmol) in THF (2.9 mL) and a solution of phenyltrimethylammonium tribromide (0.131 g; 0.348 mmol) in THF (3.5 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.057 g (65%) of the desired product as a yellow oil. ESI/APCI(+): 372, 374 (M+H). 1H NMR (DMSO-de) δ 8.62 (1H, m); 8.12 (1H, d); 7.67 (2H, m); 7.35 (3H, m); 7.16 (1H, m); 7.08 (1H, m); 6.70 (1H, s); 4.11 (3H, s); 3.67 (2H, t); 3.19 (2H,t).
Step 5: 2-((3,5-Dimethoxyphenyl)amino)-1 -(7-(2-hydroxyethyl)-1 -methyl-1 H-indol-3-yl)-2phenylethanone was prepared according to general procedure E from 2-bromo-1-(7-(2hydroxyethyl)-1-methyl-1 H-indol-3-yl)-2-phenylethanone (0.052 g; 0.140 mmol) and 3,5dimethoxyaniline (0.216 g; 1.410 mmol) in acetonitrile (0.8 mL), irradiated in a microwave oven at 100 °C for 10 min. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane, Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (40% to 95%) in heptane furnished 0.042 g (68%) of the desired product as a beige powder. ESI/APCI(+): 445 (M+H);
284
467 (M+Na). ESI/APCI(-): 443 (M-H). 1H NMR (DMSO-d6) δ 8.85 (1 H, s); 8.09 (1H, d); 7.62 (2H, m); 7.29 (2H, m); 7.0-7.2 (3H, m); 6.34(1 H, d); 6.01 (IH, s); 5.96 (2H, d); 5.72(1 H, s); 4.80(1 H, t); 4.15 (3H, s); 3.68 (2H, q); 3.61 (6H, s); 3.20 (2H, m).
EXAMPLE 320: PREPARATION OF 2-((3-hydroxy-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
A mixture of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.065 g; 0.207 mmol), 3-amino-5methoxyphenol (0.115 g; 0.828 mmol) and triethylamine (0.058 mL; 0.418 mmol) in acetonitrile (0.75 mL) was stirred at room température for 65 h. A 1N hydrochloric acid solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70 %) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 20 %) in dichloromethane furnished 0.033 g (43%) of 2-((3-hydroxy-5-methoxyphenyl)amino)-1-(1/-/-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 373 (M+H). ESI/APCI(-): 371 (M-H). 1H NMR (DMSO-cfe) 8012.12 (1H, br s);
8.93 (1H, br s); 8.85 (1H, s); 8.15 (1H, d); 7.61 (2H, d); 7.46 (1 H. d); 7.24-7.35 (2H, m); 7.19 (3H, m); 6.17 (1H, d); 6.00 (1H, d); 5.90 (1H, s); 5.84 (1H, s); 5.58 (1H, s); 3.56 (3H, s).
EXAMPLE 321: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3yl)-2-(pyridin-3-yl)ethanone
Step 1: To a solution of 3-acetylindole (2.000 g; 12.56 mmol) in DMF (26 mL) cooled to 0 °C was added portionwise sodium hydride (60% dispersion in minerai oil; 0.552 g; 13.80 mmol). After 10 min at 0 °C, methyl iodide (0.939 mL; 15.08 mmol) was added and the reaction mixture was stirred at room température for 23 h. The reaction mixture was poured into a mixture ice/water and extracted ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 50%) in heptane furnished 1.732 g (80%) of 1-(1-methyl-1H-lndol-3-yl)ethanone as a white powder. ESI/APCI(+): 174 (M+H); 196 (M+Na).
Step 2: A mixture of tris(dibenzylideneacetone)dipalladium (0.030 g; 0.033 mmol), (+) 2,2bis(diphenylphosphino)binaphthyl (0.051 g: 0.082 mmol) and sodium tert-butoxide (0.211 g; 2.300 mmol) in THF (3.9 mL) was degassed for 15 min with argon. 1 -(1-Methyl-1 H-indol-3yl)ethanone (0.200 g; 1.155 mmol), 3-bromopyridine (0.094 mL; 0.862 mmol) and THF (1.9 mL) were added. The reaction mixture was heated at 80 °C for 39 h. After cooling to room température, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with a 1N hydrochloric acid solution. The aqueous phase was basified with a 2N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of
285 methanol (0% to 10%) in dichloromethane furnished 0.093 g (39%) of 1-(1-methyl-1 H-indol-3yl)-2-(pyridrn-3-yl)ethanone. ESI/APCI(+): 251 (M+H); 273 (M+Na). 1H NMR (DMSO-c/6) δ 8.60 (1H, s); 8.55 (1H, d); 8.44 (1H, dd); 8.17 (1 H. d); 7.74 (1 H, d); 7.56 (1H, d); 7.2-7.35 (3H, m);
4.20 (2H, s); 3.91 (3H. s).
Step 3: To a solution of 1-(1 -methyl-1 /-/-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.051 g; 0.204 mmol) in THF (5 mL) was added pyridinium tribromide (0.130 g; 0.406 mmol). The reaction mixture was heated at 60 °C for 6 h. 3,5-Dimethoxyaniline (0.312 g; 2.037 mmol) was added and the reaction mixture was refluxed for 2 h. After cooling to room température, the reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 90%) in heptane furnished 0.043 g (53%) of 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1 H-indol-3yl)-2-(pyridin-3-yl)ethanone as a yellow solid. ESI/APCI(+): 402 (M+H); 424 (M+Na). ESI/APCI(): 400 (M-H). Ή NMR (DMSO-d6) δ 9.02 (1H, s); 8.94 (1H, d); 8.46 (1 H, dd); 8.22 (1H, d); 8.02 (1 H, d); 7.62 (1H, d); 7.27-7.41 (3H, m); 6.55 (1H, d); 6.14 (1H, d); 6.10 (2H, d); 5.80 (1H, s);
3.97 (3H, s); 3.68 (6H, s).
EXAMPLE 322: PREPARATION OF 2-((3-(3-hydroxypropoxy)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-phenylethanone
Step 1: To a mixture of 3-amino-5-methoxyphenol (1.000 g; 7.186 mmol) and césium carbonate (4.680 g; 14.37 mmol) in DMF (24 mL) was added 3-bromopropan-1-ol (1.100 g; 7.914 mmol). The reaction mixture was stirred at 60 °C for 20 h. After cooling to 0 °C, a saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 100%) in heptane furnished 0.758 g (53%) of 3-(3-amino-5-methoxyphenoxy)propan-1-ol as an oil. ESI/APCI(+): 198 (M+H).
Step 2: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.100 g; 0.318 mmol), 3-(3amino-5-methoxyphenoxy)propan-1-ol (0.063 g; 0.319 mmol) and triethylamîne (0.088 mL; 0.635 mmol) in acetonitrile (2 mL) was stirred at room température for 2 days. 3-(3-Amino-5methoxyphenoxy)propan-1-ol (0.063 g; 0.319 mmol) was added again and stirring was continued at room température for 2 days. The mixture was diluted with ethyl acetate and washed with a 1N hydrochloric acid solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.036 g (26%) of 2-((3-(3-hydroxypropoxy)-5methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 431
286 (M+H). ESI/APCI(-): 429 (M-H). 1H NMR (DMSO-cfe) ÔD12.14 (1H, br s); 8.90 (1H, s); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.07-7.36 (5H, m); 6.32 (1 H, d); 5.93-6.15 (3H, m); 5.71 (1H, s);
4.51 (1H, t); 3.89 (2H, t); 3.61 (3H, s); 3.51 (2H, m); 1.78 (2H, m).
EXAMPLE 323: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(7-(hydroxymethyl)-1Hindol-3-yl)-2-phenylethanone
Step 1 : A solution of (1H-indol-7-yl)methanol (0.251 g; 1.705 mmol), imidazole (0.287 g; 4.216 mmol) and TBDMSCI (0.300 g; 1.990 mmol) in THF (8 mL) was stirred at room température for 4 days. The solid was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 10%) in heptane furnished 0.344 g (77%) of 7-((( tert-butyldimethylsilyl)oxy)methyl)-1/-/-indole a colorless oil. 1H NMR (DMSO-cQ δ 10.83 (1H, s); 7.35 (1H, d); 7.23 (1H, t); 7.01 (1H, d); 6.89 (1H, t); 6.35 (1H, dd); 4.91 (2H, s); 0.83 (9H, s); 0.00 (6H, s).
Step 2: 1 -(7-(((fert-Butyldimethylsilyl)oxy)methyl)-1 H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to general procedure A from 7-(((fert-butyldimethylsilyl)oxy)methyl)-1Hindole (0.173 g; 0.662 mmol), pyridine (0.060 mL; 0.742 mmol) and a-chlorophenylacetyl chloride (0.095 mL; 0.662 mmol) in toluene (1.5 mL). The residue obtained after extraction was purified by flash chromatography on silica gel using a gradient ethyl acetate (0% to 25%) in heptane to furnish 0.060 g (22%) of the desired compound as a red-brown solid. ESI/APCI(+): 414, 416 (M+H). ESI/APCI(-): 412, 414 (M-H).
Step 3: 2-((3,5-Dimethoxyphenyl)amino)-1 -(7-(hydroxymethyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 1-(7-(((tert-butyldimethylsilyl)oxy)methyl)1H-indol-3-yl)-2-chloro-2-phenylethanone (0.060 g; 0.145 mmol) and 3,5-dimethoxyaniline (0.220 g; 1.436 mmol) in acetonitrile (0.5 mL), irradiated at 100 °C for 15 min and at 150 °C for 15 min. Purification by préparative HPLC (XBridge column; method 2) furnished 0.006 g (10%) of the desired compound as a beige solid. ESI/APCI(+): 417 (M+H). ESI/APCI(-): 415 (M-H).
EXAMPLE 324: PREPARATION OF 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1Hindol-7-yl)ethyl acetate
Step 1: 2-(3-Formyl-1H-indol-7-yl)ethyl acetate was prepared according to general procedure R from a solution of oxalyl chloride (0.806 mL; 9.207 mmol) in dichloromethane (30 mL), DMF (0.773 mL; 9.984 mmol) and a solution of 2-(1H-indol-7-yl)ethyl acetate (1.560 g; 7.676 mmol) in dichloromethane (5 mL). The residue obtained after concentration of the organic phase under reduced pressure was dried to give crude 2-(3-formyl-1H-indol-7-yl)ethyl acetate as a beige solid which was used without further purification. ESI/APCI(+): 232 (M+H). ESI/APCI(-): 230 (ΜΗ).
Step 2: fert-Butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 2-(3-formyl-1H-indol-7-yl)ethyl acetate (1.776 g; 7.680 mmol), ditert-butyl dicarbonate (2,011 g; 9.214 mmol) and DMAP (0.094 g; 0.768 mmol) in acetonitrile
287 (40 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 60%) in heptane furnished 1.770 g (70%) of the desired compound as a yellow solid. Step 3: 2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-7-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.120 g; 0,445 mmol) and triethylamine (0.090 mL; 0.646 mmol) in éthanol (0.5 mL), fert-butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.273 g; 0.824 mmol) and a solution of A/-benzylidene-5-methoxypyridin-3-amine (0.857 mmol) in éthanol (1 mL), heated at 60 °C for 72 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane furnished 0.148 g (41%) of the desired compound as a yellow oil. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H).
EXAMPLE 325: PREPARATION OF 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin3-yl)amino)-2-phenylethanone
-(7-( 2-Hydroxyethyl )-1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure S from a solution of 2-(3-(2-((5-methoxypyridin-3yl)amino)-2-phenylacetyl)-1H-indol-7-yl)ethyl acetate (0.148 g; 0.334 mmol) in a mixture of THF (2 mL) and methanol (2 mL) and potassium carbonate (0.095 g; 0.689 mmol). The reaction mixture was stirred at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 6%) in dichloromethane followed by précipitation from dichloromethane furnished 0.037 g (28%) of the desired compound as a brown powder. ESI/APCI(+): 402 (M+H).
EXAMPLE 326: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2(dimethylamino)ethyl)-1H-indol-3-yl)-2-phenylethanone
Step 1 : To a solution of 1-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1/-/-indol-3-yl)-2phenylethanone (0.178 g; 0.452 mmol) in dichloromethane (7 mL) was added a 4N hydrogen chloride solution in dioxane (1.600 mL; 6.400 mmol). The reaction mixture was stirred at room température for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was washed with a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (40% to 80%) in heptane furnished 0.102 g (81%) of 1-(7-(2-hydroxyethy!)-1/-/-indol-3-yl)-2-phenylethanone. ESI/APCI(+): 280 (M+H); 302 (M+Na). ESI/APCI(-): 278 (M-H).
Step 2: To a suspension of 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone (0.102 g;
0.365 mmol) in dichloromethane (4.9 mL) were added triethylamine (0.074 mL; 0,534 mmol) and mesyl chloride (0.032 mL; 0.413 mmol). The reaction mixture was stirred at room température for 4 h. A 2N dimethylamine solution in THF (2.100 mL; 4.200 mmol) was gradually added over 4 days at room température. The reaction mixture was then partially concentrated under reduced pressure to remove dichloromethane. A 2N dimethylamine solution in THF
288 (1.000 mL; 2.000 mmol) was added and the reaction mixture was heated at 60 °C for 6 h. A 2N dimethylamine solution in THF (1.000 mL; 2.000 mmol) was added and the reaction mixture was stirred overnight at room température. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was washed several times with a 2N hydrochloric acid solution. The acidic aqueous phases were combined, basified with a 2N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 0.064 g (57%) of 1-(7-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2phenylethanone as an orange oil which was used in the next step without further purification. ESI/APCI(+): 307 (M+H); 329 (M+Na). ESI/APCI(-): 305 (M-H).
