NOVEL 3- (INDOL-3-YL) -PYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

专利摘要:
NEW 3- (INDOL-3-YL) -PYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE. The present invention relates to a compound of Formula I or a pharmaceutically acceptable enantiomers, salts and solvates thereof. The invention also relates to the use of the compounds of Formula I as inhibitors of TDO2. The invention also relates to the use of the compounds of Formula I in the treatment and / or prevention of cancer, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as as HCV and HIV, depression, and obesity. The invention also relates to a method of making the compounds of Formula I.
公开号:BE1021252B1
申请号:E2014/0774
申请日:2014-11-06
公开日:2015-09-22
发明作者:Stefano Crosignani；Sandra Cauwenberghs；Gregory Driessens；Frederik DEROOSE
申请人:Iteos Therapeutics；
IPC主号:

专利说明:

NOVEL 3- (INDOL-3-YL) -PYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE
FIELD OF THE INVENTION
The present invention relates to novel 3- (indol-3-yl) -pyridine derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof. The compounds of the invention are inhibitors of TD02 (tryptophan 2,3-dioxygenase) and are useful as therapeutic products, particularly in the treatment and / or prevention of cancers.
STATE OF THE ART
Twenty years after the discovery of the importance of tryptophan metabolism to maintain the placental immune system, (Munn, DH et al., Science, 1998, 281, 1191-1193), additional evidence has extended its biological importance beyond beyond the immune tolerance of the non-self. According to a commonly accepted principle, tryptophan, an essential amino acid, is catabolized in the local microenvironment of tumors, preferred immune sites, or sites of inflammation (Mellor AL and Munn DH., Nat Rev Immunol, 2008, 8, 74-80). In these tissues, cancerous cells, immune cells, or specialized epithelial cells (eg syncytiotrophoblasts in the placenta) create an immunosuppressive environment that stops the antitumor immune responses in tumors and lymphatic nodules draining tumors, inducing T cell anergy and apoptosis by depletion of tryptophan and accumulation of immunosuppressive catabolites of tryptophan (Munn DH et al., J. Exp Med., 1999, 189, 1363-1372; Fallarino F et al., Cell Death Differ., 2002, 9,1069-1077). It has now been discovered that the essential enzyme in tryptophan catabolism, tryptophan 2,3-dioxygenase (TD02), which is considered to be responsible for regulating systemic levels of tryptophan in the liver, is constitutively expressed in certain cancers. . Expression of TD02 in tumor cells prevents tumor monitoring by the immune system and thus prevents tumor rejection by locally degrading tryptophan (Opitz CA et al., Nature, 2011, 478 (7368), 197-203). In addition, inhibition of TD02 by small molecules prevents tumor growth in animal models for immunotherapy (Pilotte L et al., Proc Natl Acad Sci USA, 2012,109 (7), 2497-502).
The catabolism of tryptophan in certain cancers could be increased by the expression of indolamine 2,3-dioxygenase (IDO) by the tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269-1274 ).
Because catabolism of tryptophan is mediated by inflammatory mediators, especially IFN-gamma, one can imagine an endogenous mechanism that limits excessive immune responses, thus avoiding immunopathology. In the field of cancer, this feedback loop may not be beneficial, as evidenced by the fact that catabolism of tryptophan has been implicated in inflammatory cancers such as colon cancer (Muller AJ et al., Proc. Natl Acad Sci USA, 2008, 105, 17073-8). There is convincing evidence that suppression of antitumor immune responses in precancerous lesions and tryptophan-induced catabolism induces tumor growth, which could make catabolism a prime target for therapeutic intervention (Dolusic E and Frédérick R., Expert Opin Ther Ther. Pat, 2013, 23 (10), 1367-81). Considerable effort has therefore been made to identify effective and selective inhibitors of tryptophan catabolism, to increase the efficacy of conventional chemotherapy, immune control points (Holmgaard RB et al, J Med Exp., 2013, 210 ( 7), 1389-402) or therapeutic vaccines.
Some TD02 inhibitors are described in WO2010 / 008427 and by Dolusic, E. et al. (Dolusic et al., J. Med Chem, 2011, 54, 5320-5334), however, either their affinity for the target is limited, or their pharmacokinetic properties are not appropriate for the development of a drug in humans. man. There is therefore a need to identify new TD02 inhibitors with increased efficacy for the treatment and / or prevention of cancers.
The present invention provides novel TD02 inhibitors that can be administered in a patient suffering from cancer, or a subject at risk of developing cancer. DETAILED DESCRIPTION Compounds
The present invention relates to compounds of Formula I:
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein: X and X are each independently H, halogen, alkyl, haloalkyl, preferably H or F; • i X is absent or represents -0 ', preferentially X is absent; R 1 and R 4 are each independently H, halogen, C 1 -C 6 alkyl, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR 7, COOR 7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r8, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more substituents selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; preferably R1, R2 and R3 are each independently H, halogen or methyl, preferably H or methyl, more preferably H; A represents: - a hydrogen atom; - CR4R5R6, NR4R5 or OR4 in which R4, R5 and R6 each independently represent: • a hydrogen atom; A halogen, preferably F, Cl or I, more preferably F; A hydroxyl; OR7 or NR7R8 wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl an amino; A linear or branched C1-C10 alkyl, preferably a methyl, ethyl or propyl; optionally with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 each represent independently a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from, the group comprising halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; In CR4R5R6, R4, R5 and the carbon atom to which they are attached together form a ring, said ring being preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, an aryl, a CO-alkyl, an alkyl, the alkyl group being optionally substituted with one or more groups selected from a halogen, a hydroxyl, an amino or a COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; a heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; In NR4R5, R4, R5 and the nitrogen atom to which they are attached together form a ring, said ring being preferably a heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r ", so2r7, aryl, CO-alkyl, alkyl, alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -alkyl; -C 6, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino and wherein R 11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, or R11 represents an optionally substituted alkyl group of up to three substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR, 2R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, aryl; wherein R12 and R13 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, aminoalkyl, and the like. the proviso that the compound of formula I is not 3- (pyridin-3-yl) -1H-indole; 3 - ((5- (lH-indol-3-yl) pyridin-2-yl) oxy) -2-methylquinuclidine; 5-methyl-3- (6-methylpyridin-3-yl) -1H-indole; 3-methyl-5- (5-methyl-lH-indol-3-yl) pyridin-2-amine.
According to one embodiment, the preferred compounds of Formula I are those of
Form F
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3 and A are as defined in Formula I.
According to one embodiment, the preferred compounds of Formula I are those of Formula F '
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2 and R3 are as defined in Formula I and A 'is CR4R5R6, NR4R5 or OR4, wherein R4, R5 and R6 are as defined in Formula I.
According to one embodiment, the preferred compounds of formula I are those of formula la
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein: X and X are each independently H, halogen, alkyl, haloalkyl, preferably H or F, more preferably X1 is F and X2 is H; X3 is absent or represents -0 ', preferably X3 is absent; R1, R2 and R3 are each independently H, halogen, C1-C6 alkyl, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, conr7r8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r8, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; preferably R1, R2 and R3 are each independently H, halogen or methyl, preferably H or methyl, more preferably R1, R2 and R3 are H; R4, R5 and R6 each independently represent: • a hydrogen atom; A halogen, preferably F, Cl or I, more preferably F; A hydroxyl; OR7 or NR7R8 wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl an amino • a linear or branched C1-C10 alkyl, preferably methyl, ethyl or propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7
O and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. R4, R5 and the carbon atom to which they are attached together form a ring, said ring being preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, an amino heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to one embodiment, the preferred compounds of Formula la are those of Formula la '
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, R4, R6 and R6 are as defined in Formula la.
According to a particular embodiment, in Formula la or Ia ', X1 represents F and X2 represents H. According to a particular embodiment, in Formula la or Ia', R1, R and R represent hydrogen atoms. According to a particular embodiment, in Formula la or Ia ', X1 represents F, X2 represents H and R1, R2 and R3 represent hydrogen atoms. According to a particular embodiment, in Formula la or '', R5 and R6 represent hydrogen atoms. According to a particular embodiment, in Formula la or Ia ', X1 represents F, X2 represents H, R1, R2 and R3 represent hydrogen atoms and R5 and R6 represent hydrogen atoms. According to a particular embodiment, in Formula la or '', R4 represents an alkyl, preferably a methyl.
According to one embodiment, the preferred compounds of Formula I are those of Formula Ib
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein: X1 and X2 each independently represent H, halogen, alkyl, haloalkyl, preferably H or F, more preferably X1 is F and X2 is H; X3 is absent or represents -0 ', preferably X3 is absent; R1, R2 and R3 are each independently H, halogen, C1-C6 alkyl, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, conr7r8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r8, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; preferably R, R and R are each independently H, halogen or methyl, preferably H or methyl, more preferably R1, R2 and R3 are H; R4 represents: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to one embodiment, the preferred compounds of Formula Ib are those of Formula Ib '
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3 and R4 are as defined in Formula Ib.
According to a particular embodiment, in Formula Ib or Ib ', X1 represents F and X2 represents H. According to a particular embodiment, in Formula Ib or Ib', R1, R and R represent hydrogen atoms. According to a particular embodiment, in Formula Ib or Ib ', X1 represents F, X2 represents H and R1, R2 and R3 represent hydrogen atoms.
According to a particular embodiment, in Formula Ib or Ib ', R4 represents an optionally substituted alkyl, preferably an optionally substituted methyl or ethyl, more preferably a methyl or -CH2-CH2-NR7R8 in which R7 and R8 are as defined in Formula Ib, preferably R7 and R8 represent alkyl groups, more preferably methyl groups.
According to another particular embodiment, in Formula Ib or Ib ', R4 represents an optionally substituted heterocyclyl, preferably an optionally substituted piperidine. According to one embodiment, the piperidine is substituted by an alkyl group, preferably methyl, or by SO2R7, in which R7 is as defined in Formula Ib and R7 is preferably an alkyl, more preferably a methyl.
According to one embodiment, the preferred compounds of Formula I are those of Formula I
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein: X1 and X2 each independently represent H, halogen, alkyl, haloalkyl, preferably H or F, more preferably X1 is F and X2 is H; X3 is absent or represents -0 ', preferably X3 is absent; R 1 and R 4 are each independently H, halogen, C 1 -C 6 alkyl, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR 7, COOR 7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r8, n SO2R, an aryl, a CO-alkyl, an alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; ; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; preferably R, R and R are each independently H, halogen or methyl, preferably H or methyl, more preferably H; R4, R5 and R6 each independently represent: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. R4, R5 and the nitrogen atom to which they are attached together form a ring, said ring being preferably a heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r ", so2r7, aryl, CO-alkyl, alkyl, alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 7 and R 8 are each independently hydrogen or an optionally substituted group selected from C 1 alkyl -C6, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino or R11 represents an optionally substituted alkyl group of up to three substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, aryl; wherein R12 and R13 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to one embodiment, the preferred compounds of Formula I are those of
Formulate the '
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, R4 and R5 are as defined in Formula Ie.
According to a particular embodiment, in Formula Ie or Ie ', X1 represents F and X represents H. According to another particular embodiment, in Formula Ic or Ic', X represents F and X represents F. According to a mode of particular embodiment, in Formula Ie or Ie ', R1, R2 and R3 represent hydrogen atoms. According to a particular embodiment, in Formula Ic or Ic ', X1 represents F, X2 represents H and R1, R and R represent hydrogen atoms. According to another particular embodiment, in Formula Ia or Ic ', X1 represents F, X2 represents F and R1, R2 and R3 represent hydrogen atoms.
According to a particular embodiment, in Formula Ie or Ie ', R5 represents a hydrogen atom. According to a particular embodiment, in Formula Ia or R4 and R5 represent hydrogen atoms.
According to a particular embodiment, in Formula Ic or Ic ', X1 represents F, X2 represents H, R, R and R represent hydrogen atoms and R represents a hydrogen atom. According to another particular embodiment, in formula Ia or Ie ', X represents F, X represents F, R, R and R represent hydrogen atoms and R5 represents a hydrogen atom.
In a particular embodiment, in Formula Ia or R5 is alkyl, preferably methyl. According to a particular embodiment, in formula Ia or Ic ', R4 and R5 represent alkyl groups.
According to a particular embodiment, in Formula Ia or R4 represents optionally substituted alkyl, preferably optionally substituted methyl, optionally substituted ethyl or optionally substituted propyl. In this embodiment, the alkyl group is preferably substituted by hydroxyl, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, NR7SO2R8, in which R7 and R8 preferably each independently represent a hydrogen atom or an alkyl group; more preferably the alkyl group is substituted by NHCOMe, NHSO2Me, SO2Me, SO2NH2, CONH2, NMe2, OH or COOH.
According to another particular embodiment, in Formula Ia or R4 represents an optionally substituted heterocyclyl, preferably an optionally substituted piperidine. According to one embodiment, the piperidine is substituted by an alkyl group, preferably a methyl or an ethyl, or by SO 2 R 7, in which R 7 is as defined in formula Ia and R 7 is preferably an alkyl, more preferably a methyl .
