compound, pharmaceutical composition, use of a compound, and process for the preparation of a compou

专利摘要:
COMPOUND, PHARMACEUTICAL COMPOSITION, USE OF A COMPOUND, METHOD FOR PROPHYLAXIS OR TREATMENT OF A STATE OR DISEASE CONDITION MEDIATED BY A FGFR KINASE AND PROCESS FOR THE PREPARATION OF A COMPOUND The invention concerns new compounds derived from - quinoxaline , pharmaceutical compositions comprising said compounds, processes for preparing said compounds and the use of said compounds in the treatment of diseases, for example, cancer.
公开号:BR112013013435B1
申请号:R112013013435-6
申请日:2011-11-29
公开日:2020-10-20
发明作者:Gordon Saxty；Christopher William Murray；Gilbert Ebai Besong；Christopher Charles Frederick Hamlett；Steven John Woodhead；Yannick Aimé Eddy Ligny；Patrick René Angibaud
申请人:Astex Therapeutics Limited；
IPC主号:

专利说明:

FIELD OF THE INVENTION
The invention concerns new compounds derived from quinoxaline, pharmaceutical compositions comprising said compounds, processes for the preparation of said compounds and the use of said compounds in the treatment of diseases, for example, cancer. SUMMARY OF THE INVENTION
According to a first aspect of the invention, the compounds of formula (I) are provided:
which include any tautomeric or stereochemically isomeric form thereof, where n represents an integer equal to 0, 1, 2, 3 or 4; R1 represents hydrogen, C1-6 alkyl, C2-4 alkenyl, C1-6 hydroxy-alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, C1-6 alkoxy C1-6 alkyl in which each alkyl C1-6 can be optionally substituted with one or two hydroxyl groups, C1-6 alkyl substituted with -NR4R5, C1-6 alkyl substituted with -C (= O) -NR4R5, -S (= O) 2 -C1.6 alkyl, - S (= O) 2-C1-6 haloalkyl, -S (= O) 2-NR14R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O ) 2-C1.6 haloalkyl, C1-6 alkyl substituted with -S (= O) 2-NR14R16, C1-6 alkyl substituted with -NH-S (= O) 2- C1-6 alkyl, C1-6 alkyl substituted with -NH- S (= O) 2-C1-6 haloalkyl, C-6 alkyl substituted with -NRI2-S (= O) 2-NRI4R15, R6, C1-6 alkyl substituted with R6, C1-6 alkyl substituted with -C (= O) -R6, hydroxy-C1-6 alkyl substituted with R6, C1-6 alkyl substituted with -Si (CHs) 3, C1-6 alkyl substituted with - P (= O) (OH) 2 OR C1-6 alkyl substituted with -P (= O) (Oalquila € 1-0) 2; each Rla is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkyl substituted with amino or mono- or di (alkyl examino or -NH (C3-8 cycloalkyl), C1-4 cyanoalkyl, C1 alkoxy -4 C1-4 alkyl and C1-4 alkyl substituted with one or more fluorine atoms; each R2 is independently selected from hydroxyl, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1- alkoxy 4, C1-4 hydroxyalkyl, C1-4 hydroxyalkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 hydroxyalkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkoxy, C1-4 alkyloxy, C1-4 alkoxy C1-4 alkyl wherein each C1-4 alkyl can be optionally substituted with one or two hydroxyl groups, C1-4 hydroxyalkyl C1-4 alkoxyalkyl, R13, C1-4 alkyl substituted with R13, C1-4 alkyl substituted with - C (= O) -R13, C1-4 alkoxy substituted with R13, C1-4 alkoxy substituted with -C (= O) -R13, -C (= O) -R13, C1-4 alkyl substituted with - NR7R8, alkyl C1-4 replaced with -C (= O) -NR7R8, alk xi Cl-4 substituted with -NR7R8, C1 -4 alkoxy substituted with -C (= O) -NR7R8, -NR7R8 and -C (= O) - NR7R8; OR when two groups R2 are attached to the adjacent carbon atoms they can be taken together to form a radical of the formula: -O- (C (R17) 2) PO-; -X-CH = CH-; or -X-CH = N-; where R17 represents hydrogen or fluorine, p represents 1 or 2 and X represents O or S; R3a represents -NR10Rn, hydroxyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 alkoxy substituted with -NR10Rn, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl optionally substituted with -OC (= O) - C1-6 alkyl, C1-6 hydroxyalkyl optionally substituted with -OC (= O) - C1-6 alkyl, C2-6 hydroxyalkenyl, C2-6 hydroxyalkyl, C1-6 hydroxyalkylalkyl, C1-6 cyanoalkyl, C1-6 alkyl C1-6 substituted with carboxyl, C1-6 alkyl substituted with -C (= O) -C1-6 alkyl, C1-6 alkyl substituted with -C (= O) -O- C1-6 alkyl, substituted C1-6 alkyl with C 1-6 alkoxy C 1-6 alkyl (= O) -, C 1-6 alkyl substituted with C 1-6 alkoxy C 1-6 alkyl (= O) -, C 1-6 alkyl substituted with -OC (= O ) -C1-6 alkyl, C1-6 alkoxyC1-6 alkyl where each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups or with -OC (= O) -C1-6 alkyl, C2-6 alkenyl substituted with C1-6 alkoxy 6, C2-6 alkynyl substituted with C1-6 alkoxy, C1-6 alkyl substituted with R9 and optionally substituted with -OC (= O) -C1-6 alkyl, C1-6 alkyl substituted with -C (= O) -R9, C1-6 alkyl substituted with hydroxyl and R9, C2-6 alkenyl substituted with R9, substituted C2-6 alkynyl with R9, C1-6 alkyl substituted with -NR10Rn, C2-6 alkenyl substituted with -NR10Rn, C2-6 alkynyl substituted with -NR10Rn, C1-6 alkyl substituted with hydroxyl and -NR10Rn, C1-6 alkyl substituted with one or two halogens and -NR10Rn, - C1-6 alkyl (RI2) = NO-R12, C1-6 alkyl substituted with -C (= O) -NR10R ", C1-6 alkyl substituted with -OC (= O) -NR10R" , -S (= O) 2-C1-6 alkyl, - S (= O) 2-C1-6 haloalkyl, -S (= O) 2 -NR14R15, C1-6 alkyl substituted with - S (= O) 2-alkyl C1-6, C1-6 alkyl substituted with -S (= O) 2-halo C1-6alkyl, C1-6 alkyl substituted with -S (= O) 2- NR14R15, C1-6 alkyl substituted with - NRl2-S ( = O) 2-C 1-6 alkyl, C 1-6 alkyl substituted with -NH-S (= O) 2-halo C 1-6 alkyl, C 6 alkyl substituted with -NRI2-S (= O) 2-NRI4R15, R13 , C1-6 alkyl substituted with -P (= O) (OH) 2 or C1-6 alkyl substituted with - P (= O) ( Oalkyl € 1-0) 2; R3b represents hydrogen or hydroxyl; as long as if R3a represents -NR10Rn, then R3b represents hydrogen; or R3a and R3b are taken together to form = 0, to form = NR10, to form cyclopropyl together with the carbon atom to which they are attached, to form = CH-C0-4 alkyl substituted with R3c, or to form
wherein ring A is a 5- to 7-membered saturated monocyclic heterocycle containing a heteroatom selected from N, O or S, said heteroatom not being positioned at the alpha position of the double bond, where ring A is being optionally substituted with cyano, C1.4 alkyl, hydroxy-CM alkyl, H2N-CM alkyl, (CM alkyl) NH-C1.4 alkyl, (C1-4 alkyl) 2N-CM alkyl, haloalkyl CM) NH-CM alkyl, CM alkoxy CM , -C (= O) -NH2, -C (= O) -NH (CM alkyl), -C (= O) -N (CM alkyl) 2; R3C represents hydrogen, hydroxyl, CM alkoxy, R9, -NR10Rn, cyano, -C (= O)-CM alkyl OR -CH (OH)-CM alkyl R4 and R5 each independently represents hydrogen, CM alkyl, CM hydroxy alkyl, haloalkyl CM, hydroxyalkyl CM, C1-6 alkoxy CM where each CM alkyl can be optionally substituted with one or two hydroxyl groups, -S (= O) 2-CM alkyl, -S (= O) 2-haloalkyl CM, - S (= O) 2-NRI4R15, CM alkyl substituted with -S (= O) 2-a] CM alkyl, CM alkyl substituted with -S (= O) 2-haloalkyl CM, CM alkyl substituted with -S (= O ) 2- NR14R15, CM alkyl substituted with -NH-S (= O) 2-CM alkyl, CM alkyl substituted with -NH-S (= O) 2-haloalkyl CM, CM alkyl substituted with -NH- S (= O ) 2-NR14R15, R13OUalkyl CM substituted with R13; R6 represents C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, 4- to 7-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, 4- to 7-membered monocyclic heterocyclyl, optionally and each independently being substituted by 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from cyano, alkyl CM, Cl-6 cyanoalkyl, hydroxyl, carboxyl, CM hydroxyalkyl, halogen, CM haloalkyl, CM hydroxyalkylalkyl, CM alkoxy, CM alkoxy CM alkyl, CM-OC (= O) -, -NR14R15, -C (= O) - NR14R15, CM alkyl substituted with -NR14R15, C1-6 alkyl substituted with -C (= O) -NR14R15, - S (= O) 2-C1-6 alkyl, -S (= O) 2-C1-6 haloalkyl, -S (= O) 2-NR14R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-halo C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-NR14R15, C1-6 alkyl substituted with -NH-S (= O) 2- C1-6 alkyl, C1-6 alkyl substituted with -NH- S (= 0) 2-halo C1-6 alkyl or C1-6 alkyl substituted with -NH -S (= O) 2-NRI4R15; R7 and R8 each independently represents hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or C1-6 alkyloxy; R9 represents C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, naphthyl, or 3- to 12-membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, said C3-8 cycloalkyl, C3- cycloalkenyl 8, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl each optionally and each independently being substituted with 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from = 0, C1.4 alkyl , hydroxyl, carboxyl, C1-4 hydroxyalkyl, cyano, C1-4 cyanoalkyl, C1.4-OC (= O) -, C1-4 alkyl substituted with C1-4-OC (= O) -, C1- alkyl 4- C (= OJ-, C1-4 alkoxy C1-4 alkyl where each C1-4 alkyl can be optionally substituted with one or two hydroxyl, halogen, C1-4 haloalkyl, C1-4 hydroxyalkyl, -NR14R15, - C (= O) -NRI4R15, C1-4 alkyl substituted with -NR14R15, C1-4 alkyl substituted with -C (= O) -NRI4R15, C1-4 alkoxy, -S (= O) 2-C1.4 alkyl, - S (= O) 2 -haloalkyl C1 .4, -S (= O) 2-NRI4R15, C1-4 alkyl substituted with -S (= O) 2-NRI4R15, C1-4 alkyl substituted with - NH-S (= O) 2-C1-4 alkyl, C1-4 alkyl substituted with -NH-S (= O) 2-halo C1-4 alkyl, C1-4 alkyl substituted with -NH-S (= O) 2-NRI4R15, R13, -C (= O) -R13, C1-4 alkyl substituted with R13, phenyl optionally substituted with R16, phenylalkyl C1-6 where phenyl is optionally substituted with R16, a 5- or 6-membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S wherein said heterocyclyl is optionally substituted with R16; or when two of the R9 substituents are attached to the same atom, they can be taken together to form a 4- to 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; R10 and R11 each independently represents hydrogen, carboxyl, C1-6 alkyl, C1-6 cyanoalkyl, C1-6 alkyl substituted with - NR14R15, C1-6 alkyl substituted with -C (= O) -NRI4R15, C1-6 haloalkyl, hydroxyalkyl C1-6, C1-6 hydroxyalkylalkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl wherein each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, R6, C1-6 alkyl substituted with R6, -C (= O) -R6, -C (= OJ- C1-6 alkyl, -C (= O) -C1-6 hydroxyalkyl, -C (= O) -C1-6 haloalkyl, -C (= O) - C1-6 hydroxyalkylalkyl, C1-6 alkyl substituted with -Si (CH3) 3, -S (= O) 2-C1-6 alkyl, -S (= O) 2-C1-6 haloalkyl, -S (= O ) 2- NR14R15, C-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-halo C1-6 alkyl, C1-6 alkyl substituted with - S (= O) 2-NR14R15, C1-6 alkyl substituted with - NH-S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -NH-S (= O) 2- C1-6 haloalkyl or C-6 alkyl substituted with -NH-S (= O) 2-NRI4R15; R12 K represents hydrogen or alkyl C1-4 optionally substituted with C1-4 alkoxy; R13 represents C3-8 cycloalkyl or a saturated 4- to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C3-8 cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxyl, C1-6 alkyl, -C (= O) -C1-6 alkyl, C1.6 alkoxy, or -N814815; R14 and R15 each independently represent hydrogen, or C1-4 haloalkyl, or C1-4 alkyl optionally substituted with a substituent selected from hydroxyl, CM alkoxy, amino or mono- or di (C1-4 alkyl; R16 K represents hydroxyl, halogen, cyano , C1-4 alkyl, C14 alkoxy, -NR14R15OU -C (= O) NRI4R15, its N-oxides, its pharmaceutically acceptable salts or its solvates.
In one embodiment, the compounds of the formula (I °) are provided:
which include any tautomeric or stereochemically isomeric form thereof, where n represents an integer equal to 0, 1, 2, 3 or 4; R1 represents hydrogen, C1-6 alkyl, C2-4 alkenyl, C1.6 hydroxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkylalkyl, C1-6 alkoxyC1-6 alkyl where each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, C1-6 alkyl substituted with -NR4R5, C1-6 alkyl substituted with -C (= O) -NR4R5, -S (= O) 2-C1-6 alkyl, -S (= O) 2-haloalkyl Q. 6, -S (= O) 2-NRI4R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-halo C1-6 alkyl, C1 alkyl -6 substituted with - S (= O) 2-NRI4R15, C1-6 alkyl substituted with -NH-S (= O) 2-C1.6 alkyl, C1-6 alkyl substituted with -NH-S (= O) 2-haloalkyl C1-6, C1-6 alkyl substituted with -NRI2-S (= O) 2-NRI4R15, R6, C1-6 alkyl substituted with R6, C1-6 alkyl substituted with -C (= O) -R6, hydroxyalkyl C1-6 substituted with R6, alkyl Ci. 6 substituted with -Si (CH3) 3, C1-6 alkyl substituted with -P (= O) (OH) 2 or C1-6 alkyl substituted with -P (= O) (Oalkyl € 1-0) 2; each R2 is independently selected from halogen, cyano, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, CM alkoxy, CM hydroxyalkyl, CM hydroxyalkoxy, CM haloalkoxy, CM hydroxyalkoxy, CM hydroxyalkyl, CM CMoalkylalkoxy, CM alkoxyalkoxy , CM alkoxy Cn 4 alkoxy where each CM alkyl can be optionally substituted with one or two hydroxyl groups, hydroxy aloxy CM alkyl CM, R13, CM alkyl substituted with R13, CM alkyl substituted with -C (= O) -R13, CM alkoxy substituted with R13, CM alkoxy substituted with -C (= O) -R13, -C (= O) -R13, CM alkyl substituted with -NR7R8, CM alkyl substituted with -C (= O) - NR7R8, CM alkoxy substituted with -NR7R8 , CM alkoxy substituted with -C (= O) -NR7R8, -NR7R8OU -C (= O) -NR7R8; R3a represents -NR10Rn, hydroxyl, CM alkoxy, C1-6 hydroxyalkoxy, CM alkoxy substituted with -NR10Rn, CM alkyl, C2-6 alkenyl, C2-6 alkynyl, CM haloalkyl, CM hydroxyalkyl, C2-6 hydroxyalkenyl, C2-6 hydroxyalkynyl , CM hydroxyalkylalkyl, CM cyanoalkyl, C2-6 alkynyl substituted with carboxyl, CM alkyl substituted with -C (= O) -CM alkyl, CM alkyl substituted with -C (= O) -O-alkyl CM, CM alkyl substituted with alkoxy CMalkyl CM-OC (= O) -, CM alkyl substituted with CM alkoxy CM alkyl C (= O) -, CM alkyl substituted with -OC (= O)-CM alkyl, CM alkoxy CM where each CM alkyl can be optionally substituted with one or two hydroxyl groups, C2-6 alkenyl substituted with CM alkoxy, C2-6 alkynyl substituted with CM alkoxy, CM alkyl substituted with R9, CM alkyl substituted with -C (= O) -R9, CM alkyl substituted with hydroxyl and R9, C2-6 alkenyl substituted with R9, C2-6 alkynyl substituted with R9, CM alkyl substituted with -NR10R ", C2-6 alkenyl substituted with -NR10Rn, C2-6 alkynyl substituted with -NR10Rn, CM alkyl substituted with hydroxyl and -NR10Rn, CM alkyl substituted with one or two halogens and -NR10Rn, -CM-C alkyl (R12) = NO-R12, CM alkyl substituted with - C (= O) -NR10R '', CM alkyl substituted with -OC (= O) -NR10R '', -S (= O) 2- C1-6 alkyl, -S (= O) 2-haloalkyl CM, -S (= O) 2-NR14R15, C1-6 alkyl substituted with -S (= O) 2- CM alkyl, C1-6 alkyl substituted with -S (= O) 2- C1-6 haloalkyl, C1-6 alkyl substituted with -S (= O) 2- NR14R15, C1-6 alkyl substituted with -NR12-S (= O) 2- C1-6 alkyl, C1-6 alkyl substituted with -NH- S (= O) 2-C1-6 haloalkyl, C1-6 alkyl substituted with -NRI2-S (= O) 2-NRI4R15, R13, C1-6 alkyl substituted with -P (= O) (OH) 2 or CM alkyl substituted with - P (= O) (Oalkyl CI-O) 2; R3b represents hydrogen or hydroxyl; as long as if R3a represents -NR10Rn, then R3b represents hydrogen; or R3a and R3b are taken together to form = 0, to form = NR '°, to form cyclopropyl together with the carbon atom to which they are attached, to form = CH-4 alkyl substituted with Rac, or to form
wherein ring A is a saturated 5- to 7-membered monocyclic heterocycle containing a heteroatom selected from N, O or S, said heteroatom not being positioned in the alpha position of the double bond, where ring A is being optionally substituted with cyano, CM alkyl, CM hydroxyalkyl, H2N-CM alkyl, (CM alkyl) NH-CM alkyl, (C1-4 alkyl) 2N-CM alkyl, C 1-4 haloalkyl) NH-CM alkyl, CM alkoxy CM, -C (= O ) -NH2, -C (= O) -NH (CM alkyl), -C (= O) -N (Cl-4 alkyl) 2; Rac represents hydrogen, hydroxyl, CM alkoxy, R9, -NR10Rn, cyano, -C (= O) -Calkyl CM OR -CH (OH) -Calkyl CM; R4 and R5 each independently represent hydrogen, CM alkyl, CM hydroxyalkyl, CM haloalkyl, CM hydroxyalkyl CM, CM alkoxy where each CM alkyl can be optionally substituted with one or two hydroxyl groups, -S (= O) 2-CM alkyl , -S (= O) 2-C1-6 haloalkyl, -S (= O) 2-NR14R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with - S (= O) 2-halo C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2- NR14R15, C1-6 alkyl substituted with -NH-S (= O) 2-C1-6 alkyl, alkyl C1-6 substituted with -NH-S (= O) 2-halo C1-6 alkyl, C1-6 alkyl substituted with -NH-S (= O) 2-NR14R15, R13 or C1-6 alkyl substituted with R13; R6 represents C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, 4- to 7-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; the C3-8 cycloalkyl doto, C3-8 cycloalkenyl, phenyl, 4- to 7-membered monocyclic heterocyclyl, optionally and each independently is substituted by 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from cyano, alkyl C1-6, C1-6 cyanoalkyl, hydroxyl, carboxyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, Ci.6-OC alkyl (= O) -, -NR14R15, -C (= O) -NRI4R15, C-6 alkyl substituted with -NR14R15, C1-6 alkyl substituted with -C (= O) NRI4R15, -S (= O) 2-alkyl C1-6, -S (= O) 2-halo C1-6 alkyl, -S (= O) 2-NR14R15, C1-6 alkyl substituted with - S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-halo C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-NRI4R15, C1-6 alkyl substituted with - NH-S (= O) 2-alkyl C1- 6, C1-6 alkyl substituted with -NH-S (= O) 2-C1-6 haloalkyl or C1-6 alkyl substituted with -NH-S (= O) 2-NRI4R18; R7 and R8 each independently represents hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or C1-6 alkoxy C1-6 alkyl; R9 represents C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, said C3-8 cycloalkyl, C3- cycloalkenyl 8, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl each optionally and each independently being substituted with 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from = 0, C1-4 alkyl , hydroxyl, carboxyl, C1-4 hydroxyalkyl, cyano, cyano-C1-4 alkyl, C1-4-OC alkyl (= OJ-, C1.4 alkyl substituted with C1-4 alkyl (= O) -, C1 alkyl -4- C (= OJ-, C1-4 alkoxy C1-4 alkyl where each C1-4 alkyl can optionally be substituted with one or two hydroxyl, halogen, C1-4 haloalkyl, C1-4 hydroxyalkyl, -NR14R15, -C (= O) -NRI4R15, C1-4 alkyl substituted with - NR14R15, C1-4 alkyl substituted with -C (= O) -NRI4R15, C1-4 alkoxy, -S (= O) 2-C1-4 alkyl, -S (= O) 2-haloalkyl C1.4, -S (= O) 2-NR14R15, C1-4 alkyl substituted with -S (= O) 2-NR14R15, C1-4 alkyl substituted with - NH-S (= O) 2-C1-4 alkyl , C1-4 alkyl substituted with -NH-S (= O) 2-halo C1-4 alkyl, C1-4 alkyl substituted with -NH-S (= O) 2-NRI4R15, R13, -C (= O) -R13 , C1-4 alkyl substituted with R13, phenyl optionally substituted with R16, phenylalkyl C1-6 where phenyl is optionally substituted with R16, a 5- or 6-membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S wherein said heterocyclyl is optionally substituted with R16; or when two of the R9 substituents are attached to the same atom, they can be taken together to form a 4- to 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; R10 and R11 each independently represent hydrogen, C1-6 alkyl, C1-6 cyanoalkyl, C1-6 alkyl substituted with -NR14R15, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylalkyl, C1-6 alkoxy C1-6 alkyl 6 where each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, R6, C1-6 alkyl substituted with R6, -C (= O) -R6, - C (= O) -C1-6 alkyl, -C (= O) -C1-6 hydroxyalkyl, -C (= O) -C1-6haloalkyl, - C (= O) -C1-6 hydroxyalkylalkyl, C1-6 alkyl substituted with -Si (CH3) 3, -S ( = O) 2- C1-6 alkyl, -S (= O> 2- C1-6 haloalkyl, -S (= O) 2-NRI4R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, substituted C1-6 alkyl with -S (= O) 2-C1-6 haloalkyl, C1-6 alkyl substituted with -S (= O) 2-NRI4R15, C1-6 alkyl substituted with -NH-S (= O) 2-C1-6 alkyl , C1-6 alkyl substituted with -NH- S (= O) 2- C1-6 haloalkyl or C1-6 alkyl substituted with -NH-S (= O) 2-NR14R15; R12 represents hydrogen or optionally substituted C1-4 alkyl with C1-4 alkoxy; R13 represents cycloal C3-8 alkyl or a saturated 4- to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C3-8 cycloalkyl or monocyclic heterocyclyl are optionally substituted with 1, 2 or 3 substituents each one independently selected from halogen, hydroxyl, C1-6 alkyl, -C (= O) -C1-6 alkyl, C1-6 alkoxy, or -NR14R15; R14 and R15 each independently represent hydrogen, or C1-4 haloalkyl, or C1-4 alkyl optionally substituted with a substituent selected from hydroxyl, C1-4 alkoxy, amino or mono- or di (Cylamino alkyl; R16 represents hydroxyl, halogen, cyano, C1-4 alkyl, C14 alkoxy, -NR14R15OU -C (= O) NRI4R15; its N-oxides, pharmaceutically acceptable salts or solvates thereof WO 2008/141065, WO 2004/006355, WO 2006/092430 , WO 2008/003702, WO 01/68047, WO 2005/007099, W 02004/098494, WO 2009/141386, WO 2004/030635, WO 2008/141065, WO 2011/026579, WO 2011/028947, WO2011 / 135376 and WO 00/42026 that each discloses a series of heterocyclyl derivatives. DETAILED DESCRIPTION OF THE INVENTION
Unless the context otherwise indicates, references to formulas (I) or (I) in all sections of this document (including uses, methods and other aspects of the invention) include references to all other sub-formulas (for example , Ia, I'-a, I ”-a, F” -a, Ib, I'-b, I ”-b, F” -b, Ic, Fc, I ”-c, F” -c, Id , I'-d, I ”-d, F” -d, Ie), sub-groups, preferences, embodiments and examples as defined herein.
The prefix “Cx.y” (where x and y are whole numbers) as used here refers to the number of carbon atoms in a given group. Thus, a C1-6 alkyl group containing 1 to 6 carbon atoms, a C3-8 cycloalkyl group containing 3 to 6 carbon atoms, a C1-4 alkoxy group containing 1 to 4 carbon atoms and so on.
The terms 'halo' or 'halogen' as used herein refer to a fluorine, chlorine, bromine or iodine atom.
The terms 'C1-4 alkyl', or 'Cl-6 alkyl' as used herein as a group or part of a group refer to a saturated linear or branched hydrocarbon group containing 1 to 4 or 1 to 6 atoms of carbon. Examples of these groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
The term 'CW alkyl as used herein as a group or part of a group refers to a saturated linear or branched hydrocarbon group containing 0 to 4 carbon atoms, where when the alkyl group contains zero carbon atoms o the same is absent, but the substituent R3c will still be present as required to complete the valency of the atom to which it is attached.
The terms 'C2-4 alkenyl' or 'C2-6 alkenyl' as used herein as a group or part of a group refer to a linear or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and which contains a carbon-carbon double bond.
The terms 'C2-4 alkynyl' or 'C2-6 alkynyl' as used herein as a group or part of a group refer to a linear or branched hydrocarbon group having 2 to 4 or 2 to 6 carbon atoms and which contains a carbon carbon triple bond.
The terms 'C1-4 alkoxy' or 'CI-Ô alkoxy' as used herein as a group or part of a group refer to an O-C1-4 alkyl group or an -O-C1-6 alkyl group in which C1-4 alkyl and C1-6 alkyl are as defined herein. Examples of these groups include methoxy, ethoxy, propoxy, butoxy and the like.
The terms 'C1-4 alkoxy C1-4 alkyl' or 'C1-6 alkoxy C1-4 alkyl' as used herein as a group or part of a group refer to a C1-4-O-C1-alkyl group 4 or a C1-6 alkyl -O-C1-6 alkyl group wherein C1-4 alkyl and C1-6 alkyl are as defined herein. Examples of these groups include methoxyethyl, ethoxyethyl, propoxymethyl, butoxypropyl and the like.
The term 'C3-8 cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of these groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloeptyl or cyclooctyl and the like.
The term 'C3-8 cycloalkenyl' as used herein refers to a monocyclic hydrocarbon ring of 3 to 8 carbon atoms having a carbon-carbon double bond.
The terms 'C1-4 hydroxyalkyl' or 'CI-Ô hydroxyalkyl' as used herein as a group or part of a group refer to a C1-4 alkyl group or C1-6 alkyl group as defined herein where one or more than one of the hydrogen atoms are replaced with a hydroxyl group. The terms 'hydroxyalkyl C1-4' or 'hydroxyalkyl CI-Ô' therefore include monohydroxyalkyl C1-4, monohydroxyalkyl C1-6 and also polyhydroxyalkyl C1-4 and polyhydroxyalkylalkyl. They may have one, two, three or more hydrogen atoms replaced with a hydroxyl group, so hydroxy C1-4 or hydroxyalkyl C1-6 may have one, two, three or more hydroxyl groups. Examples of these groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
The terms' C1-4 haloalkyl 'or' C1.6 haloalkyl as used herein as a group or part of a group refer to a C1-4 alkyl or C1-6 alkyl group as defined herein in which one or more than one of the hydrogen atoms is replaced with a halogen. The terms 'C1-4 haloalkyl' or 'C1-6 haloalkyl' therefore include C1-4 monoaloalkyl, C1-6 monoaloalkyl and also C1-4 polyalkyl and C1-6 polyalkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so C1-4 haloalkyl or C1-6 haloalkyl may have one, two, three or more halogens. Examples of these groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
The terms' C1-4 hydroxyalkylalkyl 'or' C1- hydroxyalkylalkyl as used herein as a group or part of a group refer to a C1-4 alkyl or C1-6 alkyl group as defined herein in which one or more than one of the hydrogen atoms are replaced with a hydroxyl group and one or more than one of the hydrogen atoms is replaced with a halogen. The terms' C1-4 hydroxyalkylalkyl 'or' C1-4 hydroxyalkylalkyl therefore refer to a C1-4 alkyl or C1-6 alkyl group in which one, two, three or more hydrogen atoms are replaced with a hydroxyl group and one, two , three or more hydrogen atoms are replaced with a halogen.
The terms 'C1-4 hydroxyalkoxy' or 'CI-Ó hydroxyalkoxy' as used herein as a group or part of a group refer to an O-C1-4 alkyl group or an -O-C1-6 alkyl group in which the C1-4 alkyl group and C1-6 alkyl group are as defined above and one or more than one of the hydrogen atoms of the C1-4 alkyl group or C1-6 alkyl group are replaced with a hydroxyl group. The terms 'C1-4 hydroxyalkoxy' or 'CI-Ô hydroxyalkoxy' therefore include C1-4 monohydroxyalkoxy, C1-6 monohydroxyoxy and also C1-4 polyhydroxyalkoxy and Ci-6- polyhydroxyoxy May have one, two, three or more 16 hydrogen atoms substituted with a hydroxyl group so the C1-4 hydroxyalkoxy or C1-6 hydroxyalkoxy may have one, two, three or more hydroxyl groups. Examples of these groups include hydroxymethoxy, hydroxyethoxy, hydroxypropoxy and the like.
The terms 'C1-4 haloalkoxy' or 'C1-4 haloalkoxy' as used herein as a group or part of a group refer to an O-C1-4 alkyl group or an -O-C1-6 alkyl group as herein defined in which one or more than one of the hydrogen atoms is replaced with a halogen. The terms' halo C1-4 alkoxy 'or haloalkoxy CI-Ó' therefore include C1-4 monoaloalkoxy, C1-6 monoaloalkoxy and also C1-4 polyalkoxy and C1-6 polyalkoxy. They can have one, two, three or more hydrogen atoms replaced with a halogen, so the C1-4 haloalkoxy or C1-6 haloalkoxy can have one, two, three or more halogens. Examples of these groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
The term 'C1-4 hydroxyalkoxy' as used herein as a group or part of a group refers to an O-C1-4 alkyl group in which the C1-4 alkyl group is as defined herein and in which one or more of the that one of the hydrogen atoms is replaced with a hydroxyl group and one or more than one of the hydrogen atoms is replaced with a halogen. The term 'hydroxyalkoxy C1.4' therefore refers to an O-C1-4 alkyl group in which one, two, three or more hydrogen atoms are replaced with a hydroxyl group and one, two, three or more hydrogen atoms are replaced with a halogen.
The term 'halo C1-4 C1-4 alkyl' as used herein as a group or part of a group refers to a C1-4 alkyl -O-C1-4 alkyl group where C1-4 alkyl is as defined herein and wherein in one or both of the C1-4 alkyl groups one or more than one of the hydrogen atoms is replaced with a halogen. The term halo C1-4 C1-4 alkyl therefore refers to a C1-4 alkyl -O-C1-4 alkyl group in which one or both of the C1-4 alkyl groups one, two, three or more hydrogen atoms are replaced with a halogen and where C 1-4 alkyl is as defined herein. Preferably, in one of the CM alkyl groups one or more than one of the hydrogen atoms is replaced with a halogen. Preferably, C1-4 haloalkoxy C1-4alkyl means C1-4alkyl substituted with C1-4 haloalkoxy.
The term 'hydroxyalkyl C1-4 C1-4alkyl' as used herein refers to a C1-4-O-C1-4alkyl group where C1-4alkyl is as defined herein and in one or both of the C1-4 alkyl groups one or more than one of the hydrogen atoms are replaced with a hydroxyl group and one or more of one of the hydrogen atoms are replaced with a halogen. The terms 'C1-4 hydroxyalkyl C1-4 alkoxyalkyl' therefore refer to a C1-4-O-C1-4alkyl group where in one or both of the C1-4alkyl groups one, two, three or more atoms of hydrogen are replaced with a hydroxyl group and one, two, three or more hydrogen atoms are replaced with a halogen and where C1-4 alkyl is as defined herein.
The term 'C2-6 hydroxyalkenyl as used herein refers to a C2-6 alkenyl group in which one or more of the hydrogen atoms are replaced with a hydroxyl group and in which C2-6 alkenyl is as defined herein.
The term 'C2-6 hydroxyalkenyl' as used herein refers to a C2-6 alkynyl group in which one or more of the hydrogen atoms are replaced with a hydroxyl group and where C2-6 alkynyl is as defined herein. .
The term C 1-6 phenylalkyl as used herein refers to a C 1-6 alkyl group as defined herein which is substituted with a phenyl group.
The terms cyanoalkyl CM OR cyanoalkyl CM as used herein refer to a CM alkyl group OR CM alkyl group as defined herein which are replaced with a cyano group.
The term "heterocyclyl" as used herein should, unless the context otherwise indicates, include both aromatic and non-aromatic ring systems. Thus, for example, the term "heterocyclyl group" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and completely saturated heterocyclyl ring systems. In general, unless the context otherwise indicates, these groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 ring members, more usually 5 to 10 ring members. Reference to 4 to 7 ring members includes 4, 5, 6 or 7 ring atoms and reference to 4 to 6 ring members includes 4, 5, or 6 ring atoms. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 members in the ring, more usually 3 to 7 and preferably 5, 6 or 7 members in the ring, more preferably 5 or 6 members in the ring. Examples of bicyclic groups are those that contain 8, 9, 10, 11 and 12 members in the ring and more usually 9 or 10 members in the ring. When reference is made here to heterocyclyl groups, the heterocyclyl ring, unless the context otherwise indicates, may optionally be substituted (i.e., unsubstituted or substituted) by one or more substituents as discussed herein.
Heterocyclyl groups can be heteroaryl groups having 5 to 12 ring members, more usually 5 to 10 ring members. The term "heteroaryl" is used here to indicate a heterocyclyl group having an aromatic character. The term "heteroaryl" encompasses polycyclic (for example bicyclic) ring systems in which one or more non-aromatic rings, provided that at least one is aromatic. In such polycyclic systems, the group can be linked by the aromatic ring, or by a non-aromatic ring.
Examples of heteroaryl groups are monocyclic and bicyclic groups that contain five to twelve members in the ring and more usually five to ten members in the ring. The heteroaryl group can be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed of five- and six-membered fused rings or six-membered fused rings or five-membered fused rings. Each ring can contain up to about five heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one nitrogen atom in the ring. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, which includes any substituents on the ring's amino group, will be less than five.
Examples of the five-membered heteroaryl groups include but are not limited to the groups of pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole.
Examples of the six-membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
A bicyclic heteroaryl group can be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring; b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 hetero atoms in the ring; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring; d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 hetero atoms in the ring; e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring; f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring; g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring; h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring; i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 hetero atoms in the ring; j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring; k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 hetero atoms in the ring; l) a furan ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms in the ring; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 hetero atoms in the ring; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring.
Particular examples of bicyclic heteroaryl groups that contain a five-membered fused ring to another five-membered ring include but are not limited to imidazothiazole (eg, imidazo [2, lb] thiazole) and imidazoimidazole (eg, imidazo [l , 2- a] imidazole).
Particular examples of bicyclic heteroaryl groups containing from a fused six-membered ring to a five-membered ring include but are not limited to the groups benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, 21 benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (eg, adenine, guanine), indazole, pyrazolopyrimidine (eg, pyrazolo [1,5-a] pyrimidine), triazolo-pyrimidine (eg [l, 2,4] triazolo [1,5-a] pyrimidine), benzodioxol, imidazo-pyridine and pyrazolopyridine (for example, pyrazolo [1,5-a] pyridine).
Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinoline, phthalazine, naphthyridine and pteridine.
Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include, tetrahydro-isoquinoline, tetrahydroquinoline, dihydrobenzthene, dihydrobenzfuran, 2,3-dihydrobenzo- [1,4,4] dioxin, benzo [1,3] dioxol, 4,5,6,7-tetrahydrobenzo-furan, tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro [1,2,4] -triazole- [4,3- a] pyrazine), indoline and indane.
A nitrogen-containing heteroaryl ring must contain at least one nitrogen atom in the ring. Each ring can, in addition, contain up to about four other heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, for example 1, 2 or 3, more usually up to 2 nitrogens, for example a single nitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, which includes any substituents on the ring's amino group, will be less than five.
Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanil, pyrazolyl, pyrininyl, pyrininyl, pyrininyl, pyrininyl, pyrininyl, pyrininyl, pyrininyl, pyridinyl, for example, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizine, purine for example, adenine [6-aminopurine], guanine [2-amino-6-hydroxipurine]), indazolyl, quinolizinyl, benzoxazinyl, benzo-diazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, naphthyridine and pteridine.
Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl and indolinyl.
The term "non-aromatic group" encompasses, unless the context otherwise indicates, unsaturated ring systems with no aromatic character, partially saturated or completely saturated heterocyclyl ring systems. The terms "unsaturated" and "partially saturated" refer to rings in which the structure (s) of the ring (s) contain atoms that share more than one valence bond, that is, the ring contains at least one multiple bond for example, a C = C or N = C bond. The term "completely saturated" refers to rings where there is no multiple bond between ring atoms. Saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, piperazine. The partially saturated heterocyclyl groups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.
Examples of non-aromatic heterocyclyl groups are groups having 3 to 12 members in the ring, more usually 5 to 10 members in the ring. These groups can be monocyclic or bicyclic, for example and typically have from 1 to 5 hetero atoms as members in the ring (more usually 1, 2, 3 or 4 hetero atoms as members in the ring), usually selected from nitrogen, oxygen and sulfur. Heterocyclyl groups may contain, for example, portions of cyclic ether (for example, as in tetrahydrofuran and dioxane), portions of cyclic thioether (for example, as in tetrahydrothiophene and dithian), portions of cyclic amine (for example, as in pyrrolidine), cyclic amide moieties (eg, as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (eg, as in imidazolidin-2-one) cyclic ester moieties (eg, as in butyrolactone), sulfones cyclic (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine).
Particular examples include morpholine, piperidine (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (for example, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg 4-tetrahydro pyranyl), imidazoline, imidazolidine, oxideazolidone pyrazolidine, piperazone, piperazine and N-alkyl piperazines such as N-methyl piperazine. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkyl piperazines.
In a non-aromatic heterocyclyl ring containing nitrogen, the ring must contain at least one nitrogen atom in the ring. Heterocyclic groups can contain, for example, cyclic amine moieties (for example, as in pyrrolidine), cyclic amides (such as a pyrrolidinone, piperidone or caprolactam), cyclic sulfonamides (such as a 1,1-dioxide isothiazolidine, [l, 2] thiazinane 1,1-dioxide or [1,2,2] thiazepane 1,1-dioxide) and combinations thereof. Particular examples of non-aromatic nitrogen-containing heterocyclyl groups include aziridine, morpholine, thiomorpholine, piperidine (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (for example, 1-pyrrolidinyl, 2 -pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole, imidazoline, imidazolidinone, oxazoline, thiazoline, 6H-1, 2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine, piperazine and N-alkyl piperazines such as N- methyl piperazine.
The heterocyclyl groups can be polycyclic fused ring systems or bridged ring systems such as the bicycloalkane oxa and aza analogs, tricycloalkanes (for example, adamantine and oxa-adamantane). For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992.
The heterocyclyl groups can each be unsubstituted or substituted by one or more substituent groups. For example, heterocyclyl groups can be unsubstituted or substituted by 1, 2, 3 or 4 substituents. Where the heterocyclyl group is monocyclic or bicyclic, they are typically unsubstituted or have 1, 2 or 3 substituents.
The term 'aryl' as used herein refers to aromatic carbocyclyl groups that include phenyl, naphthyl, indenyl and tetrahydronaphthyl groups.
In an embodiment R1 represents hydrogen, C1-6 alkyl, C2-4 alkenyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkylalkyl, C1-6 alkoxy C1-6 alkyl where each C1-6 alkyl can optionally substituted with one or two hydroxyl groups, C1-6 alkyl substituted with - NR4R6, C1-6 alkyl substituted with -C (= O) -NR4R5, -S (= O) 2-C1.6 alkyl, - S ( = O) 2-halo C1-6 alkyl, -S (= O) 2-NR14R15, C1-6 alkyl substituted with - S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-halo] kyl C1-6, C1-6 alkyl substituted with -S (= O) 2-NRI4R15, C1-6 alkyl substituted with -NH-S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -NH-S (= O ) 2-halo C1-6 alkyl, C1-6 alkyl substituted with -NRI2-S (= O) 2-NRI4R15 R6, C1-6 alkyl substituted with R6, C1-6 alkyl substituted with -C (= O) -R6, hydroxyalkyl Ci 6 substituted with R6, C1-6 alkyl substituted with -Si (CH3) 3, C1-6 alkyl substituted with -P (= O) (OH) 2 or C1-6 alkyl substituted with -P (= O) (Oalkyl Ci-óh-
In an embodiment R1 represents hydrogen, C1-6 alkyl, C2-4 alkenyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl where each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, C1-6 alkyl substituted with -NR4R5, C1-6 alkyl substituted with -C (= O) -NR4R5, -S (= O) 2-C1-6 alkyl, -S (= O) 2-NRI4R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -NH- S (= O) 2-C1-6 alkyl, R6, C1-6 alkyl substituted with R6, C1 alkyl -6 substituted with -C (= O) -R6, hydroxyalkyl C1-6 substituted with R6, or C1-6 alkyl substituted with -Si (CH3) 3.
In an embodiment R1 represents hydrogen.
In one embodiment R1 represents C1-6 alkyl. R1 can represent -CH3, -CD3, -CH2CH3, - CH2CH2CH3, -CH2CH (CH3) 2, - CH (CH3) 2, -CH2CH (CH3) 2. In one embodiment R1 represents -CH3. In another embodiment R1 represents -CD3.
In one embodiment R1 represents C2-4 alkenyl. R1 can represent -CH2-CH = CH2.
In one embodiment R1 represents C1-6 hydroxyalkyl. R1 can represent -CH2CH2OH, - CH2C (CH3) 2OH or CH2CHOHCH2OH.
In one embodiment R1 represents C1-6 haloalkyl. R1 can represent -CH2CH2F, CH2CH2CH2C1 or CH2CH2Br.
In an embodiment R1 represents C1-6 alkoxy C1-6 alkyl wherein each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups. R1 can represent - CH2CH2OCH3.
In one embodiment R1 represents -NR4R5-substituted C1-6 alkyl.
In an embodiment when R1 represents C1-6 alkyl substituted with -NR4R5, R4 and R5 each represents hydrogen. R1 can represent -CH2CH2NH2 or -CH2CH2CH2NH2.
In another embodiment when R1 represents C-6 alkyl substituted with -NR4R5, one of R4 and R5 represents hydrogen and the other represents C1-6 alkyl, for example -CH3. R1 can represent - CH2CH2NHCH3.
In another embodiment when R1 represents C1-6 alkyl substituted with -NR4R5, one of R4 and R5 represents hydrogen and the other represents -S (= O) 2-NRI4R15 where R14 and R15 each optionally represent C1-4 alkyl substituted with hydroxyl, for example -CH3. R1 can represent -CH2CH2NHS (= O) 2N (CH3) 2.
In another embodiment when R1 represents C1-6 alkyl substituted with -NR4R5, one of R4 and R5 represents hydrogen and the other represents -S (= O) 2-C1-6 alkyl. R1 can represent -CH2CH2NH- S (= O) 2CH3.
In one embodiment R1 represents C1-6 alkyl substituted with -C (= O) -NR4R5.
In one embodiment when R1 represents C1-6 alkyl substituted with -C (= O) -NR4R5, R4 and R5 each represents C1.6 alkyl, for example -CH3. R1 can represent -CH2C (= O) N (CH3) 2.
In another embodiment when R1 represents C1-6 alkyl substituted with -C (= O) -NR4R5, one of R4 and R5 represents hydrogen and the other represents C1-6 alkyl, for example -CH3. R1 can represent -CH2C (= O) NHCH3 or -C (CH3) 2C (= O) NHCH3.
In another embodiment when R1 represents C-6 alkyl substituted with -C (= O) -NR4R5, one of R4 and R5 represents hydrogen and the other represents C1-6 hydroxyalkyl, for example -CH2CH2OH. R1 can represent -C (CH3) 2C (= O) NHCH2CH2OH or CH2C (= O) NHCH2CH2OH.
In another embodiment when R1 represents C1-6 alkyl substituted with -C (= O) -NR4R5, one of R4 and R5 represents hydrogen and 0 the other represents C1-6 alkoxy C1-6 alkyl where each C1-6 alkyl can optionally be substituted with one or two hydroxyl groups, for example -CH2CH2OCH3. R1 can represent -CH <'(= ()) NHCH2 CH2OCH3 or -C (CH3) 2C (= O) NH-CH2CH2OCH3.
In another embodiment when R1 represents C1 alkyl substituted with -C (= O) -NR4R5, one of R4 and R5 represents hydrogen and the other represents C1-6 alkyl substituted with R13. R13 can represent a 5-membered saturated monocyclic heterocyclyl that contains at least one nitrogen heteroatom, for example pyrrolidine. R1 can represent -CH2-C (= O) - NH-CH2-CH2- (pyrrolidin-1-yl).
In another embodiment when R1 represents C1-6 alkyl substituted with -C (= O) -NR4R5, one of R4 and R5 represents hydrogen and 0 the other represents C1-6 alkyl substituted with -S (= O) 2-alkyl Ci-6. R1 can represent -CH2CH2CH2NHCH2CH2-S (= O) 2-CH3.
In one embodiment R1 represents -S (= O) 2-C1-6 alkyl. R1 can represent -S (= O) 2-CH3.
In one embodiment R1 represents -S (= O) 2-NRI4R15. R14 and R15 each may represent C1-4 alkyl optionally substituted with hydroxyl, for example R14 and R15 both may represent CH3. R1 can represent -S (= O) 2-N (CH3) 2.
In one embodiment R1 represents C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl. R1 can represent -CH2CH2 S (= O) 2- CH3.
In one embodiment R1 represents C1-6 alkyl substituted with -NH-S (= O) 2-C1-6 alkyl. R1 can represent -CH2CH2 NHS (= O) 2-CH3.
In an embodiment R1 represents R6. R6 can represent a 4, 5 or 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, which can be optionally substituted.
In one embodiment when R1 represents R6, R6 represents piperidinyl, for example 4-piperidinyl.
In one embodiment when R1 represents R6, R6 represents tetrahydropyranyl, for example 2-tetrahydropyranyl.
In another embodiment when R1 represents R6, R6 represents azetidinyl substituted by a C1-6 hydroxyalkyl group. The C1-6 hydroxyalkyl group can be -CH2CH2OH. R6 can represent

