NOVEL 3-INDOL SUBSTITUTED DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHOD OF USE

专利摘要:
NEW SUBSTITUTE DERIVATIVES OF 3-INDOL, PHARMACEUTICAL COMPOSITIONS AND METHOD OF USE. The present invention relates to a compound of Formula I or a pharmaceutically acceptable enantiomer, salt or solvate 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 for the treatment and / or prevention of cancer, neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases, chronic viral infections such as HCV and HIV, depression. and obesity. The invention also relates to a method of making the compounds of Formula I.
公开号:BE1021253B1
申请号:E2014/0776
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 SUBSTITUTED DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHOD OF USE
FIELD OF THE INVENTION
The present invention relates to substituted 3-indole derivatives, their enantiomers, pharmaceutically acceptable salts, solvates and prodrugs thereof. The compounds of the invention are inhibitors of TD02 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and / or prevention of cancers.
STATE OF THE ART
Two decades 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, privileged immune sites, or sites of inflammation (Mellor AL and Munn DH., Nat Rev Immunol, 2008, 8, 74-80). In these tissues, cancer cells, immune cells, or specialized epithelial cells (eg, syncytiotrophoblasts in the placenta) create an immunosuppressive environment in tumors that stops antitumor immune responses in tumors and in tumor-draining lymphatic nodules. , by 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 the catabolism of tryptophan, 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 tiyptophan (Opitz CA et al., Nature, 2011, 478 (7368), 197-203). In addition, inhibition of TD02 by small molecules prevents tumor growth in animal models of 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 indoleamine 2,3-dioxygenase (IDO) by the tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269-1274 ).
Because catabolism of tryptophan is induced by inflammatory mediators, especially IFN-gamma, it is possible to imagine that it represents 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 the suppression of antitumor immune responses in precancerous lesions and tryptophan-induced catabolism-induced cancers induces tumor growth, which could make this catabolism a prime target for therapeutic intervention (Dolusic E and Frédérick R., Opin Expert 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 Exp Med., 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; R, R and R 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, OR4, COOR4, CONR4R5, nr4cor5, nr4r5, so2r4, so2nr4r5, nr4so2r5, SO2R4, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; in which R4 and R5 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 each independently represent H, halogen or alkyl, preferably R1, R2 and R3 each represent 1 yy λ
independently H, halogen or methyl, preferably R, R and R are each H; A1, A2 and A3 each independently represent C, N or O; each of Y1, Y2 and Y3 is either absent or independently represents - a hydrogen atom; - oxo; - CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 each independently represent: • a hydrogen atom; A halogen, preferably F, Cl or I, more preferably F; A hydroxyl; OR9 or NR9R10 wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl , an amino, CO-alkyl, SO2R11, wherein R11 represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, an 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2Rn wherein R11 represents a group selected from an amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r ', nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; In CR6R7R8, R6, R7 and the carbon atom to which they are attached together form a ring, which ring is preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from a halogen, a hydroxyl, an amino or COOH; wherein R9 and R10 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; In NR6R7, R6, R7 and the nitrogen atom to which they are attached form a ring, this 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, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r ", SO2R9, aryl, CO-alkyl, alkyl, alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 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 substituents selected from the group consisting of halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NRI2R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, aryl; wherein R12 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; the dashed lines represent single bonds or double bonds; provided that A1, A2 and A3 are not all Cs; provided that when one of A1, A2 and A3 is N, the other two are not both C; provided that the compound of formula I is not 3- (benzofuran-5-yl) -6-chloro-1H-indole or 3- (benzo [d] [1,3] dioxol-5-yl) -1H -indole.
According to a preferred embodiment, the fused heterocycle which substitutes the indole ring in Formula I is aromatic.
According to a preferred embodiment, in Formula I, X1 and X2 each independently represent H or halogen, preferably H or F. According to a specific embodiment, X1 represents H and X2 represents F. According to a preferred embodiment in Formula I, R1, R2 and R3 are each H. In a specific embodiment, in Formula I, X1 and X2 each independently represent H or halogen and R1, R2 and R3 each represent H; preferably X1 is H and X2 is F and R, R and R are each H.
According to one embodiment, in Formula I, a first of A1, A2 and A3 is N, a second of A1, A2 and A3 is C and the third of A1, A2 and A3 is N or O.
According to one embodiment, in Formula I, A2 is N and one of A1 and A3 is N and the other is C.
According to one embodiment, in Formula I, A2 is C and one of A1 and A3 is N and the other is N or O.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-1
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A1, A3, Y1, Y2 and Y3 are as described in Formula I.
According to one embodiment, in Formula II-1, none of A1 and A3 is C.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-2
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A1, A3, Y1, Y2 and Y3 are as described in Formula I.
According to one embodiment, in Formula II-1, {A1, A3} are not {C, N}, {N, C} or {C, C}.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-la
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A1, Y1, Y2 and Y3 are as described in Formula I.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-1b
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A3, Y1, Y2 and Y3 are as described in Formula I.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-2a
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A1, Y1, Y2 and Y3 are as described in Formula I.
According to one embodiment, in Formula II-2a, A1 is not C.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-2b
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A3, Y1, Y2 and Y3 are as described in Formula I.
According to one embodiment, in Formula II-2b, A3 is not C.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-Ial
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, Y1 and Y3 are as described in Formula I.
According to a preferred embodiment, in Formula II-1al, Y1 is H and Y3 is as described in Formula I, preferably Y3 is: - a hydrogen atom; where R °, R and R 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 wherein R11 represents a group selected from an amine, an alkyl, a heterocyclyl (preferably piperidine,
Pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR1, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • R, R and the carbon atom to which they are attached together form a ring, this 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, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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 II-la2
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, Y * and Y2 are as described in Formula I.
According to a preferred embodiment, in Formula II-la2, Y1 is H and Y2 is as described in Formula I, preferably Y2 is: - a hydrogen atom; - CR6R7R8 wherein R6, R7 and R8 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; R6, R7 and the carbon atom to which they are attached together form a ring, which ring is 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, OR9, COOR9, conr9r10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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 II-lbl
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, Y1 and Y3 are as described in Formula I.
According to a preferred embodiment, in Formula II-lbl, Y3 is H and Y1 is as described in Formula I, preferably Y1 is: - a hydrogen atom; - CR6R7R8 wherein R6, R7 and R8 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R ', NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, conr9r10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; R6, R7 and the carbon atom to which they are attached together form a ring, which ring is 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, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, im heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
According to one embodiment, the preferred compounds of Formula I are those of Formula II-lb2
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, Y21 Y3 are as described in Formula I.
According to a preferred embodiment, in Formula II-lbl, Y3 is H and Y2 is as described in Formula I, preferably Y2 is: - a hydrogen atom; - CR6R7R8 in which R6, R7 and R8 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2Ru wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, S OR9, aryl, CO-alkyl, alkyl, alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; R6, R7 and the carbon atom to which they are attached together form a ring, which ring is 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, OR9, COOR9, conr9r10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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 II-2al
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, Y1 and Y2 are as described in Formula I.
According to a preferred embodiment, in Formula II-2al, Y1 is H and Y2 is as described in Formula I, preferably Y2 is: - a hydrogen atom; - CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 each independently represent: • a hydrogen atom; OR9 or NR9R10 wherein R9 and R10 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 CO-alkyl, SO2R11, wherein R11 is a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl alkylheteroaryl, 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; R6, R7 and the carbon atom to which they are attached together form a ring, which ring is 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, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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 II-2a2
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3 and Y2 are as described in Formula I.
According to a preferred embodiment, in Formula II-2a2, Y2 represents: a hydrogen atom; - CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 each independently represent: • a hydrogen atom; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2Rh wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, nr9cor10, NR9R10, so2r9, so2nr9r10, nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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 II-2M
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, Y2 and Y3 are as described in Formula I.
According to a preferred embodiment, in Formula II-2M, Y3 is H and Y2 is as described in Formula I, preferably Y2 is: - a hydrogen atom; - CR6R7R8 in which R6, R7 and R8 each independently represent: • a hydrogen atom; OR9 or NR9R10 wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl , an amino, CO-alkyl, SO2R11, wherein R11 represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, an 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 are each independently hydrogen or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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 II-2b2
and their pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3 and Y2 are as described in Formula I.
According to a preferred embodiment, in Formula II-2b2, Y2 represents: a hydrogen atom; - CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 each independently represent: • a hydrogen atom; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2Rn wherein R11 represents a group selected from an amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, so2nr9r ', nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In particular, the preferred compounds of Formula I of the invention are those described in
Table 1 below. TABLE 1
or their enantiomers, pharmaceutically acceptable 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 its sub-formulas may have an asymmetric center and thus exist as different stereoisomers. Therefore, the present invention includes all possible stereoisomers and includes not only racemic compounds but enantiomers individually and also their non-racemic mixtures. When a compound is desired as a single enantiomer, it can be obtained by stereospecific synthesis, by resolution of the final product or any suitable intermediate, or by chiral chromatographic methods commonly known in the art. The resolution of the final product, intermediate or starting material can be carried out using any suitable method known in the art.
The compounds of the invention may be in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of Formula I include their acid and base addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Such examples include the salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / 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 addition salts are formed from bases which form non-toxic salts. Such 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 hemi-salts of acids and bases can also be formed, for example, the hemisulphate and hemicalcium salts. Preferably, the pharmaceutically acceptable salts include hydrochloride / chloride, hydrobromide / bromide, bisulphate / sulphate, nitrate, citrate, and acetate salts.
When the compounds of the invention contain an acid group, but also a basic group, the compounds of the invention can form internal salts, such compounds also belong to the protective field of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (for example NH), the invention also covers the salts and / or isomers formed by the transfer of a hydrogen atom to a basic group or a hydrogen atom. to the molecule.
The pharmaceutically acceptable salts of the compounds of Formula I may be prepared by one or more of the following 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 or base-sensitive protecting group from an appropriate precursor of the compound of Formula I or by ring-opening a suitably selected cyclic precursor, for example, a lactone or a lactam, using the desired acid; or (iv) converting a salt of the compound of Formula I to another salt by reaction with a suitable acid or by the use of a suitably chosen ion exchange resin.
All these reactions are typically conducted in solution. The salt can precipitate out of the solution and be recovered by filtration or by evaporation of the solvent. The degree of ionization in a 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" includes all acceptable salts such as acetate, lactobionate, benzenesulphonate, laurate, benzoate, malate, bicarbonate, maleate, bisulphate, mandelate, bitartrate, mesylate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulphate, 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, glycollylarsanilate, 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 dosage form to modify the characteristics solubility or hydrolysis 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 salts formed by cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and with bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, and tetramethylammonium hydroxide.
These salts can be prepared according to standard methods, for example by reacting a free acid with an appropriate organic or inorganic base. When a basic group is present, such as an amino, an acid salt, for example hydrochloride, hydrobromide, acetate, palmoate, and derivatives, can be used as a dosage form.
Also, when an alcohol group is present, pharmaceutically acceptable esters can be used, for example, acetate, maleate, pivaloyloxymethyl, and derivatives, and esters known in the art to modify the solubility and hydrolysis characteristics for their use. as controlled release formulations and prodrugs.
All references to the compounds of Formula I include references to their enantiomers, salts, solvates, polymorphs, multi-component complexes and liquid crystals.
The compounds of the invention include the compounds of Formula I defined above, also including all their crystalline, prodrug and isomeric polymorphs and meshes (including optical, geometric, and tautomeric isomers) and isotopically labeled compounds of Formula I.
In addition, and generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, and it should be noted that the invention in its broadest definition also includes non-pharmaceutically acceptable salts. acceptable, which may for example be used in the isolation and / or purification of the compounds of the invention. For example, salts formed with optically active acids or bases can be used to form diastereoisomeric salts which facilitate the separation of the optically active isomers of the compounds of Formula I above. The invention also generally relates to any pharmaceutically acceptable prodrug and prodrug of the compounds of Formula I.
Manufacturing process
The compounds of Formula I can be prepared in various ways from reactions known to those skilled in the art.
The invention also relates to a first process for producing compounds of Formula I
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as described in Formula I; comprising: (a1) reacting a compound of Formula (i)
wherein X1 and X2 are as described in Formula I; Z1 represents H or an amino protecting group such as, for example, arylsulphonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, benzyl or any other suitable protective group known to those skilled in the art. halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy with 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 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 (ii) in which
R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as described in Formula I; Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form together a ring; to obtain a compound of Formula (iii),
wherein Z1, X1, X2, R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as described above; and (b1) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula (iii) 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 (Pp13) 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, Na2CC> 3.
According to one embodiment, step (a1) of the process of the invention may be carried out in the presence of a suitable solvent such as, but not limited to, dioxane, THF, DMF, water, alone or as a mixture, of preferably in a mixture of dioxane or THF and water.