According to a particular embodiment, in Formula Ia or R4, R5 and the nitrogen atom to which they are attached together form a ring, said ring being preferably a heterocyclyl, preferably selected from morpholine, piperazine or piperidine optionally substituted. In this embodiment, a heterocyclyl moiety is preferably substituted with NR7COR8, SO2R7, NR7SO2Ru, CO-alkyl, alkyl, the alkyl moiety being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or a COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted alkyl; and wherein R11 represents an alkyl group optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NRI2COR13, NRI2R13, SO2R12, SO2NR12R13, nr12SO2R13, SO2R12, aryl; wherein R12 and R13 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. According to a particular embodiment, the heterocyclyl group is substituted by Me, COCH 2 NH 2, SC 2 Me, NHCOCH 2 NH 2 or NHSO 2 Me.
According to a preferred embodiment, R4, R5 and the nitrogen atom to which they are attached together form a morpholine, piperazine or piperidine, optionally substituted, more preferably a morpholine, 4-methyl-piperazin-1-yl, 4- (2-aminoethanone) -piperazin-1-yl, 4-methylsulfonyl-piperazin-1-yl, 4- (2-amino-N-acetamide) -piperidin-1-yl or 4-AT-methanesulfonamide-piperidin -l-yl.
According to another particular embodiment, in Formula Ic or Ic ', R4 represents -CO-R10 in which R10 represents a group selected from an alkyl or a heterocyclyl, preferably a methyl, an ethyl, a propyl, a n- butyl, i-butyl, t-butyl, piperidine, piperazine or tetrahydrothiopyrandioxide. In this embodiment, the alkyl group or the heterocyclyl group may be substituted, preferably with NH 2, aryl or CO-alkyl; more preferably by NH 2, phenyl or COMe.
According to one embodiment, the preferred compounds of Formula I are those of Formula Ic-1
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein: X1, X2, R1, R2 and R3 are as defined in Formula Ie; X4 is CH, N or O; R9 is absent or represents H, halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2Ru, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by a or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino and the like. wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino or R11 represents an alkyl group optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, aryl; wherein R12 and R13 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to one embodiment, the preferred compounds of Formula I are those of
Formula 2
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein: X1, X2, R1, R2 and R3 are as defined in Formula Ie; and R4 represents: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 o and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to one embodiment, the preferred compounds of Formula I are those of
Formula Ic-3
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein: X1, X2, R1, R2, R3 as defined in Formula Ia; R4 represents • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R10 or -SO2R10; R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NRV, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to a particular embodiment, in Formula Ic-3, R4 is H.
According to one embodiment, the preferred compounds of Formula I are those of
Formula Id
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein:
X and X are each independently H, halogen, alkyl, haloalkyl, preferably H or F, more preferably X is F and X is H or F; X3 is absent or is -0 ', preferably X3 is absent; R 1 and R 3 are each independently H, halogen, C 1 -C 6 alkyl, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR 7 , COOR7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r8, SO2R7, an aryl, a CO-alkyl, an alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or in which R 7 and R 8 are each independently hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroary alkyl, alkylheteroaryl, amino; preferably R, R and R are each independently H, halogen or methyl, preferably H or methyl, more preferably H.
According to one embodiment, the preferred compounds of Formula Id are those of Formula Id '
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2 and R3 are as defined in Formula Id.
According to a particular embodiment, in Formula Id or Id ', X1 is F and X is H. According to another particular embodiment, in Formula Id or Id', X is F and X is F. of particular embodiment, in Formula Id or Id ', R1, R2 and R3 are all hydrogen atoms. According to a particular embodiment, in Formula Id or Id ', one of R1, R2 and R3 represents an alkyl group, preferably a methyl group, the others representing hydrogen atoms.
Particularly preferred compounds of Formula I of the invention are those shown in the table below. TABLE 1
or their pharmaceutically acceptable enantiomers, salts and solvates.
In Table 1, the term "Cpd" means compound.
The compounds in Table 1 have been named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).
The compounds of formula I and their sub-formulas may contain an asymmetric center and may therefore exist in different stereoisomeric forms. Accordingly, the present invention contains all possible stereoisomers and contains not only racemic compounds but also individual enantiomers and their non-racemic mixtures. When a product is intended as a single enantiomer, it can be obtained by stereospecific synthesis, by resolution of the final product or by any suitable intermediate, or by chiral chromatographic methods, all well known in the art. The resolution of the final product, intermediate product, or starting material can be achieved by any method known in the art.
The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of Formula I include acid addition salts and salts by formation of the corresponding base. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride salts. / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate , pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Suitable base salts are formed from bases forming non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2- (diethylamino) ethanol, ethanolamine, morpholine, 4- (2-hydroxyethyl) morpholine and zinc. The acid or base hemi-salts may also be formed, for example, by hemisulphate and hemicalcium salts. Preferably, the pharmaceutically acceptable salts include hydrochloride / chloride, hydrobromide / bromide, bisulphate / sulphate, nitrate, citrate and acetate.
When the compounds of the invention contain an acidic or basic group, the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain hydrogen-donating heteroatoms (for example NH), the invention also covers the salts and / or isomers formed by the transfer of said hydrogen atom to the basic group or atom in this molecule.
The pharmaceutically acceptable salts of the compounds of Formula I may be prepared by one or more of these methods: (i) by reacting the compound of Formula I with the desired acid; (ii) reacting the compound of Formula I with the desired base; (iii) removing an acid-labile or base-labile protecting group from the appropriate precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, such as, for example, a lactone or a lactam, using the acid that suits ; or (iv) converting a salt of the compound of Formula I to another salt by reaction with a suitable acid or by means of a suitably chosen ion exchange column.
All these reactions are typically conducted in solution. The salt can precipitate from the solution and be isolated by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to little ionized.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulfate. , camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate , phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate , panoate, valerate, and their derivatives which can be used in pharmaceutical form to modify the solubility or hydrolysis characteristics; or can be used in controlled release or prodrug formulations. Depending on the particular group of the compound of the present invention, the pharmaceutically acceptable salts of the compounds of the invention include compounds formed by cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and other bases such as ammonium , ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, Ν, Ν'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, and tetramethylammonium hydroxide.
These salts can be prepared by standard procedures, for example by reacting a free acid with a suitably chosen organic or inorganic base. When a basic group is present, such as amino, an acidic salt, for example hydrochloride, hydrobromide, acetate, palmoate, and derivatives, may be used as a dosage form.
Also, in the case where an alcohol group is present, pharmaceutically acceptable esters may be employed, for example, acetate, maleate, pivaloyloxymethyl, and their derivatives, as well as esters known in the art to modify the solubility or hydrolysis for use as controlled release or prodrug formulations.
All references to the compounds of Formula I include references to their enantiomers, salts, solvates, polymorphs, multi-compound complexes and liquid crystals.
The compounds of the invention include the compounds of Formula I as defined above, including all their crystalline polymorphs and meshes, their prodrugs and isomers (including optical, geometric and tautomeric isomers) and the isotopically labeled compounds of Formula I.
In addition, and in general, in connection with the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred; it should be noted that the invention in its broadest sense also includes salts which are not pharmaceutically acceptable, those which for example could be used in the isolation and / or purification of the compounds of the invention. For example, salts formed by optically active acids or bases could be used to form diastereoisomeric salts which can facilitate the separation of the optically active isomers of the compounds of Formula I defined above. The invention also generally covers all the pharmaceutically acceptable prodrugs and prodrugs of the compounds of Formula I.
Preparation process
The compounds of Formula I can be prepared by different routes according to reactions known to those skilled in the art.
The invention comprises a process for the manufacture of compounds of Formula I
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, X3 and A are as defined in Formula I; comprising: (a1) reacting the compound of Formula Π
wherein X and X are as defined in Formula I; Z1 is H or an amino protecting group such as, for example, arylsulphonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, benzyl or any other suitable protecting group known to those skilled in the art; Y represents a halogen (preferably iodine, bromine or chlorine), an alkylsulphonyloxy having a chain of 1 to 6 carbon atoms (preferably a methylsulphonyloxy or trifluoromethylsulphonyloxy) or arylsulphonyloxy having a chain of 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art;
with a compound of Formula III in which
R1, R2, R3, X3 and A are as defined in Formula I; Z and Z represent H or alkyl groups, with the possibility for Z2 and Z3 to form a ring; to obtain a compound of Formula IV,
wherein X 1, X 2, R 1, R 2, R 3, X 3 A and Z 1 are as defined above; and (b1) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula IV to give the compound of Formula I.
According to one embodiment, step (a1) of the process of the invention may be carried out with or without a catalyst such as, but not limited to, Pd2 (dba) 3, Pd (PPh3) 4, dichlorobis (triphenylphosphine) palladium (II) or 1,1'-bis (diphenylphosphino) ferrocene-dichloro palladium (II), Pd (OAc) 2, or Pd / C in the presence or absence of an additional ligand, such as but not limited to X- Phos, S-Phos, P (oTol) 3, PPI13, BINAP, P (/ Bu) 3 or any other suitable phosphine ligand known to those skilled in the art.
According to one embodiment, step (a1) of the process of the invention can be carried out in the presence of bases such as but not limited to K3PO4, K2CO3, Na2CO3.
According to one embodiment, step (a1) of the process of the invention can be carried out in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or their mixture, preferably in a mixture of dioxane or THF and water.
According to one embodiment, step (a1) of the process of the invention can be carried out at temperatures ranging from about 20 ° C. to about 180 ° C., with or without microwave irradiation, for a period of 10 minutes. at several hours, for example from 10 minutes to 24 hours.
According to one embodiment, the deprotection (b1) can be carried out, depending on the nature of the Z1 group, by a treatment with a base, such as but not limited to sodium hydroxide, potassium hydroxide and sodium carbonate. potassium. According to one embodiment, the deprotection can be carried out in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, ieri-butanol, THF, DMF, dioxane, water, alone or as a mixture. According to one embodiment, the deprotection can be carried out at a temperature ranging from 20 ° C. to 100 ° C., preferably at about 85 ° C., for several hours, for example from one hour to 24 hours.
According to an alternative embodiment, the deprotection (b1) can be carried out, depending on the nature of the Z1 group in the presence of strong acids, such as but not limited to HCl, TFA, HF, HBr. According to one embodiment, the deprotection can be carried out in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, teri-butanol, THF, DMF, dioxane, water, alone or as a mixture. According to one embodiment, the deprotection can be carried out at a temperature ranging from about 20 ° C. to about 100 ° C. for a period of between 10 minutes and several hours, for example from 10 minutes to 24 hours. The invention also relates to a second process for the manufacture of compounds of Formula I '
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, R4 and R5 are as defined in Formula Ie; comprising:
(a2) reacting a compound of Formula V
wherein X1, X2, R1, R2 and R3 are as defined in Formula Ie; and Z1 is H or an amino protecting group such as, for example, arylsulphonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, benzyl or any other suitable protecting group known to those skilled in the art; Y represents a halogen (preferably iodine, bromine or chlorine), alkylsulphonyloxy having a chain of 1 to 6 carbon atoms (preferably a methylsulphonyloxy or trifluoromethylsulphonyloxy) or arylsulphonyloxy having a chain of 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other suitable leaving group known to those skilled in the art;
with a compound of Formula VI
wherein R4 and R5 are as defined in Formula Ie; to obtain a compound of Formula VII
wherein X1, X2, R1, R2, R3, R4, R5 and Z1 are as defined above; and (b2) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula VII to give the compound of Formula Ia.
According to one embodiment, step (a2) of the process of the invention may be carried out in the absence or in the presence of bases such as but not limited to triethylamine, diisopropyl ethylamine, DBU, cesium carbonate, carbonate of sodium, potassium carbonate, sodium hydroxide, potassium hydroxide.
According to one embodiment, step (a2) of the process of the invention can be carried out in the presence of a suitable solvent such as but not limited to DMSO, DMF, methanol, ethanol, isopropanol, tert-butanol, THF, dioxane, dichloromethane, water.
According to one embodiment, the step (a2) of the process of the invention can be carried out at a temperature ranging from 20 ° C. to about 180 ° C., with or without microwave irradiation.
According to one embodiment, the step (a2) of the process of the invention can be carried out for a period ranging from 10 minutes to several hours, for example from 10 minutes to 24 hours.