In another embodiment when R1 represents R6, R6 represents piperidinyl substituted by a C1-6 alkyl group (= O) -. The C1-6-O-C (= O) - alkyl group can be (CH3) 3C-O-C (= O) -. R6 can represent 4-piperidinyl substituted on the nitrogen atom with (CH3) 3C-O-C (= O) -. In another embodiment when R1 represents R6, R6 represents piperidinyl substituted by a group -S (= O) 2-C1-6 alkyl. The group -S (= O) 2-C1-6 alkyl can be -S (= O) 2CH3. R6 can represent 4-piperidinyl substituted on the nitrogen atom with -S (= O) 2CH3.
In one embodiment R1 represents R6-substituted C1-6 alkyl. R6 can represent a 4, 5 or 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, which can be optionally substituted. R6 can represent pyrrolidinyl, thiophenyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl. R1 can represent methyl or ethyl each substituted with 4-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl or 4-tetrahydropyranyl. R1 can represent propyl substituted with morpholinyl where the morpholinyl is linked to propyl through Heteroatom N. In another embodiment the heterocyclyl can be replaced by a substituent selected from halogen, C1-6 alkyl, hydroxyl, C1-6 hydroxyalkyl, alkoxy C1-6, C1-6 OC alkyl (= 0) -. The substituent can be -Cl, -CH3, -OH, -CH2CH2OH, - CH2CH2CH2OH, -OCH3, (CH3) 3C-OC (= O) -. R1 can represent methyl, ethyl or propyl each substituted with 4-piperidinyl substituted on the nitrogen atom with (CH3) 3C-OC (= OJ-, 4-piperidinyl substituted on the nitrogen atom with - CH3, 4-piperazinyl substituted on the atom nitrogen with (CHs ^ CO- C (= OJ-, 4-piperazinyl substituted on the nitrogen atom with -CH2CH2OH, 4-piperazinyl substituted on the nitrogen atom with -CH2CH2CH2OH, 1- piperidinyl substituted in position 1 by -OH, or 1 -piperidinyl substituted in position 1 by -O-CH3 In another embodiment the heterocyclyl can be substituted by two substituents selected from hydroxyl, C1-6 alkoxy, C1-6-OC-alkyl (= O) -. can be -OH, -OCH3, (CHs ^ CO- C (= O) -. R1 can represent methyl substituted with 4-piperidinyl substituted on the nitrogen atom with (CH3) 3C-OC (= Oj- and in position 4 by -Oh.
In one embodiment R1 represents C1-6 alkyl substituted with -C (= O) -R6. R6 can represent a 4, 5 or 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, which can be optionally substituted. R6 can represent piperazinyl or pyrrolidinyl.
In an embodiment when R1 represents C1-6 alkyl substituted with -C (= O) -R6, R6 represents piperazinyl. R1 can represent - C (CH3) 2-C (= O) - (piperazin-4-yl).
In another embodiment when R1 represents C-6 alkyl substituted with -C (= O) -R6. R6 represents piperazinyl substituted by a C1-6-O-C (= O) - alkyl group, for example (CH3) 3C-O-C (= O) -. R1 can represent -C (CH3) 2-C (= O) - (piperazin-4-yl) substituted on the nitrogen atom in position 1 by (CH3) 3C-O-C (= O) -.
In another embodiment when R1 represents C-6 alkyl substituted with -C (= O) -R6, R6 represents pyrrolidinyl substituted by a hydroxyl group. R1 can represent -CH2- C (= O) - (pyrroleidin-1-yl) substituted in position 3 by -OH.
In one embodiment R1 represents C1-6 hydroxyalkyl substituted with R6, R6 can represent a 4-, 5- or 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, which can be optionally substituted. R6 can represent piperidinyl, for example 1-piperidinyl. R1 can represent - CH2CHOHCH2-piperidin-1-yl.
In an embodiment R1 represents C1-6 alkyl substituted with -Si (CH3) 3. R1 can represent -Q-ESiCCHsV
In one embodiment each Rla represents hydrogen.
In one embodiment each R2 is independently selected from halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1.4 hydroxyalkoxy, C1-4 haloalkoxy, C1-4 alkoxy C1-4, R13, C1-4 alkoxy substituted with R13, -C (= O) -R13, C1-4 alkyl substituted with NR7R8, C1-4 alkoxy substituted with NR7R8, -NR7R8 or -C (= O) -NR7R8 .
In one embodiment one or more R2 represents halogen, for example fluorine, chlorine or bromine.
In one embodiment one or more R2 represents cyan.
In one embodiment one or more R2 represents CM alkyl, for example -CH3.
In one embodiment one or more R2 represents C2-4 alkenyl, for example -CH = CH2.
In one embodiment one or more R2 represents CM alkoxy, for example CH3O-, (CINCHO-, CH3CH2O-, CD3O-.
In one embodiment one or more R2 represents C1-4 hydroxyalkyl, for example -CH2OH.
In one embodiment one or more R2 represents CM hydroxyalkoxy, for example - OCH2CH2OH.
In one embodiment one or more R2 represents CM haloalkoxy, for example -OCH2CH2F or -O-CHF2.
In one embodiment one or more R2 represents CM alkoxy CM, for example - CH2CH2OCH3.
In one embodiment one or more R2 represents R13. R13 may represent a saturated 5-membered monocyclic heterocyclyl containing two oxygen heteroatoms, for example dioxolanyl, particularly 2-dioxolanyl.
In one embodiment one or more R2 represents CM alkoxy substituted with R13. R13 can represent C3-8 cycloalkyl, for example cyclopropyl. One or more R2 can represent - OCH2C3H5.
In one embodiment one or more R2 represents - C (= O) -R13. R13 can represent a 5-membered saturated monocyclic heterocyclyl that contains a nitrogen heteroatom, for example pyrrolidinyl. R2 can represent -C (= O) - (1-pyrrolidinyl).
In one embodiment one or more R2 represents CM alkyl substituted with -NR7R8. In an embodiment R7 and R8 each represents hydrogen. One or more R2 can represent - CH2NH2. In another embodiment R7 and R8 each can independently represent CM alkyl, for example -CH2CH3 or -CH3. One or more R2 can represent -CH2N (CH2CH3) 2, - CH2N (CH3) 2 or CH2N (CH2CH3) (CH3).
In one embodiment one or more R2 represents -NR7R8-substituted C1-4 alkoxy. In one embodiment one of R7 and R8 represents hydrogen and the other represents C1-6 alkyl, for example -CH3. One or more R2 can represent -OCH2CH2NHCI-U In an embodiment R7 and R8 each represents hydrogen. One or more R2 can represent - OCH2CH2NH2.
In one embodiment one or more R2 represents - NR7R8. In one embodiment one of R7 and R8 represents hydrogen and the other represents C1-6 alkyl, for example -CH3.
In one embodiment one or more R2 represents - C (= O) -NR7R8. In one embodiment one of R7 and R8 represents hydrogen and the other represents C1-6 alkyl, for example -CH3.
In one embodiment n is 0, 1 or 2. In one embodiment n is equal to 0.
In one embodiment n is equal to 1. R2 can be in position 3. R2 can represent (i) C1.4 haloalkoxy, for example -O-CHF2; (ii) C1-4 alkoxy, for example CH3O- or (CHOCHO-; (iii) cyano; or (iv) -NR7R8, for example -NHCH3.
In one embodiment n is equal to 2. One R2 can be in position 3 and the other can be in position 5: (i) each R2 can represent C1-4 alkoxy, for example each R2 can be CH3O-, or the R2 in position 3 can be (CHOCHO- and R2 in position 5 can be CH3O-, or R2 in position 3 can be CH3O- and R2 in position 5 can be CD3O-; (ii) R2 in position 3 can represent halogen, for example fluorine, chlorine or bromine and R2 in position 5 can represent C1-4 alkoxy, for example CH3O-, CD3O- or CH3CH2O-; (iii) R2 in position 3 can represent C1.4 alkyl, for example example -CH3 and R2 in position 5 can represent C1-4 alkoxy, for example CH3O-, (iv) R2 in position 3 can represent cyano and 0 R2 in position 5 can represent C1-4 alkoxy, for example CH3O-; (v) R2 in position 3 can represent C1-4 alkyl substituted with NR7R8, for example - CH2NH2 or -CH2N (CH3) 2 or -CH2N (CH2CH3) 2 or -CH2N (CH2CH3) (CH3) and R2 in position 5 can represent C1-4 alkoxy, for example CH3O-; (vi) R2 in the position 3 can represent C1-4 alkoxy, for example CH3O- and R2 in position 5 can represent -C (= O) -NR7R8, for example -C (= O) NHCH3 or -C (= O) NH2; (vii) R2 in position 3 can represent C1-4 hydroxyalkoxy, for example - OCH2CH2OH and 0 R2 in position 5 can represent C1-4 alkoxy, for example CH3O- (viii) R2 in position 3 can represent -C (= O) -R13, for example -C (= O) - (pyrrolidin-1-yl) and R2 at position 5 can represent C1-4 alkoxy, for example CH3O-; (ix) R2 at position 3 can represent C1-4 alkoxy substituted with R13, for example - OCthCsHs and R2 at position 5 can represent C1-4 alkoxy, for example CH3O-; (x) R2 at position 3 can represent C1-4 alkoxy, for example CH3O- and R2 at position 5 can represent C1-4 alkoxy substituted with NR7R8, for example - OCH2CH2NHCH3 or - OCH2CH2NH2; (xi) R2 at position 3 can represent C1-4 alkoxy, for example CH3O- and R2 at position 5 can represent C2-4 alkenyl, for example -CH = CH2; (xii) R2 in position 3 can represent CM alkoxy, for example CH3O- and 0 R2 in position 5 can represent CM alkoxy, for example -CH2CH2OCH3; (xiii) R2 at position 3 can represent R13, for example 2-dioxolanyl and R2 at position 5 can represent CM alkoxy, for example CH3O-; (xiv) R2 in position 3 can represent hydroxyalkoxy CM, for example - OCH2CH2OH and R2 in position 5 can represent halogen, for example fluorine; (xv) R2 in position 3 can represent CM haloalkoxy, for example -OCH2CH2F and R2 in position 5 can represent CM alkoxy, for example CH3O-; (xvi) R2 at position 3 can represent halogen, for example fluorine and R2 at position 5 can represent -C (= O) -NR7R8, for example -C (= O) NHCH3; (xvii) R2 in position 3 can represent CM alkoxy, for example CH3O- and R2 in position 5 can represent halogen, for example fluorine; or (xviii) R2 at position 3 can represent CM hydroxyalkyl, for example - CH2OH and R2 at position 5 can represent CM alkoxy, for example CH3O-.
In one embodiment n is equal to 2. One R2 can be in position 3 and the other can be in position 5. Each R2 can represent CM alkoxy, for example each R2 can be CH3O-, (CHshCHO-, CH3CH2O-, CD3O- In one embodiment both R2 are for example CH3O-, or CD3O- In one embodiment both R2 are CH3O-.
In one embodiment n is equal to 2. One R2 can be in position 4 and the other can be in position 5. Each R2 can represent CM alkoxy, for example each R2 can be CH3O-.
In one embodiment n is equal to 2. One R2 may be at position 5 and the other may be at position 6. Each R2 may represent C1-4 alkoxy, for example each R2 may be CH3O-.
In one embodiment n is equal to 2. One R2 can be in position 2 and the other can be in position 5: (i) each R2 can represent C1-4 alkoxy, for example each R2 can be CH3O-; or (ii) R2 at position 2 can be halogen, for example chlorine and R2 at position 5 can represent C1-4 alkoxy, for example CH3O-.
In one embodiment n is equal to 3. An R2 can be in position 2, one can be in position 3 and one can be in position 5: (i) the R2 in position 2 can represent halogen, for example chlorine, R2 in position 3 and position 5 can each represent C1-4 alkoxy, for example each of these R2 can be CH3O-; or (ii) R2 in position 2 can represent C1-4 alkyl, for example -CH3, R2 in position 3 and in position 5 each can represent C1-4 alkoxy, for example each of these R2 can be CH3O-. R3a may represent -NR10Rn 'hydroxyl, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylalkyl, C1.6 haloalkyl, C1-6 alkyl substituted with -C (= O) -C1-6alkyl, C1-6 alkoxy C1-6 alkyl where each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, C1-6 alkyl substituted with R9, C1-6 alkyl substituted with - NR10Rn, C1-6 alkyl substituted with hydroxyl and -N10Rnalkyl C1 -6 substituted with one or two halogens and -NR10Rn, C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl, Ci-θ alkyl substituted with -OC (= O) -NR10R ', C1 alkyl -6 substituted with carboxyl, C1-6 alkyl substituted with -OC (= O) - NR10Rn, C1-6 alkyl substituted with -NRl2-S (= O) 2-alkyl C1-6, C1-6 alkyl substituted with -NRI2-S (= O) 2-NRI4R15 C1-6alkyl substituted with hydroxyl and R9, -Calkyl | 6-C (RI2) = NO-R12, C1-6 alkyl substituted with -C (= O) - NR10Rn, C1-6 alkyl substituted with -C (= O) -R9, C2-6 alkynyl substituted with R9, hydroxyalkoxy C1-6, C2-6 alkenyl, C2-6 alkynyl, R13 or C1-6 alkyl substituted with C1-6 alkoxy C1-6-C-alkyl (= O) -.
In an embodiment R3a is -NR10Rn, hydroxyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl substituted with -C (= O) - C1-6 alkyl, C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl, C1-6 alkyl substituted with R9, C1-6 alkyl substituted with -NR10Rn, C1-6 alkyl substituted with hydroxyl and -NR10Rn, C1-6 alkyl substituted with -C (= O) - NR10Rn.
In one embodiment R3a represents -NR10Rn. In one embodiment one of R10 and R11 represents hydrogen and the other represents C1-4 alkyl substituted with -NR14R15. One of R14 and R15 can represent hydrogen and the other can represent C1-4 alkyl. R3a can represent -NHCH2CH2NHCH (CH3) 2.
In an embodiment R10 and R11 each independently represents hydrogen, C1-6 alkyl, C1-6 alkyl substituted with -NR14R15OU C1-6 haloalkyl.
In an embodiment R3a represents hydroxyl.
In one embodiment R3a represents C1-6 alkyl. R3a can represent -CH3, -CH2CH3, - CH2CH2CH3 or -CH2CH (CH3) 2.
In one embodiment R3a represents C1-6 hydroxyalkyl. R3a can represent -CH2CH2OH, - CH2CH2CH2OH, -CH2CHOHCH3, - CH2CHOHCH2CH3, -CH2CHOHCH (CH3) 2, - CH2CH2C (OH) (CH3) 2, - CH2CHOHCH2OH or -CH2C (CH3) 2θH. In one embodiment R3a represents -CH2CH2OH.
In one embodiment R3a represents C1-6 haloalkyl. R3a can represent -CH2CH2CH2CI or - CH2CH2CH2CH2CI.
In one embodiment R3a represents C1-6 hydroxyalkylalkyl, for example R3a can represent -CH2CHOHCF3.
In an embodiment R3a represents C-6 alkyl substituted with -C (= O) -C1-6 alkyl, for example R3a can represent CH3- C (= O) -CH2-, (CH3) 2CH-C (= O ) -CH2- In one embodiment R3a represents CH, -C (= O) -CH2-.
In an embodiment R3a represents C1-6 alkoxy C1-6 alkyl wherein each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups. R3a can represent - CH2CH2OCH3, - CH2CH2OCH2CH3 OR -CH2CHOHCH2OCH3.
In an embodiment R3a represents C1-6 alkyl substituted with R9.
In one embodiment when R3a represents R6-substituted Cu 6 alkyl, R9 represents optionally substituted C3-8 cycloalkyl, for example cyclopropyl or cyclopentyl. R3a can represent - CH2-C3H5 or -CH2C5H9.
In an embodiment where the C3-8 cycloalkyl is cyclopropyl it is replaced by a C1-4 hydroxyalkyl, for example - CH2OH.
In another embodiment where C3-8 cycloalkyl is cyclopropyl it is replaced by a C1-6-O-C (= O) - alkyl, for example CH2CH2-O-C (= O) -
In an embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents an optionally substituted aromatic monocyclic 5-membered heterocyclyl containing a nitrogen and an oxygen heteroatom, for example isoxazolyl. In one embodiment the heterocyclyl is substituted with one or two C1-4 alkyl groups, for example -CH3 groups. R3a can represent methyl substituted with 5-isoxazoyl substituted in position 3 with -CH3 or methyl substituted with 3-isoxazoyl substituted in position 5 with -CH3.
In one embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents an optionally substituted 6-membered saturated monocyclic heterocyclyl containing a nitrogen and an oxygen heteroatom, for example morpholinyl. R3 can represent ethyl or propyl substituted by 4-morpholinyl.
In one embodiment the heterocyclyl is substituted with one or two CM alkyl groups, for example -CH3 groups. R3a can represent ethyl or propyl substituted by 4-morpholinyl substituted in positions 2 and 6 by -CH3.
In another embodiment the heterocyclyl is substituted with phenylalkyl CM, where the phenyl is optionally substituted with R16, for example -CH2-C6H5. R3 may represent methyl substituted by 2-morpholinyl substituted in position 4 by -CH2-C6H5.
In one embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a saturated monocyclic heterocyclyl or a 3, 4, 5 or 6-membered aromatic containing one or two oxygen heteroatoms, for example ethylene oxide, ethylene, tetrahydrofuranyl, dioxolanil, tetrahydropyranyl or furanyl. R3a can be methyl substituted with 2-tetrahydrofuranyl, 2-dioxolane, ethylene oxide, 2-furanyl or 4-tetrahydropyranyl,
In one embodiment when R3a represents C9 alkyl substituted by R9, R9 represents a monocyclic saturated heterocyclyl or a 3, 4, 5 or 6 membered aromatic containing one or two oxygen heteroatoms, for example oxiranyl (ethylene oxide, epoxide). Heterocyclyl can be substituted by alkyl CM-R3a can be