According to one embodiment, step (a1) 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, over a period ranging from 10 minutes to several minutes. 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 treating with bases, such as, but not limited to, sodium hydroxide, potassium hydroxide, potassium carbonate. 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, terbutanol, THF, DMF, dioxane, water, alone or in 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 another 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 in the absence of a suitable solvent such as methanol, ethanol, isopropanol, tert-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 ranging from 10 minutes to 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 its pharmaceutically acceptable enantiomers, salts and solvates, wherein X1, X2, R1, R2, R3, A *, A2, A3, Y1, Y2 and Y3 are as described in Formula I; provided that at least one of Y1, Y2 and Y3 is not H or absent; comprising: (a2) alkylating a compound of Formula (iv)
wherein X1, X2, R1, R2, R3, A1, A2, A3, are as described in Formula I, Y1, Y2 and Y3 'respectively represent Y1, Y2 and Y3 as defined in Formula I provided that at least one of Y1 ', Y2' and Y3 'is H; Z1 represents H or an amino protecting group such as, for example, arylsulphonyl, tert-butoxycarbonyl, methoxymethyl, para-methoxybenzyl, benzyl or any other protective group known to those skilled in the art so as to obtain a compound of Formula (v)
wherein X1, X2, R1, R2, R3, A1, A2, A3, Y1, Y2, Y3 and Z1 are defined above with the proviso that at least one of Y1, Y2 and Y3 is not H or absent ; and (b2) in the case where Z1 is not H, deprotecting the indole nitrogen of the compound of Formula (v) to give the compound of Formula I.
According to one embodiment, the alkylation step (a2) is carried out in the presence of the compound of Formula (vi)
Y4-X wherein Y4 is Y1, Y2 or Y3, as defined in Formula I, provided that Y4 is not H or absent; X represents a halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifhioro-methylsulfonyloxy) or an arylsulphonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p- tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
According to one embodiment, step (a2) of the process of the invention may be carried out in the presence of bases such as, but not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert -butoxide, potassium / err-butoxide, sodium hydride, lithium diisopropyl amide, butyl lithium.
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, DMF, methanol, ethanol, isopropanol, tert-butanol, THF, dioxane, dichloromethane, water.
According to one embodiment, step (a2) of the process of the invention may be carried out in the presence or in the absence of a catalytic amount of iodine salts, such as, but not limited to, tetrabutylammonium iodide.
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, step (a2) of the process of the invention may be carried out over 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 producing compounds of Formula II-2al in which Y1 is H:
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, and Y2 are as described in Formula I; comprising: (a3) reacting a compound of Formula (vii)
wherein X1, X2, R1, R2, R3 are as described above; 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; with a compound of Formula (viii)
wherein Y2 is defined above; and Y is hydroxyl, halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl). or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art; to obtain a compound of Formula (ix)
wherein X1, X2, R1, R2, R3, Y2 and Z1 are defined above; and (b3) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula (ix) to give the compound of II-2al wherein Y1 is H.
According to one embodiment, when Y represents a hydroxyl, step (a3) of the process of the invention can be carried out in the presence of a suitable amide coupling agent, such as, but not limited to, HATU, DCC, DIC, BOP, PyBOP, in the presence or absence of additional additives such as, but not limited to, HOBt.
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, triethylamine, diisopropylethylamine, DBU, cesium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide , potassium hydroxide.
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, dichloromethane, DMF, THF, dioxane.
According to one embodiment, step (a3) also comprises adding a suitable acid, such as, but not limited to, acetic acid, when it is necessary to achieve complete cyclization.
According to one embodiment, step (a3) 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, step (a3) of the process of the invention may be carried out over a period ranging from 10 minutes to several hours, for example from 10 minutes to 24 hours.
According to one embodiment, the deprotection step (b3) can be carried out under the conditions described above for the 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 may 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 derivatives by treatment with a solvolysis or hydrogenolysis agent.
Preferred starting materials for solvolysis or hydrogenolysis are those which conform to Formula I and those of the same family, but which contain protected amino and / or hydroxyl groups in place of one or more amino groups. and / or a corresponding free hydroxyl, preferably those which contain an amino protecting group in place of an H atom bound to an N atom, in particular those which carry a group R * -N, in which R * represents a grouping amino protecting, instead of an NH group, and / or those which carry a protecting group of a hydroxyl in place of a H atom of a hydroxyl group, for example those which obey Formula I, but which carry a -COOR ** group, wherein R ** represents a hydroxyl protecting group in place of a -COOH group.
It is also possible that a plurality of amino protecting groups and / or a hydroxyl group - 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, alkoxycarbonyl, 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 the hydroxyl protecting group 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 released from their functional derivatives - depending on the protective group used - for example by strong inorganic acids, such as hydrochloric acid, perchloric acid or 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 approximately 3 to 5N HCl in dioxane at 15-30 ° C, and the FMOC moiety may be cleaved using a solution between about 5 and 50% of dimethylamine, diethylamine or piperidine 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 20-30 ° C and between 1-10 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 20-30 ° 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); nitriles, 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 substituted or unsubstituted alkyl halide, preferably in an inert solvent, such as dichloromethane or THF and / or 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, in "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.
Applications The invention also relates to the use of the compounds of the invention or their pharmaceutically acceptable enantiomers, salts and solvates as TD02 inhibitors.
Also, in a particular embodiment, the invention relates to the use of the compounds of Formula I and its sub-formulas, in particular those of Table 1 above, or their pharmaceutically acceptable enantiomers, salts and sovates, as inhibitors of TD02.
Also, according to another aspect, the invention relates to the use of these compounds or enantiomers, salts and solvates for the synthesis of active pharmaceutical ingredients, such as TD02 inhibitors.
In one embodiment, the invention relates to the use of the compounds of Formula I and its sub-formulas in particular those of Table 1 above, or their pharmaceutically acceptable enantiomers, salts and solvates, to enhance immune recognition and destruction of cancer cells.
The compounds of the invention are therefore useful as medicaments, particularly for the prevention and / or treatment of cancer.
In one embodiment, the compounds of the invention or their pharmaceutically acceptable enantiomers, salts and solvates are for use in the treatment and / or prevention of cancer, neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases, 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, Alzheimer's and Huntington's diseases, chronic viral infections such as HCV and HIV, depression and obesity, which comprises administering to a mammal to treating a sufficient therapeutic amount of a compound of the invention or a pharmaceutically acceptable enantiomer, salt or solvate thereof.
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 particularly useful in the treatment and / or prevention of cancer.
In one embodiment, the compounds of the invention are particularly useful in the treatment and / or prevention of cancer. The invention also relates to the use of the compounds of Formula I or their 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.
Formulations 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 drug 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, 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, in need of 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 vehicles, diluents, excipients for use in such a preparation, will be obvious to the patient. skilled in the art; see also the latest version of Remington's Pharmaceutical Sciences.
Some preferred but non-limiting examples of such preparations include tablets, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, hard or soft 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 carriers, 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, magn esium 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 dosage form, and may be suitably packaged, for example in a box, blistered, in vials, bottles, sachets, ampoules or in any form of single-dose container. or multidose (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, moieties comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyanohaloalkoxy, 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 as part of another substituent refers to a hydrocarbon radical of Formula CnFLn + 1 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 isomers thereof (e.g. -pentyl, iso-pentyl), and hexyl and its isomers (eg, n-hexyl, isohexyl).
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 monovalent, saturated or unsaturated 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 quaternized. 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, cinnolinyl, quinazolinyl, quinoxalinyl.
The term "arylalkyl" refers to any -alkyl-alkyl 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 isotopically labeled compounds of Formula I. 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 means 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 300 MHz Braker Fourier and TMS used as internal reference.
Microwave chemistry was performed on Biotage's Initiator Microwave System EU single-mode microwave reactor.
The preparative HPLC purifications were carried out using the Waters Fractionlynx system (a mass-bound autopurification system) equipped with an Xbridge ™ Prep Cl 8 OBD column 19x150 mm 5 μιη, 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 · 6-fluoro-1- (nhenylsulfon-1-indole)
The compound of interest was prepared according to the method already described (Bioorg, Chem Chem 2011, 19, 4702, 1795).
Intermediate 2; 6-fluoro-3-iodo-l- (phenvlsulfonvI> -l // - indole
The compound of interest was prepared according to the method already described (WO2010 / 136491 A1). Intermediate 3: 6-t4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl) -I-indazole
A mixture of 6-bromo-1/7-indazole (700 mg, 3.55 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi (1) , 3.2-dioxaborolane) (1.50 g, 5.91 mmol), Pd (dppf) Cl2-DCM (290 mg, 0.36 mmol) and KOAc (1.04 g, 10.6 mmol) in DMF (20 mL) is stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo, suspended in EtOAc (30 mL), filtered through Celite, and evaporated to give 866 mg (100%) of the compound of interest as a brown semisolid, directly used in the next transformation without purification. . LC-MS for C13H17BN2O2 + H + [M + H] +: calcd. 245.1; found: 245.0.
Intermediate 4: 6-fluoro-1-tphenylsulfonyl-1H-indol-3-yl-1H-indazole
Pd (dppf) Cl2'DCM (82 mg, 0.1 mmol) is added to a mixture of 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 400 mg, 1.00 mmol), 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (Intermediate 3, 366 mg, 1.50 mmol) and CS2CO3 (978 mg, 3.00 mmol) in DME (9 mL) and water (3 mL) under a nitrogen atmosphere. The mixture is heated at 150 ° C for 1 hour in a microwave reactor. The mixture is filtered through Celite and diluted with EtOAc (100 mL) and water (100 mL). The aqueous phase is extracted with EtOAc (50 mL). The organic phases are combined and then washed with a saturated aqueous solution of NaCl, dried over Na 2 SO 4 anhydrous, filtered, concentrated and purified by chromatography on silica gel (petroleum ether / EtOAc = 5/1 - 2/1) to give 390 mg (100%) of the compound of interest as a yellow solid. LC-MS for C21H14FN3O2S + H + [M + H] +: calcd. 392.1; found: 391.8. H NMR (300 MHz, DMSO-d6) δ [pm]: 13.13 (s, 1H), 8.20-8.11 (m, 4H), 7.93 -7.78 (m, 4H), 7.77-7.70 (m, 1H), 7.65 - 7.60 (m, 2H), 7.44 (dd, J = 9.3, 2.1 Hz, 1H), 7.26 (ddd, J = 9.3.9.0.2.1 Hz, 1H).
Intermediate 5: tert-butyl-4-t6-f6-fluoro-1- (nhenylsulfonyl) -1H-indol-3-yl-1H-indazol-1-ylmethylformin-1-carhoxyate and fert-butyl 4- (T6) - (6-fluoro-l- (phenvlsulfonvll-l / 7-indol-3-vn-2 / f-indazol-2-vllmcthvnpincridine-l-carboxvlatc
A mixture of 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 4; 1.00 g; 2.55 mmol), tert-butyl 4 - (((methylsulfonyl) oxy) methyl) piperidine The carboxylate (1.10 g, 3.75 mmol) and CS2CO3 (1.66 g, 5.09 mmol) in DMF (40 mL) is stirred at 60 ° C overnight under a nitrogen atmosphere. The mixture is cooled to room temperature, diluted with EtOAc (100 mL), filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 6/1 - 2/1) to give 1.11 g (74%). a mixture of the compounds of interest as a yellow solid. LC-MS for C32H33FN4O4S + H + [M + H] +: calcd. 589.2; found: 588.9.
Intermediate 6: 6 - (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piDeridyl-4-ylmethyl) indyldihydrazide and 6- (6-fluoro-1- (naphthyl) sulfonyl) ) 1H-indol-3-yl-2-iminidin-4-ylmethyl-2H-indazole hydrochloride
An aqueous solution of concentrated HCl (16 mL, 37%) is added to a solution of tert-butyl 4 - ((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) 1H-indazol-1-yl) methyl) piperidine-1-carboxylate and tert-butyl 4 - ((6- (6-fluoro-1 - (phenylsulfonyl) -1H-indol-3-yl) -2/7 -indazol-2-yl) methyl) piperidine-1-carboxylate (Intermediate 5, 1.06 g, 1.80 mmol) in MeOH (40 mL). The reaction mixture was stirred for 1 hour and evaporated in vacuo to give 1.55 g (quant.) Of the compound of interest as a yellow solid, directly used in the next transformation without purification. LC-MS for CaylUsFN ^ S + 1f [M + H] +: calcd. 489.2; found: 488.9.