According to one embodiment, the deprotection step (b2) can be carried out under the conditions described above for the deprotection (bl). The invention also relates to a third process for the manufacture of compounds of Formula Ic-2
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3 and R4 are as defined in Formula Ic-2; comprising:
(a3) the introduction of a compound of formula VIII
wherein X1, X2, R1, R2, R3 are as defined in Formula Ic-2; Z1 is H or an amino protecting group such as, for example, arylsulphonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, benzyl or any other suitable protecting group known to those skilled in the art; Z4 represents an alkyloxycarbonyl group, such as, for example, as Boc or Cbz;
with a compound of Formula IX
wherein R4 is as defined in Formula Ic-2; and Y is halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having a chain of 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having a chain of 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other suitable leaving group known to those skilled in the art;
to obtain a compound of Formula X
wherein X1, X2, R1, R2, R3, R4, Z1 and Z4 are as defined above;
(a4) reacting a compound of Formula X to give compound of Formula XI
wherein X1, X2, R1, R2, R3, R4 and Z1 are as defined above; and (b3) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula XI to give the compound of Formula Ic-2.
According to one embodiment, step (a3) of the process of the invention may be carried out in the presence of bases such as but not limited to sodium hydride, lithium diisopropylamide, butyl lithium, sodium hydroxide, hydroxide potassium, cesium carbonate, sodium carbonate, potassium carbonate.
According to one embodiment, step (a3) of the process of the invention may be carried out in the presence of a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, ierf-butanol, THF, dioxane, dichloromethane, water.
According to one embodiment, step (a3) of the process of the invention may be carried out in the presence or absence of catalytic amounts of suitable iodine salts, such as but not limited to tetrabutylammonium iodide.
According to one embodiment, step (a3) of the process of the invention may be carried out at a temperature ranging from 20 ° C. to about 180 ° C., with or without microwave irradiation.
According to one embodiment, step (a3) of the process of the invention can be carried out for a period ranging from 10 minutes to several hours, for example from 10 minutes to 24 hours.
According to one embodiment, step (a4) of the process of the invention may be carried out by treatment with acids, such as but not limited to hydrochloric acid, trifluoroacetic acid, hydrobromic acid or hydrofluoric acid.
According to one embodiment, step (a4) of the process of the invention may be carried out in the presence of an appropriate solvent such as but not limited to THF, dioxane, DCM, DMF, methanol, ethanol, isopropanol, tert-butanol, water, alone or in mixture.
According to one embodiment, step (a4) of the process of the invention can be carried out at temperatures ranging from 20 ° C. to about 100 ° C., in the presence or absence of microwave irradiation.
According to one embodiment, step (a4) of the method of the invention can be carried out over several hours, for example from one hour to 24 hours.
According to one embodiment, the deprotection step (b3) can be carried out under the conditions described above for deprotection (bl).
In general, the synthetic routes for any individual compound of Formula I will depend on the specific substituents of each molecule and the availability of the necessary intermediates; these factors are evaluated by those skilled in the art.
According to another general method, the compounds of Formula I can be converted to alternative compounds of Formula I, according to suitably chosen interconversion techniques well known to those skilled in the art.
The compounds of formula I and the formulas of the same family can also be obtained by releasing the compounds of formula I from one of their functional derivatives by treatment with a solvolysis or hydrogenolysis agent.
Preferred starting compounds for solvolysis or hydrogenolysis are those compounds of Formula I and its derivatives, but which contain a protecting group of amino and / or hydroxyl function in place of one or more amine groups and / or hydroxyl groups, preferably these groups carry an amine protecting group in place of a hydrogen atom bonded to a nitrogen atom, in particular these groups carry a group R * -N, in which R * represents a amine protecting group, instead of an H atom, and / or these groups carry a hydroxyl protecting group in place of a hydrogen atom of a hydroxyl group, for example these groups obey the Formula I, but bear a -COOR ** group, in which R ** represents a hydroxyl protecting group, in place of an H atom. Π is also possible that a plurality of amino protecting groups and / or A hydroxyl - whether identical or different - are present in the molecule of the starting material. If the protective groups present are different from each other, they can in many cases be selectively cleaved.
The term "amino protecting group" is known in general terms and refers to groups which are capable of protecting (blocking) an amino group against chemical reactions, but which are easily removed after the chemical reaction of interest has been carried out on another part of the molecule. Typically, these groups are, in particular, substituted or unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the protective amino groups are removed after the reaction of interest (or a sequence of reactions); their type and size are nevertheless of little importance; however, groups having carbon chains of 1 to 20 carbon atoms, especially 1 to 8 carbon atoms are preferred. The term "acyl group" should be understood in its broadest sense in connection with the present process. This includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy-icarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino protecting groups are BOC and Mtr, but also CBZ, Fmoc, benzyl and acetyl.
The term "hydroxyl protecting group" is likewise known in general terms and refers to moieties which are capable of protecting a hydroxyl group against chemical reactions, but which are easily removed after the chemical reaction of interest has occurred. was performed on another part of the molecule. Typically, these groups are the aryl, aralkyl and acyl groups, but also alkyl, substituted or unsubstituted, mentioned above. The type and size of hydroxyl protecting groups are of little importance since they are removed after the reaction of interest or a sequence of reactions; groups having carbon chains of 1 to 20 carbon atoms, especially 1 to 10 carbon atoms are preferred. Examples of such hydroxyl protecting groups are inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, of which benzyl and tert-butyl are particularly preferred.
The compounds of formula I and the formulas of the same family are obtained from their functional derivatives - depending on the protective group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or acid sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA and sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, but also alcohols, such as methanol, ethanol or isopropanol, and water. The mixtures of the solvents mentioned above are also possible. TFA is preferably used in excess without the addition of another solvent, and the perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in a 9: 1 ratio. The reaction temperatures for the cleavage are advantageously between about 0 ° C. and 50 ° C., preferably between 15 ° C. and 30 ° C. (room temperature).
The BOC, OtBu and Mtr groups may, for example, be preferentially cleaved using TFA in dichloromethane or using HCl at a concentration of approximately 3 to 5N in dioxane at 15-30 ° C, and the FMOC group may be cleaved using a solution of dimethylamine, diethylamine or piperidine of about 5 to 50% in DMF at 15-30 ° C.
The protecting groups which can be cleaved by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (by for example a rare metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents for this type of reaction are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally conducted at temperatures between about 0 ° C and 100 ° C and pressures between about 1 and 200 bar, preferably between 20 ° C and 30 ° C and between 1 and 10 bar. The hydrogenolysis of the CBZ group is carried out in good yields, for example, with 5 to 10% Pd / C in methanol or using ammonium formate (as a hydrogen substitute) on Pd / C in methanol / DMF at 20 ° C-30 ° C.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitrates, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, alone or as a mixture.
The esters may be hydrolysed, for example, using HCl, H 2 SO 4, or using LiOH, NaOH or KOH in water, water / THF, water / THF / ethanol or water / dioxane, at temperatures ranging from 0 ° C. at 100 ° C.
The free amine groups may also be acetylated according to conventional procedures using an acyl chloride or an anhydride or alkylated using a substituted or unsubstituted alkyl halide, preferably in an inert solvent, such as dichloromethane or THF and or in the presence of a base, such as triethylamine or pyridine, at temperatures ranging from -60 ° C to + 30 ° C.
For all methods of protection and deprotection, refer to Philip J. Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis" , Wiley Interscience, 3rd Edition 1999.
The reaction schemes as described in the Examples section only illustrate the invention and should not be construed as limiting the invention of any kind.
Uses The invention also relates to the use of the compounds of the invention or its pharmaceutically acceptable enantiomers, salts and solvates as TD02 inhibitors.
Thus, in a particularly preferred embodiment, the invention relates to the use of the compounds of Formula I and the formulas of the same family, in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates, such as TD02 inhibitors.
Also, in another aspect, the invention relates to the use of pharmaceutically acceptable compounds or enantiomers, salts and solvates for the synthesis of active pharmaceutical ingredients, such as TD02 inhibitors.
According to one embodiment, the invention relates to the use of the compounds of Formula I and the formulas of the same family, in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates, for increasing the recognition immune system and the destruction of cancer cells.
The compounds of the invention are therefore useful as medicaments, particularly in the prevention and / or treatment of cancer.
According to one embodiment, the compounds of the invention or one of its pharmaceutically acceptable enantiomers, salts, solvates or prodrugs are useful for their use in the treatment and / or prevention of cancer, neurodegenerative diseases such as Parkinson's disease. , Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity. The invention also relates to a method of treating or preventing cancer, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, which comprises administering to a mammal requiring it a therapeutically sufficient amount of the compound of the invention or a pharmaceutically acceptable enantiomer, salt or solvate.
Various cancers are known in the art. The cancer may be metastatic or non-metastatic. Cancer can be hereditary or sporadic. In some embodiments, the cancer is selected from the group consisting of: leukemia and multiple myeloma. Other cancers that can be treated according to the methods of the invention include, for example, benign and malignant solid tumors as well as benign and malignant non-solid tumors.
Examples of solid tumors include, but are not limited to: cancer of the biliary system, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, cancer of the uterus endometrium, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms tumor); sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell cancer and squamous cell cancer), testicular cancer including germ-cell tumors (seminomas, and non-seminomas) teratoma and choriocarcinoma), stromal tumors, germ cell tumors, and thyroid cancer (including adenocarcinoma of the thyroid and medullary carcinoma).
Examples of non-solid tumors include but are not limited to hematologic neoplasms. In the context of the invention, hematological neoplasm is a term of art that includes lymphoid disorders, myeloid disorders, and AIDS-associated leukemias.
Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (eg, lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin lymphoma and lymphocytic lymphoma). The chronic lymphoid leukemias include, for example, chronic lymphocytic leukemias of T cells and chronic lymphoid leukemias of B cells. The invention also relates to a method for delaying the onset of cancer in the patient comprising administering a quantity of pharmaceutically effective compound of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof in a patient in need thereof.
Preferably, the patient is a warm-blooded animal, more preferably a human.
The compounds of the invention are especially useful in the treatment and / or prevention of cancer.
In one embodiment, the compounds of the invention are especially useful in the treatment and / or prevention of cancer. The invention also relates to the use of the compounds of Formula I or its pharmaceutically acceptable enantiomers, salts and solvates for the manufacture of a medicament for treating and / or preventing cancer.
According to another feature of the present invention, a method for modulating the TD02 activity is provided, in a patient, preferably a warm-blooded animal, and even more preferably a human, in need of such treatment, which comprises the administering to said patient a sufficient amount of a compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
Compositions The invention also relates to pharmaceutical compositions comprising a compound of Formula I or one of its pharmaceutically acceptable enantiomers, salts and solvates and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant. As indicated above, the invention also encompasses pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable enantiomer, salt and solvate as an active ingredient, additional therapeutic agents and / or active ingredients.
Another object of this invention is a medicament comprising at least one compound of the invention, one of its pharmaceutically acceptable enantiomers, salts and solvates as an active ingredient.
According to another feature of the present invention, is also understood to be the use of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for modulating TD02 activity in a patient, having need for such treatment, which comprises administering to said patient a sufficient amount of the compound of the present invention, one of its pharmaceutically acceptable enantiomers, salts and solvates. Generally, for pharmaceutical use, the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant and optionally one or more additional pharmaceutically active compounds.
According to non-limiting examples, such formulations may be in a form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration (of which ocular application), administration by inhalation, patch for skin, implant, suppository, etc. Such administration forms - which may be solid, semi-solid or liquid, depending on the method of administration - but also the methods and carriers, diluents, excipients for use in such a preparation, will be obvious to the patient. skilled in the art (see the latest version of Remington's Pharmaceutical Sciences).