In one embodiment when R3a represents R9-substituted C1-6 alkyl, R9 represents an optionally substituted 4-membered heterocyclyl that contains an oxygen heteroatoms, for example oxetanyl and the heterocyclyl can be substituted with a C1-4 alkyl group, for example -CH3. R3a can be methyl substituted with 3-oxetanil substituted in position 3 by -CH3.
In an embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents an optionally substituted 6-membered aromatic monocyclic heterocycle containing one or two nitrogen atoms, for example pyridinyl or pyrazinyl. R3a can represent methyl substituted with 3-pyridinyl or 2-pyrazinyl.
In one embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents an optionally substituted 6-membered aromatic monocyclic heterocyclyl containing a nitrogen heteroatom, for example pyridinyl, substituted with a halogen, for example chlorine or bromine. R3a can represent methyl substituted with 3-pyridinyl substituted in position 6 with chlorine or 2-pyridinyl substituted in position 6 with bromine.
In an embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents an optionally substituted 6-membered saturated monocyclic heterocyclyl containing two nitrogen atoms, for example piperazinyl substituted with R13, for example said R13 represents piperidinyl being replaced with an alkyl CM-C (= O) -, for example -C (= O) -CH3. R3a can represent ethyl substituted with 1-piperazinyl substituted in position 4 with 4-piperidinyl substituted in position 1 with -C (= O) -CH3.
In one embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a partially saturated 6-membered monocyclic heterocyclyl containing a nitrogen hetero atom that can be optionally substituted. R3a can represent ethyl or propyl substituted with 1,2,3,6-tetrahydropyridine.
In another embodiment when R3a represents R9-substituted C1-6 alkyl, R9 represents an optionally substituted 4-membered saturated monocyclic heterocyclyl containing a nitrogen heteroatom, for example azetidinyl. The heterocyclyl can be replaced, for example, with one or two halogens, for example fluorine. R3a can represent propyl substituted with 1-azetidinyl substituted in position 3 by two fluorine atoms. The heterocyclyl can also be replaced with a hydroxyl group. R3a can represent propyl substituted by 1-azetidinyl substituted in position 3 by an -OH.
In another embodiment when R3a represents CM alkyl substituted by R9, R9 represents a saturated 5-membered monocyclic heterocyclyl that contains a nitrogen heteroatom, for example pyrrolidinyl. R3a can represent ethyl or propyl substituted with 1-pyrrolidinyl or 2-pyrrolidinyl. The heterocyclyl can be replaced. For example, heterocyclyl is replaced with: a) one or two halogens, for example fluorine. R3a can represent propyl substituted with 1-pyrrolidinyl substituted in position 3 with one or two fluorine atoms; b) a CM haloalkyl, for example -CH2 Cl. R3a can represent propyl substituted with 1-pyrrolidinyl substituted in position 2 with -CH2CI; c) a hydroxyl group. R3a can represent ethyl or propyl substituted with 1-pyrrolidinyl substituted in position 3 with -OH; d) a group = 0. R3a can represent ethyl or propyl substituted with 1-pyrrolidinyl substituted in position 2 with = 0; e) a -S (= O) 2-CM alkyl group and the CM alkyl may be -CH3. R3a can represent propyl substituted with 1-pyrrolidinyl substituted in position 3 with -S (= O) 2-CHa; f) a -NR14R15 group. In an embodiment R14 and R15 each represents hydrogen. R3 can represent ethyl or propyl substituted with 1-pyrrolidinyl substituted in position 3 with -NH2. In another embodiment R14 and R15 each independently represents C1-4 alkyl optionally substituted with hydroxyl, for example -CH3. R3 can represent ethyl substituted with 1-pyrrolidinyl substituted in position 3 with -N (CH3) 2. In another embodiment one of R14 and R15 is hydrogen and the other is C1-4 alkyl optionally substituted with hydroxyl, for example -CH3. R3 can represent propyl substituted with 1-pyrrolidinyl substituted in position 3 with -NHCH3; g) one or two C1-4 alkyl groups, for example -CH3 or - CH (CH3) 2. R3a can represent ethyl or propyl substituted with 1-pyrrolidinyl substituted in position 2 with -CH3, 1-pyrrolidinyl substituted in position 2 and in 5 with -CH3 or 1-pyrrolidinyl substituted in position 2 with two -CH3; h) a carboxyl group. R3a can represent ethyl substituted with 1-pyrrolidinyl substituted in position 2 with -C (= O) OH; i) a C1.4 hydroxyalkyl, for example -CH2OH, -C (CH3) 2OH or -CH2CH2OH. R3a can represent ethyl or propyl substituted with 1-pyrrolidinyl substituted in position 2 with -CH2OH; j) R13. In one embodiment R13 represents a 6-membered saturated monocyclic heterocyclyl that contains a nitrogen heteroatom. In another embodiment R13 represents a 6-membered saturated monocyclic heterocyclyl that contains a nitrogen and an oxygen hetero atom. In another embodiment R13 represents a 6-membered saturated monocyclic heterocyclyl that contains a nitrogen and an oxygen heteroatom and the heterocyclyl is substituted, for example substituted with two C1-6 alkyl groups, for example two -CH3 groups. R3a can represent propyl substituted with 1-pyrrolidinyl substituted in position 3 with 1-piperidinyl, or propyl substituted with 1-pyrrolidinyl substituted in position 3 with 4-morpholinyl substituted in positions 2 and 6 with positions -CH3; k) a cyan group. R3a can represent ethyl or propyl substituted with 1-pyrrolidinyl substituted in position 3 with -CN; l) a C1-4 cyano-alkyl, for example -CH2CN. R3 can represent propyl substituted with 1-pyrrolidinyl substituted in position 2 with -CH2CN; m) a C1-4 alkyl substituted with -NH-S (= O) 2-C1-4 haloalkyl for example -CH2NH-S (= O) 2-CF3. R3a can represent propyl substituted with 1-pyrrolidinyl substituted in position 2 with -CH2NH-S (= O) 2-CF3; or n) a C1-6-OC (= O) - alkyl, for example (CHg ^ COC (= O) - or CH3-OC (= O) -. R3a can represent methyl or ethyl substituted by 2-pyrrolidinyl substituted in position 1 by (CFF) 3C-OC (= O) - or replaced by 1-pyrrolidinyl substituted in position 2 by CH3-OC (= O) -.
In another embodiment when R3a represents R9-substituted ethyl, R9 represents a 5-membered saturated monocyclic heterocyclyl that contains a nitrogen heteroatom, for example 1- pyrrolidinyl and pyrrolidinyl is substituted with a group = 0 in position 2.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a 6-membered saturated monocyclic heterocyclyl that contains a nitrogen heteroatom, for example piperidinyl. R3a can represent methyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl. The heterocyclyl can be replaced. For example, heterocyclyl is replaced with: a) one or two halogens, for example fluorine. R3a can represent ethyl substituted with 1-piperidinyl substituted in position 4 with two fluorine atoms; b) a hydroxyl group. R3a can represent methyl or ethyl substituted with 1-piperidinyl substituted in position 4 with an -OH or 4-piperidinyl substituted in position 4 with an -OH; c) a -NR14R15 group. In one embodiment R14 and R15 each represents hydrogen. R3a can represent ethyl substituted with 1-piperidinyl substituted in the 3 position or in the 4 position with -NH2. In another embodiment R14 and R15 each independently represents C1-4 alkyl optionally substituted with hydroxyl, for example -CH3. R3a can represent ethyl substituted with 1-piperidinyl substituted in position 4 with -N (CH3) 2; d) one or two C1-4 alkyl groups, for example -CH3 or - CH (CH3) 2. R3a can represent methyl, ethyl or propyl substituted with 1-piperidinyl substituted in position 2 with -CH3, 1-piperidinyl substituted in position 2 and in 6 with -CH3, 4-piperidinyl substituted in position 1 with - CH (CH3) 2, 4-piperidinyl substituted in position 1 with -CH3, 1-piperidinyl substituted in position and 3 in 5 with -CH3; e) a C1-4 hydroxyalkyl, for example -CH2OH, -C (CH3) 2OH or -CH2CH2OH. R3a can represent ethyl substituted with 1-piperidinyl substituted in position 4 with -C (CH3) 2OH, 1-piperidinyl substituted in position 4 with -CH2CH2OH; 1-piperidinyl substituted in position 4 with - CH2OH; f) a cyan group. R3a can represent ethyl or propyl substituted with 1-piperidinyl substituted in position 3 with -CN; g) a C 1 -C 6 alkyl (= O) -, for example CH 3 CH 2-O-C (= O) -, (CH 3) 3 C-O-C (= O) - OR CH, -O-C (= O) -. R3a can represent methyl or ethyl substituted with 1-piperidinyl substituted in position 4 with CH3CH2-O-C (= OJ-, 4-piperidinyl substituted in position 1 with (CH,), COC (= O) -; h) an alkyl Ci.6-OC (= O) -, for example (CH,) 3C-OC (= O) - and a hydroxyl group. R3a can represent methyl substituted with 4-piperidinyl substituted in position 4 with -OH and in position 1 with (CH3) 3C-O-C (= O) -; i) a C alkyl | 6-O-C (= O) -, for example (CH3) 3C-O-C (= O) - and a C1-4 alkoxy group, for example -OCH3. R3a can represent methyl substituted with 4-piperidinyl substituted in position 4 with -OCH3 and in position 1 with (CH3) sC-O-C (= O) -; j) a C1-4 alkoxy group, for example -OCH3. R3a can represent methyl or ethyl substituted with 1-piperidinyl substituted in position 4 with -OCH3 or 4-piperidinyl substituted in position 4 with -OCH3; k) a C1-4 haloalkyl group, for example -CF3. R3a can represent propyl substituted with 1-piperidinyl substituted in position 4 with -CF3; or l) a -C (= O) -NR14R15 where R14 and R15 both represent hydrogen. R3a may represent ethyl substituted with 1-piperidinyl substituted in position 3 with -C (= O) -NH2.
In another embodiment when R3a represents C1-6 alkyl substituted by R9, R9 represents a bicyclic heterocyclyl containing a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms. In one embodiment, the bicyclic heterocyclyl contains a benzene ring fused to a 5-membered ring that contains 1 heteroatom in the ring. In one embodiment the ring heteroatom is a nitrogen heteroatom. In one embodiment the bicyclic heterocyclyl is substituted with two groups = 0 in the 5-membered ring that contains a ring heteroatom. R3a can represent ethyl, propyl or butyl substituted with isoindolyl-1,3, -dione or two (for example, isoindol-2-yl-1,3-dione or two, also known as phthalamidyl).
In one embodiment when R3a represents C1-6 alkyl (for example ethyl or propyl) substituted with R9, R9 represents an optionally substituted monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S. In one embodiment R9 represents a 4-, 5- or 6-membered saturated monocyclic heterocycle substituted with two substituents which are attached to the same atom and which are taken together to form a 4- to 7-membered saturated monocyclic heterocycly containing at least one heteroatom selected from N, O or S ; For example R3a can represent ethyl substituted with 2-oxa-6-aza-spiro [3.3] heptane or R3a can represent ethyl substituted with 1-piperidyl substituted in position 4 by 1,4-dioxolane for example, to form 1, 4-dioxa-8-azospiro [4,5] decane.
In another embodiment when R3a represents R9-substituted C1-6 alkyl, R9 represents an optionally substituted aromatic monocyclic 5-membered heterocyclyl containing a sulfur heteroatom, for example thiophenyl. R3a may represent methyl substituted with 2-thiophenyl. In one embodiment, the 5-membered aromatic monocyclic heterocyclyl containing a sulfur heteroatom is replaced with a chlorine. R3a can represent methyl substituted with 2-thiophenyl substituted in position 5 with chlorine.
In another embodiment when R3a represents R9-substituted C1-6 alkyl, R9 represents an optionally substituted aromatic monocyclic 5-membered heterocyclyl containing a sulfur and a nitrogen hetero atom, for example thiazolyl. The 5-membered heterocyclyl can be substituted with, for example, a C1-4 alkyl, for example -CH3. R3a can represent methyl substituted with 4-thiazolyl substituted in position 2 with -CH3.
In another embodiment when R3a represents C1-6 alkyl substituted by R9, R9 represents a 6-membered saturated monocyclic heterocyclyl containing two nitrogen atoms, for example piperazinyl. R3a can represent ethyl or propyl substituted with 1-piperazinyl. The heterocyclyl can be replaced. For example the heterocyclyl is substituted with a) a CM-C (= O) - alkyl, for example CH3-C (= O) -. R3a can represent ethyl substituted with 1-piperazinyl substituted in position 4 with CH3-C (= O) -; b) a C1-4 hydroxyalkyl, for example -CH2CH2OH. R3a can represent ethyl substituted with 1-piperazinyl substituted in position 4 with - CH2CH2OH; c) C1-4 alkyl, for example -CH3. R3a can represent ethyl or propyl substituted with 1-piperazinyl substituted in positions 3 and 5 with -CH3 or 1-piperazinyl substituted in position 4 with -CH3; d) one = 0. R3a can represent ethyl substituted with 1-piperazinyl substituted in position 3 with = 0; or e) a -C (= O) -R13. R13 can be C3-8 cycloalkyl, for example cyclopropyl. R3a can represent ethyl substituted with 1-piperazinyl substituted in position 4 with -C (= OJ-C3H5.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a 5-membered aromatic monocyclic heterocyclyl containing four nitrogen atoms, for example tetrazolyl. R3 may represent ethyl substituted with 5-tetrazolyl.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a 5-membered aromatic monocyclic heterocyclyl containing one oxygen and two nitrogen atoms, for example 1, 3, 4-oxadiazolyl. The heterocyclyl can be replaced. For example, heterocyclyl can be substituted with a group - NR14R15, where each of R14 and R15 is hydrogen. Alternatively one of R14 and R15 can be hydrogen and the other can represent C1-4 alkyl optionally substituted with hydroxyl, for example -CH2CH2OH. R3a can represent methyl substituted with 2- (1,3,4-oxadiazolyl) substituted in position 5 with -NH2 or 2- (1,3,4-oxadiazolyl) substituted in position 5 with - NH-CH2CH2OH.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents an optionally substituted aromatic monocyclic 5-membered heterocyclyl containing two nitrogen atoms, for example pyrazolyl or imidazolyl. R3a can represent methyl, ethyl or propyl substituted with 1-pyrazyl or 2-imidazoyl. The heterocyclyl can be replaced. For example, heterocyclyl can be substituted with C1-4 alkyl, for example -CH3 or -CH2CH3. R3a can represent methyl, ethyl or propyl substituted with 1-imidazolyl substituted in position 2 with -CH3, 3-pyrazolyl substituted in positions 1 and 5 with -CH3, 1-imidazolyl substituted in positions 2 and 5 with -CH3, 1-imidazolyl substituted in positions 2 and 4 with -CH3, 2-imidazolyl substituted in position 1 with -CH3 or 2-imidazolyl substituted in position 1 with -CH2CH3
In an embodiment when R3a represents Cu 6 alkyl substituted with R9, R9 represents an optionally substituted aromatic monocyclic 5-membered heterocyclyl containing two nitrogen atoms, for example imidazolyl. The heterocyclyl can be replaced. For example, heterocyclyl is substituted with -S (= O) 2-NRI4R15. R14 and R15 can each represent C1-4 alkyl optionally substituted with a substituent selected from hydroxyl, C1-4 alkoxy, amino or mono- or di (Cu 4 alkyl) amino, for example -CH3. R3a can represent methyl substituted with 2-imidazoyl substituted in position 1 with -S (= O) 2-N (CH ,) 2.
In another embodiment when R3a represents R9-substituted C1-6 alkyl, R9 represents an optionally substituted aromatic monocyclic 5-membered heterocyclyl containing three nitrogen atoms, for example triazolyl. R3 may represent methyl substituted with 4- (1,2,3-triazolyl). The heterocyclyl can be replaced. For example the heterocyclyl is substituted with a) one or two hydroxyCi., 4alkyl group, for example - CH2CH2OH. R3a can represent methyl substituted with 4- (1,2,3-triazolyl) substituted in position 1 with -CH2CH2OH or 4 (1,2,3-triazolyl) substituted in position 2 with -CH2OH; b) a C1-4 alkyl substituted by the C1-6-O-C alkyl group (= OJ-, for example -CH2-C (= O) OCH2CH3. R3a can represent methyl substituted with 4- (1,2,3-triazolyl) ) replaced in position 1 with -CH2- C (= O) -OCH2CH3.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a saturated 5-membered monocyclic heterocyclyl that contains a nitrogen and an oxygen heteroatom, for example oxazolidinyl. The heterocyclyl can be substituted, for example substituted with a = 0. R3a can represent ethyl or propyl substituted with 3-oxazolidinyl substituted in position 2 with = 0.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a 6-membered saturated monocyclic heterocyclyl containing a nitrogen and a sulfur heteroatom, for example thiomorpholinyl. The heterocyclyl can be substituted, for example substituted with two groups = 0 in the sulfur heteroatom. R3a can represent propyl substituted with 4-thiomorpholinyl substituted in position 1 by two groups = 0.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents a saturated 7-membered monocyclic heterocyclyl containing two nitrogen atoms, for example homopiperazinyl. R3a may represent ethyl substituted with 1-homopiperazinyl.
In another embodiment when R3a represents C1-6 alkyl substituted with R9, R9 represents phenyl or naphthyl, in particular phenyl. R3a can represent -CHO-CÓHS. When R9 represents phenyl or naphthyl, in particular phenyl, the phenyl or naphthyl group can be replaced, for example by a chlorine. R3a can represent methyl substituted with phenyl substituted in positions 2, 3 or 4 with chlorine.
In one embodiment R3a represents C1-6 cyanoalkyl, for example -CH2CN, -CH2CH2CN or -CH2CH2CH2CN. In one embodiment R3a represents -CH2CN or -CH2CH2CN.
In an embodiment R3a represents hydroxyl substituted C1-6 alkyl, halo or -NR10Rn. In another embodiment R3a represents hydroxyl substituted C1-6 alkyl or -NR10Rn. In yet another embodiment R3a represents C1-6 alkyl substituted with -NR10Rn.
In one embodiment when R3a represents C1-6 alkyl substituted with -NR10Rn, R10 and R11 have the following meanings: a) each of R10 and R11 represents hydrogen. R3a can represent -CH2CH2NH, -CH2CH2CH2NH2 or -CH2CH2CH2CH2NH2; b) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl, for example -CH3, -CH2CH3 or -CH (CH3) 2- R3a can represent -CH2NHCH3, - CH2CH2NHCH3, - CH2CH2CH2NHCH3, CH2CH2NHCH2CH3, -CH2CH2NHCH ( CH3) 2, - CD2-CD2-NHCH (CH3) 2 OR - CH2CH2CH2NHCH (CH3) 2; c) each of R10 and R11 independently represents C1-6 alkyl, for example -CH3, -CH2CH3 or -CH (CH3) 2. R3a can represent - CH2CH2N (CH3) 2, -CH2CH2N (CH2CH3) 2, - CH2CH2N (CH2CH3) (CH (CH3) 2); d) one of R10 and R11 represents hydrogen and the other represents C1-6 haloalkyl, for example -CH2CF3, -CH2CHF2 or -CH2CH2F. R3a can represent -CH2CH2NHCH2CF3 - CH2CH2CH2NHCH2CF3, CH2CH2NHCH2CHF2 or -CH2CH2NHCH2CH2F; e) one of R10 and R11 represents hydrogen and the other represents - C (= O) -C1-6 alkyl, for example -C (= O) -Me. R3a can represent - CH2CH2NH-C (= O) -CH3; f) one of R10 and R11 represents hydrogen and the other represents - S (= O) 2-C1-6 alkyl, for example -S (= O) 2-CH3, -S (= O) 2-CH2CH3 or -S (= O) 2- CH (CH3) 2. R3a can represent - CH2CH2NH-S (= O) 2-CH3, CH2CH2CH2NH-S (= O) 2-CH3, -CH2CH2NH-S (= O) 2-CH2CH3 OR CH2CH2NH-S (= O) 2-CH (CH3 )two; g) one of R10 and R11 represents hydrogen and the other represents - S (= O) 2-NRI4R15, where R14 and R15 each represent C1-4 alkyl optionally substituted with hydroxyl, for example -CH3. R3a can represent -CH2CH2NH-S (= O) 2-N (CH3) 2 or -C ^ CHA'FFNH-SM)): - N (CH3) 2; h) one of R10 and R11 represents hydrogen and the other represents C1-6 hydroxyalkyl, for example -CH2CH2OH. R3a can represent - CH2CH2NHCH2CH2OH; i) one of R10 and R11 represents hydrogen and the other represents - C (= O) - C1-6 hydroxyalkylalkyl, for example -C (= O) -C (OH) (CH3) CF3. R3a can represent - CH2CH2CH2NH-C (= O) -C (OH) (CH3) CF3 or -CH2CH2NH-C (= O) -C (OH) (CH3) CF3; j) one of R10 and R11 represents hydrogen and the other represents - C (= O) -R6. R6 can represent C3-8 cycloalkyl, for example cyclopropyl. R3a can represent -CH2CH2NHC (= O) -C3Hs. Alternatively, R6 may represent a 6-membered saturated monocyclic heterocyclyl that contains a nitrogen heteroatom, for example piperidinyl. The heterocyclyl can be substituted, for example substituted by a C1-6 alkyl group, for example -CH3 to form N-methyl piperidinyl. R3a can represent - CH2CH2NH-C (= O) - (piperidin-3-yl) where piperidinyl is replaced in position 1 by -CH3; k) one of R10 and R11 represents hydrogen and the other represents C1-6 cyanoalkyl, for example -CH2CH2CN. R3a can represent - CH2CH2NHCH2CH2CN; l) one of R10 and R11 represents hydrogen and the other represents R6. R6 can represent C3-8 cycloalkyl, for example cyclopropyl or cyclopentyl, or R6 can represent a 6-membered saturated monocyclic heterocyclyl that contains a nitrogen heteroatom, for example piperidinyl. The heterocyclyl can be substituted, for example substituted with four C1-6 alkyl groups, for example -CH3 to form for example 2,2,6,6-tetramethyl-piperidinyl. R3a can represent -CH2CH2NHC3H5, - CH2CH2NHC5H9 or -CH2CH2NH- (2,2,6,6-tetramethylpiperidin-4-yl). Or, the heterocyclyl can be replaced by a -S (= O) 2NR14R15, for example - S (= O) 2NH2. R3a can represent -CH2CH2NH- (piperidin-4-yl) where piperidinyl is substituted in position 1 by -S (= O) 2NH2; m) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl substituted with R6. R6 can represent C3-8 cycloalkyl, for example cyclopropyl. R3a can represent - CH2CH2NHCH2C3H5. Alternatively R6 may represent a saturated 5-membered monocyclic heterocyclyl containing an oxygen hetero atom. R3a can represent - CH2CH2NHCH2- (tetrahydrofuran-2-yl); n) one of R10 and R11 represents hydrogen and the other represents - C (= O) -C1-6 haloalkyl, for example -C (= O) -CF3. R3a can represent - CH2CH2NHC (= O) -CF3 OR - CH2CH2CH2NHCX = O) -CT3: o) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl substituted with -Si (CH3) 3. R3a can represent - CH2CH2NHCH2Si (CH3) 3; p) one of R10 and R11 represents C1-6 alkyl and the other represents R6-substituted C1-6 alkyl. R6 can represent phenyl. In one embodiment one of R10 and R11 represents -CH3 and the other represents -CFE-COFFEE. R3a can represent -CFECFENCCF ^ CFE-CÓHS. OR q) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl substituted with -NR14R15. One of R14 and R15 can represent hydrogen and the other can represent C1-4 alkyl, for example -CH (CH3) 2- R3can represent -CH2NHCH2CH2NHCH (CH3) 2
In an embodiment R10 and R11 each independently represents hydrogen, C1-6 alkyl, C1.6 alkyl substituted with -NR14R15OU C1-6 haloalkyl.
In one embodiment R3a represents -CH2CH2NH2, - CH2CH2CH2NH2, -CH2NHCH3, -CH2CH2NHCH (CH3) 2, -CH2CH2N (CH3) 2, - CH2CH2NHCH2CF3OU - CH2NHCH2CH2NHCH (CH3) 2.
In an embodiment R10 represents hydrogen or C1-6 alkyl, for example hydrogen, -CH3, - CFECHj or -CH (CH3) 2. In an embodiment R10 is hydrogen.
In an embodiment R11 represents hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C (= O) -C1-6 alkyl, -S (= O) 2-C1-6 alkyl, -S (= O) 2- NR14R15, C1-6 hydroxyalkyl, -C (= O) -C1-6 hydroxyalkylalkyl, -C (= O) -R6, C1-6 cyanoalkyl, R6, -C (= O) -R6, C1-6 alkyl substituted with R6, -C (= O) - C1-6 haloalkyl, C1-6 alkyl substituted with -Si (CH3) 3.
In one embodiment R11 represents hydrogen, -CH3, -CH2CH3, -CH (CH3) 2, -CH2CF3, -CH2CHF2, -CH2CH2F, -C (= O) -CH3, - S (= O) 2-CH! . -S (= O) 2-CH2CH3, -S (= O) 2-CH (CH3) 2, -S (= O) 2-N (CH3) 2, - CH2CH2OH, -O (= O) -C ( OH) (CH3) CF3, -C (= O) - cyclopropyl, - CH2CH2CN, cyclopropyl, cyclopentyl, 2,2,6,6-tetramethyl-piperidinyl, -Q-EQHs, -CH2- tetrahydrofuranyl, -C (= O ) - (1-methyl-piperidin-3-yl), -C (= O) -CF3, CH2Si (CH3) 3, -CH2-C6H5.
In one embodiment R3a represents -CH2CH2NH2, - CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH2CH2NHCH3, - CH2CH2 CH2NHCH3, <H2CH2NHCH2CH3, -CH2CH2NHCH (CH3CH2CH2) (2) -CH2CH2 (CH2CH3) (CH (CH3) 2), -CH2CH2CH2NHCH2CF3, -CH2CH2NHCH2CHF2 or -CH2CH2NHCH2CH2F, - CH2CH2NH-C (= O) -CH3, -CH2CH2NH-S (= O) 2-CH3, -CHNCH2 ) 2-CH3, -CH2CH2NH-S (= O) 2-CH2CH3, -CH2CH2NH-S (= O) 2-CH (CH3) 2, -CH2CH2NH-S (= O) 2-N (CH3) 2, - CH2CH2 CH2NH-S (= O) 2-N (CH3) 2, - CH2CH2NHCH2CH2OH, -CH2CH2CH2NH-C (= O) -C (OH) (CH3) CF3, CH2CH2NH-C (= O) - C (OH) ( CH3) CF3, -CH2CH2NH-C (= O) -C3H5, - CH2CH2NHCH2CH2CN, CH2CH2NHC3H5, - CH2CH2NHC5H9, -CH2CH2-NHCO- (piperidin-3-ila) where piperidin-3-ila is substituted in position 1 with , -CH2CH2NHCH2C3H5, -CH2CH2NHCH2 (tetrahydrofuran-2-yl), - CH2CH2NHC (= O) -CF3, -CH2CH2 CH2NHC (= O) -CF3, -CH2CH2NH- (2,2,6,6-tetramethyl-piperidin-4 -ila), -CFECFENHCFESiCCFE ^, -CFECFENCCF ^ CFE- C6H5
In an embodiment R3a represents hydroxyl substituted C1-6 alkyl and -NR10Rn.
In one embodiment when R3a represents C1-6 alkyl substituted with hydroxyl and -NR10Rn, each of R10 and R11 represents hydrogen. R3a can represent -CH2CHOHCH2NH2.
In one embodiment when R3a represents C1-6 alkyl substituted with hydroxyl and - NR10Rn, one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl, for example -CH3, -CH (CH3) 2. R3a can represent -CH2C (CH3) (OH) CH2NHCH (CH3) 2, CH2CHOHCH2NHCH3 or -CH2CHOHCH2NHCH (CH3) 2. In one embodiment R3a represents -CH2C (CH3) (OH) CH2NHCH (CH3) 2.
In one embodiment when R3a represents C1-6 alkyl substituted with hydroxyl and - NR10Rn, one of R10 and R11 represents hydrogen and the other represents C1-6 haloalkyl, for example -CH2CF3. R3a can represent -CH2CHOHCH2NHCH2CF3.
In one embodiment R3a represents C1-6 alkyl substituted with one or two halo atoms and - NR10Rn. In one embodiment each of R10 and R11 represents hydrogen. R3a can represent - CH2CHFCH2NH2.
In an embodiment R3a represents C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl. R3 can represent -CH2C (= O) -O- CH3, -CH2C (= O) -O-CH2CH3 OR -CH2CH2-C (= O) -O-CH2CH3. In one embodiment R3a represents CfEC ^ Oj-O-CH ,, or -CfEC ^ Oj-O-CfECH ,.
In one embodiment R3a represents C1-6 alkyl (e.g. methyl) substituted with C1-6 alkoxy C1-6 alkyl (= O) -. R3a represents -CH2-C (= O) -CH2OCH3.
In an embodiment R3a represents C-6 alkyl substituted with -C (= O) -NR10R'1
In one embodiment when R3a represents C1-6 alkyl substituted with -C (= O) -NR10R'R10 and R11 have the following meanings: a) R10 and R11 each represent hydrogen. R3a can represent -CH2C (= O) NH2; b) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl, for example, -CH3 or -CH (CH3) 2. R3a can represent - CH2C (= O) NHCH! OR -CH2C (= O) NHCH (CH3) 2; c) one of R10 and R11 represents hydrogen and the other represents C1-6 alkoxy C1-6 alkyl wherein each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, for example -CH2CH2OCH3. R3a can represent -CH2C (= O) -NHCH2CH2OCH3; d) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl substituted with R6. R6 can be a saturated 5-membered monocyclic heterocycle that contains a nitrogen heteroatom, for example pyrrolidinyl. Alternatively R6 may be a monocyclic heterocycle which is aromatic with 5 members and contains two nitrogen atoms, for example imidazolyl. R3a can represent -CH2C (= O) -NH-CH2CH2- (Pyrrolidin-1-yl) or -CH2C (= O) - NH-CH2CH2- (imidazol-2-yl); e) one of R10 and R11 represents hydrogen and the other represents C1-6 hydroxyalkyl, for example -CH2CH2OH. R3a can represent - CH2C (= O) -NHCH2CH2OH; OR f) one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl substituted with -NR14R15 where R14 and R15 are both hydrogen. R3a can represent -CH2C (= O) - NHCH2CH2N H2.
In an embodiment R3a represents - CH2C (= O) NHCH (CH3) 2.
In one embodiment R3a represents C1-6 alkyl substituted with carboxyl. R3a can represent '-CH2C (= O) OH or - CH2CH2C (= O) OH.
In one embodiment R3a represents C1-6 alkyl substituted with -O-C (= O) -NR10R'In one embodiment one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl, for example -CH3. R3a can represent -CH2CH2-O-C (= O) -NHCH3.
In one embodiment R3a represents C1-6 alkyl substituted with -NR12-S (= O) 2-C1-6 alkyl. In an embodiment R12 represents hydrogen. R3a can represent -CH2CH2NH-S (= O) 2-CH3, - CH2CH2CH2NH-S (= O) 2-CH3, -CH2CH2NH-S (= O) 2-CH (CH3) 2OU CH2CH2NH-S (= O) 2 - CH2CH3.
In one embodiment R3a represents C-6 alkyl substituted with -NRI2S (= O) 2-NRI4R15. In one embodiment R12 represents hydrogen and R14 and R15 each represents -CH3. R3a can represent -CH2CH2NH-S (= O) 2-N (CH3) 2 or - CH2CH2CH2NH-S (= O) 2- N (CH3) 2.
In one embodiment R3a represents hydroxyl-substituted C1-6 alkyl and R9.
In one embodiment when R3a represents hydroxyl substituted C1-6 alkyl and R9, R9 represents a 5-membered saturated monocyclic heterocyclyl containing a nitrogen heteroatom, for example pyrrolidinyl. R3a can represent propyl substituted with -OH and 1-pyrrolidinyl. Heterocyclyl can be substituted. For example, heterocyclyl is substituted with a) two halogens, for example two fluorine atoms. R3a can represent propyl substituted with -OH and 1-pyrrolidinyl where 1-pyrrolidinyl is substituted in position 3 with two fluorine atoms; or b) a cyan group. R3a can represent propyl substituted with -OH and 1-pyrrolidinyl where 1-pyrrolidinyl is substituted in position 3 with a cyano group.
In one embodiment when R3a represents hydroxyl-substituted C1-6 alkyl and R9, R9 represents a 6-membered saturated monocyclic heterocycle that contains a nitrogen and an oxygen heteroatom, for example morpholinyl. R3a can represent propyl substituted with -OH and 4-morpholinyl.
In one embodiment when R3a represents hydroxy substituted Q. 6 alkyl and R9, R9 represents a 6-membered saturated monocyclic heterocycle that contains a nitrogen heteroatom, for example piperidinyl. R3a can represent propyl substituted with -OH and 1-piperidinyl.
In an embodiment when R3a represents hydroxyl-substituted C1-6 alkyl and R9, R9 represents an optionally substituted bicyclic heterocyclyl containing a nitrogen hetero atom, said bicyclic heterocyclyl can be substituted for example with two groups = 0. R3a can represent hydroxyl substituted propyl and 1,3-dione isoindole.
In one embodiment R3a represents -C1-6 alkyl (RI2) = N-O-R12. R12 independently can be chosen from hydrogen and C1-4 alkyl optionally substituted with C1-4 alkoxy, for example -CH3 or - CH (CHa) 2 OR CH2OCH3 R3a can represent -CH2C (CH3) = NOH, - CH2C (CH2OCH3) = NOH OR -CH2C (CH (CH3) 2) = NOH.
In an embodiment R3a represents C1-6 alkyl substituted with -C (= O) -R9. R9 can represent a saturated 5- membered monocyclic heterocycle that contains a nitrogen heteroatom, for example pyrrolidinyl. R3a can represent -CH2-C (= O) -R9 and R9 is 1-pyrrolidinyl.
In one embodiment R3a represents C2-6 alkynyl substituted with R9. R9 may represent a 5-membered aromatic monocyclic heterocycle containing two nitrogen atoms, for example imidazolyl. The heterocyclyl can be substituted, for example substituted with C1-4 alkyl, for example -CH3. R3a can represent -CH2-OC - (2-imidazolyl) where 2-imidazolyl is substituted in position 1 with -CH3 or CH2-C = C - (5-imidazolyl) where 5-imidazolyl is substituted in position 1 with -CH3.
In one embodiment R9 is a monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, said monocyclic heterocycly optionally being substituted with 1 substituent selected from = 0 or C1-4 alkyl.
In one embodiment R3a represents C1-6 alkyloxy C1-6 alkyl wherein each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups. R3a can represent - CH2CHOHCH2 OCH3.
In one embodiment R3a represents C2-6 alkenyl. R3a can represent -CH2-CH = CH2.
In an embodiment R3a represents C2-6 alkynyl. R3a can represent -CH2-OC-H
In an embodiment R3a represents R13.
In one embodiment when R3a represents R13, R13 represents a saturated 4-membered monocyclic heterocycle that contains an oxygen hetero atom. R3a can represent 3-oxetanil.
In another embodiment when R3a represents R13, R13 represents an optionally substituted C3-8 cycloalkyl. For example, the C3-8 cycloalkyl can be replaced with an NR14R15 where one of R14 and R15 represents hydrogen and the other represents C1-4 alkyl optionally substituted with hydroxyl, for example -CH (CH3) 2. R3a can represent cyclohexanil substituted in position 4 with -NH-CH (CH3) 2-
In an embodiment R14 and R15 each independently represents hydrogen or C1-4 alkyl.
In one embodiment R3a represents C1-6 alkyl substituted with R9, where R9 is a substituted heterocyclyl saturated with R13, where R13 is a saturated heterocyclyl which is optionally substituted, for example substituted with -C (= O) -alkyl C1-6. In one embodiment R9 is piperazinyl substituted with R13, where R13 is piperidinyl substituted with -C (= O) -C1-6 alkyl.
In an embodiment R3b represents hydrogen.
In an embodiment R3b represents hydroxyl.
In one embodiment R3a represents hydroxyl and R3b represents hydrogen.
In an embodiment R3a and R3b are taken together to form = 0, to form = NR10, to form cyclopropyl together with the carbon atom to which they are attached, to form = CH- Co-4 alkyl substituted with R3c, or to form
wherein ring A is a 5- to 7-membered saturated monocyclic heterocycle containing a heteroatom selected from N, O or S, said heteroatom not being positioned at the alpha position of the double bond, where ring A is being optionally substituted with cyano, CM alkyl, C1-4 hydroxyalkyl, H2N-CM alkyl, (C1-4 alkyl) NH-CM alkyl, (CM ^ N-CM alkyl, (C1-4 haloalkyl) NH-CM alkyl, CM alkoxy CM, -C (= O) -NH2, - C (= O) -NH (CM alkyl), -C (= O) -N (CI_4 alkyl) 2.
In an embodiment R3a and R3b are taken together to form = 0, to form cyclopropyl together with the carbon atom to which they are attached, to form = CH- Rac-substituted Co-4 alkyl, or to form
wherein ring A is a saturated 5- to 7-membered monocyclic heterocycle containing a heteroatom selected from N, O or S, said heteroatom not being positioned at the alpha position of the double bond.
In an embodiment R3a and R3b are taken together to form = 0.
In an embodiment R3a and R3b are taken together to form cyclopropyl together with the carbon atom to which they are attached.
In one embodiment R3a and R3b are taken together to form Rac-substituted CH-alkyl = CH-alkyl. R3c has the following meaning: a) R3c can represent cyan. R3a and R3b can be taken together to form = CH-CN; b) R3c can represent -C (= O) -C1-6 alkyl. F3a and R3b can be taken together to form = CHC (= O) -CH3; c) R3C can represent hydroxyl. R3a and R3b can be taken together to form = CHCH2OH.
In one embodiment R3c represents hydroxyl, C1-6 alkoxy, R9, -NR10Rn, cyano, -C (= OJ-C1-6 alkyl or -CH (OH) -C1-6 alkyl.
In one embodiment R3c represents hydroxyl, - NR10Rn’ciano, or -C (= O) -C1-6 alkyl.
In an embodiment R3a and F3b are taken together to form = CH-alkyl Co-4 in the Z configuration.
In an embodiment R3c represents -NR10Rn
In an embodiment R10 and R11 each independently represents C1-6 alkyl, for example - CH3. R3a and R3b can be taken together to form = CHCH2N (CH3) 2.
In one embodiment one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl, for example -CH (CH3) 2, R3a and R3b can be taken together to form = CHCH2NHCH (CH3) 2.
In one embodiment one of R10 and R11 represents hydrogen and the other represents C1-6 haloalkyl, for example -CH2CF3. R3a and R3b can be taken together to form = CHCH2NHCH2CF3.
In an embodiment R10 and R11 each independently represents hydrogen, C1-6 alkyl, C1.6 alkyl substituted with -NR14R15OU haloalkyl C1-6.
In an embodiment R14 and R15 each independently represents hydrogen or C1-4 alkyl.
In an embodiment R3a and R3b are taken together to form
'wherein ring A is a saturated 5- to 7-membered monocyclic heterocycle containing a heteroatom selected from N, O or S, said heteroatom not being positioned in the alpha position of the double bond. Ring A can represent a saturated monocyclic 6-membered heterocycle containing a nitrogen heteroatom, for example piperidin-3-yl.
In an embodiment R3c represents hydrogen.
In another embodiment, the compound of formula (I) as defined herein is selected from the following compounds or is one of the following compounds: {(Z) -3 - (3,5-Dimethoxy-phenyl) - 3 - [3 - (1-methyl-1 H-pyrazol-4-yl) - quinoxalin-6-yl] -alyl} dimethyl-amine; {(Z) -3 - (3,5-Dimethoxy-phenyl) -3 - [3 - (1-methyl-1 H-pyrazol-4-yl) -quinoxalin-6-yl] -ally} isopropyl-amine; {(Z) -3 - (3,5-Dimethoxy-phenyl) -3 - [3 - (1-methyl-1 H-pyrazol-4-yl) - quinoxalin-6-yl] -ally} - (2, 2,2-trifluoro-ethyl) -amine; {(S) -3- (3,5-Dimethoxy-phenyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-6-yl] -prtopyl} isopropyl-amine; {3 - (3,5-Dimethoxy-phenyl) -3 - [3 - (1-methyl-1 H-pyrazol-4-yl) - quinoxalin-6-yl] prtopyl} isopropyl-amine; such an N-oxide, a pharmaceutically acceptable salt thereof or a solvate thereof.
In another embodiment the compound of formula (I) as defined herein is selected from compounds 10, 8, 14, 19a and 29 (see Table A1).
According to another aspect of the invention, the compounds of formula (I) are provided:
which include any tautomeric or stereochemically isomeric form thereof, where n represents an integer equal to 0, 1, or 2; R1 represents C1-6 alkyl; R2 represents Cl, 4 alkoxy; R3a represents -NR10Rn, hydroxyl, hydroxy-C1-6 alkyl, C1-6 alkyl substituted with -C (= O) - C1-6 alkyl, C1-6 alkyl substituted with R9, C1-6 cyanoalkyl, substituted C1-6 alkyl with -NR10Rn, hydroxyl substituted C1-6 alkyl and -NR19Rn, C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl, C1-6 alkyl substituted with -C (= O) - NR10Rn; R3b represents hydrogen or hydroxyl; or R3a and R3b are taken together to form = 0, to form cyclopropyl together with the carbon atom to which they are attached, to form = CH-alkyl substituted with R3c-Co-4, or to form
wherein ring A is a 5- to 7-membered saturated monocyclic heterocycle containing a heteroatom selected from N, O or S, said heteroatom not being positioned at the alpha position of the double bond, where ring A is being optionally substituted with cyano, C1-4 alkyl, C1-4 hydroxyalkyl, H2N-C1-4 alkyl, H (C1-4 alkyl) N-C1-4 alkyl, (C1-4 alkyl) 2N-C1-4 alkyl, C1-4 alkoxy C1-4 alkyl, -C (= O) -NH2, - C (= O) -NH (C1.4 alkyl), -C (= O) -N (C1-4 alkyl) 2; R3C represents hydroxyl, C1-6 alkoxy, R9, -NR10Rn, cyano, -C (= O) -C1-6alkyl; R6 represents C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, 4, 5, 6 or 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, 4, 5, 6 or 7 membered monocyclic heterocyclyl, optionally and each independently being substituted by 1, 2, 3, 4 or 5 substituents, each substituent being independently selected cyano, C1-6 alkyl, C1-6 cyanoalkyl, hydroxyl, carboxyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxy, C1-6 alkyl, C1-6 alkyl (= O) -, -NR14R15, -C (= O) -NR14R15, C1-6 alkyl substituted with -NR14R15, C1-6 alkyl substituted with -C (= O) -NR14R15, - S (= O) 2-C1-6 alkyl, - S (= O) 2-C1-6 haloalkyl, -S (= O) 2-NR14R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2 - C1-6 haloalkyl, C1-6 alkyl substituted with -S (= O) 2-NR14R15, C1-6 alkyl substituted with -NH-S (= O) 2-C1-6 alkyl, substituted C1-6 alkyl with - NH-S (= O) 2-C 1-6 haloalkyl or C 1-6 alkyl substituted with -NH-S (= O) 2-NR14R15; R9 represents C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl or a 3- to 12-membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, said C3-8 cycloalkyl, C3-8 cycloalkenyl, aryl or a 3 to 12 membered monocyclic or bicyclic heterocyclyl each optionally and each independently substituted with 1 to 5 substituents, each substituent independently being selected from = 0, C1-4 alkyl, hydroxyl, carboxyl, C1-4 hydroxyalkyl, cyano , C1-4 cyano-alkyl, CM-OC (= O) - alkyl, C1-4 alkyl substituted with C1-6-OC alkyl (= O) -, CM-C alkyl (= O) -, C1-4 alkoxy C1-4 alkyl where each C1-4 alkyl can be optionally substituted with one or two hydroxyl, halogen, C1-4 haloalkyl, C1-4 hydroxyalkylalkyl groups, -NR14R15, - C (= O) -NRI4R15, C1-4 alkyl substituted with -NR14R15, C1-4 alkyl substituted with -C (= O) -NRI4R15, C1-4 alkoxy, -S (= O) 2-C1-4 alkyl, -S (= O) 2- C1-4 haloalkyl , -S (= O) 2NRI4R15, C1-4 alkyl substituted with -S (= O) 2- NR14R15, C1-4 alkyl substituted with - NH-S (= O) 2-C1-4 alkyl, C1-4 alkyl substituted with -NH-S (= O) 2-haloalkyl C1-4, C1-4 alkyl substituted with - NH-S (= O) 2-NRI4R15, R13, -C (= O) -R13, C1-4 alkyl substituted with R13, phenyl optionally substituted with R16, phenylalkyl C1- 6 wherein the phenyl is optionally substituted with R16, a 5- or 6-membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S wherein said heterocyclyl is optionally substituted with R16; or when two of the R9 substituents are attached to the same atom, they can be taken together to form a 4, 5, 6 or 7 membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; R10 and R11 each independently represent hydrogen, C1-6 alkyl, C1-6 cyanoalkyl, C1-6 alkyl substituted with -NR14R15, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylalkyl, C1-6 alkoxy C1-6 alkyl 6 where each C1-6 alkyl can be optionally substituted with one or two hydroxyl groups, R6, C1-6 alkyl substituted with R6, -C (= O) -R6, - C (= O) -C1-6 alkyl, -C (= O) -Hydroxyalkyl CM, -C (= O) -haloalkyl CM, -C (= O) -hydroxyaloalkyl CM, C1-6 alkyl substituted with -Si (CH3) 3, -S (= O) 2- alkyl C1-6, -S (= O) 2-haloalkyl CM, -S (= O) 2- NR14R15, C1-6 alkyl substituted with -S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-C1-6 haloalkyl, C-6 alkyl substituted with -S (= O) 2-NR14R15, C1-6 alkyl substituted with -NH-S (= O) 2-CM alkyl, C1-6 alkyl substituted with -NH- S (= O) 2-C 1-6 haloalkyl or C 1-6 alkyl substituted with -NH-S (= O) 2-NR14R15; R12 represents hydrogen or CM alkyl optionally substituted with CM alkoxy; R13 represents C3-8 cycloalkyl or a saturated 4- to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C3-8 cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxyl, CM alkyl, - (C = O)-CM alkyl, CM alkoxy, OR -NR14R15; R14 and R15 each independently represent hydrogen, or haloalkyl CM, OUalkyl CM optionally substituted with a substituent selected from hydroxyl, CM alkoxy, amino or mono- or di (CM alkyl) amino; R16 represents hydroxyl, halogen, cyano, CM alkyl, CM alkoxy, -NR14R15 OU - C (= O) NRI4R15; such an N-oxide, a pharmaceutically acceptable salt thereof or a solvate of these.
In accordance with yet another aspect of the invention, the compounds of formula (I) are provided:
which include any tautomeric or stereochemically isomeric form thereof, where n represents an integer equal to 0 or 2; R1 represents methyl; R2 represents C1-4 alkoxy, for example CH3O-; R3a represents -NR10Rn, for example -NHCH2CH2NHCH (CH3) 2, hydroxyl, C1-6 hydroxyalkyl, for example -CH2CH2OH, C1-6 alkyl substituted with - C (= O) -C1-6 alkyl, for example CH3-C ( = O) -CH2-, C1-6 alkyl substituted with R9, for example methyl substituted with ethylene oxide through position 2 of ethylene oxide, where ethylene oxide is substituted in position 2 with -CH3, ethyl substituted with 1-pyrrolidinyl which is substituted in position 2 with = 0, C1-6 cyanoalkyl, for example -CH2CN or -CH2CH2CN, C1-6 alkyl substituted with -NR10Rn, for example CH2CH2NH2, -CH2CH2CH2NH2, -CH2NHCH3, -CH2CH2NHCH (CH3) 2- CH2CH2N (CH3) 2, -CH2CH2NHCH2CF3, OU - CH2NHCH2CH2NHCH (CH3) 2, hydroxyl substituted C1-6 alkyl and -NR10Rn, for example - CH2C (CH3) (OH) CH2NHCH (CH3) 2, substituted C1-6 alkyl -C (= O) -O- C1-6 alkyl, for example -CH2C (= O) -O-CH3 or - CH2-C (= O) -O-CH2CH3, C1-6 alkyl substituted with -C (= O) -NR10Rn, for example - CH2C (= O) NHCH (CH3) 2; R3b represents hydrogen or hydroxyl; R3a and R3b are taken together to form: = 0; cyclopropyl together with the carbon atom to which they are attached; = CH-4 Co-4 alkyl substituted with R3c, for example = CH-CN, = CH-C (= O) -CH3, = CHCH2OH, = CH-CH2N (CH3) 2, = CH-CH2NCH (CH3) 2, or = OH-CH2NHCH2CF3; OR
wherein ring A represents piperidin-3-yl; such an N-oxide, a pharmaceutically acceptable salt thereof or a solvate of these.
In one embodiment the compound of formula (I) is a compound of formula (Ia):
which include any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R1 and R2 are as defined herein.
In one embodiment the compound of the formula (I) is a compound of the formula (I'-a):
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n and R2 are as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (I "-a)
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof 10 or a solvate thereof, wherein R2 is as defined herein.
In one embodiment the compound of the formula (I) is the compound of the formula (I '”- a)
and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
In one embodiment the compound of formula (I) is a compound of formula (Ib):
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R1, R2 and R3c are as defined herein.
In one embodiment the compound of the formula (I) is a compound of the formula (I'-b):
which include any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R2 and R3c are as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (I "-b)
which include any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 and R3c are as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (I '”- b)
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R3c is as defined herein.
The compound of the formulas (I'-b), (I ”-b) or (I '” - b) can be in the E or Z configuration, preferably in the Z configuration.
A preferred subgroup of the compounds of formulas (Ib), (I'-b), (I ”-b) or (I '” - b) are those compounds that have the following double bond geometry as shown in (E- b '), (I ”-b') and (I '” - b') below:

