Patent Application
20120053170
The present invention relates to nicotinamide derivatives, to the compositions comprising them and to their therapeutic application, in particular as anticancer drugs. The invention also relates to the process for the preparation of these compounds and to some of the intermediates.
International Application WO 2005/051366 describes compounds of general formula (A):
in which Z represents a phenyl or indanyl group and not a pyridinyl group.
International Application WO 2007/016538 describes compounds of general formula (B):
in which Q can represent an R13—NR12—C(═O)— group, it being possible for R13 to be a 2-, 3- or 4-pyridinyl group, R4 and R5 representing a hydrogen atom or an alkyl, alkoxy, —OH, —CF3 or —CN group. These compounds are used in the treatment of obesity.
In the context of the present invention:
According to a 1st aspect, a subject-matter of the present invention is a compound of formula (I):
in which:
R1 represents a hydrogen atom, a (C1-C6)alkyl group, a (C3-C6)cycloalkyl group, for example a cyclopropyl group, or a phenyl group. R′1 represents a hydrogen atom or a (C1-C6)alkyl group. More particularly, R′1 represents a hydrogen atom. R1 and/or R′1 can be chosen from those described in Table I.
R2 represents:
The heterocycloalkyl group formed by Ra and Rb can, for example, be the pyrrolidinyl
piperidinyl
piperazinyl
or N—(C1-C4 alkyl)piperazinyl
in particular N-methylpiperazinyl, azepanyl
thiomorpholinyl
1-oxothiomorpholinyl
or 1,1-dioxothiomorpholinyl
group.
The heterocycloalkyl group formed by Ra and Rb can optionally be substituted by one or more substituent(s), identical to or different from one another when there are several of them, chosen from: —OH; (C1-C4)alkoxy: for example methoxy; or (C1-C4)alkyl: for example methyl.
Thus, the substituted heterocycloalkyl can be the 3-hydroxypiperidinyl
or 4-hydroxypiperidinyl
4-methoxypiperidinyl
cis-3,5-dimethylpiperidinyl
or cis-2,6-dimethylpiperidinyl
group.
R2 can be chosen from one of those described in Table I.
The pyridine nucleus can comprise from 1 to 4 R3 substituents chosen from a hydrogen atom, a fluorine atom, a (C1-C4)alkyl group or an —NRcRd group in which Rc and Rd represent a hydrogen atom or a (C1-C4)alkyl group. R3 can be chosen from those described in Table I. Preferably, R3 is in the 5 and/or 6 position on the pyridine nucleus. Preferably, the number of R3 substituents is equal to 1 and/or R3 is in the 5 or 6 position on the pyridine nucleus, as is represented below:
R3 is more preferably still in the 6 position. Preferably. R3 represents a hydrogen atom or —NH2.
L represents a —CH═CH— or —(CH2)nNH— group in which the NH group is attached to the C═O and n is an integer having the value 0, 1 or 2. Preferably, n is equal to 1. L can be one of those described in Table I. Preference is also given, in the case where L represents the —CH═CH— group, to the E isomers rather than the Z isomers.
Z and Z′ represent N or CH. For example, Z and Z′ can respectively represent N and CH, CH and CH or N and N:
x is an integer having the value 1 or 2, representing the number of fluorine atom(s) attached to the central phenyl nucleus. More particularly, x has the value 1.
The subgroup of formula (I′):
in which R1, R′1, R2, R3 and x are as defined above, is singled out.
The subgroup of formula (I″):
in which R1 represents a (C1-C4)alkyl group, R2 represents a (C1-C6)alkyl group optionally substituted by the —NRaRb group in which Ra and Rb form, together with the nitrogen atom to which they are connected, the (C4-C6)heterocycloalkyl group optionally comprising, in the ring, the —S(O)q— group with q=0, 1 or 2 or the —NH— or —N(C1-C4 alkyl)- group and R3 and x are as defined above, is singled out. More particularly, x has the value 1. More particularly still, x has the value 1 and the fluorine atom is in the 3 position.
Mention may be made, among the compounds which are subject-matters of the invention, of those in Table I.
The compounds of the invention, including the compounds given in the examples, can exist in the form of bases or of addition salts with acids. Such addition salts also come within the invention. These salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids, for example of use in the purification or isolation of the compounds, also come within the invention. The compounds according to the invention can also exist in the form of hydrates or solvates, namely in the form of combinations or associations with one or more molecules of water or with a solvent. Such hydrates and solvates also come within the invention.
The compounds can comprise one or more asymmetric carbon atoms. They can thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and their mixtures, come within the invention.
According to the present invention, the N-oxides of the compounds comprising an amine or a nitrogen atom also come within the invention.
According to a 2nd aspect, a subject-matter of the invention is the process for the preparation of the compounds of the invention and some of the reaction intermediates.
Preparation of the Compounds of Formula (I) or (I′) for which L=—(CH2)nNH—
These compounds can be prepared according to one of the following schemes 1-3.
A coupling of Suzuki type of P1 and P2 is carried out. Hal represents a halogen atom (chlorine, bromine, iodine). The coupling is carried out in the presence of a palladium (in the (0) or (II) oxidation state) complex in a basic medium. The complex can, for example, be Pd(PPh3)4, PdCl2(PPh3)2, Pd(OAc), PdCl2(dppf) or bis[di(tert-butyl)(4-dimethylaminophenyl)-phosphine]dichloropalladium(II). The most frequently used complexes are palladium(0) complexes. The base can, for example, be K2CO3, NaHCO3, Et3N, K3PO4, Ba(OH)2, NaOH, KF, CsF, Cs2CO3, and the like. The coupling can be carried out in a mixture of an ethereal solvent and of an alcohol, for example a dimethoxyethane (DME)/ethanol mixture; it can also be a toluene/water mixture. The temperature is between 50 and 120° C. The reaction time can, in some cases, be lengthy (see Ex. 1.3.).
Further details on Suzuki coupling, on the operating conditions and on the palladium complexes which can be used will be found in: N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483; A. Suzuki in “Metal-catalyzed cross-coupling reactions”; Diederich. F. and Stang, P. J., Editors, Wiley-VCH; Weinhein, Germany, 1998, chap. 2, 49-97; Littke, A. and Fu, G., Angew. Chem. Int. Ed., 1999, 38, 3387-3388 and Chemler, S. R. Angew. Chem. Int. Ed., 2001, 40, 4544-4568.
K and K′ represent a hydrogen atom, an alkyl group or an aryl group which are optionally connected to one another to form, together with the boron atom and the two oxygen atoms, a 5- to 7-membered ring optionally substituted by at least one (C1-C4)alkyl group or to which is optionally fused, over two consecutive carbon atoms on the said ring, a phenyl group. For example, use may be made of one of the following groups:
According to Scheme 2, a Suzuki coupling (see above) is carried out between P1 and P3, in order to obtain P4, and then P4 is reacted with P5 in the presence of an agent which makes it possible to introduce the “C═O” unit (for example phosgene, triphosgene or N,N′-disuccinimidyl carbonate DSC). The reaction which makes it possible to introduce “C═O” is preferably carried out in the presence of a base, such as, for example, triethylannine, and at a temperature of between −5° C. and ambient temperature. The solvent can be THF. See Ex. 1.4.