Step 3: To a solution of 1-(7-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.063 g; 0.206 mmol) in THF (2.5 mL) cooled to 0 °C was added a solution of phenyltrimethylammonium tribromide (0.110 g; 0.292 mmol) in THF (3 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 5 h. 3,5-Dimethoxyaniline (0.154 g; 1,005 mmol) was added. The reaction mixture was refluxed for 2 h and was stirred overnight at room température. 3,5Dimethoxyaniline (0.051 g; 0.553 mmol) was added and the reaction mixture was stirred at room température for 65 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (2% to 10%) in dichloromethane followed by purification by préparative TLC using methanol (10%) in dichloromethane as eluent furnished 0.029 g (31%) of 2-((3,5-dimethoxyphenyi)amino)-1-(7-(2(dimethylamino)ethyl)-1H-indol-3-yl)-2-phenylethanone as a beige powder. ESI/APCI(+): 458 (M+H). ESI/APCI(-): 456 (M-H). 1H NMR (DMSO-d6) δ 12.24 (1 H. br s); 8.89 (1H, s); 8.04 (1H, d); 7.64 (2H, m); 7.29 (1H, t); 7.05-7.2 (4H, m); 6.34 (1H, d); 6.10 (1H, d); 6.06 (2H, d); 5.72 (1H, s); 3.68 (6H, s); 3.08 (2H, m); 2.79 (2H, m); 2.43 (6H, m).
EXAMPLE 327: PREPARATION OF 2-((3-hydroxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone
A suspension of 2-bromo-1-(1/7-indol-3-yl)-2-phenylethanone (0.098 g; 0.312 mmol) and 3aminophenol (0.068 g; 0.623 mmol) in acetonitrile (1 mL) was stirred at room température for 24
h. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0% to 50%) in heptane furnished
0.065 g (61%) of 2-((3-hydroxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 343 (M+H). ESI/APCl(-): 341 (M-H).
EXAMPLE 328: PREPARATION OF ethyl 4-(3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-516765
289 methoxyphenoxy)butanoate
Step 1: To a solution of 3-amino-5-methoxyphenol (0.500 g; 3.593 mmol) in THF (10 mL) was added di-fert-butyl dicarbonate (0.863 g, 3.954 mmol) in THF (2 mL). The reaction mixture was refluxed overnight. After cooling to room température, the reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished 0.427 g (50%) of fert-butyl (3hydroxy-5-methoxyphenyl)carbamate as an oil. ESI/APCI(+): 240 (M+H).
Step 2: A mixture of fert-butyl (3-hydroxy-5-methoxyphenyl)carbamate (0.200 g; 0.836 mmol), potassium carbonate (0.231 g; 1,671 mmol), ethyl 4-bromobutyrate (0.245 g; 1.256 mmol) and potassium iodide (0.014 g; 0.084 mmol) in acetone (5 mL) was stirred at 60 °C for 65 h, After cooling to room température, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 40%) in heptane furnished 0.189 g (64%) of ethyl 4-(3-((tert-butoxycarbonyl)amino)-5methoxyphenoxy)butanoate as an oil. ESI/APCI(+): 354 (M+H) ; 376 (M+Na).
Step 3: Ethyl 4-(3-((tert-butoxycarbonyl)amino)-5-methoxyphenoxy)butanoate (0.104 g; 0.294 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (3.000 mL; 12.00 mmol). The reaction mixture was stirred at room température overnight. The reaction mixture was partially concentrated. The residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The phases were separated. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 0.054 g (72%) of ethyl 4-(3-amino-5methoxyphenoxy)butanoate as an orange oil.
Step 3: Ethyl 4-(3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5-methoxyphenoxy)butanoate was prepared according to general procedure C from 2-bromo-1-(1H-indol-3-yl)-2phenylethanone (0.102 g; 0.324 mmol), ethyl 4-(3-amino-5-methoxyphenoxy)butanoate (0.082 g; 0.324 mmol) and triethylamine (0.090 mL; 0.647 mmol) in acetonitrile (2 mL), irradiated in a microwave oven at 100 °C for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50 %) in heptane followed by précipitation from diethyl ether furnished 0.057 g (36%) of the desired compound as a white solid. ESI/APCI(+): 487 (M+H). ESI/APCI(-): 485 (M-H).
EXAMPLE 329: PREPARATION OF 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1(1H-indol-3-yl)-2-(p-tolyl)ethanone
Step 1: 1-(1H-lndol-3-yl)-2-(p-tolyl)ethanone was prepared according to general procedure O from a solution of 1H-indole (0.350 g; 2.988 mmol) in dichloromethane(15 mL), a 1M diethylaluminum chloride solution in hexane (3.880 mL; 3.880 mmol) and a solution of 2-(p16765
290 tolyljacetyl chloride (0.655 g; 3.884 mmol) in dichlorométhane (2 mL). The residue obtained after extraction was purified by précipitation from dichlorométhane to give 0.417 g (56%) ofthe desired compound as a white solid. ESI/APCI(+): 250 (M+H). ESI/APCI(-): 248 (M-H) Step 2: 2-Bromo-1-(1/7-indol-3-yl)-2-(p-tolyl)ethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2-(p-tolyl)ethanone (0.417 g; 1.673 mmol) in THF (11 mL) and phenyltrimethylammonium tribromide (0.692 g; 1.840 mmol). The reaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 80%) in heptane furnished 0.642 g of crude 2bromo-1-(1H-indol-3-yl)-2-(p-tolyl)ethanone as a pink solid which was used in the next step without further purification. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H) Step______3: 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(ptolyl)ethanone was prepared according to general procedure C from 2-bromo-1-(1H-indol-3-yl)2-(p-tolyl)ethanone (0.075 g; 0.228 mmol), 3-(2-(fert-butoxy)ethoxy)-5-methoxyaniline (0.060 g; 0.251 mmol) and triethylamine (0.064 mL; 0.456 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10 to 80%) in heptane furnished 0.058 g (52%) of the desired compound as a brown solid. ESI/APCI(+): 487 (M+H). ESIZAPCI(-): 485 (M-H)
EXAMPLE 330: PREPARATION OF 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Hindol-3-yl)-2-(p-tolyl)ethanone 2-((3-(2-(fert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(p-tolyl)ethanone (0.058 g; 0.119 mmol) was dissolved in a 4 N hydrogen chloride solution in dioxane (1.5 mL; 6.000 mmol). The reaction mixture was stirred at room température for 16 h. The reaction mixture was neutralized with a saturated sodium bicarbonate solution and was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50% to 100%) In heptane furnished 0.030 g (58%) of 2-((3-(2hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-îndol-3-yl)-2-(p-tolyl)ethanone as a solid. ESi/APCI(+): 431 (M+H). ESI/APCI(-): 429 (M-H). Ή NMR (DMSO-cfe) ÔD8.85 (1H, s); 8.15 (1H, d); 7.40-7.56 (3H, m); 7.12-7.27 (2H, m); 7.08 (2H, d); 6.27 (1H, d); 6.03 (3H, br s); 5.70 (1H, s); 4.79 (1H, t); 3.83 (2H, d); 3.58-3.68 (5H, m); 2.20 (3H, s).
EXAMPLE 331: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1Hindol-3-yl)-2-phenylethanone
Step 1: To a solution of 1H-indole-5-carbaldehyde (5.000 g; 34.45 mmol) in THF (200 mL) cooled to 0 °C were added methyltriphenylphosphonium bromide (14.77 g; 41.33 mmol) and a solution of potassium tert-butoxide (5.800 g; 51.67 mmol) in THF (50 mL). The reaction mixture was stirred at room température for 24 h. The reaction mixture was partially concentrated under reduced pressure. The residue was poured into a mixture ice/water and extracted with ethyl
291 acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in heptane furnished
3.110 g (63%) of 5-vinyl-1 H-indole as a beige solid. ESI/APCI(+): 144 (M+H). ESI/APCI(-): 142 (M-H).
Step 2: To a solution of 5-vinyl-1 H-indole (2.960 g; 20.67 mmol) in THF (100 mL) was added dropwise a 1M borane-tetrahydrofuran complex solution in THF (20.70 mL; 20.70 mmol) and the reaction mixture was stirred for 2.5 h. A 10% sodium hydroxide solution (8.240 mL; 24.83 mmol) and a 30% hydrogen peroxide solution (2.350 mL; 24.83 mmol) were added sequentially and the reaction mixture was stirred at room température for 3.5 h. The reaction was quenched by addition of a saturated ammonium chloride solution. The reaction mixture was stirred vigorously for 5 min and partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 2.310 g (66%) of 2-(1/7-indol-5-yl)ethanol as an oil. ESI/APCI(+):162 (M+H); 184 (M+Na).
Step 3: 5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1 H-indole was prepared according to general procedure N from 2-(1H-indol-5-yl)ethanol (0.464 g; 2.878 mmol), TBDMSCI (0.954 g; 6.330 mmol) and DBU (0.651 mL; 4.319 mmol) in THF (10 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 16%) in heptane furnished 0.582 g (73%) of the desired compound as a yellow oil. ESI/APCI(+): 276 (M+H).
Step 4: 1-(5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1/7-indol-3-yl)-2-phenylethanone was prepared according to general procedure O from a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1Hindole (0.580 g; 2.106 mmol) in dichloromethane (15 mL), a 1M diethylaluminum chloride solution in hexane (2.740 mL; 2.740 mmol) and a solution of phenylacetyl chloride (0.365 mL; 2.739 mmol) in dichloromethane (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 80%) in heptane furnished 0.182 (22%) of the desired compound. ESI/APCI(+): 394 (M+H). ESIZAPCI(-): 392 (M-H)
Step 5: 2-Bromo-1-(5-(2-hydroxyethyl)-1/7-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)1H-indol-3-yl)-2-phenylethanone (0.182 g; 0.462 mmol) in THF (3 mL) and phenyltrimethylammonium tribromide (0.191 g; 0.509 mmol). The reaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane furnished 0.083 g (50%) of the desired compound as a brown solid. ESI/APCI(+): 358, 360 (M+H). ESI/APCI(-): 356, 358 (M-H).
Step 6: 2-((3,5-Dimethoxyphenyl)amino)-1 -(5-(2-hydroxyethyl)-1 H-indol-3-yl)-2-phenylethanone was prepared according to general procedure E from 2-bromo-1-(5-(2-hydroxyethyl)-1H-indol-3yl)-2-phenylethanone (0.040 g; 0.112 mmol) and 3,5-dimethoxyaniline (0.086 g; 0.558 mmol) in
292 acetonitrile (0.5 mL), irradiated in a microwave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane furnished 0.032 g (65%) of the desired compound as a grey solid. ESI/APCI(+): 431 (M+H). ESIZAPCI(-): 429 (M-H)
EXAMPLE 332: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(7-(2hydroxyethyl)-1H-indol-3-yl)ethanone
Step 1: 1 -(7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1 H-indol-3-yl)-2-(4-fluorophenyl)ethanone was prepared according to general procedure O from a solution of 7-(2-((terîbutyldimethylsilyl)oxy)ethyl)-1H-indole (0.434 g, 1.576 mmol) in dichloromethane (9 mL), a 1M diethylaluminum chloride solution in hexane (2.048 mL; 2.048 mmol) and 2-(4fluorophenyl)acetyl chloride (0.353 g, 2.048 mmol) in dichloromethane (1 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane furnished 0.149 g (23%) of the desired compound. ESI/APCI(+): 412 (M+H). ESI/APCI(-): 410 (M-H). 0.137 g (29%) of 2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)ethanone was also isolated.
Step 2: 2-Bromo-2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1Hindol-3-yl)ethanone (0.137 g; 0.461 mmol) in THF (3 mL) and phenyltrimethylammonium tribromide (0.203 g; 0.540 mmol). The reaction mixture was stirred at room température overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 0.097 g (56%) of the desired compound. ESI/APCI(+): 376, 378 (M+H). ESI/APCI(-): 374, 376 (M-H).
Step 3: 2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(7-(2-hydroxyethyl)-1 H-indol-3yl)ethanone was prepared accerding to general procedure Ê from 2-bromo-2-(4-fluorophenyl)-1(7-(2-hydroxyethyl)-1H-indol-3-yl)ethanone (0.050 g; 0,133 mmol) and 3,5-dîmethoxyaniline (0.102 g; 0.665 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane furnished 0.036 g (58%) of the desired compound as a solid. ESI/APCI(+); 449 (M+H). ESI/APCI(-): 447 (M-H). 1H NMR (DMSO-d6) Ô 8.86 (1 H, s); 8.01 (1 H. d); 7.66 (2H, dd); 6.99-7.20 (4H, m); 6.35 (1H, d); 6.12 (1 H, d); 6,05 (2H. d); 5.72 (1 H. s); 3.69 (2H. t); 3.62 (6H, s); 3.02 (2H, t).
EXAMPLE 333: PREPARATION OF 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1Hindol-5-yl)propyl acetate
Step 1: 3-(1H-lndol-5-yl)propyl acetate was prepared according to general procedure Q from 3(1/7-indol-5-yl)propan-1-ol (1.400 g; 7.989 mmol), DMAP (0.976 g; 8.185 mmol) and acetic anhydride (1.900 mL; 20.14 mmol) in dichloromethane (150 mL). Purification by flash chromatography on silica gel using dichloromethane as eluent furnished 1.590 g (92%) of the
293 desired compound as a colorless oil. ESI/APCI(+): 218 (M+H)
Step 2: 3-(3-Formyl-1H-indol-5-yl)propyl acetate was prepared according to general procedure R from a solution of oxalyl chloride (0.800 mL; 9.139 mmol) in dichloromethane (40 mL), DMF (0.750 mL; 9.687 mmol) and a solution of 3-(1 H-indol-5-yl)propyl acetate (1.590 g; 7.318 mmol) in dichloromethane (15 mL). The residue obtained after concentration of the organic phase under reduced pressure was dried to give 1.700 g (95%) of the desired compound as a beige solid which was used without further purification. ESI/APCI(+): 246 (M+H). ESI/APCI(-): 244 (ΜΗ).