In an embodiment the compound of formula (I) is a compound of formula (Ic):
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R1, R2 and R3a are as defined herein.
In one embodiment the compound of the formula (I) is a compound of the formula (I'-c):
which includes any stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R2 and R3a are as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (I "-c)
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 and R3a are as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (I '”- c)
which includes any stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R3a is as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (Id):
which includes any stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R1, R2 and R3a are as defined herein.
In an embodiment the compound of formula (I) is a compound of formula (Fd):
which includes any stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein n, R2 and R3a are as defined herein.
In one embodiment the compound of formula (I) is a compound of formula (I "-d)
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 and R3a are as defined herein.
In one embodiment the compound of the formula (I) is a compound of the formula (I '”- d)
which includes any tautomeric or stereochemically isomeric form thereof; and an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R3a is as defined herein.
For the avoidance of doubt, it should be understood that each general and specific preference, embodiment and example for a substituent can be combined with each general and specific preference, embodiment and example for one or more, preferably all other substituents as defined herein and that all such embodiments are covered by this application. Methods for the Preparation of the Compounds of Formula (I)
In this section, as in all other sections of this application unless the context otherwise indicates, references to formula (I) also include all other subgroups and their examples as defined herein.
In general, the compounds of formula (I) can be prepared 5 according to Reaction Scheme 1 which follows. Layout 1

In scheme 1, an intermediate of formula (II) is reacted with a solution of ethyl glyoxalate, in the presence of a suitable solvent, such as for example an alcohol, for example, ethanol and the like which result in an intermediate of formula (III). The intermediate of formula (III) is further reacted with an agent that introduces the starting group, such as for example phosphorus oxychloride, which results in an intermediate of formula (IV), which is further reacted with an intermediate of formula (V ) in the presence of a suitable catalyst, such as for example tetracis (triphenylphosphino) palladium (0), a suitable base, such as for example Na2COs and a suitable solvent or solvent mixture such as for example ethylene glycol dimethyl ether and water, to give a compound of the formula (I- a). The compounds of the formula (Ia) can also be prepared by reacting an intermediate of the formula (VI) in which W3 represents a suitable group, such as for example halo, for example, bromine and the like, with bis (pinacolate) diboro in the presence of a suitable catalyst, such as for example PdCE and a suitable ligand, such as for example 1,1-bis (diphenylphosphino) ferrocene, in the presence of a salt, such as for example potassium acetate and a suitable solvent, such such as dioxane, followed by the reaction of the intermediate resulting from formula (VII) with an intermediate of formula (VIII) where W2 represents a suitable starting group, such as for example halo, for example, chlorine and the like, in presence of a catalyst, such as for example dichlorobis (triphenylphosphine) palladium, a suitable base, such as for example Na2CÜ3 and a suitable solvent, such as for example tetrahydrofuran. A compound of formula (Ia) can also be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (XIII) in the presence of CO as a reagent, a suitable catalyst, such as for example palladium (II) acetate ), a suitable ligand, such as for example tricyclohexylphosphine, a suitable base, such as for example triethylamine and a suitable solvent, such as for example toluene. Layout 2

In scheme 2, the intermediates of formula (VI) are reacted with an intermediate of formula (IX) in the presence of a suitable catalyst, such as for example palladium (II) acetate, a suitable base, such as for example potassium acetate and tetrabutylammonium bromide as the solid base and a suitable solvent, such as for example N, N-dimethylformamide, to give a compound of the formula (Ib). The compounds of formula (Ib) can also be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (X) in the presence of a suitable catalyst, such as for example palladium (II) acetate, a suitable ligand , such as for example tri-o-tolylphosphine, a suitable base, such as for example triethylamine and a suitable solvent, such as for example acetonitrile, which results in an intermediate of formula (XI), which can then be reacted with an intermediate of formula (XII) where W4 represents a suitable starting group, such as for example halo, for example, bromine, in the presence of a suitable catalyst, such as for example palladium (II) acetate, a suitable base, such as for example potassium acetate and tetrabutylammonium bromide as the solid base and a suitable solvent, such as for example N, N-dimethylformamide. Layout 3