Some preferred but non-limiting examples of such preparations include hard or soft tablets, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, gelatin capsules, sterile packaged suppositories, drops, sterile injectable solutions and powders (which are generally rehydrated before use) for administration as a food bolus and / or in continuous administration, which may be formulated with transporters, excipients and diluents which are suitable as such for such compositions, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanths, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol , cellulose, water (sterile), methylcellulose, methyl- and propylhydroxybenzoates, talc, m agnesium stearate, edible oils, vegetable and mineral oils, singly or in combination. The compositions may optionally contain other substances which are commonly used in pharmaceutical compositions, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, coatings, agents and the like. preservatives, flavoring agents, flavoring agents, flow regulators, salting agents, etc. The compositions may be formulated so as to cause rapid, controlled or delayed release of the active compounds contained in the composition.
The pharmaceutical preparations of the invention are preferably in unit dosage form, and may be suitably packaged, for example in a box, blistered, in vials, bottles, sachets, ampoules or in any form of single or multidose dosage (which can be appropriately labeled); optionally with one or more leaflets containing the information and / or instructions for use of the product in question.
Depending on the preventive or curative nature and the route of administration, the active compound of the invention may be administered as a single dose once daily, or in one or more doses per day, or substantially continuously, for example as a drip infusion. -to-drop.
DEFINITIONS
In the present invention, the following terms will have the following definitions:
When groups may be substituted, these groups may be substituted by one or more substituents, and preferably with one, two or three substituents. The substituents may be selected from, but are not limited to, for example, the groups comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The preferred ones are fluorine and chlorine.
The term "alkyl" as such or part of another substituent refers to a hydrocarbon radical of Formula CnH2n + i wherein n is a number greater than or equal to 1. Generally, the alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms. The alkyl groups can be linear or branched and can be substituted as indicated in the present application. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl; n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (eg n-pentyl, iso-pentyl), and hexyl and isomers thereof (e.g., n-hexyl, iso-hexyl).
The term "haloalkyl" alone or in combination means an alkyl radical having the meaning defined above in which one or more hydrogens are substituted by a halogen as defined above. Non-limiting examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl and their derivatives.
The term "cycloalkyl" as used herein is a cyclic alkyl group, i.e., a saturated or unsaturated mono-valent hydrocarbon group having 1 or 2 ring structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbon groups. The cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to the present invention, comprise between 3 and 10, preferably between 3 and 8 and even more preferentially between 3 and 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl being particularly preferred.
When at least one carbon atom in a cycloalkyl group is substituted with a heteroatom, the resulting ring is referred to as "heterocyclyl".
The terms "heterocyclyl" used herein as such or as part of another moiety refer to non-aromatic, fully saturated or partially unsaturated cyclic moieties (eg, 3- to 7-membered unicycles, bicycles of 7 to 11 members, or containing a total of 3 to 10 atoms in the ring) which have at least one heteroatom in at least one ring containing a carbon atom. Each hetero ring containing heterocyclic ring may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein nitrogen and sulfur may be optionally oxidized and nitrogen may be optionally quaternarized. Any carbon atom of the heterocyclic group may be substituted by an oxo function (for example piperidone, pyrrolidinone). The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system when valence permits. The cycles of the multi-ring heterocycles can be fused, bridged and / or joined by one or more spiro atoms. Examples of non-limiting heterocyclic groups include piperidinyl, azetidinyl, tetrahydropyranyl, piperazinyl, imidazolinyl, morpholinyl, oxetanyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, indolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, pyrrolizinyl.
The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (eg, phenyl) or multiple aromatic rings fused together (eg, naphthyl) or covalently linked, typically containing from 5 to 12 atoms. , preferably 6 to 10, wherein at least one ring is an aromatic ring. The aromatic ring may optionally comprise one or two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused to the latter. Aryl is intended to include partially hydrogenated derivatives of the carbocyclic systems listed herein. Non-limiting examples of aryl include phenyl, biphenylyl, biphenylenylnaphthalenyl, indenyl.
The term "heteroaryl" used herein as such or as part of another group refers to, but is not limited to, aromatic rings containing from 5 to 12 carbon atoms or ring systems containing 1 to 2 rings which are fused or covalently bound, typically containing 5 to 6 atoms, at least one ring is an aromatic ring, wherein one or more carbon atoms in one or more of these rings is substituted by an oxygen atom, nitrogen and / or sulfur wherein the nitrogen and sulfur atom may be optionally oxidized and the nitrogen may be optionally quaternized. Such rings may be fused to aryl, cycloalkyl, heteroaryl or heterocyclyl rings. Non-limiting examples of heteroaryl include: pyridazinyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnoyl, quinazolinyl, quinoxalinyl.
The term "arylalkyl" refers to any -alkyl-aryl group. The term "alkylaryl" refers to any -aryl-alkyl group.
The term "heteroarylalkyl" refers to any -alkyl-heteroaryl group. The term "alkylheteroaryl" refers to any -heteroaryl-alkyl group.
The term "alkoxy" refers to any O-alkyl group. The term "haloalkoxy" refers to any O-haloalkyl group.
The term "oxo" refers to the moiety = 0.
The term "amino" denotes the -NH 2 group or any group derived by substitution of one or two hydrogen atoms by an aliphatic or aromatic organic group. Preferably, the groups derived from -NH 2 are alkylamino groups, that is to say N-alkyl groups, comprising a monoalkylamino or a dialkylamino. According to a specific embodiment, the term "amino" denotes NH 2, NHMe or NMe 2.
The term "amino protecting group" refers to a protecting group of an amine function. According to a preferred embodiment, the amino protecting group is selected from the group comprising: arylsulphony, tert-butoxycarbonyl, methoxymethyl, para-methoxy benzyl or benzyl.
The term "leaving group" refers to a molecular fragment that starts with a pair of electrons upon heterolytic disruption of a bond. According to a preferred embodiment, the leaving group is selected from the group comprising: a halogen, preferably iodine, bromine or chlorine; an alkylsulphonyloxy having 1 to 6 carbon atoms, preferably methylsulphonyloxy or trifluoromethylsulphonyloxy; or arylsulfonyloxy having 6 to 10 carbon atoms, preferably phenyl- or p-tolylsulfonyloxy.
The term "solvated" is used in this application to describe a compound of the invention which contains a stoichiometric or substoichiometric amount of one or more pharmaceutically acceptable solvent molecules such as ethanol.
The term "hydrate" refers to a solvate in which said solvent is water.
The compounds of the invention include the compounds of Formula I as defined above, including all their polymorphs and crystalline meshes, their prodrugs and prodrugs, and the compounds of Formula I isotopically labeled. The invention also generally covers all the pharmaceutically acceptable prodrugs and prodrugs of the compounds of Formula I.
The term "prodrug" as used herein refers to pharmaceutically acceptable derivatives of the compounds of Formula I, such as for example esters, whose in vivo biotransformation product generates a biologically active drug. Prodrugs are generally characterized by increased bioavailability and are readily metabolized in vivo in biologically active compounds.
The term "predrug" as used in this application refers to any compound that will be modified to form a drug species, wherein the changes occur within or outside the body, and either before or after the pre-drug reaches the part of the body for which the administration of the drug has been prescribed.
The term "patient" refers to a warm-blooded animal, more preferably a human, who must receive or receive medical care or who is or will be the target of medical treatment.
The term "human" refers to a subject of both genders, at any stage of development (eg newborn, infant, child, adolescent, adult).
The terms "treat" and "treatment" used in the present application include calming, ameliorating or abrogating a condition or disease and / or its associated symptoms.
The terms "prevent" and "prevent" used in the present application means a method for delaying or preventing the onset of a condition or conditions and / or its associated symptoms, preventing the patient from developing the condition or disease, or reducing the patient's risk of developing the condition or illness.
The term "therapeutically sufficient amount" (or simply "sufficient amount") used in this application refers to the amount of active agent or active ingredient that is sufficient to cause the therapeutic or prophylactic effects in the treated patient.
The term "administration", or one of its variants (e.g. "administer"), means to provide an active agent or an active ingredient, alone or as part of a pharmaceutically acceptable composition, to a patient in whom the condition, symptoms or the disease must be treated or avoided.
By "pharmaceutically acceptable" it is understood that the ingredients of the pharmaceutical compositions are compatible with each other and are not harmful to the treated patient.
The term "pharmaceutical carrier" as used herein refers to a carrier or an inert medium used as a solvent or diluent in which the pharmaceutically active agent is formulated and / or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions and liposomes.
EXAMPLES
The present invention will be better understood with the following examples. These examples are representative of specific embodiments of the invention, and are not intended to limit the scope of the invention.
I. EXAMPLES OF CHEMISTRY
The MS data provided in the examples described below were obtained as follows: Agilent 6110 LC / MS mass spectrometer (ESI) or Waters Acquity SQD (ESI).
The NMR data provided in the examples described below were obtained as follows: Bruker Ultrashield ™ 400 PLUS and Bruker Fourier 300 MHz and TMS used as internal reference.
Microwave chemistry was performed on Biotage's Initiator Micro Wave System EU single-mode microwave reactor.
Preparative HPLC purifications were performed using the Waters Fractionlynx system (a mass-bound autopurification system) equipped with a 19x150mm 5μm Xbridge ™ Prep C18 OBD column, unless indicated otherwise. All HPLC purifications were performed with a gradient of CH3CN / H2O / NH4HCO3 (5mM), CH3CN / H2O / TFA (0.1%), or CH3CN / H2O / NH3 H2O (0.1%). 1.1. SYNTHESIS OF INTERMEDIATE COMPOUNDS Intermediate 1: 3-bromo-6-fluoro-1- (phenylsulfonyl) -1H-indole
A solution of bromine (0.64 g, 4.0 mmol) in DCM (20 mL) is added dropwise to a solution of 6-fluoro-1- (phenylsulfonyl) -1H-indole (as described in Bioorg Med. Chem., 2011, 19, 4782, 1795, 1.0 g, 3.6 mmol) in DCM (20 mL) at 0 ° C. The reaction mixture is stirred at 0 ° C for 30 minutes, and poured onto saturated Na 2 S 2 O 3 solution (10 mL) and stirred at room temperature for 10 minutes. The organic phase is separated and the aqueous phase is extracted with DCM (10 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaHCO3 (20 mLx2), water (20 mLx2), a saturated aqueous solution of NaCl (20 mL), then dried over Na2SC> 4 anhydrous, filtered and concentrated. to give 1.26 g (99%) of the compound of interest as a pink solid. H NMR (400MHz, DMSO-d6) δ [pm]: 8.21 (s, 1H), 8.13-8.11 (m, 2H), 7.83-7.73 (m, 2H), 7.66-7.62 (m, 2H), 7.52 - 7.49 (m, 1H), 7.30 - 7.26 (m, 1H).
Intermediate 2: 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -lindole
Pd (dppf) Cl2-DCM (231 mg, 0.28 mmol) is added to a solution of 3-bromo-6-fluoro-1- (phenylsulfonyl) -1 -findole (Intermediate 1, 1.00 g, 2.82 mmol), acid 6-chloropyridin-3-ylboronic acid (889 mg, 5.65 mmol), K / 3 PO 4 (1.80 g, 8.48 mmol) in dioxane (40 mL) and water (4 mL) under a nitrogen atmosphere. The mixture is heated at 100 ° C for 6 hours. The mixture is filtered through Celite, diluted with EtOAc (100 mL) and water (100 mL). The aqueous phase is extracted with EtOAc (50 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl, dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by chromatography on silica gel (petroleum ether / EtOAc = 1/1) to give 0.61 g (56% ) of the compound of interest as a yellow solid. LC-MS: m / z 387.0 [M + H] +. H NMR (400MHz, DMSO-4) δ [pm]: 8.79 (d, J = 2.4Hz, 1H), 8.37 (s, 1H), 8.23 (dd, J = 8.4, 2.4Hz, 1H), 8.17 - 8.13 (m, 2H), 7.87 (dd, J = 8.8, 5.2Hz, 1H), 7.82 (dd, J = 9.7, 2.2Hz, 1H), 7.76-7.71 (m, 1H), 7.67-7.63 (m , 2H), 7.62 (d, / = 8.4 Hz, 1H), 7.25 (ddd, J = 9.2, 8.8, 2.2 Hz, 1H).
Intermediate 3: 5-f-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-ylcarbamate of iron-butyl
Pd (dppf) Cl2-DCM (110 mg, 0.133 mmol) is added to a solution of 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 535 mg, 1.33 mmol), tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-ylcarbamate (640 mg, 2.0 mmol), K3PO4 (848 mg, 3.99 mmol) in dioxane (20 mL) and water (2 mL) under a nitrogen atmosphere. The mixture is stirred at 90 ° C overnight. The mixture is filtered through Celite, diluted with EtOAc (100 mL) and water (100 mL). The aqueous phase is extracted with EtOAc (50 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl, dried over anhydrous Na 2 SO 4, filtered, concentrated, and purified by chromatography on silica gel (petroleum ether / EtOAc = 10/1 - 2/1) to give 400 g. mg (64%) of the compound of interest as a yellow solid. LC-MS: m / z 468.1 [M + H] +.
Intermediate 4: 4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yloxy) piperidine-1-carboxilate of iron-butyl
A mixture of tert-butyl 4- (5-bromopyridin-2-yloxy) piperidine-1-carboxylate (as described in WO2007 / 146759A1, 1.30 g, 3.64 mmol), 4,4,4 ', 4', 5, 5.5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane (1.38 g, 5.44 mmol), Pd (dppf) Cl2-DCM (297 mg, 0.36 mmol), KOAc (1.07) 10.9 mmol) in DMF (30 mL) is stirred at 80 ° C. for 6 hours under a nitrogen atmosphere, the mixture is concentrated in vacuo, suspended in EtOAc (50 mL), filtered through celite, and concentrated to give the compound of interest as a brown semi-solid, directly used in the next transformation without purification LC-MS: m / z 405.2 [M + H] +.
Intermediate 5: 5.6-difluoro-3-iodo-1Z / indole