Step 3: tert-Butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 3-(3-formyl-1H-indol-5-yl)propyl acetate (1.710 g; 6.931 mmol), ditert-butyl dicarboxylate (1.820 g; 8.339 mmol) and DMAP (0.090 g; 0.737 mmol) in acetonitrile (35 mL) to furnish 2.350 g (98%) of the desired product as a pale yellow solid. ESI/APCI(+): 346 (M+H). 1H NMR (DMSO-d6) δ 10.06 (1H, s); 8.63 (1 H, s); 8.02 (1H, d); 7.98 (1H, s); 7.31 (1H, dd); 3.99 (2H, t); 2.76 (2H, t); 2.01 (3H, s); 1.92 (2H, m); 1.66 (9H, s).
Step 4: 3-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-5-yl)propyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.132 g; 0.489 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), tert-butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1-carboxylate (0.340 g; 0.984 mmol) and a solution of A/-benzylidene-5-methoxypyridin-3-amine (0.980 mmol) in éthanol (1 mL), heated at 60 °C for 72 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane furnished 0.224 g (50%) of the desired compound as a yellow oil. ESI/APCI(+): 458 (M+H). ESI/APCI(-): 456 (M-H).
EXAMPLE 334: PREPARATION OF 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin3-yl)amino)-2-phenylethanone
1-(5-(3-Hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure S from a solution of 3-(3-(2-(5-methoxypiridin-3yl)amino)-2-phenylacetyl)-1H-indol-5-yl)propyl acetate (0.224 g; 0.490 mmol) in THF (3 mL) and methanol (3 mL) and potassium carbonate (0.135 g; 0.977 mmol). The reaction mixture was heated at 45 °C for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane followed by précipitation from dichloromethane furnished 0.072 g (35%) of the desired compound as a white solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H)
EXAMPLE 335: PREPARATION OF 2-(3-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)-1-(1/7-indol-3-yl)ethanone
Step 1: 2-(3-Fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to general procedure O from a solution of 1 H-indole (0.292 g; 2.492 mmol) in dichloromethane (15 mL), a 1M diethylaluminum chloride solution in hexane (3.240 mL; 3.240 mmol) and a solution of 2-(316765
294 fluorophenyljacetyl chloride (0.559 g; 3.184 mmol) in dichloromethane (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 80%) in heptane furnished 0.459 g (73%) of the desired compound as a solid. ESI/APCI(+): 254 (M+H).
ESI/APCI(-): 252 (M-H).
Step 2: 2-Bromo-2-(3-fluorophenyl)-1-(1/7-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(3-fluorophenyl)-1-(1H-indol-3-yl)ethanone (0.459 g; 1.812 mmol) in THF (12 mL) and phenyltrimethylammonium tribromide (0.749 g; 1.994 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 80%) in heptane furnished 0.466 g (77%) of the desired compound as a brown solid. ESI/APCI(+): 332, 334 (M+H). ESIZAPCI(-): 330, 332 (M-H).
Step 3: To a solution of 2-bromo-2-(3-fluorophenyl)-1-(1H-indol-3-yl)ethanone (0.054 g, 0.164 mmol) and triethylamine (0.046 mL, 0.328 mmol) in acetonitrile (0.3 mL) was added 2-(3-amino-
5-methoxyphenoxy)ethanol (0.030 g, 0.164 mmol). The reaction mixture was stirred at room température for 4 days and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10% to 100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (2% to 8%) in dichloromethane furnished 0.030 g (42%) of 2-(3-fluorophenyl)-2-((3-(2-hydroxyethoxy)-
5-methoxyphenyl)amino)-1-(1H-indol-3-yl)ethanone as a yellow solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H).
EXAMPLE 336: PREPARATION OF 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1 H-indol-7-yl)ethyl acetate
Step 1 : A solution of 5-methoxy-/\/-((5-methoxypyrazin-2-yl)methylene)pyridin-3-amine in éthanol was prepared by heating a solution of 5-methoxypyrazine-2-carbaldehyde (0.130 g; 0.941 mmol) and 5-methoxypyridin-3-amine (0.133 g; 1.071 mmol) in éthanol (0.5 mL) at 60 °C for 16 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 245 (M+H).
Step 2: 2-(3-(2-(5-Methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7~ yl)ethyl acetate was prepared according to general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.717 mL; 0.500 mmol) in éthanol (1 mL), tert-butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1carboxylate (0.331 g; 0.998 mmol) and a solution of 5-methoxy-N-((5-methoxypyrazin-2yl)methylene)pyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane furnished 0.281 g (59%) of the desired compound as a beige solid. ESI/APCI(+): 476 (M+H). ESIZAPCI(-): 474 (M-H).
EXAMPLE 337: PREPARATION OF 1-(7-(2-hydroxyethyl)-1/-/-indol-3-yl)-2-(5-methoxypyrazin-
2-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone
295
1-(7-(2-Hydroxyethyl )-1 H-indol-3-yl )-2-( 5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-(5methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate (0.280 g; 0.589 mmol) in a mixture of THF (4 mL) and methanol (4 mL) and potassium carbonate (0.163 g; 1.178 mmol). The reaction mixture was stirred at room température for 16 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.084 g (33%) of the desired compound as a solid. ESI/APCI(+): 434 (M+H). ESI/APCI(-): 432 (M-H). 1H NMR (DMSO-cfe) δ 8.76 (1H, s); 8.53 (1 H, s); 8.26 (1H, s); 8.02 (1H, d); 7.87 (1H, d); 7.55 (1H, d); 7.04-7.19 (2H, m); 6.85 (1H, s); 6.69 (1H, d); 6.37 (1H, d); 3.86 (3H, s); 3.66-3.77 (5H, m); 3.03 (2H, t).
EXAMPLE 338: PREPARATION OF 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)acetyl)-1 H-indol-7-yl)ethyî acetate
Step 1: A solution of 5-methoxy-/V-(pyrazolo[1,5-a]pyridin-2-ylmethylene)pyridin-3-amine in éthanol was prepared by heating a solution of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.139 g; 0.951 mmol) and 5-methoxypyridin-3-amine (0,121 g: 0.975 mmol) in éthanol (0.5 mL) at 60 °C for 5,5 h. The formation of the imine was quantitative and the solution was used without further purification. ESI/APCI(+): 253 (M+H).
Step 2: 2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-7yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.550 mmol) in éthanol (1 mL), tert-butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1carboxylate (0.331 g; 0.998 mmol) and a solution of 5-methoxy-N-(pyrazolo[1,5-a]pyridin-2ylmethylene)pyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane furnished 0.130 g (27%) of the desired compound as a red oil. ESI/APCI(+): 484 (M+H). ESI/APCI(-): 482 (M-H)
EXAMPLE 339: PREPARATION OF 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-
3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone
1- (7-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-
2- yl)ethanone was prepared according to general procedure S from a solution 2-(3-(2-((5methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-7-yl)ethyl acetate (0.130 g, 0.269 mmol) in THF (2 mL) and methanol (2 mL) and potassium carbonate (0.074 g, 0.538 mmol). The reaction mixture was stirred at room température for 16 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.053 g (44%) of the desired compound as a solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H). 1H NMR (DMSO-cfe) δ 12.05 (1H, br s); 8.77 (1H, s); 8.60 (1H, d); 8.03 (1 H, d); 7.89 (1H, d); 7.59 (1H, d); 7.51 (1H, d); 7.00-7.23 (3H, m); 6.76-6.91 (2H, m);
296
6.55-6.68 (2H, m); 6.42 (1 H. d); 4.70 (1 H, brs); 3.61-3.79 (5H, m); 3.01 (2H, t).
EXAMPLE 340: PREPARATION OF 2-(3-(2-(5-fluoropyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1 H-indol-7-yl)ethyl acetate
Step 1: A solution of A/-((5-fluoropyridin-3-yl)methylene)-5-methoxypyridin-3-amine in éthanol was prepared by heating a solution of 5-fluoronicotinaldehyde (0.125 g: 0.999 mmol) and 5methoxypyridin-3-amine (0.124 g; 0.999 mmol) in éthanol (0.5 mL) at 60 °C for 4 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 2-(3-(2-(5-Fluoropyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.500 mmol) in éthanol (1 mL), tert-butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1carboxylate (0.331 g; 0.998 mmol) and a solution of N-((5-fluoropyridin-3-yl)methylene)-5methoxypyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by précipitation from dichloromethane furnished 0.254 g (55%) of the desired compound as a white solid. ESI/APCI(+): 463 (M+H). ESI/APCI(-): 461 (M-H).
EXAMPLE 341: PREPARATION OF 2-(5-fluoropyridin-3-yl)-1-(7-(2-hydroxyethyl)-1 H-indol-3-yl)-
2-((5-methoxypyridin-3-yl)amino)ethanone 2-(5-Fluoropyridin-3-yl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-(5fluoropyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1/-/-indol-7-yl)ethyl acetate (0.190 g; 0.411 mmol) in a mixture of THF (3 mL) and methanol (3 mL) and potassium carbonate (0.114 g; 0.822 mmol). The reaction mixture was stirred at room température for 16 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.074 g (43%) of the desired compound as a white solid. ESI/APCI(+): 421 (M+H). ESI/APCI(-)r 419 (M-H). 1H NMR (DMSO-c/e) δ 8.93 (1H, s); 8.79 (1H, s); 8.44 (1H, d); 8.02 (1H, d); 7.83-7.96 (2H, m); 7.55 (1H, d); 7.03-7.21 (2H, m); 6.79-6.93 (2H, m); 6.36 (1 H, d); 3.65-3.79 (5H, m); 3.03 (2H, t).
EXAMPLE 342: PREPARATION OF 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1Hindol-5-yl)ethyi acetate
Step 1: 2-(1 H-lndol-5-yl)ethyl acetate was prepared according to general procedure Q from 2(1H-indol-5-yl)ethanol 2.310 g; 14.33 mmol), DMAP (3.500 g; 28.66 mmol) and acetic anhydride (3.500 mL; 37.26 mmol) in dichloromethane (250 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in heptane furnished 2.580 g (89%) of the desired compound as an oil.
Step 2: 2-(3-Formyl-1/-/-indol-5-yl)ethyl acetate was prepared according to general procedure R from a solution of oxalyl chloride (1.330 mL; 15.23 mmol) in dichloromethane (8 mL), DMF (1.180 mL; 15.23 mmol) and a solution of 2-(1H-indol-5-yl)ethyl acetate (2.580 g; 12.69 mmol)
297 in dichloromethane (20 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30% to 100%) in heptane furnished 2.780 g (95%) of the desired compound as a beige solid. ESI/APCI(+): 232 (M+H); 254 (M+Na). ESI/APCI(-): 230 (M-H).
Step 3: tert-Butyl 5-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate was prepared according to general procedure F from 2-(3-formyl-1/7-indol-5-yl)ethyl acetate (2.780 g; 12.02 mmol), ditert-butyl dicarbonate (2.150 g; 14.43 mmol) and DMAP (0.294 g; 2.406 mmol) in acetonitrile (50 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50 %) in heptane furnished 3.940 (99%) of the desired compound as a beige solid. ESI/APCI(+): 354 (M+Na).
Step 4: 2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-5-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 5-(2-acetoxyethyl)-3-formyl-1H-indole-1 -carboxylate (0.331 g; 0.999 mmol) and a solution of /V-benzylidene-5-methoxypyridin-3-amine (0.996 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.216 g (49%) the desired compound as a solid. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H).
EXAMPLE 343: PREPARATION OF 1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-
3-yl)amino)-2-phenylethanone
-(5-(2-Hydroxyethyl)-1 /7-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to general procedure S from a solution of 2-(3-(2-((5-methoxypyridin-3yl)amino)-2-phenylacetyl)-1H-indol-5-yl)ethyl acetate (0,216 g; 0.487 mmol) in THF (5 mL) and methanol (5 mL) and potassium carbonate (0.135 g; 0.977 mmol). The reaction mixture was stirred at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by précipitation from acetonitrile furnished 0.075 g (38%) of as a beige solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (MH).1H NMR (DMSO-de) 5Π12.10 (1H, br s); 8.86 (1H, s); 8.02 (1H, s); 7.85 (1H, d); 7.66 (2H, d);
7.51 (1H, d); 7.38 (1H, d); 7.26-7.35 (2H, m); 7.17-7.25 (1H, m); 7.09 (1H, d); 6.79 (1 H. s); 6.68 (1H, d); 6.17 (1H, d); 4.62 (1H, t); 3.72 (3H, s); 3.54-3.66 (2H, m); 2.80 (2H, t).
EXAMPLE 344: PREPARATION OF 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1 H-indol-5-yl)ethyl acetate
2-(3-(2-(5-Methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL;
0.505 mmol) in éthanol (1.5 mL), tert-butyl 5-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g; 0.999 mmol) and a solution of 5-methoxy-N-((5-methoxypyrazin-2yl)methylene)pyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight.
298
Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.311 g (65%) ofthe desired compound as a solid. ESI/APCI(+): 476 (M+H). ESI/APCI(-): 474 (M-H).
EXAMPLE 345: PREPARATION OF 1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-(5-methoxypyrazin2-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone
1- (5-(2-Hydroxyethyl)-1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-(5methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1 H-indol-5-yl)ethyl acetate (0.311 g; 0.654 mmol) in THF (7.5 mL) and methanol (7.5 mL) and potassium carbonate (0.181 g; 1.210 mmol). The reaction mixture was stirred at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by précipitation from acetonitrile furnished 0.165 g (58%) the desired compound as a beige solid. ESI/APCI(+): 434 (M+H). ESI/APCI(-): 432 (M-H). 1H NMR (DMSO-cfe) ÔD12.10 (1H, br s); 8.75 (1 H, s); 8.52 (1H, s); 8.26 (1H, s); 8,01 (1H, s); 7.86 (1 H, d); 7.56 (1H, d); 7.40 (1 H, d); 7.11 (1H, d); 6.84 (1 H, br s); 6.68 (1H, d); 6.33 (1H, d); 4.64 (1H, t); 3.86 (3H, s); 3.74 (3H, s); 3.55-3.67 (2H, m); 2.81 (2H, t).