In scheme 3, an intermediate of formula (XVII) preferably in its salt form, for example, HCI salt form and (XVIII) is reacted with paraformaldehyde in the presence of a suitable solvent, such as for example an alcohol, for example, ethanol , then a suitable POP agent to introduce a suitable protecting group P, such as for example -C (= O) -OC (CH3) 3 where POP is (CH3) 3C-OC (= O) -O- C ( = O) -OC (CH3) 3), is added in the presence of a suitable base, such as for example triethylamine and a suitable solvent, such as for example dichloromethane, which results in an intermediate of formula (XVI), which is still reacted with p-toluenesulfonidrazide in the presence of a suitable solvent, such as for example an alcohol, for example, ethanol, to give an intermediate of formula (XV). The intermediate of formula (XV) is then further reacted with an intermediate of formula (VI) in the presence of a suitable catalyst, such as for example tris (dibenzylidenoacetone) dipaladium (0), a suitable ligand, such as for example 2-dicyclohexylphosphino -2 ', 4', 6'-triisopropyl-1,1biphenyl a suitable base, such as for example lithium tert-butoxide and a suitable solvent, such as for example dioxane, which results in an intermediate of the formula (XIV), the E and Z isomers that can be separated by the appropriate separation techniques such as column chromatography. The intermediate of the formula (XIV) can then be converted into a compound of the formula (Ib-1) by deprotection in the presence of a suitable acid, such as for example HCl and a suitable solvent, such as for example an alcohol, for example, methanol. A compound of the formula (Ib-2) is prepared by reacting an intermediate of the formula (XX) with p-toluenesulfonidrazide in the presence of a suitable acid, such as for example hydrochloric acid and a suitable solvent, such as for example diethyl ether and water, which result in an intermediate of the formula (XIX), the E and Z isomers of those that can be separated by the appropriate separation techniques such as column chromatography. The intermediate of formula (XIX) can then be reacted with an intermediate of formula (VI) in the presence of a suitable catalyst, such as for example tris (dibenzylidene-acetone) dipaladium (0), a suitable ligand, such as for example 2 - dicyclohexylphosphine-2 ', 4', 6'-triisopropyl-l, l'-biphenyl a suitable base, such as for example lithium tert-butoxide and a suitable solvent, such as for example dioxane, which results in a compound of the formula (Ib-2). A compound of the formula (Ib-3) is prepared by reacting an intermediate of the formula (XXI) with a suitable reducing agent, such as for example diisobutylaluminum hydride and a suitable solvent, such as for example tetrahydrofuran. The intermediate of formula (XXI) is prepared by reacting an intermediate of formula (VI) with an intermediate of formula (XXII) in the presence of a suitable catalyst, such as for example palladium (II) acetate, a suitable ligand, such as such as tri-o-tolylphosphine, a suitable base, such as for example triethylamine and a suitable solvent, such as for example acetonitrile. Layout 4

In scheme 4, a compound of the formula (Ib-3) is reacted with an agent that introduces the starting group, such as for example methanesulfonyl chloride, in the presence of a suitable base, such as for example triethylamine and a suitable solvent, such as for example dichloromethane, which results in an intermediate of formula (XXII) where W5 represents a suitable starting group 15, such as for example halo, for example chlorine, which is then further reacted with NHRI 1 in the presence of a suitable solvent, such as for example acetonitrile, to give a compound of the formula (Ib-1). Layout 5

In scheme 5, a compound of the formula (Ic-1) is prepared by reacting an intermediate of the formula (XXI) with magnesium in the presence of a suitable solvent, such as for example tetrahydrofuran and an alcohol, for example, methanol and its compounds. similar. A compound of the formula (Ic-2) 5 is prepared by reacting an intermediate of the formula (XXIV) with potassium cyanide in the presence of a suitable solvent, such as for example N, N-dimethylformamide. The intermediate of the formula (XXIV) is prepared by reacting a compound of the formula (Ic-3) with methanesulfonyl chloride in the presence of a suitable base, such as for example triethylamine and a suitable solvent, such as for example acetonitrile. (Ic-3) can be prepared by reducing (Ib-3) for example using LiAlH4, in an aprotic solvent such as THF. The intermediate of the formula (XXIV) is converted into a compound of the formula (Ic-4) by reaction with HR9 in the presence of a suitable base, such as for example sodium hydride and a suitable solvent, such as for example N, N-dimethylformamide . Layout 6

In scheme 6, a compound of the formula (Ia) is reacted with 5 trimethylsulfoxonium iodide in the presence of a suitable base, such as for example potassium tert butoxide and a suitable solvent, such as for example dimethoxymethane and dimethyl sulfoxide which results in an intermediate of the formula (XXV), which can be converted into a compound of the formula (Id-1) by reaction with NHR10Rn in the presence of a suitable solvent, such as for example an alcohol, for example, ethanol and the like. Layout 7

In scheme 7, an intermediate of formula (XII) as defined above and (XXVI) where P represents a suitable protecting group as defined above, is reacted with butyllithium in hexane in the presence of a suitable solvent, such as for example tetrahydrofuran, ether diethyl or 5 mixtures thereof which results in an intermediate of the formula (XXVII), which is further reacted with p-toluenesulfonidrazide in the presence of a suitable solvent, such as for example an alcohol, for example, ethanol, to give an intermediate of the formula ( XXVIII). The intermediate of formula (XXVIII) is then further reacted with an intermediate of formula (VI) in the presence of a suitable catalyst, such as for example tris (dibenzylidenoacetone) dipaladium (0), a suitable ligand, such as for example 2- dicyclohexylphosphine-2 ', 4', 6'-triisopropyl-1, l'-biphenyl, a suitable base, such as for example lithium tert-butoxide and a suitable solvent, such as for example dioxane, which results in a intermediate of the formula (XXIX). The intermediate of the formula (XXIX) is then converted to an intermediate of the formula (XXX) by hydrogenation in the presence of a suitable catalyst, such as for example palladium on charcoal and a suitable solvent, such as for example an alcohol, for example, methanol. The intermediate of formula (XXX) can then be converted into a compound of formula (Ie) by reaction with a suitable acid, such as, for example, hydrochloric acid, in the presence of a suitable solvent, such as, for example, an alcohol, for example, methanol.
The compounds of formula (I) can also be prepared according to the reactions described above, but starting from the intermediate of formula (VI ') below prepared according to Scheme 8. Scheme 8

In scheme 8, step 1 is carried out in the presence of a suitable catalyst, such as for example tetracis (triphenylphosphine) -palladium 15 (0) and a suitable solvent, such as for example toluene. for step 2, the reactions can be applied as described above starting from an intermediate of formula (VI). It is considered to be within the knowledge of the person skilled in the art to recognize in what condition and for which definition of Rla a protection group is appropriate in step as well as in step 2.
In general, it is considered to be within the knowledge of the person skilled in the art to recognize in what condition and in which part of the molecule a protecting group may be appropriate. For example, a protecting group on the R1 substituent or on the pyrazole moiety, on the R2 substituent or combinations thereof. The qualified person is also considered to be able to recognize the most practicable protection group, such as for example -C (= O) O-alkyl CM OR

The present also comprises deuterated compounds. These deuterated compounds can be prepared by using the appropriate deuterated intermediates during the synthesis process. For example an intermediate of the formula (XII-a)
can be converted into an intermediate of the formula (XII-b)
by reaction with iodomethane-D3 in the presence of a suitable base, such as for example cesium carbonate and a suitable solvent, such as for example acetonitrile.
The compounds of formula (I) can also be converted to one another through reactions known in the art or transformations of functional groups.
For example, compounds of formula (I) in which R3a and R3b are taken together to form = 0, can be converted into a compound of formula (I) in which R3a represents hydroxyl and R3b represents hydrogen, by reaction with an suitable reduction, such as for example sodium borohydride and the like, in the presence of a suitable solvent, such as for example tetrahydrofuran or an alcohol, such as for example methanol and the like, or mixtures thereof. The compounds of formula (I) in which R3a and R3b are taken can also be converted into a compound of formula (I) in which R3a represents NR10Rn- by reaction with NHR10Rn in the presence of a suitable reducing agent, such as for example borohydride sodium, in the presence of a suitable solvent, such as for example an alcohol, for example, methanol.
The compounds of formula (I) in which R3a and R3b are taken together to form = CH-alkyl Co-4 substituted with R3c can be converted to a compound of formula (I) in which R3a represents substituted -CH2- C0-4 alkyl with R3c and R3b represents hydrogen by reaction with magnesium in the presence of a suitable solvent, such as for example tetrahydrofuran or an alcohol, such as for example methanol and the like, or mixtures thereof, or by hydrogenation in the presence of a suitable catalyst, such as for example palladium, in the presence of a suitable solvent, such as for example an alcohol, for example, methanol and the like.
The compounds of formula (I) in which R3a represents hydroxyl substituted C1-6 alkyl, can be converted to a compound of formula (I) in which R3a represents NR10Rn substituted C1-6 alkyl by reaction with NHR10Rn in the presence of chloride methanesulfonyl, a suitable base 87, such as for example triethylamine and a suitable solvent, such as for example acetonitrile.
The compounds of formula (I) in which R3a represents cyano-substituted C1-6 alkyl can be converted into a compound of formula (I) in which R3a represents amino substituted C2-6 alkyl by reaction with ammonia in the presence of Nickel and a suitable solvent, such as for example tetrahydrofuran.
Compounds of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl, can be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with hydroxyl, by reaction with lithium aluminum hydride in the presence of a suitable solvent, such as for example tetrahydrofuran. The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl and R3b represents hydrogen, can also be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) - NR10Rn and R3b represents hydrogen, by reaction with NHR10Rn
The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with oxiranyl, can be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with hydroxyl and NR10Rn, by reaction with NHR10Rn in the presence of a suitable solvent, such as for example N, N-dimethylformamide and an alcohol, for example, ethanol.
The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) -C1-6 alkyl, for example, -CH2-C (= O) -CH3, can be converted into a compound of formula (I) where R3a represents C1-6 alkyl substituted with oxiranyl, by reaction with trimethylsulfoxonium iodide in the presence of a suitable base, such as for example potassium tert-butoxide and a suitable solvent, such as for example dimethoxymethane and sulfoxide dimethyl.
The compounds of formula (I) in which R1 represents tetrahydropyranyl can be converted into a compound of formula (I) in which R1 represents hydrogen, by reaction with a suitable acid, such as for example HCI or trifluoroacetic acid, in the presence of a solvent suitable, such as for example dichloromethane, dioxane, or an alcohol, for example, methanol, isopropanol and the like.
Compounds of formula (I) in which R1 or R3a represent C1-6-OH alkyl, can be converted into a compound of formula (I) in which R1 or R3a represent CI-6-F alkyl by reaction with diethylamino sulfur trifluoride in the presence of a suitable solvent, such as for example dichloromethane and in the presence of catalytic amounts of an alcohol, such as for example ethanol. Likewise, a compound of the formula (I) in which R1 or R3a represent C-6 alkyl substituted by R6 or R9 in which said R6 or R9 is substituted with OH, can be converted into a compound of the formula (I) in wherein R1 or R3a represent C6-alkyl substituted with R6 or R9 wherein said R6 or R9 is substituted with F, by reaction with diethylaminosulfur trifluoride in the presence of a suitable solvent, such as for example dichloromethane.
The compounds of formula (I) in which R1 or R3a represent R6-alkyl substituted with R6 or R9 in which said R6 or R9 are substituted with -C (= O) -O-C1-6 alkyl, can be converted to a compound of the formula (I) in which R1 or R3a represent C-6 alkyl substituted with R6 or R9 in which said R6 or R9 are substituted with -CH2-OH, by reaction with LiAlH4 in the presence of a suitable solvent, such as for example tetrahydrofuran.
Compounds of formula (I) in which R3a represents C1-6 alkyl substituted with 1,3-dioxo-2H-isoindol-2-yl, can be converted to a compound of formula (I) in which R3a represents C1-6 alkyl substituted with amino, by reaction with hydrazine monohydrate in the presence of a suitable solvent, such as for example an alcohol, for example, ethanol.
The compounds of formula (I) in which R1 or R3a represent C1-6 alkyl substituted with amino, can be converted into a compound of formula (I) in which R1 or R3a represent C1-6 alkyl substituted with - NH-S (= O) 2-C1-6 alkyl, by reaction with CI-S (= O) 2-C1-6 alkyl in the presence of a suitable base, such as for example triethylamine and a suitable solvent, such as for example dichloromethane.
The compounds of formula (I) in which R1 or R3a represent halo-substituted C1-6 alkyl, can be converted to a compound of formula (I) in which R1 or R3a represent NR4R5 or NR10Rn-substituted C1-6 alkyl by reaction with NHR4R5 or NHR10Rn, using such a large excess amino or in the presence of a suitable base, such as for example K2CO3 and a suitable solvent, such as for example acetonitrile, N, N-dimethylacetamide or 1-methyl] -pyrrolidinone.
Compounds of formula (I) in which R1 represents hydrogen can be converted into a compound of formula (I) in which R1 represents C1-6 polyalalkyl or C1-6 polyhydroxyalkyl or C1-6 alkyl or -S (= O) 2 - NR14R15OU -S (= O) 2-C1-6 alkyl, by reaction with polyaloalkyl CI-ÓW OR polyhydroxyalkyl C1-6-W or C1-6 alkyl or WS (= O) 2-NRI4R15 or W- S ( = O) 2-C 1-6 alkyl, where W represents a suitable starting group, such as for example halo, for example, bromine and the like, in the presence of a suitable base, such as for example sodium hydride or K2CO3 or triethylamine or 4-dimethylamino-pyridine or diisopropylamine and a suitable solvent, such as for example N, N-dimethylformamide or acetonitrile or dichloromethane.
Compounds of formula (I) in which R1 represents hydrogen can also be converted into a compound of formula (I) in which R1 represents C1-6-OH alkyl by reaction with W-C1-6-O-Si (CH3) 2 alkyl (C (CH3) 3) in the presence of a suitable base, such as for example sodium hydride and a suitable solvent, such as for example N, N-dimethylformamide.
The compounds of formula (I) in which R1 represents hydrogen, can also be converted into a compound of formula (I) in which R1 represents ethyl substituted with -S (= O) 2-C1-6 alkyl, by reaction with C1-4 alkyl. 6-vinylsulfone, in the presence of a suitable base, such as for example triethylamine and a suitable solvent, such as for example an alcohol, for example, methanol or by reaction with C1-6-2-bromoethylsulfonone in the presence of an agent suitable deprotection, such as for example NaH and a suitable solvent, such as for example dimethylformamide.
Compounds of formula (I) in which R1 represents hydrogen can also be converted into a compound of formula (I) in which R1 represents
in the presence of a suitable base, such as for example sodium hydride and a suitable solvent, such as for example N, N-dimethylformamide.
The compounds of formula (I) in which R1 represents R6-substituted C1-6 alkyl in which said R6 is substituted with -C (= O) -O-C1-6 alkyl or -S (= O) 2-NR14R15OU in whereas R3a represents C1-6 alkyl substituted with R1) wherein said R9 is substituted with -C (= O) -O-C1-6 alkyl or -S (= O) 2-NR14R15, can be converted into a compound of formula (I) in which R6 or R9 are unsubstituted by reaction with a suitable acid, such as for example HCI and a suitable solvent, such as for example dioxane, acetonitrile or an alcohol, for example, isopropyl alcohol. The compounds of formula (I) in which R1 represents R6-substituted C1-6 alkyl in which said R6 is a portion of the ring comprising a nitrogen atom which is substituted with -CH2-OH or in which R3a represents C1-alkyl 6 substituted with R9 wherein said R9 is a portion of the ring comprising a nitrogen atom which is substituted with -CH2-OH, can be converted into a compound of formula (I) in which R6 or R9 are unsubstituted, by reaction with sodium hydroxide, in the presence of a suitable solvent, such as for example tetrahydrofuran.
The compounds of formula (I) in which R1 represents R6-substituted C1-6 alkyl or R3a represents R9-substituted C1-6 alkyl, in which said R6 or said R9 are unsubstituted, can be converted into a compound of the formula (I) in which said R6 or said R9 are replaced with C1-6 alkyl, by reaction with W-C1-6 alkyl where W is as defined above, in the presence of a suitable base. Such as for example sodium hydride and a suitable solvent, such as for example N, N-dimethylformamide.
The compounds of formula (I) in which R1 or R3a represent C1-6 hydroxyalkyl, can be converted into the corresponding carbonyl compound by reaction with Dess-Martin periodinane, in the presence of a suitable solvent, such as for example dichloromethane.
The compounds of formula (I) in which R1 represents R6-substituted C1-6 alkyl or R3a represent R9-substituted C1-6 alkyl, wherein said R6 or said R9 are substituted with C1-6-halo alkyl, can be converted to a compound of formula (I) in which said R6 or said R9 are replaced with C1-6-CN alkyl, by reaction with sodium cyanide, in the presence of a suitable solvent, such as for example water or an alcohol , for example, ethanol.
The compounds of formula (I) in which R1 represents C1-6 alkyl substituted with R6 in which said R6 is unsubstituted or in which R3 represents C1-6 alkyl substituted by R9 in which said R9 is unsubstituted can be converted to a compound of formula (I) in which R6 or R9 are replaced with -CH3 or -CH (CH3) 2, by reaction with formaldehyde or acetone and NaBH, CN, in the presence of a suitable solvent, such as for example tetrahydrofuran or a alcohol, for example, methanol.
Compounds of formula (I) in which R1 contains an OH-substituted R6 substituent or in which R3a contains an OH-substituted R9 substituent can be converted to a compound of formula (I) in which R6 or R9 substituents are substituted with C1-6alkoxy, by reaction with W-C1-6alkyl, in the presence of a suitable base, such as for example sodium hydride and a suitable solvent, such as for example N, N-dimethylformamide.
The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) -O- C1-6 alkyl, can be converted to a compound of formula (I) in which R3a represents C1-6 alkyl replaced with COOH, by reaction with LiOH in the presence of a suitable solvent, such as for example tetrahydrofuran. Said compounds of formula (I) wherein R3a represents C1-6 alkyl substituted with COOH, can be converted to a compound of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) -NH2 OR -C (= O) -NHCH ,, by reaction with NH (Si (CH3) s) 2 or MeNH3 + Cl_ in the presence of suitable peptide binding reagents such as for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl and 1-hydroxybenzotriazole, a suitable base, such as for example triethylamine and a suitable solvent such as for example dichloromethane. The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= O) -O- C1-6 alkyl, can also be converted into a compound of formula (I) in which R3a represents C1- alkyl 6 replaced with 2-imidazolyl by reaction under N2 with ethylenediamine and trimethylalumin in the presence of a suitable solvent, such as for example toluene and heptane. This compound of formula (I) in which R3a represents C-6 alkyl substituted with 2-imidazolyl, can be converted to a compound of formula (I) in which R3a represents C-6 alkyl substituted with -C (= O) -NH - (CH2) 2-NH2 by reaction with sodium hydroxide.
The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with, can be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with 2 OH's, by reaction with a suitable acid, such as for example trifluoroacetic acid, and a suitable solvent, such as for example dioxane or water. These compounds of formula (I), in which R3a represents C1-6 alkyl substituted with, can also be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with OH and NR10Rn, by reaction with NH2R10Rn optionally in saline form, such as such as NHR1OR11 + C1, optionally in the presence of a suitable base, such as for example sodium hydride or Na2CO3 or triethylamine or Kl and in the presence of a suitable solvent, such as for example N, N-dimethylformamide or an alcohol, for example example, 1-butanol or ethanol. The compounds of formula (I) in which R3a represents C1.3 alkyl substituted with - C (= O) -O- C1-6 alkyl, can be converted to a compound of formula (I) in which R3a represents C_3 alkyl substituted with -C (CH3) 2-OH, by reaction with iodomethane and Mg powder, in the presence of a suitable solvent, such as for example diethyl ether or tetrahydrofuran.
The compounds of formula (I) in which R3a represents -CH2-CH = CH2, can be converted to a compound of formula (I) in which R3a represents -CH2-CHOH-CH2-OH, by reaction with potassium permanganate and a suitable solvent, such as for example acetone or water.
The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with -C (= OJ- C1-4 alkyl, can be converted to a compound of formula (I) where R3a represents C1-6 alkyl substituted with - C (CI-4 alkyl) = N-OH, by reaction with hydroxylamine, in the presence of a suitable base, such as for example pyridine and a suitable solvent, such as for example an alcohol, for example, ethanol.
The compounds of formula (I) in which R3a represents C1-6 alkyl substituted with NH2, can be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with - NH-C (= O) -R6 or with - NH-C (= O) -C1-6 alkyl or with -NH-C (= O) -polyhydroxy-C1-6 alkyl or with - NH-C (= O) -Polyalkyl C1-6 or with - NH-C (= OJ-polyhydroxypolialoCvalquila, by reaction with the corresponding COOH analogue, for example, R6-COOH or CF3-C (CH3) (OH) - COOH and the like, in the presence of suitable peptide binding reagents such as 1-hydroxy-benzotriazole and 1- (3-dimethylamino) -propyl) carbodiimide optionally in the presence of a suitable base, such as for example triethylamine. Said compounds of formula (I) in which R3a represents C1-6 alkyl substituted with NH2, can also be converted into a compound of formula (I) in which R3a represents C1-6 alkyl substituted with NHC (= O) - CF3, by reaction with trifluoroacetic anhydride, in the presence of a suitable base, such as for example triethylamine and a suitable solvent, such as for example tetrahydro-furan. Said compounds of formula (I) in which R3a represents C1-6 alkyl substituted with NH2, can also be converted to a compound of formula (I) in which R3a represents C1-6 alkyl substituted with -NH- C1-6 polyalkylalkyl, for example, -NH-CH2-CH2-F, by reaction with C 1-6 -W polyalkylalkyl, with W as defined above, for example, iodine-2-fluoroethane, in the presence of a suitable base, such as for example K2CO3 and a suitable solvent, such as for example N, N-dimethylformamide or dioxane.
Compounds of formula (I) in which R3a represents cyano-substituted C1-6 alkyl can be converted to a compound of formula (I) in which R3a represents tetrazolyl-substituted C1-6 alkyl by reaction with sodium azide and NH4 + CT in the presence of a suitable solvent, such as for example N, N-dimethylformamide.
The compounds of formula (I) in which R3a represents CH2-C = CH, can be converted into a compound of formula (I) in which R3a represents
by reaction with ethyl azidoacetate in the presence of Cul and a suitable base, such as for example diisopropylamine and a suitable solvent, such as for example tetrahydrofuran.
Compounds of formula (I) in which R3a represents C1I <C cn, can be converted into a compound of formula (I) in which R3a represents
by reaction with sodium azide and formaldehyde, in the presence of a suitable catalyst, such as for example CUSO4 and L sodium ascorbate, a suitable acid, such as for example acetic acid and a suitable solvent, such as for example dioxane.
The compounds of formula (I) in which R3a represents C2-6 alkynyl, can be converted into a compound of formula (I) in which R3a represents R9-substituted C2-6 alkynyl by reaction with W-R9 where W is as defined above, in the presence of a suitable catalyst, such as for example dichlorobis (triphenylphosphino) palladium, a suitable co-catalyst such as Cul, a suitable base, such as for example triethylamine and a suitable solvent, such as for example dimethyl sulfoxide .
The compounds of formula (I) in which R3a represents NR '° substituted C1-6 alkyl (benzyl) can be converted to a compound of formula (I) in which R3a represents NHR10-substituted C1-6 alkyl by reaction with chloroformiate 1-chloroethyl in the presence of a suitable solvent, such as for example dichloromethane
The compounds of formula (I) in which R2 represents halo, for example, bromine, can be converted into a compound of formula (I) in which R2 represents cyano, by reaction with zinc cyanide, in the presence of a suitable catalyst, such as as for example Pd2 (dba) 3 and a suitable ligand, such as for example 1,1-bis (diphenylphosphino) ferrocene, in the presence of a suitable solvent, such as for example N, N-dimethylformamide.
Said substituent R2 being cyano can be converted to -CH2-NH2 by hydrogenation in the presence of NH3 and Nickel.
Another aspect of the invention is a process for the preparation of a compound of formula (I) as defined herein, which process comprises: (I) reacting an intermediate of formula (IV) in which Wi represents a suitable starting group, with an intermediate of formula (V) in the presence of a suitable catalyst, a suitable base and a suitable solvent or solvent mixture,

With R1, R2 en as defined herein; (1a) reacting an intermediate of formula (VI) where W3 represents a suitable starting group, with an intermediate of formula (XIII) in the presence of CO, a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent,

With R1, R2 en as defined herein; (lib) reacting an intermediate of formula (VI ') where W3 represents a suitable starting group, with an intermediate of formula (XIII) in the presence of CO, a suitable catalyst, a suitable ligand,

With R1, R2, Rla and as defined herein; (llla) reacting an intermediate of formula (VII) with an intermediate of formula (VIII) in which W2 represents a suitable starting group, in the presence of a catalyst, a suitable base and a suitable solvent,

With R1, R2 en as defined herein; (Illb) reacting an intermediate of formula (VII ') with an intermediate of formula (VIII) in which W2 represents a suitable starting group, in the presence of a catalyst, a suitable base and a suitable solvent,

With R1, R2, Rla and as defined herein; (IVa) reacting an intermediate of formula (VI) with an intermediate of formula (IX) in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent,

With R1, R2, R3 'en as defined herein; (IVb) reacting an intermediate of formula (VI ') with an intermediate of formula (IX) in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent,

With R1, R2, Rla, R3c and as defined herein; (Va) reacting an intermediate of formula (XI) with an intermediate of formula (XII) where W4 represents a suitable starting group, in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent,

With R1, R2, Race n as defined herein; (Vb) reacting an intermediate of formula (XI ') with an intermediate of formula (XII) where W4 represents a suitable starting group, in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent ,

With R1, R2, Rla, R3c and as defined herein; (Via) deprotect an intermediate of formula (XIV) in the presence of a suitable acid and a suitable solvent,

With R1, R2, R11 and as defined herein; (VIb) deprotect an intermediate of the formula (XIV ') in the presence of a suitable acid and a suitable solvent,

With R1, R2, R1a, R11 and as defined herein; (Vila) to react an intermediate of formula (XIX) with an intermediate of formula (VI) in the presence of a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent,

With R1, R2, R10, R11 and as defined herein; (Vllb) to react an intermediate of formula (XIX) with an intermediate of formula (VI ') in the presence of a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent,

With R1, R2, Rla, R10, R11 and as defined herein; (Villa) to react an intermediate of the formula (XXI) with a suitable reducing agent and a suitable solvent,

With R1, R2 en as defined herein; (VTTTb) react an intermediate of formula (XXI ') with a suitable reducing agent and a suitable solvent,

With R1, R2, Rla and as defined herein; (IXa) an intermediate of the formula (XXIII) reacts in which Ws represents a suitable starting group, with NHR11 in the presence of a suitable solvent,

With RJ, R2, R11 en as defined herein; (IXb) an intermediate of the formula (XXIII ') reacts in which W5 represents a suitable starting group, with NHR11 in the presence of a suitable solvent,

With R1, R2, Rla, R11 and as defined herein; (Xa) react an intermediate of the formula (XXI) with magnesium in the presence of a suitable solvent,

With R1, R2, Rla and as defined herein; (Xb) reacting an intermediate of the formula (XXI ') with magnesium in the presence of a suitable solvent,

With R1, R2, Rla and as defined herein; (Xia) reacting an intermediate of the formula (XXIV) with potassium cyanide in the presence of a suitable solvent,

With R1, R2 en as defined herein; (Xlb) to react an intermediate of the formula (XXIV ') with potassium cyanide in the presence of a suitable solvent,

With R1, R2, Rla and as defined herein; (Xlla) react an intermediate of the formula (XXIV) with HR9 in the presence of a suitable base and a suitable solvent,

With R1, R2, R9 and as defined herein; (Xllb) to react an intermediate of the formula (XXIV ') with HR9 in the presence of a suitable base and a suitable solvent,

With R1, R2, Rla, R9 en as defined herein; (Xllla) to react an intermediate of the formula (XXV) with NHR10Rn in the presence of a suitable solvent,

With R1, R2, R10, R11 and as defined herein; (XlIIb) to react an intermediate of the formula (XXV ') with NHR10Rn in the presence of a suitable solvent,
with R1, R2, Rla, R10, R11 and as defined herein; (XlVa) an intermediate of the formula (XXX) reacts in which P represents a suitable protecting group, with a suitable acid in the presence of a suitable solvent

With R1, R2 en as defined herein; (XlVb) an intermediate of the formula (XXX ') reacts in which P represents a suitable protecting group, with a suitable acid in the presence of a suitable solvent

With R1, R2, Rla and as defined herein; (XVa) react a compound of the formula (Ib-3) with a reducing agent H in the presence of a suitable solvent,

With R1, R2 en as defined herein; (XVb) reacting a compound of the formula (I-b'-3) with a reducing agent H in the presence of a suitable solvent,

