Amidoheteroaryl aroyl hydrazide ethynes

Abstract

The present invention relates to novel amidoheteroaryl aroyl hydrazide ethynes as tyrosine kinase inhibitors, process of preparation thereof, and use of the compounds for preparation of pharmaceutical compositions in the therapeutic treatment of disorders related to tyrosine kinases in humans.

Claims

1. A compound of Formula I ##STR00017## or a pharmaceutically acceptable salt thereof wherein, R.sub.1 is selected from C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-NH.sub.2, C.sub.1-6 alkyl-NH(C.sub.1-6 alkyl), C.sub.1-6 alkyl-N(C.sub.1-6 alkyl).sub.2, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, and NH(C.sub.3-6 cycloalkyl); R.sub.1 is optionally substituted with one or more group independently selected from the group consisting of C.sub.1-4 alkyl, halogen, CN, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, NH.sub.2 and hydroxy; R.sub.2 and R.sub.3 are individually selected from a group of hydrogen, halogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl.

2. The compound of Formula I of claim 1 wherein, R.sub.1 is C.sub.3-6 cycloalkyl; and R.sub.2 and R.sub.3 are independently selected from a group consisting of hydrogen, halogen, C.sub.1-4 alkyl and C.sub.1-4 haloalkyl.

3. The compound of Formula I as in claim 1 selected from the group consisting of: Cyclopropanecarboxylic acid (5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)amide; N-(5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-dimethylaminoacetamide; N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)acetamide; Cyclopropanecarboxylic acid [5-(2-methyl-5-{N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide; 1-(5-{5-[N-(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)-3-cyclopropylurea; N-(5-{5-[N-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)-2,2,2-trifluoroacetamide; and N-(5-{5-[N-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)butyramide.

4. The compound of Formula I of claim 3, wherein the compound is cyclopropanecarboxylic acid (5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)amide.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In one aspect the present invention provides a compound of Formula I

(2) ##STR00002##
and pharmaceutically acceptable salts thereof wherein,

(3) R.sub.1 is selected from C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-NH.sub.2, C.sub.1-6 alkyl-NH(C.sub.1-6 alkyl), C.sub.1-6 alkyl-N(C.sub.1-6 alkyl).sub.2, C.sub.3-6 alkenyl, C.sub.1-6 alkyl, C.sub.3-6 alkynyl, C(O) heterocyclyl, heterocyclyl-C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, NH(C.sub.3-6 cycloalkyl) and heterocyclyl wherein heterocyclyl is 5-6 membered non-aromatic ring containing 1 to 2 heteroatom individually selected from N, O or S;

(4) R.sub.1 is optionally substituted with one or more group independently selected from C.sub.1-4 alkyl, halogen, CN, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, NH.sub.2 and hydroxy;

(5) R.sub.2 and R.sub.3 are individually selected from a group of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, heterocyclyl-C.sub.1-4 alkyl and heteroaryl wherein, heterocyclyl is 5-6 membered non-aromatic ring containing 1 to 2 heteroatom independently selected from N, O or S and is unsubstituted or substituted with C.sub.1-4 alkyl and heteroaryl is 5-6 membered aromatic ring containing 1 to 2 heteroatom independently selected from N, O or S and is unsubstituted or substituted with C.sub.1-4 alkyl.

(6) In one embodiment, R.sub.1 is C.sub.3-6 cycloalkyl.

(7) In one embodiment, the compound of Formula I is selected from a group comprising: Cyclopropanecarboxylic acid (5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)amide; N-(5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-dimethylaminoacetamide; N-(5-{5-[N-(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-3-(4-methyl-piperazin-1-yl)propionamide; N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-(4-dimethylaminopiperidin-1-yl)acetamide; N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-(3-dimethylaminopyrrolidin-1-yl)acetamide; N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)acetamide; Cyclopropanecarboxylic acid [5-(2-methyl-5-{N-[4-(4-methylpiperazin-1-ylmethyl)benzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide; Cyclopropanecarboxylic acid [5-(2-methyl-5-{N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide; 1-(5-{5-[N-(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)-3-cyclopropylurea; N-(5-{5-[N-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)-2,2,2-trifluoroacetamide; Cyclopropanecarboxylic acid [5-(2-methyl-5-{N-[4-(4-methylpiperazin-1-yl-methyl)-3-trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide; N-(5-{5-[N-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)butyramide;