EXAMPLE 346: PREPARATION OF 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)acetyl)-1 H-indol-5-yl)ethyl acetate
2- (3-(2-((5-Methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-5-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), tert-butyl 5-(2-acetoxyethyl)-3-formyl-1 H-indole-1 -carboxylate (0.331 g; 0.999 mmol) and a solution of 5-methoxy-/V-(pyrazolo[1,5-a]pyridin-2ylmethylene)pyridin-3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 ’C overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.218 g (45%) of the desired compound as a solid. ESI/APCI(+): 484 (M+H). ESI/APCI(-): 482 (M-H).
EXAMPLE 347: PREPARATION OF 1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-
3- yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone
1- (5-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-
2- yl)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-((5methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-îndol-5-yl)ethyl acetate (0.218 g; 0.451 mmol) in THF (5 mL) and methanol (5 mL) and potassium carbonate (0.124 g; 0.904 mmol). The reaction mixture was stirred at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by précipitation from éthanol furnished 0.077 g (39%) of the desired compound as a pink solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H). 1H NMR (DMSO-d6) 5011.95 (1 H,
299 br s); 8.68 (1H, s); 8.52 (1H, d); 7.94 (1H, s); 7.81 (1 H. d); 7.52 (1H, d); 7.44 (1H, d); 7.29 (1H, d); 7.04-7.15 (1H, m); 7.01 (1 H. d); 6.68-6.83 (2H. m); 6.58 (1H, s); 6.52 (1H, d); 6.31 (1H, d); 4.55 (1 H. t); 3.64 (3H, s); 3.46-3.58 (2H, m); 2.72 (2H, t),
EXAMPLE 348: PREPARATION OF 2-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1 H-indol-7-yl)ethyl acetate
Step 1 : A solution of A/-(4-fluorobenzylidene)-5-methoxypyridin-3-amine in éthanol was prepared by heating a solution of 4-fluorobenzaldehyde (0.120 g; 0.967 mmol) and 5methoxypyridin-3-amine (0.121 g; 0.975 mmol) in éthanol (0.5 mL) at 60 °C for 20 h. The formation of the imine was quantitative and the solution was used without further purification.
Step 2: 2-(3-(2-(4-Fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamîne (0.070 mL; 0.505 mmol) in éthanol (1 mL), tert-butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1carboxylate (0.331 g; 0.998 mmol) and a solution of A/-(4-fluorobenzylidene)-5-methoxypyridin3-amine (0.999 mmol) in éthanol (1 mL), heated at 70 °C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane furnished 0.191 g (41%) of the desired compound as a beige solid. ESI/APCI(+): 462 (M+H). ESI/APCI(-): 460 (M-H).
EXAMPLE 349: PREPARATION OF 2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2((5-methoxypyridin-3-yl)amino)ethanone 2-(4-Fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-(4fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate (0.190 g; 0,412 mmol) in a mixture of THF (3 mL) and methanol (3 mL) and potassium carbonate (0.114 g; 0.823 mmol). The reaction mixture was stirred at room température for 16 h. Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 5) furnished 0.038 g (22%) of the desired compound as a yellow powder. ESI/APCI(+): 420 (M+H). ESI/APCI(-): 418 (M-H).
EXAMPLE 350: PREPARATION OF 4-(3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5methoxyphenoxy)butanoic acid
To a solution of ethyl 4-(3-((2-(1 /-/-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5methoxyphenoxy)butanoate (0.050 g; 0.103 mmol) in dioxane (3 mL) was added a 1N sodium hydroxide solution (0.308 mL; 0.308 mmol). The reaction mixture was stirred at room température for 4 days. A 1N hydrochloric acid solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure.
Purification by préparative HPLC (Xbridge column; method 2) followed by purification by flash
300 chromatography on silica gel using a gradient of methanol (1% to 7%) in dichloromethane furnished 0.009 g (19%) of 4-(3-((2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5methoxyphenoxyjbutanoîc acid as a beige solid. ESl/APCI(+): 459 (M+H). ESI/APCI(-): 457 (ΜΗ). 1H NMR (DMSO-de) ÔO12.14 (1H, brs); 8.89 (1H, s); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.25-7.35 (2H, m); 7.12-7.24 (3H, m); 6.31 (1 H, d); 5.99-6.12 (3H, m); 5.71 (1H, s); 3.84 (2H, t); 3.61 (3H, s); 2.73 (1 H, br s); 2.32 (2H, t); 1.86 (2H, m).
EXAMPLE 351: PREPARATION OF 2-(3-(2-((3,5-dimethoxyphenyl)amino)-2-(pyrazolo[1,5a]pyrîdin-2-ylJacetyl)-1 H-indol-5-yl)ethyl acetate 2-(3-(2-((3,5-Dimethoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-5-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride (0.135 g; 0.500 mmol) and triethylamine (0.070 mL; 0.505 mmol) in éthanol (1.5 mL), fert-butyl 5-(2-acetoxyethyl)-3-formyl-1/7-indole-1 -carboxylate (0.331 g; 0.999 mmol) and a solution of 3,5-dimethoxy-N-(pyrazolo[1,5-a]pyridin-2ylmethylene)aniline (0.999 mmol) in éthanol (1 mL), heated at 70 °C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane furnished 0.250 g (50%) of the desired compound as an oil. ESI/APCI(+): 513 (M+H). ESI/APCI(-): 511 (M-H).
EXAMPLE 352: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1Hindol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone 2-((3,5-Dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-
2- yl)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-((3,5dimethoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyrîdin-2-yl)acetyl)-1 H-indol-5-yl)ethyl acetate (0.250 g; 0.488 mmol) in THF (5 mL) and methanol (5 mL) and potassium carbonate (0.135 g; 0.977 mmol). The reaction mixture was stirred at room température for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 70%) in dichloromethane followed by précipitation from éthanol furnished 0.086 g (37%) of the desired compound as a beige solid. ESI/APCI(+): 471 (M+H). ESI/APCI(-): 469 (M-H). 1H NMR (DMSO-d6) ÔO11.99 (1 H, br s); 8.74 (1 H, s); 8.58 (1H, d); 8.01 (1 H, s); 7.59 (1H, d); 7.36 (1 H, d); 7.00-7.20 (2H, m); 6.80 (1H, t); 6.64 (1 H, s); 6.26 (2H, s); 6.09 (2H, s); 5.74 (1H, s); 4.62 (1H, t); 3.62 (6H, s); 3.58 (2H, m); 2.79 (2H, t).
EXAMPLE 353: PREPARATION OF 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-ylJacetyl)-1 H-indol-5-yl)propyl acetate
3- (3-(2-((5-Methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-Îndol-5-yl)propyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0.5 mL), fert-butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1carboxylate (0.353 g; 1.022 mmol) and a solution of 5-methoxy-A/-(pyrazolo[1,5-a]pyridin-216765
301 ylmethylene)pyridin-3-amine (0.951 mmol) in éthanol (2 mL), heated at 60 °C for 72 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane furnished 0.233 g (46%) of the desired compound as a brown solid. ESI/APCI(+): 498 (M+H). ESI/APCI(-): 496 (M-H).
EXAMPLE 354: PREPARATION OF 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyrldin-
3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone
To solution of 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1 Hindol-5-yl)propyl acetate (0.233 g; 0.468 mmol) in a mixture of methanol (3 mL), THF (3 mL) and water (0.5 mL) was added potassium carbonate (0.135 g; 0.977 mmol). The reaction mixture was stirred at room température for 3 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a citric acid buffer (pH 5) solution. The organic phase was dried over magnésium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 7%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 3) furnished 0.040 g (19%) of 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone as a beige solid. ESI/APCI(+): 456 (M+H). ESI/APCI(-): 454 (M-H).
EXAMPLE 355: PREPARATION OF 3-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1 H-indol-5-yl)propyl acetate
3-(3-(2-( 5-Methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g; 0.500 mmol) and triethylamine (0.100 mL; 0.717 mmol) in éthanol (0,5 mL), tert-butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1carboxylate (0.340 g; 0.984 mmol) and a solution of 5-methoxy-/V-((5-methoxypyrazin-2yl)methylene)pyridin-3-amine (0.941 mmol) in éthanol (1 mL), heated at 60 °C for 48 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane furnished 0.397 g (64%) of the desired compound as a brown solid. ESI/APCI(+): 490 (M+H). ESI/APCI(-): 488 (M-H).
EXAMPLE 356: PREPARATION OF 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-(5-methoxypyrazin2-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone
1-(5-(3-Hydroxypropyl)-1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure S from a solution of 3-(3-(2-(5methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1/7-indol-5-yl)propyl acetate (0.297 g; 0.607 mmol) in THF (4 mL) and methanol (4 mL) and potassium carbonate (0.171 g;
1.237 mmol). The reaction mixture was heated at 45 °C for 5 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 10%) in dichloromethane furnished 0.090 g (33%) of the desired product as a pale yellow solid. ESI/APCI(+): 448 (M+H).
302
EXAMPLE 357: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-phenylethanone
Step 1: To a suspension of 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone (0.089 g; 0.319 mmol) in dichloromethane (4.3 mL) were added triethylamine (0.065 mL; 0.498 mmol) and mesyl chloride (0.028 mL; 0.468 mmol). The reaction mixture was stirred at room température for 5 h. Water was added and the phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give quantitatively 2-(3-(2-phenylacetyl)-1H-indol-7-yl)ethyl methanesulfonate which was used without further purification. ESI/APCI(+): 358 (M+H).
To a solution of 2-(3-(2-phenylacetyl)-1H-indol-7-yl)ethyl methanesulfonate (0.319 mmol) in methanol (3.6 mL) was added sodium thiomethoxide (0.045 g; 0.642 mmol). After 18 h at room température, sodium thiomethoxide (0.045 g; 0.642 mmol) was added again. The reaction mixture was stirred at room température for 8.5 h. After addition of sodium thiomethoxide (0.018 g; 0.257 mmol), stirring at room température was continued for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15% to 50%) in heptane furnished 0.041g (42%) of 1-(7-(2-(methylthio)ethyl)-1H-indol-3-yl)-2phenylethanone as a white powder. ESI/APCI(+): 310 (M+H). ESI/APCI(-): 308 (M-H).
Step 2: To a solution of 1-(7-(2-(methylthio)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.087 g; 0.236 mmol) in dichloromethane (1 mL) cooled to 0 °C was added portionwise 3chloroperoxybenzoic acid (0.125 g; 0.507 mmol). After 2 h at room température, 3chloroperoxybenzoic acid (0.040 g; 0.174 mmol) was added. The reaction mixture was stirred at room température for 2 h. The reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (40% to 90%) in heptane furnished 0.037 g (46%) of 1-(7-(2-(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-phenylethanone as a white powder. ESI/APCI(+): 342 (M+H); 364 (M+Na). ESI/APCI(-): 340 (M-H).
Step 3: To a solution of 1-(7-(2-(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.037 g; 0.108 mmol) in THF (1.3 mL) cooled to 0 °C was added a solution of phenyltrimethylammonium tribromide (0.058 g; 0.154 mmol) in THF (1.6 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 4 h. 3,5-Dimethoxyaniline (0.167 g; 1.090 mmol) was added. The reaction mixture was refluxed for 3 h and was stirred overnight at room température. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a 1N hydrochloric acid solution. The phases were separated. The organic phase was washed with
303 a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using of ethyl acetate (40% to 90%) in heptane furnished 0.035 g (66%) of 2-((3,5dimethoxyphenyl)amino)-1-(7-(2-(methylsulfonyl)ethyl)-1 H-indol-3-yl)-2-phenylethanone as a beige powder. ESI/APCI(+): 493 (M+H); 515 (M+Na). ESI/APCI(-): 491 (M-H). 1H NMR (DMSOd6) δ 12.22 (1 H, br s); 8.93 (1 H, s); 8.06 (1H, t); 7.63 (2H, m); 7.26 (2H, m); 7.13-7.20 (3H, m);
6.35 (1H, d); 6.11 (1H, d); 6.06 (2H, s); 5.71 (1H, s); 3.61 (6H, s); 3.47 (2H, m); 3.33 (2H, m); 3.02 (3H, s).
EXAMPLE 358: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(3hydroxypropyl)-1H-indol-3-yl)ethanone
Step 1: 1-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1/-/-indol-3-yl)-2-(4-fluorophenyl)ethanone was prepared according to general procedure O from a solution of 5-(3-((fertbutyldimethylsilyl)oxy)propyl)-1H-indole (0.130 g; 0.449 mmol) in dichloromethane (2.5 mL), a 1M diethylaluminum chloride solution in hexane (0.584 mL; 0.584 mmol) and a solution of 2-(4fluorophenyl)acetyl chloride (0.101 g; 0.584 mmol) in dichloromethane (1 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 100%) in heptane furnished 0.042 g (22%) of the desired compound. ESI/APCI(+): 426 (M+H). ESIZAPCI(-): 424 (M-H).
Step 2: 2-Bromo-2-(4-fluorophenyl)-1 -(5-(3-hydroxypropyl)-1 H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 1-(5-(3-((tertbutyldimethylsilyl)oxy)propyl)-1H-indol-3-yl)-2-(4-fluorophenyl)ethanone (0.042 g; 0.099 mmol) in THF (1 mL) and phenyltrimethylammonium tribromide (0.045 g; 0.118 mmol). Purification by flash chromatography on silica gel using a gradient of methanol (1% to 10%) in dichloromethane furnished 0.020 g (52%) of the desired compound. ESI/APCI(+): 390, 392 (M+H). ESI/APCI(-); 388, 390 (M-H).
