WO2015110467A1 - Process for the preparation of substituted n-(5-benzenesulfonyl-1h-indazol-3-yl)-benzamides - Google Patents

Process for the preparation of substituted n-(5-benzenesulfonyl-1h-indazol-3-yl)-benzamides Download PDF

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WO2015110467A1
WO2015110467A1 PCT/EP2015/051133 EP2015051133W WO2015110467A1 WO 2015110467 A1 WO2015110467 A1 WO 2015110467A1 EP 2015051133 W EP2015051133 W EP 2015051133W WO 2015110467 A1 WO2015110467 A1 WO 2015110467A1
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formula
compound
defined above
indazol
methyl
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PCT/EP2015/051133
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French (fr)
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Alessandro Arcari
Germano D'arasmo
Andrea Lombardi Borgia
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Nerviano Medical Sciences S.R.L.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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  • the present invention relates to a process for the preparation of substituted N-(5-benzenesulfonyl-1 H-indazol-3-yl)- benzamides and to the useful intermediate compounds of such process.
  • WO2008/074749 describes and claims such substituted indazole derivatives, processes for their preparation, pharmaceutical compositions comprising them and their use as therapeutic agents, particularly in the treatment of cancer and cell proliferation disorders.
  • the 1- protective group when the 1- protective group is trityl, its activating effect, through electron donation, enhances the reactivity of the 3-amino group, making it possible to efficiently carry out couplings with less reactive aroyl chlorides, such as, for example, benzoyl chlorides that bear bulky substituents at position 2.
  • aroyl chlorides such as, for example, benzoyl chlorides that bear bulky substituents at position 2.
  • this process is described in the above mentioned patent application WO2008/074749.
  • substituted N-(5-benzenesulfonyl-1 H-indazol-3-yl)-benzamide derivatives can be advantageously prepared in high yields and purity according to a synthetic process that is shorter, requires a lower number of chromatographic purifications and is suitable for plant scale production, which comprises, as the key steps, the coupling of an activated benzoic acid with a 5-phenylsulfanyl-1 H-indazol-3- ylamine scaffold and the subsequent oxidation of the phenylsulfanyl residue to the corresponding benzenesulfonyl residue.
  • R5 and R6 are independently hydrogen or fluorine
  • Step II 4-Bromo-2-((R)-2-hydroxy-1-methyl-ethylamino)-benzoic acid tert-butyl ester
  • Step V 4-Bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (V)
  • the reaction mixture is stirred at 50°C until complete conversion into 4-bromo-N-[5-(3,5-difluoro-benzenesulfonyl)- 1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide, monitored by HPLC method n. 2.
  • the solvent is distilled away at 34-45 °C under reduced pressure till a residual oil is obtained and 65 L of EtOAc are added; the evaporation and addition of EtOAc are repeated twice.
  • Example 21 starting from N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4- methyl-piperazin-1-yl)-2-nitro-benzamide was obtained 2-amino-N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4- methyl-piperazin-1-yl)-benzamide.

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Abstract

The present invention relates to a process for the preparation of substituted N-(5-benzenesulfonyl-1 H-indazol-3-yl)-benzamides and to the useful intermediate compounds of such process. Such derivatives are described and claimed in WO2008/074749, which also discloses processes for their preparation. The process of the present invention allows to obtain the desired products in high yields and purity and with a limited number of steps. The synthesis starts from 5-iodo-1 H-indazol-3-ylamine and comprises, as the key steps, the coupling of an activated benzoic acid with a 5-phenylsulfanyl-1 H-indazol-3-ylamine scaffold and the subsequent oxidation of the sulfur atom, followed by further functional group transformations, which furnish the desired products. The compounds prepared according to the process of the present invention are endowed with protein kinase inhibiting activity and, more particularly, IGF-1R or ALK inhibiting activity. The compounds are therefore useful in the treatment of a variety of cancers, cell proliferative disorders and diseases associated with protein kinases.

Description

PROCESS FOR THE PREPARATION OF SUBSTITUTED N-(5-BENZENESULFONYL-1 H-INDAZOL-3-YL)- BENZAMIDES
The present invention relates to a process for the preparation of substituted N-(5-benzenesulfonyl-1 H-indazol-3-yl)- benzamides and to the useful intermediate compounds of such process.
WO2008/074749 describes and claims such substituted indazole derivatives, processes for their preparation, pharmaceutical compositions comprising them and their use as therapeutic agents, particularly in the treatment of cancer and cell proliferation disorders.
Such compounds are endowed with protein kinase inhibiting activity and, more particularly, IGF-1 R or ALK inhibiting activity. More specifically, the compounds prepared according to this invention are useful in the treatment of a variety of cancers and of cell proliferative disorders. The compounds may be also active as inhibitors of other protein kinases and thus be effective in the treatment of diseases associated with other protein kinases.
These compounds, and analogues thereof, can be prepared according to a known chemical process comprising, as the key step to build the N-(5-benzenesulfonyl-1 H-indazol-3-yl)-benzamide core, the coupling between an activated benzoic acid, such as, for example, a benzoyl chloride, and a 5-benzenesulfonyl-1 H-indazol-3-ylamine scaffold. Such scaffold can be either unprotected or, more conveniently, 1 -protected. In particular, when the 1- protective group is trityl, its activating effect, through electron donation, enhances the reactivity of the 3-amino group, making it possible to efficiently carry out couplings with less reactive aroyl chlorides, such as, for example, benzoyl chlorides that bear bulky substituents at position 2. For reference, this process is described in the above mentioned patent application WO2008/074749.
In this respect, we have now surprisingly found that substituted N-(5-benzenesulfonyl-1 H-indazol-3-yl)-benzamide derivatives can be advantageously prepared in high yields and purity according to a synthetic process that is shorter, requires a lower number of chromatographic purifications and is suitable for plant scale production, which comprises, as the key steps, the coupling of an activated benzoic acid with a 5-phenylsulfanyl-1 H-indazol-3- ylamine scaffold and the subsequent oxidation of the phenylsulfanyl residue to the corresponding benzenesulfonyl residue.
As a matter of fact, the 3-amino group of a 5-phenylsulfanyl-1 H-indazol-3-ylamine is electron-richer than that of a 5-benzenesulfonyl-1 H-indazol-3-ylamine and the introduction of an activating 1-trityl group is not required in order to efficiently carry out a coupling with benzoyl chlorides, even with those bearing bulky substituents at position 2. Moreover, 5-phenylsulfanyl-1 H-indazol-3-ylamines can be prepared according to a one-step procedure starting from the commercially available 5-iodo-1 H-indazol-3-ylamine.
Therefore, it is a first object of the present invention a process for preparing a substituted N-(5-benzenesulfonyl- 1 H-indazol-3-yl)-benzamide of formula (I):
Figure imgf000003_0001
wherein:
R1 and R2 are independently hydrogen, an optionally substituted straight or branched C1-C6 alkyl, or R1 and R2, taken together with the carbon atom to which they are bonded, form an optionally substituted heterocyclyl group; R3 and R4 are independently hydrogen, an optionally substituted group selected from straight or branched Ο-Οβ alkyl and heterocyclyl, or R3 and R4, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group;
R5 and R6 are independently hydrogen or fluorine;
said process comprising:
a) coupling the compound of formula (II):
Figure imgf000003_0002
II
with a benzenethiol of formula (III):
Figure imgf000003_0003
III
wherein R5 and R6 are as defined above;
b) acylating the resultant compound of formula (IV):
Figure imgf000003_0004
wherein R5 and R6 are as defined above, with a carboxylic derivative of formula (V):
Figure imgf000004_0001
wherein X is a nitro group or -N(CHR1 R2)COCF3, wherein R1 and R2 are as defined above, W is hydroxy, halogen or a suitable leaving group, such as for example acetoxy, trifluoroacetoxy, and imidazol-1-yl, and Hal is chlorine, bromine or iodine;
c) oxidizing the resultant compound of formula (VI):
Figure imgf000004_0002
wherein R5, R6, Hal and X are as defined above; then
either
d) deprotecting the resultant compound of formula (VII):
Figure imgf000004_0003
wherein R5, R6 and Hal are as defined above, and X is -N(CHR1 R2)COCF3, wherein R1 and R2 are as defined above;
e) coupling the resultant compound of formula (VIII):
Figure imgf000004_0004
wherein R1 , R2, R5, R6 and Hal are as defined above, with an amine of formula (IX):
H
IX
R3^R4 wherein R3 and R4 are as defined above, to give the compound of formula (I) as defined above;
or
f) coupling the compound of formula (VII), as defined above, wherein R5, R6 and Hal are as defined above, and X is a nitro group, with the amine of formula (IX), as defined above;
g) reducing the nitro group of the resultant compound of formula (X):
Figure imgf000005_0001
wherein R3, R4, R5 and R6 are as defined above;
h) coupling the resultant compound of formula (XI):
Figure imgf000005_0002
wherein R3, R4, R5 and R6 are as defined above, with a carbonyl derivative of formula (XII):
X o
XII
R1 R2 wherein R1 and R2 are as defined above, to give the compound of formula (I) as defined above;
and optionally converting said compound of formula (I) into a pharmaceutically acceptable salt.
Any intermediates and/or the final compounds may be isolated and purified using conventional procedures, for example chromatography and/or crystallization and salt formation.
The compounds of formula (I) as defined above can be converted into pharmaceutically acceptable salts. The compounds of formula (I) as defined above, or the pharmaceutically acceptable salts thereof, can be subsequently formulated with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition. The new process is shown in Scheme V.
Scheme 1
Figure imgf000006_0001
wherein R1 , R2, R3, R4, R5, R6, X, Hal and W are as defined above.