A solution of iodine (837.5 mg, 3.3 mmol) in DMF (6.3 mL) is added to a mixture of 5,6-difluoro-1H-indole (500 mg, 3.27 mmol) and KOH (458 mg; mmol) in DMF (6.2 mL). The mixture is stirred at ambient temperature for 12 hours. Π is then poured on an ice / water mixture (60 ml) and then extracted with EtOAc (20 mlx3). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (100 mL) and dried over anhydrous Na 2 SO 4, filtered, concentrated to give 930 mg (100%) of the compound of interest as a red solid. Π is directly used in the next transformation without purification. NMR (400 MHz, DMSO-δ) δ [pm]: 11.68 (s, 1H), 7.61 (d, J = 2.5Hz, 1H), 7.47 (dd, J = 11.0, 6.9Hz, 1H), 7.21; (dd, J = 10.8, 7.9 Hz, 1H).
Intermediate 6: 5.6-difluoro-3-iodo-1- (phenylsulfonyl) -1H-indole
NaH (266.4 mg, 60%, 6.66 mmol) was added to a solution of 5,6-difluoro-3-iodo-1H-7-indole (Intermediate 5, 930 mg, 3.33 mmol) in THF (20 mL). 0 ° C under nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes before a solution of benzenesulfonyl chloride (763.4 mg, 4.32 mmol) in THF (2 mL) was added dropwise. The reaction mixture is stirred at room temperature for 12 hours, quenched with ice / water (60 mL) and extracted with EtOAc (30 mLx3). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (100 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by chromatography on silica gel (petroleum ether / EtOAc = 10/1 - 3/1). to give 1.01 g (72%) of the compound of interest as a yellow solid. H NMR (400MHz, DMSO-d6) δ [pm]: 8.19 (s, 1H), 8.14-8.10 (m, 2H), 8.07-8.00 (m, 1H), 7.78-7.72 (m, 1H), 7.66 - 7.61 (m, 2H), 7.41 (dd, J = 10.2.7.8 Hz, 1H).
Intermediate 7: 1- (Methylsulfonyl) piperidin-4-amine TFA (10.6 mL, 143 mmol) is added to a solution of tert-butyl (1- (methylsulfonyl) piperidin-4-yl) carbamate (2.72 g, 9.77 mmol). ) in DCM (30 mL). The mixture is stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue is triturated in diethyl ether (30 mL), filtered, and washed with diethyl ether (30 mL). The solid is dissolved in H2O (60 mL), the pH is adjusted to pH = 11 with an aqueous NaOH solution, and extracted with DCM / i-PrOH (10/1, 60 mLx10). The organic phases are combined and dried over anhydrous Na2SO4, filtered and concentrated to give 1.4 g (80%) of the compound of interest as a yellow oil. LC-MS: m! Z 179.0 [M + H] +. H NMR (300 MHz, CDCl 3) δ [pm]: 3.50 - 3.38 (m, 2H), 2.82 (s, 3H), 2.80 - 2.61 (m, 3H), 1.80 - 1.70 (m, 2H), 1.33 - 1.23 (m, 2H).
Intermediate 8: 1- (1- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) propane-1,3-diamine
A solution of 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 600 mg, 1.55 mmol) in propane-1,3-diamine (1.5 mL) is heated at 180 ° C for 2 hours in a microwave reactor. The mixture is cooled to ambient temperature, poured onto H2O (30 mL) and then filtered. The solid is dissolved in EtOAc (30 mL), dried over anhydrous Na2SC4, filtered, and concentrated to give 600 mg (91%) of the compound of interest as a yellow semi-solid, directly used in the next transformation without purification. ! LC-MS: mlz 424.9 [M + H] +.
Intermediate 9: Afl- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) propane-1,3-diamine
A solution of NaOH (102 mg, 2.55 mmol) in water (1 mL) is added to a solution of N1- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3- yl) pyridin-2-yl) propane-1,3-diamine (Intermediate 8, 219 mg, 0.52 mmol) in MeOH (15 mL). The mixture is stirred at 80 ° C for 1 hour, concentrated, and purified by flash reverse phase chromatography to give 145 mg (100%) of the compound of interest as a white solid. LC-MS: m / z 285.0 [M + H] +.
/.2. SYNTHESIS OF FINAL COMPOUNDS
Compound 1: 6-fluoro-3- (6-methylpyridin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (6-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H -indole
Pd2dba3 (40 mg, 0.044 mmol) and S-Phos (40 mg, 0.097 mmol) are added to a solution of 3-bromo-6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 0.87 mmol), 2-methyl-5- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) pyridine (381 mg, 1.74 mmol), K3PO4 (922 mg, 4.34 mmol) in dioxane (5 mL) and water (1 mL) under a nitrogen atmosphere. The mixture is heated at 125 ° C for 30 minutes in a microwave reactor. The mixture diluted with EtOAc (20 mL) and water (10 mL). The organic phase is separated; washed with saturated aqueous NaCl solution (5 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel chromatography (petroleum ether / EtOAc = 10/1 - 2/1) to give 160 mg ( 50%) of the compound of interest as a red solid. LC-MS: m / z 367.1 [M + H] +. 2nd step:
A solution of NaOH (105 mg, 2.62 mmol) in water (0.5 mL) is added to a solution of 6-fluoro-3- (6-methylpyridin-3-yl) -1- (phenylsulfonyl) -1 / / -indole (Step 1, 160 mg, 0.44 mmol) in MeOH (10 mL). The reaction mixture is stirred at 85 ° C for 30 minutes, concentrated, diluted with H2O (5 mL), and extracted with Et2O (10 mLx3). The organic phases are combined and then washed with water (10 mLx2), saturated aqueous NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to give 33.3 mg (34 mL). %) of the compound of interest as a white solid. LC-MS: m / z 227.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.53 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 7.96 (dd, J = 8.0, 2.3 Hz, 1H), 7.82 (dd, J = 8.8, 5.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H) , 6.96 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 2.50 (s, 3H).
Compound 2: 6-fluoro-3- (6- (piperidin-4-yloxy) pyridin-3-yl) -lif-indole Step 1: 4- (5- (6-Fluoro-1- (phenylsulfonyl) -1H- tert-butyl indol-3-yl) pyridin-2-yloxy) piperidine-1-carboxylate
Pd (dppf) Cl2-DCM (149 mg, 0.18 mmol) is added to a solution of 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (as described in WO2010 / 136491A, 730 mg; 1.82 mmol), tert-butyl 4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yloxy) piperidine-1-carboxylate (Intermediate 4 1.47 g, 3.64 mmol), K3PO4 (1.16 g, 5.46 mmol) in dioxane (20 mL) and water (2 mL) under a nitrogen atmosphere. The mixture is stirred at 90 ° C overnight. The mixture is filtered through Celite, diluted with EtOAc (100 mL) and water (100 mL). The aqueous phase is extracted with EtOAc (50 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl, dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by chromatography on silica gel (petroleum ether / EtOAc = 10/1 - 5/1) to give 580 mg (58%) of the compound of interest as a yellow solid. LC-MS: mlz 552.1 [M + H] +. H NMR (400 MHz, CDCl 3) δ [pm]: 8.33 (d, J = 2.3 Hz, 1H), 7.97 - 7.89 (m, 2H), 7.79 (dd, J = 9.6, 2.3 Hz, 1H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 7.62 (s, 1H), 7.61-7.55 (m, 2H), 7.49 (dd, J = 9.9, 5.6 Hz, 2H), 7.05 (td, J = 8.9). , 2.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 5.33 - 5.18 (m, 1H), 3.85 - 3.74 (m, 2H), 3.36 - 3.23 (m, 2H), 2.04 - 1.92 ( m, 2H), 1.71 - 1.80 (m, 2H), 1.48 (s, 9H). Step 2: 6-Fluoro-1- (phenylsulfonyl) -3- (6- (piperidin-4-yloxy) pyridin-3-yl) -1H-indole HCl in Et2O (4 M, 10 mL) is added to a solution 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yloxy) piperidine-1-carboxylic acid-4-carboxylate (Step 1, 580 mg; mmol) in MeOH (10 mL). The mixture is stirred for 30 minutes. The reaction mixture is concentrated in vacuo, diluted with water (10 mL), neutralized with saturated aqueous NaHCO 3 solution, and extracted with EtOAc (30 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (30 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated to give 473 mg (100%) of the compound of interest in the form of a yellow solid, directly used in the next transformation without purification. LC-MS: m / z 452.1 [M + H] +. H NMR (300 MHz, DMSO-4) δ [pm]: 8.48 (d, J = 2.4 Hz, 1H), 8.17 - 8.07 (m, 3H), 8.02 (dd, J = 8.6, 2.5 Hz, 1H) , 7.84 - 7.77 (m, 2H), 7.75 -7.71 (m, 1H), 7.65 - 7.58 (m, 2H), 7.21 (td, J = 9.2, 2.3 Hz, 1H), 6.88 (d, J = 8.6 Hz) , 1H), 5.16-4.97 (m, 1H), 3.00-2.93 (m, 2H), 2.61-2.53 (m, 2H), 1.98-1.44 (m, 2H), 1.56-1.44 (m, 2H). Step 3:
Following the general method used for the preparation of Compound 1 Step 2, using 6-fluoro-1- (phenylsulfonyl) -3- (6- (piperidin-4-yloxy) pyridin-3-yl) as starting material // -indole (Step 2, 240 mg, 0.53 mmol), 57 mg (34%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS: mlz 312.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.42 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.6, 2.4 Hz, 1H), 7.77 (dd, J = 8.7, 5.3 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.22 (dd, J = 10.0, 2.3 Hz, 1H), 6.93 (ddd, J = 9.5, 8.7, 2.3). Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.13 - 4.98 (m, 1H), 3.03 - 2.88 (m, 2H), 2.61 - 2.55 (m, 2H), 2.04 - 1.90 (m, 2H), 1.54 - 1.45 (m 2H).
Compound 3: 6-fluoro-3- (6- (1-methylpiperidin-4-yloxy) pyridin-3-yl) -1 H -indole
The compound of interest is obtained (5mg, 3%) as a yellow solid after purification by preparative HPLC in Step 3 of Compound 2. LC-MS: mlz 326.1 [M + H] +. H NMR (300 MHz, DMSCM6) δ [pm]: 11.58 (br s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 8.5, 2.4 Hz, 1H), 7.77 ( dd, J = 8.8, 5.3 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 10.0, 2.3 Hz, 1H), 7.02 - 6.81 (m, 2H), 5.32 -5.11 (m, 1H), 3.31 - 3.01 (m, 4H), 2.69 (s, 3H), 2.31 - 2.16 (m, 2H), 2.12 - 1.95 (m, 2H).
Compound 4: 2- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yloxy) -NH-dimethylethanamine
Following the general method used for the preparation of Compound 27, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole as starting material (Intermediate 2; mg, 0.65 mmol), 2- (dimethylamino) ethanol (3.0 mL), and NaH (518 mg, 12.9 mmol, 60% in mineral oil), 113 mg (58%) of the compound of interest is obtained as a solid. white after purification by chromatography on silica gel (DCM / MeOH = 10/1). LC-MS: mlz 300.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.43 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.5, 2.4 Hz, 1H), 7.77 (dd, J = 8.7, 5.4 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.94 (ddd, J = 9.6, 8.7, 2.4). Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.37 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 5.9 Hz, 2H), 2.23 (s, 6H).
Compound 5: 6-Fluoro-3- (6-methoxypyridin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (6-methoxypyridin-3-yl) -1- (phenylsulfonyl) -1H-indole ✓
According to the general method used for the preparation of Compound 1 Step 1, using as starting material 3-bromo-6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 300 mg; 0.85 mmol), acid 6 methoxypyridin-3-ylboronic acid (195 mg, 1.28 mmol), K3PO4 (451 mg, 2.12 mmol), Pd2dba3 (76 mg, 0.083 mmol), and S-phos (81 mg, 0.20 mmol), 319 mg (98%) of the compound of interest is obtained in the form of a white solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 50/1 -10/1). LC-MS: m / z 383.1 [M + H] +. H NMR (300 MHz, DMSO-d6) δ [pm]: 8.52 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 8.16 - 8.09 (m, 2H), 8.05 (dd, J = 8.6, 2.5 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.73 - 7.69 (m, 1H), 7.65 - 7.59 (m, 2H), 7.22 (td, / = 9.2, 2.3 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H). 2nd step:
Following the general method used for the preparation of Compound 1 step 2, using 6-fluoro-3- (6-methoxypyridin-3-yl) -1- (phenylsulfonyl) -1H-indole as starting material (Step 1 315 mg, 0.82 mmol), 170 mg (85%) of the compound of interest is obtained as a white solid. LC-MS: m / z 243.1 [M + H] +. H NMR (400 MHz, DMSO-d6) δ [pm]: 11.45 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.5, 2.4 Hz, 1H), 7.78 (dd, J = 8.8, 5.3 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.94 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H).
Compound 6: 6-Fluoro-3- (6- (1- (methylsulfonyl) piperidin-4-yloxy) pviadin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (6 - ((1- (Methylsulfonyl) piperidin-4-yl) oxy) pyridin-3-yl) -1- (phenylsulfonyl) -1H-indole
Following the general method used for the preparation of Compound 14 Step 2, using 6-fluoro-1- (phenylsulfonyl) -3- (6- (piperidin-4-yloxy) pyridin-3-yl) -l as starting material / 7-indole (Compound 2 Step 2, 240 mg, 0.53 mmol), 280 mg (100%) of the compound of interest is obtained as a yellow solid, directly used in the next transformation without purification. LC-MS: m / z 530.1 [M + H] +. H NMR (400 MHz, DMSO-rf 6) δ [pm]: 8.51 (d, J = 2.3Hz, 1H), 8.17 (s, 1H), 8.15-8.11 (m, 2H), 8.06 (dd, J = 8.5, 2.5 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.76 - 7.71 (m, 1H), 7.65 - 7.60 (m, 2H), 7.22 (td, J = 9.1, 2.2 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.25 - 5.16 (m, 1H), 3.45 - 3.37 (m, 2H), 3.18 - 3.12 (m, 2H), 2.92 (s, 3H), 2.15 - 2.03 (m. , 2H), 1.88 - 1.75 (m, 2H). 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 6-fluoro-3- (6 - ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridin-3-yl as starting material) 1- (phenylsulfonyl) -1H-indole (Step 1, 280 mg, 0.52 mmol), 51 mg (25%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 390.0 [M + H] +. NMR (400 MHz, DMSCM6) δ [pm]: 11.46 (br s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.5, 2.4 Hz, 1H), 7.77 ( dd, J = 8.8, 5.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 10.0, 2.3 Hz, 1H), 6.94 (ddd, J = 9.4, 8.8, 2.3 Hz). , 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.18 (tt, J = 4.0, 4.0 Hz, 1H), 3.45 - 3.37 (m, 2H), 3.18 -3.09 (m, 2H), 2.92 ( s, 3H), 2.14 - 2.05 (m, 2H), 1.82 - 1.78 (m, 2H).
Compound 7: 5- (6-fluoro-1H-indol-3-yl) -NH-dimethylpyridin-2-amine Step 1: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -N, N-dimethylpyridin-2-amine
Following the general method used for the preparation of Compound 34 Step 1, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1 / f-indole as starting material (Intermediate 2 200 mg, 0.52 mmol) and dimethylamine (8.0 mL, 16 mmol, 2 M in THF), 180 mg (88%) of the compound of interest is obtained as a brown solid after purification by chromatography on silica gel (ether petroleum / EtOAc = 10 / 1-5 / 1). LC-MS: mlz 396.1 [M + H] +. 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 5- (6-fluoro-1- (phenylsulfonyl) -lindol-3-yl) -N, N-dimethylpyridine as starting material -2-amine (Step 1, 180 mg, 0.46 mmol), 35 mg (30%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS: m / z 256.1 [M + H] +. H NMR (400 MHz, DMSO-d6) δ [pm]: 11.31 (s, 1H), 8.40 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.6, 2.3 Hz, 1H), 7.73 (dd, J = 8.8, 5.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 10.0, 2.4 Hz, 1H), 6.91 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 3.05 (s, 6H).
Compound 9: 4- (5- (6-Fluoro-1H-indol-3-yl) pyridin-2-yl) morpholine Step 1: 4- (5- (6-Fluoro-1- (phenylsulfonyl) -1H- indol-3-yl) pyridin-2-yl) morpholine
A solution of 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 250 mg, 0.65 mmol) in morpholine (6.5 mL) is heated at 180 ° C for 3 hours in a microwave reactor. The mixture is concentrated in vacuo to give 283 mg (100%) of the compound of interest as a yellow semi-solid, directly used in the next transformation without purification. LC-MS: m / z 438.1 [M + H] +. NMR (400 MHz, DMSO-4) δ [pm]: 8.48 (d, J = 2.4 Hz, 1H), 8.15 - 8.05 (m, 3H), 7.90 (dd, J = 8.8, 2.4 Hz, 1H) , 7.83 - 7.76 (m, 2H), 7.74 -7.70 (m, 1H), 7.65 - 7.59 (m, 2H), 7.21 (td, J = 9.1, 2.3 Hz, 1H), 6.94 (d, J = 8.8 Hz , 1H), 3.75 - 3.68 (m, 4H), 3.52 - 3.47 (m, 4H). 2nd step:
According to the general method used for the preparation of Compound 1 Step 2, using 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2- as starting material yl) morpholine (Step 1, 283 mg, 0.65 mmol), 60 mg (31%) of the compound of interest is obtained as a white solid after purification by preparative TLC (petroleum ether / EtOAc = 1/1). LC-MS: m / z 298.1 [M + H] +. NMR (400 MHz, DMSO-d6) δ [pm]: 11.34 (s, 1H), 8.46 (s, 1H), 7.85 (dd, J = 8.7, 1.7 Hz, 1H), 7.75 (dd, J = 8.7, 5.4 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 9.8, 1.8 Hz, 1H), 6.94 (ddd, J = 9.5, 8.7, 1.8 Hz, 1H), 6.91 (d, 7 = 8.7 Hz, 1H), 3.86 - 3.65 (m, 4H), 3.56 - 3.37 (m, 4H).