Intermediate 7: 1- (4- (4H) -6-fluoro-1- (1H-naphthyl) -1H-indol-3-yl) -Il-7-indazol-1-ylmethylaminidine-1-yl
Acetyl chloride (116.6 mg, 1.48 mmol) is added to a solution of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piperidin-4-ylmethyl) ) -1H-indazole hydrochloride and 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole hydrochloride ( Intermediate 6, 650 mg, 1.24 mmol) and Εί3Ν (372 mg, 3.68 mmol) in DCM (30 mL) under a nitrogen atmosphere. The reaction mixture is stirred for 1 hour and quenched with a saturated aqueous solution of NaHCO3 (30 mL). The aqueous phase is extracted with DCM (70 mL> <2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (20 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by preparative TLC (EtOAc) to give 267 mg (40%) of the compound of interest. in the form of a yellow solid. LC-MS for C29H27FN4O3S + H + [M + H] +: calcd. 531.2; found: 530.9.
Intermediate 8: 3- [6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-ol-1H-indazol-1-yl) -dropanamide
A mixture of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -17-indazole (Intermediate 4, 200 mg, 0.51 mmol), 3-bromopropanamide (389 mg, 2.56 mmol) K2CO3 (211 mg, 1.53 mmol) and KI (85 mg, 0.51 mmol) in DMF (6 mL) is heated at 130 ° C for 2 hours in a microwave reactor. The mixture is poured into H2O (20 mL) and the aqueous phase is extracted with EtOAc (50 mL> <2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (100 mLx3), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica singlet chromatography (petroleum ether / EtOAc = 2 / 1-0 / 1) to give 95 mg (40%) of the compound of interest as a yellow solid. LC-MS for C24H19FN4O3S + H + [M + H] +: calcd. 463.1; found: 462.8.
Intermediate 9: 4- (6- (6-Fluoro-1- (Dhenylsulfonyl) -1H-indol-3-yl) indol-1-ylpiperidine-1-carboxylate and fert-butyl-4-methyl-4- (6-fluoro-1- (dhenylsulfonyl) -1H-indol-3-yl); (6-Fluoro-1-piphenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-ylpiperidine-1-carboxylate
A mixture of 6-fluoro-3-iodo-1- (phenylsulfonyl) -17H -indole (Intermediate 4; 560 mg; 1.43 mmol), tert-butyl 4 - ((methylsulfonyl) oxy) piperidine-1-carboxylate (0.60 2.15 mmol) and CS2CO3 (1.00 g, 3.07 mmol) in DMF (22 mL) is stirred at 60 ° C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered, and evaporated to give 820 mg (quant.) Of a mixture of compounds of interest as a yellow solid, directly used in the next transformation without purification. LC-MS for C31H31FN4O4S + H + [M + H] +: calcd. 575.2; found: 574.8.
Intermediate 10: 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazolylhydrochloride and 6-fluoro-1-phenylsulphonyl 1H-indol-3-yl-2- (piperidin-4-yl) -2H-indazohydrochloride
According to the general method used for the preparation of Intermediate 6, using tert-butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) as starting materials. 1H-indazol-1-yl) piperidine-1-carboxylate and / e-butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (-indazol-2-yl) piperidine-1-carboxylate (Intermediate 9, 820 mg, 1.43 mmol), 730 mg (100%) of a mixture of the compounds of interest is obtained as a yellow solid, directly used in the next transformation without purification. LC-MS for C26H23FN4O2S + H + [M + H] +: calcd. 475.2; found: 474.8.
Intermediate 11: 5- (4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-vinyl-indazole
A mixture of 5-bromo-1H-indazole (500 mg, 2.54 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi , 3.2-dioxaborolane) (1.29 g, 5.08 mmol), Pd (dppf) Cl 2 DCM (200 mg, 0.24 mmol) and KOAc (1.24 g, 12.6 mmol) in DMF (10 mL) is stirred at 90 ° C. for 15 hours under nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with H2O (50 mLx2), saturated aqueous NaCl (50 mL), dried over anhydrous Na2SC4, filtered through Celite, and evaporated to give 1.18. g (quant.) of the compound of interest as a yellow oil, directly used in the next transformation without purification. LC-MS for C13H17BN202 + H + [M + H] +: calcd. 245.1; found: 245.2.
Intermediate 12: 5-t6-fluoro-1-phenylsulfonyl-1H-indol-3-yl-1H-indazole
Pd (dppf) Cl2'DCM (40 mg, 0.05 mmol) is added to a mixture of 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 200 mg, 0.50 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (Intermediate 11, 345 mg unpurified mixture, 0.74 mmol) and CS2CO3 (488). mg, 1.50 mmol) in DME (6 mL) and water (2 mL) under a nitrogen atmosphere. The mixture is heated at 150 ° C for 30 minutes in a microwave reactor. The mixture is filtered through Celite and diluted with EtOAc (100 mL) and water (100 mL). The aqueous phase is extracted with EtOAc (50 mL). The organic phases are combined and then washed with a saturated aqueous solution of NaCl, dried over anhydrous Na 2 SO 4, filtered and evaporated to give 300 mg (quant.) Of the compound of interest in the form of a yellow oil, directly used in the following transformation. without purification. LC-MS for C21H14FN3O2S + I1 [M + H] +: calcd. 392.1; found: 392.0.
Intermediate 13: 2- (5- (6-fluoro-1- (phenylsulfonyl) -1H-7-mdol-3-yl) -1H-imidazol-1-ylacetamide and 2- (5- (6-fluoro-1 - (phenvlsulfonvB-l // - indol-3-vB-21 / indazol-2-vOacctamide
A mixture of 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 12, 500 mg, 1.28 mmol), 2-bromoacetamide (900 mg; 6.52 mmol), K2CO3 (540 mg, 3.91 mmol) and KI (220 mg, 1.33 mmol) in DMF (12 mL) is heated at 130 ° C for 4 hours in a microwave reactor. The mixture is poured into H2O (10 mL) and extracted with EtOAc (20 mL> <4). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (20 ml), dried over anhydrous Na 2 SO 4, filtered and evaporated to give 353 mg (62%) of a mixture of the compounds of interest in the form of a brown solid. , directly used in the next transformation without purification. LC-MS for C23H17FN4O3S + H + [M + H] +: calcd. 449.1; found: 448.8.
Intermediate 14: Fert-butyl 4-f (5- (6-fluoro-1-phenylsulfonyl) -2H-indol-3-yl] -1-indazol-1-ylmethyl] piperidine-1-carboxylate and 4- (f5-f6) -fert-butyl -fliioro-l- (phenvlsulfonvlVl // - indol-3-vD-2Zilr-mdazol-2-vDmethvl) piperidine-l-carboxylate
According to the general method used for the preparation of Intermediate 5, using as starting materials 5- (6-fluoro-1- (phenylsulfonyl) -17H-indol-3-yl) -1H-indazole (Intermediate 12 1.50 g, 3.83 mmol) and tert-butyl 4- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylate (1.34 g, 4.57 mmol), 1.97 g (88%) of a mixture of the compounds of interest is obtained in the form of a brown oil, directly used in the next transformation without purification. LC-MS for CsiHssFN ^ S + H * [M + H] +: calcd. 589.2; found: 588.8.
Intermediate 15: tert-butyl 4-t (5- (6-fluoro-1H-indol-3-yl) -17-indazol-1-ylmethylfinfinidine-1-carboxylate
A solution of NaOH (679 mg, 17.0 mmol) in water (2 mL) is added to a solution of tert-butyl 4 - ((5- (6-fluoro-1- (phenylsulfonyl) -1H- indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-carboxylate and tert-butyl 4 - ((5- (6-fluoro-1 - (phenylsulfonyl) -1H-indol) 3-yl) -27 -indazol-2-yl) methyl) piperidine-1-carboxylate (Intermediate 14, 2.00 g, 3.40 mmol) in MeOH (40 mL). The reaction mixture is stirred at 85 ° C for 30 minutes, concentrated, and purified by silica gel chromatography (petroleum ether / EtOAc = 3/1) to give 1.18 g (77%) of the compound of interest as the title compound. yellow solid. LC-MS for C6α6FN ^ + H * [M + H] +: calcd. 449.2; found: 448.9
Intermediate 16: 3- (5-tert-fluoro-1-phenylsulfonyl) -1H-indol-3-yl-1H-indazol-1-ylpropanamide and 3- (5- (6-fluoro-1-yl) phenylsulfonyl) // - indol-3-yl) -2 // - indazol-2-vfipropanamide
Following the general method used for the preparation of Intermediate 8, using 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole as starting material ( Intermediate 12, 490 mg, 1.25 mmol), 492 mg (85%) of a mixture of the compounds of interest is obtained as a brown solid, directly used in the next transformation without purification. LC-MS for C11H3N5S + H * [M + H] +: calcd. 463.2; found: 462.8.
Intermediate 17; 4- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -indazol-1-ylpiperidine-1-carboxylate
tert-butyl 4- (methylsulfonyloxy) piperidine-1-carboxylate (1.93 g, 6.91 mmol) is added to a mixture of 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1 // indazole (Intermediate 12, 1.80 g, 4.60 mmol) and CS2CO3 (3.75 g, 11.5 mmol) in DMF (35 mL) under a nitrogen atmosphere. The reaction mixture is stirred at 70 ° C overnight. The mixture is poured into an ice / water mixture (180 mL) and extracted with EtOAc (80 mLx3). The organic phases are combined and then washed with water (50 ml), saturated aqueous NaCl solution (50 ml), dried over Na 2 SO 4 anhydrous, filtered, concentrated and purified by chromatography on silica gel (petroleum ether / EtOAc = 5/1 - 2/1) to give 1.75 g (66%) of the compound of interest as a yellow solid. LC-MS for C31H31FN4O4S + H + [M + H] +: calcd. 575.2; found: 574.9.
Intermediate 18: 4- (5-tert-6-fluoro-1H-indol-3-yl) -7-indazol-1-ylpiperidine-1-carboxylate
A solution of NaOH (800 mg, 20.0 mmol) in water (6 mL) is added to a solution of tert-butyl 4- (5- (6-fluoro-1- (phenylsulfonyl) -17-indol- 3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate (Intermediate 17, 1.75 g, 3.05 mmol) in MeOH (60 mL). The reaction mixture is stirred at 85 ° C for 6 hours and evaporated in vacuo. The residue is dissolved in EtOAc (80 mL), washed with water (40 mL), saturated aqueous NaCl solution (40 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography ( petroleum ether / EtOAc = 5/1 - 2/1) to give 600 mg (45%) of the compound of interest as a yellow oil. LC-MS for C25H27FN4O2 + H + - (CH3) 2C = CH2 [M + H- (CH3) 2C = CH2] +: calcd. 379.2; found: 378.9.
Intermediate 19: 1- [4 - (Y6- (6-fluoro-1- (N-phenylsulfonyl) -1H-indol-3-yl-2H-indazol-2-yl) methyldipiperidin-1-yl) ethanone
358 mg (54%) of the compound of interest is obtained as a yellow solid after purification by preparative TLC (EtOAc) as a regioisomer with intermediate 7. LC-MS for C29H27FN4O3S + H + [M + H] +: calcd. 531.2; found: 530.9.
Intermediate 20: 3- (6- (6-fluoro-1- (phenyl) -benzyl-1H-indol-3-yl) -2-indazol-2-vinylnanamide
The compound of interest (70 mg, 29%) is obtained as a yellow solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 2/1 - 0/1) during the preparation of Intermediate 8 .
Intermediate 21: Fert-butyl 4- (N-6-fluoro-1H-indol-3-yl) -2H-imino-2-yl) methyl) piperidine-1-carboxylate
The compound of interest (377 mg, 25%) is obtained as a yellow solid after purification by silica gel chromatography (petroleum ether / EtOAc = 3/1) during the preparation of Intermediate 15. LC-MS for C26H29FN4O2 + H + [M + H] +: calcd. 449.2; found: 448.9
Intermediate 22: 5- (6-fluoro-1H-mdol-3-yl-2-piperidin-4-ylmethyl) -2H-mdazole
A solution of tert-butyl 4 - ((5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-carboxylate (Intermediate 21; 189 mg, 0.42 mmol) in saturated 1,4-dioxane in HCl (10 mL) is stirred at room temperature for 1 hour. The reaction mixture is concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (50 mL> <3). The aqueous phase is basified with an aqueous solution of NaOH at pH = 13 and extracted with EtOAc (80 mL> <3). The organic phases are combined and dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC (DCM / MeOH = 10/1) to give 136 mg (93%) of the compound of interest as a yellow solid. LC-MS for C21H21FN4 + H + [M + H] +: calcd. 349.2; found: 348.9.