Moreover, it is another object of the present invention some useful intermediate compounds as well as the processes for their preparation. The general terms as used herein, unless otherwise specified, have the meaning reported below.
The term "straight or branched Ο-Οβ alkyl" refers to a saturated aliphatic hydrocarbon radical, including straight chain and branched chain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, 2-propyl, n-butyl, iso- butyl, tert-butyl, pentyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent groups are preferably 1 to 3, independently selected from the group consisting of NR7R8, OR9 and an optionally substituted heterocyclyl, wherein R7, R8 and R9 are independently a straight or branched Ο-Οβ alkyl. The term "heterocyclyl" refers to a 3- to 7-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Not limiting examples of heterocyclyl groups are, for instance, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrazolinyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl, thiazolinyl, isothiazolinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl, examethyleneiminyl, homopiperazinyl, and the like. A heterocyclyl group may be substituted or unsubstituted. When substituted, the substituent groups are preferably one or two substituents, independently selected from the group consisting of NR7R8, a straight or branched Ο-Οβ alkyl and heterocyclyl, wherein R7 and R8 are as defined above.
The term "nitro" indicates a -NO2 group.
The term "hydroxy" indicates a -OH group.
The term "halogen" refers to bromine, chlorine, iodine or fluorine, more preferably chlorine.
A preferred class of compounds of formula (I) prepared with the process of the present invention are the compounds wherein:
R5 and R6, as defined above, are at 3 and 5 positions on the benzene ring and
R1 , R2, R3 and R4 are as defined above.
A particularly preferred class of compounds of formula (I) prepared with the process of the present invention are the compounds wherein:
R5 and R6, as defined above, are at 3 and 5 positions on the benzene ring and
R1 and R2 are independently hydrogen, an unsubstituted straight or branched Ο-Οβ alkyl or a straight or branched
C1-C6 alkyl substituted with one 0R9 group, wherein R9 is as defined above, or R1 and R2, taken together with the carbon atom to which they are bonded, form a tetrahydro-pyran-4-yl group, and
R3 and R4 are as defined above.
Preferred specific compounds (cpd) of formula (I) are the compounds listed below:
1. N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)- benzamide;
2. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2- (tetrahydro-pyran-4-ylamino)-benzamide;
3. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-ethyl-amino]-2-(tetrahydro- pyran-4-ylamino)-benzamide;
4. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(4-ethyl-[1 ,4]diazepan-1-yl)-2-(tetrahydro-pyran-4- ylamino)-benzamide; N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(4-dimethylamino-piperidin-1-yl)-2-(tetrahydro- pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-2- (tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-{[2-(isopropyl-methyl-amino)-ethyl]-methyl-arnino}- 2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-2- (tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2- (tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-(2-methoxy-1-methoxyiriethyl-ethylaiTiino)-4-(4- methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(2- methoxy-1-methoxymethyl-ethylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(2- methoxy-1-methyl-ethylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2- methoxy-1-methyl-ethylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2- isobutylamino-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-(2-methoxy-1-iriethyl-ethylairiino)-4-(4-methyl- piperazin-1 -yl)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-2- (tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4- ylamino)-benzamide;
4-[(2-dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-(tetrahydro- pyran-4-ylamino)-benzamide;
N-[5-(3-fluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4- ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-2-(tetrahydro-pyran 4-ylamino)-benzamide;
4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-( pyran-4-ylamino)-benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-(2-methoxy-ethylarnino)-4-(4-methyl-piperazin-1-yl) benzamide;
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(2- methoxy-ethylamino)-benzamide; 24. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylam piperazin-1 -yl)-benzamide;
25. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-rnethyl- piperazin-1 -yl)-benzamide;
26. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(2-dimethylamino-1-rnethyl-ethylamino)-2- (tetrahydro-pyran-4-ylamino)-benzamide;
27. 4-(2-diethylamino-1-methyl-ethylamino)-N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-(tetrahydro- pyran-4-ylamino)-benzamide, and
28. N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-2-(tetrahydro-pyran- 4-ylamino)-benzamide.
As stated above, the present invention also provides an intermediate compound of formula (IV):
Figure imgf000009_0001
wherein R5 and R6 are as defined above.
Preferably, the present invention provides an intermediate compound of formula (IV), wherein R5 and R6 are fluorines at 3 and 5 positions of the benzene ring.
It is a further object of the present invention a process for preparing an intermediate compound of formula (IV), as defined above, by coupling the 5-iodo-1 H-indazol-3-ylamine of formula (II) with a benzenethiol of formula (III), as defined above, under copper (I) or copper (II) catalysis.
The present invention also provides an intermediate com ound of formula (VI):
Figure imgf000009_0002
wherein R5, R6, X and Hal are as defined above.
It is still another object of the present invention a process for preparing an intermediate compound of formula (VI) as defined above, by acylating a compound of formula (IV) as defined above, with a carboxylic derivative of formula (V) as defined above, in the optional presence of a proton scavenger and of an activating agent.
It is also provided an intermediate compound of formula (VII):
Figure imgf000010_0001
wherein R5, R6, X and Hal are as defined above.
It is still another object of the present invention a process for preparing an intermediate compound of formula (VII) as defined above, by oxidation of a compound of formula (VI), as defined above.
It is also provided an intermediate compound of formula VIII):
Figure imgf000010_0002
wherein R1 , R2, R5, R6 and Hal are as defined above.
Preferably, the present invention provides an intermediate com ound of formula (VIII), which is:
Figure imgf000010_0003
It is still another object of the present invention a process for preparing an intermediate compound of formula (VIII) as defined above, by cleavage of the trifluoroacetyl group of a compound of formula (VII), wherein R5, R6 and Hal are as defined above and X is -N(CHR1 R2)COCF3, wherein R1 and R2 are as defined above, under basic conditions.
According to step a), the coupling of the 5-iodo-1 H-indazol-3-ylamine of formula (II) with a benzenethiol of formula (III) to give a compound of formula (IV) is performed under catalysis of a copper (II) or, more preferably, of a copper (I) salt, for instance copper (I) iodide, copper (I) bromide, copper (I) chloride or copper (I) acetate, and in the presence of a base, such as, for example, sodium carbonate, potassium carbonate or potassium phosphate tribasic. Preferably, the reaction is carried out at a temperature ranging from 20° to 100°C in an organic solvent such as, for example, ethanol, 1-propanol, 2-propanol, diethylene glycol, Ν,Ν-dimethylformamide, 1 ,4-dioxane, dimethoxyethane or mixtures thereof. Analogous transformations were described, for instance, in Organic Letters 2002, 4, 3517.
According to step b), a compound of formula (VI) can be obtained by reacting a compound of formula (IV) with a compound of formula (V) in a variety of ways and experimental conditions, which are widely known in the art for acylation reactions. Preferably, a compound of formula (V), wherein W is hydroxy, is converted into its corresponding acid chloride, wherein W is chlorine, in the presence of thionyl chloride or oxalyl chloride, in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1 ,4-dioxane, N,N- dimethylformamide or a mixture thereof, at a temperature ranging from about -10°C to reflux and for a period of time varying from about 1 h to about 96 h. The acid chloride is isolated by evaporation of the solvent and further reacted with (IV) in the presence of a base such as pyridine, triethylamine or Ν,Ν-diisopropylethylamine, at a temperature ranging from about -40°C to reflux and for a period of time varying from about 1 h to about 96 h. A suitable solvent may also be added, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran and 1 ,4-dioxane. Alternatively, a compound of formula (IV) is reacted with a compound of formula (V) wherein W is hydroxy in the presence of an activating agent such as hydroxybenzotriazole, dicyclohexyl carbodiimide, diisopropyl carbodiimide, 1-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloric acid salt, O-(benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate. Preferably, this reaction is carried out in a suitable solvent, such as, for instance, tetrahydrofuran, dichloromethane, toluene, 1 ,4-dioxane, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, and in the presence of a proton scavenger such as, for example, pyridine, triethylamine, N,N- diisopropylethylamine, at a temperature ranging from room temperature (about 22°C) to reflux, for a time ranging from about 30 min to about 96 h.
According to step c), the conversion of a compound of formula (VI) to give a compound of formula (VII) can be accomplished in a variety of ways, according to conventional methods for oxidizing sulfides to sulfones. Preferably, this reaction is carried out in a suitable solvent such as, for instance, methanol, ethanol, tert-butanol, water, tetrahydrofuran, 1 ,4-dioxane, dichloromethane, acetonitrile, or a mixture thereof, in the presence of a suitable oxidizing agent, such as, for instance, 3-chloroperbenzoic acid, hydrogen peroxide, urea hydrogen peroxide, potassium peroxymonosulfate (Oxone™). Typically, the reaction is carried out at a temperature ranging from -78 °C to reflux and for a time varying from about 30 min to about 96 h.
According to step d) of the process, a compound of formula (VII) wherein R5, R6 and Hal are as defined above and X is -N(CHR1 R2)COCF3 is transformed into a compound of formula (VIII) by removal of the trifluoroacetyl group, according to conventional methods. For example, the reaction may be carried out by treatment with an organic or inorganic base such as potassium carbonate, sodium hydroxide, ammonia, triethylamine, N,N- diisopropylethylamine in a suitable solvent, such as, for instance, tetrahydrofuran, dichloromethane, toluene, 1 ,4- dioxane, methanol, ethanol, water or mixtures thereof, at a temperature ranging from room temperature (about 22°C) to reflux, for a time ranging from about 30 min to about 96 h.