According to Scheme 3, the compound of formula (I) is obtained by an amidation reaction starting from P6 and the amine R2NH2 or a salt of this amine, for example hydrochloride (see Ex. 3.2). The amidation can advantageously be carried out in the presence of an acid activator (also known as coupling agent), such as, for example, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6, see also B. Castro and J. R. Dormoy, Tetrahedron Letters, 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylannine) at ambient temperature in a solvent, such as tetrahydrofuran (THE) or dimethylformamide (DMF).
P6 is, for its part, obtained by a coupling reaction of Suzuki type between P2 and the compound P8 of formula:
according to a scheme similar to Scheme 1.
P8 is obtained from the acid P7 by monosubstitution by an amine of formula R1R′1NH. In the case of an aliphatic amine, the reaction can be carried out at ambient temperature and in a protic solvent, such as an alcohol or water, or in an aprotic solvent, such as THF. In the case of an aniline, a strong base, such as, for example, LiHMDS (((CH3)3Si)2NLi), is added, and the reaction is carried out under hot conditions. The monosubstitution is described on pages 14 and 15 of FR 2917412, in the case where Z═N and Z′═CH, but can be applied to other Z/Z′ combinations. See also Ex. 1.1.
In the case where Z and Z′ both represent N and Hal represents a chlorine atom. P8 can also be obtained from the commercial compound 2,4-dichloro-5-pyrimidinecarboxylic acid ethyl ester:
Scheme 5, which uses an ester functional group subsequently converted to an acid functional group, also applies to the case where Z═N and Z′═CH: see the conditions in Chem. Pharm. Bull., 2000, 48(12), 1847-1853 (reactions of Tables 1 and 2).
P1 is obtained from the acid P8 by amidation using the amine R2NH2 or a salt of this amine, for example the hydrochloride. The amidation can advantageously be carried out in the presence of an acid activator (also known as coupling agent), such as, for example, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6, see also Castro. B. and Dormoy, J. R. Tetrahedron Letters, 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylamine) at ambient temperature in a solvent, such as tetrahydrofuran (THF) or dimethylformamide (DMF). See Ex. 1.2.
The compounds P3 for which K and K′ form the following group
are commercially available or can be prepared according to the coupling reaction between a fluorinated bromoaniline and bis(pinacolato)diboron which is described in Scheme 2 on pages 150-151 of WO 2007/064931: 3-F(4-amino-3-fluorophenylboronic acid pinacol ester, CAS No. 819058-34-9, Boron Molecular Inc., PO Box 12592, Research Triangle Park, NC 27709); 2-F (4-amino-2-fluorophenylboronic acid pinacol ester, CAS No. 819057-45-9, Boron Molecular, described on page 185 of WO 2007/064931); 2-F, 5-F (CAS No. 939807-75-7, compound described on page 184 of WO 2007/064931); 3-F, 5-F (CAS No. 939968-08-8, described on page 182 of WO 2007/064931).
The compounds P3 for which K and K′ represent a hydrogen atom can be prepared from the fluorinated bromoaniline by the reactions described in Tetrahedron Letters, 2003, 44, 7719-7722.
The compounds P2 are obtained from the compounds P3 and P5 in the presence of an agent which makes it possible to introduce the “C═O” unit, according to a reaction as described above.
The amines R2NH2 are commercial products or products already described in published documents; for example:
A method for producing compounds in which R2 represents a (C1-C6)alkyl group substituted by the —NRaRb group in which Ra and Rb form, together with the nitrogen atom to which they are connected, the (C4-C6)heterocycloalkyl group optionally comprising, in the ring, the —S(O)q— group with q=0, 1 or 2 or the —NH— or —N(C1-C4 alkyl)- group is described in Scheme 6, which takes its inspiration from Scheme 3 of Bioorg. Med. Chem., 2007, 15, 365-373 or from Scheme 2 of Bioorg. Med. Chem. Lett., 2008, 18, 1378-1381:
Another method, described in Scheme 6′, takes its inspiration from FIG. 2 of Bioorg. Med. Chem. Lett., 2006, 16, 1938-1940:
P5 can be either commercially available or prepared according to the methods known to a person skilled in the art. Use may be made, for example, of the hydrogenation of the cyano compound in order to obtain P5 with n=1:
The hydrogenation conditions may be those described in Ex. 19 and 20 of WO 00/46179 or in Synlett, 2001, 10, 1623-1625.
The compounds 3-picolylamine (CAS No. 3731-52-0), 3-(2-aminoethyl)pyridine (CAS No. 20173-24-4), 2-amino-5-aminomethylpyridine (CAS No. 156973-09-0), 2-methyl-5-aminomethylpyridine (CAS No. 56622-54-9), 3-methyl-5-aminomethylpyridine (CAS No. 771574-45-9), 2-(BOC-amino)-5-(aminomethyl)pyridine (CAS No. 187237-37-2) and 2,5-diaminopyridine (CAS No. 4318-76-7) are commercial products. 2-Amino-5-aminomethylpyridine can also be prepared according to EP 0607804. 5-Aminomethyl-2-(dimethylamino)pyridine (CAS No. 354824-17-2) is commercially available or can be prepared according to J. Agr. Food Chem., 2008, 56(1), 204-212. 2-Amino-3-methyl-5-aminomethylpyridine (CAS No. 187163-76-4) can be obtained by catalytic hydrogenation of the compound 6-amino-5-methylnicotinonitrile (CAS No. 183428-91-3), the amine functional group being doubly protected by BOC. The catalytic hydrogenation of 6-methylamino-3-pyridinecarbonitrile (CAS No. 261715-36-0) makes possible access to 2-methylamino-5-aminomethylpyridine.
The preparation of 5-aminomethyl-2-(dimethylamino)pyridine (CAS No. 779324-37-7) and of 5-aminomethyl-2-(dimethylamino)pyridine (CAS No. 354824-17-2) in the hydrochloride form is also described on page 106 of WO 2007/044449 (Ex. 207 and 208).
Preparation of the Compounds of Formula (I) in which L=—CH═CH—
These compounds are obtained by an amidation reaction between P4 and the acid P10 or the acyl halide P′10 derived from P10. The amidation using P10 can advantageously be carried out in the presence of an acid activator, such as, for example, BOP.