Intermediate 23: tert-butyl 4- (5-t-fluoro-1-yl) phenylsulfonyl-1H-indol-3-yl-2H-indazol-2-vitaminoinendin-1-carboxviate
The compound of interest (380 mg, 14%) is obtained in the form of a yellow solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 5/1 - 2/1) during the preparation of Intermediate 17 LC-MS for C31H31FN4O4S + H + [M + H] +: calcd. 575.2; found: 574.9.
Intermediate 24: Fert-butyl 4- (5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-ylpiperidine-1-carboxylate
According to the general method used for the preparation of Intermediate 15, using as starting material 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -butyl starting material // - indazo] -2-yl) piperidine-1-carboxylate (Intermediate 23, 1.75 g, 3.04 mmol), 0.6 g (45%, not really pure) of the compound of interest is obtained as a yellow oil purification by chromatography on silica gel (petroleum ether / EtOAc = 5 / 1-2 / 1). LC-MS for C18H17FN3 + 1M [M + H] +: calcd. 435.5; found: 434.9.
Intermediate 25: Fert-butyl 5-bromo-1H-henzoh-limidazole-1-carboxyvinate and tert-butyl 6-bromo-1H-benzo [1] -libidazole-1-carboxylate
BOCO (1.33g, 6.09mmol), Et3N (770mg, 7.61mmol) and DMAP (62mg, 0.51mmol) was added to a mixture of 5-bromo-1H-benzo [ ] Imidazole (1.00g; 5.08). mmol) in THF (50 mL). The mixture is stirred at room temperature overnight under a nitrogen atmosphere and evaporated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with H2O (80 mL * 2), saturated aqueous NaCl (80 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 1.30 g (86%) d a mixture of the compounds of interest as a yellow oil, directly used in the next transformation without purification. LC-MS for C n HisBr ChCH + H ^CH 2 CCH 2 [M + H- (CH 3) 2 C = CH 2] +: calcd. 241.0; found: 240.9. * H NMR (300 MHz, CDCl 3) δ [pm]: 8.42 (s, 0.5H), 8.40 (s, 0.5H), 8.20 (s, 0.5H), 7.95 (s, 0.5H), 7.88 (d, J = 8.7 Hz, 0.5H), 7.66 (d, J = 8.7 Hz, 0.5H), 7.55-7.44 (m, 1H), 1.71 (s, 9H) as a mixture of tautomers.
Intermediate 26: tert-biityl 5-f4.4.5,5-tetramethyl-1,3.2-dioxaborolan-2-v 11-1H-benzoimidazole-1-carboxylate and fert-butyl 6- (4.4.5.5-tetramethyl-1.3) .2-dioxaborolan-2-νΠ-Ι // - henzol </ limidazole-l-carboxylate
Following the general method used for the preparation of Intermediate 3, using tert-butyl 5-bromo-1H-benzo [1H] imidazole-1-carboxylate and tert-butyl 6-bromo-1 as starting materials. // - Benzo [</] imidazole-1-carboxylate (Intermediate 25, 500 mg, 1.68 mmol), 1.09 g (quant.) of a mixture of the compounds of interest is obtained as a yellow oil, directly used in the next transformation without purification. LC-MS for C18H25BN2O4 + H + [M + H] +: calcd. 345.2; found: 345.0.
Intermediate 27: 5-t6-fluoro-1- (n-phenylsulfonyl) -1H-indol-3-yl-1H-benzoimidazole
According to the general method used for the preparation of Intermediate 4, using tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l as starting materials 1H-benzo [ ] imidazole-1-carboxylate and tert-butyl 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [ imidazole-1-carboxylate (Intermediate 26, 730 mg unpurified mixture, 0.46 mmol) and 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 2, 300 mg, 0.75 mmol) ), 550 mg (quant.) Of the compound of interest is obtained as a black oil, directly used in the next transformation without purification. LC-MS for C21H14FN3O2S + H + [M + H] +: calcd. 392.1; found: 391.9.
Intermediate 28: 5-bromo-2-methyl-1H-benzyl-1-iminidazole-1-carboxylate
According to the general method used for the preparation of Intermediate 25, using 5-bromo-2-methyl-1H-benzoimidazole (3.0 g, 13.51 mmol), 1.14 g (27 g) as the starting material. %) of the compound of interest is obtained as a white solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 8/1 - 5/1). LC-MS for C13H15BrN2O2 + H + - (CH3) 2C = CH2 [M + H- (CH3) 2C = CH2] +: calcd. 256.0; found: 256.8. NMR (300 MHz, CDCl 3) δ [pm]: 7.79 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.76 (m, 2H), 7.41 (dd, J = 8.7 , 2.0 Hz, 1H), 2.82 (s, 3H), 1.72 (s, 9H).
Intermediate 29: 2-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzoflmidazole-1-carboxylate
Following the general method used for the preparation of Intermediate 3, using tert-butyl 5-bromo-2-methyl-1H-benzo [i] imidazole-1-carboxylate as starting material (Intermediate 28; 1.14). 3.67 mmol), 1.51 g (quant.) of the compound of interest is obtained as a white solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 5/1). LC-MS for C19H27BN2O4 + H + [M + H] +: calcd. 359.2; found: 359.0. * H NMR (400 MHz, DMSO-tcd) δ [pm]: 7.91 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 2.72 (s , 3H), 1.66 (s, 9H), 1.32 (s, 12H).
Intermediate 30: 5- (6-fluoro-1- (Dhenylsulfonyl) -1H-indol-3-yl-2-methyl-1H-benzo [imidazole]
According to the general method used for the preparation of Intermediate 4, using as starting materials tert-butyl 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Yl) -1-benzo [1] imidazole-1-carboxylate (Intermediate 29, 1.08 g, 3.01 mmol) and 6-fluoro-3-iodo-1 - (phenylsulfonyl) -1 Tf-indole (Intermediate 2; mg, 1.99 mmol), 870 mg (quant.) of the compound of interest is obtained as a black solid after purification by chromatography on silica gel (DCM / MeOH = 40/1 - 20/1). LC-MS for C22H16FN3O2S + H + [M + H] +: calcd. 406.1; found: 405.8.
Intermediate 31: 4- (4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl) benzene-1.2-diamine
Pd (dppf) Cl2DCM (2.36 g, 2.89 mmol) is added to a mixture of 4-bromobenzene-1,2-diamine (10.8 g, 57.7 mmol), KOAc (17.0 g, 173 mmol) and 44.4.4 '. , 4 ', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (16.1 g, 63.4 mmol) in dioxane (200 mL) under a nitrogen atmosphere . The reaction mixture is stirred at 100 ° C for 16 hours, cooled to room temperature, filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 5/1 - 2/1) to give 11.6 g (86 ° C). %) of the compound of interest as a brown oil. LC-MS for C12H19BN2O2 + H + [M + H] +: calcd. 235.2; found: 235.0. H NMR (400 MHz, CDCl 3) δ [pm]: 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), d, J = 7.7 Hz, 1H, 1.32 (s, 12H).
Intermediate 32: 4- (6-Αιιοι · ο-1- (ρΙΐΜΐνΐ8ΐι1ίοιινΓ) -ίΗ: -ίιιοο1-3-νΠ06ηζΜΐ6-1.2- diamine
A mixture of 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 2: 19.9 g, 49.6 mmol), 4- (4,4,5,5-tetramethyl-1,3), 2-dioxaborolan-2-yl) benzene-1,2-diamine (Intermediate 31, 11.6 g, 49.6 mmol), Pd (dppf) Cl 2 · DCM (2.0 g, 2.45 mmol), K 2 CO 3 (20.5 g, 148 mmol) in dioxane (300 mL) and water (60 mL) was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, filtered, concentrated and purified by silica gel chromatography (DCM / MeOH = 200/1 - 20/1) to give 7.0 g (37%) of the compound of interest as the title compound. brown oil. LC-MS for C20H16FN3O2S + H + [M + H] +: calcd. 382.1; found: 381.8. NMR (400 MHz, CDCl 3) δ [pm]: 7.90 (d, J = 7.6 Hz, 1H), 7.77 (dd, J = 9.7, 2.0 Hz, 1H), 7.68 (dd, J = 8.7, 5.3 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.49 - 7.43 (m, 2H), 7.01 (ddd, J = 9.3, 8.7, 2.3 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.78 (d, J = 7.6 Hz, 1H).
Intermediate 33: 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yn-2-12- (methylthiolethoxy) -1,7-benzolr / limidazole
HATU (748 mg, 1.97 mmol) and Et3N (265 mg, 2.62 mmol) is added to a mixture of 4- (6-fluoro-1- (phenylsulfonyl) -1 F -indol-3-yl) benzene-1, 2-diamine (Intermediate 32, 500 mg, 1.31 mmol) and 3- (methylthio) propanoic acid (157 mg, 1.31 mmol) in DCM (10 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture is stirred at room temperature for 30 minutes, diluted with DCM (60 mL), washed with water (30 mL), saturated aqueous NaCl solution (20 mL> <2), dried over anhydrous Na 2 SO 4, filtered, and evaporated. The residue was diluted with toluene (10 mL) and refluxed for 30 hours. The reaction mixture is evaporated in vacuo and purified by chromatography on silica gel (petroleum ether / EtOAc = 100/1 - 6/1) to give 460 mg (75%) of the compound of interest as a brown oil, directly used in the next transformation without purification. LC-MS for C24H20FN3O2S2 + H + [M + H] +: calcd. 466.1; found: 465.8.
Intermediate 34: 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (2- (m-ethylsulfonyl) eth-1-yl) benzo [imidazole]
mCPBA (500 mg, 2.46 mmol, 85%) is added in several portions to a solution of 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (2- ( methylthio) ethyl) -1H-benzo [ ] imidazole (Intermediate 33; 460 mg, 0.99 mmol) in DCM (15 mL) at 0 ° C. The reaction mixture is slowly warmed to room temperature and stirred for 30 minutes. The mixture is washed with a saturated aqueous solution of NaHSO 3 (20 mL) and the aqueous phase is extracted with DCM (30 mL> <2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (20 mL), dried over anhydrous NaiSCL, filtered, and evaporated to give 170 mg (34%) of the compound of interest in the form of a brown solid, directly used in the next transformation without purification. LC-MS for C24H20FN304S2_H ~ [M-H] ~: calcd. 496.1; found: 495.9. * H NMR (300 MHz, CDCl 3) δ [pm]: 7.97-7.89 (m, 2H), 7.83-7.75 (m, 1H), 7.75 -7.66 (m, 3H), 7.65-7.52 (m, 2H), 7.51 - 7.41 (m, 3H), 7.09 - 6.98 (m, 1H), 3.70 - 3.61 (m, 2H), 3.59 - 3.48 (m, 2H), 2.97 (s, 3H).
Intermediate 35: tert-butyl (5-fluoro-1- (n-phenylsulfonyl) -1H-indol-3-yl) -1H-benzohflimidazol-2-ylmethyl (meth) carbamate
DIPEA (187 mg, 1.45 mmol) is added to a solution of 2- (tert-butoxycarbonyl (methyl) amino) acetic acid (165 mg, 0.87 mmol) and HATU (364 mg, 0.96 mmol) in THF (10 mL). and DMF (1 mL). The reaction mixture is stirred for 10 minutes before 4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol). not added. The mixture is stirred at room temperature for 60 minutes. The mixture is concentrated in vacuo, diluted with EtOAc (30 mL), washed with water (30 mL * 3), dried over anhydrous Na2SC4, filtered, and evaporated. The resulting solid was taken up in AcOH (10 mL) and stirred at 50 ° C for 6 hours. The mixture is cooled to room temperature, neutralized with saturated aqueous Na2CO3 solution at pH = 8, and extracted with EtOAc (50 mLx3). The organic phases are combined and dried over anhydrous Na2SO4, filtered, and evaporated to give 640 mg (100%) of the compound of interest as a black solid, directly used in the next transformation without purification. LC-MS for C28H27FN4O4S + H + [M + H] +: calcd. 535.2; found: 534.8.
Intermediate 36: tert-butyl (5- (6-fluoro-1H-indol-3-yl) -benzoyl) -2-dimethoxy Methyl karbamate
According to the general method used for the preparation of Intermediate 15, using tert-butyl (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) 7-Benzo [(imidazol-2-yl) methyl (methyl) carbamate (Intermediate 36, 640 mg of unpurified mixture, 0.87 mmol), 470 mg (100%) of the compound of interest is obtained in the form of black solid, directly used in the next transformation without purification. LC-MS for C22H23FN4O2 + H + [M + H] +: calcd. 395.2; found: 394.9.