According to step e), the coupling of a compound of formula (VIII) with an amine of formula (IX) to give a compound of formula (I) can be carried out in a variety of ways, according to conventional methods well known in the literature for Buchwald-Hartwig aminations. Preferably a compound of formula (VIII) is reacted with a compound of formula (IX) in a suitable solvent, such as, for example, tetrahydrofuran, 1 ,4-dioxane, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethoxyethane, acetonitrile, toluene, in the presence of catalytic amounts of a palladium derivative, such as, for example, tris(dibenzylideneacetone)dipalladium(0), palladium diacetate, and a phosphine ligand, such as, for example, 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, in the presence of a base, such as, for instance, sodium or lithium bis(trimethylsilyl)amide, sodium or potassium tert- butoxide, sodium, potassium or cesium carbonate, at a temperature ranging from 0 °C to reflux and for a period of time varying from about 15 min to about 96 h.
According to step f), the coupling of a compound of formula (VII) wherein R5, R6 and Hal are as defined above and X is a nitro group, with an amine of formula (IX) to give a compound of formula (X) can be accomplished in a way analogous to that specified above, under step e).
According to the step g) of the process, the reduction of a compound of formula (X) into a compound of formula (XI) can be carried out in a variety of ways, according to conventional methods for reducing a nitro to an amino group. Preferably, this reaction is carried out in a suitable solvent such as, for instance, methanol, ethanol, water, tetrahydrofuran, 1 ,4-dioxane, Ν,Ν-dimethylformamide, acetic acid, or a mixture thereof, in the presence of a suitable reducing agent, such as, for instance, hydrogen and a hydrogenation catalyst, or by treatment with cyclohexene or cyclohexadiene, or formic acid or ammonium formate and a hydrogenation catalyst, or a metal such as iron or zinc in the presence of an inorganic acid, such as hydrochloric acid, or by treatment with tin (II) chloride, at a temperature ranging from 0°C to reflux and for a time varying from about 1 h to about 96 h. The hydrogenation catalyst is usually a metal, most often palladium, which can be used as such or supported on carbon.
According to step h), the reaction of a compound of formula (XI) with an aldehyde or a ketone of formula (XII) to give a compound of formula (I), can be conducted in a variety of ways, according to conventional methods for carrying out reductive alkylations. Preferably, this reaction is carried out in a suitable solvent such as, for instance, methanol, Ν,Ν-dimethylformamide, dichloromethane, tetrahydrofuran, or a mixture thereof, in the presence of a suitable reducing agent such as, for instance, sodium borohydride, tetra-alkylammonium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxy borohydride and in presence of an acid catalyst, such as, for instance, acetic acid or trifluoroacetic acid, at a temperature ranging from about 0°C to reflux and for a time varying from about 1 h to about 96 h.
According to any variant of the process for preparing the compounds of formula (I), the starting materials and any other reactant, i.e. compounds of formula (II), (III), (V), (IX) and (XII) are either commercially available, known or easily prepared according to well-known methods described, for instance, in: B.M. Trost and I. Fleming, Comprehensive Organic Synthesis, 1991 , Pergamon Press; A.R. Katritzky, 0. Meth-Cohn and C.W. Rees, Comprehensive Organic Functional Group Transformations, 1995, Elsevier Pergamon; A.R. Katritzky and R.J.K. Taylor, Comprehensive Organic Functional Group Transformations II, 2005, Elsevier Pergamon.
In particular, the compound of formula (II) is commercially available and the compounds of formula (V), for instance those wherein W represent a halogen atom, e.g. a chlorine atom, are either commercially available, known or can be easily obtained from the corresponding carboxylic acids, that are either known or can be prepared by working according to conventional synthetic methods.
EXPERIMENTAL SECTION
The following examples illustrate but do not limit the invention.
In the examples below, as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings.
Figure imgf000013_0001
1H-NMR spectra were recorded in DMSO-cfe or CDCI3 at a constant temperature of 28°C on a Varian Inova 400 spectrometer (operating at 400.5 MHz and equipped with 5mm 1H{15N, 31 P} z axis PFG Indirect Detection Probe) and on a Varian Inova 500 spectrometer (operating at 499.75 MHz and equipped with 5mm 1H{13C,15N} z axis PFG Indirect Detection Cold-Probe or alternatively with 5mm 1H{13C-15N} z axis PFG Triple Resonance Probe). Residual solvent signal was used as reference (δ = 2.50 or 7.27 ppm). Data are reported as follows: chemical shift (4 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, bs = broad singlet, td = triplet of doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, m = multiplet), coupling constants {J, Hz), and number of protons. Electrospray (ESI) mass spectra were obtained on a Finnigan LCQ ion trap.
Two HPLC methods have been applied for process monitoring and purity assay. They have been run on Agilent 1100 series instrument and are defined in Table 1 (method n.1) and Table 2 (method n.2). Table 1
Figure imgf000014_0001
Table 2
HPLC method n.2
Column Zorbax Eclipse XDB-C8 4.6 x 150, 5.0 m
Column temperature 20°C
Injection volume 5 μΙ_
Flow 1.0 mL/min
Run time 20 min/min
Post run time 3.0 min
Wavelength 220 nm, 240 nm (bandwidth 4 nm)
Wavelength reference 600, 100 nm
Mobile phase A NH4OAc 5 mM pH 5.2 AcOH
Mobile phase B ACN
Gradient elution Minutes %A %B
0 60 40
15 20 80
16 20 80
20 60 40
Post-run 3 60 40 PREPARATION 1
4-Bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (V)
[Hal = Br; W = OH; X = -N(CHR1 R2)COCF3; CHR1 R2 = (R)-2-methoxy-1 -methyl-ethyl]
Step I. 4-Bromo-2-fluoro-benzoic acid tert-but l ester
Figure imgf000015_0001
9.88 Kg of 4-bromo-2-fluorobenzoic acid in 20 L of DCM and 40 L of t-BuOH are added with 280 g of dimethylaminopyridine; the reaction mixture is heated to 40°C under stirring and a solution of 15 Kg of B0C2O in 20 L of DCM is dropped over 3 h. When the reaction is complete (monitoring by HPLC method n. 1), the mixture is cooled at 20°C and 20 L of DCM and 20 L of 1 N HCI are sequentially added. The two phases are separated and the aqueous one is extracted with 20 L of DCM. The combined organic phases are washed sequentially with 20 L of 1 N HCI, 20 L of water, 20 L of 5% aqueous NaHCC solution and again with 20 L of water. The organic phase is evaporated to residue; 20 L of DCM are added and evaporated to give 4-bromo-2-fluoro-benzoic acid tert-butyl ester as oily residue that is used as such in the next step.
Step II. 4-Bromo-2-((R)-2-hydroxy-1-methyl-ethylamino)-benzoic acid tert-butyl ester
Figure imgf000015_0002
A solution of 6.95 Kg of D-alaninol in 5 L of DCM is added to the oily 4-bromo-2-fluoro-benzoic acid tert-butyl ester of Step I. The mixture is heated to 103°C distilling away the solvent and then is stirred at the same temperature for 40 h. When the reaction is complete (monitoring by HPLC method n. 1), the mixture is cooled to 50°C; 50 L of water and 50 L of EtOAc are added. The phases are separated and the aqueous one is extracted with 40 L of EtOAc. The combined organic phases are washed with 20 L of water followed by 20 L of 1 N HCI and finally washed three times with 20 L of water. The organic phase is separated, concentrated under reduced pressure to oily residue and stripped with 20 L of DCM to obtain 11.4 Kg of 4-bromo-2-((R)-2-hydroxy-1-methyl-ethylamino)- benzoic acid tert-butyl ester.
1H NMR (499.75 MHz, DMSO-cie), δ: 7.87 (d, J=7.9 Hz, 1 H), 7.68 (d, J=8.5 Hz, 1 H), 6.99 (d, J=1.8 Hz, 1 H), 6.73 (dd, J1=1.9 Hz, J2=8.5 Hz, 1H), 4.97-4.90 (m, 1 H), 3.70-3.63 (m, 1 H), 3.52-3.43 (m, 2H), 1.57 (s, 9H), 1.19 (d, J=5.6 Hz, 3H).
Step III. 4-Bromo-2-((R)-2-methoxy-1-methyl-ethylamino)-benzoic acid tert-butyl ester
Figure imgf000015_0003
4.35 Kg of Mel are added at -15°C to 7.9 Kg of 4-bromo-2-((R)-2-hydroxy-1-methyl-ethylamino)-benzoic acid tert- butyl ester in 28 L of THF. To the obtained stirred suspension, 4.1 Kg of tBuOK suspended in 20 L of THF are added portionwise keeping the temperature at -15°C and monitoring by HPLC method n. 1. When the reaction is complete the mixture is added with water (24 L) and DCM (35 L). After separation of the phases the organic one is washed twice with water (24 L) and concentrated for the first time at reduced pressure to oily residue. The residue is further added with 16 L of DCM and concentrated for the second time to oily residue, then it is added with 17 L of DCM, obtaining a yellow solution of 4-bromo-2-((R)-2-methoxy-1-methyl-ethylamino)-benzoic acid tert-butyl ester. If water content is < 0.1% (KF) this solution is used as such in the next step otherwise stripping with DCM is repeated till the desired value is reached.
Step IV. 4-Bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl
Figure imgf000016_0001
The solution of 4-bromo-2-((R)-2-methoxy-1-methyl-ethylamino)-benzoic acid tert-butyl ester in 17 L of DCM of Step III is cooled to -10°C then a solution of 4.2 L of TFAA in 4 L of DCM is dropped in at least 1 h under stirring. When the starting material conversion, monitored by HPLC method n. 1 , is complete, the mixture is added with 22.5 L of 2.5% aqueous NaHC03 solution and the phases are separated. The aqueous phase is extracted once with DCM (8 L). The collected organic phases are washed with 10.5 L of 10% aqueous sodium chloride solution and then with 11 L of water. The organic phase is evaporated under reduced pressure to oily residue, added with 16 L of DCM and distilled under reduced pressure to oil to be stripped. Further 16 L of DCM is added and the solution distilled under reduced pressure to match the condition of KF < 0.1% obtaining the crude 4-bromo-2-[((R)- 2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester as oil that is used as such in the next step.