P10 can be either commercially available or prepared according to the methods known to a person skilled in the art. For example, trans-3-(3-pyridyl)acrylic acid is sold by Sigma-Aldrich. (6-Aminopyridin-3-yl)acrylic acid (CAS No. 234098-57-8; compound E: CAS No. 167837-43-6) is described in J. Med. Chem., 2002, 45(15), 3246-3256 (see Scheme 4). P10 can be prepared from a bromoaniline and acrylic acid according to the teaching of J. Med. Chem., 2002, 45(15), 3246-3256. Use may also be made of a coupling using a bromoaniline and an alkyl acrylate and then the ester functional group can be saponified to give the acid functional group (see, in this connection, the method which makes it possible to prepare (6-aminopyridin-3-yl)acrylic acid described in section [483] of US 2008269220 or [354] of EP1726580).
P10 can also be prepared according to J. Org. Chem., 1998, 63, 8785-8789, from the corresponding β-formylpyridine or else according to J. Med. Chem., 1989, 32(3), 583-93 from 2-chloro-5-nitropyridine. The acyl halide P′10 is obtained by a reaction known to a person skilled in the art from the acid P10 and an acylating agent, such as, for example, SOCl2 or (COCl)2.
These compounds can also be prepared according to the following scheme 8:
According to Scheme 8, P4 is reacted with acryloyl chloride in the presence of a base, such as, for example, triethylamine, and at a temperature of between 0° C. and ambient temperature, in order to produce P11. The solvent can be dichloromethane (DCM) (see Ex. 4.1).
P11 is then reacted with P12 (Hal represents a halogen atom) in the presence of a palladium complex, such as, for example, Pd(OAc)2, tri(ortho-tolyl)phosphine and a base, such as, for example, diisopropylethylamine. The solvent can, for example, be propionitrile. The temperature is between ambient temperature and the reflux temperature of the solvent.
It may be necessary to use, in at least one of the stages, a protective group (PG) in order to protect one or more chemical functional group(s), in particular a primary or secondary amine functional group. For example, when Ra and Rb both represent a hydrogen atom, the amidation of Scheme 3 is carried out using, for R2NH2, the compound 2HN—(C1-C6)alkyl-NH-PG, where PG advantageously represents BOC (tert-butoxycarbonyl). Likewise, when the heterocycloalkyl group formed by Ra and Rb represents the piperazinyl
group, the —NH— functional group thereof can advantageously be protected using the following compound R2NH2
where PG advantageously represents BOC. Likewise, when R3 represents the —NH2 or —NHRc group, the amine functional group can advantageously be protected by one or two PG group(s), preferably BOC or FMOC (9-fluorenylmethyl carbamate). Use may be made, for example, of the following compound P5:
or else of the following compounds P10 or P′10:
The chemical functional group(s) is/are subsequently obtained by a stage of deprotection (final or intermediate), the conditions of which depend on the nature of the functional group(s) protected and on the protective group used. Reference may be made to “Protective Groups in Organic Synthesis” by T. Greene, Wiley, 4th ed., ISBN=978-0-471-69754-1, in particular to chap. 7 as regards the protective groups for the amine functional group. In the case of the protection of the —NH2 or —NH— functional groups by BOC, the deprotection stage is carried out in an acidic medium using, for example. HCl or trifluoroacetic acid (TFA). Thus, if appropriate, the associated salt (hydrochloride or trifluoroacetate) is obtained.
The salts are obtained during the deprotection stage described above or else by bringing the acid into contact with the compound in its base form.
In the preceding Schemes, the starting compounds and the reactants, when their method of preparation is not described, are commercially available or are described in the literature or else can be prepared according to methods which are described therein or which are known to a person skilled in the art. A person skilled in the art may also take his inspiration from the operating conditions given in the examples which are described below.
The N-oxides of the compounds comprising an amine or a nitrogen atom are prepared according to the methods known to a person skilled in the art by reaction of the amine with organic peracids, such as peracetic acid, trifluoroperacetic acid, performic acid, perbenzoic acid or the derivatives of perbenzoic acid, such as 3-chloroperbenzoic acid, at temperatures of between 0° C. and 90° C., preferably at temperatures of less than 50° C.
According to a 3rd aspect, the invention relates to a pharmaceutical composition comprising a compound as defined above in combination with a pharmaceutically acceptable excipient. The excipient is chosen from the normal excipients known to a person skilled in the art according to the pharmaceutical form and the method of administration desired. The method of administration can, for example, be orally or intravenously.
According to a 4th aspect, a subject-matter of the invention is a medicament which comprises a compound as defined above and the use of a compound as defined above in the manufacture of a medicament. It may be of use in treating a pathological condition, in particular cancer. The medicament (and a compound according to the invention) can be administered in combination with one (or more) anticancer drug(s). This treatment can be administered simultaneously, separately or else sequentially. The treatment will be adjusted by the practitioner according to the patient and the tumour to be treated.
According to a 5th aspect, the invention also relates to a method for the treatment of the pathologies indicated above which comprises the administration, to a patient, of an effective dose of a compound according to the invention or one of its salts, the salts being pharmaceutically acceptable, or hydrates or solvates.
The following examples illustrate the preparation of some compounds in accordance with the invention. The numbers of the compounds given in the examples refer to those given in the table below, in which the chemical structures and the physical properties of a few compounds according to the invention are illustrated.
In the examples, the following abbreviations are used:
AcOEt: ethyl acetate
MeOH: methanol
DIPEA: diisopropylethylamine
The compounds were analysed by coupled HPLC-UV-MS (liquid chromatography, ultraviolet (UV) detection and mass detection). The device used is composed of an Agilent chromatographic sequence equipped with an Agilent diode array detector and with a Waters ZQ single quadrupole mass spectrometer or a Waters Quattro-Micro triple quadrupole mass spectrometer.
The compounds were analysed by coupled HPLC-UV-MS (liquid chromatography, ultraviolet (UV) detection and mass detection). The device used is composed of a chromatographic sequence equipped with a diode array detector (Agilent HP1110 or Waters Acquity HPLC) and with a quadrupole mass spectrometer (Waters ZQ, QM or SQD).
The liquid phase chromatography/mass spectrometer (LC/MS) spectra were recorded in positive electrospray (ESI) mode, in order to observe the ions resulting from the protonation of compounds analysed (MH+) or from the formation of adducts with other cations, such as Na+, K+, and the like. The HPLC conditions are chosen from one of the following methods:
10:90
5.95
5.95 (4.8
10:90 (15
5:95 (2.9 min)
5:95 (6 min)
100:0 or
100:0 (16 min)
100:0
100:0 or 99:1
100:0 (20 min)
The 1H NMR spectra are recorded on a Bruker Avance 250/Bruker Avance 400 or Bruker Avance II 500 spectrometer. The central peak of the d6-DMSO (2.50 ppm) is used as internal reference. The following abbreviations are used: s: singlet; d: doublet; dd: split doublet; t: triplet; q; quartet; m: broad unresolved peak/multiplet; br.s: broad signal.