(8) In a preferred embodiment, the compound of Formula I is selected from a group comprising: Cyclopropanecarboxylic acid (5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)amide; Cyclopropanecarboxylic acid [5-(2-methyl-5-{N-[4-(4-methylpiperazin-1-ylmethyl)benzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide; Cyclopropanecarboxylic acid [5-(2-methyl-5-{N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide; Cyclopropanecarboxylic acid [5-(2-methyl-5-[N-[4-(4-methylpiperazin-1-yl-methyl)-3-trifluoromethylbenzoyl]-hydrazinocarbonyl]phenylethynyl)pyridin-2-yl]amide;

(9) In one embodiment of the process for preparing compounds of the present invention, the compounds of Formula I can be prepared as per following general scheme 1

(10) ##STR00003##

(11) The process involves condensation of the hydrazide of Formula III with the diarylacetylenic compound of Formula II, wherein R.sub.1, R.sub.2 & R.sub.3 are as previously defined for compound of Formula I, and L is a leaving group. Preferably the condensation reaction is carried out in the presence of an inert base and/or a suitable catalyst in an inert solvent.

(12) The compound of the Formula II in activated form (i.e. C(O)-L) is especially an acid halide, an ester an anhydride or a cyclic imide.

(13) The esters of Formula II can be selected from, for example vinyl esters obtainable, for example, by transesterification of a corresponding ester with vinyl acetate, carbamoylvinyl esters or by treatment with a C.sub.2-5 alkoxyacetylene. Other active esters are of the amidino type, such as N,N-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N-disubstituted carbodiimide, for example, N,N-dicyclohexylcarbodiimide), or N,N-disubstituted amidino esters (obtainable, for example, treatment of the corresponding acid with N,N-disubstituted cyanamide), suitable aryl esters, especially phenyl esters suitably substituted by electron-attracting substituents (obtainable, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example, 4-nitrophenol, 2,4,5-trichlorophenol, or 2,3,4,5,6-pentachloro-phenol in the presence of a condensation agent, such as N,N-dicyclohexylcarbodiimide). Other suitable active esters include cyanomethyl esters (obtainable, for example, by treatment of the corresponding acid with chloroacetonitrile in the presence of a base), thio esters, especially unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for example, by treatment of the corresponding acid with unsubstituted or substituted, for example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method), amino or amido esters (obtainable, for example, by treatment of the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, for example, N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1-hydroxybenzotriazole, for example by the anhydride or carbodiimide method).

(14) The anhydrides of the compound of Formula II may be formed with carbonic acid semiderivatives, such as corresponding esters, for example carbonic acid alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with haloformic, such as chloroformic, acid); alkyl esters or with a 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, for example 1-alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; anhydrides with dihalogenated, especially dichlorinated phosphoric acid (obtainable, for example, by treatment of the corresponding acid with phosphorus oxychloride), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treatment of the corresponding acid with an unsubstituted or substituted acyl halide, for example, pivaloyl chloride or trifluoroacetyl chloride). Anhydrides may also be with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid, with a suitable organic sulfonic acid halide, such as alkane- or aryl-, for example methane- or p-toluenesulfonyl chloride), or with organic phosphonic acids (obtainable, for example, by treatment of the corresponding acid with a suitable organic phosphonic anhydride or phosphonic cyanide).

(15) Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as with imidazoles (obtainable, for example, by treatment of the corresponding acid with N,N-carbonyldiimidazole; imidazolide method), or pyrazoles, for example 3,5-dimethylpyrazole.

(16) Formula II in activated form is preferably generated in situ from the corresponding acid (i.e. when L=OH). For example, N,N-disubstituted amidino esters can be formed in situ by reacting a mixture of the acid of Formula II (i.e. when L=OH) and the compound of Formula III in the presence of a suitable condensating agent for example N,N-dicyclohexylcarbodiimide. Reactive mixed anhydrides of the acid may also be generated with an organic phosphonic acid in situ by reaction with propylphosphonic anhydride or diethylcyanophosphonate in the presence of suitable base for e.g. triethylamine or 4-(N,N-dimethylamino)pyridine. The reaction may be carried out in a manner known per se, the reaction conditions being dependent especially on how the acid group of Formula II has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of a condensation agent. Customary condensation agents are, for example, carbodiimides such as N,N-diethyl-, N,N-diisopropyl, N,N-dicyclohexyl- or N-ethyl-N-(3-diethylaminopropyl)-carbodiimide; suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, for example, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The bases normally used for aiding the condensation are either inorganic bases such as sodium or potassium carbonate, or organic bases, such as pyridine, triethyamine, N,N-diisopropylethylamine or 4-(dimethylamino)pyridine.