1H NMR (499.75 MHz, DMSO-de), δ: 7.97-7.85 (m, 2H), 7.77 and 7.66 (2d, J=1.8 Hz, 1 H), 4.91-4.84 and 4.48-4.40 (2m, 1 H), 3.49-3.45 and 3.30-3.20 (2m, 2H), 3.33 and 3.02 (2s, 3H), 1.53 (s, 9H), 1.26 and 0.88 (2d, J=6.9 Hz, 3H). Mixture of rotamers.
Step V. 4-Bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (V)
[H l = Br; W = OH; X = -N(CHR1 R2)COCF3; CHR1 R2 = (R)-2-methoxy-1 -methyl-ethyl]
Figure imgf000016_0002
The 4-bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester of Step IV is dissolved in 40 L of DCM and added with 17.9 Kg of TFA at room temperature (about 22 °C). The reaction mixture is stirred at that temperature until the HPLC monitoring (method n. 1) shows complete reaction, then is evaporated to residue and stripped five times with toluene (20 L each time). The residue is dissolved in 30 L of DCM and extracted four times with 30 L of 4% aqueous NaHC03 solution. 100 L of DCM are added to the combined aqueous phases and the pH is adjusted to the range 1-4 by adding a solution of 23% aqueous HCI under stirring. The phases are separated and the organic one is evaporated to residue stripping twice with 20 L of DCM, affording 6.51 Kg of 4-bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid as an oil (overall yield from 4-bromo-2-((R)-2-hydroxy-1-methyl-ethylamino)-benzoic acid tert-butyl ester: 70.8%). 1H NMR (499.75 MHz, DMSO-de), δ: 8.00-7.82 (m, 2H), 7.78 and 7.65 (2d, J=2.0 Hz, 1 H), 4.88-4.81 and 4.51-4.43 (2m, 1 H), 3.47-3.23 (m, 2H), 3.32 and 3.08 (2s, 3H), 1.21 and 0.90 (2d, J=7.0 Hz, 3H)(mixture of rotamers).
EXAMPLE 1
N-[5-(3,5-Difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino) -(4-meth piperazin-1-yl)-benzamide (I), cpd 25
[CHR1 R2 = (R)-2-methoxy-1 -methyl-ethyl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Step a)
5-(3,5-Difluoro-phenylsulfanyl)-1 H-indazol-3-ylamine (IV)
= 3-F; R6 = 5-F]
Figure imgf000017_0001
11.5 Kg of potassium carbonate, 9.0 Kg of 5-iodo-1 H-indazol-3-ylamine, 5.85 L of diethylene glycol, and 657 g of copper (I) iodide in 6.7 L of 2-propanol are heated to 60°C under nitrogen atmosphere. 7.2 Kg of 3,5-d ifluoro- benzenethiol are added and the mixture is heated to reflux at about 85°C under stirring until reaction completion. While cooling the reaction mixture to room temperature (about 22°C), 330 L of water are added. The suspension is finally cooled to room temperature (about 22°C). The product is filtered and the cake is washed twice with 50 L of water; the wet cake is dissolved in 110 L of ethyl acetate, washed seven times with 100 L of a solution prepared by mixing 630 L of water, 90 kg of NaCI and 36 L of NH4OH, and once with brine solution prepared dissolving 9.0 Kg of NaCI in 95 L of water. The organic phase is filtered on a 20 μίη filter and then passed on a R54SP Zeta Carbon CUNO filter. After partial evaporation of the solution till about 45 L, 62 L of n-heptane are added to precipitate the product. The mixture is further evaporated till about 45 L then about 16 L of n-heptane are added. The suspension is filtered washing twice with 18.0 L of n-heptane and the wet cake is dried under vacuum at 50°C. 8.42 Kg of 5- (3,5-difluoro-phenylsulfanyl)-1 H-indazol-3-ylamine have been obtained (yield = 87.5%, 99.4% purity by HPLC method n. 2).
1H NMR (400.5 MHz, DMSO-cie), δ: 11.74 (bs, 1 H), 8.06 (s, 1 H), 7.30-7.40 (m, 2H), 6.98 (tt, J=9.2 Hz, 1 H), 6.58- 6.73 (m, 2H), 5.53 (bs, 2H).
Step b)
4-Bromo-N-[5-(3,5-difluoro-phenylsulfanyl)-1 H-indazol-3-yl]-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2- trifluoro-acetyl)-amino]-benzamide (VI) = Br; X = -N(CHR1 R2)COCF3; CHR1 R2 = (R)-2-methoxy-1-methyl-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000018_0001
6.5 Kg of 4-bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid are suspended in 49 L of DCM then 67 mL of DMF and 5.37 Kg of oxalyl chloride are added in sequence. The reaction mixture is stirred at room temperature (about 22°C) until complete conversion into 4-bromo-2-[((R)-2-methoxy-1-methyl- ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoyl chloride. The reaction is monitored by HPLC method n. 1. The mixture is evaporated to residue, then added with 6.5 L of DCM and evaporated again; this procedure is repeated 4 times. The final residue is dissolved in 29.5 L of DCM and the 83% of the solution is slowly dropped into a stirred solution of 3.76 Kg of 5-(3,5-difluoro-phenylsulfanyl)-1 H-indazol-3-ylamine in 52.5 L of anhydrous pyridine pre-cooled to - 15°C. The reaction is run stirring at -15°C and conversion is monitored by HPLC method n. 2. If necessary, more DCM solution of the acid chloride of 4-bromo-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]- benzoic acid is added to complete the reaction. 57 L of water are added at -15°C to quench the reaction mixture; the organic phase is separated and washed twice with 30 L of 1 N HCI, twice with 28 L of 4% aqueous NaHCC solution, and once with 30 L of water. The DCM solution is evaporated to residue and stripped four times with 7.5 L of toluene. The crude 4-bromo-N-[5-(3,5-difluoro-phenylsulfanyl)-1 H-indazol-3-yl]-2-[((R)-2-methoxy-1-methyl- ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide thus obtained is used as such in the next step.
Step c¾
4-Bromo-N-[5-(3,5-difluoro-benzenesulfo^
trifluoro-acetyl)-amino]-benzamide (VII)
= Br; X = -N(CHR1 R2)COCF3; CHR1 R2 = (R)-2-methoxy-1-methyl-ethyl; R5 = 3-F; R6 = 5-F]
The crude 4-bromo-N-[5-(3,5-difluoro^henylsulfanyl)-1 H-indazol-3-yl]-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2- trifluoro-acetyl)-amino]-benzamide of Step b) is dissolved in 110 L of acetonitrile, heated to 40°C and added with a solution of 27 Kg of Oxone™ (potassium peroxymonosulfate) in 110 L of water. The reaction mixture is stirred at 40°C until complete conversion, monitored by HPLC method n. 2, into 4-bromo-N-[5-(3,5-difluoro- benzenesulfonyl)-1 H-indazol-3-yl]-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2 rifluoro-acetyl)-amino]-benz
When the oxidation is complete the reaction is cooled to room temperature (about 22°C) and 55 L of water are added. The mixture is extracted first with 130 L of DCM and then with 60 L of DCM; the pooled organic phases are washed twice with 100 L of water. The DCM is partially evaporated to about 45 L, 200 L of MeOH are added and DCM is completely removed by distillation to a volume of about 45 L. Additional 60 L of MeOH are finally added. The methanolic solution of 4-bromo-N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-[((R)-2-methoxy-1- methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide thus obtained is used in the next step.
Step d¾
4-Bromo-N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylam benzamide (VIII)
= Br; CHR1 R2 = (R)-2-methoxy-1-methyl-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000019_0001
The methanolic solution of 4-bromo-N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-[((R)-2-methoxy-1- methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide of Step c) is heated to 50°C and 37 L of TEA are added. The reaction mixture is stirred at 50°C until complete conversion into 4-bromo-N-[5-(3,5-difluoro-benzenesulfonyl)- 1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide, monitored by HPLC method n. 2. The solvent is distilled away at 34-45 °C under reduced pressure till a residual oil is obtained and 65 L of EtOAc are added; the evaporation and addition of EtOAc are repeated twice. The final EtOAc solution is washed once with 37 L of 20% brine solution and once with 35 L of water; the organic phase is evaporated to about 10 L and added with 100 L of EtOAc; at this point the water content of the solution is measured (IPC: KF must be < 0.35%) and if necessary a further addition and evaporation of EtOAc is run. In another vessel, 150 L of n-heptane are charged at room temperature (about 22°C) then the ethyl acetate solution (about 110 L) is charged drop-wise leading to precipitation of the product which is isolated by filtration. The cake is washed with about 3 L of n-heptane then the solid is dried in oven at 50°C under vacuum to give 6.5 Kg of crude product which is crystallized from about 62 L of EtOH 96% to give 5.3 Kg of purified 4-bromo-N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2- methoxy-1-methyl-ethylamino)-benzamide (yield = 67.4% from 5-(3,5-difluoro-phenylsulfanyl)-1 H-indazol-3- ylamine; 98.9% purity by HPLC method n. 2).
1H NMR (400.5 MHz, DMSO-cie), δ: 13.37 (s, 1 H), 10.88 (s, 1 H), 8.51 (d, J=1.3 Hz, 1 H), 7.95 (d, J=7.9 Hz, 1 H), 7.91 (dd, J1=9.0 Hz, J2=1.8 Hz, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.71- 7.74 (m, 2H), 7.69 (d, J=9.0 Hz, 1 H), 7.58-7.65 (m, 1 H), 7.00 (d, J=1.7 Hz, 1 H), 6.79 (dd, J1=8.5 Hz, J2=1.8 Hz, 1 H), 3.75-3.87 (m, 1 H), 3.35-3.40 (m, 2H), 3.28 (s, 3H), 1.15 (d, J=6.5 Hz, 3H).