Step 3: 2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(5-(3-hydroxypropyl)-1 H-indol-3yl)ethanone was prepared according to general procedure E from 2-bromo-2-(4-fluorophenyl)-1(5-(3-hydroxypropyl)-1H-indol-3-yl)ethanone (0.020 g; 0.051 mmol) and 3,5-dimethoxyaniline (0.039 g; 0.256 mmol) in acetonitrile (0.5 mL), irradiated in a microwave oven at 100 °C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20% to 100%) in heptane furnished 0.008 g (34%) of the desired compound as a solid. ESI/APCI(+): 463 (M+H). ESI/APCI(-): 461 (M-H).
EXAMPLE 359: PREPARATION OF 3-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1 /7-indol-5-ylJpropyl acetate
3- (3-(2-(4-Fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-
4- methylthiazol-3-ium chloride (0,133 g; 0.486 mmol) and triethylamine (0.100 mL; 0.717 mmol)
304 in éthanol (0.5 mL), tert-butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1-carboxylate (0.350 g;
1.013 mmol) and a solution of A/-(4-fluorobenzylidene)-5-methoxypyridin-3-amine (0.967 mmol) in éthanol (1 mL), heated at 60 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane furnished 0.193 g (40%) of the desired compound as a brown oil. ESI/APCI(+): 476 (M+H). ESI/APCI(-): 474 (M-H).
EXAMPLE 360: PREPARATION OF 2-(4-fluorophenyl)-1-(5-(3-hydroxypropyl)-1A7-indol-3-yl)-2((5-methoxypyridin-3-yl)amino)ethanone
2-(4-Fluorophenyl)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was prepared according to general procedure S from a 3-(3-(2-(4fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate (0.193 g; 0.406 mmol) in a mixture of THF (3 mL) and methanol (3 mL) and potassium carbonate (0.117 g; 0.847 mmol). The reaction mixture was heated at 45 °C for 5 h. Purification by flash chromatography on silica gel using a gradient of methanol (0% to 5%) in dichloromethane followed by précipitation from dichloromethane furnished 0.027 g (15%) of the desired product as a white solid. ESI/APCI(+): 434 (M+H). ESI/APCI(-): 432 (M-H).
EXAMPLE 361: PREPARATION OF 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(2hyd roxyethyl )-1 H-indol-3-yl )ethanone
Step 1: 2-(4-Fluorophenyl)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)ethanone was prepared according to general procedure O from 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1 H-indole (0.430 g; 1.561 mmol) in dichloromethane (5 mL), a 1M diethylaluminium chloride solution in hexane (0.322 mL; 0.322 mmol) and a solution of 2-(4-fluorophenyl)acetyl chloride (0.322 mL; 2,351 mmol) in dichloromethane (5 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2% to 70%) in heptane furnished 0.062 (13%) the desired compound. ESI/APCI(+): 298 (M+H). ESI/APCI(-): 296 (M-H).
Step 2: To a solution of 2-(4-fluorophenyl)-1-(5-(2-hydroxyethyl)-1/7-indol-3-yl)ethanone (0.060 g; 0.202 mmol) in THF (2.5 mL) cooled to 0 °C was added a solution of phenyltrimethylammonium tribromide (0.106 g; 0.282 mmol) in THF (2.5 mL). The reaction mixture was stirred at 0 °C for 1 h and at room température for 5 h. 3,5-Dimethoxyaniline (0.309 g; 2.021 mmol) was added and the reaction mixture was refluxed for 2 h. After cooling to room température, a 1N hydrochloric acid solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5% to 50%) in dichloromethane followed by purification by préparative HPLC (XBridge column; method 2) furnished 0.025 g (28%) of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1 -(5-(2hydroxyethyl)-1H-indol-3-yl)ethanone as a white solid. ESI/APCI(+): 449 (M+H). ESI/APCI(-): 447 (M-H). 1H NMR (DMSO-cfe) ÔD12.07 (1H. br s); 8.84 (1H, d); 7.99 (1 H. s); 7.59-7.72 (2H, m); 7.36 (1H, d); 7.02-7.19 (3H, m); 5.98-6.13 (3H, m); 5.74 (1 H, s); 3.62 (6H, s); 3.52-3.60 (2H,
305
m); 2.78 (2H, t).
Without being lîmiting, some more examples of compounds of the présent invention which can be prepared by using similar protocole as described herein are the following:
4-(3-((1-(4,6-dimethylpyridin-3-yl)-2-(1H-indol-3-yl)-2-oxoethyl)amino)-5methoxyphenyl)butanoic acid;
2-(6-(hydroxymethyl)pyridin-3-yl)-1-(1/-/-indol-3-yl)-2-((3-methoxy-5-(2(methylsulfonyl)ethyl)phenyl)amino)ethanone;
2- ((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-7-(2-hydroxyethyl)-1H-indol-3-yl)-2-( tetrahydrofuran-
3- yl)ethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-((methylsulfonyl)methyl)-1H-indol-3-yl)-2-(tetrahydro-2/7pyran-4-yl)ethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-(3-(dimethylamino)propyl)-1/7-indol-3-yl)-2-(3,5dimethylisoxazol-4-yl)ethanone;
2-((1,2,4]triazo lo [1,5-a]pyrid in-7-yl )-1 -(7-(3-aminopropyl)-1 H-indo l-3-y 1)-2-((3,5dîmethoxyphenyl)amino)ethanone;
2- ( benzo[d]isoxazol-3-yl )-2-((3,5-dimethoxyphenyl)amino)-1-(7-(3-hydroxypropyl)-1/-/-indol-3yl)ethanone;
3- (3-(2-((3,5-dimethoxyphenyl)amino)-2-(5-phenylisoxazol-3-yl)acetyl)-1H-indol-5-yl)propanoic acid;
1-(5-(2-aminoethyl)-1/-/-indol-3-yl )-2-((3,5-dimethoxyphenyl)amino)-2-(5-methyl-1-phenyl-1Hpyrazol-3-yl)ethanone;
1- methyl-4-((2-(5-(2-(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)pyrrolidin-
2- one;
1- (1/7-indol-3-yl)-2-((3-methoxy-5-((methylamino)methyl)phenyl)amino)-2-(3-methyl-3Himidazo[4,5-b]pyridin-2-yl)ethanone;
2- (6,7-dihydro-4H-pyrano[3,4-c/]thiazol-2-yl)-2-((3-(2-hydroxyethyl)-5-methoxyphenyl)amino)-1(1H-indol-3-yl)ethanone;
2-((3-(2-aminoethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(1 -methyl-1 Hbenzo[d]imidazol-2-yl)ethanone;
2-(benzo[c/]thiazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxy-5-(2-(pyrrolidin-1yl)ethoxy)phenyl)amino)ethanone;
2-((3-(difluoromethoxy)phenyl)amino)-1-(1H-indol-3-yl)-2-(thiazolo[4,5-b]pyrazin-2-yl)ethanone;
2-(3-((1-(benzo[b]thiophen-2-yl )-2-( 1/-/-indol-3-yl)-2-oxoethyl)amino)-5-methoxyphenyl)acetic acid;
2-((3-(3-aminopropoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(thieno[2,3-b]pyridin-2yl)ethanone;
306
1-(5-(aminomethyl )-1 H-indol-3-yl )-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[5I4-c]pyridin-2yljethanone;
1-(7-(aminomethyl)-1H-indol-3-yl )-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[4,5-c]pyridin-2yl)ethanone;
1-(5-(2-aminoethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[4,5-b]pyridin-2yljethanone;
1- (1/7-indol-3-yl)-2-((3-methoxy-5-(2-(methylsulfonyl)ethoxy)phenyl)amino )-2-(5-methyl-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethanone;
2- ((3l5-dimethoxyphenyl)amino)-1-(1/7-indol-3-yl)-2-(5-methyl“4l5,6,7-tetrahydrothiazolo[4,5c]pyridin-2-yl)ethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1/7-indol-3-yl)-2-(p-tolyl)ethanone; 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7-(2-hydroxyethyi )-1/7indol-3-yl)ethanone;
2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1/7-indol-3-yl)-2phenylethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-(dimethylamino)ethyl)-1/7-indol-3-yl)-2-(4fluorophenyljethanone;
2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(2-hydroxyethyl)-1 -methyl-1 H-indazol-3yljethanone;
2-(4-fiuorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1 H-indazol-3yl)ethanone;
2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1-methyl-1H-indazo!-3-yl)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone;
2-(4-fluorophenyl)-1-(1/7-indol-3-yl)-2-((3-methoxy-5((methyisulfonyl)methyl)phenyl)amino)ethanone;
2- ((3,5-dimethoxyphenyl)amino)-2-(3-methylpyridin-2-yl)-1-(7-((methylsulfonyl)methyl)-1/7-indol-
3- yl)ethanone; and
3-(3-(2-(6-cyanopyridin-2-yl )-2-((3,5-dimethoxyphenyl)amino)acetyl)-1/7-indol-5-yl)propanoic acid.
Part B
EXAMPLE 362: ANTIVIRAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION
For Dengue virus: Vero-B cells (5 χ 104) were seeded in 96-weil plates. One day later, culture medium was replaced with 100 pL assay medium containing a 2* serial dilution of the compound (concentration range: 50 pg/mL - 0.004 pg/mL) and 100 pL of dengue virus inoculum (DENV). Following a 2 hour incubation period, the cell monolayer was washed 3 times with assay medium to remove residual, non-adsorbed virus and cultures were further incubated for either 4 days (DENV-2 NGC), 5 days (DENV-4 strain Dak HD 34 460) or 7 or 8 days (DENV16765
307
Djibouti strain D1/H/IMTSSA/98/606 and DENV-3 strain H87 prototype) in the presence of the inhibitor. Supematant was harvested and viral RNA load was determined by real-time quantitative RT-PCR. The 50% effective concentration (EC50), which is defined as the compound concentration that is required to inhibit viral RNA réplication by 50%, was determined using logarithmic interpolation.
The antiviral activity of the compounds against DENV-2 NGC was also tested in adenocarcinomic human alveolar basal épithélial cells (A549 cells), using the above described protocol with the différence that less cells/well were seeded (2 χ 104 cells/well).
For the yellow fever virus: Vero-B cells (5 χ 104) were seeded in 96-well plates. One day later, culture medium was replaced with 100 pL assay medium containing a 2x serial dilution of the compound (concentration range 50 pg/mL - 0.004 pg/mL) and 100 pL of yellow fever virus inoculum (YFV-17D). Following a 2 hour incubation period, the cell monolayer was washed 3 times with assay medium to remove residual, non-adsorbed virus and cultures were further incubated for 4 days in the presence of the inhibitor. Supematant was harvested and viral RNA load was determined by real-time quantitative RT-PCR. The 50% effective concentration (ECS0), which is defined as the compound concentration that is required to inhibit viral RNA réplication by 50%, was determined using logarithmic interpolation.
Quantitative reverse transcriptase-PCR (RT-qPCR)
RNA was isolated from 100 pL (or in some circumstances 150 pL) supematant with the NucleoSpin 96 Virus kit (Macherey-Nagel, Düren, Germany) as described by the manufacturer. The sequences of the TaqMan primers (DENV-For, DENV-Rev, YFV-For, YFV-Rev; Table 2) and TaqMan probes (DENV-Probe and YFV-Probe; Table 2) were selected from non-structural gene 3 (NS3) or NS5, of the respective flaviviruses using Primer Express software (version 2.0; Applied Bîosystems, Lennik, Belgium). The TaqMan probe was fluorescently labelled with 6carboxyfluorescein (FAM) at the 5' end as the reporter dye, and with minor groove binder (MGB) at the 3’ end as the quencher (Table 2). One-step, quantitative RT-PCR was performed in a total volume of 25 pL, containing 13.9375 pL H2O, 6.25 pL master mix (Eurogentec, Seraing, Belgium), 0.375 pL forward primer, 0.375 pL reverse primer, 1 pL probe, 0.0625 pL reverse transcriptase (Eurogentec) and 3 pL sample. RT-PCR was performed using the ABI 7500 Fast Real-Time PCR System (Applied Bîosystems, Branchburg, New Jersey, USA) using the following conditions: 30 min at 48 °C and 10 min at 95 °C, followed by 40 cycles of 15 s at 95 °C and 1 min at 60 °C. The data was analyzed using the ABI PRISM 7500 SDS software (version 1,3.1; Applied Bîosystems). For absolute quantification, standard curves were generated using 10-fold dilutions of template préparations of known concentrations.
Table 2: Primers and probes used for real-time, quantitative RT-PCR.