26.1 g (0.136 mol) of 2,6-dichloronicotinic acid and 180 ml of 70% aqueous ethylamine solution are mixed in a round-bottom flask. The mixture is stirred at ambient temperature (AT) for 5 days. It is evaporated under reduced pressure (RP). The residue is taken up in 100 ml of water. The solution is cooled with an ice bath and acidified to pH 3 with a 5N HCl solution. The precipitate is filtered off, washed with cold water and dried under vacuum over P2O5 at 60° C. 24.93 g (91.4%) of white solid are obtained. M.p.=157-159° C.
5.0 g (24.92 mmol) of 6-chloro-2-(ethylamino)nicotinic acid are dissolved in 300 ml of THF in a round-bottom flask. 10.41 ml (74.77 mmol) of triethylamine, then 7.08 ml (49.84 mmol) of 1-(2-aminoethyl)piperidine and subsequently 11.02 g (24.92 mmol) of BOP are added. The mixture is stirred at AT for 15 h. The solvent is evaporated and the residue is taken up in ethyl acetate. The organic phase is washed with water and then with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (1 to 10% DCM-MeOH gradient). 7.5 g are obtained (yd: 96.8%). LCMS: M+ 310, rt (retention time)=1.01 min.
5 g (16.1 mmol) of 6-chloro-2-ethylamino-N-[2-(piperidin-1-yl)ethyl]nicotinamide are introduced into a 1 litre three-necked flask. 4-Amino-3-fluorophenylboronic acid pinacol ester (1.1 eq., 4.2 g), 300 ml of 1,2-dimethoxyethane, 60 ml of ethanol and 120 ml of a saturated NaHCO3 solution are added. Argon is bubbled in for 15 min and then palladiumtetrakis Pd(PPh)4 (0.1 eq., 1.86 g) is added. The mixture is heated at reflux (˜100° C.) for 16 h. The mixture is concentrated, the residue is taken up in DCM and the organic phase is washed with H2O, twice, and H2O/NaCl, dried over sodium sulphate and concentrated. The product is subjected to flash chromatography on a column of silica, 400 g, 99/1 to 90/10 DCM/methanol gradient, 4.8 g (yd=78%) of 6-(4-amino-3-fluorophenyl)-2-ethylamino-N-[2-(piperidin-1-yl)ethyl]nicotinamide are obtained. LCMS (TFA3): MH+ 386, rt=0.90 min.
3.5 g (9.1 mmol) of 6-(4-amino-3-fluorophenyl)-2-ethylamino-N-[2-(piperidin-1-yl)ethyl]-nicotinamide are dissolved in 300 ml of anhydrous THF in a 1 litre round-bottom flask. DMAP (1.2 eq., 1.33 g) and N,N′-disuccinimidyl carbonate ([74124-79-1], 1.2 eq., 2.8 g) are added. The mixture is stirred at AT for 5 h. Triethylannine (3 eq., 3.8 ml) and 2-[di(boc)amino]-5-(aminomethyl)pyridine (1.2 eq., 3.53 g) are then added and the mixture is stirred overnight at AT. The mixture is concentrated. The residue is taken up in DCM and the organic phase is washed with H2O, twice, and H2O/NaCl, dried and concentrated. The residue is subjected to flash chromatography on silica, 95/5 to 79/20 DCM/MeOH gradient+1% of 20% NH4OH. After concentrating, the fraction thus obtained is taken up in 200 ml of DCM and then 35 ml (50 eq.) of TFA are added under cold conditions. The mixture is stirred at AT until the “di(boc)amino” product has disappeared. The mixture is concentrated and then the residue is taken up in a 10% Na2CO3 solution. The organic phase is extracted with DCM and concentrated. The residue is crystallized from ethyl acetate under hot conditions. The product is filtered off, rinsed with AcOEt and dried in an oven. 3 g (yd=63%) of 6-{4-[3-(6-aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-yl)ethyl]nicotinamide are obtained, LCMS (TFA3): MH+ 535, rt=0.79 min; 1H NMR (250 MHz, d6-DMSO) δ ppm 1.22 (t, 3H), 1.29-1.68 (m, 6H), 2.26-2.47 (m, 6H), 3.28-3.42 (m, 2H), 3.43-3.62 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.79-8.07 (m, 4H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.49 (s, 1H). M.p. (melting point)=175-177° C.
0.5 g (2.49 mmol) of 6-chloro-2-(ethylamino)nicotinic acid is dissolved in 30 ml of THF. 1.04 ml (0.76 mmol) of triethylamine, 0.304 g (4.98 mmol) of 2-hydroxyethylamine and 1.10 g (2.49 mmol) of BOP are added. The mixture is stirred at AT for 70 h. The solvent is evaporated and the residue is taken up in ethyl acetate; the organic phase is washed with water and then with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (DCM/MeOH 1-5%). 600 mg (yd=99%) are obtained. LCMS (TFA3): MH+ 244, rt=1.03 min.
5.0 g (21.09 mmol) of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 3.09 g (25.31 mmol) of DMAP (4-dimethylaminopyridine) are dissolved in 500 ml of THF. 6.48 g (23.31 mmol) of DSC are added and the mixture is stirred at AT for 18 h. 8.81 ml (63.27 mmol) of triethylamine and 8.18 g (23.31 mmol) of di(tert-butyl) [5-(aminomethyl)pyridin-2-yl]imidodicarbonate are added. The mixture is stirred at AT for 5 h. The solvent is evaporated and the residue is taken up in DCM. The organic phase is washed with water and than with a saturated NaCl solution. It is dried over sodium sulphate, filtered and evaporated. The residue is purified by flash chromatography. 12 g of product composed of a 50/50 mixture of pinacolic ester and of boronic acid are obtained. LCMS (LS) MH+ 587, rt=6.17 min, and MH+ 505, rt=4.97 min.
0.3 g (1.23 mmol) of compound obtained in stage 2.1, 0.794 g (1.35 mmol) of compound obtained in stage 2.2, 15 ml of saturated NaHCO3 solution, 38 ml of DME and 7 ml of ethanol are placed in a three-necked flask. The mixture is degassed with argon and then 0.142 g (0.12 mmol) of Pd(PPh3)4 is added. The mixture is heated at reflux for 6 h. The solvents are evaporated and the residue is taken up in DCM. The organic phase is washed with water and then with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (DCM/MeOH 0-15%). 600 mg (yd=73%) are obtained. LCMS (TFA3): MH+ 668, rt=1.44 min.
0.6 g (0.9 mmol) of the compound obtained in stage 2.3 is dissolved in 20 ml of DCM. The solution is cooled with an ice bath and 2.08 ml (27 mmol) of TFA are added. The mixture is stirred at AT for 18 h. The solvents are evaporated and the residue is taken up in an Na2CO3 solution. The product is filtered off, rinsed with water and dried in an oven over P2O5. 200 mg (yd=47.6%) are obtained. LCMS (TFA3): MH+ 468, rt=0.72 min; 1H NMR (250 MHz, d6-DMSO) δ ppm 1.22 (t, 3H), 331 (s, 2H), 3.43-3.62 (m, 4H), 4.13 (d, 2H), 4.71 (t, 1H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.78-7.98 (m, 3H), 8.01 (d, 1H), 8.28 (t, 1H), 8.34-8.47 (m, 2H), 8.49 (d, 1H).