Intermediate 37: 2- (Chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1-indol-3-yl-1H-benzo [limidazole]
HATU (3.80 g, 10.0 mmol) is added to a solution of 4- (6-fluoro-1- (phenylsulfonyl) -177-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 3.81 g; mmol), chloroacetic acid (945 mg, 10.0 mmol) and Et3N (2.02 g, 20.0 mmol) in DCM (40 mL) at 0 ° C. The reaction mixture is stirred at room temperature for 1 hour, diluted with water (50 mL), and evaporated in vacuo to remove DCM. The aqueous mixture is extracted with EtOAc (40 mL> <3). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (30 mL> <2), dried over anhydrous Na 2 SO 4, filtered and evaporated. The resulting brown oil is taken up in AcOH (20 mL) and stirred at 50 ° C for 16 hours. The mixture is concentrated in vacuo to remove AcOH. The residue is diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (30 mLx2), saturated aqueous NaCl (30 mLx2), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography. (DCM / MeOH = 200/1 - 50/1) to give 3.20 g (84%) of the compound of interest as a brown solid. LC-MS for C22H15C1FN3O2S + H + [M + H] +: calcd. 440.1; found: 439.8.
Intermediate 38: 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzohl-2-limidazol-2-propanolic acid
A solution of 4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol) and succinic anhydride (160 mg; 1.60 mmol) in 1,4-dioxane (8 mL) is heated at 80 ° C for 48 hours. The mixture is concentrated and purified by chromatography on silica gel (DCM / MeOH = 18/1) to give 0.60 g (99%) of the compound of interest as a white solid. LC-MS for C24H18FN3O4S + H + [M + H] +: calcd. 464.1; found: 464.0. H NMR (400MHz, DMSO-1/6) δ [pm]: 12.30 (s, 1H), 8.15 (d, J = 7.7Hz, 2H), 8.06 (s, 1H), 7.87-7.80 (m, 2H), 7.77 - 7.70 (m, 2H), 7.66 - 7.60 (m, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.24 (ddd, J); = 9.3, 8.7, 2.2 Hz, 1H), 3.57 (s, 1H), 3.07 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H).
Intermediate 39: 6- [6-fluoro-1-phenylsulfonyl] -1H-indol-3-yl-2,3-dihydro-1 H -benzoyl] pyrrolo [1,2-fllimidazol-1-one]
NH4Cl (120 mg, 2.24 mmol) is added to a solution of 3- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [</] imidazol-2-yl) propanoic acid (Intermediate 38, 521 mg, 1.12 mmol), HATU (855 mg, 2.25 mmol) and Et3N (454 mg, 4.49 mmol) in THF (15 mL) under a nitrogen atmosphere. The mixture is stirred at ambient temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (50 mL> <2) and EtOAc (50 mL> <2). 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 evaporated to give 556 mg (quant.) Of the compound of interest in the form of a yellow solid, directly used in the next transformation without purification. LC-MS for C24H16FN3O3S + H + [M + H] +: calcd. 446.1; found: 446.0.
Intermediate 40: 5- (4.4.5.5-tetramethyll-1.3.2-dioxaborolan-2-ylbenzofloxazole
According to the general method used for the preparation of Intermediate 3, using 5-bromobenzo [/] oxazole (500 mg, 2.52 mmol) as the starting material, 576 mg (93%) of the compound of interest is obtained under white solid form after purification by silica gel chromatography (petroleum ether / EtOAc = 100/1 - 30/1). LC-MS for C13H16NO3 + H + [M + H] +: calcd. 246.1; found: 246.0. NMR (400 MHz, CDCl3) δ [pm]: 8.26 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H); ), 1.37 (s, 12H).
Intermediate 41: 5- (6-fluoro-1- (phenylsulfonyl) -indol-3-yl) benzoyloxazole
According to the general method used for the preparation of Intermediate 4, using 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [1 /] as starting materials oxazole (Intermediate 40, 330 mg, 1.35 mmol) and 6-fluoro-3-iodo-1- (phenylsulfonyl) -lind-indole (Intermediate 2, 540 mg, 1.35 mmol), 423 mg (80%) of the compound of Interest is obtained as a white solid after purification by recrystallization in MeOH. LC-MS for C21H13FN2O3S + H + [M + H] +: calcd. 393.1; found: 392.8. * H NMR (400 MHz, CDCl 3) δ [pm]: 8.16 (s, 1H), 7.99 - 7.93 (m, 3H), 7.81 (dd, J = 9.5, 2.1 Hz, 1H), 7.73 - 7.65 (m, 3H), 7.62 - 7.57 (m, 2H), 7.53 - 7.47 (m, 2H), 7.07 (ddd, J = 9.2, 8.7.2.2 Hz, 1H).
Intermediate 42: 2-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) benzo [loxazol]
According to the general method used for the preparation of Intermediate 3, using as starting material 5-bromo-2-methylbenzo [i] oxazole (564 mg, 2.66 mmol), 688 mg (100%) of the title compound. interest is obtained in the form of brown semi-solid, directly used in the next transformation without purification. LC-MS for C14H18BNO3 + H + [M + H] +: calcd. 260.1; found: 260.0.
Intermediate 43: 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl-2-methylbenzyl / loxazole
According to the general method used for the preparation of Intermediate 4, using as starting materials 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [ ] oxazole (Intermediate 42; 688 mg; 2.66 mmol) and 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 2; 711 mg; 1.77 mmol); %) of the compound of interest is obtained as a yellow solid after purification by chromatography on silica gel (petroleum ether / EtOAc = 5 / 1-2 / 1). LC-MS for C22H15FN2O3S + H + [M + H] +: calcd. 407.1; found: 406.8. H NMR (400MHz, DMSCMO δ [pm]: 8.20 - 8.14 (m, 3H), 7.97 (d, J = 0.8 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.79 - 7.70 (m, 2H); 7.69 - 7.60 (m, 3H), 7.23 (ddd, J = 9.2, 8.8, 2.4 Hz, 1H), 2.65 (s, 3H) 1.2 SYNTHESIS OF FINAL COMPOUNDS Compound 1: 6-fluorophenone l // - indole-3-yl-l // - indazole
A solution of NaOH (200 mg, 5.00 mmol) in water (2 mL) is added to a solution of 6- (6-fluoro-1- (phenylsulfonyl) -1H-7-indol-3-yl) 1H-indazole (Intermediate 4, 390 mg, 1.00 mmol) in MeOH (15 mL). The reaction mixture is stirred at 80 ° C for 2 hours, evaporated, and purified by silica gel chromatography (petroleum ether / EtOAc = 5/1 - 2/1) to give 50 mg (20%) of the title compound. interest in the form of white solid. LC-MS for C15H10FN3 + H + [M + H] +: calcd. 252.1; found: 252.1. HNMR (300 MHz, DMSO - ) Δ [pm]: 12.94 (s, 1H), 11.45 (s, 1H), 8.05 (s, 1H), 7.88 (dd, J = 8.8, 5.4 Hz, 1H). ), 7.79 (d, J = 8.4 Hz, 1H), 7.77 - 7.73 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 10.0.2.2 Hz, 1H), 6.99 (ddd, J = 9.3, 8.8.2.2 Hz, 1H).
Compound 2: 2- (6- (6-fluoro-1-yl) -3-yl-1H-indazol-1-dacetamide
A mixture of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 4, 300 mg, 0.77 mmol), 2-bromoacetamide (1.05 g, 7.61 g). mmol), KI (290 mg, 1.75 mmol), K2CO3 (986 mg, 7.13 mmol) in DMF (16.5 mL) is stirred at 60 ° C. for 48 hours under a nitrogen atmosphere. The mixture is cooled to room temperature, diluted with EtOAc (100 mL), filtered, concentrated and purified by preparative HPLC to give 25 mg (11%) of the compound of interest as a yellow solid. LC-MS for C17H13FN4O + H + [M + H] +: calcd. 309.1; found: 308.9. H NMR (400MHz, DMSO-4) δ [pm]: 11.46 (s, 1H), 8.03 (s, 1H), 7.96 (dd, J = 8.7, 5.4Hz, 1H), 7.80-7.77 (m, 2H), 7.76 - 7.73 (m, 2H), 7.55 (br s, 1H), 7.46 (dd, J = 8.3, 1.3 Hz, 1H), 7.26 (br s, 1H), 7.22 (dd, J = 9.9, 2.4 Hz, 1H), 6.96 (ddd, J = 9.6, 8.8, 2.4, 1H), 5.11 (s, 2H).
Compound 3: 6- (6-fluoro-1H-indol-3-yl) - (piperidin-4-ylmethyl) -1H-indazole hydrochloride
According to the general method used for the preparation of Example 1, using as starting materials 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piperidine) 4-ylmethyl) -1H-indazole hydrochloride and 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H- Indazole hydrochloride (Intermediate 6, 136 mg, 0.26 mmol), 3 mg (3%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC with 0.1% HCl as buffer. LC-MS for C21H21FN4 + H + [M + H] +: calcd. 349.2; found: 349.0. * H NMR (300 MHz, DMSO-ifc) δ [pm]: 11.52 (s, 1H), 9.26 (br s, 1H), 8.90 (br s, 1H), 8.39 (s, 1H), 7.87 (dd, / = 8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.77-771 (m, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 9.9, 2.3 Hz, 1H) ), 6.97 (ddd, J = 9.4, 8.8, 2.3 Hz, 1H), 4.38 (d, J = 6.9 Hz, 2H), 3.18 - 3.18 (m, 2H), 2.91 - 2.72 (m, 2H), 2.38 - 2.22 (m, 1H), 1.73-1.59 (m, 2H), 1.58-1.40 (m, 2H).
Compound 4: 1- [4- (6-Fluoro-1H-mdol-3-yl) -H-indazol-1-ylmethyl] piperidin-1-yl] ethanone
According to the general method used for the preparation of Example 1, using as starting material 1- (4 - ((6- (6-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) 1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone (Intermediate 7, 267 mg, 0.50 mmol), 12 mg (6%) of the compound of interest is obtained as a white solid. after purification by preparative HPLC. LC-MS for C23H23FN4O-H · [M-H] ': calcd. 389.2; found: 389.0. * H NMR (400 MHz, DMSO-c / 6) δ [pm]: 11.51 (s, 1H), 8.05 (s, 1H), 7.95 (dd, J = 8.8, 5.4 Hz, 1H), 7.87 (s, 1H), 7.80 - 7.76 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 9.9, 2.0 Hz, 1H), 6.99 (ddd, J = 9.4, 8.8, 2.0 Hz). , 1H), 4.40 - 4.30 (m, 3H), 3.82 - 3.73 (m, 1H), 2.99 - 2.89 (m, 1H), 2.50 - 2.40 (m, 1H), 2.26 - 2.14 (m, 1H), 1.95 (s, 3H), 1.56 - 1.44 (m, 2H), 1.30 - 1.16 (m, 2H).
Compound 5: 3- (6- (6-fluoro-1H-indol-3-yl-1H-indazol-1-yl) propanamide
According to the general method used for the preparation of Example 1, using as starting material 3- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- indazol-1-yl) propanamide (Intermediate 8, 95 mg, 0.21 mmol), 35 mg (53%) of the compound of interest is obtained as a white solid after purification by preparative TLC (EtOAc). LC-MS for C18H15FN4O + H + [M + H] +: calcd. 323.1; found: 323.1. H NMR (300MHz, DMSO-1/6) δ [pm]: 11.48 (s, 1H), 8.05 (dd, J = 8.8, 5.6Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.79 - 7.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (br s, 1H), 7.24 (dd, J = 9.9, 2.2Hz, 1H), 6.99 (ddd, J = 9.4, 8.8, 2.2 Hz, 1H), 6.87 (brs, 1H), 4.64 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.6 Hz, 2H).
Compound 6: 6- [6-fluoro-17H-indol-3-yl] -1- (nineridine-4-yl) 17Mndazole
According to the general method used for the preparation of Example 1, using 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (4-piperidin) as starting materials. -yl) -17-indazole hydrochloride and 6- (6-fluoro-1- (phenylsulfonyl) -177-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole hydrochloride (Intermediate 10 700 mg of unpurified mixture, 1.37 mmol), 12.3 mg (3%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS for C20H19FN4 + H + [M + H] +: calcd. 335.2; found: 334.9. * H NMR (300 MHz, DMSO-C &); δ [pm]: 11.49 (s, 1H), 8.04 (s, 1H), 7.94 (dd, J = 9.0, 5.4 Hz, 1H), 7.88 (s, 1H) ), 7.80 - 7.75 (m, 2H), 7.46 (dd, J = 8.4, 1.3 Hz, 1H), 7.25 (dd, J = 9.8, 2.4 Hz, 1H), 6.99 (ddd, J = 9.7, 8.9, 2.4 Hz, 1H), 4.87-4.75 (m, 1H), 3.20 -3.10 (m, 2H), 2.86-2.75 (m, 2H), 2.10-2.00 (m, 2H), 2.00-1.92 (m, 2H).