(17) Alternatively, the preparation of compounds of Formula I in the present invention can be performed by reacting compounds of Formula IV with the compounds of Formula V, Scheme 2, using similar condensation methods as described above (for Scheme 1); wherein R.sub.1, R.sub.2, R.sub.3 and L are as previously defined.

(18) ##STR00004##

(19) Compounds of Formula IV can be prepared from compounds of Formula II and hydrazine of Formula Ma, Scheme 3, utilizing the coupling procedures as described for Scheme 1, vide supra.

(20) ##STR00005##

(21) In a similar manner the compounds of Formula III can be prepared by the reaction of compounds of hydrazine hydrate and Formula V, Scheme 4.

(22) ##STR00006##

(23) The compounds of Formula II can be prepared by methods known in the literature. Suitable approaches for the preparation of the compounds for Formula II are provided in Scheme 5.

(24) ##STR00007##

(25) As illustrated in Scheme 5, the ethynyl moiety of pyridine of Formula VIII is coupled with phenyl ring of Formula IX, or the ethynyl moiety of phenyl ring of Formula VII is coupled with pyridine ring of Formula VI; wherein W represents a leaving group like OTf, Cl, Br or I, preferably Br or I; L represent OH or O-alkyl. The coupling reaction can be performed using well known prior art methods, such as metal catalyzed coupling reactions, for example a palladium catalyzed Sonogashira coupling reaction (refer Malleron, J-L., Fiaud, J-C., Legros, J-Y. Handbook of Palladium Catalyzed Organic Reactions, San Diego: Academic Press, 1997). Alternatively, the compound of Formula II is prepared from the vicinal dihalo compound of Formula IIa (where Z represents halo) by tandem dehydrohalogenations.

(26) A strategy similar to the above can be utilized for the synthesis of compounds of Formula I as shown in Scheme 6, i.e. coupling the ethynyl moiety of pyridine ring of Formula VIII to the phenyl ring in Formula XI, or the ethynyl moiety of phenyl ring of Formula X to the pyridine ring in Formula VI; wherein W, R.sub.1, R.sub.2 and R.sub.3 are as previously defined.

(27) ##STR00008##

(28) The compounds of Formula X & Formula XI can be conveniently prepared by acylation of the hydrazide of Formula III with compounds of Formula VII & Formula IX, respectively, as shown in Scheme 7; wherein L, W, X, R.sub.1, R.sub.2 and R.sub.3 are as previously defined.

(29) ##STR00009##

(30) The compounds of Formula I can also be prepared by acylation of the amine of Formula XII as shown in Scheme 8.

(31) ##STR00010##

(32) Where the above starting compounds VI, VII, VIII and IX contain functional groups that may interfere with the coupling reaction, are protected using suitable protecting groups that can be conveniently removed later.

(33) Characterization data for some of the representative compounds of Formula I are provided in the Table-1.