Primer/Probe Sequence (5’ —* 3’) * Source 0 Target
DENV-For TCGGAGCCGGAGTTTACAAA (SEQ ID N.1) DENV 2 NGC NS3
308
DENV-Rev TCTTAACGTCCGCCCATGAT (SEQ ID N.2)
DENV-Probe FAM-ATTCCACACAATGTGGCAT-MGB (SEQ ID N.3)
DenS GGATAGACCAGAGATCCTGCTGT (SEQ ID N.4) DENV-1,-3,-4 NS5
DenAS1-3 CAÎTCCATTTTCTGGCGTTC (SEQ ID N.5) DENV-1,-3
DenAS4 CAATCCATCTTGCGGCGCTC (SEQ ID N.6) DENV-4
DEN_1-3 probe FAM-CAGCATCATTCCAGGCACAG-MGS (SEQ ID N.7) DENV-1,-3
DEN_4 probe FAM-CAACATCAATCCAGGCACAG-MGB (SEQ ID N.8) DENV-4
YFV-For TGGCATATTCCAGTCAACCTTCT (SEQ ID N.9) YFV-17D NS3
YFV-Rev GAAGCCCAAGATGGAATCAACT (SEQ ID N. 10)
YFV-Probe FAM-TTCCACACAATGTGGCATG-MGB (SEQ ID N.11)
Reporter dye (FAM) and quencher (MGB/TAMRA) éléments are Indicated In bold and Halles.
bThe nucléotide sequence and position of the primera and probes within the genome were deduced from the nucléotide sequence of DENV 2 NGC (GenBank accession no. M29095; Irie et al.. 1989), dengue virus serotype 1 Djibouti straln D1/H/IMTSSA/98/606 (Genbank Accession Number AF298808), dengue virus serotype 3 strain H87 prototype (c93130), dengue virus serotype 4 straln Dak HD 34 460 (only partial, unpubllshed sequences available) and YFV-17D (GenBank accession no. X03700; Rice et al., 1985). Cytotoxic assay
Potential cytotoxic effects of the compounds were evaluated in uninfected quiescent Vero-B cells. Cells were seeded at 5 χ 104 cells/well in a 96-well plate in the presence of twofold serial dilutions (ranging from 50 pg/mL - 0,004 pg/mL) of compound and incubated for 4 days. Culture medium was discarded and 100 pL 3-(4,5-dimethylthiazol-2-yl)-5-(3carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium/phenazinemethosulfate (MTS/PMS; Promega, Leiden, The Netherlands) in PBS was added to each well. Following a 2-hour incubation period at 37 °C, the optical density was determined at 498 nm. Cytotoxic activity was calculated using the following formula: % cell viability - 100 χ (ODCompound/ODCc), where ODcompound and ODcc correspond to the optical density at 498 nm of the uninfected cell cultures treated with compound and that of uninfected, untreated cell cultures, respectively. The 50% cytotoxic concentration (i.e., the concentration that reduces the total cell number with 50%; CC50) was calculated using linear interpolation.
A similar protocol was used to assess cytotoxicity in A549 cells with the différence that cells were seeded at 2χ 104 cells/well.
Table 3 shows the activity against DENV-2 in Vero-B cells and the cytotoxicity of some example compounds of the invention.
309
Code ECS0 (μΜ) CCS0 (μΜ) SI Code EC50 (μΜ) CC60 (μΜ) SI
CPD-001 0.08 29 380 CPD-036 0.04 14 333
CPD-002 0.01 16 2307 CPD-037 1.20 19 16
CPD-003 0.11 13 114 CPD-039 2.48 15 6
CPD-004 0.19 11 57 CPD-040 4.24 >129 >30
CPD-005 0.93 5 6 CPD-041 0.50 14 29
CPD-006 0.75 6 8 CPD-042 12.51 > 138 > 11
CPD-007 2.53 5 2 CPD-043 0.29 > 126 >440
CPD-008 2.42 12 5 CPD-044 6.48 65 10
CPD-009 0.66 4 7 CPD-045 0.06 > 139 >2183
CPD-010 0.07 18 244 CPD-046 0.65 17 26
CPD-011 1.66 23 14 CPD-047 0.42 16 39
CPD-012 0.05 14 297 CPD-048 2.09 >115 >54
CPD-013 0.002 9 5726 CPD-049 0.08 > 134 > 1642
CPD-014 0.02 8 354 CPD-050 2.40 87 36
CPD-015 0.02 22 1065 CPD-051 2.47 > 125 >51
CPD-016 5.01 54 11 CPD-052 3.72 52 14
CPD-018 0.37 19 52 CPD-053 0.02 18 774
CPD-019 0.14 71 514 CPD-054 2.09 >115 >54
CPD-020 0.14 16 114 CPD-055 0.07 50 759
CPD-021 1.62 > 115 >70 CPD-056 0.45 >139 >312
CPD-022 12.80 77 6 CPD-057 6.05 15 2
CPD-023 0.30 16 53 CPD-058 2.85 64 22
CPD-024 0.50 14 27 CPD-059 1.25 16 13
CPD-025 0.68 48 69 CPD-060 10.33 >113 >10
CPD-026 17.19 > 138 >8 CPD-061 1.71 59 34
CPD-027 0.13 15 111 CPD-062 0.58 > 134 >230
CPD-028 135.17 > 144 > 1 CPD-063 14.33 > 134 >9
CPD-029 0.84 65 78 CPD-064 8.75 72 8
CPD-030 0.09 > 126 >1412 CPD-065 12.10 90 7
CPD-031 50.19 > 145 >2 CPD-066 6.32 95 15
CPD-032 55.53 > 146 >2 CPD-067 0.04 20 546
CPD-033 9.15 71 8 CPD-068 1.32 12 9
CPD-034 46.49 > 151 >3 CPD-069 2.13 71 33
' CPD-035 2.11 14 7 CPD-070 3.27 90 27
310
Code EC50(pM) CC00(pM) SI Code EC50(pM) CCfio(pM) SI
CPD-071 60.85 135 2 CPD-109 0.53 84 159
CPD-072 6.84 68 10 CPD-110 0.58 73 127
CPD-073 2.35 76 32 CPD-111 0.44 >115 >263
CPD-074 0.81 77 95 CPD-112 3.27 12 4
CPD-075 1.52 102 67 CPD-113 0.49 >112 >232
CPD-076 3.77 115 31 CPD-114 1.10 52 48
CPD-077 0.04 13 313 CPD-115 10.58 49 5
CPD-078 11.64 109 9 CPD-116 0.14 13 88
CPD-080 0.99 > 124 > 125 CPD-117 3.57 > 133 >37
CPD-081 10.76 50 5 CPD-118 0.01 13 943
CPD-082 61.85 109 2 CPD-119 0.03 13 372
CPD-083 0.03 26 941 CPD-120 0.02 11 674
CPD-084 0.03 > 127 >4185 CPD-121 5.76 60 10
CPD-085 0.07 16 227 CPD-122 0.02 16 785
CPD-086 0.04 12 329 CPD-123 0.05 15 337
CPD-087 0.80 > 128 > 161 CPD-124 0.56 3 5
CPD-088 2.53 > 121 >48 CPD-125 7.19 > 138 > 19
CPD-089 0.67 > 139 >208 CPD-126 0.07 16 241
CPD-090 2.90 13 5 CPD-127 2.15 72 33
CPD-092 0.10 19 184 CPD-128 0.56 63 113
CPD-093 16.79 87 5 CPD-129 1.09 > 108 >99
CPD-094 0.14 11 77 CPD-130 0.03 15 749
CPD-096 2.90 > 121 >42 CPD-131 0.01 13 1779
CPD-097 2.32 12 5 CPD-132 0.05 12 235
CPD-098 10.69 > 121 > 11 CPD-133 0.04 19 499
CPD-099 1.76 12 7 CPD-134 0.46 49 106
CPD-100 12.03 42 3 CPD-135 40.66 > 124 >3
: CPD-101 4.90 11 2 CPD-136 0.22 > 120 >545
i CPD-102 0.62 65 105 CPD-137 0.05 > 128 >2762
CPD-103 12.43 >138 > 11 CPD-138 0.27 20 74
CPD-104 0.35 65 186 CPD-139 0.02 20 915
; CPD-105 1.23 14 11 CPD-140 2.15 53 24
CPD-106 8.93 > 120 > 13 CPD-141 1.63 44 27
CPD-107 7.88 20 3 CPD-142 0.10 13 137
311
Code ECS0(pM) CC50(MM) SI Code EC50 (μΜ) CCS0(pM) SI
CPD-144 0.06 20 320 CPD-198 0.14 16 119
CPD-146 0.05 25 498 CPD-199 24.90 >120 >4
CPD-148 0.07 44 594 CPD-200 2.24 54 24
CPD-149 0.03 14 554 CPD-201 12.23 74 6
CPD-150 0.03 105 3956 CPD-202 8.33 104 12
CPD-151 0.09 > 133 > 1443 CPD-203 0.73 > 134 >185
CPD-152 0.09 75 814 CPD-205 0.06 14 244
CPD-153 0.29 >133 >454 CPD-206 0.02 12 625
CPD-154 0.06 44 778 CPD-207 3.83 16 4
CPD-155 0.08 15 191 CPD-208 0.37 >102 >279
CPD-156 0.02 11 665 CPD-209 1.12 >100 >89
CPD-157 0.05 15 299 CPD-210 0.20 13 68
CPD-158 0.09 63 746 CPD-211 2.83 >111 >39
CPD-159 0.11 67 624 CPD-212 0.42 >110 >260
CPD-170 0.44 26 58 CPD-213 0.06 15 256
CPD-173 0.02 69 3693 CPD-214 0.03 16 469
CPD-174 10.07 61 6 CPD-215 0.16 14 90
CPD-179 5.30 135 26 CPD-216 0.84 > 106 >127
CPD-180 56.97 > 145 >2 CPD-217 0.25 11 44
CPD-181 4.22 > 122 >28 CPD-218 2.39 13 6
CPD-182 3.01 12 4 CPD-219 0.52 86 166
CPD-183 15.20 86 6 CPD-221 29.28 80 3
CPD-184 22.42 70 3 CPD-222 0.13 >129 > 1003
CPD-186 4.35 40 9 CPD-223 57.95 > 128 >2
CPD-187 3.18 58 18 CPD-224 0.05 > 134 >2622
CPD-189 0.93 >145 > 156 CPD-225 0.38 >134 >357
CPD-190 1.71 11 7 CPD-226 0.07 73 1005
CPD-191 2.58 13 5 CPD-227 0.27 > 124 >454
CPD-192 5.62 50 9 CPD-228 1.62 13 8
CPD-193 0.72 > 133 >185 CPD-229 2.40 >115 >48
CPD-194 0.94 61 65 CPD-230 0.12 21 176
CPD-195 12.73 65 5 CPD-231 1.22 18 15
CPD-196 62.56 >139 >2 CPD-232 0.10 > 125 > 1206
CPD-197 3.30 >139 >42 CPD-233 0.01 11 817
312
Code EC50 (μΜ) CC50 (μΜ) SI Code EC50 (μΜ) CC50 (μΜ) SI
CPD-234 0.05 15 319 CPD-270 0.13 > 128 > 1001
CPD-235 0.004 13 3701 CPD-272 0.47 > 124 >263
CPD-236 0.02 69 4562 CPD-273 0.32 > 122 >382
CPD-237 1.35 > 113 >84 CPD-274 0.39 100 257
CPD-238 0.04 >125 >3548 CPD-275 9.96 > 126 > 13
CPD-239 22.65 > 125 >6 CPD-276 2.62 23 9
CPD-240 0.11 63 578 CPD-277 0.29 16 54
CPD-241 0.04 58 1531 CPD-278 0.27 > 125 >455
CPD-242 0.04 59 1340 CPD-279 0.18 > 124 >682
CPD-243 1.69 13 8 CPD-280 0.78 > 139 >179
CPD-245 0.08 16 192 CPD-281 0.21 > 128 >612
CPD-246 0.32 16 51 CPD-282 0.26 > 128 >490
CPD-247 0.42 15 37 CPD-283 0.17 56 323
CPD-248 0.56 15 27 CPD-284 0.62 74 120
CPD-249 0.10 53 553 CPD-285 0.04 50 1327
CPD-250 0.22 15 65 CPD-286 1.05 > 126 > 120
CPD-251 0.07 14 195 CPD-287 0.44 > 132 >303
CPD-252 0.48 68 140 CPD-288 0.12 77 620
CPD-254 0.02 13 743 CPD-289 0.06 68 1150
CPD-255 0.04 63 1535 CPD-290 0.88 > 125 >142
CPD-256 0.19 83 433 CPD-291 0.06 53 872
CPD-257 0.45 17 37 CPD-292 0.06 68 1043
CPD-258 1.47 72 49 CPD-293 0.001 65 50498
CPD-259 0.54 14 26 CPD-294 0.02 41 2598
CPD-260 0.08 > 126 >1681 CPD-295 0.03 18 679
CPD-261 0.39 15 40 CPD-296 0.05 31 605
CPD-262 0.06 71 1099 CPD-297 0.03 22 668
CPD-263 2.18 13 6 CPD-298 0.42 >116 >278
CPD-264 0.51 > 124 >244 CPD-299 0.02 62 3136
CPD-265 0.02 > 124 >5616 CPD-300 1.29 50 39
CPD-266 0.06 > 124 >2222 CPD-301 0.08 89 1097
CPD-267 1.30 79 61 CPD-302 0.65 15 23
CPD-268 0.46 15 34 CPD-303 0.52 71 135
CPD-269 0.48 13 28 CPD-305 0.09 >116 >1263
313
Code EC50 (μΜ) CC50 (μΜ) SI Code EC50 (μΜ) CC50 (μΜ) SI
CPD-307 0.18 > 124 >702 CPD-338 0.01 > 124 >16618
CPD-309 0.54 74 138 CPD-339 0.09 19 205
CPD-310 0.06 25 454 CPD-340 0.02 > 119 >6223
CPD-311 2.58 77 30 CPD-341 0.002 12 6121
CPD-312 4.67 69 15 CPD-343 0.19 >119 >637
CPD-313 0.04 58 1464 CPD-344 0.09 94 1054
CPD-314 0.21 50 240 CPO-345 0.21 106 493
CPD-315 0.05 13 265 CPD-346 0.01 54 9945
CPD-316 0.02 29 1180 CPD-347 0.98 6 6
CPD-317 0.58 88 153 CPD-348 0.10 14 151
CPD-318 0.06 54 967 CPD-350 0.01 46 3462
CPD-319 0.12 20 172 CPD-351 0.11 65 605
CPD-320 0.07 > 124 > 1781 CPD-352 0.29 71 247
CPD-321 0.11 33 310 CPD-353 0.10 56 582
CPD-322 0.02 51 2855 CPD-355 0.03 44 1511
CPD-323 0.35 58 166 CPD-356 0.12 13 113
CPD-324 0.01 30 3306 CPD-357 1.35 55 40
CPD-325 0.09 68 731 CPD-358 0.18 63 345
CPD-326 0.001 13 9127 CPD-359 0.10 52 501
CPD-327 0.35 11 33 CPD-360 0.04 > 124 >3541
CPD-328 0.01 13 1231 CPD-361 0.09 50 586
CPD-329 0.01 41 2980 CPD-362 0.09 41 470
CPD-330 4.63 > 139 >30 CPD-364 1.12 62 55
CPD-331 0.02 14 736 CPD-365 2.03 12 6
CPD-332 0.04 20 527 CPD-366 0.26 78 293
CPD-333 0.04 90 2078 CPD-367 0.04 >103 >2863
CPD-334 0.07 122 1746 CPD-369 0.01 11 1306
CPD-335 0.02 18 909 CPD-370 0.06 66 1152
CPD-336 0.01 > 123 >8498 CPD-371 0.03 12 389
CPD-337 0.005 15 3237
Table 4 shows the effect against DENV-1, DENV-3 and DENV-4 in Vero-B cells of some example compounds of the invention.