1.2 g (5.98 mmol) of 6-chloro-2-(ethylamino)nicotinic acid, 3.86 g (6.58 mmol) of di(tert-butyl) {5-[({[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl}amino)methyl]-pyridin-2-yl}imidodicarbonate, 80 ml of DME, 15 ml of ethanol and 40 ml of saturated NaHCO3 solution are placed in a three-necked flask. The mixture is degassed with argon and then heated at reflux for 18 h. The solvents are evaporated and the residue is taken up in water. The product is filtered off, rinsed with water and dried in an oven over P2O5. It is purified by flash chromatography. DCM/MeOH 1-20%. 1.8 g of a mixture of mono- and di(BOC) compounds are obtained. LCMS (LS) MH+ 525, rt=4.60 min, and MH+ 625, rt=5.59 min.
0.2 g (0.32 mmol) of the compound obtained in stage 3.1 is dissolved in 30 ml of THF. 0.115 g (0.64 mmol) of 2-(azepan-1-yl)ethanamine hydrochloride, 0.18 ml (0.13 mmol) of triethylannine and 0.142 g (0.32 mmol) of BOP are added. The mixture is stirred at AT for 18 h. It is evaporated, the residue is taken up in DCM and the organic phase is washed with water and then with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography. DCM/MeOH 0-10%. 0.250 g of a mono- and di(BOC) mixture is obtained. This product is dissolved in 15 ml of DCM, the solution is cooled with an ice bath and 0.5 ml of TFA is added. The mixture is stirred at AT for 18 h. It is evaporated and the residue is taken up in an Na2CO3 solution. The precipitate is filtered off, washed with water and dried in an oven over P2O5. 0.13 g (yd=7496) is obtained. LCMS (TFA3) MH+ 549, rt=0.85 min; 1H NMR (400 MHz, d6-DMSO) ppm 1.22 (t, 3H), 1.56 (m, 8H), 2.67 (m, 6H), 3.32 (m, 2H), 3.45-3.63 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.43 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.34 (d, 1H), 7.83-8.00 (m, 4H), 8.27 (t, 1H), 8.35 (t, 1 H), 8.41 (t, 1H), 8.49 (s, 1H).
0.385 g (1 mmol) of the compound obtained in stage 1.3 is dissolved in 20 ml of DCM. 0.28 ml (2 mmol) of triethylamine and 0.111 g (1.1 mmol) of DMAP are added, followed by 0.2 ml (2.2 mmol) of acryloyl chloride. The mixture is stirred at ambient temperature for 18 h. The solvents are evaporated and the residue is taken up in DCM. The organic phase is washed with an Na2CO3 solution and then with a saturated NaCl solution. It is dried over sodium sulphate and filtered and then the filtrate is evaporated. The residue is purified by flash chromatography (95/5/0.2 DCM/CH3OH/20% NH4OH). 0.195 g (44.4%) is obtained. LCMS (TFA3) MH+ 440, rt=2.44 min.
0.187 g (0.43 mmol) of the compound obtained in stage 4.1 is dissolved in 15 ml of propionitrile. 0.074 g (0.43 mmol) of 2-amino-5-bromopyridine and 0.11 ml (0.64 mmol) of DIPEA are added. The mixture is degassed with argon for 30 minutes and then 0.01 g (0.04 mmol) of Pd(OAc)2 and 0.022 g (0.07 mmol) of tri(ortho-tolyl)phosphine are added. The mixture is brought to reflux for 3 h. After returning to ambient temperature, the mixture is diluted with DCM and filtered through a Whatman filter. The filtrate is evaporated and the residue is purified by flash chromatography, 85/15/0.2 DCM/CH3OH/20% NH4OH. 0.120 g (53%) is obtained.
0.25 g (0.65 mmol) of the compound obtained in stage 1.3 is dissolved in 20 ml of DCM, and 0.27 ml (1.95 mmol) of triethylamine is added. The reaction medium is cooled in an ice bath and 0.163 g (0.97 mmol) of (E)-3-(pyridin-3-yl)acryloyl chloride is added dropwise. Stirring is carried out at ambient temperature for 18 h. The organic solution is washed with a 10% NaOH solution, dried over Na2SO4 and filtered and the filtrate is evaporated. The residue is purified by flash chromatography, SiO2, C18, CH3OH/H2O 50/50-90/10. 0.035 g (10.4%) is obtained.
0.35 g (0.55 mmol) of [5-(3-{4-[6-ethylamino-5-(2-(piperidin-1-yl)ethylcarbamoyl)pyridin-2-yl]-2-fluorophenyl}ureidomethyl)pyridin-2-yl]carbamic acid tert-butyl ester is suspended in 35 ml of DCM and 10 ml of CHCl3. The suspension is cooled with an ice bath and 0.105 g (0.61 mmol) of meta-chloroperbenzoic acid is added. The mixture is stirred under cold conditions for 0.5 h and then at ambient temperature for 2 h. The organic phase is washed with an NaHCO3 solution, then with H2O and then with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography on neutral Al2O3, DCM/CH3OH— 98/2 to 92/8. 0.340 g (94.7%) is obtained. LCMS (TFA3) MH+ 651, rt=2.07 min.
0.328 g (0.5 mmol) of the compound obtained in stage 6.1 is dissolved in 20 ml of CH2Cl2. The solution is cooled with an ice bath and 0.85 ml (11.1 mmol) of TEA is added. The mixture is stirred at ambient temperature for 44 h. It is evaporated and the residue is taken up in a 10% Na2CO3 solution and extracted with DCM. The organic phase is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography on neutral Al2O3, DCM/CH3OH-95/5 to 88/12. 0.213 g (76.9%) is obtained.
The chemical shifts 8 are given in ppm.
Compound No. 2: (400 MHz) 1.22 (t, 3H), 1.35-1.81 (m, 6H), 2.54-3.16 (m, 6H), 3.45-3.57 (m, 4H), 4.13 (d, 2H), 5.88 (s, 2H), 6.44 (d, 1H), 7.02-7.14 (m, 2H), 7.35 (dd, 1H), 7.85-7.92 (m, 2H), 7.98 (d, 1H), 8.16 (dd, 1H), 8.35 (t, 1H), 8.61 (br. s., 1H), 8.75 (s, 1H).
Compound No. 3: (250 MHz) 1.22 (t, 3H), 1.32-1.60 (m, 6H), 2.40-2.06 (m, 6H), 3.29-3.46 (m, 2H), 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1H), 7.35 (dd, 1H), 7.88 (d, 1H), 8.00-8.19 (m, 2H), 8.25-8.39 (m, 1H), 8.50-8.63 (m, 2H), 8.68 (s, 1H), 8.75 (t, 1 H).