(34) TABLE-US-00001 TABLE 1 Compd ID IUPAC Name .sup.1H NMR ( ppm) in DMSO-d.sub.6 as solvent I.1 cyclopropanecarboxylic acid (5- 0.89 (m, 4H), 1.13-1.16 (t, 1H, J = 7.0 Hz), 2.52 (s, 3H), 2.60 (s, {5-[N-(2-chloro-6- 3H), 7.31-7.35 (m, 1H), 7.38-7.43 (m, 2H), 7.53 (d, 1H, J = 8.0 methylbenzoyl)hydrazinocarbonyl]- Hz), 7.92-7.95 (m, 1H), 8.02-8.05 (m, 1H), 8.18-8.22 (m, 2H), 2-methyl-phenylethynyl}- 8.62 (m, 1H), 10.52 (s, 1H), 10.71 (s, 1H), 11.12 (s, 1H). pyridin-2-yl)amide I.2 N-(5-{5-[N-(2-chloro-6-methyl- 2.42 (s, 3H), 2.69 (s, 3H), 2.93 (s, 6H), 4.28 (br, 2H), 7.33 (m, benzoyl)hydrazinocarbonyl]-2- 1H), 7.40-7.43 (m, 2H), 7.56 (d, 1H, J = 8.1 Hz), 7.60-7.68 (m, methyl-phenylethynyl}-pyridin-2- 1H), 7.95 (m, 1H), 8.14-8.18 (m, 3H), 8.69 (m, 1H), 9.99 (br, yl)-2-dimethylaminoacetamide 1H), 10.53 (s, 1H), 10.72 (s, 1H), 11.46(s, 1H). I.3 N-(5-{5-[N-(2-Chloro-6- 2.52 (s, 3H), 2.60 (s, 3H), 2.88 (s, 3H), 3.07 (m, 2H), 3.70-3.73 methylbenzoyl)hydrazinocarbonyl]- (m, 8H), 7.31-7.34 (m, 1H), 7.39-7.44 (m, 2H), 7.56 (d, 1H, J = 2-methyl-phenylethynyl}- 8.1 Hz), 7.95 (d, 1H, J = 8.1 Hz), 8.09 (d, 1H, J = 8.0 Hz), 8.18- pyridin-2-yl)-3-(4-methyl- 8.21 (m, 2H), 8.64 (s, 1H), 10.53 (s, 1H), 10.72 (s, 1H), 11.09 (s, piperazin-1-yl)propionamide 1H), 11.80 (m, 2H). I.4 N-(5-{5-[N-(2-Chloro-6-methyl- 1.70-1.73 (m, 2H), 2.00 (m, 2H), 2.27-2.33 (m, 2H), 2.52 (s, 3H), benzoyl)hydrazinocarbonyl]-2- 2.60 (s, 3H), 2.66 (br, 5H), 2.91-2.97 (m, 3H), 3.03-3.06 (m, 3H), methyl-phenylethynyl}-pyridin-2- 7.32-7.33 (m, 1H), 7.38-7.39 (m, 2H), 7.55 (d, 1H, J = 8.0 Hz), yl)-2-(4-dimethylamino piperidin- 7.94 (d, 1H, J = 8.0 Hz), 8.08-8.11 (m, 1H), 8.19 (s, 1H), 8.23(d, 1-yl)acetamide 1H, J = 8.6 Hz), 8.63 (m, 1H), 10.26 (s, 1H), 10.53 (s, 1H), 10.72(s, 1H). I.5 N-(5-{5-N-(2-Chloro-6-methyl- 2.55 (s, 3H), 2.61 (s, 3H), 2.72-2.86 (m, 6H), 2.93-3.00 (m, 2H), benzoyl)hydrazine carbonyl]-2- 4.10 (br, 2H), 4.43 (br, 2H), 7.32-7.38 (m, 1H), 7.40-7.43 (m, methyl-phenyl ethynyl}-pyridin-2- 2H), 7.56 (d, 1H, J = 8.0 Hz), 7.94-7.97 (m, 1H), 8.14-8.19 (m, yl)-2-(3-dimethylaminopyrrolidin- 3H), 8.69 (s, 1H), 10.54 (s, 1H), 1072 (s, 1H), 11.45(s, 1H). 