Compound 10: 6-Fluoro-3- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (6- (4-methylpiperazin) l-yl) pyridin-3-yl) -l- (phenylsulfonyl) -LH-indole
Following the general method used for the preparation of Compound 9 Step 1, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole as starting material (Intermediate 2; mg, 0.65 mmol) and 1-methylpiperazine (7.0 mL), 308 mg (100%) of the compound of interest is obtained as a yellow semi-solid, directly used in the next transformation without purification. LC-MS: m / z 451.1 [M + H] +. H NMR (300 MHz, DMSO-d6) δ [pm]: 8.45 (d, J = 2.1 Hz, 1H), 8.14 - 8.08 (m, 2H), 8.06 (s, 1H), 7.86 (dd, J = 9.0, 5.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.72 - 7.67 (m, 1H), 7.65 - 7.57 (m, 2H), 7.25 - 7.15 (m, 1H), 6.93 (d, J = 8.9 Hz, 1H), 3.57-3.47 (m, 4H), 2.73-2.43 (m, 4H), 2.22 (s, 3H). 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 6-fluoro-3- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1- (phenylsulfonyl) as starting material -177-indole (Step 1, 308 mg, 0.65 mmol), 130 mg (64%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 311.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.33 (s, 1H), 8.44 (d, J = 2.0Hz, 1H), 7.82 (dd, J = 8.9, 2.0Hz, 1H), 7.74 (dd, J = 8.7, 5.4 Hz, 1H), 7.58 (s, 1H), 7.20 (dd, J = 9.9, 1.9 Hz, 1H), 6.88 (ddd, J = 9.5, 8.7, 1.9 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 3.53 - 3.45 (m, 4H), 2.44 - 2.39 (m, 4H), 2.23 (s, 3H).
Compound 14: N- (1- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) piperidin-4-v-methanesulfonamide Step 1: 1- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) piperidin-4-amine
Following the general method used for the preparation of Step 1 Compound 9, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-7-indole as starting material (Intermediate 2 250 mg, 0.65 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (648 mg, 3.24 mmol), 291 mg (100%) of the compound of interest is obtained as a yellow solid after purification by preparative TLC. (DCM / MeOH = 10/1). LC-MS: m / z 451.1 [M + H] +. H NMR (300 MHz, DMSO-4) δ [pm]: 8.46 (d, J = 2.2 Hz, 1H), 8.14 - 8.03 (m, 3H), 7.88 (dd, J = 8.8, 2.2 Hz, 1H) , 7.69 - 7.81 (m, 3H), 7.71 - 7.69 (m, 2H), 7.26 - 7.15 (m, 1H), 6.99 (d, J = 9.1 Hz, 1H), 4.47 - 4.31 (m, 2H), 4.16. -4.04 (m, 1H), 2.99 - 2.91 (m, 2H), 2.06 - 1.94 (m, 2H), 1.63-1.47 (m, 2H). Step 2: N- (1- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) piperidin-4-yl) methanesulfonamide
MsCl (109 mg, 0.96 mmol) is added dropwise at 0 ° C. to a solution of 1- (5- (6-fluoro-1- (phenylsulfonyl) -177-indol-3-yl) pyridin-2-yl. piperidin-4-amine (Step 1, 290 mg, 0.64 mmol) and EtsN (0.23 mL, 1.64 mmol) in DCM (20 mL). The mixture is stirred at room temperature for 30 minutes. The mixture is diluted with DCM (50 mL), washed with saturated aqueous NaHCO3 (50 mLx3), saturated aqueous NaCl (50 mL), and concentrated to give 338 mg (100%) of the compound of interest. as a yellow solid, directly used in the next transformation without purification. LC-MS: m / z 529.1 [M + H] +. Step 3:
Following the general method used for the preparation of Compound 1 Step 2, using N- (1- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2 as starting material -yl) piperidin-4-yl) methanesulfonamide (Step 2, 200 mg, 0.38 mmol), 27 mg (18%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 389.1 [M + H] +. H NMR (400 MHz, DMSO - / 6) δ [pm]: 11.33 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.9, 2.3 Hz, 1H) , 7.74 (dd, J = 8.8, 5.5 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 9.9, 2.4 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.00 -6.84 (m, 2H), 4.27-4.16 (m, 2H), 3.47-3.37 (m, 1H), 3.05-2.97 (m, 2H), 2.95 (s, 3H), 1.96-185 ( m, 2H), 1.48 - 1.41 (m, 2H).
Compound 15: 5- (6-Fluoro-1H-indol-3-yl) pyridin-2-amine Step 1: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl hydrochloride ) pyridin-2-amine
Following the general method used for the preparation of Compound 2 Step 1, using tert-butyl 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2 as starting material. ylcarbamate (Intermediate 3, 310 mg, 0.66 mmol), 290 mg (100%) of the compound of interest is obtained as a brown solid, directly used in the next transformation without purification. LC-MS: m / z 368.1 [M + H] +. 2nd step:
AT
According to the general method used for the preparation of Compound 1 Step 2, using 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2- hydrochloride as starting material. Amine (Step 1, 290 mg, 0.66 mmol), 75 mg (50%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS: m / z 228.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.26 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 8.7, 5.5 Hz, 1H), 7.66 (dd, J = 8.5, 2.2 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 10.0, 2.2 Hz, 1H), 6.90 (ddd, J = 9.5, 8.7, 2.2 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 5.85 (s, 2H).
Compound 16: 5- (5,6-difluoro-17H-indol-3-yl) pyridin-2-amine Step 1: (5- (5,6-difluoro-1- (phenylsulfonyl) -1H-indol-3- yl) tert-butyl pyridin-2-yl) carbamate
According to the general method used for the preparation of Intermediate 3, using as starting material 5,6-difluoro-3-iodo-1- (phenylsulfonyl) -177-indole (Intermediate 12, 300 mg, 0.72 mmol), 320 mg (92%) of the compound of interest is obtained in the form of a yellow solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 1/1). LC-MS: m / z 486.1 [M + H] +. Step 2: 5- (5,6-Difluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-amine hydrochloride
According to the general method used for the preparation of Compound 2 Step 2, using as starting material (5- (5,6-difluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2 yl) tert-butyl carbamate (Step 1, 320 mg, 0.66 mmol), 300 mg (> 100%) of the compound of interest is obtained as a yellow solid, directly used in the next transformation without purification. LC-MS: m / z 386.1 [M + H] +. Step 3:
Following the general method used for the preparation of Compound 1 Step 2, using as starting material 5- (5,6-difluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridinyl chloride. -2-amine (Step 2, 300 mg), 26 mg (16%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 246.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.37 (br s, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.59 (s, 1H). ), 7.42 (dd, J = 11.2, 7.1 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 5.86 (s, 2H).
Compound 18: N- (1-Ethylpiperidin-4-yl) -5- (6-fluoro-1H-indol-3-yl) pyridin-2-amine Step 1: N- (1-Benzylpiperidin-4-yl) 5- (6-fluoro-lH-indol-3-yl) pyridin-2-amine
Following the general method used for the preparation of Compound 9 Step 1, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole as starting material (Intermediate 2 600 mg, 1.55 mmol), 1-benzylpiperidin-4-amine (1.0 mL), and NMP (1.0 mL), 60 mg (10%) of the compound of interest is obtained as a yellow solid after purification by preparative TLC. (DCM / MeOH = 10/1). LC-MS: m / z 401.1 [M + H] +. 2nd step:
A mixture of N- (1-benzylpiperidin-4-yl) -5- (6-fluoro-1H-indol-3-yl) pyridin-2-amine (Step 1, 60 mg, 0.15 mmol) and 10% Pd / C (10 mg) in EtOH (20 mL) is hydrogenated at 60 ° C at 50 psi. The mixture was filtered through celite, concentrated, and purified by preparative HPLC to give 3 mg (6%) of the compound of interest as a white solid. LC-MS: m / z 339.1 [M + H] +. H NMR (300 MHz, DMSCM6) δ [pm]: 11.25 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.7, 5.4 Hz, 1H), 7.63 (dd , J = 8.6, 2.4 Hz, 1H), 7.49 (d, 7 = 2.1 Hz, 1H), 7.18 (dd, J = 10.1, 2.3 Hz, 1H), 6.89 (ddd, J = 9.0, 8.7, 2.3 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 3.80 - 3.56 (m, 1H), 2.86 - 2.80 (m, 2H), 2.32 (q, J = 7.2 Hz, 2H), 2.07-1.79 (m, 4H), 1.53-1.33 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).
Compound 19: 5- (6-fluoro-1H-indol-3-yl) -N- (1- (methylsulfonyl) piperidin-4-yl) pyridin-2-amine
Following the general method used for the preparation of Compound 27 using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole as starting material (Intermediate 2; mg, 0.65 mmol) and 1- (methylsulfonyl) piperidin-4-amine (Intermediate 13, 1.21 g, 6.78 mmol), 31 mg (12%) of the compound of interest is obtained as a white solid. LC-MS: m / z 389.1 [M + H] +. H NMR (300 MHz, DMSO-/ δ) δ [pm]: 11.25 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.70 (dd, J = 8.5, 5.3 Hz, 1H) , 7.65 (dd, J = 8.5, 2.1 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 10.2, 2.0Hz, 1H), 6.88 (ddd, J = 9.5, 8.5). , 2.0 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 7.4 Hz, 1H), 3.94 - 3.79 (m, 1H), 3.55 - 3.49 (m, 2H), 2.94 - 2.87 (m, 2H), 2.87 (s, 3H), 2.07 - 1.97 (m, 2H), 1.56 - 1.39 (m, 2H).
Compound 20: N- (3- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-ylamino) pOpyl) acetamide
AcCl (96 mg, 1.22 mmol) is added at 0 ° C to a mixture of N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) propan-1, 3-diamine (Intermediate 9, 240 mg, 0.84 mmol) and Et3N (248 mg, 2.45 mmol) in DCM (30 mL). The mixture is stirred at ambient temperature for 1 hour. The mixture was diluted with DCM (50 mL), washed with saturated aqueous NaHCO 3 solution (50 mLx3), saturated aqueous NaCl solution (50 mL), dried over anhydrous Na 2 SCO 4, filtered, concentrated, and purified. preparative HPLC to give 81 mg (29%) of the compound of interest as a white solid. LC-MS: m / z 327.1 [M + H] +. H NMR (300 MHz, DMSO-d6) δ [pm]: 11.27 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.88 (t, J = 5.7 Hz, 1H), 7.71 (dd , J = 8.8, 5.5 Hz, 1H), 7.65 (dd, J = 8.6, 2.2 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 10.0, 2.4 Hz, 1H) , 6.90 (ddd, J = 9.5, 8.8, 2.4 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.47 (t, J = 5.6 Hz, 1H), 3.34 (dt, 7 = 12.6, 7.1). Hz, 2H), 3.11 (dt, J = 12.7, 6.7 Hz, 2H), 1.80 (s, 3H), 1.66 (tt, J = 7.1, 6.7 Hz, 2H).
Compound 21: Ar-13- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-ylamino) propyl) methanesulfonamide
MsCl (132 mg, 1.15 mmol) is added at 0 ° C. to a mixture of Al- (5- (6-fluoro-177-indol-3-yl) pyridin-2-yl) propane-1,3-diamine ( Intermediate 9, 220 mg, 0.77 mmol) and Et3N (234 mg, 2.31 mmol) in DCM (60 mL). The mixture is stirred at ambient temperature for 1 hour. The mixture is diluted with DCM (50 mL), washed with saturated aqueous NaHCCb solution (50 mLx3), saturated aqueous NaCl solution (50 mL), dried over anhydrous NaiSCL, filtered, concentrated, and purified by preparative HPLC to prepare the mixture. give 80 mg (29%) of the compound of interest as a yellow solid. LC-MS: m / z 363.1 [M + H] +. H NMR (300 MHz, DMSO-d6) δ [pm]: 11.27 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.9, 5.4 Hz, 1H), 7.67. (dd, J = 8.7, 2.4 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 10.1, 2.2 Hz, 1H), 7.03 (t, J = 5.9 Hz, 1H) , 6.90 (ddd, J = 9.6, 8.9, 2.2 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 6.48 (t, J = 5.4 Hz, 1H), 3.39 -3.22 (m, 2H), 3.08 - 2.98 (m, 2H), 2.89 (s, 3H), 1.84 - 1.59 (m, 2H).
Compound 25: N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) -NH-N, N-dimethylethane-1,2-diamine Step 1: N1- (5- ( 6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) -N2, N2-dimethylethane-1,2-diamine
Following the general method used for the preparation of Compound 9 Step 1, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole as starting material (Intermediate 2; mg, 0.65 mmol) and dimethylethylenediamine (4.0 mL), 283 mg (100%) of the compound of interest is obtained as a yellow semi-solid, directly used in the next transformation without purification. LC-MS: m / z 439.1 [M + H] +. 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using N1- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2 as starting material. Yl) -IV2, N2-dimethylethane-1,2-diamine (Step 1, 283 mg, 0.65 mmol), 30 mg (15%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 299.2 [M + H] +. H NMR (400 MHz, MeOH-74) δ [pm]: 8.38 (d, J = 2.3Hz, 1H), 7.83 (dd, J = 8.6, 2.3Hz, 1H), 7.72 (dd, δ = 8.8, 5.2 Hz, 1H), 7.41 (s, 1H), 7.14 (dd, J = 9.8, 2.3 Hz, 1H), 6.89 (ddd, J = 9.6, 8.8, 2.3Hz, 1H), 6.78 (d, J = 8.6). , 1H), 3.73 - 3.69 (m, 2H), 3.34 - 3.32 (m, 2H), 2.98 (s, 6H).
Compound 26; N- (2- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-ylamino) ethyl) methanesulfonamide hydrochloride Step 1: N1 - (5- (6-fluoro-1- (- phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) ethane-1,2-diamine
According to the general method used for the preparation of Intermediate 8, using 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole as starting material (Intermediate 2; mg, 0.77 mmol) and 1,2-ethylenediamine (1.5 mL), 315 mg (100%) of the compound of interest is obtained as a yellow semi-solid, directly used in the next transformation without purification. LC-MS: m / z 410.8 [M + H] +. Step 2: N1- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) ethane-1,2-diamine
According to the general method used for the preparation of Intermediate 9, using as starting material / V1- (5- (6-fluoro-1- (phenylsulfonyl) -17-indol-3-yl) pyridin-2- yl) ethane-1,2-diamine (Step 1, 315 mg, 0.77 mmol), 235 mg (> 100%) of the compound of interest is obtained as a white solid after purification by flash reverse phase chromatography. LC-MS: m / z 271.0 [M + H] +. Step 3:
According to the general method used for the preparation of Compound 21, using N] - (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) ethane-1,2 as starting material -diamine (Step 2, 220 mg), 72 mg (26%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC (0.1% HCl in H 2 O / MeCN). LC-MS: m / z 349.1 [M + H] +. H NMR (300 MHz, DMSO-d6) δ [pm]: 13.89 (brs, 1H), 11.66 (s, 1H), 8.77 (brs, 1H), 8.28 (dd, J = 9.0, 1.6 Hz, 1H), 8.10 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 8.8, 5.3 Hz, 1H), 7.32 (t, J = 6.0 Hz, 1H), 7.26 ( dd, J = 9.9, 2.3 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.00 (ddd, J = 9.3, 8.8, 2.3 Hz, 1H), 3.62 - 3.53 (m, 2H), 3.28 3.16 (m, 2H), 2.96 (s, 3H).
Compound 27: 2- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-ylamino) ethanoI
A mixture of 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 250 mg, 0.65 mmol) and 2-aminoethanol (4 mL) in DMSO (3 mL) is heated at 180 ° C for 3 hours in a microwave reactor. The mixture is diluted with H2O (20 mL) and extracted with EtOAc (20 mLx3). The organic phases are combined and then washed with water (10 mL × 3), a saturated aqueous solution of NaCl (10 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by preparative TLC (DCM / MeOH = 10/1). ) to give 48 mg (27%) of the compound of interest as a yellow solid. LC-MS: m / z 272.1 [M + H] +. NMR (400 MHz, MeOH-d4) δ [pm]: 8.23 (d, J = 2.2Hz, 1H), 7.76 (dd, J = 8.7, 2.2Hz, 1H), 7.69 (dd, J = 8.7, 5.3 Hz, 1H), 7.37 (s, 1H), 7.12 (dd, J = 9.8, 2.2 Hz, 1H), 6.88 (ddd, J = 9.2, 8.7, 2.2 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 3.77 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H).
Compound 30: 2- (5- (6-fluoro-17β-indol-3-yl) pyridin-2-ylamino) acetic acid Step 1: 2- (tert-butoxycarbonyl) (5- (6-fluoro) -1 - (phenylsulfonyl) -1H-indol-3-ylpyridin-2-yl) amino) ethyl acetate