With R1, R2, Rla and n as defined herein; (XVI) converting a compound of formula (I) to another compound of formula (I).
In another embodiment, the invention provides a new intermediate. In one embodiment, the invention provides a new intermediate of formula (II) - (XXV). In another embodiment the invention provides a compound of the formula Ia, I'-a, I ”-a, I '” - a, Ib, I'-b, I ”-b, I'” - b, F -b ', l ”-b', l” 'b', Ic, I'-c, I ”-c, I '” - c, Id, Fd, I ”-d, l”' - d, Io , Ib-1, I-b-2, Ib-3, Ic-1, Ic-2, Ic-3, Ic-4, Id-1,1-e, I-a ', I-b', I -b'-l, I-b'-2,1-b'-3,1- c'-l, I-c'-2,1-c'-4,1-d'-l, I- and ', l-c'-3. Salts, Solvates or their Pharmaceutically Acceptable Derivatives
In this section, as in all other sections of this application, unless the context otherwise indicates, references to formula (I) include references to all other subgroups, preferences, embodiments and their examples as defined herein.
Unless otherwise specified, a reference to a particular compound also includes ionic forms, salts, solvates, isomers (which include stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and their protected forms, for example , as discussed below; preferably, the ionic forms, or their salts or tautomers or isomers or N-oxides or solvates; and more preferably, the ionic forms, or salts or tautomers or solvates or their protected forms, even more preferably their salts or tautomers or solvates. Many compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All of such salts are within the scope of this invention and references to the compounds of formula (I) include the salt forms of the compounds. It will be assessed that references to “derivatives” include references to ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and their protected forms.
According to one aspect of the invention, a compound as defined herein or a salt, stereochemical isomer, tautomer, N-oxide or solvate thereof is provided. According to another aspect of the invention there is provided a compound as defined herein or a salt, tautomer, N-oxide or solvate thereof. According to another aspect of the invention, a compound as defined herein or a salt or solvate thereof is provided. References to compounds of formula (I) and their subgroups as defined herein include within their scope the salts or solvates or tautomers or N-oxides of the compounds.
The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 119. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms which can then be converted to pharmaceutically acceptable salts. Such forms other than pharmaceutically acceptable salts, which can be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
The salts of the present invention can be synthesized from the precursor compound that contains a basic or acidic portion by conventional chemical methods such as the methods described in Pharmaceutical Salts: Properties, Selection and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. In general, such salts can be prepared by reacting the free acid and base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or a mixture of the two; in general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the invention can exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed.
Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic acids (e.g., L-ascorbic), L-aspartic, benzenesulfonic, benzoic , 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+) - (lS)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclical, dodecylsulfuric, ethane-l, 2- disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactic, gentisic, glycoheptonic, D-glyconic, glycuronic (eg, D-glucuronic), glutamic (eg, L-glutamic), glycolic a-oxoglutaric, hypuric, hydrobromic , hydrochloric, iodide, isethionic, lactic (e.g., (+) - L-lactic, (±) -DL-lactic), lactobionic, maleic, malic, (-) - L-malic, malonic, (±) -DL -mandelic, methanesulfonic, naphthalenesulfonic (for example, naphthalene-2-sulfonic), naphthalene-1,5-disulfonic, l-hydroxy-2-naphthoic, nicotinic, nitric, leic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, pyruvic, salicylic, 4-amino-salicylic, sebaceous, stearic, succinic, sulfuric, tannic, (-i -) - Thiocyanic L-tartaric, toluenesulfonic (eg, p-toluenesulfonic), undecylenic and valeric, as well as acylated amino acids and cation exchange resins.
A particular group of salts consists of salts formed from acetic, hydrochloric, iodide, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate, ethanate) naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glycuronic and lactobionic. Another group of acid addition salts includes salts formed from acetic, adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, glyconic, glyuronic, hypuric, hydrochloric, glutamic, DL-malic, methanesulfonic, sebatic, stearic, succinic and tartaric.
If the compound is anionic, or has a functional group that can be anionic (for example, -COOH can be -COO), then a salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K +, alkaline earth metal cations such as Ca2 + and Mg2 + and other cations such as Al3 +. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (for example, NH3R +, NH2R2 +, NHR3 +, NR4 +).
Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids, such as lysine and arginine . An example of a common quaternary ammonium ion is N (CH3) 4+.
Where the compounds of the formula (I) contain an amine function, they can form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I). The compounds of formula (I) which contain an amine function can also form N-oxides. A reference here to a compound of formula (I) which contains an amine function also includes N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (for example, a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience , pages. More particularly, N-oxides can be manufactured by the LW Deady procedure (Syn. Comm. (1977), 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
The compounds of the invention can form solvates, for example with water (i.e., hydrates) or common organic solvents. As used herein, the term "solvate" means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, which include hydrogen bonding. In certain cases the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. The term "solvate" is intended to cover solvates both in the solution phase and in isolation. Non-limiting examples of suitable solvates include the compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the invention can exert their biological effects while in solution.
Solvates are well known in pharmaceutical chemistry. They can be important for the processes for the preparation of a substance (for example, in relation to its purification, the storage of the substance (for example, its stability) and the ease of handling of the substance and are often formed as part of the stages of isolation or purification of a chemical synthesis A person skilled in the art can determine by means of standard and long-used techniques whether a hydrate or other solvates were formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (for example, single-crystal X-ray crystallography or X-ray powder diffraction) and NMR and Solid State (SS-NMR, also known as Magic-Angle Rotating NMR or MAS-NMR.) Such techniques are just as much a part of the chemist's standard analytical toolkit enabled as NMR, IR, HPLC and MS. Alternatively, the skilled person can deliberately form a solvate using crystallization conditions that include an amount of the solvent required for the particular solvate. Consequently, the standard methods described above can be used to establish whether solvates have formed. Also covered by formula (I) are any complexes (for example, inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds. In addition, the compounds of the present invention can have one or more polymorphic (crystalline) forms or amorphous forms and as such are intended to be included in the scope of the invention.
The compounds of formula (I) can exist in several different isomeric and tautomeric geometric forms and references to compounds of formula (I) all include such forms. For the avoidance of doubt, where a compound can exist in one of several isomeric or tautomeric geometric shapes and only one is specifically described or shown, all others are nevertheless covered by formula (I). Other examples of forms include, for example, the keto-, enol- and enolate forms, as, for example, in the tautomeric pairs that follow: keto / enol (illustrated below), imine / enamine, imide / imino alcohol, amidine / enediamines , nitrous / oxime, thiocet / enethiol and nitro / aci-nitro.