Compound No. 4: (250 MHz) 1.22 (t, 3H), 1.32-1.60 (m, 6H), 2.40-2.65 (m, 6H), 3.29-3.46 (m, 2H), 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1H), 7.35 (dd, 1H), 7.88 (d, 1H), 8.00-8.19 (m, 2H), 8.25-8.39 (m, 1H), 8.50-8.63 (m, 2H), 8.68 (s, 1H), 8.75 (t, 1H).
Compound No. 5: (250 MHz) 1.28-1.65 (m, 6H), 2.32-2.47 (m, 6H), 3.35-3.52 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.02 (t, 2H), 7.26-7.52 (m, 4H), 7.75 (d, 2H), 7.82-8.04 (m, 3H), 8.16 (d, 1H), 8.34 (t, 1H), 8.53 (s, 1H), 8.69 (t, 1H), 11.06 (s, 1H).
Compound No. 6: (250 MHz) 0.97 (d, 6H), 1.21 (t, 3H), 1.57 (br. s., 1H), 2.58-2.87 (m, 3H), 3.23-3.34 (m, 2H), 3.43-3.61 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.80-8.10 (m, 4H), 8.28 (t, 1H), 8.34-8.48 (m, 2H), 8.51 (d, 1H).
Compound No. 7: (250 MHz) 1.22 (t, 3H), 2.66 (t, 2H), 2.89-3.17 (m, 8H), 3.31-3.42 (m, 2H), 3.45-3.61 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.17 (d, 1H), 7.35 (dd, 1H), 7.83-8.03 (m, 4H), 8.28 (t, 1H), 8.34-8.46 (m, 2H), 8.50 (d, 1H).
Compound No. 9: (250 MHz) 0.49-0.60 (m, 2H), 0.77-0.94 (m, 2H), 1.29-1.57 (m, 6H), 2.28-2.48 (m, 6H), 2.99-3.11 (m, 1H), 3.31-3.42 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1H), 7.36 (dd, 1H), 7.88 (d, 1H), 8.05-8.23 (m, 2H), 8.28-8.38 (m, 1H), 8.50-8.64 (m, 2H), 8.69 (s, 1H), 8.77 (d, 1H).
Compound No. 10: (250 MHz) 1.27-1.70 (m, 6H), 2.49-2.87 (m, 6H), 3.40-3.58 (m, 2H), 4.14 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.07 (t, 1H), 7.15 (t, 1H), 7.36 (dd, 1H), 7.40-7.50 (m, 2H), 7.77 (d, 2H), 7.88 (d, 1H), 8.03 (dd, 1H), 8.13 (dd, 1H), 8.38 (t, 1H), 8.63 (d, 1H), 8.81-9.04 (m, 2H), 11.15 (s, 1H).
Compound No. 11: (250 MHz) 1.20 (t, 3H), 1.29-1.66 (m, 6H), 2.11-2.47 (m, 6H), 3.25-3.40 (m, 2H), 3.42-3.62 (m, 2H), 4.11 (d, 2H), 5.76 (s, 2H), 6.43 (d, 1H), 6.61 (br. s., 1H), 6.97 (d, 1H), 7.12 (d, 1H), 7.35 (d, 1H), 7.62 (d, 1H), 7.77-8.05 (m, 3H), 8.28-8.48 (m, 2H), 8.91 (s, 1H).
Compound No. 12: (250 MHz) 1.22 (t, 3H), 1.57-1.86 (m, 4H), 2.43-2.52 (m, 4H), 2.57 (t, 2H), 3.29-3.43 (m, 2H), 3.43-3.60 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.80-8.04 (m, 4H), 8.28 (t, 1H), 8.35-8.48 (m, 2H), 8.51 (br. s., 1H).
Compound No. 13: (250 MHz) 1.22 (t, 3H), 2.75 (d, 3H), 3.43-3.66 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.82-8.04 (m, 4H), 8.28 (t, 1H), 8.35-8.62 (m, 3H).
Compound No. 14: (250 MHz) 1.22 (t, 3H), 3.27 (s, 3H), 3.35-3.62 (m, 6H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.37 (dd, 1H), 7.82-8.07 (m, 4H), 8.28 (t, 1H), 8.50 (br. s., 3H).
Compound No. 16: (400 MHz) 1.22 (t, 3H), 2.56 (t, 2H), 2.66-2.75 (m, 4H), 2.82-3.04 (m, 4H), 3.34-3.41 (m, 2H), 3.45-3.60 (m, 2H), 4.13 (d, 2H), 5.87 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1 H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.82-7.99 (m, 4H), 8.27 (t, 1H), 8.34-8.47 (m, 2H), 8.50 (d, 1H).
Compound No. 17: (250 MHz) 1.22 (t, 3H), 1.29-1.62 (m, 6H), 2.04 (s, 3H), 2.29-2.47 (m, 6H), 3.30-3.41 (m, 2H), 3.44-3.60 (m, 2H), 4.13 (d, 2H), 5.62 (s, 2H), 6.96 (t, 1H), 7.16 (d, 1 H), 7.22 (s, 1H), 7.76 (s, 1H), 7.82-8.06 (m, 3H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.48 (d, 1 H).
Compound No. 18: (250 MHz) 0.32-0.57 (m, 1H), 0.78 (d, 6H), 1.18 (t, 3H), 1.35-1.70 (m, 5H), 2.39 (t, 2H), 2.79 (d, 2H), 3.22-3.38 (m, 2H), 3.41-3.56 (m, 2H), 4.09 (d, 2H), 5.78 (s, 2 H), 6.39 (d, 1H), 6.92 (t, 1H), 7.11 (d, 1H), 7.30 (dd, 1H), 7.74-7.98 (m, 4H), 8.23 (t, 1H), 8.28-8.42 (m, 2H), 8.44 (d, 1H).
Compound No. 19: (250 MHz) 1.11 (d, 6H), 1.02-1.32 (m, 3H), 1.21 (t, 3H), 1.30-1.73 (m, 3H), 2.37-2.51 (m, 2H), 2.59-2.78 (m, 2H), 3.11-3.20 (m, 2H), 3.42-3.59 (m, 2H), 4.13 (d, 2 H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.83-8.01 (m, 4H), 8.28 (t, 1H), 8.35-8.59 (m, 3H).
Compound No. 20: (250 MHz) 0.94-1.13 (m, 4H), 1.22 (t, 3H), 1.30-1.68 (m, 6H), 2.41-2.65 (m, 6H), 3.31-3.68 (m, 4H), 5.70 (s, 2H), 6.43 (d, 1H), 6.67 (br. s., 1H), 7.16 (d, 1H), 7.29 (d, 1 H), 7.73-8.07 (m, 4H), 8.19-8.34 (m, 1H), 8.42 (br. s., 2H), 8.54 (s, 1H).