NaH (25 mg, 0.62 mmol, 60% in mineral oil) is added at 0 ° C. to a solution of 5- (6-fluoro-1- (phenylsulfonyl) -1 # -indol-3-yl) pyridin-2-one. tert-butyl ylcarbamate (Intermediate 3, 240 mg, 0.51 mmol) in DMF (20 mL) under a nitrogen atmosphere. The mixture is stirred at room temperature for 30 minutes and cooled to 0 ° C. BrCHiCC 3 (103 mg, 0.62 mmol) was added and the mixture was again stirred at room temperature for 2 hours. The mixture is poured into H2O (40 mL) and the aqueous phase is extracted with EtOAc (50 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (40 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated to give 284 mg (100%) of the compound of interest in the form of a brown oil, directly used. in the next transformation without purification. LC-MS: mlz 554.1 [M + H] +. Step 2: 2 - ((5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) amino) ethyl acetate hydrochloride Concentrated aqueous HCl (2 mL) is added to a solution of ethyl 2 - ((tert-butoxycarbonyl) (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) amino) acetate ( Step 1: 284 mg, 0.51 mmol) in dioxane (2 mL). The mixture was stirred at room temperature for 1 hour and concentrated to give 268 mg (100%) of the compound of interest as a yellow oil, directly used in the next transformation without purification. LC-MS: mlz 454.1 [M + H] +. Step 3:
According to the general method used for the preparation of Compound 1 Step 2, using as starting material 2 - ((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl hydrochloride ) pyridin-2-yl) amino) ethyl acetate (Step 2, 268 mg, 0.51 mmol), 20 mg (13%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS: m / z 284.2 [M-H] -. H NMR (400 MHz, DMSO-d6) δ [pm]: 13.35 (br s, 1H), 11.61 (s, 1H), 8.45 (br s, 1H), 8.22 (d, J = 9.3 Hz, 1H) , 8.16 (s, 1H), 7.78 (d, J = 2.6 Hz, 1H), 7.75 (dd, J = 8.7, 5.3 Hz, 1H), 7.26 (dd, J = 9.9, 2.4Hz, 1H), 7.18 ( d, J = 9.3 Hz, 1H), 6.98 (ddd, J = 9.5, 8.7, 2.4 Hz, 1H), 4.25 (s, 2H).
Compound 31; 2- (5- (6-Fluoro-L-indol-3-yl) pyridin-2-ylamino) -acetamide Step 1: (2-Amino-2-oxoethyl) (5- (6-fluoro-1- (phenylsulfonyl) tert-butyl 1H-indol-3-yl) pyridin-2-yl) carbamate
Following the general method used for the preparation of Step 1 Compound, using as starting materials 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-ylcarbamate. -butyl (Intermediate 6, 240 mg, 0.51 mmol), NaH (25 mg, 0.62 mmol, 60% in mineral oil), 2-bromoacetamide (159 mg, 1.15 mmol), and K1 (190 mg, 1.15 mmol) 180 mg (44%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS: m / z 525.1 [M + H] +. H NMR (400 MHz, DMSO-40 δ [pm]: 8.66 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 8.17 - 8.08 (m, 3H), 7.90 (d, J = 8.6 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.81 (dd, J = 9.8, 2.3 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.65 - 7.60 (m, 2H), 7.41 (s, 1H), 7.24 (td, J = 9.1, 2.4 Hz, 1H), 6.97 (s, 1H), 4.53 (s, 2H), 1.47 (s, 9H).
Step 2: 2 - ((5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2-yl) amino) acetamide
Following the general method used for the preparation of Step 2 Compound, using as starting material (2-amino-2-oxoethyl) (5- (6-fluoro-1- (phenylsulfonyl) -177-indol-3-yl) tert-butyl pyridin-2-yl) carbamate (Step 1, 142 mg, 0.27 mmol), 114 mg (100%) of the compound of interest is obtained as a green oil, directly used in the next transformation without purification. LC-MS: mlz 425.1 [M + H] +. Step 3:
Following the general method used for the preparation of Compound 1 Step 2, using as starting material 2 - ((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridin-2 -yl) amino) acetamide (Step 2, 100 mg, 0.24 mmol), 13 mg (19%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS: m / z 285.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 11.48 (s, 1H), 8.21 (s, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.74 (dd, J = 8.6, 5.6 Hz, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.32-7.10 (m, 3H), 6.94-7.00 (m, 2H), 3.97 (s, 2H).
Compound 34; 5- (6-Fluoro-1H-indol-3-yl) -N-methylpyridin-2-amine Step 1: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -N -méthylpyridin-2-amine
A solution of 3- (6-chloropyridin-3-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 300 mg, 0.78 mmol) and methylamine (15.0 mL, 30 mmol, 2.0 M in THF) in DMSO (2 mL) is stirred at 130 ° C for 48 h in an autoclave. The mixture is cooled to room temperature and concentrated to vacuo. The residue is purified by silica gel chromatography (petroleum ether / EtOAc = 10/1 - 5/1) to give 70 mg (23%) of the compound of interest as a yellow solid. LC-MS: m / z 382.1 [M + H] +. 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -N-methyl-2-pyridin-2 as starting material -amine (Step 1, 70 mg, 0.18 mmol), 28 mg (63%) of the compound of interest is obtained as a yellow solid after purification by preparative TLC (petroleum ether / EtOAc = 1/1). LC-MS: m / z 242.1 [M + H] +. H NMR (400 MHz, MeOH-1/4) δ [pm]: 8.10 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.57 (dd, J = 8.7, 5.3 Hz, 1H), 7.25 (s, 1H), 7.00 (dd, J = 9.6, 2.2 Hz, 1H), 6.76 (ddd, J = 9.3, 8.7, 2.2 Hz, 1H), 6.54 (d, J). = 8.7 Hz, 1H), 2.81 (s, 3H).
Compound 44; 6-Fluoro-3- (dvridin-3-yl) -1H-indole Step 1: 6-Fluoro-1- (phenylsulfonyl) -3- (pyridin-3-yl) -1H-indole
Pd2dba3 (260 mg, 0.28 mmol) and S-Phos (260 mg, 0.63 mmol) are added to a solution of 3-bromo-6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 2.82 mmol), pyridin-3-ylboronic acid (400 mg, 3.25 mmol), K3PO4 (1.41 g, 6.60 mmol) in dioxane (20 mL) and water (2 mL) under a nitrogen atmosphere. The mixture is heated at 125 ° C for 30 minutes in a microwave reactor. The mixture is diluted with EtOAc (20 mL) and water (10 mL). The organic phase is separated, washed with a saturated aqueous solution of NaCl (5 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated, and purified by chromatography on silica gel (petroleum ether / EtOAc = 1/1) to give 200 g. mg (20%) of the compound of interest as a white solid. LC-MS: m / z 353.0 [M + H] +. ✓
2nd step:
A solution of NaOH (68 mg, 1.7 mmol) in water (2 mL) is added to a solution of 6-fluoro-1- (phenylsulfonyl) -3- (pyridin-3-yl) -1H-indole ( Step 1, 150 mg, 0.43 mmol) in MeOH (5 mL). The reaction mixture was stirred at 80 ° C for 30 minutes, concentrated, diluted with H2O (5 mL), and extracted with Et2O (10 mLx3). The organic phases are combined and then washed with water (10 mLx2), saturated aqueous NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to give 60 mg (66 mL). %) of the compound of interest as a white solid. LC-MS: m / z 213.2 [M + H] +. H NMR (400 MHz, DMSO-40 δ [pm]: 11.59 (br s, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.44 (dd, J = 4.7, 1.6 Hz, 1H), 8.08 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.37 (dd, J = 8.8, 5.4 Hz, 1H), 7.84 (s, 1H), 7.44 (dd, J = 8.0, 4.7 Hz, 1H), 7.25 (dd, J = 9.9.2.4 Hz, 1H), 6.98 (ddd, J = 8.8, 7.2, 2.4 Hz, 1H).
Compound 45: 6-Fluoro-3- (2-methylpyridin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (2-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H -indole
According to the general method used for the preparation of Compound 1 Step 1, using 3-bromo-6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 120 mg, 0.34 mmol) as starting materials and 2-methyl-3- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) pyridine (381 mg, 1.74 mmol), 100 mg (81%) of the compound of interest is obtained in the form of a red solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 10 / 1-2 / 1). LC-MS: mlz 367 [M + H] +. 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 6-fluoro-3- (2-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H-indole as starting material (Step 1 100 mg, 0.27 mmol), 17.5 mg (28%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 225.2 [M-H] H NMR (400 MHz, DMSO - / 6) δ [pm]: 11.55 (br s, 1H), 8.42 (dd, J = 4.7, 1.6 Hz , 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 7.53 (s, 1H), 7.37 (dd, J = 8.6, 5.7 Hz, 1H), 7.28 (dd, J = 7.6, 4.7 Hz, 1H), 7.24 (dd, J = 10.0, 2.2 Hz, 1H), 6.90 (ddd, J = 9.6, 8.6, 2.2Hz, 1H), 2.48 (s, 3H).
Compound 46: 6-Fluoro-3- (4-methylpyridin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (4-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H- indole
Following the general method used for the preparation of Compound 1 Step 1, using as starting materials 3-bromo-6-fluoro-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 200 mg, 0.56 mmol) and (4-methylpyridin-3-yl) boronic acid (100 mg, 0.73 mmol), 50 mg (24%) of the compound of interest is obtained as a white solid after purification by silica gel chromatography (petroleum ether / EtOAc = 10/1 - 1/1). LC-MS: mlz 367.1 [M + H] +. 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 6-fluoro-3- (4-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H-ndole as starting material (Step 1 50 mg, 0.14 mmol), 5 mg (16%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 227.1 [M + H] +. H NMR (400 MHz, CDCl 3) δ [pm]: 8.66 (s, 1H), 8.58 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 7.37 (dd, J = 8.6, 5.3 Hz). , 1H), 7.25 (d, J = 4.9 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 9.4, 1.9 Hz, 1H), 6.93 (ddd, J = 9.2, 8.6, 1.9 Hz, 1H), 2.32 (s, 3H).
Compound 47: 5.6-difluoro-3- (p-ridin-3-vi) -1 / 7-indole Step 1: 5,6-difluoro-1- (phenylsulfonyl) -3- (pyridin-3-yl) -1H -indole
AT
According to the general method used for the preparation of Compound 1 Step 1, using as starting material 5,6-difluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 6; 250 mg; 0.60 mmol). ), 100 mg (45%) of the compound of interest is obtained as a yellow solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 1/1). LC-MS: m / z 371.1 [M + H] +. H NMR (400 MHz, DMSO-4) δ [pm]: 8.94 (d, J = 1.7 Hz, 1H), 8.60 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.20 - 8.13 (m, 3H), 8.07 (dd, J = 10.9, 6.9 Hz, 1H), 7.91 (dd, J = 10.9, 7.7 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.66 - 7.61 (m , 2H), 7.50 (dd, J = 8.0.4.7 Hz, 1H). 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using as starting material 5,6-difluoro-1- (phenylsulfonyl) -3- (pyridin-3-yl) -1H-indole (Step 1 100 mg, 0.27 mmol), 36 mg (58%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 231.1 [M + H] +. H NMR (400MHz, DMSO-4) δ [pm]: 11.68 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 4.7Hz, 1H), 8.08 (d , J = 7.9 Hz, 1H), 7; 91 (s, 1H), 7.83 (dd, J = 11.7, 7.9 Hz, 1H), 7.49 (dd, / = 11.0, 7.2 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H).
Compound 48: 6-Fluoro-3- (5-methylpyridin-3-yl) -1H-indole Step 1: 6-Fluoro-3- (5-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H- indole
Following the general method used for the preparation of Compound 1 Step 1, using as starting materials 6-fluoro-3-iodo-1- (phenylsulfonyl) -17 -indole (Intermediate 1; 465 mg; 1.16 mmol) and 3 methyl-5- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) pyridine (762 mg, 3.48 mmol), 220 mg (52%) of the compound of interest is obtained in the form of a yellow oil after purification by reverse phase chromatography. LC-MS: m / z 367.1 [M + H] +. 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 6-fluoro-3- (5-methylpyridin-3-yl) -1- (phenylsulfonyl) -1H-indole as starting material (Step 1; mg, 0.60 mmol), 44.9 mg (33%) of the compound of interest is obtained as a brown solid after purification by reverse phase chromatography. LC-MS: m / z 22ΊΛ [M + H] +. H NMR (400 MHz, DMSO - / 6) δ [pm]: 11.54 (s, 1H), 8.71 (d, J = 1.7 Hz, 1H), 8.28 (s, 1H), 7.88 (s, 1H) , 7.86 (dd, J = 8.8, 5.5 Hz, 1H), 7.80 (s, 1H), 7.24 (dd, J = 9.8, 2.0 Hz, 1H), 6.97 (ddd, J = 9.4, 8.8, 2.0 Hz, 1H). ), 2.37 (s, 3H).
Compound 49: 3- (6-Fluoro-1H-indol-3-yl) pyridine 1-oxide Step 1: 3- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridine 1 mCPBA (187 mg, 0.67 mmol, 80% in water) is added to a solution of 6-fluoro-1- (phenylsulfonyl) -3- (pyridin-3-yl) -lindole (Compound Step 1, 200 mg, 0.57 mmol) in anhydrous DCM (5 mL) at 0 ° C. The mixture is stirred at room temperature for 16 hours and diluted with saturated aqueous NaHCO 3 solution (10 mL). The aqueous phase is extracted with DCM (20 mL). The organic phases are combined and then washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by silica gel chromatography (DCM / MeOH = 20/1) to give 175 mg ( 83%) of the compound of interest as a white solid. * H NMR (400 MHz, CDCl3) δ [pm]: 8.47 (s, 1H), 8.22 (d, J = 5.6, 1.2 Hz, 1H), 7.99 -7.89 (m, 2H), 7.81 (dd, J = 9.4, 2.3 Hz, 1H), 7.77 (s, 1H), 7.67-7.60 (m, 2H), 7.56 -7.50 (m, 2H), 7.49-7.44 (m, 1H), 7.42-7.36 (m, 1H) , 7.10 (td, J = 8.9, 2.2 Hz, 1H). 2nd step:
Following the general method used for the preparation of Compound 1 Step 2, using 3- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) pyridine 1-oxide as starting material (Step 1 170 mg, 0.46 mmol), 60 mg (57%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS: m / z 229.1 [M + H] +. H NMR (400 MHz, DMSO-d6) δ [pm]: 11.74 (s, 1H), 8.55 (s, 1H), 8.10 (dd, J = 6.5 Hz, 1H), 7.98 (d, J = 2.7 Hz). , 1H), 7.86 (dd, J = 8.8, 5.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.0, 6.5 Hz, 1H), 7.27 (dd, J = 9.8, 2.4 Hz, 1H), 7.01 (ddd, J = 9.5, 8.8, 2.4 Hz, 1H).
EXAMPLES OF BIOLOGY II.l. TESTS FOR DETERMINING THE ENZYMATIC ACTIVITY OF TD02
The compounds of the present invention inhibit the enzymatic activity of human TD02.
To measure the enzymatic activity of TD02, the reaction mixtures contain (final concentrations) a buffer potassium phosphate buffer (50 mM, pH 7.5), ascorbic acid (0.25 M), methylene blue (0.125 μΜ), catalase (40 units bovine liver, Sigma), and recombinant human TD02 enzyme (prepared according to Dolusic et al., J. Med Chem 2011, 54, 5320-5334, 0.9 μg) with or without the compounds of the present invention. present invention at the indicated concentrations (total volume 112.5 μL). The reaction is initiated by the addition of 37.5 μL of L-Trp (final concentration of 1 mM) at room temperature. The reaction is carried out at room temperature for one hour and stopped by the addition of 30 μl of 30% (w / v) trichloroacetic acid.
To convert / V-formylkynurenine to kynurenine, the reaction mixture is incubated at 65 ° C for 30 min. Then 150 μl of the reaction mixture is mixed with 120 μl of 2.5% (w / v) 4- (dimethylamino) -benzaldehyde in acetic acid and incubated for 5 min at room temperature. Kynurenine concentrations are determined by measuring asorbance at 480 nm. A standard curve was previously established with pure kynurenine. TDO activity is measured as described above using ten different concentrations of the compounds of the present invention. The data is analyzed using the Prism program (GraphPad Software, Inc.). The biological activity of the Representative Examples is summarized in the table below (*: 10 μΜ <IC50 <100 μΜ; **: 1 μΜ <IC50 <10 μΜ; ***: IC50 <1 μΜ):
//.2. CELL TESTING FOR THE DETERMINATION OF TD02 ACTIVITY
The compounds of the present invention inhibit the activity of human TD02 in cells. The assay is performed on flat-bottom 96-well plates in which murine P815 mastocytoma cells overexpress hTD02 (preparation according to Pilotte et al., PNAS, 2012,109 (7), 2497-2502), at concentration of 5 × 10 4 cells / well in a final volume of 200 μl. To determine the activity of TDO or DDO, the cells are incubated overnight at 37 ° C with 5% CO 2 in IMDM (Invitrogen) enriched with 2% FBS and 2% penicillin / streptomycin in the presence of the compounds of the present invention. , at different concentrations.
The plates are centrifuged for 5 min at 1000 rpm, and 100 μl of the supernatant is collected in a conical flask, 30 μl of 30% TCA is added and then centrifuged at 3000 x g for 10 minutes. 100 μl of the supernatant are collected in a flat bottom flask and 100 μl of 2% (w / v) 4- (dimethylamino) -benzaldehyde in acetic acid and incubated for 5 min at room temperature. Kynurenin concentrations are determined by measuring the absorbance at 480 nm. A standard curve was previously established with pure kynurenine. TDO activity is measured as described above using ten different concentrations of the compounds of the present invention. The data is analyzed using the Prism program (GraphPad Software, Inc.). The biological activity of the Representative Examples is summarized in the following table (*: 10 μΜ <IC50 <100 μΜ; **: 1 μM <IC50 <10 μM; ***: IC50 <1 μM):