Step e
N-[5-(3,5-Difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino) -(4-m piperazin-1-yl)-benzamide (I), cpd 25
[CHR1 R2 = (R)-2-methoxy-1 -methyl-ethyl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000020_0001
74.6 g of palladium acetate and 86.4 L of THF are charged in the reactor and the suspension is degassed twice by applying vacuum and then nitrogen. 194.2 g of RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl) are charged and the mixture is again carefully degassed; a solution of 4.8 Kg of 4-bromo-N-[5-(3,5-difluoro- benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide in 57.6 L of THF, previously degassed, is dropped at room temperature (about 22°C) into the catalyst solution. 4.6 L of N-methylpiperazine and 29.3 L of a 1.0 M THF solution of lithium bis(trimethylsilyl)amide are added degassing after each addition: finally the reaction mixture is heated to 60°C and stirred at this temperature. When the reaction, monitored by HPLC method n. 2, is complete, 20% aqueous NaCI solution (about 14.5 L) is added. The reaction mixture is cooled to room temperature (about 22°C), then stirring is switched off and the phases separated. The organic phase is washed with 28 L of an aqueous solution made by mixing aqueous NaCI (3 Kg of NaCI in 20 L of water) and 5 L of a 15% aqueous solution of 1 ,3,5-triazine-2,4,6-trithiol trisodium salt and then further washed with 23 L of 10% aqueous NaCI solution. The washed organic phase is then added with a mixture of 240 g of silica gel and 750 mL of 15% aqueous solution of 1 ,3,5-triazine-2,4,6-trithiol trisodium salt and stirred overnight at room temperature (about 22°C). The suspension is filtered and the filtrate after evaporation is purified by column chromatography on silica gel (100 Kg), eluting with about 500 L of DCM/EtOH 98:2 then with about 500 L of DCM/EtOH 95:5. The pooled fractions are checked by TLC (silica gel, DCM/EtOH 9:1), concentrated and the solution (about 100 L) is treated with 330 g of Siliabond DMT for 18 h, then the suspension is filtered. The filtrate is concentrated to 80 L and added with 210 L of n-heptane. After further distillation to reach a volume of 100 L, the suspension is cooled to 20°C and stirred for at least 3 h before filtration. The filtered product is washed with 25 L of n-heptane and dried under vacuum at 50°C to give 2.75 Kg of N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((R)-2-methoxy-1- methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide (yield 55.45%; 99.02 % purity by HPLC Method n. 2). 1H NMR (400.5 MHz, DMSO-cie), δ: 13.25 (bs, 1 H), 10.42 (bs, 1 H), 8.47 (m, 1 H), 8.19 (d, J=7.8 Hz, 1 H), 7.89 (dd, J1 =8.9 Hz, J2=1.8 Hz, 1 H), 7.80 (d, J=9.1 Hz, 1 H), 7.72 (m, 2H), 7.66 (d, J=9.0 Hz, 1 H), 7.62 (m, 1 H), 6.26 (dd, J1 =9.1 Hz, J2=2.3 Hz, 1 H), 6.14 (d, J=2.3 Hz, 1 H), 3.82 (m, 1 H), 3.42-3.27 (m, 6H), 3.29 (s, 3H), 2.45 (m, 4H), 2.23 (s, 3H), 1.16 (d, J=6.4 Hz, 3H).
EXAMPLE 2
N-(5-benzenesulfonyl-1 H-indazol-3-yl) -(4-methyl^iperazin-1-yl)-2-(tetrahydro^yran -ylamino)- benzamide (I), cpd 1
[CHR1 R2 = tetrahydro-pyran-4-yl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = H; R6 = H]
Step a)
5-Phenylsulfanyl-1 H-indazol-3-ylamine (IV) = H; R6 = H]
Figure imgf000021_0001
Operating as described in Step a) of Example 1, coupling 5-iodo-1 H-indazol-3-ylamine with benzenethiol, obtained 5-phenylsulfanyl-1 H-indazol-3-ylamine.
ESI(+) MS: m/z242 (MH+).
Step b)
N-(5-Phenylsulfanyl-1H-indazol-3-yl)-4-bromo-2-nitro-benzamide (VI)
= Br;X=N02; R5 = H;R6 = H]
Figure imgf000021_0002
Operating as described in Step b) of Example 1, starting from 5-phenylsulfanyl-1 H-indazol-3-ylamine and acylating with 4-bromo-2-nitro-benzoyl chloride, was obtained 4-bromo-2-nitro-N-(5-phenylsulfanyl-1 H-indazol-3-yl)- benzamide.
1H NMR (400.5 MHz, DMSO-cie), δ: 13.06 (s, 1H), 11.29 (s, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.13 (s, 1H), 8.10 (dd, J1=8.2 Hz, J2=1.6 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.38-7.43 (m, 1H), 7.27-7.32 (m, 2H), 7.19 (d, J=7.5 Hz, 1H), 7.14-7.17 (m, 2H).
ESI(+) MS: m/z470 (MH+).
Step c)
N-(5-Benzenesulfonyl-1H-indazol-3-yl)-4-bromo-2-nitro-benzamide (VII)
= Br;X=N02; R5 = H;R6 = H]
Figure imgf000021_0003
Operating as described in Step c) of Example 1, starting from 4-bromo-2-nitro-N-(5-phenylsulfanyl-1 H-indazol-3-yl)- benzamide, was obtained N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-bromo-2-nitro-benzamide.
1H NMR (400.5 MHz, DMSO-cie), δ: 13.35 (s, 1H), 11.50 (s, 1H), 8.72 (s, 1H), 8.41 (d, J=1.3 Hz, 1H), 8.08-8.19 (m, 1H), 7.89-7.97 (m, 2H), 7.79-7.88 (m, 2H), 7.64-7.70 (m, 2H), 7.58-7.64 (m, 2H).
Step ft
N-(5-Benzenesulfonyl-1H-indazol-3-yl) -(4-methyl^iperazin-1-yl)-2-nitro-benzamide (X) [NR3R4 = 4-methyl-piperazin-1-yl; R5
Figure imgf000022_0001
Operating as described in Step e) of Example 1 , starting from N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-bromo-2- nitro-benzamide, was obtained N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-2-nitro- benzamide.
1H NMR (400.5 MHz, DMSO-d6), δ: 13.27 (bs, 1 H), 11.19 (bs, 1 H), 8.61 (m, 1 H), 7.91 (m, 2H), 7.79 (dd, J1=8.90 Hz, J2=1.83 Hz, 1 H), 7.57-7.72 (m, 5H), 7.47 (d, J=2.5 Hz, 1 H), 7.27 (dd, J1 =9.15 Hz, J2=2.5 Hz, 1 H), 2.36 (m, 4H), 2.45 (m, 4H), 2.23 (s, 3H).
Step q)
2-Amino-N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide (XI)
= 4-methyl-piperazin-1-yl; R5 = H; R6 = H]
Figure imgf000022_0002
Operating as described in WO2008/074749, Example 21 , starting from N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4- methyl-piperazin-1-yl)-2-nitro-benzamide was obtained 2-amino-N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4- methyl-piperazin-1-yl)-benzamide.
1H NMR (400.5 MHz, DMSO-cie), δ: 13.17 (bs, 1 H), 10.36 (bs, 2H), 8.45 (bs, 1 H), 7.92 (m, 2H), 7.77 (dd, J1 =8.78 Hz, J2=1.70 Hz, 1 H), 7.73 (d, J=9.03 Hz, 1 H), 7.55-7.67 (m, 4H), 6.57 (bs, 2H), 6.26 (dd, J1=9.03 Hz, J2=2.32 Hz, 1 H), 6.19 (d, J=2.32 Hz, 1 H), 3.21 (m, 4H), 2.42 (m, 4H), 2.21 (s, 3H).
Step h¾
N-(5-Benzenesulfonyl-1 H-indazol-3-yl) -(4-methyl^iperazin-1-yl)-2-(tetrahydro^yran -ylamino)- benzamide (I), cpd 1
[CHR1 R2 = tetrahydro-pyran-4-yl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = H; R6 = H]
Figure imgf000023_0001
Operating as described in WO2008/074749, Example 23, starting from 2-amino-N-(5-benzenesulfonyl-1 H-indazol- 3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide was obtained N-(5-benzenesulfonyl-1 H-indazol-3-yl)-4-(4-methyl- piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1 H), 10.44 (bs, 1 H), 8.41 (bs, 1 H), 8.29 (d, J=7.81 Hz, 1 H), 7.95 (m, 2H), 7.83 (m, 2H), 7.58-7.70 (m, 4H), 6.29 (dd, J1 =9.03 Hz, J2=2.07 Hz, 1 H), 6.18 (d, J=2.07 Hz, 1 H), 3.82-3.88 (m, 2H), 3.74 (m, 1 H), 3.54 (m, 2H), 3.28-3.32 (m, 4H), 2.46 (m, 4H), 2.68 (s, 3H), 1.99 (m, 2H), 1.40 (m, 2H).