Where compounds of formula (I) contain one or more chiral centers and can exist in the form of two or more optical isomers, references to compounds of formula (I) include all of their optical isomeric forms (for example, enantiomers, epimers and diastereoisomers ), as individual optical isomers, or mixtures (for example, racemic mixtures) of two or more optical isomers, unless the context requires otherwise. Optical isomers can be characterized and identified by their optical activity (that is, as isomers + and -, or isomers of /) or they can be characterized in terms of their absolute stereochemistry using the nomenclature "R and S" developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114 and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415. Optical isomers can be separated by various techniques that include chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by the formation of diastereoisomeric salts with chiral acids such as (+) - tartaric acid, (-) -pyroglutamic acid, (-) - di-toluoyl-L-tartaric acid , (+) - mandelic acid, (-)-malic acid and (-) - camphorsulfonic acid, separating the diastereoisomers by preferential crystallization and then dissociating the salts to give the individual enantiomer from the free base.
Where the compounds of formula (I) exist as two or more optical isomeric forms, an enantiomer in a pair of enantiomers can exhibit advantages over other enantiomers, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or just one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound of the formula (I) having one or more chiral centers, in which at least 55% (for example, at least 60%, 65%, 70%, 75%, 80%, 85 %, 90% or 95%) of the compound of formula (I) is present as a single optical isomer (for example, enantiomer or diastereoisomer). In a general embodiment, 99% or more (for example, substantially all) of the total amount of the compound of formula (I) can be present as a single optical isomer (for example, enantiomer or diastereoisomer).
The compounds of the invention include compounds with one or more isotopic substitutions and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D) and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 12O, 13C and 14O and 16O and 18O. Isotopes can be radioactive or non-radioactive. In an embodiment of the invention, the compound does not contain any radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound can contain one or more radioisotopes. The compounds that contain such radioisotopes can be useful in a diagnostic context.
Esters such as carboxylic acid esters and acyloxy esters of the compounds of formula (I) which carry a carboxylic acid group or a hydroxyl group are also covered by formula (I). In an embodiment of the invention, formula (I) includes within its scope esters of compounds of formula (I) which carry a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of formula (I) that carry a carboxylic acid group or a hydroxyl group. Examples of esters are compounds containing the group - C (= O) OR, where R is a substituent ester, for example, a C1-6 alkyl group, a heterocyclyl group, or a C5-20 aryl group, preferably a C1-6 alkyl group. Particular examples of ester groups include, but are not limited to, -C (= O) OCH3, -C (= O) OCH2CH3, -C (= O) OC (CH3) 3 and - C (= O) OPh . Examples of acyloxy groups (reverse ester) are represented by -OC (= O) R, where R is an acyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5 aryl group -20, preferably a C1-7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC (= O) CH3 (acetoxy), - OC (= O) CH2CH3, -OC (= O) C (CH3) 3, -OC (= O ) PII and -OC (= O) CH2Ph.
For example, some prodrugs are esters of the active compound (for example, a physiologically acceptable metabolically unstable ester). By "pro drugs" is meant, for example, any compound that is converted in vivo to a biologically active compound of the formula (I). During metabolism, the ester group (- C (= O) OR) is cleaved to produce the active drug.
Such esters can be formed by esterifying, for example, any of the carboxylic acid (-C (= O) OH) groups in the precursor compound, with, where appropriate, before protecting any of the other reactive groups present in the precursor compound , followed by deprotection if required.
Examples of such metabolically unstable esters include those of the formula -C (= O) OR where R is: C1-6 alkyl (for example, -Me, -Et, -nPr, -iPr, -nBu, -sBu, - iBu, -tBu); C1-6 aminoalkyl [e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) -ethyl); and acyloxy-alkyl-C1-7 [e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxycarbonyloxymethyl; 1-isopropoxycarbonyloxyethyl; cyclohexylcarbonyloxymethyl; 1 -cyclohexylcarbonyloxyethyl; cyclohexyloxycarbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1 - (4-tetrahydro-pyranyloxy) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxymethyl; and 1 - (4-tetrahydropyranyl) carbonyloxyethyl]. Also, some prodrugs are enzymatically activated to produce the active compound, or a compound that, in another chemical reaction, produces the active compound (for example, as in antigen-directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug (GDEPT) and ligand directed enzyme prodrug therapy (LIDEPT) etc.). For example, the prodrug can be a sugar derivative or other glycoside conjugate, or it can be an amino acid ester derivative. Protein Tyrosine Kinases (PTK)
The compounds of the invention described herein inhibit or modulate the activity of certain tyrosine kinases and thus the compounds will be useful in the treatment or prophylaxis, in particular in the treatment, of disease states or conditions mediated by these tyrosine kinases, in particular FGFR. FGFR
The fibroblast growth factor (FGF) family of protein tyrosine kinase (PTK) receptors regulates a diverse array of physiological functions including mitogenesis, wound healing, cell differentiation and angiogenesis and development. Both normal and malignant cell growth and proliferation are affected by changes in the local concentration of FGFs, the extracellular signaling molecules that act as autocrine as well as paracrine factors. Autocrine FGF signaling can be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state. FGFs and their receptors are expressed at increased levels in various tissues and cell lines and overexpression is believed to contribute to the malignant phenotype. In addition, several oncogenes are homologues of genes encoding growth factor receptors and there is a potential for aberrant activation of FGF-dependent signaling in human pancreatic cancer (Knights et al., Pharmacology and Therapeutics 2010 125: 1 (105-117 ); Korc M. et al Current Cancer Drug Targets 2009 9: 5 (639-651)).
The two prototypical members are the acid fibroblast growth factor (aFGF or FGF1) and the basic fibroblast growth factor (bFGF or FGF2) and so far, at least twenty distinct members of the FGF family have been identified. The cellular response to FGFs is transmitted via four types of fibroblast growth factor (FGFR) receptors for high-affinity transmembrane protein tyrosine kinase numbered 1 to 4 (FGFR1 to FGFR4).
The disruption of the FGFR1 pathway should affect tumor cell proliferation since this kinase is activated in many types of tumor in addition to proliferating endothelial cells. The overexpression and activation of FGFR1 in the tumor-associated vasculature has suggested a role for these molecules in tumor angiogenesis.
A recent study has shown a link between FGFR1 expression and tumorigenicity in Classic Lobular Carcinomas (CLC). CLCs are responsible for 10 to 15% of all breast cancers and, in general, lack the expression of p53 and Her2 while retaining the expression of the estrogen receptor. A gene amplification of 8pl2-pl 1.2 has been demonstrated in ~ 50% of CLC cases and this has been shown to be linked with increased expression of FGFR1. Preliminary studies with siRNA directed against FGFR1, or a small molecule inhibitor of the receptor, showed that the cell lines that harbor this amplification are particularly sensitive to inhibition of this signaling pathway. Rhabdomyosarcoma (RMS), which is the most common pediatric soft tissue sarcoma, probably results from abnormal proliferation and differentiation during skeletal myogenesis. FGFR1 is overexpressed in primary rhabdomyosarcoma tumors and is associated with hypomethylation of a 5 'CpG island and abnormal expression of the AKT1, NOG and BMP4 genes. FGFR1 has also been linked to squamous lung cancer, colorectal cancer, glioblastoma, astrocytomas, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer.
The fibroblast growth factor 2 receptor has a high affinity for acidic and / or basic fibroblast growth factors, as well as keratinocyte growth factor ligands. The fibroblast growth factor 2 receptor also propagates the potent osteogenic effects of FGFs during osteoblast growth and differentiation. Mutations in the fibroblast growth factor 2 receptor, which lead to complex functional changes, have been shown to induce abnormal ossification of cranial sutures (craniosynostosis), implying a major role of FGFR signaling in intramembranous bone formation. For example, in Apert syndrome (AP), characterized by the ossification of premature cranial suture, most cases are associated with point mutations that engender gain of function in the fibroblast growth factor 2 receptor. In addition, the mutation screening in patients with syndromic craniosynostosis it indicates that several recurrent FGFR2 mutations are responsible for the severe forms of Pfeiffer syndrome. Particular mutations 118 of FGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2.
Several severe anomalies in human skeletal development, including Apert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata and Pfeiffer syndromes, are associated with the occurrence of mutations in the fibroblast growth factor 2 receptor. Most, if not all cases of Pfeiffer Syndrome (PS) are also caused by the de novo mutation of the fibroblast growth factor 2 receptor gene and it has recently been shown that mutations in the fibroblast growth factor 2 receptor disrupt one of the cardinal rules that control the specificity of ligand. Namely, two forms of fibroblast growth factor receptor mutant junction, FGFR2c and FGFR2b, have acquired the ability to bind to and be activated by atypical FGF ligands.
This loss of ligand specificity leads to aberrant signaling and suggests that the severe phenotypes of these disease syndromes result from the ectopic ligand-dependent activation of fibroblast growth factor 2 receptor.
Genetic aberrations of FGFR3 receptor tyrosine kinase such as chromosomal translocations or point mutations result in ectopically expressed or unregulated, constitutively active FGFR3 receptors. Such abnormalities are linked to a subset of myelomas and in bladder, hepatocellular, oral squamous cell and cervical carcinoma carcinoma. Consequently, FGFR3 inhibitors would be useful in the treatment of multiple myeloma, bladder and cervical carcinomas. FGFR3 is also overexpressed in bladder cancer, in particular invasive bladder cancer. FGFR3 is often activated by a mutation in urothelial carcinoma (UC). Increased expression was associated with the mutation (85% of the mutant tumors showed high-level expression) but also 42% of the tumors with no detectable mutation showed overexpression, which include many invasive muscle tumors. FGFR3 is also linked to endometrial and thyroid cancer.
The overexpression of FGFR4 has been linked to an insufficient prognosis in prostate and thyroid carcinoma. In addition, a germline polymorphism (Gly388Arg) is associated with an increased incidence of lung, breast, colon, liver (HCC) and prostate cancers. In addition, a truncated form of FGFR4 (which includes the kinase domain) has also been found to be present in 40% of pituitary tumors but not present in normal tissue. Overexpression of FGFR4 was observed in liver, colonic and lung tumors. FGFR4 has been implicated in colorectal and liver cancers where the expression of its FGF 19 ligand is often elevated. FGFR4 is also linked to astrocytomas, rhabdomyosarcoma.
Fibrotic conditions are a major medical problem that results from abnormal or excessive deposition of fibrous tissue. This occurs in many diseases, including liver cirrhosis, glomerulo nephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural wound healing process. The mechanisms of pathological fibrosis are not fully understood but are considered to result from the actions of various cytokines (which include tumor necrosis factor (TNF), fibroblast growth factors (FGF's), platelet-derived growth factor (PDGF) and transforming growth beta (TGFβ) involved in the proliferation of fibroblasts and the deposition of extracellular matrix proteins (which include collagen and fibronectin), resulting in alteration of the structure and function of the tissue and the subsequent pathology.
Several preclinical studies have demonstrated the over-regulation of fibroblast growth factors in preclinical models of pulmonary fibrosis. TGFβl and PDGF have been reported to be involved in the fibrogenic process and another published work suggests an increase in FGF’s and the consequent increase in fibroblast proliferation, may be in response to elevated TGFβl. The potential therapeutic benefit of targeting the fibrotic mechanism in conditions such as idiopathic pulmonary fibrosis (IPF) is suggested by the reported clinical effect of the anti-fibrotic agent pirfenidone. Idiopathic pulmonary fibrosis (also referred to as cryptogenic fibrosing alveolitis) is a progressive condition that involves excoriation of the lung. Gradually, the air sacs in the lungs become replaced by fibrotic tissue, which thickens, causing an irreversible loss of the tissue's ability to transfer oxygen into the bloodstream. Symptoms of the condition include shortness of breath, chronic dry cough, fatigue, chest pain and loss of appetite resulting in rapid weight loss. The condition is extremely serious with approximately 50% mortality after 5 years.
As such, compounds that inhibit FGFR will be useful in providing a means of preventing the growth and induction of apoptosis in tumors, particularly by inhibiting angiogenesis. It is therefore anticipated that the compounds will prove useful in the treatment or prevention of proliferative disorders such as cancers. In particular tumors with receptor tyrosine kinase activation mutants or receptor tyrosine kinase upregulation may be particularly sensitive to inhibitors. Patients with activation mutants of any of the specific RTK isoforms discussed here may also find treatment with RTK inhibitors particularly beneficial. Vascular Endothelial Growth Factor (VEGFR)
Chronic proliferative diseases are often accompanied by profound angiogenesis, which can contribute to or maintain an inflammatory and / or proliferative state, or which leads to tissue destruction through the invasive proliferation of blood vessels.
Angiogenesis is generally used to describe the development of new or replacement blood vessels, or neovascularisation. It is a necessary and physiological normal process by which the vasculature is established in the embryo. Angiogenesis does not occur, in general, in most normal adult tissues, the exceptions being the ovulation, menstruation and wound healing sites. Many diseases, however, are characterized by persistent and unregulated angiogenesis. For example, in arthritis, new capillary blood vessels invade the joints and destroy cartilage. In diabetes (and many different eye diseases), new vessels invade the macula or retina or other eye structures and can cause blindness. The atherosclerosis process has been linked to angiogenesis. Tumor growth and metastasis has been found to be dependent on angiogenesis.
The recognition of the involvement of angiogenesis in the main diseases has been accompanied by research to identify and develop inhibitors of angiogenesis. These inhibitors are generally classified in response to separate targets in the angiogenesis cascade, such as in activation of endothelial cells by an angiogenic signal; synthesis and release of degradative enzymes; endothelial cell migration; proliferation of endothelial cells; and formation of capillary tubules. Therefore, angiogenesis occurs in many stages and attempts are underway to discover and develop compounds that work to block angiogenesis in these various stages.
There are publications that disclose that angiogenesis inhibitors, which work by several mechanisms, are beneficial in diseases such as cancer and metastasis, eye diseases, arthritis and hemangioma.
The vascular endothelial growth factor (VEGF), a polypeptide, is mitogenic for endothelial cells in vitro and stimulates angiogenic responses in vivo. VEGF has also been linked to inadequate angiogenesis 122. VEGFR (s) are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylation of specific tyrosine residues in proteins involved in cell function, thereby regulating cell growth, survival and differentiation.
Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1); VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction. Of particular interest is VEGFR-2, which is a PTK transmembrane receptor expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the path of signal transduction that initiates tumor angiogenesis. VEGF expression can be constitutive for tumor VEGF cells and can also be upregulated in response to certain stimuli. One such stimulus is hypoxia, where VEGF expression is over-regulated in both the tumor and associated host tissues. The VEGF ligand activates VEGFR-2 by binding to its extracellular VEGF binding site. This leads to VEGFRs receptor dimerization and autophosphorylation of tyrosine residues in the VEGFR-2 intracellular kinase domain. The kinase domain operates to transfer an ATP phosphate to tyrosine residues, thus providing binding sites for protein signaling downstream of VEGFR-2 leading to the onset of angiogenesis.
Inhibition at the VEGFR-2 kinase domain binding site would block tyrosine residue phosphorylation and serve to disrupt the onset of angiogenesis.
Angiogenesis is a physiological process of formation of new blood vessels mediated by the various cytokines called angiogenic factors. Although its potential pathophysiological role in solid tumors has been extensively studied for more than 3 decades, the enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods in both bone marrow and lymph nodes in patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be completely elucidated, experimental data suggest that several angiogenic factors play a role in the progression of the disease. Biological markers of angiogenesis have also been shown to be of relevance in prognosis in CLL. This indicates that VEGFR inhibitors may also be of benefit to patients with leukemias such as CLL.
In order for a tumor mass to go beyond a critical size, it must develop an associated vasculature. It has been proposed that targeting a tumor vasculature would limit tumor expansion and be a useful cancer therapy. Observations of tumor growth indicated that small tumor masses may persist in tissue without any specific tumor vasculature. The growth arrest of non-vascularized tumors was attributed to the effects of hypoxia on the tumor center. More recently, a variety of pro-angiogenic and anti-angiogenic factors have been identified and led to the concept of “angiogenic change,” a process in which disruption of the normal ratio of angiogenic and inhibitory stimuli in a tumor mass allows for autonomous vascularization. The angiogenic change appears to be controlled by the same genetic changes that drive malignant conversion: the activation of oncogenes and the loss of tumor suppressor genes. Several growth factors act as positive regulators of angiogenesis. First among these are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin. Proteins such as thrombospondin (Tsp-1), angiostatin and endostatin function as negative regulators of angiogenesis.
Inhibition of VEGFR2 but not VEGFR1 markedly disrupts angiogenic change, persistent angiogenesis and initial tumor growth in a mouse model. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regressed during treatment after an initial period of growth suppression. This resistance to VEGF block involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other pro-angiogenic factors, which include members of the FGF family. These other pro-angiogenic signs are functionally involved in revascularization and resumption of tumor growth in the evasion phase, as FGF block communicates progression in the face of VEGF inhibition.
There is evidence for normalization of glioblastoma blood vessels and in patients treated with a pan-VEGF receptor tyrosine kinase inhibitor, AZD2171, in a phase 2 study. Determination of MRI of normalization in weight in combination with circulating biomarkers provides an effective means to assess the response to antiangiogenic agents. PDGFR
A malignant tumor is the product of uncontrolled cell proliferation. Cell growth is controlled by a delicate balance between factors that promote growth and that inhibit growth. In normal tissue the production and activity of these factors results in differentiated cells that grow in a controlled and regulated manner that maintains the normal integrity and functioning of the organ. The malignant cell has escaped this control; the natural balance is disturbed (through a variety of mechanisms) and unregulated, aberrant cell growth occurs. A growth factor of importance in tumor development is the plaque-derived growth factor (PDGF) which comprises a family of peptide growth factors that signal through cell surface tyrosine kinase receptors (PDGFR) and stimulate various cell functions that include growth, proliferation and differentiation. Advantages of a selective inhibitor
The development of FGFR kinase inhibitors with a differentiated selectivity profile provides a new opportunity for the use of these targeted agents in patient subgroups whose disease is induced by FGFR dysregulation. Compounds that exhibit reduced inhibitory action on additional kinases, particularly VEGFR2 and PDGFR-beta, offer the opportunity to have a different side effect or toxicity profile and as such allow a more effective treatment of these indications. VEGFR2 and PDGFR-beta inhibitors are associated with toxicities such as hypertension or edema respectively. In the case of VEGFR2 inhibitors, this hypertensive effect is often dose limiting, may be contraindicated in certain patient populations and requires clinical control. Biological Activity and Therapeutic Uses
The compounds of the invention and their subgroups have fibroblast growth factor receptor (FGFR) inhibitory or modulating activity and / or vascular endothelial growth factor receptor (VEGFR) inhibitory or modulating activity, and / or inhibitory or modulating activity platelet-derived growth factor receptor (PDGFR) and which will be useful in preventing or treating disease states or conditions described herein. In addition, the compounds of the invention and their subgroups, will be useful in preventing or treating kinase-mediated diseases or conditions. References to the prevention or prophylaxis or treatment of a disease state or condition such as cancer include within its scope alleviating or reducing the incidence of cancer.
As used herein, the term "modulation", as applied to the activity of a kinase, is intended to define a change in the level of biological activity of the protein kinase. Thus, modulation encompasses physiological changes that effect an increase or decrease in the activity of the relevant protein kinase. In the latter case, modulation can be described as "inhibition". Modulation can arise directly or indirectly and can be mediated by any mechanism and at any physiological level, which includes for example at the level of gene expression (which includes for example transcription, translation and / or post-translational modification), at the level of expression of genes that encode regulatory elements that act directly or indirectly on the levels of kinase activity. Thus, modulation may imply elevated / suppressed or over- or underexpressed kinase expression, which includes gene amplification (i.e., multiple gene copies) and / or expression increased or decreased by a transcriptional effect, as well as as hyper- (or hypo-) activity and (de) activation of protein kinase (s) (which include (de) activation) by the mutation (s). The terms “modulated”, “modulation” and “modular” must be interpreted accordingly.
As used herein, the term "mediated", as used for example, in conjunction with a kinase as described herein (and applied for example to the various physiological processes, diseases, conditions, conditions, therapies, treatments or interventions) is intended to operate limitingly so that the various processes, diseases, states, conditions, treatments and interventions for which the term is applied are those in which the kinase plays a biological role. In cases where the term is applied to a disease, state or condition, the biological role played by a kinase may be direct or indirect and may be necessary and / or sufficient for the manifestation of the symptoms of the disease, state or condition (or its etiology) or progression). Thus, kinase activity (and at particular aberrant levels of kinase activity, for example, kinase overexpression) need not necessarily be the proximal cause of the disease, state or condition: instead, diseases, kinase-mediated states or conditions include those having multifactorial etiologies and complex progressions in which the kinase in question is only partially involved. In cases where the term is applied to treatment, prophylaxis or intervention, the role played by the kinase may be direct or indirect and may be necessary and / or sufficient for the operation of the treatment, prophylaxis or result of the intervention. Thus, a disease state or condition mediated by a kinase includes the development of resistance to any particular cancer drug or treatment.
Thus, for example, the compounds of the invention may be useful in alleviating or reducing the incidence of cancer.
More particularly, the compounds of the formulas (I) and their subgroups are inhibitors of FGFRs. For example, the compounds of the invention have activity against FGFR1, FGFR2, FGFR3, and / or FGFR4 and in particular FGFRs selected from FGFR1, FGFR2 and FGFR3; or in particular the compounds of formula (I) and their subgroups are inhibitors of FGFR4.
Preferred compounds are compounds that inhibit one or more FGFR selected from FGFR1, FGFR2, FGFR3 and FGFR4. Preferred compounds of the invention are those having IC 50 values of less than 0.1 pM.
The compounds of the invention also have activity against VEGFR.
In addition, many of the compounds of the invention exhibit selectivity for FGFR 1, 2, and / or 3, and / or 4 compared to 0 VEGFR (in particular VEGFR2) and / or PDGFR and such compounds represent a preferred embodiment of the invention. In particular, the compounds exhibit selectivity in VEGFR2. For example, many of the compounds of the invention have IC50 values against FGFR1, 2 and / or 3 and / or 4 that are between one tenth and one hundredth of the IC50 against VEGFR (in particular VEGFR2) and / or PDGFR B. In particular the compounds Preferred inventions have at least 10 times more activity against or inhibiting FGFR in particular FGFR1, FGFR2, FGFR3 and / or FGFR4 than VEGFR2. More preferably the compounds of the invention have at least 100 times more activity against or inhibiting FGFR in particular FGFR1, FGFR2, FGFR3 and / or FGFR4 than VEGFR2. This can be determined using the methods described here.
As a consequence of their activity in modulating or inhibiting FGFR, and / or VEGFR kinases, the compounds will be useful in providing a means of preventing growth or inducing neoplasia apoptosis, particularly by inhibiting angiogenesis. It is therefore anticipated that the compounds will prove to be useful in the treatment or prevention of proliferative disorders such as cancers. In addition, the compounds of the invention would be useful in the treatment of diseases in which there is a disorder of proliferation, apoptosis or differentiation.
In particular tumors with VEGFR activating mutants or VEGFR upregulation and patients with high serum lactate dehydrogenase levels may be particularly sensitive to the compounds of the invention. Patients with activation mutants of any of the specific RTK isoforms discussed herein may also find treatment with the compounds of the invention particularly beneficial. For example, overexpression of VEGFR in acute leukemia cells where the clonal parent can express VEGFR. Also, particular tumors with activating or upregulating or overexpressing mutants of any of the FGFR isoforms such as FGFR1, FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to the compounds of the invention and so patients as discussed here with such particular tumors may also find treatment with the compounds of the invention particularly beneficial. It may be preferred that the treatment be related to or directed to a mutated form of one of the receptor tyrosine kinases, as discussed herein. The diagnoses of tumors with such mutations can be performed using techniques known to a person skilled in the art and as described herein such as RTPCR and FISH.
Examples of cancers that can be treated (or inhibited) include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (for example, colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (e.g. adenocarcinoma, small cell lung cancer and non-small cell lung cancer, squamous lung cancer), esophagus, head and neck, biliary bladder, ovary, pancreas (e.g. pancreatic exocrine carcinoma), stomach, gastrointestinal cancer (also known as gastric) (for example, gastrointestinal stromal tumors), cervix, endometrium, thyroid, prostate, or skin (for example squamous cell carcinoma or protruding dermatofibrosarcoma); pituitary cancer, a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B cell lymphoma (eg, diffuse large B cell lymphoma), T cell lymphoma, Hodgkin lymphoma, non-lymphoma Hodgkin's, hair cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome or promyelocytic leukemia; multiple myeloma; follicular thyroid cancer; hepatocellular cancer, a tumor of mesenchymal origin (for example, Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schvanoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctantoma; follicular thyroid cancer; or Kaposi's sarcoma. In particular, squamous lung cancer, breast cancer, colorectal cancer, glioblastoma, astrocytomas, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastric cancer, hepatocellular cancer, cancer of the cervix, multiple myeloma, bladder cancer, endometrial cancer, urothelial cancer, colonic cancer, rhabdomyosarcoma, cancer of the pituitary gland.
Certain cancers are resistant to treatment with private drugs. This may be due to the type of the tumor or it may arise due to treatment with the compound. In this regard, references to multiple myeloma include multiple myeloma sensitive to bortezomib or refractory multiple myeloma. Similarly, references to chronic myelogenous leukemia include chronic myelogenous leukemia sensitive to imitanib and refractory chronic myelogenous leukemia. Chronic myelogenous leukemia is also known as chronic myeloid leukemia, chronic granulocytic leukemia or CML. Likewise, acute myelogenous leukemia, is also called acute myeloblastic leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia or AML.
The compounds of the invention can also be used in the treatment of hematopoietic diseases of abnormal cell proliferation whether premalignant or stable such as myeloproliferative diseases. Myeloproliferative diseases ("MPD" s) are a group of bone marrow diseases in which excess cells are produced. They are related to, and may progress to, myelodysplastic syndrome. Myeloproliferative diseases include poilicitemia vera, essential thrombocythemia and primary myelofibrosis. Another hematological disorder is hypereosinophilic syndrome. T-cell lymphoproliferative diseases include those derived from natural killer cells.
In addition, the compounds of the invention can be used for gastrointestinal cancer (also known as gastric) for example, gastrointestinal stromal tumors. Gastrointestinal cancer refers to the malignant conditions of the gastrointestinal tract, which include the esophagus, stomach, liver, biliary system, pancreas, intestines and anus.
Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is a cancer.
Particular subsets of cancers include multiple myeloma, bladder, cervical, prostate and thyroid carcinomas, lung, breast and colon cancers.
Another subset of cancers includes multiple, bladder, hepatocellular myeloma, oral squamous cell carcinoma and cervical carcinomas.
The compound of the invention, having FGFR inhibitory activity such as FGFR1, can be particularly useful in the treatment or prevention of breast cancer, in particular Classic Lobular Carcinomas (CLC).
Since the compounds of the invention have FGFR4 activity they will also be useful in the treatment of prostate or pituitary cancers, or they will be useful in the treatment of breast cancer, lung cancer, prostate cancer, liver cancer (HCC) or lung cancer .
In particular the compounds of the invention as FGFR inhibitors, are useful in the treatment of multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer and carcinoma of oral squamous cell.
Other subsets of cancer are multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer and thyroid carcinomas.
In particular, the compounds of the invention are useful in the treatment of multiple myeloma (in particular multiple myeloma with t translocation (4; 14) or FGFR3 overexpression), prostate cancer (hormone-refractory prostate carcinomas), endometrial cancer (in particular tumors endometrial cells with activating mutations in FGFR2) and breast cancer (in particular lobular breast cancer).
In particular, the compounds are useful in the treatment of lobular carcinomas such as CPB (classic lobular carcinoma).
Since the compounds have activity against FGFR3 they will be useful in the treatment of multiple myeloma and bladder cancer.
In particular, the compounds are useful for the treatment of multiple positive myeloma in t translocation (4; 14).
In one embodiment the compounds can be useful for treating sarcoma. In one embodiment the compounds can be useful for the treatment of lung cancer, for example, squamous cell carcinoma.
Since the compounds have activity against FGFR2 they will be useful in the treatment of endometrial, ovarian, gastric, hepatocellular, uterine, cervical and colorectal cancers. FGFR2 is also overexpressed in epithelial ovarian cancer, so the compounds of the invention may be specifically useful in the treatment of ovarian cancer such as epithelial ovarian cancer.
In one embodiment, the compounds may be useful for the treatment of lung cancer, in particular NSCLC, squamous cell carcinoma, liver cancer, kidney cancer, breast cancer, colonic cancer, colorectal cancer, prostate cancer.
The compounds of the invention may be useful in the treatment of cancers with upregulated FGFR. Such cancers include brain (eg, gliomas), breast, esophageal, lung, and colorectal cancers.
The compounds of the invention may also be useful in the treatment of tumors pretreated with a VEGFR2 inhibitor or VEGFR2 antibody (for example, Avastin).
In particular, the compounds of the invention may be useful in the treatment of tumors resistant to VEGFR2. VEGFR2 inhibitors and antibodies are used in the treatment of thyroid and renal cell carcinomas, so the compounds of the invention may be useful in the treatment of VEGFR2-resistant thyroid and renal cell carcinomas.
Cancers can be cancers that are sensitive to inhibition of any one or more of the FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, one or more FGFRs selected from FGFR1, FGFR2 or FGFR3.
Whether a particular cancer is one that is sensitive or not to inhibition of FGFR or VEGFR signaling can be determined by means of a cell growth assay as shown below or by a method as presented in the section with the heading "Diagnostic Methods".
The compounds of the invention and in particular those compounds having FGFR inhibitory activity, or VEGFR, can be particularly useful in the treatment or prevention of cancers of a type associated with or characterized by the presence of high levels of FGFR, or VEGFR, for example cancers alluded to in this context in the introductory section of this application.
The compounds of the present invention can be useful for the treatment of the adult population. The compounds of the present invention can be useful for the treatment of the pediatric population.
It has been found that some FGFR inhibitors can be used in combination with other anticancer agents. For example, it may be beneficial to combine an inhibitor that induces apoptosis with another agent that acts through a different mechanism to regulate cell growth, thereby treating two of the characteristics of cancer development. Examples of such combinations are shown below.
The compounds of the invention may be useful in the treatment of other conditions that result from disorders in proliferation such as insulin-dependent or type II diabetes mellitus, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as Alzheimer's , motor neuron disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease eg autoimmune diseases and neurodegenerative diseases.
One subset of disease states and conditions for which the compounds of the invention may be useful consists of inflammatory diseases, cardiovascular diseases and wound healing.
FGFR and VEGFR are also known to play a role in apoptosis, angiogenesis, proliferation, differentiation and transcription and therefore the compounds of the invention may also be useful in the treatment of diseases that follow other than cancer; chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, hypersensitivity reactions, asthma, COPD, rhinitis and upper respiratory tract disease; cardiovascular diseases for example cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, myocardial infarctions associated with ischemic injury, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.
In addition, FGFR2 mutations are associated with several severe abnormalities in human skeletal development and thus the compounds of the invention may be useful in the treatment of abnormalities in human skeletal development, which include abnormal ossification of cranial sutures (craniosynostosis), Apert syndrome ( AP), Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyratee syndrome, Pfeiffer syndrome.
The compound of the invention, having FGFR inhibitory activity such as FGFR2 or FGFR3, can be particularly useful in the treatment or prevention of diseases of the skeleton. Diseases of the particular skeleton are achondroplasia or Thanatophoric dwarfism (also known as Thanatophoric dysplasia).
The compound of the invention, having FGFR inhibitory activity such as FGFR1, FGFR2 or FGFR3, can be particularly useful in the treatment or prevention of pathologies in which progressive fibrosis is a symptom. Fibrotic conditions in which the compounds of the inventions may be useful in their treatment include diseases that exhibit abnormal or excessive deposition of fibrous tissue for example in liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural healing process injury. In particular, the compounds of the inventions may also be useful in the treatment of pulmonary fibrosis, in particular in idiopathic pulmonary fibrosis.
Overexpression and activation of FGFR and VEGFR in the tumor-associated vasculature also suggested a role for the compounds of the invention in preventing and initiating disruption of tumor angiogenesis. In particular the compounds of the invention may be useful in the treatment of cancer, metastasis, leukemias such as CLL, eye diseases such as age-related macular degeneration in particular the wet form of age-related macular degeneration, ischemic proliferative retinopathies such as retinopathy prematurity (ROP) and diabetic retinopathy, rheumatoid arthritis and hemangioma.
The activity of the compounds of the invention as inhibitors of FGFR1-4, VEGFR and / or PDGFR A / B can be measured using the assays shown in the examples below and the level of activity displayed by a given compound can be defined in terms of the ICso- Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 pM, more preferably less than 0.1 pM.
The invention provides compounds that have FGFR inhibitory or modulating activity and that may be useful in preventing or treating disease states or conditions mediated by FGFR kinases.
In one embodiment, a compound is provided as defined herein for use in therapy, for use as a medicine. In another embodiment, a compound as defined herein is provided for use in the prophylaxis or treatment, in particular in the treatment, of a disease state or condition mediated by an FGFR kinase.
Thus, for example, the compounds of the invention may be useful in alleviating or reducing the incidence of cancer. Therefore, in another embodiment, a compound is provided as defined herein for use in the prophylaxis or treatment, in particular in the treatment, of cancer. In one embodiment, the compound as defined herein is for use in the prophylaxis or treatment of FGFR-dependent cancer. In one embodiment, the compound as defined herein is for use in the prophylaxis or treatment of cancer mediated by FGFR kinases.
Accordingly, the invention provides inter alia: - A method for the prophylaxis or treatment of a disease state or condition mediated by an FGFR kinase, which method comprises administering to a patient in need thereof a compound of formula (I) as herein defined. - A method for the prophylaxis or treatment of a disease state or condition as described herein, which method comprises administering to a patient in need thereof a compound of formula (I) as defined herein. - A method for the prophylaxis or treatment of cancer, which method comprises administering to a patient in need of him a compound of formula (I) as defined herein. - A method to relieve or reduce the incidence of a disease state or condition mediated by a FGFR kinase, which method comprises administering to a patient in need of it a compound of formula (I) as defined herein. - A method of inhibiting a FGFR kinase, which method comprises contacting the kinase with a compound that inhibits the kinase of formula (I) as defined herein. - A method of modulating a cellular process (e.g. cell division) by inhibiting the activity of a FGFR kinase using a compound of formula (I) as defined herein. - A compound of formula (I) as defined herein for use as a modulator of a cellular process (for example cell division) by inhibiting the activity of a FGFR kinase. - A compound of the formula (I) as defined herein for use in the prophylaxis or treatment of cancer, in particular in the treatment of cancer. - A compound of formula (I) as defined herein for use as a FGFR modulator (e.g., inhibitor). - The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a FGFR kinase, the compound having formula (I) as defined herein . - The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition as described herein. - The use of a compound of formula (I) as defined herein for the manufacture of a medicine for the prophylaxis or treatment, in particular the treatment, of cancer. - The use of a compound of formula (I) as defined herein for the manufacture of a medicament to modulate (for example, inhibit) FGFR activity. - Use of a compound of formula (I) as defined herein in the manufacture of a medicament to modulate a cellular process (for example cell division) by inhibiting the activity of a FGFR kinase. - The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition characterized by the over-regulation of a FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4). - The use of a compound of formula (I) as defined herein for the manufacture of a medicine for the prophylaxis or treatment of cancer, cancer being one that is characterized by the over-regulation of a FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4). - The use of a compound of formula (I) as defined herein for the manufacture of a drug for the prophylaxis or treatment of cancer in a patient selected from a subpopulation who has one of the genetic aberrations of the FGFR3 kinase. - The use of a compound of formula (I) as defined herein for the manufacture of a medicine for the prophylaxis or treatment of cancer in a patient who has been diagnosed as part of a sub-population that has one of the genetic aberrations of the kinase of FGFR3. - A method for the prophylaxis or treatment of a disease or condition characterized by the upregulation of an FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising administering a compound of formula (I) as defined herein . - A method for relieving or reducing the incidence of a disease or condition characterized by the upregulation of an FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising administering a compound of formula (I) as herein defined. - A method for the prophylaxis or treatment of (or alleviating or reducing the incidence of) cancer in a patient suffering from or suspected of suffering from cancer; a method which comprises (i) subjecting a patient to a diagnostic test to determine whether the patient has one of the genetic aberrations of the FGFR3 gene; and (ii) when the patient does not have said variant, then administer to the patient a compound of formula (I) as defined herein having FGFR3 kinase inhibitory activity. - A method for the prophylaxis or treatment of (or alleviating or reducing the incidence of) a disease state or condition characterized by the over-regulation of an FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4); a method that comprises (i) subjecting a patient to a diagnostic test to detect a characteristic marker of an upregulation of a FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4) and (ii) where the diagnostic test it is indicative of upregulation of a FGFR kinase, after that administering to the patient a compound of formula (I) as defined herein having FGFR kinase inhibitory activity.
In one embodiment, the disease mediated by FGFR kinases is a disease related to oncology (for example, cancer). In one embodiment, the disease mediated by FGFR kinases is a disease unrelated to oncology (for example, any disease disclosed herein excluding cancer). In one embodiment the disease mediated by FGFR kinases is a condition described here. In one embodiment the disease mediated by FGFR Kinases is a skeletal condition described here. Particular abnormalities in the development of the human skeleton include abnormal ossification of cranial sutures (craniosynostosis), Apert syndrome (AP), Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, achondroplasia and Thanatophoric dwarfism (also known as thanatophoric dysplasia). Mutated Kinases
Drug-resistant kinase mutations can arise in patient populations treated with kinase inhibitors. These occur, in part, in the regions of the protein that binds to or interacts with the particular inhibitor used in therapy. Such mutations reduce or increase the inhibitor's ability to bind to and inhibit the kinase in question. This can occur in any of the amino acid residues that interact with the inhibitor or are important to support the binding of said inhibitor to the target. An inhibitor that binds to a target kinase without requiring interaction with the mutated amino acid residue is unlikely to be affected by the mutation and will remain an effective inhibitor of the enzyme.
A study in samples from a patient with gastric cancer showed the presence of two mutations in FGFR2, Serl67Pro in exon Illa and a 940-2A-G junction site mutation in exon 111c. These mutations are identical to the germline activating mutations that cause craniosynototic syndromes and were observed in 13% of the primary gastric cancer tissues studied. In addition, activating mutations in FGFR3 were observed in 5% of the patient samples tested and overexpression of FGFRs was correlated with an insufficient prognosis in this patient group.
In addition, there are chromosomal translocations or point mutations that have been observed in FGFR that gives rise to overexpressed function gain or constitutively active biological states.
The compounds of the invention would therefore find particular application in relation to cancers that express a mutated molecular target such as FGFR. The diagnosis of tumors with such mutations can be performed using techniques known to a person skilled in the art and as described herein such as RTPCR and FISH.
It has been suggested that mutations of a threonine residue conserved at the ATP binding site of FGFR would result in resistance to the inhibitor. The amino acid valine 561 was mutated into a methionine in FGFR1 which corresponds to the previously reported mutations found in Abl (T315) and EGFR (T766) that have been shown to confer resistance to selective inhibitors. Assay data for FGFR1 V561M showed that this mutation conferred resistance to a tyrosine kinase inhibitor compared to that of the wild type. Diagnostic Methods
Prior to administration of a compound of formula (I), a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one that would be susceptible to treatment with a compound having activity against FGFR, and / or VEGFR.
For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one that is characterized by a genetic abnormality or abnormal protein expression that leads to over-regulation of FGFR levels or activity, and / or VEGFR or sensitizing a pathway for normal FGFR, and / or VEGFR activity or for over-regulation of these growth factor signaling pathways such as levels of growth factor ligand or growth factor ligand activity or for the upregulation of a biochemical pathway downstream of FGFR, and / or VEGFR activation.
Examples of such abnormalities that result in the activation or sensitization of the FGFR signal, and / or VEGFR include the loss of, or inhibition of apoptotic pathways, over-regulation of receptors or ligands, or the presence of mutant variants of receptors or ligands for example , PTK variants. Tumors with FGFR1, FGFR2 or FGFR3 or FGFR4 mutants or upregulation, in particular overexpression of FGFR1, or FGFR2 or FGFR3 function gain mutants may be particularly sensitive to FGFR inhibitors.
For example, point mutations that engender the function gain in FGFR2 have been identified under several conditions. In particular activating mutations in FGFR2 have been identified in 10% of endometrial tumors.
In addition, FGFR3 receptor tyrosine kinase genetic aberrations such as chromosomal translocations or point mutations that result in ectopically expressed or unregulated, constitutively active FGFR3 receptors have been identified and linked to a subset of multiple myelomas, bladder and cervical carcinomas . A particular T674I mutation of the PDGF receptor has been identified in patients treated with imatinib. In addition, a gene amplification of 8pl2-pl 1.2 has been demonstrated in ~ 50% of lobular breast cancer (CLC) cases and this has been shown to be linked with increased expression of FGFR1. Preliminary studies with siRNA directed against FGFR1, or a small molecule inhibitor of the receptor, showed that the cell lines that harbor this amplification are particularly sensitive to inhibition of this signaling pathway.
Alternatively, a biological sample taken from a patient can be analyzed for the loss of a negative regulator or suppressor of FGFR or VEGFR. In the present context, the term "lose" encompasses the deletion of a gene encoding the regulator or suppressor, the truncation of the gene (for example by the mutation), the truncation of the transcribed product of the gene, or the inactivation of the transcribed product (for example , by point mutation) or sequestration by another gene product.
The term upregulation includes elevated expression or overexpression, which includes gene amplification (i.e., multiple copies of genes) and increased expression by a transcriptional effect and hyperactivity and activation, which include activation by mutations. Thus, the patient can be subjected to a diagnostic test to detect a FGFR, and / or VEGFR over-regulation marker feature. The term diagnosis includes screening. By marker we include genetic markers that include, for example, measuring the DNA composition to identify FGFR, and / or VEGFR mutations. The term marker also includes markers that are characteristic of FGFR and / or VEGFR over-regulation, which include enzyme activity, enzyme levels, enzyme status (e.g., phosphorylated or not) and mRNA levels of the previously mentioned proteins.
Diagnostic tests and screenings are typically conducted on a biological sample selected from tumor biopsy samples, blood samples (scattered tumor cell isolation and enrichment), stool biopsies, phlegm, chromosome analysis, pleural fluid, peritoneal fluid , oral lancing, biopsy or urine.
Methods for identifying and analyzing mutations and upregulation of proteins are known to a person skilled in the art. Screening methods may include, but are not limited to, standard methods such as polymerase reverse-transcriptase reaction (RT-PCR) or in-situ hybridization such as fluorescence in-situ hybridization (FISH).
The identification of an individual that carries a FGFR and / or VEGFR mutation may mean that the patient would be particularly suitable for treatment with an FGFR and VEGFR inhibitor. Tumors can preferably be screened for the presence of a variant of FGFR and VEGFR before treatment. The screening process will typically involve direct sequencing, oligonucleotide microarray analysis, or a specific mutant antibody. In addition, the diagnosis of tumors with such mutations can be performed using techniques known to a person skilled in the art and as described herein such as RT-PCR and FISH.
In addition, mutant forms, for example of FGFR or VEGFR2, can be identified by direct sequencing, for example, tumor biopsies using PCR and methods for sequencing PCR products directly as previously described herein. The skilled technician will recognize that all such well-known techniques for detecting the previously mentioned overexpression, activation or mutations of proteins may be applicable in the present case.
In RT-PCR screening, the level of mRNA in the tumor is assessed by creating a copy of the mRNA cDNA followed by the amplification of the cDNA by the PCR. Methods of PCR amplification, selection of inhibitors and conditions for amplification, are known to a person skilled in the art. Nucleic acid and PCR manipulations are performed by standard methods, as described for example in Ausubel, F. M. et al., Eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M. A. et al., Eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RTPCR (eg Roche Molecular Biochemicals) can be used, or methodology as presented in United States patents 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864 and 6,218,529 and incorporated herein by reference. An example of an in situ hybridization technique for evaluating mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).
In general, in situ hybridization comprises the main steps that follow: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and to reduce non-specific binding; (3) hybridizing the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove unbound nucleic acid fragments in hybridization and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are long enough, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization with the target nucleic acid (s) under severe conditions . Standard methods for performing FISH are described in Ausubel, F. M. et al., Eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hibridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed .; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.
The methods for the gene expression profile are described by (DePrimo et al. (2003), BMC Cancer, 3: 3). In summary, the protocol is as follows: the double stranded cDNA is synthesized from the total RNA using an oligomer (dT) 24 for the preparation of the first strand cDNA synthesis, followed by the synthesis of the second filament cDNA with primers. random hexamers. The double-stranded cDNA is used as a standard for in vitrode transcription of cRNA using biotinylated ribonucleotides. The cRNA is chemically fragmented according to the protocols described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight in Human Genome Arrangements.
Alternatively, protein products expressed from mRNAs can be assayed by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for the detection of specific proteins. Detection methods would include the use of site-specific antibodies. The skilled person will recognize that all of such well-known techniques for the detection of FGFR, and / or VEGFR upregulation, or detection of FGFR variants and mutants, and / or VEGFR could be applicable in the present case.
Abnormal levels of proteins such as FGFR or VEGFR can be measured using standard enzyme assays, for example, those assays described herein. Activation or overexpression would also be detected in a tissue sample, for example, tumor tissue. By measuring tyrosine kinase activity with an assay such as that of Chemicon International. The tyrosine kinase of interest would be immunoprecipitated from the sample lysate and its activity measured.
Alternative methods for measuring the overexpression or activation of FGFR or VEGFR, which include their isoforms, include measuring the micro vessel density. This can be measured for example using the methods described by Orre and Rogers (Int J Cancer (1999), 84 (2) 101-8). The test methods also include the use of labels, for example, in the case of VEGFR these include CD31, CD34 and CD105.
Therefore, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the compounds of the invention.
The compounds of the invention are particularly useful in treating a patient having a mutated FGFR. The G697C mutation in FGFR3 is seen in 62% of oral squamous cell carcinomas and causes the constitutive activation of kinase activity. Activating mutations of FGFR3 have also been identified in cases of bladder carcinoma. These mutations were of 6 types with varying degrees of prevalence: R248C, S249C, G372C, S373C, Y375C, K652Q. In addition, a Gly388Arg polymorphism in FGFR4 has been found to be associated with the increased incidence and aggressiveness of prostate, colon, lung, liver (HCC) and breast cancer.
Therefore in another aspect the invention includes the use of a compound according to the invention for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and found to be suffering from, or being at risk of suffering from, a disease or condition that would be susceptible to treatment with a compound having activity against FGFR.
A patient's particular mutations are screened to include G697C, R248C, S249C, G372C, S373C, Y375C, K652Q mutations in the FGFR3 and Gly388Arg polymorphism in FGFR4.
In another aspect the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected from a subpopulation who has a variant of the FGFR gene (for example G697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).
Determination of vessel normalization MRI (for example, using MRI echo gradient, spin echo and contrast enhancement to measure blood volume, relative vessel size and vascular permeability) in combination with circulating biomarkers (circulating progenitor cells (CPCs ), CECs, SDF1 and FGF2) can also be used to identify tumors resistant to VEGFR2 for treatment with a compound of the invention. Pharmaceutical Compositions and Combinations
In view of their useful pharmacological properties, the object compounds can be formulated in various dosage forms for administration purposes.
In one embodiment, the pharmaceutical composition (e.g., formulation) comprises at least one active compound of the invention together with one or more carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, pharmaceutically acceptable lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
To prepare the pharmaceutical compositions of this invention, an effective amount of a compound of the present invention, such as the active ingredient, is combined in admixture with a pharmaceutically acceptable carrier, which carrier can take a wide variety of forms depending on the form of preparation desired for the administration. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, optical, rectal, intravaginal, or transdermal administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral, rectal, percutaneous administration, or by parenteral injection. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical means can be used, such as, for example, water, glycols, oils, alcohols and the like in the case of liquid oral preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will usually comprise sterile water, at least in the greater part, through other ingredients, to aid solubility for example, it may be included. Injectable solutions, for example, can be prepared in which the carrier comprises saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions can also be prepared in which case suitable liquid carriers, suspending agents and the like can be used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant harmful effect to the skin. . Said additives can facilitate administration to the skin and / or can be useful in preparing the desired compositions. These compositions can be administered in various ways, for example, as a transdermal patch, as a spot-on, as an ointment. It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used in the specification and claims here refers to the physically separated units suitable as unit dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. required. Examples of such unit dosage forms are tablets (which include labeled or coated tablets), capsules, pills, powder packs, ostia, injectable solutions or suspensions, full teaspoon, full tablespoon and the like and their multiples segregated.
It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used in the specification and claims here refers to the physically separated units suitable as unit dosages, each unit containing a predetermined amount of active ingredient, calculated to produce the desired therapeutic effect, in association with the carrier. pharmacist required. Examples of such unit dosage forms are tablets (which include labeled or coated tablets), capsules, pills, powder packs, ostia, injectable solutions or suspensions, full teaspoons, full tablespoons and the like and their multiples segregated.
The compound of the invention is administered in an amount sufficient to exert its anti-tumor activity.
Those skilled in the art can easily determine the effective amount of test results presented hereinafter. In general it is considered that a therapeutically effective amount would be from 0.005 mg / kg to 100 mg / kg of body weight and in particular from 0.005 mg / kg to 10 mg / kg of body weight. It may be appropriate to administer the required dose as single, double, triple, quadruple or more sub-doses at appropriate intervals throughout the day. Said sub-doses can be formulated as unit dosage forms, for example, containing from 0.5 to 500 mg, in particular from 1 mg to 500 mg, more in particular from 10 mg to 500 mg of active ingredient in the form of unit dosage.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of the present invention. , and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on weight total composition.
As another aspect of the present invention, a combination of a compound of the present invention with another anti-cancer agent is considered, especially for use as a medicine, more specifically for use in the treatment of cancer or related diseases.
For the treatment of the above conditions, the compounds of the invention can be advantageously used in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants in cancer therapy. Examples of anticancer agents or adjuvants (agents that support therapy) include, but are not limited to: - platinum coordination compounds, for example cisplatin optionally combined with amifostine, carboplatin or oxaliplatin; - taxane compounds for example paclitaxel, protein linked to paclitaxel (Abraxane®) or docetaxel; topoisomerase I inhibitors such as camptothecin compounds for example irinotecan, SN-38, topotecan, topotecan hcl; topoisomerase II inhibitors such as anti-tumor derivatives of epipodophyllotoxins or podophyllotoxin for example etoposide, etoposide phosphate or teniposide; anti-tumor vinca alkaloids for example vinblastine, vincristine or vinorelbine; - antitumor nucleoside derivatives for example 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine; - alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mefalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with mesna, pipobroman, tazazolone, procarzazole, uracil; - antitumor anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxyl, idarubicin, mitoxantrone, epirubicin, epimibicin hcl, valrubicin; - molecules that target the IGF-1 receptor, for example picropodophyllin; - tetracarcine derivatives for example tetrocarcin A; - glucocorticoiden for example prednisone; - antibodies for example trastuzumab (HER2 antibody), rituximab (CD20 antibody), gentuzumab, gentuzumab ozogamycin, cetuximab, pertuzumab, bevacizumab, alentuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumbos, panitumumb8, panitumumbos, panitumumbos, panitumumbos, - estrogen receptor antagonists or estrogen receptor modulators or inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole; - aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole; differentiating agents such as retinoids, vitamin D or retinoic acid and agents blocking retinoic acid metabolism (RAMBA) for example acutane; - DNA methyl transferase inhibitors for example azacytidine or decitabine; - antifoliators for example premetrexed disodium; - antibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mitramycin; - antimetabolites for example clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacytidine, cytarabine, floxuridine, pentostatin, thioguanine; - apoptosis-inducing agents and antiangiogenic agents such as Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid; - tubulin binding agents for example combrestatin, colchicines or nocodazole; - kinase inhibitors (eg, EGFR inhibitors (epithelial growth factor receptor), MTKI (multiple target kinase inhibitors), mTOR inhibitors) eg flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, tensirolimus; - farnesyltransferase inhibitors for example tipifarnib; - histone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide acid hydroxamide (SAHA), depsipeptide (FR 901228), NVPLAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat; - Inhibitors of the ubiquitin-proteasome pathway for example PS-341, MLN.41 or bortezomib; - Yondelis; - Telomerase inhibitors, for example telomestatin; - matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat. - Recombinant interleukins eg aldesleukin, denileucin diphthitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b - MAPK inhibitors - Retinoids such as alitretinoin, bexarotene, tretinoin - Arsenic trioxide - Asparaginase - Steroids eg dromostanol propionate, dromostanol propionate megestrol, nandrolone (decanoate, fenpropionate), dexamethasone - gonadotropin-releasing hormone agonists or antagonists eg abarelix, goserelin acetate, histrelin acetate, leuprolide acetate - thalidomide, lenalidomide - mercaptopurine, pegotamine, pegone, pate - BH3 mimetics eg ABT-737 - MEK inhibitors eg PD98059, AZD6244, CI-1040 - colony stimulating factor analogs eg filgrastim, pegfilgrastim, sargramostim; erythropoietin or analogues thereof (for example, darbepoetin alfa); interleukin 11; oprelvequine; zoldronate, zoldronic acid; fentanyl; bisphosphonate; palifermin. - an inhibitor of steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17), for example, abiraterone, abiraterone acetate.
The compounds of the present invention also have therapeutic applications in cells that sensitize tumors to radiotherapy and chemotherapy.
Consequently the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers" or can be given in combination with another "radiosensitizer" and / or "chemosensitizer".
The term "radiosensitizer", as used herein, is defined as a molecule, preferably a molecule of low olecular weight, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and / or to promote the treatment of diseases that they are treatable with ionizing radiation.
The term "chemosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and / or promote the treatment of diseases that are treatable with chemotherapeutic products.
Several mechanisms for the mode of action of radiosensitizers have been suggested in the literature, which include: hypoxic cell radiosensitizers (eg, 2-nitroimidazole compounds and benzotriazine dioxide compounds) that mimic oxygen or alternatively behave as bioreductive agents under hypoxia; non-hypoxic cell radiosensitizers (eg halogenated pyrimidines) can be analogous to DNA bases and preferably incorporate into the DNA of cancer cells and thus promote radiation-induced disruption of DNA molecules and / or hinder DNA repair mechanisms normal; and several other potential mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease.
Many cancer treatment protocols currently use radiosensitizers in conjunction with x-ray radiation. Examples of x-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromo deoxyuridine (BUdR), 5-iododesoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin and therapeutically effective analogs and derivatives thereof.
Photodynamic therapy (PDT) for cancers uses visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Fotofrin, benzoporphyrin derivatives, ethioporphyrin tin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, phthalocyanine zinc and therapeutically effective derivatives same.
Radiosensitizers can be administered in conjunction with a therapeutically effective amount of one or more other compounds, which include but are not limited to: compounds that promote the incorporation of radiosensitizers into target cells; compounds that control the flow of therapeutic products, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.
Chemosensitizers can be administered in conjunction with a therapeutically effective amount of one or more other compounds, which include but are not limited to: compounds that promote the incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic products, nutrients, and / or oxygen to the target cells; chemotherapeutic agents that act on the tumor or other therapeutically effective compounds for the treatment of cancer or other disease. Calcium antagonists, for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the effectiveness of such compounds in drug-sensitive malignancies.
In view of their useful pharmacological properties, the compounds of the combinations according to the invention, that is, the one or more other medicinal agents and the compound according to the present invention can be formulated in various dosage forms for administration purposes. The compounds can be formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition that contains all compounds.
The present invention therefore also relates to a pharmaceutical composition comprising the one or more other medicinal agents and the compound according to the present invention together with a pharmaceutical carrier.
The present invention also relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition to inhibit the growth of tumor cells.
The present invention also relates to a product containing as a first active ingredient a compound according to the invention and as another active ingredient one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients who suffer from cancer.
The one or more other medicinal agents and the compound according to the present invention can be administered simultaneously (for example, in separate or unitary compositions) or sequentially in each order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is obtained. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimens for each compound of the combination will depend on the other particular medicinal agent and the compound of the present invention that are administered, their route of administration, the particular tumor is treated and the particular host that is treated. The ideal method and order of administration and the quantities and dosage regimen can be easily determined by those skilled in the art using conventional methods and in view of the information presented here.
The weight ratio of the compound according to the present invention and the one or more other anticancer agent (s) when given as a combination can be determined by the person skilled in the art. Said reason and the exact dosage and frequency of administration depend on the particular compound according to the invention and the other anti-cancer agent (s) used, the particular condition being treated, the severity of the condition being treated , age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medications the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount can be decreased or increased depending on the response of the treated patient and / or depending on the prescribing physician's assessment of the compounds of the present invention. A particular weight ratio for the present compound of formula (I) and another anti-cancer agent can vary from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
The platinum coordination compound is advantageously administered at a dosage of 1 to 500 mg per square meter (mg / m2) of body surface area, for example 50 to 400 mg / m2, particularly for cisplatin at a dosage of about 75 mg / m2 and for carboplatin at about 300 mg / m2 per course of treatment.
The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg / m2) of body surface area, for example from 75 to 250 mg / m2, particularly parafor paclitaxel in a dosage of about 175 to 250 mg / m2 and for docetaxel at about 75 to 150 mg / m2 per course of treatment.
The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg / m2) of body surface area, for example from 1 to 300 mg / m2, particularly for irinotecan at a dosage of about 100 to 350 mg / m2 and for topotecan at about 1 to 2 mg / m2 per course of treatment.
The antitumor podophyllotoxin derivative is advantageously administered at a dosage of 30 to 300 mg per square meter (mg / m2) of body surface area, for example 50 to 250 mg / m2, particularly for etoposide at a dosage of about 35 at 100 mg / m2 and for teniposide at about 50 to 250 mg / m2 per course of treatment.
The vinca antitumor alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg / m2) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg / m2, for vincristine in a dosage from about 1 to 2 mg / m2 and for vinorelbine in a dosage of about 10 to 30 mg / m2 per course of treatment.
The antitumor nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg / m2) of body surface area, for example from 700 to 1500 mg / m2, particularly for 5-FU in a dosage of 200 at 500 mg / m2, for gemcitabine at a dosage of about 800 to 1200 mg / m2 and for capecitabine at about 1000 to 2500 mg / m2 per course of treatment.
Alkylating agents such as nitrogen mustard or nitrosourea are advantageously administered in a dosage of 100 to 500 mg per square meter (mg / m2) of body surface area, for example 120 to 200 mg / m2, particularly for cyclophosphamide in a dosage of about 100 to 500 mg / m2, for chlorambucil in a dosage of about 0.1 to 0.2 mg / kg, for carmustine in a dosage of about 150 to 200 mg / m2 and for lomustine in a dosage about 100 to 150 mg / m2 per course of treatment.
The antitumor anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg / m2) of body surface area, for example from 15 to 60 mg / m2, particularly for doxorubicin at a dosage of about 40 at 75 mg / m2, for daunorubicin in a dosage of about 25 to 45 mg / m2 and for idarubicin in a dosage of about 10 to 15 mg / m2 per course of treatment.
The anti-estrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice daily, continuing the therapy long enough to obtain and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60 mg once a day, continuing the therapy long enough to obtain and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally at a dosage of about 20 to 100 mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.
Antibodies are advantageously administered at a dosage of about 1 to 5 mg per square meter (mg / m2) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered at a dosage of 1 to 5 mg per square meter (mg / m2) of body surface area, particularly 2 to 4 mg / m2 per course of treatment.
These dosages can be administered for example once, twice or more per course of treatment, which can be repeated for example every 7, 14, 21 or 28 days.
The compounds of formula (I), pharmaceutically acceptable addition salts, in particular pharmaceutically acceptable acid addition salts and their stereoisomeric forms can have valuable diagnostic properties in which they can be used to detect or identify the formation of a complex between a labeled compound and other molecules, peptides, proteins, enzymes or receptors.
Detection or identification methods can use compounds that are labeled with labeling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances, etc. Examples of radioisotopes include 125I, 131I, 3H and 14C. Enzymes are usually made detectable by conjugating an appropriate substrate, which in turn catalyzes a detectable reaction. And its examples include, for example, beta-galactosidase, betaglycosidase, alkaline phosphatase, peroxidase and malate dehydrogenase, preferably horseradish peroxidase. Luminous substances include, for example, luminol, luminol derivatives, luciferin, aequorin and luciferase.
Biological samples can be defined as body tissue or body fluids. Examples of bodily fluids are cerebrospinal fluid, blood, plasma, serum, urine, phlegm, saliva and the like. General Synthetic Pathways
The following examples illustrate the present invention but are examples only and are not intended to limit the scope of the claims in any way. Experimental Part
Hereinafter, the term 'DCM' means dichloromethane, 'TEA' means triethylamine, 'ACN' means acetonitrile, 'EtOAc' means ethyl acetate, 'DMSO' means dimethyl sulfoxide, 'Et20 ”means diethyl ether,' EtOH ' means ethanol, 'THF' means tetrahydrofuran, DMF 'means N, N-dimethylformamide,' X-Phos 'means dicyclohexyl [2', 4, 6'-tris (l-methylethyl) [l, l'-biphenyl] -2 -il] -phosphine, 'POCI3' means phosphoric trichloride, 'Pd2 (dba) 3' means tris (dibenzylidene) acetone dipaladium (0), 'SFC' means supercritical fluid chromatography. A. Preparation of the intermediates Example Al
a) Preparation of intermediary 1
A mixture of 3,4-diaminobenzophenone) (1.1 g; 5.2 mmol) and the 50% solution of ethyl glyoxalate in toluene) (0.77 ml; 3.9 mmol) in ethanol (20 ml) refluxed overnight. The precipitate was filtered off, the filtrate was evaporated to dryness, absorbed in ethyl acetate, washed with brine, dried (MgSCE), filtered off and the solvent was evaporated to dryness. This residue (1.09 g) was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 300 g), mobile phase (Gradient 0.1% NH4OH, 98% DCM, 2% iPrOH up to 0.1% NH4OH, 96% DCM, 4% iPrOH)]. The product fraction was collected and the solvent was evaporated, yielding 263 mg of intermediate 1 (27%).
b) Preparation of intermediary 2
Intermediate 1 (1.5 g, 6 mmol) in POCI3 (15 ml) was heated to 80 ° C for 45 minutes, then cooled to room temperature and evaporated to dryness. The crude product was absorbed in CH2 Cl2 and water was added slowly, then the solution was made basic with 3N aqueous NaOH solution. The organic layer was dried (MgSCE), filtered off and the solvent was evaporated to dryness, yielding 1.34 g of intermediate 2 (83%). Example A2