314
DENV-1 DENV-3 DENV-4 DENV-1 DENV-3 DENV-4
Code ECS0(pM) ECS0(pM) EC50(pM) Code ECS0(pM) ECm (μΜ) EC50 (μΜ)
CPD-001 1.60 29.40 4.45 CPD-128 7.50 18.37 ND
CPD-002 0.54 <0.5 27.20 CPD-130 0.35 1.70 7.42
CPD-004 4.53 8.55 ND CPD-131 0.25 0.68 4.77
CPD-010 1.29 3.54 5.43 CPD-132 2.45 3.47 ND
CPD-012 4.42 <0.5 ND CPD-133 2.25 4.17 ND
CPD-013 0.09 <0.5 1.81 CPD-137 0.67 3.81 2.78
CPD-019 0.67 2.18 8.38 CPD-138 3.21 6.52 ND
CPD-020 15.08 ND ND CPD-139 0.65 0.46 3.81
CPD-025 7.89 12.95 11.76 CPD-142 1.71 3.97 ND
CPD-027 2.10 9.90 3.70 CPD-144 2.89 3.08 ND
CPD-029 2.82 ND ND CPD-146 0.69 2.72 4.25
CPD-030 4.80 6.24 13.15 CPD-148 1.65 5.54 2.87
CPD-036 2.43 3.42 5.85 CPD-149 2.88 4.01 5.72
CPD-043 3.38 5.88 4.76 CPD-150 1.28 1.07 8.87
CPD-045 0.64 0.87 11.05 CPD-151 0.53 2.10 4.87
CPD-049 2.21 10.54 2.27 CPD-152 2.05 0.99 5.62
CPD-051 5.76 24.23 32.63 CPD-153 6.26 2.26 3.68
CPD-053 1.64 11.18 7.11 CPD-154 3.92 4.40 9.87
CPD-055 1.86 3.38 4.44 CPD-155 2.94 ND ND
CPD-056 10.57 69.18 5.92 CPD-156 0.61 2.12 3.37
CPD-067 <0.5 1.20 ND CPD-157 1.31 0.85 5.10
CPD-077 1.42 2.07 4.27 CPD-158 2.50 2.19 7.20
CPD-083 0.54 0.71 2.52 CPD-159 1.48 3.16 6.86
CPD-084 <0.5 2.38 3.09 CPD-173 30.71 ND ND
CPD-086 0.97 1.05 3.57 CPD-193 23.67 18.93 5.44
CPD-087 6.05 ND ND CPD-194 ND ND 18.69
CPD-092 ND 0.93 6.73 CPD-203 5.09 5.06 5.32
CPD-104 3.85 24.02 14.88 CPD-206 0.37 0.67 1.52
CPD-116 4.19 9.30 ND CPD-208 ND 6.65 6.95
CPD-118 0.44 3.68 ND CPD-210 1.03 ND ND
CPD-119 0.69 1.74 2.91 CPD-212 ND 5.90 2.64
CPD-120 2.31 5.18 ND CPD-213 0.81 2.54 2.85
CPD-122 3.64 8.25 ND CPD-214 0.15 0.99 4.16
CPD-123 1.60 2.56 2.64 CPD-219 ND 22.07 ND
CPD-126 2.99 8.50 6.29 CPD-222 1.81 3.27 3.14
ND: not determined
315
DENV-1 DENV-3 DENV-4 DENV-1 DENV-3 DENV-4
Code EC50 (μΜ) EC90(pM) EC90 (μΜ) Code ECm (μΜ) EC90(pM) EC90(pM)
CPD-225 ND 2.99 1.16 CPD-289 0.80 0.91 10.22
CPD-226 0.92 0.81 8.64 CPD-291 0.80 0.80 8.67
CPD-227 ND 2.91 7.45 CPD-292 0.83 1.11 7.08
CPD-229 2.81 42.99 7.55 CPD-293 0.06 0.04 1.15
CPD-230 0.35 3.53 2.56 CPD-294 0.23 0.67 7.21
CPD-232 0.85 2.69 1.15 CPD-295 0.34 1.38 6.29
CPD-233 0.22 1.29 3.09 CPD-296 0.99 1.83 3.31
CPD-234 0.76 2.00 4.19 CPD-297 ND 0.57 6.68
CPD-235 0.09 0.27 3.02 CPD-298 2.02 5.79 4.52
CPD-236 0.17 0.31 2.45 CPD-299 0.50 0.78 3.65
CPD-237 ND ND 8.31 CPD-300 5.29 21.12 4.13
CPD-238 0.54 1.65 10.17 CPD-301 1.12 0.50 4.25
CPD-240 1.20 2.38 8.73 CPD-303 3.26 ND ND
CPD-241 0.62 0.62 5.69 CPD-305 0.44 1.02 2.56
CPD-242 0.40 0.57 7.87 CPD-307 2.43 ND 11.49
CPD-245 0.70 2.38 3.01 CPD-309 0.62 0.70 2.80
CPD-249 1.13 4.57 1.98 CPD-310 1.11 0.65 9.37
CPD-252 ND 12.56 2.29 CPD-313 0.72 1.11 5.84
CPD-254 0.67 0.80 1.15 CPD-314 1.70 2.80 8.76
CPD-255 0.75 1.66 3.36 CPD-315 0.38 1.01 1.97
CPD-256 6.76 4.49 19.90 CPD-316 0.39 0.32 4.42
CPD-258 ND ND 9.42 CPD-317 4.13 12.84 10.63
CPD-260 6.63 22.63 5,44 CPD-318 0.22 2.32 10.84
CPD-262 2.33 6.73 8.49 CPD-319 2.84 1.70 2.27
CPD-265 0.29 1.64 4.88 CPD-320 0.96 1.17 9.44
CPD-266 0.70 4.32 3.51 CPD-321 0.40 0.32 2.74
CPD-270 1.57 1.87 ND CPD-322 0.30 0.32 3.00
CPD-273 0.58 7.66 8.41 CPD-323 3.62 4.99 ND
CPD-278 2.84 13.20 5.80 CPD-324 0.27 0.19 5.32
CPD-279 0.62 0.89 8.66 CPD-325 0.87 1.84 7.16
CPD-281 0.85 5.57 1.12 CPD-326 0.05 0.09 1.89
CPD-282 1.24 3.12 13.13 CPD-327 1.42 4.61 2.25
CPD-283 2.83 7.14 7.89 CPD-328 0.20 0.13 2.84
CPD-285 0.84 2.20 2.31 CPD-329 0.27 0.32 2.92
CPD-288 1.90 2.70 6.33 CPD-331 0.39 0.39 3.28
ND: not determined
316
DENV-1 DENV-3 DENV-4 DENV-1 DENV-3 DENV-4
Code ECjq (PM) ECS0 (μΜ) ECS0 (μΜ) Code ECso(PM) EC5û(pM) ECao (μΜ)
CPD-332 0.72 1.35 2.84 CPD-344 ND 0.79 25.90
CPD-333 0.39 0.49 5.92 CPD-345 ND 1.73 2.94
CPD-334 1.29 0.81 16.77 CPD-346 ND 0.04 1.27
CPD-335 0.32 0.42 2.38 CPD-348 ND ND 3.75
CPD-336 0.26 0.35 5.77 CPD-350 ND 0.28 3.11
CPD-337 0.09 0.23 0.95 CPD-351 ND 2.02 9.58
CPD-338 0.35 0.25 1.82 CPD-352 ND 3.03 8.60
CPD-339 0.81 0.82 2.93 CPD-353 ND 0.17 7.18
CPD-340 0.18 0.24 6.39 CPD-355 ND 0.30 6.17
CPD-341 ND 0.05 3.36 CPD-359 ND ND 5.48
CPD-343 ND 3.11 ND CPD-360 ND ND 5.78
ND: not determined
Table 5 shows the effect against YFV in Vero-B cells of some example compounds of the invention.
Code EC50(HM) CC50 (μΜ) SI
CPD-001 9.16 43 5
CPD-002 2.81 25 9
CPD-010 <0.6 12 >22
CPD-012 <0.5 12 >23
CPD-013 0.52 11 20
CPD-019 6.18 56 9
CPD-193 <0.5 >133 >250
Table 6 shows the effect against DENV-2 in A549 cells of some example compounds of the invention.
317
Code EC50(pM) CC50 (μΜ) SI
CPD-010 0.066 16 242
CPD-131 0.008 11 1447
CPD-236 0.019 65 3428
CPD-242 0.010 47 4642
CPD-255 0.029 59 2030
CPD-293 0.003 >117 > 43103
CPD-294 0.015 61 4048
CPD-320 0.006 > 124 > 22522
CPD-328 0.006 12 2140
CPD-334 0.024 85 3536
CPD-336 0.005 > 123 > 22523
CPD-338 0.026 > 124 >4808
CPD-340 0.027 >119 >4425
CPD-346 0.008 60 7559
CPD-350 0.008 63 7758
CPD-360 0.027 > 124 >4630
EXAMPLE 363: IN VIVO ACTIVITY OF THE COMPOUNDS OF THE INVENTION AGAINST DENGUE INFECTION
A dengue viremia model in mice as described in Schul W, Liu W, Xu HY, Flamand M, Vasudevan SG. J. Infect Dis. 2007; 95(5):665-74) (included herein by reference) can be used to examine the in vivo efficacy of compounds. In this model, AG129 mice (lacking alpha/beta interferon and gamma interferon receptors) are intraperitoneally inoculated with 2 χ10θ plaqueforming units (PFU) of DENV-2 (strain TSV01 ) on day 0. The infected mice (6 or 8 animais per group) are immediately treated with the compound to test at one or more selected doses via IP, IV or SC injection or via oral administration and the vehicle as a control for three consecutive days. On day 4, blood samples are taken, and viral tîters are determined using a plaque assay. A dengue mortality model in AG129 mice (lacking alpha/beta interferon and gamma interferon receptors) as described in Tan et al (PLoS Negl Trop Dis 2010; 4(4) and Ann Acad Med Singapore 2011;40:523-32) (included herein by reference) was established to examine the in vivo efficacy of compound CPD-242. Female AG129 mice (B&K Universal, UK), 7-9 weeks old, were divided randomly in 3 test groups (n = 4 or 5 per group): 1 infected group that only received vehicle and 2 infected groups that were treated either with the test compound CPD242 (60 mg/kg/day, sc, twice daily, dissolved in a 10% DMSO, 5% Solutol in Saline (0.9%)) or with the reference compound Celgosivir (100 mg/kg/day; ip, twice daily, dissolved in 0.9% NaCI). The mice were subcutaneously inoculated on day 0 with 1 x107 plaque-formîng units (PFU) of the non-mouse-adapted DENV-2 strain D2Y98P, a highly infectious strain in AG 129 mice, which results in severe disease and eventually death within 2 weeks. The infected mice
318 were subsequently treated BID for 17 consecutive days with either vehicle, Celgosivir or CPD242. Mice were euthanized as soon as they had signs of virus-induced paralysis and/or had lost >=30 % bodyweight. The results obtained in this in vivo experiment are shown in Figure 1 and clearly indicate that treatment of dengue infected AG129 mice with CPD-242 led to a highly 5 significant delay (p: 0.0017) in virus-induced morbidity (day of euthanasia is presented).

Claims (15)

    319 CLAIMS
  1. - 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylmethylamino)ethanone (CAS nr. 875860-58-5); or
    1. A compound of formula (B) for use in the prévention or treatment of a flavivirus infection in an animal, mammal or human, wherein
    - each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
    - each of X1, X2, X3, X5, X6, X7, and X8 is independently selected from CR3, N, NR4, O, and S;
    - each of X4 and X9 is independently selected from C, CH, and N;
    - X10 is selected from C, CH, and N;
    whereby at least five of X1 to X10 are selected from CR3, C, and CH; and at least one of X1 to X10 is a heteroatom;
    - p is 0,1, or 2;
    - q is 0,1, or 2;
    - cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a;
    - R1 is selected from alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-hetero alkyl, heterocycleheteroalkenyl, and heterocycle-heteroalkynyl;
    and wherein said alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three Z1b;
    - Rz is selected from hydrogen, -C(O)Z3, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and
    320 heteroalkynyl;
    and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, are optionally substituted with one, two, or three Z1c;
    - each R3 is independently selected from hydrogen and Z1;
    - each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, -S(=O)Zz, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, -C(=O)Z3, -C(=O)OZz, -C(=O)NZ4Z5, -C(=O)H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocyclealkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF31 cyano, nitro, -C(=O)OH, -C(O)Oalkyl, and -N(CH3)2, -NH2, -NHC(=O)O-CMalkyl, -O-alkyl;
    - each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl,’trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl;
    and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)Oalkyl, -NH2, -NHCH3; N(CH3)2, -NH-C(=O)O-C1.4alkyl, morpholinyl, -S(O)2CMalkyl, and -O-alkyl;
    321
    - each Z2 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-alkyl, -OCF3, -S(=O)2Cwalkylt cyano, nitro, -C(=O)OH, -C(=O)O-Ci.4alkyl, -NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
    - each Z3 is independently selected from hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(=O)OH, -NH2, and -N(CH3)2;
    - each Z4 and Z5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, 16765
    322
    C(=O)OH or-NH2;
    and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(=O)OH, or -NH2;
    and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
  2. - 2-(benzo[d][1,3]dioxol-5-ylmethylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 920816-95-1).