Compound 7: 1- (4-flu-6-fluoro-1H-imid-3-yl) -1H-indazol-1-ylpiperidin-1-yethanone
AcCl (84.6 mg, 1.08 mmol) is added to a solution of 6- (6-fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -177-indazole (Example 6; mg, 0.90 mmol) and Et3N (5.0 mL, 36 mmol) in DCM (30 mL) under a nitrogen atmosphere. The mixture is stirred for 1 hour and quenched with saturated aqueous NaHCO3 solution (30 mL). The aqueous phase is extracted with DCM (60 mLx2). The organic phases are combined and then washed with a saturated aqueous solution of NaCl (20 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by preparative HPLC to give 15 mg (4%) of the compound of interest in the form of a yellow solid. . LC-MS for C22H21FN4O + H + [M + H] +: calcd. 377.2; found: 376.9. H NMR (400 MHz, DMSO-c / 6) δ [pm]: 11.49 (s, 1H), 8.05 (s, 1H), 7.96 (dd, J = 8.8, 5.4 Hz, 1H), 7.91 (s, 1H), 7.81 - 7.76 (m, 2H), 7.47 (dd, 7 = 8.4, 1.2 Hz, 1H), 7.25 (dd, J = 9.9, 2.4 Hz, 1H), 6.99 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 5.08 - 4.95 (m, 1H), 4.58 -4.48 (m, 1H), 4.03 - 3.93 (m, 1H), 3.33 - 3.27 (m, 1H), 2.90 - 2.78 (m, 1H) , 2.07 (s, 3H), 2.10-1.88 (m, 4H).
Compound 8: 5- (6-fluorenyl) -1H-indol-3-yl-1H-indazole
Following the general method used for the preparation of Example 1, using 5- (6-fluoro-1- (phenylsulfonyl) -17-indol-3-yl) -1-as the starting material. -indazole (Intermediate 12, 270 mg of unpurified mixture, 0.45 mmol), 40 mg (32%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS for CisHioFNa + H * [M + H] +: calcd. 252.1; found: 252.1. * H NMR (300 MHz, DMSO - </ 6) δ tppm]: 13.02 (s, 1H), 11.34 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.86 (dd, J). = 8.8, 5.4 Hz, 1H), 7.66 (dd, J = 9.0, 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.22 (dd , J = 10.0, 2.4 Hz, 1H), 6.95 (ddd, J = 9.7, 8.8, 2.4 Hz, 1H).
Compound 9: 2- [5- (6-fluoro-1H-indol-3-yl] H -indazol-1-ylacetamide]
Following the general method used for the preparation of Example 1, using 2- (5- (6-fluoro-1- (phenylsulfonyl) -1 Ti-indol-3-yl) -1H-indazol as starting materials. 1-yl) acetamide and 2- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) acetamide (Intermediate 13, 353 mg; 0.79 mmol), 34.1 mg (14%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC and chiral preparative HPLC. LC-MS for C17H13FN4O + H + [M + H] +: calcd. 309.1; found: 308.9. H NMR (300MHz, DMSO-D6) δ [pm]: 11.39 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (dd, J = 8.8, 5.3Hz, 1H); , 7.72 - 7.61 (m, 3H), 7.58 (br s, 1H), 7.30 (br s, 1H), 7.23 (dd, J = 10.0.2.3 Hz, 2H), 6.99 (dd, J = 9.5, 8.8, 2.3 Hz, 1H), 5.08 (s, 2H).
Compound 10: 5- (6-fluoro-1H-indol-3-yl) -1- (n-deridin-4-yl) -2-indanyl
A solution of tert-butyl 4 - ((5- (6-fluoro-17H-indol-3-yl) -17H-indazol-1-yl) methyl) piperidine-1-carboxylate (Intermediate 15, 1.18 g; 2.63 mmol) in 1,4-dioxane saturated with HCl (20 mL) is stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo, diluted with water (100 mL), and extracted with EtOAc (50 mLx3). The aqueous phase is basified with an aqueous solution of NaOH at pH = 13 and extracted with EtOAc (100 mL> <3). The organic phases are combined and then dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by preparative TLC (DCM / MeOH = 8/1) to give 31 mg (33%) of the compound of interest as a yellow solid. LC-MS for C21H21FN4 + H + [M + H] +: calcd. 349.2; found: 349.0. H NMR (300 MHz, DMSO-δ) δ [pm]: 11.42 (s, 1H), 8.60 (br s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.86 (dd, J = 8.8, 5.3 Hz, 1H), 7.79 - 7.65 (m, 3H), 7.30 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 4.38 (d, J = 6.7 Hz, 2H), 3.26 - 3.15 (m, 2H), 2.86 - 2.71 (m, 2H), 2.30 - 2.13 (m, 1H), 1.72 - 1.60 (m, 2H), 1.55 - 1.36 (m, 2H).
Compound 11: 1- (4-t (5- (6-fluoro-1H-indol-3-yl) -7H-indazol-1-ylmethylpiperidin-1-yl) ethanone
Following the general method used for the preparation of Example 7, using 5- (6-fluoro-1H-7-indol-3-yl) -1- (piperidin-4-ylmethyl) -177- as the starting material. Indazole (Example 10, 204 mg, 0.59 mmol), 65 mg (28%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS for C23H23FN4O + H + [M + H] +: calcd. 391.2; found: 390.9. H NMR (300 MHz, DMSO-/ δ) δ [pm]: 11.38 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (dd, J = 8.9, 5.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.22 (dd, J = 10.0.2.4 Hz, 1H), 6.96 (ddd, J = 9.6, 8.9, 2.3 Hz , 1H), 4.39 - 4.30 (m, 3H), 3.83 - 3.73 (m, 1H), 3.00 - 2.87 (m, 1H), 2.50 - 2.40 (m, 1H), 2.26 - 2.10 (m, 1H), 1.96 (s, 3H), 1.54-1.43 (m, 2H), 1.30-100 (m, 2H).
Compound 12: 3- (5- (6-fluoro-1H-7-indol-3-yl) -1H-indazol-1-yl) propanamide
Following the general method used for the preparation of Example 1, using as starting materials 3- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -177-indazol 1-yl) propanamide and 3- (5- (6-fluoro-1- (phenylsulfonyl) -17H-indol-3-yl) -2H-indazol-2-yl) propanamide (Intermediate 16; 492 mg) 1.06 mmol), 33.9 mg (10%) of the compound of interest is obtained as a white solid after purification by preparative HPLC and chiral preparative HPLC. LC-MS for C18H15FN4O + H + [M + H] +: calcd. 323.1; found: 322.9. * H NMR (300 MHz, DMSO - / 6) δ [pm]: 11.34 (s, 1H), 8.27 (d, J = 0.8 Hz, 1H), 7.93 -7.91 (m, 1H), 7.88 (dd, J = 8.8, 5.4 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.56 (dd, J = 9.0, 1.6 Hz, 1H), 7.43 (br s, 1H), 7.21 (dd, J = 10.0.2.3). Hz, 1H), 6.95 (ddd, J = 9.6, 8.8.2.3 Hz, 1H), 6.92 (brs, 1H), 4.62 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H).
Compound 13: 5- (6-fluoro-1H-7-indol-3-yl) -niniminin-4-yl-1H-indazole
Saturated 1,4-dioxane in HCl (10 mL) is added to a solution of tert-butyl 4- (5- (6-fluoro-17H-indol-3-yl) -1H-indazol-1 -yl) piperidine-1-carboxylate (Intermediate 18, 180 mg, 0.41 mmol) in 1,4-dioxane (20 mL). The reaction mixture is stirred overnight. The precipitate formed is isolated by filtration and purified by preparative HPLC to give 56 mg (40%) of the compound of interest as a yellow solid. LC-MS for C20H19FN4 + H + [M + H] +: calcd. 335.2; found: 334.9. 1H NMR (300 MHz, DMSO-4) δ [pm]: 11.36 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.86 (dd, J = 8.8, 5.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.8, 1.6 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.22 (dd, J = 10.0.2.4 Hz, 1H). ), 6.95 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 4.73 - 4.60 (m, 1H), 3.14 - 3.04 (m, 2H), 2.76 - 2.64 (m, 2H), 2.20 (brs, 1H), 2.05 -1.93 (m, 2H), 1.91-1.82 (m, 2H).
Compound 14: 1- (4-15-t6-fluoro-1H-7-indol-3-yl) -1H-indazol-1-n-dininidine-1-dimetone
According to the general method used for the preparation of Example 7, using 5- (6-fluoro-17H-indol-3-yl) -1- (piperidin-4-yl) -l as starting material. 7-indazole (Example 13, 53 mg, 0.16 mmol), 16 mg (27%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS for C22H21FN4O + H + [M + H] +: calcd. 377.2; found: 376.9. NMR (300 MHz, MeOH - / / 4) δ [pm]: 8.25 (s, 1H), 7.92 - 7.89 (m, 1H), 7.83 (dd, J = 8.8, 5.3 Hz, 1H), 7.66 - 7.63 ( m, 2H), 7.46 (s, 1H), 7.12 (dd, J = 10.0, 2.3Hz, 1H), 6.88 (ddd, J = 9.6, 8.8, 2.3 Hz, 1H), 4.86 - 4.66 (m, 2H); , 4.16 - 4.06 (m, 1H), 3.42 -3.32 (m, 1H), 2.93-2.81 (m, 1H), 2.32-2.00 (m, 4H), 2.18 (s, 3H).
Compound 15: 2- [6- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-dacetamide
A mixture of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 4, 300 mg, 0.77 mmol), 2-bromoacetamide (1.05 g; 7.61 mmol), KI (290 mg, 1.75 mmol) and K2CO3 (986 mg, 7.13 mmol) in DMF (16.5 mL) is stirred at 60 ° C for 48 hours under a nitrogen atmosphere. The mixture is cooled to room temperature, diluted with EtOAc (100 mL), filtered, concentrated and purified by preparative HPLC to give 50 mg (21%) of the compound of interest as a yellow solid. LC-MS for C17H13FN4O + H + [M + H] +: calcd. 309.1; found: 308.9. * H NMR (400 MHz, DMSO-ü 6) δ [pm]: 11.42 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.81 - 7.72 (m, 2H), 7.66 (br s, 1H), 7.39 (dd, J = 8.7, 1.4 Hz, 1H), 7.35 (br s, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.97 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 5.09 (s, 2H).
Compound 16: 1- (4 - ((6-fluoro-1H-indol-3-yl) -2H-lndazol-2-yl) methylenepiperidin-1-ylthanone
According to the general method used for the preparation of Example 1, using as starting material 1- (4 - ((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2 (β-indazol-2-yl) methyl) piperidin-1-yl) ethanone (Intermediate 19, 358 mg, 0.67 mmol), 10 mg (4%) of the compound of interest is obtained as a white solid after purification by preparative HPLC. LC-MS for C23H23FN4O + H + [M + H] +: calcd. 389.9; found: 389.9. * H NMR (400MHz, DMSO-1/6) δ [pm]: 11.43 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.77 - 7.71 (m, 2H), 7.39 (d, J = 8.6 Hz, 1H), 7.23 (dd, J = 10.0, 2.3 Hz, 1H), 6.97 (dd, J = 9.6, 8.8, 2.3 Hz , 1H), 4.40 - 4.30 (m, 3H), 3.85 - 3.75 (m, 1H), 3.05 - 2.90 (m, 1H), 2.50 - 2.42 (m, 1H), 2.31 - 2.22 (m, 1H), 1.97 (s, 3H), 1.60 - 1.40 (m, 2H), 1.30 - 1.00 (m, 2H).
Compound 17: 3- (6- (6-fluoro-1H-mdo-3-yl) -2H-indazol-2-yl) propanamide
According to the general method used for the preparation of Example 1, using as starting material 3- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -27- indazol-2-yl) propanamide (Intermediate 20, 75 mg, 0.16 mmol), 20 mg (38%) of the compound of interest is obtained as a white solid after purification by preparative TLC (EtOAc). LC-MS for C18H15FN4O + H + [M + H] +: calcd. 323.1; found: 323.1. H NMR (300 MHz, MeOH - ) Δ [pm]: 8.16 (s, 1H), 7.87 (dd, J = 8.8, 5.3 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.13 (dd, J = 9.8, 2.3Hz, 1H), 6.90 (ddd, J = 9.6, 8.8). , 2.3 Hz, 1H), 4.73 (t, J = 6.7 Hz, 2H), 2.94 (t, J = 6.7 Hz, 2H).