Compound No. 21: (250 MHz) 1.13 (t, 3H), 1.27-1.69 (m, 6H), 2.16-2.47 (m, 6H), 3.32-3.43 (m, 4H), 4.11 (d, 2H), 5.81 (s, 2H), 6.43 (d, 1H), 6.61-8.82 (m, 2H), 7.23 (d, 2H), 7.35 (d, 1H), 7.87 (s, 1H), 7.92 (d, 1H), 8.27 (br. s., 1H), 8.41 (br. s., 1H), 9.03 (s, 1H).
Compound No. 22: (250 MHz) 1.19 (t, 3H), 1.30-1.64 (m, 6H), 2.31-2.50 (m, 6H), 3.32-3.42 (m, 2H), 3.41-3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 6.89-7.06 (m, 2H), 7.35 (dd, 1H), 7.70-7.83 (m, 1H), 7.88 (d, 1H), 7.96 (d, 1H), 8.09 (t, 1H), 8.35 (t, 1H), 8.43 (t, 1H), 8.67 (d, 1H).
Compound No. 23: (250 MHz) 1.22 (t, 3H), 1.33-1.68 (m, 6H), 2.52-2.92 (m, 6H), 3.15-3.27 (m, 2H), 3.34-3.50 (m, 2H), 4.12 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.80-6.90 (m, 2H), 6.94 (t, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.52-7.66 (m, 2H), 7.78-7.93 (m, 2H), 8.13-8.37 (m, 2 H), 8.43 (d, 1H).
Compound No. 24: (250 MHz) 0.39-0.51 (m, 2H), 0.51-0.59 (m, 2H), 0.59-0.75 (m, 2H), 0.75-0.90 (m, 2H), 2.68-2.86 (m, 1H), 2.86-3.09 (m, 1H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.21 (d, 1H), 7.35 (dd, 1H), 7.83-8.13 (m, 4H), 8.29 (t, 1H), 8.38-8.65 (m, 3H).
Compound No. 25: (250 MHz) 0.35-0.55 (m, 2H), 0.69-0.84 (m, 2H), 1.41-2.01 (m, 8H), 2.85-3.05 (m, 1H), 4.13 (d, 2H), 4.13-4.26 (m, 1H), 5.83 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.22 (d, 1H), 7.35 (dd, 1H), 7.84-8.08 (m, 4H), 8.22-8.37 (m, 2H), 8.44-8.57 (m, 2H)
Compound No. 26: (250 MHz) 0.37-0.55 (m, 2H), 0.71-0.83 (m, 2H), 0.89 (t, 3H), 1.18-1.41 (m, 2H), 1.41-1.63 (m, 2H), 2.84-3.05 (m, 1H), 3.21 (q, 2H), 4.13 (d, 2H), 5.86 (s, 2H), 6.45 (d, 1H), 6.98 (t, 1H), 7.23 (d, 1H), 7.36 (dd, 1H), 7.83-8.09 (m, 4H), 8.29 (t, 1H), 8.39-8.68 (m, 3H)
Compound No. 27: (250 MHz) 1.22 (t, 3H), 1.29-1.58 (m, 6H), 2.28-2.47 (m, 6H), 3.30-3.41 (m, 2H), 3.43-3.62 (m, 2H), 4.37 (d, 2H), 7.16 (d, 1H), 7.23 (t, 1H), 7.39 (dd, 1H), 7.69-7.79 (m, 1H), 7.82-8.03 (m, 3H), 8.26 (t, 1H), 8.31-8.46 (m, 2H), 8.49 (dd, 1H), 8.56 (d, 1H), 8.64 (d, 1H).
Compound No. 28: (250 MHz) 1.22 (t, 3), 1.23-1.6 (m, 6), 2.30-2.50 (m, 6), 2.75 (d, 3), 3.34 (m, 2), 3.52 (qui, 2), 4.13 (d, 2), 6.39 (q, 1), 6.43 (d, 1), 6.98 (t, 1), 7.16 (d, 1), 7.37 (dd, 1), 7.80-8.02 (m, 4), 8.28 (t, 1), 8.37 (t, 1), 8.41 (t, 1), 8.49 (d, 1).
Compound No. 29: (250 MHz) 1.22 (t, 3H), 1.29-1.60 (m, 6H), 2, 31-247 (m, 6H), 3.00 (s, 6H), 3.26-3.42 (m, 2H), 3.45-3.60 (m, 2H), 4.18 (d, 2H), 6.64 (d, 1H), 7.01 (s, 1H), 7.16 (d, 1H), 7.49 (dd, 1H), 7.81-8.01 (m, 3H), 8.06 (d, 1H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.51 (d, 1H)
Compound No. 30: (250 MHz) 1.22 (t, 3H), 1.30-1.63 (m, 6H), 2.29-2.47 (m, 6H), 3.29-3.40 (m, 2H), 3.44-3.63 (m, 2H), 4.22 (d, 2H), 5.32 (s, 2H), 6.86 (s, 1H), 7.03-7.22 (m, 2H), 7.71 (s, 1H), 7.79-8.02 (m, 4H), 8.28 (t, 1H), 8.33-8.51 (m, 2H), 8.58 (s, 1H)
Compound No. 31: (500 MHz) 1.23 (t, 3H), 1.34-1.43 (m, 2H), 1.45-1.57 (m, 4H), 2.31-2.49 (m, 6H), 3.31-3.30 (m, 2H), 3.46-3.59 (m, 2H), 4.43 (d, 2H), 7.17 (d, 1H), 7.27 (t, 1H), 7.62-7.76 (m, 1H), 7.88 (dd, 1H), 7.91-8.02 (m, 2H), 8.24 (t, 1H), 8.38 (t, 1H), 8.42 (t, 1H), 8.46 (s, 1H), 8.49 (d, 1H), 8.69 (d, 1H)
Compound No. 32: (400 MHz) 1.22 (t, 3H), 1.33-1.61 (m, 6H), 2.31 (s, 3H), 2.51 (s, 6H), 3.34-3.43 (m, 2H), 3.46-3.60 (m, 2H), 4.34 (d, 2H), 716 (d, 1H), 7.21 (t, 1H), 7.54 (s, 1H), 7.87 (d, 1H), 7.90-8.05 (m, 2H), 8.21-8.29 (m, 1H), 8.29-8.37 (m, 2H), 8.37-8.49 (m, 2H), 8.62 (d, 1H)
Compound No. 33: (250 MHz) 1.22 (t, 3H), 1.31-1.59 (m, 6H), 2.22-2.47 (m, 6H), 3.29-3.41 (m, 2H), 3.53 (m, 2H), 5.67 (s, 2H), 6.45 (d, 1H), 7.17 (d, 1H), 7.51 (dd, 1H), 7.80-8.05 (m, 4H), 8.27 (t, 1H), 8.41 (d, 2H), 8.70 (br. s., 2H).