    - 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 1090733-87-1);
    2. A compound of formula (B) for use as a medicine, wherein
    - each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
    - each of X1, X2, X3, X5, X6, X7, and Xe is independently selected from CR3, N, NR4, O, and S;
    - each of X4 and X9 is independently selected from C, CH, and N;
    - X10 is selected from C, CH, and N;
    whereby at least five of X1 to X10 are selected from CR3, C, and CH; and at least one of X1 to X10 is a heteroatom;
    - p is 0, 1, or 2;
    -q is 0, 1, or 2;
    - cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a;
    - R1 is selected from alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-hetero alkyl, heterocycleheteroalkenyl, and heterocycle-heteroalkynyl;
    and wherein said alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl,
    323 arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three Z1b;
    - R2 is selected from hydrogen, -C(O)Z3, aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;
    and wherein said aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, are optionally substituted with one, two, or three Z1c;
    - each R3 is independently selected from hydrogen and Z1;
    - each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, -S(=O)Z2, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4ZS, -C(=O)H, aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocyclealkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    and wherein said aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl are optionally substituted with one, two, or three substituents selected from aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, cyano, nitro, -C(=O)OH, -C(O)Oalkyl, and -N(CH3)2, -NH2, -NHC(=O)O-ClJtalkyl, -O-alkyl;
    - each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZz, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl;
    and wherein said aikyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl,
    324 heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)0H, -C(O)Oalkyl, -NH2, -NHCH3; N(CH3)2, -NH-C(=O)O-C.Malkyl1 morpholinyl, -S(O)2C1.4alkyl, and -O-alkyl;
    - each Z2 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-alkyl, -OCF3, -S(=O)2Cwalkyl, cyano, nitro, -C(=O)OH, -C^OJO-C^alkyl, -NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
    - each Z3 is independently selected from hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, C(=O)OH, -NH21 and -N(CH3)2;
    - each Z4 and Z5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,
    325 heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, or -NH2;
    and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(=0)0H, or-NH2;
    and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof.
  3. - 3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-212);
    3. A compound of formula (B), wherein
    - each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
    - each of X1, X2, X3, X5, X6, X7, and X8 is independently selected from CR3, N, NR4, O, and S;
    - each of X4 and X9 is independently selected from C, CH, and N;
    - X10 îs selected from C, CH, and N;
    whereby at least five of X1 to X10 are selected from CR3, C, and CH; and at least one of X1 to X10 is a heteroatom;
    - p is 0, 1, or 2;
    - q is 0, 1, or 2;
    - cycle B is selected from aryl and heterocycle, wherein said aryl and heterocycle are optionally substituted with one, two, or three Z1a;
    - R1 is selected from alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl,
    326 arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-hetero alkyl, heterocycleheteroalkenyl, and heterocycle-heteroalkynyl;
    and wherein said alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three Z1b;
    - R2 is selected from hydrogen, -C(O)Z3, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;
    and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, are optionally substituted with one, two, or three Z1c;
    - each R3 is independently selected from hydrogen and Z1;
    - each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, -S(=O)Z2, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocyclealkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and hetero cycl e- heteroa I ky ny I ;
    and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF31 cyano, nitro, -C(=O)OH, -C(O)Oalkyl, and -N(CH3)2, -NH2, -NHC^OJO-CMalkyl, -O-alkyl;
    - each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)zNZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl,
    327 heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl;
    and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -0-C(0)Me, cyano, nitro, -C(O)OH, -C(O)Oalkyl, -NH2, -NHCH3; N(CH3)21 -NH-C(=O)O-CMalkyi, morpholinyl, -S(O)2ClJ(alkyl, and -O-alkyl;
    - each Zz is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-alkyl, -OCF3, -S(=O)2C1_4alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-ClJtalkyl, -NH2, and -N(CH3)2| pyrrolidinyl, piperidinyl, and piperazinyl;
    - each Z3 is independently selected from hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF31 cyano, nitro, C(=O)OH, -NH2, and -N(CH3)2;
    - each Z4 and Z5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,
    328 heteroalkenyl, heteroalkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycleheteroalkynyl;
    wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, and heterocycle-heteroalkynyl, are optionally substituted with one, two, or three substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, or -NH2;
    and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which is optionally substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, -SH, trifluoromethyl, -O-alkyl, -OCF3, cyano, nitro, -C(=O)OH, or -NH2;
    and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof;
    with the proviso that compound per se of formula (B) is not
    - N-( 5-(2-(7-ethyl-1 H-indol-3-yl)-2-oxo-1 -phenylethylamîno)-2-methoxyphenyl)methanesulfonamide (CAS nr. 1294288-37-1);
  4. 4. The compound of formula (B) according to any one of claims 1-3, for use in the prévention or treatment of a flavivirus infection in an animal, mammal or human; for use as a medicine; or per se; wherein
    H ; wherein the wavy line ( JVW J indicates the point of attachment to the carbonyl of the main formula (B); wherein said moiety is 5 optîonally substituted with one or two Z1;
    - cycle B is selected from
    330 wherein the wavy line (—) indicates the point of attachment to the carbon atom of the main formula (B), and wherein the depicted cycles may be optîonally substituted with one, two, or three Z1a;
    - R1 is selected from C^alkyl, C3.7cycloalkyl, aryl, heterocycle;
    and wherein said C^alkyl, C3.7cycloalkyl, aryl, and heterocycle, are optîonally substituted with one, two, or three Z1b;
    - R2 is selected from hydrogen, -C(O)Z3, and C^alkyl;
    and wherein said C^alkyl is optîonally substituted with one, two, or three Z1c;
    - each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ2, -O-C(=O)Z3, =0, -SZ2, =S, -S(=O)Z2, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z5, -NZ4S(=O)2Z2, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, NZ4C(=O)NZ4Z5, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, -C(=O)H, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-C^alkyl;
    and wherein said C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Cvealkyl, are optîonally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -0(0)00,. 6alkyl, -NHZ, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl; -S(O)2CMalkyl, and -O-C^alkyl;
    - each Z2 is independently selected from C^alkyl, aryl, heterocycle, and heterocycle-C^alkyl;
    wherein said C,.6alkyl, aryl, heterocycle, and heterocycle-ClJ6alkyl, are optîonally substituted with one, two, or three substituents selected from hydroxyl, =0, halogen, SH, =S, trifluoromethyl, difluoromethyl, -O-C^alkyl, -OCF3, -S(=O)2Ci^alkyl, cyano, nitro, -C(=0)0H, -C(=O)O-CMalkyl, -NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
    331
    - each Z3 is independently selected from hydroxyl, C^alkyl, aryl, and heterocycle;
    wherein said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
    - each Z4 and Z5 is independently selected from hydrogen, C^alkyl, aryl, C3.7cycloalkyl, and heterocycle;
    and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof;
  5. 5. The compound of formula (B) according to any one of daims 1-4, for use in the prévention or treatment of a flavivirus infection in an animal, mammal or human; for use as a medicine; or per se; wherein
    - each Z1, Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =O, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, heteroC^alkyl, aryl, heterocycle, and heterocycle-Cvealkyl;
    and wherein said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -O-C(O)Me, cyano, -C(O)OH, C(O)OC^alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl; -S(O)2CMalkyl, and -OC^alkyl;
    - each Z2 is independently selected from C^alkyl, aryl, and heterocycle-C^alkyl;
    wherein said C^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-Ci^alkyl, -S(=O)2CV 4alkyl, -C(=O)OH, -C(=O)O-CMalkyl, -NH2, and -N(CH3)21 pyrrolidinyl, piperidînyl, and piperazinyl;
    - each Z3 is independently selected from hydroxyl, C^alkyl, and heterocycle;
    wherein said C^ealkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
    - each Z4 and Zs is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl;
    and isomers (in particular stereo-isomers or tautomers), solvatés, salts (in particular
    332 pharmaceutically acceptable salts) or prodrugs thereof;
  6. 6. The compound according to any one of claims 1-5, wherein the compound has the structure of formula (D), (D) wherein
    - each dotted line represents an optional double bond whereby maximally 6 non-adjacent dotted lines can form a double bond;
    - each of X1, X2, X3, X5, X6, X7, and Xe is independently selected from CR3, N, NR4, O, and S;
    - each of X4 and X9 is independently selected from C, CH, and N;
    whereby at least five of X1 to X9 are selected from CR3, C, and CH; and at least one of X1 to X9 is a heteroatom;
    - p is 0, 1, or 2;
    - q is 0, 1, or 2;
    - cycle B, R1, and R2 are as defined in any one of claims 1-5.
  7. 7. The compound of formula (D) according to claim 6, wherein
    333 substituted with one or two Z1;
    ί^Ν υχτυ cycle B is selected from the point of attachment to the carbon atom
  8. 8. The compound according to any one of daims 1-7, wherein the compound has the structure of formula (G), wherein cycle B, R1, R2, X1, Z1, and R4 are as defined in any one of daims 1-7, and n is selected from 0; 1; 2 and 3.
  9. 9. The compound according to any one of daims 1-8, wherein the compound has the structure of formula (H), (H) wherein
    - cycle B, each Z1 independently, and each Z1b independently, are as defined in any one of daims 1-5;
    - m is selected from 0, 1, 2, and 3;
    - n is selected from 0, 1, 2, and 3; and
    - X1 and X2, are as defined in any one daims 6-8.
  10. 10. The compound according to any one of daims 1-9, wherein the compound has the structure of formula (I), (l) wherein
    - each Z1 independently, and each Z1b independently, are as defined in any one of claims 1-5;
    - cycle B is selected from aryl and heteroaryl; wherein said aryl, heteroaryl may optionally be substituted with halogen, C^alkyl, or C1.4alkoxy;
    - n is selected from 0, 1, 2, and 3; and
    - m is selected from 0,1,2, and 3;
    10 of the main formula (A), and wherein the depicted cycles may be optionally substituted with one, two, or three Z1a;
    334
    - Z1b, is selected from the group consisting of halogen, hydroxyl, -OZ2, =0, -S(=O)2Z3, S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, -NZ4Z5, -NZ4C(=O)Z2, cyano, -C(=O)Z3, C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, aryl, and heterocycle;
    and wherein said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -O-C(O)Me, cyano, -C(O)OH,, -NHCH3; -N(CH3)2, -S(O)2Ci_4alkyl, and — O-C^alkyl;
    - R2 is selected from hydrogen, -C(O)Z3, and Cvealkyl; wherein said C^alkyl is optionally substituted with one, two, or three Z1c;
    - each Z1, Z1a, and Z1c is independently selected from the group consisting of halogen, hydroxyl, -OZ2, -O-C(=O)Z3, =0, -S(=O)2Z3, -S(=O)2NZ4Z5, trifluoromethyl, trifluoromethoxy, NZ4Z5, -NZ4C(=O)Z2, -NZ4C(=O)-OZ2, cyano, -C(=O)Z3, -C(=O)OZ2, -C(=O)NZ4Z5, C^alkyl, heteroCi^alkyl, aryl, heterocycle, and heterocycle-Ci.6alkyl;
    wherein said C^alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, =0, -O-C(O)Me, cyano, -C(O)OH, -0(0)00;. 6alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-CMalkyl, morpholînyl, -S(O)2CMalkyl, and -O-C^alkyl;
    - Z2 is independently selected from C^alkyl, aryl, and heterocycle-C^alkyl;
    wherein said C^alkyl, and aryl, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C^alkyl, -S(=O)2Ci. 4alkyl, -C(=O)OH, -C(=O)O-CMalkyl, -NH2, and -N(CH3)2, pyrrolidinyl, piperidinyl, and piperazinyl;
    - Z3 is independently selected from hydroxyl, Ci.6alkyl, and heterocycle;
    335 wherein said C^lkyl and heterocycle are optionally substituted with one, two, or three substituents selected from C^alkyl and -N(CH3)2;
    - each Z4 and Z5 is independently selected from hydrogen, C^alkyl, and C3.7cycloalkyl.
  11. 11. The compound according to any one of claims 1-10, wherein the carbon atom substituted with cycle B is in the R configuration.
  12. 12. The compound according to any one of claims 1-10, wherein the carbon atom substituted with cycle B is in the S configuration.
  13. 13. The compound according to claim 1, wherein the flavivirus infection is an infection with a Dengue virus or a yellow fever virus.
  14. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingrédient an effective amount of the compound according to any one of claims 1-12 or a pharmaceutically acceptable sait thereof.
    15. A method for the préparation of the compound according to any one of claims 1-12 comprising the step of
    - reacting compound of formula (X1) with the amine R1R2NH in a suitable solvent, wherein cycle A, cycle B, R1, and R2 hâve the meaning according to any one of the embodiments presented herein, and LG is a leaving group as known by the skilled in the art, preferably selected from chlorine, bromine, and iodine; or
    - reacting the imine of formula (X2) with an aldéhyde of formula (X3) in the presence of a catalyst and a suitable solvent to obtain compound of formula (A1), wherein cycle A, cycle 5 B, and R1, hâve the meaning according to any one of the embodiments presented herein, and provided that in cycle A of formulae (X3) and (A1), a carbon atom is binding to the carbonyl.
    16. The use of a compound according to any one of claims 1-12 or a pharmaceutically acceptable sait thereof in a method of manufacturing a médicament for use in a method of treatment or prévention of Flaviviral infections in humans.
  15. 15 17. The use according to claim 16, wherein the Flaviviral infection is an infection by the Dengue virus or yellow fever virus.
OA1201400135 2011-09-26 2012-09-26 Viral replication inhibitors. OA16765A (en)

Applications Claiming Priority (2)

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US61/626,410 2011-09-26
GB1116559.4 2011-09-26

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OA16765A true OA16765A (en) 2015-12-14

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