1-yl)acetamide I.6 N-(5-{5-[N-(2-Chloro-6-methyl- 2.18 (s, 3H), 2.52 (s, 3H), 2.60 (s, 3H), 7.33 (m, 1H), 7.40-7.41 benzoyl)hydrazinocarbonyl]-2- (m, 2H), 7.55 (d, 1H, J = 8.1 Hz), 7.93-7.95 (m, 1H), 8.03-8.06 methyl-phenylethynyl}-pyridin-2- (m, 1H), 8.18-8.23 (m, 2H), 8.61 (m, 1H), 10.53 (s, 1H), 10.72 yl)acetamide (s, 1H), 10.82 (s, 1H). I.7 Cyclopropanecarboxylic acid [5- 0.88-0.90 (m, 4H), 1.36 (m, 1H), 2.03 (m, 1H), 2.41 (br, 6H), (2-methyl-5-{N-[4-(4-methyl- 2.69-2.72 (m, 3H), 2.92-2.97 (m, 3H), 3.61 (br, 3H), 7.50-7.55 piperazin-1-ylmethyl)benzoyl]- (m, 3H), 7.87-7.92 (m, 3H), 8.00-8.02 (m, 1H), 8.09 (s, 1H), hydrazinocarbonyl}phenyl- 8.16 (d, 1H, J = 8.6 Hz), 8.58(s, 1H), 10.70 (br, 2H), 11.15 (s, ethynyl)pyridin-2-yl]amide 1H). I.8 Cyclopropanecarboxylic acid [5- 0.73-0.74 (m, 4H), 1.92 (m, 1H), 2.08 (s, 3H), 2.45 (s, 3H), 7.41 (2-methyl-5-{N-[3-(4-methyl- (d, 1H, J = 8.0 Hz), 7.62 (br, 1H), 7.77 (d, 1H, J = 7.8 Hz), 7.87- imidazol-1-yl)-5-trifluoromethyl- 7.89 (m, 1H), 7.99 (s, 1H), 8.05 (m, 2H), 8.19 (s, 1H), 8.31(s, benzoyl]-hydrazinocarbonyl}phenyl- 2H), 8.46 (s, 1H), 10.66 (s, 1H), 10.80 (s, 1H), 10.96 (s, 1H). ethynyl)pyridin-2-yl]amide I.9 1-(5-{5-[N-(2-Chloro-6- 0.51-0.72 (m, 4H), 2.38 (s, 3H), 2.55 (s, 3H), 3.51 (m, 1H), 7.33- methylbenzoyl)hydrazinocarbonyl]- 7.39 (m, 3H), 7.55-7.64 (m, 2H), 7.93 (m, 3H), 8.15(s, 1H), 8.48 2-methylphenylethynyl}- (s, 1H), 9.40 (s, 1H), 10.52 (s, 1H), 10.70 (s, 1H). pyridin-2-yl)-3-cyclopropylurea I.10 N-(5-{5-[N-(2-(Chloro-6-methyl- 2.52 (s, 3H), 2.62 (s, 3H), 7.33 (m, 1H), 7.40-7.41 (m, 2H), 7.57 benzoyl)hydrazinocarbonyl]-2- (d, 1H, J = 9.2 Hz), 7.96 (d, 1H, J = 8.0 Hz), 8.12 (d, 1H, J = 8.6 methylphenylethynyl}-pyridin-2- Hz), 8.19 (s, 1H), 8.21 (s, 1H), 8.76 (s, 1H), 10.53 (s, 1H), 10.72 yl)-2,2,2-trifluoroacetamide (s, 1H), 12.34 (s, 1H). I.11 Cyclopropanecarboxylic acid [5- 0.89-0.90 (m, 4H), 2.09 (m, 1H), 2.23 (s, 3H), 2.38-2.51 (br, 6H), (2-methyl-5-[N-[4-(4-methyl- 2.61 (br, 5H), 3.22 (m, 2H), 7.56 (d, 1H, J = 8.2 Hz), 7.91-7.93 piperazin-1-yl-methyl)-3-trifluoro- (m, 1H), 7.99 (d, 2H, J = 8.3 Hz), 8.02-8.05 (m, 1H), 8.14 (m, methylbenzoyl]-hydrazino- 1H), 8.20 (m, 1H), 8.22(m, 1H), 8.24-8.26 (m, 1H), 8.29 (m, 1H), carbonyl}phenylethynyl)pyridin- 8.62 (m, 1H), 10.70 (s, 1H), 10.80 (s, 1H), 11.12 (s, 1H). 2-yl]amide I.12 N-(5-{5-[N-(2-(Chloro-6- 0.96 (t, 3H), 1.65 (m, 2H), 2.47 (t, 2H), 2.52 (s, 3H), 2.60 (s, 3H), methylbenzoyl)hydrazinocarbonyl]- 7.31-7.35 (m, 1H), 7.38-7.43 (m, 2H), 7.53 (d, 1H, J = 8.1 Hz), 2-methylphenylethynyl}- 7.92-7.95 (m, 1H), 8.02-8.05 (m, 1H), 8.18 (m, 1H), 8.22 (m, pyridin-2-yl)butyramide 1H), 8.62 (m, 1H), 10.52 (s, 1H), 10.71 (s, 1H), 10.76 (s, 1H).