Compound No. 34: (400 MHz) 1.22 (t, 3H), 1.40 (d, 2H), 1.53 (quin, 4H), 2.41-2.60 (m, 6H), 2.45 (s, 3H), 3.34-3.42 (m, 2H), 3.47-3.57 (m, 2H), 4.32 (d, 2H), 7.11-7.21 (m, 2H), 7.23 (d, 1H), 7.61 (dd, 1H), 7.87 (d, 1H), 7.90-8.03 (m, 2H), 8.25 (t, 1H), 8.41 (s, 3H), 8.60 (d, 1H)
Compound No. 35: (400 MHz) 1.22 (t, 3H), 1.32-1.45 (m, 2H), 1.64-1.78 (m, 2H), 2.06 (t, 2H), 2.43 (t, 2H), 2.64-2.77 (m, 2H), 3.32 (s, 2H), 3.37-3.48 (m, 1H), 3.48-3.57 (m, 2H), 4.13 (d, 2H), 4.52 (d, 1H), 5.83 (s, 2H), 6.43 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.34 (dd, 1H), 7.86 (d, 2H), 7.89-7.99 (m, 2H), 8.27 (t, 1H), 8.33-8.45 (m, 2H), 8.49 (d, 1H)
Compound No. 36: (250 MHz) 0.94-1.15 (m, 1H), 1.22 (t, 3H), 1.30-1.52 (m, 1H), 1.52-1.69 (m, 1H), 1.80-1.97 (m, 3H), 2.44 (t, 2H), 2.62-2.77 (m, 1H), 2.85 (dd, 1H), 3.28-3.39 (m, 2H), 3.39-3.62 (m, 3H), 4.13 (d, 2H), 4.56 (d, 1H), 5.83 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.82-8.03 (m, 4H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.51 (d, 1H)
Compound No. 37: (400 MHz) 0.99 (d, 12), 1.22 (t, 3), 2.51 (m, 2), 2.99 (m, 2), 3.19 (q, 2), 3.53 (qui, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (dd, 1), 7.80-8.00 (broad unresolved peak, 4); 8.27 (t, 1), 8.37 (t, 1), 8.42-8.54 (broad unresolved peak, 2)
Compound No. 38: (400 MHz) 1.22 (t, 3), 1.40 (m, 2), 1.82 (m, 2), 2.12 (t, 2), 2.44 (t, 2), 2.72 (m, 2), 3.15 (sep, 1), 3.22 (s, 3), 3.32 (m, 2), 3.52 (qui, 2), 4.15 (d, 2), 5.84 (s, 2), 6.43 (d, 1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (dd, 1), 7.80-8.00 (m, 4), 8.27 (t, 1), 8.37 (t, 1), 8.40 (t, 1), 8.49 (d, 1).
Compound No. 39: (250 MHz) 1.22 (t, 3H), 1.30-1.57 (m, 6H), 1.66 (t, 2H), 2.18-2.41 (m, 6H), 3.16-3.29 (m, 2H), 3.40-3.60 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1 H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.81-8.03 (m, 4H), 8.28 (t, 1H), 8.36-8.58 (m, 3H).
Compound No. 40: (400 MHz) 1.22 (t, 3), 1.30-1.59 (m, 10), 2.23 (t, 2), 2.28 (br. s., 4), 3.23 (q, 2); 3.52 (qui, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.99 (t, 1), 7.14 (d, 1), 7.34 (dd, 1), 7.82-8.00 (m, 4), 8.26 (t, 1), 8.43 (m, 2), 8.51 (br. s. 1).
Compound No. 41: (400 MHz) 1.22 (t, 3H), 2.14 (s, 3H), 2.18-2.49 (m, 10H), 3.31-3.39 (m, 2H), 3.44-3.58 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.43 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.34 (dd, 1H), 7.81-7.89 (m, 2H), 7.89-7.98 (m, 2H), 8.27 (t, 1H), 8.32-8.45 (m, 2H), 8.49 (d, 1H)
Compound No. 42: (250 MHz) 1.22 (t, 3H), 2.02 (br. s., 1H), 2.27-2.38 (m, 4H), 2.41 (t, 2H), 2.62-2.74 (m, 4H), 3.22-3.41 (m, 2H), 3.44-3.59 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 7.00 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.82-8.02 (m, 4H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.51 (d, 1H)
Compound No. 43: 1H NMR (500 MHz, d6-DMSO) δ ppm 1.24 (t, 3H), 1.35-1.44 (m, 2H), 1.51 (quin, 4H), 2.33-2.50 (m, 6H), 3.33-3.41 (m, 2H), 3.50-3.59 (m, 2H), 6.48-6.56 (m, 3H), 6.86 (d, 1H), 7.22 (d, 1H), 7.49 (d, 1H), 7.66 (dd, 1H), 7.90-8.06 (m, 3H), 8.16 (d, 1H), 8.31 (t, 1H), 8.41 (q, 2H), 9.88 (s, 1H).
Compound No. 44: 1H NMR (250 MHz, d6-DMSO) δ ppm 1.23 (t, 3H), 1.31-1.64 (m, 6H), 2.23-2.47 (m, 6H), 3.29-3.41 (m, 2H), 3.46-3.65 (m, 2H), 7.21 (s, 1H), 7.26 (d, 1H), 7.51 (dd, 1H), 7.69 (d, 1H), 7.93-8.13 (m, 4H), 8.31 (t, 1H), 8.37-8.47 (m, 2H), 8.62 (d, 1H), 885 (d, 1H), 10.17 (s, 1H).
Compound No. 45: 1H NMR (250 MHz, d6-DMSO) δ ppm 1.22 (t, 7H), 1.96-2.26 (m, 2H), 3.16 (d, 4H), 3.40 (t, 2H), 3.52 (ddt, 2H), 3.71 (d, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 7.07 (t, 1H), 7.13 (d, 1H), 7.35 (dd, 1H), 7.73 (d, 1H), 7.80-7.96 (m, 3H), 8.28 (t, 1H), 8.55 (br. s., 2 H), 11.05 (br. s., 1H)
The compounds described in Table I have formed the subject of pharmacological trials which make it possible to determine the anticancer activity. They were tested in vitro on the HCT116 tumour line (ATCC-CCL247). The cell proliferation and viability were determined in a test using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) according to Fujishita T. et al., Oncology, 2003, 64(4), 399-406. In this test, the mitochondrial ability of the living cells to convert MTS to a coloured compound is measured after incubating the test compound for 72 hours. The concentration of compound which results in a 50% loss of cell proliferation and viability is denoted IC50.
For the compounds of Table I, an IC50<1000 nM (1 μM) is found with regard to the HCT116 line. Some compounds (for example Nos. 1, 5, 11, 19, 27) even exhibit an activity <1 nM.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0901365 | Mar 2009 | FR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR10/50511 | 3/22/2010 | WO | 00 | 11/10/2011 |