权利要求:
Claims (14)
[1]
1. A compound of Formula I

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein: X1 and X2 each independently represent H, halogen, alkyl, haloalkyl, preferably H or F; T i X is absent or represents -0 ', preferably X is absent; R1, R2 and R3 are each independently H, halogen, C1-C6 alkyl, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r8, n SO2R, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; preferably R, R and R are each independently H, halogen or methyl, preferably H or methyl, more preferably H; A represents: - a hydrogen atom; - CR4R5R6, NR4R5 or OR4 in which R4, R5 and R6 each independently represent: • a hydrogen atom; Halogen, preferably F, Cl or I, more preferably F; • hydroxyl; OR7 or NR7R8 wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl an amino; a linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. in CR4R5R6, R4, R5 and the carbon atom to which they are attached together form a ring, said ring being preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO, alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or a COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino-one, and the like. heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 'and R' each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, an amino in NR4R5, R4, R5 and the nitrogen atom to which they are attached together form a ring, said ring being preferably a heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2Rn, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino and the like. wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino or R11 represents an alkyl group optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, aryl; wherein R12 and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, aminoalkyl, and the like. the proviso that the compound of formula I is not 3- (pyridin-3-yl) -1H-indole; 3 - ((5- (lH-indol-3-yl) pyridin-2-yl) oxy) -2-methylquinuclidine; 5-methyl-3- (6-methylpyridin-3-yl) -LH-indole; 3-methyl-5- (5-methyl-lH-indol-3-yl) pyridin-2-amine.
[2]
2. The compound of claim 1 of Formula la

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein: X1, X2, R1, R2 and R3 are as defined in claim 1; R4, R5 and R6 each independently represent: • a hydrogen atom; Halogen, preferably F, Cl or I, more preferably F; • hydroxyl; OR7 or NR7R8 wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl an amino; a linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 o and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. R4, Rs and the carbon atom to which they are attached together form a ring, said ring being preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7 , CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, wherein the alkyl group is optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH. ; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino a heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
[3]
3. The compound according to claim 1 of Formula Ib '

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein: X1, X2, R1, R2 and R3 are as defined in claim 1; R4 represents: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
[4]
4. The compound of claim 1 of Formula I '

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein: X, X, R, R and R are as defined in claim 1; R4, R5 and R6 each independently represent: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. R4, R5 and the nitrogen atom to which they are attached together form a ring, said ring being preferably a heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, nr7cor8, nr7r8, so2r7, so2nr7r8, nr7so2r ", so2r7, aryl, CO-alkyl, alkyl, alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1-4 alkyl; -C6, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino or R11 represents an optionally substituted alkyl group of up to three sub stituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NRI2SO2R13, SO2R12, aryl; wherein R12 and R13 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
[5]
5. The compound of claim 4 of Formula Ic-1

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein: 1 <2 4 <2 "X, X, R, R and R are as defined in claim 1; X4 is CH, N or O; R9 is absent or represents H, halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2Ru, SO2R7, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, an alkylaryl, a heteroaryl, a heteroarylalkyl, an alkylheteroaryl, an amino and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl the, alkylheteroaryl, amino or R11 represents an alkyl group optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, aryl; in which R and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
[6]
6. The compound of claim 4 of Formula Ic-2

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein X1, X2, R1, R2 and R3 are as defined in claim 1; and R4 represents: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7 and R8 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino. -CO-R10 or -SO2R10 wherein R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
[7]
7. The compound of claim 4 of Formula Ic-3

or a pharmaceutically acceptable enantiomer, salt and solvate thereof, wherein X1, X2, R1, R2 and R3 are as defined in claim 1; and R4 represents: • a hydrogen atom; A linear or branched C1-C10 alkyl, preferably a methyl, an ethyl or a propyl; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, wherein R7Q and R each independently represent a hydrogen atom or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2Rs, SO2R7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R and R each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R10 or -SO2R10; R10 represents a group selected from alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR7, COOR7, CONR7R8, NR7COR8, NR7R8, SO2R7, SO2NR7R8, NR7SO2R8, SOR7, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R7 and R8 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
[8]
8. The compound of claim 1 of Formula Id '

or one of its pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2 and R3 are as defined in claim 1, provided that X1, X2, R1, R2 and R3 are not all simultaneously H .
[9]
The compound of claim 1 selected from the group consisting of: 6-fluoro-3- (6-methylpyridin-3-yl) -1H-indole 6-fluoro-3- (6- (piperidin-4-yloxy) ) pyridin-3-yl) -1H-indole 6-fluoro-3- (6 - ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) -1H-indole 2 - ((5- ( 6-fluoro-1H-indol-3-yl) pyridin-2-yl) oxy) -N, N-dimethylethanamine 6-fluoro-3- (6-methoxypyridin-3-yl) -1H-indole 5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) oxy) -N, N-dimethylethanamine 1-fluoro-1H-indol-3-yl) -N- (1- (methylsulfonyl) piperidin-4-yl) pyridin-2-amine 5- (6-fluoro-1H-indol-3-yl) -N, N N-5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) -N-methylacetamide 4- (5- (6-fluoro-1H-indol-3-dimethylpyridin-2-amine) 6-fluoro-3- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-indole 2-amino-1 - (4- (5- (5- (4-methyl-1-yl) -methyl) pyridin-2-yl) -methyl (6-Fluoro-1H-indol-3-yl) pyridin-2-yl) piperazin-1-yl) ethanone 6-fluoro-3- (6- (4- (methylsulfonyl) piperazin-1-yl) pyridin 3-yl) -1H-indole 2-amino-N- (1- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) piperidin-4-yl) acetamide N- ( 1- (5- (6-Fluoro-1H-indol-3-yl) pyridin-2-yl) piperidin-4-yl) methanesulfon 5- (6-Fluoro-1H-indol-3-yl) pyridin-2-amine 5- (5,6-difluoro-1H-indol-3-yl) pyridin-2-amine 5- (6-fluoro) amide 1 H -indol-3-yl) -N- (piperidin-4-yl) pyridin-2-amine N- (1-ethylpiperidin-4-yl) -5- (6-fluoro-1H-indol-3-yl) yl) pyridin-2-amine 5- (6-fluoro-1H-indol-3-yl) -N- (1 - (methylsulfonyl) piperidin-4-yl) pyridin-2-amine N- (3 - (( 5- (6-Fluoro-1H-indol-3-yl) pyridin-2-yl) amino) propyl) acetamide N- (3 - ((5- (6-fluoro-1H-indol-3-yl)) pyridin-2-yl) amino) propyl) methanesulfonamide 5- (6-fluoro-1H-indol-3-yl) -N- (3- (methylsulfonyl) propyl) pyridin-2-amine 3- (5- ( 6-fluoro-1H-indol-3-yl) pyridin-2-yl) amino) propane-1-sulfonamide 3 - ((5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) ) amino) propanamide N1- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) -N2, N2-dimethylethane-1,2-diamine N- (2 - ((5- ( 6-fluoro-1H-indol-3-yl) pyridin-2-yl) amino) ethyl) methanesulfonamide 2 - ((5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) amino) ethanol 5- (6-fluoro-1H-indol-3-yl) -N- (2- (methylsulfonyl) ethyl) pyridin-2-amine 2 - ((5- (6-fluoro-1H-indol-3) yl) pyridin-2-yl) amino) e thanesulfonamide 2 - ((5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) amino) acetic acid 2 - ((5- (6-fluoro-1H-indol-3-yl) pyridin -2-yl) amino) acetamide (5- (6-Fluoro-1H-indol-3-yl) pyridin-2-yl) amino) methanesulfonamide 5- (6-fluoro-1H-indol-3-yl) - N-methylpyridin-2-amine 5- (6-fluoro-1H-indol-3-yl) -N-methylpyridin-2-amine N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) piperidine-4-carboxamide 2-amino-N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) -3-phenylpropanamide 2-amino-N- ( 5- (6-Fluoro-1H-indol-3-yl) pyridin-2-yl) propanamide 2-amino-N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) 2-aminobutanamide-amino-N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) acetamide N- (5- (6-fluoro-1H-indol-3-yl) acetamide N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) piperazine-1-carboxamide 4-acetyl-N- (5- (6-yl) pyridin-2-yl) acetamide 1-fluoro-1H-indol-3-yl) pyridin-2-yl) piperazine-1-carboxamide N- (5- (6-fluoro-1H-indol-3-yl) pyridin-2-yl) tetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide-6-fluoro-3- (pyridin-3-yl) -1H-indole 6-fluoro-3 - (2-methylpyridin-3-yl) yl) -1H-indole 6-fluoro-3- (4-methylpyridin-3-yl) -1H-indole 5,6-difluoro-3- (pyridin-3-yl) -1H-indole 6-fluoro 3- (5-methylpyridin-3-yl) -1H-indole 3- (6-fluoro-1H-indol-3-yl) pyridine 1 -oxide or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
[10]
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable enantiomer, salt and solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.
[11]
A medicament comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
[12]
12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable enantiomer, salt and solvate thereof for use in the treatment and / or prevention of cancer, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity
[13]
13. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable enantiomer, salt and solvate thereof for use as a TD02 inhibitor.
[14]
A process for producing a compound of formula I as claimed in claims 1 to 9 or a pharmaceutically acceptable enantiomer, salt and solvate thereof, which comprises: (a1) reacting a compound of formula II

wherein X1 and X2 are defined in claim 1; Z1 is H or an amino protecting group such as, for example, arylsulphonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, benzyl or any other suitable protecting group known to those skilled in the art; Y represents a halogen (preferably iodine, bromine or chlorine), an alkylsulphonyloxy having 1 to 6 carbon atoms (preferably a methylsulphonyloxy or trifluoromethylsulphonyloxy) or arylsulphonyloxy having from 6 to 10 carbon atoms (preferably phenyl- or p- tolylsulfonyloxy), or any other suitable leaving group known to those skilled in the art; with a compound of Formula ΙΠ

wherein I R, R, R, X and A are defined in claim 1; and Z and Z represent H or alkyl groups, with the possibility for y Ί Z and Z to form a ring; to obtain a compound of Formula IV,

wherein X 1, X 2, R 1, R 2, R 3, X 3, A and Z 1 are as defined above; and (b1) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula IV, to give compound of Formula I.

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同族专利:

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2019-08-19| FG| Patent granted|Effective date: 20150922 |

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2019-08-19| MM| Lapsed because of non-payment of the annual fee|Effective date: 20181130 |

优先权:

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申请号 | 申请日 | 专利标题

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US201461996974P| true| 2014-02-12|2014-02-12|

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US14/179440|2014-02-12|

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EP14/179440|2014-02-12|

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EP14154911|2014-02-12|PCT/IB2015/051036| WO2015121812A1|2014-02-12|2015-02-11|Novel 3--pyridine derivatives, pharmaceutical compositions and methods for use|

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US14/619,589| US9758505B2|2014-02-12|2015-02-11|3--pyridine derivatives, pharmaceutical compositions and methods for use|

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JP2016568160A| JP2017505346A|2014-02-12|2015-02-11|Novel 3--pyridine derivatives, pharmaceutical compositions and methods of use|

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EP15706941.0A| EP3105225A1|2014-02-12|2015-02-11|Novel 3--pyridine derivatives, pharmaceutical compositions and methods for use|

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CA2939164A| CA2939164A1|2014-02-12|2015-02-11|Novel 3--pyridine derivatives, pharmaceutical compositions and methods for use|