Compound 18: 6- (6-fluoro-1H-indol-3-yr) -2- (piperidin-4-yl-2H-indazole)
The compound of interest (26 mg, 5%) is obtained as a yellow solid after purification by preparative HPLC during the preparation of Example 6. LC-MS for C20H19FN4 + H + [M + H] +: calcd. 335.2; found: 334.9. NMR (400 MHz, DMSO-d 6) δ [pm]: 11.41 (s, 1H), 8.36 (s, 1H), 7.91 (dd, J = 8.6, 5.4 Hz, 1H), 7.83 (s, 1H); , 7.75 - 7.70 (m, 2H), 7.39 (d, J = 8.6,1.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.97 (ddd, J = 9.6, 8.8, 2.4 Hz , 1H), 4.62 - 4.50 (m, 1H), 3.22 -3.13 (m, 2H), 2.82 - 2.70 (m, 2H), 2.16 - 1.93 (m, 4H).
Compound 19: 1- (4- (6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) -piperidin-1-yl-kethanone
According to the general method used for the preparation of Example 7, using 6- (6-fluoro-177-indol-3-yl) -2- (piperidin-4-yl) -2 1 -indazole as starting material (Example 18, 300 mg, 0.90 mmol), 20 mg (6%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS for C22H21FN4O + H + [M + H] +: calcd. 377.2; found: 376.9. H NMR (400MHz, DMSO-1/6) δ [pm]: 11.42 (s, 1H), 8.40 (s, 1H), 7.89 (dd, J = 8.7, 5.4Hz, 1H), 7.80 (s, 1H), 7.75 - 7.71 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 10.0, 2.3 Hz, 1H), 6.96 (dd, J = 9.4, 8.7, 2.3 Hz , 1H), 4.81 - 4.71 (m, 1H), 4.56 - 4.43 (m, 1H), 4.02 - 3.94 (m, 1H), 3.32 - 3.22 (m, 1H), 2.82 - 2.73 (m, 1H), 2.21 - 1.86 (m, 4H), 2.07 (s, 3H).
Compound 20: 2-i5-i6-fluoro-1H-indol-3-yl-2H-indazol-2-yr) acctamide
The compound of interest (71 mg, 29%) is obtained as a yellow solid after purification by preparative HPLC and chiral preparative HPLC as regio-isolate with Example 9. LC-MS for C17H13FN40 + H + [M + H] +: calcd. 309.1; found: 308.9. * H NMR (300 MHz, DMSCMe) δ [pm]: 11.38 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.90 (dd, J = 8.7, 5.5 Hz, 1H), 7.70 7.55 (m, 4H), 7.37 (s, 1H), 7.22 (dd, J = 9.9, 2.3 Hz, 1H), 6.96 (ddd, J = 9.6, 8.7 2.3 Hz, 1H), 5.08 (s, 2H); .
Compound 21: 1- (4 - ((5- (6-fluoro-17H-indol-3-yl) -2 H -indazol-2-ylmethyl) pyridin-1-yethanone
According to the general method used for the preparation of Example 7, using 5- (6-fluoro-177-indol-3-yl) -2- (piperidin-4-ylmethyl) -2 / 7- as the starting material. Indazole (Intermediate 22, 100 mg, 0.29 mmol), 5 mg (4%) of the compound of interest is obtained as a whitish solid after purification by preparative HPLC. LC-MS for C23H23FN4O + H + [M + H] +: calcd. 391.2; found: 390.9. NMR (400 MHz, MeOH-1/4) δ [pm]: 8.14 (s, 1H), 7.90 (s, 1H), 7.84 (dd, J = 8.8, 5.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.46 (s, 1H), 7.12 (dd, J = 9.8, 2.3 Hz, 1H), 6.89 (dd, J = 9.7, 8.8, 2.3 Hz, 1H), 4.54-4.47 (m, 1H), 4.11 (d, J = 7.0 Hz, 2H), 3.92 - 3.85 (m, 1H), 3.09 - 3.00 (m, 1H), 2.62 - 2.53 (m, 1H), 2.37 - 2.24 (m, 1H), 2.06 (s). , 3H), 1.63-1.54 (m, 2H), 1.34 - 1.13 (m, 2H).
Compound 22: 3- (5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-vinylnanamido]
The compound of interest (48 mg, 14%) is obtained as a white solid after purification by preparative HPLC and chiral preparative HPLC during the preparation of Example 12. LC-MS for C18H15FN40 + H + [M + H] + : calcd. 323.1; found: 322.9. H NMR (300 MHz, DMSCMO δ [pm]: 11.39 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.87 (dd, J = 8.7, 5.4 Hz, 1H), 7.74 - 7.66 (m, 3H), 7.43 (s, 1H), 7.23 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (ddd, J = 9.3, 8.7 2.0 Hz, 1H), 6.89 (s, 1H), 4.61 (t, J = 6.8 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H).
Compound 23: 5- (6-fliioro-1H-indol-3-yl) -2- (4-piperidin-4-yl) -2-mdazole-1,4-dioxane saturated with HCl (10 mL) is added to a solution of tert- butyl 4- (5- (6-fluoro-17H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (Intermediate 24, 180 mg, 0.41 mmol) in 1, 4-dioxane (20 mL) The reaction mixture is stirred at room temperature overnight, filtered, and purified by preparative HPLC to give 59 mg (43%) of the compound of interest as a yellow solid. C2H, 9FN4 + H + [M + H] +: calcd 335.4, found: 334.9! H NMR (300 MHz, DMSO-d6) δ [pm]: 11.37 (s, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.87 (dd, J = 8.8, 5.4 Hz, 1H), 7.68-7.63 (m, 2H), 7.55 (dd, J = 9.0.1.6 Hz, 1H), 7.22 (dd, J = 10.0). , 2.4 Hz, 1H), 6.96 (ddd, J = 9.7, 8.8, 2.4 Hz, 1H), 4.59-4.43 (m, 1H), 3.11 - 3.02 (m, 2H), 2.70 - 2.59 (m, 2H), 2.26 (br s, 1H), 2.10-1.89 (m, 4H).
Compound 24: 1- (4- (5- (6-fluoro-1H-indol-3-yn-2H-indazol-2-yl) piperidin-1-yl)
According to the general method used for the preparation of Example 7, using 5- (6-fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -2 as starting material 7-indazole (Example 23, 53 mg, 0.16 mmol), 16 mg (27%) of the compound of interest is obtained as a whitish solid after purification by preparative HPLC. LC-MS for C22H21FN4O + H + [M + H] +: calcd. 377.4; found: 376.9 * H NMR (300 MHz, DMSO- <4) δ [pm]: 8.25 (s, 1H), 7.90 (s, 1H), 7.83 (dd, J = 8.8, 5.3 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.45 (s, 1H), 7.11 (dd, J = 9.8, 2.4 Hz, 1H), 6.88 (ddd, J = 9.6, 8.8, 2.4Hz, 1H), 4.78-4.67 (m, 2H), 4.15-4.06 (m, 1H), 3.40-3.34 (m, 1H), 2.91 - 2.80 (m, 1H), 2.30 - 2.00 (m, 4H), 2.17 (s, 3H).
Compound 25: 5- (6-fluoro-1H-indol-3-yl) H-benzoimidazole
Following the general method used for the preparation of Example 1, using as starting material 5- (6-fluoro-1- (phenylsulfonyl) -1 T -indol-3-yl) -1H-benzo [d] imidazole (Intermediate 27, 550 mg of unpurified mixture, 0.46 mmol), 5 mg (3%) of the compound of interest is obtained as a yellow solid after purification by preparative HPLC. LC-MS for Cl5H, oFN3 + H + [M + H] +: calcd. 252.1; found: 252.0. NMR (300 MHz, DMSO-δ) δ [pm]: 12.44 - 12.33 (m, 1H), 11.38 - 11.30 (m, 1H), 8.22 - 8.17 (m, 1H), 7.88 - 7.72 (m, 2H) , 7.71 - 7.44 (m, 3H), 7.25 - 7.18 (m, 1H), 7.01-6.90 (m, 1H).
Compound 26: 5- (6-fluoro-1H-indol-3-yl) -2-methyl-1H-benzordlimidazole
According to the general method used for the preparation of Example 1, using 5- (6-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-methyl-1/7 as starting material benzo [c] imidazole (Intermediate 30, 870 mg unpurified mixture, 1.99 mmol), 240 mg (45%) of the compound of interest is obtained as a whitish solid after purification by preparative HPLC. LC-MS for C18H18FNs + H * [M + H] +: calcd. 266.1; found: 265.9. * H NMR (400 MHz, DMSO - </ 6) δ [pm]: 12.16 (s, 1H), 11.34 (s, 1H), 7.82 (dd, J = 8.7, 5.5 Hz, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 10.0.1.9 Hz, 1H), 6.95 ( ddd, J = 9.6, 8.7.1.9 Hz, 1H), 2.50 (s, 3H).
Compound 38: 5- [6-fluoro-1H-indol-3-yl] -2- (2- (methylsulfonyl) ethyl] -1H-benzo [imidazole]
According to the general method used for the preparation of Example 1, using as starting material 5- (6-fluoro-1- (phenylsulfonyl) -1 7 -indol-3-yl) -2- (2- (Methylsulfonyl) ethy 1) -177-benzo [imidazo] e (Intermediate 34, 170 mg, 0.34 mmol), 20 mg (16%) of the compound of interest is obtained as a white solid after purification by preparative TLC. (DCM / MeOH = 10/1) and preparative HPLC. LC-MS for C18H16FN3O2S + H + [M + H] +: calcd. 358.1; found: 358.1. 1H NMR (400MHz, DMSO- <fc) δ [pm]: 12.35 (s, 0.45H), 12.35 (s, 0.55H), 11.37 (s, 0.55H), 11.33 (s, 0.45H), 7.85 - 7.79 (m, 1H), 7.77 (s, 0.45H), 7.66 - 7.63 (m, 1H), 7.62 - 7.57 (m, 1H), 7.52 - 7.41 (m, 1.55H), 7.24 - 7.19 (m, 1H); ), 6.99 - 6.91 (m, 1H), 3.71 - 3.65 (m, 2H), 3.32 - 3.27 (m, 2H), 2.32 (s, 3H) as a mixture of tautomers.
Compound 44: 1- (5H-Fluoro-1H-indol-3-yl) -1H-benzo [6nimidazol-2-yl] -N-methylmethylamine
An aqueous solution of concentrated HCl (3 mL, 37%) is added to a solution of tert-butyl (5- (6-fluoro-17H-indol-3-yl) -17-benzo [i] imidazol -2-yl) methyl (methyl) carbamate (Intermediate 36, 470 mg unpurified mixture, 0.87 mmol) in THF (30 mL). The reaction mixture is stirred at 51 ° C for 3 hours, evaporated in vacuo, diluted with water (80 mL), and extracted with EtOAc (50 mLx3). The aqueous phase is basified with an aqueous solution of NaOH at pH = 13 and extracted with EtOAc (80 mL> <3). The organic phases are combined and then dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by preparative TLC (DCM / MeOH = 10/1) and preparative HPLC to give 40 mg (16%) of the compound of interest as a white solid. LC-MS for C17H15FN4 + H + [M + H] +: calcd. 295.1; found: 294.9. NMR (400 MHz, DMSO-d6) δ [pm]: 11.34 (s, 1H), 7.82 (dd, J = 8.7, 5.4 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 10.0.2.3 Hz, 1H), 6.95 (ddd, J = 9A, 8.7.2.3 Hz). , 1H), 3.87 (s, 2H), 2.34 (s, 3H).
Compound 45: 4 - ((5- (6-fluoro-1H-indol-3-yl) -1H-henzo [(1)] - ((5- (6-fhioro) 1- (N-phenylsulfonyl) -indol-3-yl) -NH-benzohyl imidol-2-ylmethylmorpholine
A solution of 2- (chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -17H-indol-3-yl) -177-benzo [7] imidazole (Intermediate 37, 100 mg, 0.23 mmol) and morpholine (59 mg, 0.68 mmol) in DMF (2 mL) is stirred at 80 ° C for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H20 (20 mL), saturated aqueous NaCl (30 mLx2), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC (DCM / MeOH = 20 / ml). 1) to give 56 mg (50%) of the compound of interest as a brown solid. LC-MS for C26H23FN4O3S-U-E [M + H] +: calcd. 491.2; found: 490.9. 2nd step :
According to the general method used for the preparation of Example 1, using as starting material 4 - ((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1 Benzo [(imidazol-2-yl) methyl) morpholine (Step 1, 56 mg, 0.11 mmol), 13 mg (32%) of the compound of interest is obtained as a white solid after purification. by preparative TLC (DCM / MeOH = 20/1). LC-MS for C20H19FN4O + H + [M + H] +: calcd. 351.2; found: 351.2. H NMR (400 MHz, MeOH-t 2 O δ [pm]: 7.71 (dd, J = 8.4, 5.2Hz, 1H), 7.67 (s, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.41 ( d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.01 (dd, J = 10.0, 2.4 Hz, 1H), 6.78 (ddd, J = 9.2, 8.4, 2.4Hz, 1H), 3.72 (s). , 1H), 3.66 - 3.61 (m, 4H), 2.50 -2.44 (m, 4H).