EXAMPLE 3
Operating as described in Steps a)-d) of Example 1 , by using the appropriate compound of formula (V) and the appropriate amine of formula (IX), the following compounds were obtained:
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2^
benzamide (I), cpd 22
= H; R2 = methoxymethyl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000023_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.26 (bs, 1 H), 10.45 (bs, 1 H), 8.50 (d, J=1.2 Hz, 1 H), 8.23 (bt, J=5.0 Hz, 1 H), 7.90 (dd, J1 =8.9, J2=1.8 Hz, 1 H), 7.82 (d, J=9.1 Hz, 1 H), 7.73 (m, 2H), 7.67 (dd, J1 =8.9 Hz, J2=0.7 Hz, 1 H), 7.64 (m, 1 H), 6.29 (dd, J1=9.0 Hz, J2=2.3 Hz, 1 H), 6.11 (d, J=2.3 Hz, 1 H), 3.57 (bt, J=5.2 Hz, 2H), 3.36-3.30 (m, 6H), 3.30 (s, 3H), 2.48 (m, 4H), 2.29 (bs, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino) -(4-m piperazin-1-yl)-benzamide (I), cpd 24
[CHR1 R2 = (S)-2-methoxy-1-methyl-ethyl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000024_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.25 (bs, 1H), 10.42 (bs, 1H), 8.47 (m, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.72 (m, 2H), 7.66 (d, J=9.0 Hz, 1H), 7.62 (m, 1H), 6.26 (dd, J1=9.1 Hz, J2=2.3 Hz, 1H), 6.14 (d, J=2.3 Hz, 1H), 3.82 (m, 1H), 3.42-3.27 (m, 6H), 3.29 (s, 3H), 2.45 (m, 4H), 2.23 (s, 3H), 1.16 (d, J=6.4 Hz, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylH-[(2-dimethylamino-ethyl)-me^
methoxy-1-methyl-ethylamino)-benzamide (I), cpd 12
R1 = methyl; R2 = methoxymethyl; R3 = methyl; R4 = 2-dimethylamino-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000024_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.24 (bs, 1H), 10.33 (bs, 1H), 8.47 (m, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.90 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.73 (m, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.64 (m, 1H), 6.05 (dd, J1=9.0 Hz, J2=2.3 Hz, 1H), 5.89 (d, J=2.3 Hz, 1H), 3.76 (m, 1H), 3.50 (m, 2H), 3.46-3.34 (m, 2H), 3.30 (s, 3H), 3.00 (s, 3H), 2.49 (m, 2H), 2.27 (bs, 6H), 1.19 (d, J=6.3 Hz, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylH-[(2-dimethylamino-ethyl)-methyl-amin
methoxy-ethylamino)-benzamide (I), cpd 23
= H; R2 = methoxymethyl; R3 = methyl; R4 = 2-dimethylamino-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000024_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.23 (bs, 1H), 10.34 (bs, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.28 (bt, J=5.1 Hz, 1H), 7.89 (dd, J1=9.0 Hz, J2=1.8 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.72 (m, 2H), 7.66 (dd, J1=8.9 Hz, J2=0.6 Hz, 1H), 7.62 (m, 1H), 6.06 (dd, J1=9.0 Hz, J2=2.2 Hz, 1H), 5.83 (d, J=2.2 Hz, 1H), 3.57 (bt, J=5.2 Hz, 2H), 3.51 (m, 2H), 3.32 (m, 2H), 3.29 (s, 3H), 2.99 (s, 3H), 2.52 (m, 2H), 2.28 (bs, 6H). N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]^
(tetrahydro-pyran-4-ylamino)-benzamide (I), cpd 26
= tetrahydro-pyran-4-yl; R3 = H; R4 = 2-dimethylamino-1-methyl-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000025_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.21 (bs, 1 H), 10.26 (bs, 1 H), 8.45 (d, J=1.1 Hz, 1 H), 8.33 (d, J=7.4 Hz, 1 H), 7.90 (dd, J1 =8.9, J2=1.8 Hz, 1 H), 7.74-7.69 (m, 3H), 7.66 (dd, J1=8.9 Hz, J2=0.6 Hz, 1 H), 7.63 (m, 1 H), 5.97-5.89 (m, 3H), 3.85 (m, 2H), 3.65-3.52 (m, 2H), 3.47 (m, 2H), 2.34 (m, 1 H), 2.20 (s, 6H), 2.16 (m, 1 H), 1.98 (m, 2H), 1.41 (m, 2H), 1.16 (d, J=6.2 Hz, 3H).
4-(2-diethylamino-1-methyl-ethylamino)-N-^
pyran-4-ylamino)-benzamide (I), cpd 27
= tetrahydro-pyran-4-yl; R3 = H; R4 = 2-diethylamino-1-methyl-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000025_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.23 (bs, 1 H), 10.26 (bs, 1 H), 8.46 (d, J=1.1 Hz, 1 H), 8.35 (d, J=7.3 Hz, 1 H), 7.90 (dd, J1 =8.9, J2=1.8 Hz, 1 H), 7.74-7.69 (m, 3H), 7.67 (dd, J1 =8.9 Hz, J2=0.6 Hz, 1 H), 7.64 (m, 1 H), 5.97-5.86 (m, 3H), 3.86 (m, 2H), 3.56 (m, 2H), 3.47 (m, 2H), 2.64-2.54 (m, 2H), 2.50-2.41 (m, 3H), 2.24 (dd, J1 =12.8 Hz, J2=8.3 Hz, 1 H), 1.99 (m, 2H), 1.40 (m, 2H), 1.17 (d, J=6.3 Hz, 3H), 0.99 (t, J=7.1 Hz, 6H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-2-(tetrahydro-pyran-4- ylamino)-benzamide (I), cpd 28
-yl; R3 = H; R4 = 1-methyl-piperidin-4-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000025_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1 H), 10.28 (bs, 1 H), 8.46 (d, J=1.1 Hz, 1 H), 8.30 (d, J=7.1 Hz, 1 H), 7.90 (dd, J1 =8.9, J2=1.8 Hz, 1 H), 7.75-7.70 (m, 3H), 7.67 (dd, J1 =8.9 Hz, J2=0.6 Hz, 1 H), 7.64 (m, 1 H), 6.04 (bd, J=7.8 Hz, 1 H), 5.95 (dd, J1=9.0 Hz, J2=2.0 Hz, 1 H), 5.91 (d, J=2.0 Hz, 1 H), 3.86 (m, 2H), 3.56 (m, 1 H), 3.49 (m, 2H), 2.76 (m, 2H), 2.59 (m, 1 H), 2.21 (s, 3H), 2.08 (m, 2H), 1.97 (m, 2H), 1.89 (m, 2H), 1.42 (m, 4H).
EXAMPLE 4
Operating as described in Steps a)-c), and f)-h) of Example 2, by using the appropriate benzenethiol of formula (III), the appropriate amine of formula (IX) and the appropriate carbonyl derivative of formula (XII), the following compounds were obtained:
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-ylH-[(2-dimethylamino-ethyl)-me^
(tetrahydro-pyran-4-ylamino)-benzamide (I), cpd 2
HR1 R2 = tetrahydro-pyran-4-yl; R3 = methyl; R4 = 2-dimethylamino-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000026_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.25 (bs, 1 H), 10.37 (bs, 1 H), 8.47 (m, 1 H), 8.34 (bd, J=7.4 Hz, 1 H), 7.91 (dd, J1 =8.9 Hz, J2=1.8 Hz, 1 H), 7.81 (d, J=9.1 Hz, 1 H), 7.72 (m, 2H), 7.68 (d, J=8.9 Hz, 1 H), 7.64 (m, 1 H), 6.07 (dd, J1 =9.1 Hz, J2=2.2 Hz, 1 H), 5.90 (d, J=2.2 Hz, 1 H), 3.89-3.82 (m, 2H), 3.67 (m, 1 H), 3.54-3.46 (m, 4H), 3.00 (s, 3H), 2.47 (m, 2H), 2.26 (bs, 6H), 2.04-1.96 (m, 2H), 1.47-1.36 (m, 2H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl] -[(2-dimethylamino-ethyl)-ethyl-amino]
pyran-4-ylamino)-benzamide (I), cpd 3
HR1 R2 = tetrahydro-pyran-4-yl; R3 = ethyl; R4 = 2-dimethylamino-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000026_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1 H), 10.33 (bs, 1 H), 8.45 (m, 1 H), 8.33 (bd, J=7.4 Hz, 1 H), 7.90 (dd, J1 =8.9 Hz, J2=1.8 Hz, 1 H), 7.79 (d, J=9.2 Hz, 1 H), 7.71 (m, 2H), 7.66 (d, J=8.9 Hz, 1 H), 7.63 (m, 1 H), 6.02 (dd, J1 =9.1 Hz, J2=2.2 Hz, 1 H), 5.86 (d, J=2.2 Hz, 1 H), 3.88-3.81 (m, 2H), 3.62 (m, 1 H), 3.51-3.38 (m, 6H), 2.42 (m, 2H), 2.22 (bs, 6H), 2.02-1.94 (m, 2H), 1.47-1.36 (m, 2H), 1.12 (bt, J=6.8 Hz, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1 H-indazol-3-yl]-4-(4-ethyl-[1,4]diazepan-1-yl)-2-(tetrahydro-pyran-4- ylamino)-benzamide (I), cpd 4
[CHR1 R2 = tetrahydro-pyran-4-yl; NR3R4 = 4-ethyl-[1 ,4]diazepan-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000027_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.23 (bs, 1H), 10.35 (bs, 1H), 8.46 (m, 1H), 8.34 (bd, J=7.3 Hz, 1H), 7.90 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.71 (m, 2H), 7.66 (d, J=8.9 Hz, 1H), 7.63 (m, 1H), 6.10 (m, 1H), 5.90 (m, 1H), 3.83 (m, 2H), 3.69 (m, 1H), 3.62-3.48 (m, 6H), 2.71 (m, 2H), 2.53-2.44 (m, 4H), 1.97 (m, 2H), 1.87 (m,2H), 1.40 (m, 2H), 1.00 (bs, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-i^
4-ylamino)-benzamide (I), cpd 5