(35) The compounds of the present invention can be used to treat disorders mediated by tyrosine kinases.

(36) The following examples serve to illustrate the invention without limiting the invention in its scope. The methods of preparing some of the starting compounds used in the examples are described as reference examples.

EXAMPLES

Example 1

Preparation of cyclopropanecarboxylic acid (5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)amide (Formula I.1)

(37) ##STR00011##

(38) A mixture of 3-({6-[(cyclopropylcarbonyl)amino]pyridin-3-yl}ethynyl)-4-methylbenzoic acid, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in N,N-dimethylformamide was stirred at ambient temperature for 1 hr. 2-chloro-6-methylbenzohydrazide was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and finally dried in vacuo to get a white solid.

Example 2

N-(5-{5-[N-(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-dimethylaminoacetamide (Formula I.2)

(39) ##STR00012##

(40) Starting from 3-[(6-{[(dimethylamino)acetyl]amino}pyridin-3-yl)ethynyl]-4-methylbenzoic acid the compound of Formula I.2 was prepared by the process disclosed in example 1.

Example 3

N-(5-{5-[N-(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-3-(4-methyl-piperazin-1-yl)propionamide (Formula I.3)

(41) ##STR00013##

(42) Starting from compound of Formula II-3, the compound of Formula I.3 was prepared by the process disclosed in example 1.

Example 4

N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-(4-dimethylaminopiperidin-1-yl)acetamide (Formula I.4)

(43) ##STR00014##

(44) Starting from compound of Formula II-4, the compound of Formula I.4 was prepared by the process disclosed in example 1.

Example 5

N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-2-(3-dimethylaminopyrrolidin-1-yl)acetamide (Formula I.5)

(45) ##STR00015##

(46) Starting from compound of Formula II-5, the compound of Formula I.5 was prepared by the process disclosed in example 1.

Example 6

N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)acetamide (Formula I.6)

(47) ##STR00016##

(48) Starting from 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid, the compound of Formula I.6 was prepared by the process disclosed in example 1.

Example 7

1-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)-hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)-3-cyclopropylurea (I.9)

(49) A solution of 2-amino-5-iodopyridine in DMF was added to a stirred mixture of diphenylphosphoryl azide, cyclopropane carboxylic acid and triethyl amine in toluene at 25 to 30 C. and stirred at 120-125 C. for 3 hrs. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 20% ethyl acetate in hexane) to provide 1-cyclopropyl-3-(5-iodo-pyridin-2-yl) urea.

(50) A mixture of 2-chloro-6-methylbenzoic acid N-(3-ethynyl-4-methyl benzoyl) hydrazide, 1-cyclopropyl-3-(5-iodo-pyridin-2-yl)urea, Pd(Pd).sub.2Cl.sub.2), CuI and triethylamine in DMF was heated at 90 C. for 16 hrs under nitrogen atmosphere. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 2% Methanol in MDC) to provide the title compound.

(51) Pharmacological Activity

(52) In-vitro Cell Proliferation Assay

(53) K562/U937 cells (2104 per well) were incubated with the test compounds/vehicle in a total volume of 200 L of media at 37 C. with 5% CO2. On day 4, 20 L MTT 5 mg/ml was added and the cells were incubated for 4-5 hours followed by addition of 100 L of 10% SDS prepared in 0.06N HCl. The cells were incubated overnight at 37 C. with 5% CO2. On Day 5 the optical density was measured at 570 nm with 630 nm as reference wavelength. The optical density in the vehicle treated wells was compared with that of the test compound treated wells.

(54) Results for the representative compounds of Formula I are provided in Table-2.

(55) TABLE-US-00002 TABLE 2 Compd. c-Abl kinase (K562 cells); % Inhibition ID 100 nM 10 nM 1 nM I.1 87.0 91.1 84.7 I.2 82.9 82.5 71.6 I.3 87.9 85.5 75.0 I.4 86.9 81.4 76.5 I.5 82.1 81.7 71.4 I.6 91.0 91.6 88.4 I.7 85.9 78.6 24.6 I.8 86.1 84.0 68.9 I.9 87.8 83.6 61.0 I.10 73.3 78.5 39.8 I.11 57.2 58.3 54.0 I.12 ND 80.6 33.6 ND: Not determined
Mutated Abl (T315I) (Human)Kinase

(56) In a final reaction volume of 25 L, mutated Abl (T315I) (human) (5-10 mU) is incubated with 8 mM MOPS pH7.0, 0.2 mM EDTA, 5004 EAIYAAPFAKKK, 10 mM Mg(OAc)2 and [-33P-ATP] [specific activity approx. 500 cpm/pmol, concentration as required]. The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 L of a 3% phosphoric acid solution. 10 L of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

(57) The compounds of Formula I showed good inhibitory action on the mutated Abl T315I cell line. Activity data on the mutated Abl T315I cell line for some representative compound is provided in Table-3.

(58) TABLE-US-00003 TABLE 3 Abl-T315I Compd. % Inhibition ID 30 nM 3 nM I.1 98.0 87.0 I.2 87.0 50.0 I.3 94.0 59.0 I.4 95.0 70.0 I.5 96.0 66.0 I.6 89.0 68.0