Compound 46: 3-15-16-fluoro-1H-indol-3-yll-1H-benzyliminidazol-2-vinylnanamide Step 1: 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1-indol-3 vlVl // - benzoh /] imidazol-2-vllpropanamide
A solution of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2,3-dihydro-1H-benzo [] pyrrolo [1,2-a] imidazol 1 -one (Intermediate 39, 456 mg of unpurified mixture, 0.92 mmol) in THF saturated with NH3 (100 mL) is stirred at 137 ° C. for 24 hours in an autoclave. The reaction mixture was cooled to room temperature and evaporated to give 480 mg (100%) of the compound of interest as a yellow solid, directly used in the next transformation without purification. LC-MS for C24H19FN4O3S + H + [M + H] +: calcd. 463.1; found: 462.8. Step 2: KOH (116 mg, 2.07 mmol) is added to a solution of 3- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [ imidazol-2-yl) propanamide (Step 1, 480 mg of unpurified mixture, 0.92 mmol) in EtOH (10 mL). The reaction mixture is stirred at 50 ° C for 4 hours. The mixture was neutralized with 2M aqueous HCl, concentrated, and purified by preparative HPLC to give 50 mg (17%) of the compound of interest as a white solid. LC-MS for C18H15FN4O + H + [M + H] +: calcd. 323.1; found: 322.9. * H NMR (400 MHz, DMSO-4) δ [pm]: 12.15 (s, 1H), 11.33 (s, 1H), 7.82 (dd, J = 8.7, 5.5 Hz, 1H), 7.67 (s, 1H) , 7.61 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.48-7.38 (m, 2H), 7.22 (dd, J = 10.0, 2.0Hz, 1H), 6.95 ( ddd, J = 9.6, 8.7, 2.0 Hz, 1H), 6.86 (s, 1H), 3.03 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H).
Compound 47: 5- (6-fluoro-1H-indol-3-yl) benzoyloxazole
According to the general method used for the preparation of Example 1, using as starting material 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 41, 423 mg, 1.08 mmol), 60 mg (22%) of the compound of interest is obtained as a white solid after purification by silica gel chromatography (petroleum ether / EtOAc = 100/1 - 6 / 1). LC-MS for C5H9FN2O + H + [M + H] +: calcd. 253.1; found: 253.0. H NMR (400 MHz, CDCl 3) δ [pm]: 8.30 (br s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.84 (dd, J = 8.8, 5.2 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 9.4.2.2 Hz, 1H), 6.98 (ddd, J = 9.4, 8.8.2.2 Hz, 1H) .
Compound 48: 5- (6-fluoro-1H-indol-3-yl) -2-methylbenzotloxazole
Following the general method used for the preparation of Example 1, using 5- (6-fluoro-1- (phenylsulfonyl) -17-indol-3-yl) -2-methylbenzo [c] as starting material. /] oxazole (Intermediate 43, 718 mg, 1.77 mmol), 184 mg (39%) of the compound of interest is obtained as a brown solid after purification by recrystallization from petroleum ether / EtOAc = 4/1. LC-MS for C16H11FN2O + H + [M + H] +: calcd. 267.1; found: 267.0. NMR (400 MHz, DMSO-d6) δ [pm]: 11.45 (s, 1H), 7.87 (s, 1H), 7.83 (dd, J = 8.8, 5.2Hz, 1H), 7.73-7.68 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 10.0, 2.4 Hz, 1H), 7.23 (ddd, J = 9.2, 8.8, 2.4 Hz, 1H), 2.63 (s, 3H); ).
II. EXAMPLES OF BIOLOGY
II. 1. 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 at the indicated concentrations (total volume of 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):
IL 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 χ 104 cells / well in a final volume of 200 μl. To determine the activity of TDO or IDO, 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 μM <IC50 <100 μM; **: 1 μM <IC50 <10 μM; ***: IC50 <1 μM):

权利要求:
Claims (10)
[1]
1. Compound of Formula I

and its pharmaceutically acceptable enantiomers, salts and solvates, wherein: X and X are each independently H, halogen, alkyl, haloalkyl, preferably H or F; R1, R2 and R3 are each independently H, halogen, alkyl, C1-C6, alkoxy, haloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, OR4, COOR4, CONR4R5, NR4COR5, NR4R5, SO2R4, SO2NR4R5, NR4SO2R5, SO2R4, aryl, CO-alkyl an alkyl group, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R4 and R5 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 represent feel each independently H, halogen or methyl, preferably R, R and R are each H; A1, A2 and A3 each independently represent C, N or O; each of Y1, Y2 and Y3 is either absent or independently represents - a hydrogen atom; - oxo; - CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 each independently represent: • a hydrogen atom; A halogen, preferably F, Cl or I, more preferably F; • a hydroxyl; OR9 or NR9R10 wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl , an amino, CO-alkyl, SO2R11, wherein R11 represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, an 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NRVO, NR9SO2R10, SOR9, aryl, CO-alkyl, wherein R9 and R10 each represent independently a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; A heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; -CO-R11 or -SO2R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl, OR9, COOR9, conr9r10, nr9cor10, nr9r10, so2r9, so2nr9r10, nr9so2r10, SOR9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; In CR6R7R8, R6, R7 and the carbon atom to which they are attached together form a ring, which ring is preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxyl , OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 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, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; In NR6R7, R6, R7 and the nitrogen atom to which they are attached form a ring, this 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, OR9, COOR9, CONR9R10, nr9cor10, nr9r10, so2r9, ss2nr9r10, NR9SO2Rh, SO2R9, aryl, CO-alkyl, alkyl, the group alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 each independently represent a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, 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 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-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; the dashed lines represent single bonds or double bonds; provided that A1, A2 and A3 are not all Cs; provided that when one of A1, A2 and A3 is N, the other two are not both C; provided that the compound of formula I is not 3- (benzofuran-5-yl) -6-chloro-1H-indole or 3- (benzo [d] [1,3] dioxol-5-yl) - lH-indole.
[2]
2. The compound according to claim 1, wherein a first of A1, A2 and A3 is N, a second of A1, A2 and A3 is C and the third of A1, A2 and A3 is N or O.
[3]
3. The compound of claim 1 or claim 2, wherein A2 is N and one of A1 and A3 is N and the other is C.
[4]
4. The compound according to any one of claims 1 to 3, wherein A2 is C and one of A1 and A3 is N and the other is N or O.
[5]
The compound of claim 1 selected from the group consisting of: 6- (6-fluoro-1H-indol-3-yl) -1H-indazole-2- (6- (6-fluoro-1H) -indol-3-yl) -1H-indazol-1-yl) acetamide 6- (6-fluoro-1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole 1 - (4 - ((6- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone - 3 - (6- (6- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone 1H-indol-3-yl) -1H-indazol-1-yl) propanamide-6- (6-fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1 H-indazole 1- (4- (6- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidin-1-yl) ethanone - 5 - (6- 1-fluoro-1H-indol-3-yl) -1H-indazole-2- (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) acetamide 5- ( 6-fluoro-1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole 1- (4 - ((5- (6-fluoro-1H-indol-3-yl) (1 H -indazol-1-yl) methyl (1) piperidin-1-yl) ethanone 3 - (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide - 5- (6-fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole 1- (4- (5- (6-fluoro-1H) -propanamide; indol-3-yl) -1 H-indazol-1-yl ) piperidin-1-yl) ethanone - 2- (6- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) acetamide 1 - (4 - ((6- (6- 1H-indol-3-yl) -2H-indazol-2-yl) methyl (1-piperidin-1-yl) ethanone-3 - (6- (6-fluoro-1H-indol-3-yl)) 2H-indazol-2-yl) propanamide-6- (6-fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole 1 - (4- (6- ( 6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidin-1-yl) ethanone - 2- (5- (6-fluoro-1H-indol-3-yl) - 2H-indazol-2-yl) acetamide 1- (4 - ((5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) ethanone (5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) propanamide-5- (6-fluoro-1H-indol-3-yl) -2- (Piperidin-4-yl) -2H-indazole 1- (4- (5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidin-1-yl) ethanone 5 - (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazole 5- (6-fluoro-1H-indol-3-yl) -2-methyl-1H-benzo [d] ] Imidazole - (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methanamine 1- (5- (6-fluoro-1H-indol) 3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-dimethylmethanamine - 2 - ((( 5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) amino) ethanol - N - ((5- (6-fluoro-1H-indole) 3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide-2-amino-N - ((5- (6-fluoro-1H-indol-3-yl) -1H-benzo [ d] imidazol-2-yl) methyl) acetamide-N - ((5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) methanesulfonamide - 5 - (6-fluoro-1H-indol-3-yl) -2 - ((4-methylpiperazin-1-yl) methyl) -1H-benzo [d] imidazole 5- (6-fluoro-1H); indol-3-yl) -2 - ((4- (methylsulfonyl) piperazin-1-yl) methyl) -1H-benzo [d] imidazole-2- (5- (6-fluoro-1H-indol-3) 1H-benzo [d] imidazol-2-yl) ethanamine-N- (2- (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -yl) ethyl) acetamide - N- (2- (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) methanesulfonamide 5- (6-fluoro) 1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) -1H-benzo [d] imidazole-5- (6-fluoro-1H-indol-3-yl) -2- ( piperidin-4-yl) -1H-benzo [d] imidazole 5- (6-fluoro-1H-indol-3-yl) -2- (1 - (methylsulfonyl) piperidin-4-yl) -1H- benzo [d] imidazole - 5- (6-fluoro) 1H-indol-3-yl) -1H-benzo [d] imidazol-2-amine-N- (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol -2-yl) acetamide - N- (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methanesulfonamide 1 - (5- (6-fluoro) 1 H -indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N-methylmethanamine-4 - ((5- (6-fluoro-1H-indol-3-yl) -1H) benzyl [d] imidazol-2-yl) methyl) morpholine 3- (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanamide 5- ( 6-fluoro-1H-indol-3-yl) benzo [d] oxazole 5- (6-fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazole-5- (6-fluoro) 1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole 1- (4- (5- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol) 2-yl) piperidin-1-yl) ethanone - N- (5- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) acetamide - N- (5- (6) 1-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanesulfonamide - 6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole 6- (6-fluoro) 1 H -indol-3-yl) -2-methylbenzo [d] oxazole-6- (6-fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole 1- (4- (6- (6-Fluoro-1H-indol-3-yl) ben zo [d] oxazol-2-yl) piperidin-1-yl) ethanone - N- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) acetamide - N- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanesulfonamide or a pharmaceutically acceptable enantiomer, salt or solvate.
[6]
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable enantiomer, salt or solvate, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.
[7]
A medicament comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable enantiomer, salt or solvate.
[8]
8. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable enantiomer, salt or solvate thereof for use in the treatment and / or prevention of cancer, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease. and Huntington, chronic viral infections such as HCV and HIV, depression and obesity.
[9]
9. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable enantiomer, salt or solvate thereof for use as a TD02 inhibitor.
[10]
10. Process for the manufacture of a compound of formula I according to claim 1 to 5 or a pharmaceutically acceptable enantiomer, salt or solvate thereof, characterized in that it comprises: (a1) reacting a compound of formula (i)

wherein X1 and X2 are as defined in claim 1; Z1 is F1 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 with 1 to 6 carbon atoms (preferably methylsulphonyloxy or trifluoromethylsulphonyloxy) or an arylsulphonyloxy having 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 (ii) in which

R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as defined in claim 1; and 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 (iii),

wherein Z1, X1, X2, R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as defined above; and (b1) in the case where Z1 is not H, deprotecting the indole amine of the compound of Formula (iii) to give the compound of Formula I.

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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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US201461996975P| true| 2014-03-18|2014-03-18|

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EP14160578|2014-03-18|

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EP14218296|2014-03-18|

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US14218296|2014-03-18|JP2016557605A| JP2017507983A|2014-03-18|2015-03-17|Novel 3-indole substituted derivatives, pharmaceutical compositions, and methods of use|

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EP15714653.1A| EP3119763A1|2014-03-18|2015-03-17|Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use|

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CA2942761A| CA2942761A1|2014-03-18|2015-03-17|Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use|

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PCT/IB2015/051957| WO2015140717A1|2014-03-18|2015-03-17|Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use|