= tetrahydro-pyran-4-yl; NR3R4 = 4-dimethylamino-piperidin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000027_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.24 (bs, 1H), 10.42 (bs, 1H), 8.45 (m, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.808d, J=9.1 Hz, 1H), 7.71 (m, 2H), 7.66 (dd, J1=8.9 Hz, J2=0.6 Hz, 1H), 7.62 (m, 1H), 6.25 (m, 1H), 6.14 (m, 1H), 3.89 (m, 2H), 3.82 (m, 2H), 3.70 (m, 1H), 3.51 (m, 2H), 2.80 (m, 2H), 2.32 (m, 1H), 2.21 (s, 6H), 1.95 (m, 2H), 1.82 (m, 2H), 1.5-1.3 (m, 4H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol^
(tetrahydro-pyran-4-ylamino)-benzamide (I), cpd 6
= tetrahydro-pyran-4-yl; R3 = methyl; R4 = 1-methyl-pyrrolidin-3-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000027_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.25 (bs, 1H), 10.38 (bs, 1H), 8.47 (m, 1H), 8.34 (d, J=7.4 Hz, 1H), 7.91 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.73 (m, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.64 (m, 1H), 6.17 (dd, J1=9.1 Hz, J2=2.3 Hz, 1H), 6.02 (d, J=2.3 Hz, 1H), 4.60 (m, 1H), 3.84 (m, 2H), 3.72 (m, 1H), 3.53 (m, 2H), 2.94 (s, 3H), 2.9-2.7 (m, 2H), 2.4-2.1 (m, 6H), 1.99 (m, 2H), 1.77 (m, 1H), 1.41 (m, 2H). N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl] -{[2-(isopropyl-methyl-amino)-ethyl]-methy
(tetrahydro-pyran-4-ylamino)-benzamide (I), cpd 7
CHR1R2 = tetrahydro-pyran-4-yl; R3 = methyl; R4 = 2-(isopropyl-methyl-amino)-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000028_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1H), 10.34 (bs, 1H), 8.45 (m, 1H), 8.33 (d, J=7.3 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.71 (m, 2H), 7.65 (d, J=8.9 Hz, 1H), 7.62 (m, 1H), 6.03 (m, 1H), 5.88 (m, 1H), 3.83 (m, 2H), 3.64 (m, 1H), 3.51-3.38 (m, 4H), 2.99 (s, 3H), 2.77 (m, 1H), 2.50 (m, 2H), 2.22 (s, 3H), 1.98 (m, 2H), 1.40 (m, 2H), 0.93 (bd, 6H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-inda
(tetrahydro-pyran-4-ylamino)-benzamide (I), cpd 8
HR1R2 = tetrahydro-pyran-4-yl; R3 = methyl; R4 = 2-morpholin-4-yl-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000028_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.24 (bs, 1H), 10.37 (bs, 1H), 8.47 (m, 1H), 8.35 (d, J=7.4 Hz, 1H), 7.92 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.73 (m, 2H), 7.66 (d, J=9.0 Hz, 1H), 7.64 (m, 1H), 6.07 (m, 1H), 5.90 (m, 1H), 3.85 (m, 2H), 3.68 (m, 1H), 3.60 (m, 4H), 3.57-3.46 (m, 4H), 3.01 (s, 3H), 2.50-2.42 (m, 6H), 2.00 (m,2H), 1.42 (m, 2H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2- (tetrahydro-pyran-4-ylamino)-benzamide (I), cpd 9
HR1R2 = tetrahydro-pyran-4-yl; R3 = methyl; R4 = 3-dimethylamino-propyl; R5 = 3-F; R6 = 5-F]
Figure imgf000028_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.23 (bs, 1H), 10.34 (bs, 1H), 8.46 (m, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.90 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.71 (m, 2H), 7.66 (d, J=9.0 Hz, 1H), 7.63 (m, 1H), 6.07 (dd, J1=9.1 Hz, J2=2.3 Hz, 1H), 5.89 (d, J=2.3 Hz, 1H), 3.84 (m, 2H), 3.67 (m, 1H), 3.50 (m, 2H), 3.41 (m, 2H), 2.97 (s, 3H), 2.24 (m, 2H), 2.15 (s, 6H), 1.99 (m, 2H), 1.66 (m, 2H), 1.40 (m, 2H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino) methyl-piperazin-1-yl)-benzamide (I), cpd 10
R1 = methoxymethyl; R2 = methoxymethyl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000029_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.25 (bs, 1H), 10.42 (bs, 1H), 8.47 (m, 1H), 8.31 (bd, J=8.3 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.70 (m, 2H), 7.66 (d, J=8.9 Hz, 1H), 7.62 (m, 1H), 6.27 (dd, J1=9.0 Hz, J2=2.2 Hz, 1H), 6.19 (d, J=2.2 Hz, 1H), 3.86 (m, 1H), 3.43 (d, J=5.0 Hz, 4H), 3.30 (m, 4H), 3.28 (s, 6H), 2.49 (m,4H),2.26 (bs, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol^
methoxy-1-methoxymethyl-ethylamino)-benzamide (I), cpd 11
R1 = methoxymethyl; R2 = methoxymethyl; R3 = methyl; R4 = 2-dimethylamino-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000029_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.23 (bs, 1H), 10.33 (bs, 1H), 8.48 (m, 1H), 8.38 (bd, J=7.8 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.78 (d, J=9.1 Hz, 1H), 7.71 (m, 2H), 7.66 (d, J=9.5 Hz, 1H), 7.63 (m, 1H), 6.06 (dd, J1=9.1 Hz, J2=2.1 Hz, 1H), 5.93 (d, J=2A Hz, 1H), 3.80 (m, 1H), 3.53-3.44 (m, 6H), 3.29 (s, 6H), 2.50-2.40 (m, 2H), 2.99 (s, 3H), 2.26 (bs, 6H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2- methoxy-1-methyl-ethylamino)-benzamide (I), cpd 13
R1 = methyl; R2 = methoxymethyl; R3 = methyl; R4 = 3-dimethylamino-propyl; R5 = 3-F; R6 = 5-F]
Figure imgf000029_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1H), 10.31 (bs, 1H), 8.46 (m, 1H), 8.24 (d, J=7.6 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H), 7.77 (d, J=9.1 Hz, 1H), 7.71 (m, 2H), 7.66 (d, J=9.0 Hz, 1H), 7.63 (m, 1H), 6.06 (dd, J1=9.0 Hz, J2=2.2 Hz, 1H), 5.89 (d, J=2.2 Hz, 1H), 3.76 (m, 1H), 3.44-3.32 (m, 4H), 3.29 (s, 3H), 2.97 (s, 3H), 2.29 (m, 2H), 2.19 (bs, 6H), 1.69 (m, 2H), 1.18 (d, J=6.3 Hz, 3H).
N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]^
isobutylamino-benzamide (I), cpd 14
R1 = H; R2 = isopropyl; R3 = methyl; R4 = 3-dimethylamino-propyl; R5 = 3-F; R6 = 5-F]
Figure imgf000030_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1H), 10.35 (bs, 1H), 8.47 (m, 1H), 8.39 (bt, J=5.1 Hz, 1H), 7.90 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.69 (m, 2H), 7.66 (d, J=8.9 Hz, 1H), 7.63 (m, 1H), 6.05 (dd, J1=9.0 Hz, J2=2.3 Hz, 1H), 5.80 (d, J=2.3 Hz, 1H), 3.41 (m, 2H), 3.01-2.95 (m, 5H), 2.26 (m, 2H), 2.17 (s, 6H), 1.91 (m, 1H), 1.67 (m, 2H), 0.98 (d, J=6.6 Hz, 6H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino) -(4-met piperazin-1-yl)-benzamide (I), cpd 15
R1 = methyl; R2 = methoxymethyl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000030_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.25 (bs, 1H), 10.42 (bs, 1H), 8.47 (m, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.89 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.72 (m, 2H), 7.66 (d, J=9.0 Hz, 1H), 7.62 (m, 1H), 6.26 (dd, J1=9.1 Hz, J2=2.3 Hz, 1H), 6.14 (d, J=2.3 Hz, 1H), 3.82 (m, 1H), 3.42-3.27 (m, 6H), 3.29 (s, 3H), 2.45 (m, 4H), 2.23 (s, 3H), 1.16 (d, J=6.4 Hz, 3H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]^
pyran-4-ylamino)-benzamide (I), cpd 16
[CHR1R2 = tetrahydro-pyran-4-yl; R3 = methyl; R4 = 2-piperidin-1-yl-ethyl; R5 = 3-F; R6 = 5-F]
Figure imgf000031_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.24 (bs, 1H), 10.36 (bs, 1H), 8.47 (m, 1H), 8.33 (bd, J=7.3 Hz, 1H), 7.90 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.72 (m, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.64 (m, 1H), 6.05 (m, 1H), 5.89 (m, 1H), 3.85 (m, 2H), 3.66 (m, 1H), 3.54-3.45 (m, 4H), 3.00 (s, 3H), 2.48-2.37 (m, 6H), 2.00 (m, 2H), 1.56-1.36 (m, 8H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-inte^
ylamino)-benzamide (I), cpd 17
CHR1R2 = tetrahydro-pyran-4-yl; NR3R4 = 4-methyl-piperazin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000031_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.27 (bs, 1H), 10.47 (bs, 1H), 8.48 (d, J=1.1 Hz, 1H), 8.29 (d, J=7.8 Hz, 1H), 7.92 (dd, J1=8.90, J2=1.82 Hz, 1H), 7.82 (d, J=9.14 Hz, 1H), 7.73 (m, 2H), 7.68 (dd, J1=8.91 Hz, J2=0.74 Hz, 1H), 7.64 (m, 1H), 6.28 (dd, J1=9.0 Hz, J2=2.07 Hz, 1H), 6.07 (d, J=2.07 Hz, 1H), 3.83 (m, 2H), 3.74 (m, 1H), 3.53 (m, 2H), 3.27.3.34 (m, 4H), 2.46 (m, 4H), 2.25 (s, 3H), 1.97 (m, 2H), 1.39 (m, 2H).
4-[(2-dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(^^ pyran-4-ylamino)-benzamide (I), cpd 18
= tetrahydro-pyran-4-yl; R3 = methyl; R4 = 2-dimethylamino-ethyl; R5 = 3-F; R6 = H]
Figure imgf000031_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.22 (bs, 1H), 10.35 (bs, 1H), 8.45 (m, 1H), 8.34 (d, J=7.3 Hz, 1H), 7.86 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.84-7.78 (m, 3H), 7.70-7.63 (m, 2H), 7.55 (m, 1H), 6.06 (dd, J1=9.0 Hz, J2=2.1 Hz, 1H), 5.90 (d, J=2.1 Hz, 1H), 3.90-3.83 (m, 2H), 3.67 (m, 1H), 3.55-3.45 (m, 4H), 3.00 (s, 3H), 2.42 (m, 2H), 2.22 (s, 6H), 2.01 (m, 2H), 1.42 (m, 2H).
N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl] -(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-yl^ benzamide (I), cpd 19 HR1R2 = tetrahydro-pyran-4-yl; NR3R4 = 4-methyl-piperazin-1-yl; R5
Figure imgf000032_0001
1H NMR (400.5 MHz, DMSO-cie), δ: 13.23 (bs, 1H), 10.45 (bs, 1H), 8.43 (m, 1H), 8.28 (d, J=7.8 Hz, 1H), 7.86 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H), 7.83-7.76 (m, 3H), 7.69-7.62 (m, 2H), 7.53 (m, 1H), 6.27 (dd, J1=9.1 Hz, J2=2.1 Hz, 1H), 6.16 (d, J=2A Hz, 1H), 3.82 (m, 2H), 3.73 (m, 1H), 3.52 (m, 2H), 3.28 (m, 4H), 2.48 (m, 4H), 2.27 (s, 3H), 1.97 (m, 2H), 1.39 (m, 2H).
N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-2-(^^
4-ylamino)-benzamide (I), cpd 20
= tetrahydro-pyran-4-yl; NR3R4 = 4-pyrrolidin-1-yl-piperidin-1-yl; R5 = 3-F; R6 = 5-F]
Figure imgf000032_0002
1H NMR (400.5 MHz, DMSO-cie), δ: 13.26 (bs, 1H), 10.44 (bs, 1H), 8.46 (m, 1H), 8.28 (bd, J=7.6 Hz, 1H), 7.90 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.71 (m, 2H), 7.67 (d, J=8.9 Hz, 1H), 7.63 (m, 1H), 6.27 (m, 1H), 6.15 (m, 1H), 3.82 (m, 4H), 3.72 (m, 1H), 3.51 (m, 2H), 2.87 (m, 2H), 2.58 (m, 4H), 2.25 (m, 1H), 2.00-1.88 (m, 4H), 1.72 (m, 4H), 1.50 (m, 2H), 1.38 (m, 2H).
4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3^^
pyran-4-ylamino)-benzamide (I), cpd 21
HR1R2 = tetrahydro-pyran-4-yl; R3 = methyl; R4 = 3-dimethylamino-propyl; R5 = 3-F; R6 = H]
Figure imgf000032_0003
1H NMR (400.5 MHz, DMSO-cie), δ: 13.21 (bs, 1H), 10.34 (bs, 1H), 8.44 (m, 1H), 8.34 (bd, J=7.4 Hz, 1H), 7.86 (dd, J1=8.9 Hz, J2=1.8 Hz, 1H), 7.82-7.77 (m, 3H), 7.70-7.63 (m, 2H), 7.54 (m, 1H), 6.07 (dd, J1=8.9 Hz, J2=2.3 Hz, 1H), 5.90 (d, J=2.3 Hz, 1H), 3.85 (m, 2H), 3.68 (m, 1H), 3.51 (m, 2H), 3.42 (m, 2H), 2.98 (s, 3H), 2.25 (m, 2H), 2.17 (s, 6H), 2.00 (m, 2H), 1.67 (m, 2H), 1.42 (m, 2H).

Claims

1. A process for preparing a substituted N-(5-benzenesulfonyl-1 H-indazol-3-yl)-benzamide of formula (I):
Figure imgf000033_0001
wherein:
R1 and R2 are independently hydrogen, an optionally substituted straight or branched C1-C6 alkyl, or R1 and R2, taken together with the carbon atom to which they are bonded, form an optionally substituted heterocyclyl group;
R3 and R4 are independently hydrogen, an optionally substituted group selected from straight or branched Ο-0β alkyl and heterocyclyl, or R3 and R4, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group;
R5 and R6 are independently hydrogen or fluorine;
said process comprising:
a) coupling the compound of formula (II):
Figure imgf000033_0002
II
with a benzenethiol of formula (III):
Figure imgf000033_0003
III
wherein R5 and R6 are as defined above;
b) acylating the resultant compound of formula (IV):
Figure imgf000033_0004
wherein R5 and R6 are as defined above, with a carboxylic derivative of formula (V):
Figure imgf000033_0005
wherein X is a nitro group or -N(CHR1 R2)COCF3, wherein R1 and R2 are as defined above, W is hydroxy, halogen or a suitable leaving group, and Hal is chlorine, bromine or iodine;
c) oxidizing the resultant compound of formul (VI :
Figure imgf000034_0001
wherein R5, R6, Hal and X are as defined above; then
either
d) deprotecting the resultant compound of formula (VII):
Figure imgf000034_0002
wherein R5, R6 and Hal are as defined above, and X is -N(CHR1 R2)COCF3, wherein R1 and R2 are as defined above;
e) coupling the resultant compound of formula (VIII):
Figure imgf000034_0003
wherein R1 , R2, R5, R6 and Hal are as defined above, with an amine of formula (IX):
R3' 4 IX
wherein R3 and R4 are as defined above, to give the compound of formula (I) as defined above;
or
f) coupling the compound of formula (VII), as defined above, wherein R5, R6 and Hal are as defined above, and X is a nitro group, with the amine of formula (IX), as defined above;
g) reducing the nitro group of the resultant compound of formula (X):
Figure imgf000035_0001
wherein R3, R4, R5 and R6 are as defined above;
h) coupling the resultant compound of formula (XI):
Figure imgf000035_0002
wherein R3, R4, R5 and R6 are as defined above, with a carbonyl derivative of formula (XII):
o
R1 X I"
R2
wherein R1 and R2 are as defined above, to give the compound of formula (I) as defined above;
and optionally converting said compound of formula (I) into a pharmaceutically acceptable salt.
2. An intermediate compound of formula (IV):
Figure imgf000035_0003
wherein R5 and R6 are independently hydrogen or fluorine.
3. The intermediate compound of formula (IV), according to claim 2, wherein R5 and R6 are fluorines at 3 and 5 positions of the benzene ring.
4. A process for preparing the intermediate compound of formula (IV), as defined in claim 2, wherein R5 and R6 are independently hydrogen or fluorine, by coupling the 5-iodo-1 H-indazol-3-ylamine of formula (II):
Figure imgf000035_0004
with a benzenethiol of formula ι
Figure imgf000036_0001
III
wherein R5 and R6 are as defined above, under copper (I) or copper (II) catalysis.
5. An intermediate compound of formula (VI):
Figure imgf000036_0002
as defined in claim 1.
6. A process for preparing the intermediate compound of formula (VI), as defined in claim 5, by acylating the compound of formula (IV) as defined in claim 1 , with the carboxylic derivative of formula (V) as defined in claim 1 , in the optional presence of a proton scavenger and of an activating agent.
7. An intermediate compound of formula (VII):
Figure imgf000036_0003
as defined in claim 1.
8. A process for preparing the intermediate compound of formula (VII), as defined in claim 7, by oxidation of a compound of formula (VI), as defined in claim 1.
9. An intermediate compound of formula (VIII :
Figure imgf000036_0004
as defined in claim 1.
10. The intermediate compound of formula (VIII), according to claim 9, which is:
Figure imgf000037_0001
11. A process for preparing the intermediate compound of formula (VIII), as defined in claim 9, by cleavage of the trifluoroacetyl group of a compound of formula (VII), wherein R5, R6 and Hal are as defined in claim 1 and X is -N(CHR1 R2)COCF3, wherein R1 and R2 are as defined in claim 1 , under basic conditions.
PCT/EP2015/051133 2014-01-23 2015-01-21 Process for the preparation of substituted n-(5-benzenesulfonyl-1h-indazol-3-yl)-benzamides WO2015110467A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008074749A1 (en) * 2006-12-20 2008-06-26 Nerviano Medical Sciences S.R.L. Indazole derivatives as kinase inhibitors for the treatment of cancer
WO2009138440A1 (en) * 2008-05-15 2009-11-19 Nerviano Medical Sciences S.R.L. Carbamoyl derivatives of bicyclic carbonylamino-pyrazoles as prodrugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008074749A1 (en) * 2006-12-20 2008-06-26 Nerviano Medical Sciences S.R.L. Indazole derivatives as kinase inhibitors for the treatment of cancer
WO2009138440A1 (en) * 2008-05-15 2009-11-19 Nerviano Medical Sciences S.R.L. Carbamoyl derivatives of bicyclic carbonylamino-pyrazoles as prodrugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CANDIANI ET AL.: "Development of scaffold synthesis for the preparation of new insulon-like growth factor 1 receptor inhibitors", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 13, no. 3, 21 January 2009 (2009-01-21), pages 456 - 462, XP002735952 *

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