Preparation of intermediate 3 a) 7-bromo-2 (1H) -quinoxalinone (47.2 g; 210 mmol) was added to the phosphorus chloride (470 ml). The reaction mixture was stirred at 100 ° C for 2 hours, cooled to room temperature and evaporated to dryness. The crude product was absorbed in DCM and poured into ice, water and K2CO3 powder. The mixture was filtered through celite. Celite was washed twice with DCM. The organic layer was decanted, dried over MgSCE, filtered and evaporated to dryness to give 49 g (96%) of 7-bromo-2-chloroquinoxaline (gray solid). MP = 146 ° C. 7-bromo-2-chloro-quinoxaline was also alternatively prepared using the following procedure:
Thionyl chloride (407.5 ml; 5.59 mol), then N, N-dimethylformamide (34.6 ml; 0.45 mol) were added to the drops to a mixture of 7-bromo-2 (1H) -quinoxalinone (500 g; 2.24 mol) in toluene (7.61 liters). The reaction mixture was stirred at 80 ° C for 17 hours, then cooled to 35 ° C and cautiously poured into water. The two-phase mixture was stirred for 30 minutes and then decanted. The organic layer was evaporated to dryness and the residue crystallized from tert-butyl methyl ether, filtered and the precipitate washed with tert-butyl methyl ether and dried to give 407 g (74.7%) of 7-bromo-2-chloro -quinoxaline. The filtrate was evaporated and re-crystallized from tert-butyl methyl ether to provide a second fraction of 72 g (13.2%) of 7-bromo-2-chloro-quinoxaline. b) Under N2, 7-bromo-2-chloro-quinoxaline (20 g; 82.1 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2 -yl) -1H-pyrazole (17.1 g; 82.1 mmol), 2 M aqueous sodium carbonate solution (41.1 ml; 82.1 mmol) in ethylene glycol dimethyl ether (200 ml) were degassed by bubbling with nitrogen for 15 minutes. Tetracis (triphenylphosphino) palladium (0) (0.95 g; 0.82 mmol) was added and heated to reflux for 15 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over MgSÜ4, filtered and evaporated to dryness to give 29.9 g. The crude compound was purified by silica gel chromatography (Irregular SiOH, 20 to 45 pm, MATREX 1000 g; 0.1% NH4OH mobile phase, 98% DCM, 2% CH3OH). The pure fractions were collected and concentrated to dryness to give 19.5 g (82%) of 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline. MP = 172 ° C. 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline was also alternatively prepared using the following procedure: 7-bromo-2-chloro-quinoxaline (502 g; 2.06 mol), 1-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-pyrazole (450.42 g; 2.16 mol) , triphenylphosphine (10.82 g; 0.041 mol) and palladium (II) acetate were added to a mixture of sodium carbonate (240.37 g; 2.267 mol), 1,2-dimethoxyethane (5.48 liters) and water (1.13 liter). The reaction mixture was stirred at reflux for 20 hours, then 1-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-pyrazole (42.9 g; 0.206 mol) was added and the reaction mixture was refluxed until complete conversion (4 hours). The reaction mixture was poured into water, stirred for 2 hours at room temperature, filtered and the precipitate was washed with water. The precipitate was then triturated in methanol and filtered. The precipitate was washed with methanol and dried to give 532.2 g (89%) of 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (yellowish white powder). c) 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (2.5 g; 8.0 mmol), bis (pinacolate) diboro (2.4 g; 9.6 mmol ), l, l'-bis (diphenylphosphino) ferrocenodichloropalladium (II) (291 mg; 0.4 mmol) and potassium carbonate (2.3 g; 23.9 mmol) in anhydrous dioxane (30 ml) were heated at 100 ° C for 90 minutes. The mixture was poured into water and the 10% aqueous NH4 Cl solution, then ethyl acetate was added. The organic layer was dried, (MgSO4), filtered and evaporated. The crude product was absorbed in pentane and the precipitate was filtered, yielding 1.6 g (60%) of intermediate 3. (cas number 1083325-88-5) Example A3

Preparation of intermediate 4 The experiment was carried out 9 times in the same amount of 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (1 g, 3.5 mmol) and all reaction mixtures crude aggregates for purification: 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (1 g; 3.5 mmol), acrylonitrile (0.69 ml; 10.4 mmol), palladium (II) acetate (47% Pd) (39 mg; 0.17 mmol), tri-o-tolylphosphine (105 mg; 0.35 mmol) and TEA (1.4 ml; 10.4 mmol) in ACN (3 ml) were stirred at reflux for 48 hours. The 9 experiments were combined for the job. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite®. Celite® was washed with EtOAco. The filtrate was evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 300g), mobile phase (99% DCM, 1% MeOH)]. The pure fractions were collected and the solvent was evaporated, yielding 2.6 g (32%) of intermediate 4, mp = 179 ° C. Example A4

Preparation of intermediate 5 Potassium tert-butoxide (1.2 g; 10.4 mmol) was added portionwise to a solution of trimethylsulfoxonium iodide (2.3 g; 10.4 mmol) in dimethoxymethane (80 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and the solution was added dropwise to a solution of compound 2 (2.6 g; 6.9 mmol) in DMSO (30 ml) at 5 ° C under N2 flow. The reaction mixture was stirred at 5 ° C for 1 hour, then at room temperature for 48 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried, (MgSOzQ, filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (Gradient 60% DCM, 40% EtOAc to 30% DCM, 70% EtOAc)]. The desired product fractions were collected and the solvent was evaporated, yield of 700 mg (26%) of intermediate 5. Example A5

Preparation of intermediate 6 Methanesulfonyl chloride (976 pl; 12.6 mmol) was added to a solution of compound 22 (1.7 g; 4.2 mmol) and TEA (2.34 ml; 16.8 mmol) in ACN (5 ml) at 5 ° C under N2. The reaction mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with DCM. The organic layer was dried (MgSCE), filtered and evaporated to dryness, yielding 2 g (98%) of intermediate 6, which was used without further purification for the next step. Example A6
a) Preparation of the intermediary 7
Preparation of the salt in isopropylamine HCI: 5 to 6 N hydrochloric acid solution in 2-propanol (7.2 ml; 39.5 mmol) carefully added to an isopropylamine solution (2.7 ml; 31.7 mmol) in Et2O (20 ml) from 0 to 5o C. The reaction mixture was stirred for 15 minutes, then evaporated to dryness, salt yield in isopropylamine HCI. 3,5-dimethoxyacetophenone (5.7 g; 31.7 mmol), isopropylamine HCl salt and paraformaldehyde (2.37 g; 79 mmol) in EtOH (8.8 ml) were stirred at 140 ° C for 12 minutes in a sealed tube. After cooling to room temperature, this solution was added to a solution of di-tert-butylcarbonate (13.8 g; 63.3 mmol) and TEA (13.2 ml; 95 mmol) in DCM (100 ml) at room temperature. The reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was washed successively with 1 N HCl, 10% aqueous K2CO3 solution and water. The organic layer was dried, (MgSO4), filtered and evaporated. The residue (10.1 g) was purified by silica gel chromatography [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (80% HEPTAN, 20% EtOAc)] yielding 4.8 g ( 43%) of the intermediate 7.
b) Preparation of the intermediary 8
Intermediate 7 (4.2 g; 12 mmol) and p-toluenesulfonidrazide (2.34 g; 12.6 mmol) in EtOH (30 ml) were stirred at reflux for 4 hours. The solvent was evaporated and the residue was absorbed in Et 2 O, stirred for 15 minutes and the precipitate was filtered off and dried yielding 2.6 g (42%) of intermediate 8. The filtrate was evaporated and the residue (4 , 2 g) was purified by silica gel chromatography [(Irregular SiOH, 20 to 45 µm, 450 g); mobile phase (70% HEPTANE, 30% EtOAc)] to give another batch of 1.6 g (26%) of intermediate 8. c) Preparation of intermediates 9 and 10
Intermediate 9 (Z) intermediate 10 (E) Under N2, a suspension of 2-dicyclohexylphosphine-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (58.7 mg; 0.12 mmol), tris (dibenzylidenoacetone) - dipaladium (56 mg; 0.06 mmol), lithium tert-butoxide (0.71 g; 7.4 mmol) and intermediate 8 (1.6 g, 3 mmol) in 1 , 4-dioxane (20 ml) were stirred at room temperature for 1 to 2 minutes, then bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (0.89 g, 3.1 mmol) was added. The reaction mixture was stirred at 110 ° C for 12 hours. This experiment was combined with 2 identical experiments (performed on 556 mg of bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline and on 150 mg of bromo-2- (1-methyl-1H-pyrazole) -4-il) - quinoxaline) for work. Water and EtOAc were added. The organic layer was dried, (MgSOzt), filtered and evaporated. The residue was purified by silica gel chromatography [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (98% DCM, 2% MeOH)]. Fractions of the desired product were collected and the solvent was evaporated to give 1.4 g (impure fraction) of a mixture of intermediate 9 and 10 and 638 mg (21%) of intermediate 10. The impure fraction (1.4 g) was purified by chiral SFC [(CHIRALPAK AD-H, 5 pm, 250 x 20 mm, mobile phase (75% CO2, 25% EtOH)). The pure fractions were collected and the solvent was evaporated to give 750 mg ( 25%) of intermediate 9 and 70 mg (2.3%) of intermediate 10. Example A7
Preparation of intermediaries 11 and 12
intermediate 11 intermediate 12
3-Dimethylaminopropiophenone hydrochloride (1.6 g; 5.8 mmol) was added to a solution of p-toluenesulfonidrazide (1.1 g; 5.8 mmol) in a 5 to 6 N hydrochloric acid solution in 2- propanol (7.2 ml), Et2Ü (4.2 ml) and distilled water (2.6 ml) at room temperature. The reaction mixture was stirred overnight. The extra p-toluenesulfonidrazide (1.1 g; 5.8 mmol) was added and the reaction mixture was stirred for 48 hours. The mixture was basified with 1 N NaOH and extracted with DCM. The organic layer was decanted, washed with brine, dried, (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 10 to 40 pm, 300 g), mobile phase (Gradient 0.1% NH4OH, 97% DCM, 3% MeOH 0.2 % NH4OH, 96% DCM, 4% MeOH)]. The desired fractions were collected and the solvent was evaporated, yielding 1.5 g (64%) of intermediate 11 and 340 mg (14.5%) of intermediate 12. * means relative stereochemistry Example A8

Preparation of intermediate 13 The experiment was performed twice on (3.1 g; 13.1 mmol) of ethyl ester of (2E) -3- (3,5-dimethoxyphenyl) -2-propenoic acid: 7-Bromo-2 - (1-methyl-1H-pyrazol-4-yl) -quinoxaline (4.7 g; 16.4 mmol), the ethyl ester of (2E) - 3- (3,5-dimethoxyphenyl) -2-propenoic acid (3.1 g; 13.1 mmol), palladium (II) acetate (47% Pd) (147 mg; 0.66 mmol), tri-tolylphosphine (400 mg; 1.3 mmol) and TEA (5.5 ml; 39.4 mmol) in ACN (9 ml) were stirred at reflux for 36 hours.
The combined experiments for the job.
After cooling to room temperature, water was added. The reaction mixture was filtered through a pad of Celite®. Celite00 was washed with DCM. The organic layer was separated, dried, (MgSOA, filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 400 g), mobile phase (70% EtOAc, 30% HEPTANE)]. The desired fractions were collected and the solvent was evaporated to give 16.4 g of a mixture. The fraction was purified once again by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g) , mobile phase (30% HEPTAN, 70% EtOAc)], producing 5g (43%) of intermediate 13, mp = 139 ° C. Example A9

Preparation of intermediate 14 Methanesulfonyl chloride (770 pl; 9.9 mmol) was added dropwise to a solution of compound 11 (2 g; 5 mmol), TEA (1.7 ml; 12.4 mmol) in DCM ( 50 ml) at 5 ° C under N2 flow. The reaction mixture was stirred at 5 ° C for 30 minutes, then for 1 hour at room temperature. TEA (1.7 ml; 12.4 mmol.) And methanesulfonyl chloride (770 pl; 9.9 mmol) were added to the mixture at 5 ° C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and CH2 Cl2 was added. The organic layer was separated, dried, (MgSCU), filtered and the solvent was evaporated. The residue (2.96 g) was purified by silica gel chromatography [(Irregular SiOH, 15 to 40 pm, 90 g), mobile phase (gradient from 95/5 DCM / MeOH to 90/10 DCM / MeOH], 820 mg yield of intermediate 14 (39%). Example AIO
a) Preparation of intermediate 1.6 n-Butyllithium 1.6 M in hexane (17 ml; 27 mmol) was added dropwise to a stirred solution of 1-bromo-3,5-dimethoxy-benzene (5.9 g; 27 mmol ) in THF (50 ml) at -78 ° C under nitrogen. The reaction mixture was stirred for 20 minutes then allowed to reach 0 ° C then cooled to -78 ° C. This solution was added to a solution of 3 - [(methoxymethylamino) carbonyl] -1-piperidinocarboxylic acid 1,1-dimethylethyl ester (6.7 g; 24.6 mmol) in Et2O (35 ml) at -78 ° C. The reaction mixture was allowed to reach room temperature and stirred for 4 hours. Water was added and the reaction mixture was extracted twice with EtOAc, dried, (MgSÜ4), filtered and evaporated. The residue was purified by silica gel chromatography [(Irregular SiOH, 20 to 45 pm, 450 g of MATREX), mobile phase (85% HEPTAN, 15% EtOAc)] to give 330 mg (3.8%) intermediate 15.
b) Preparation of the intermediary 16
Intermediate 15 (0.62 g; 1.77 mmol) and p-toluenesulfonidrazide (0.35 g; 1.86 mmol) in ethanol (6 ml) were stirred successively at reflux for 4 hours at 60 ° C for 6 hours and at room temperature 5 overnight. The solvent was evaporated, yield of 900 mg (98%) of intermediate 16.
c) Preparation of intermediate 17 Under N2, a suspension of 2-dicyclohexylphosphine-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (58.7 mg; 0.12 mmol), tris (dibenzylidenoacetone) di-10 palladium (56 mg; 0.06 mmol), lithium tert-butoxide (0.71 g; 7.4 mmol) and intermediate 16 (1.6 g; 3.08 mmol) in 1 , 4-dioxane (20 ml) was stirred at room temperature for less than 2 minutes then 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (0.89 g; 3.1 mmol) was added. The reaction mixture was stirred at 110 ° C for 12 hours. Water and EtOAc were added. The organic layer was dried, (MgSOzQ, filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.1% NH4OH, 98% DCM, 2% MeOH)] to give 395mg (42%) of intermediate 17.
d) Preparation of the intermediary 18
Intermediate 17 (395 mg; 0.73 mmol) was hydrogenated at room temperature in MeOH (4 ml) with Pd (10% dry carbon) (50 5 mg) as a catalyst at atmospheric pressure for 6 hours. The catalyst was separated by filtration on a Celite® pad. Celite® was washed with CH2C12 / MeOH. The filtrate was evaporated to give 375 mg (95%) of intermediate 18. B. Preparation of compounds Example B1

Preparation of compound 1 Intermediate 2 (1.3 g; 4.8 mmol), 1-methyl-4- (4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1 g; 4.8 mmol), the 2 M aqueous sodium carbonate solution (2.4 ml; 4.8 mmol) in ethylene glycol dimethyl ether (20 ml) were degassed with N2 for 15 minutes. Pd (PPli3) 4 (0.55 g; 0.48 mmol) was added and the reaction mixture was refluxed overnight. The mixture was poured into H2O and EtOAc. The organic layer was washed with brine, dried, (MgSCU), filtered and the solvent was evaporated to dryness. The residue (2.2 g) was purified by chiral SFC [(CH1RALPAK AD-H, 5 pm, 250 x 20 mm), mobile phase (40% CO2, 60% EtOH)], yield: 800 mg of compound 1 (53%). Example B2

Preparation of compound 2 To a mixture of intermediate 3 (3 g, 8.9 mmol) in THF (100 ml), 3,5-dimethoxybenzoyl chloride (3.6 g, 18 mmol), 2 M aqueous carbonate solution were added sodium (70 ml; 140 mmol), 10 dichlorobis (triphenylphosphino) palladium (II) (313 mg; 0.45 mmol) at room temperature under N2. The mixture was stirred at 50 ° C for 2 hours, filtered through a pad of Celite®, washed with DCM and water. The organic layer was decanted and dried, (MgSCU), filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 90 g), mobile phase 15 (0.1% NH4OH, 97% DCM, 3% MeOH)], yield of two 120 mg and 60 mg fractions of compound 2. Example B3
Preparation of compounds 3 and 4
A mixture of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (1 g; 3.45 mmol), 3- (3,5-dimethoxyphenyl) -2-propenonitrile (654 mg ; 3.5 mmol), palladium (II) acetate (47% Pd) (39 mg; 0.17 mmol), potassium carbonate (1.24 g; 12.7 mmol) and tetrabutylammonium bromide (1, 8 g; 5.6 mmol) in N, N-dimethylformamide (15 ml) in a sealed tube was heated to 140 ° C using a single mode microwave (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W for 40 minutes. After cooling to room temperature, water was added. The mixture was filtered through a pad of Celite®. Celite® was washed with EtOAc. The organic layer was decanted, washed with brine, dried (MgSÜ4), filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 90 g), mobile phase (gradient of 0% NH4OH, 100% DCM, 0% MeOH to 0.1% NH4OH , 95% DCM, 5% MeOH)] The pure fractions were collected and evaporated to dryness. The residue (245 mg) was purified by reverse phase chromatography [(X-Bridge-C18, 5 pm, 30 * 150 mm), mobile phase (60% NH4HCO3 gradient (0.5% solution), 40% of ACN 0% NH4HCO3 (0.5% solution), 100% ACN)], yield of 20 mg (1.5%) compound 3 and 70 mg of residue that was purified by chiral SFC [(CHIRALPAK AD -H, 5 pm, 250 x 20 mm), mobile phase (0.3% isopropylamine, 60% CO2, 20% EtOH, 20% iPrOH)], yield 33 mg (2.4%) of compound 4. Example B4 (alternative preparation of B3)
Preparation of compound 4
compound 4
The experiment was carried out 9 times on the same scale as 7-bromo- 2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (1.88 g, 6.5 mmol):
A mixture of 7-bromo-2- (1-methyl-1 H-pyrazol-4-yl) -quinoxaline (1.88 g, 6.5 mmol), 3- (3,5-dimethoxyphenyl) -2-propenonitrile (1 g; 5.5 mmol), palladium (II) acetate (47% Pd) (73 mg; 0.33 mmol), TEA (2.7 ml; 19.5 mmol) and tri-o-tolylphosphine (0.2 g; 0.65 mmol) in acetonitrile (3.9 ml) were stirred at reflux overnight. After cooling down to room, the 9 experiments were combined for work. Water and DCM were added. The organic layer was separated, dried over MgSCU, filtered and evaporated to give 24.3 g of the crude product.
The residue was purified by silica gel chromatography [(Irregular SiOH, 20 to 45 pm, 1000 g), mobile phase (gradient of 20% heptane, 80% AcOEt to 0% heptane, 100% AcOEt)] , producing 5 g (21%) of compound 4. Example B5 (alternative preparation of B2)

Preparation of compound 2 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (8 g; 28 mmol), 3,5-dimethoxybenzenoboroic acid (9.4 g; 52 mmol), tricyclohexyl - phosphine (145 mg; 0.52 mmol), palladium (II) acetate (47% Pd) (39 mg; 0.17 mmol), TEA (9.6 ml; 69 mmol) in toluene (50 ml) under 5 bars of CO (gas) at 100 ° C for 66 hours. This experiment was combined with a similar experiment done on 2 g of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline. The mixture was diluted with DCM and water. The organic layer was dried (MgSOd), filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH 20 to 45 pm 1000 g), mobile phase (20% HEPTAN, 80% EtOAc)], yield 2.65 g (20%) of compound 2 , mp = 162 ° C. Example B6
Preparation of compounds 5 and 6

A mixture of intermediate 5 (700 mg; 1.8 mmol) and N-isopropylethylenediamine (98%) (4.55 ml; 36 mmol) in ethanol (7 ml) was heated to reflux overnight in a sealed tube. The ethanol was evaporated. The residue (1.5 g) was first purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.8% NH4OH, 92% DCM, 8% MeOH )]. The expected fractions of the compound were collected and the solvent was evaporated. The residue (467 mg) was purified by chiral SFC [(AMINO, 6 pm, 150 x 21.2 mm), mobile phase (0.3% ISOPROPYLAMINE, 60% CO2, 40% MeOH)]. The expected fractions of the compound were collected and the solvent was evaporated. The residue was then purified by chiral SFC [(CHIRALPAK AD-H, 5 pm, 250 x 20 mm), mobile phase (0.3% ISOPROPYLAMINE, 65% CO2, 35% EtOH)]. The expected 2 fractions of the compounds were combined and the solvent was evaporated to give 125 mg of an enantiomer (first fraction) and 130 mg of another enantiomer (second fraction).
The first fraction (125 mg, 14%) was converted to the HCI Salt (5 eq.) In MeOH. Et2O was added. The precipitate was filtered off and dried to give 138 mg of a brown solid product. This product was basified with a mixture of ice water and NH4OH. DCM was added and the organic layer was separated, dried, (MgSOzi) and the solvent was evaporated, yielding 94 mg of residue. This residue was purified by chromatography on silica gel [(Stability Silica, 5 pm, 150 x 30.0 mm), mobile phase (gradient of 0.2% NH4OH, 98% DCM, 2% MeOH to 1, 1% NH4OH, 89% DCM, 11% MeOH)], yielding 57 mg (6.5%) of compound 5.
The second fraction (130 mg, 15%) was converted to the HCI Salt (5 eq.) In MeOH. Et2O was added. The precipitate was filtered and dried to give 92 mg of a brown solid. This product was basified with a mixture of ice water and NH4OH. DCM was added and the organic layer was separated, dried, (MgSÜ4) and the solvent was evaporated, yielding 94 mg of residue. This residue was purified by chromatography on silica gel [(Stability Silica, 5 pm, 150 x 30.0 mm), mobile phase (gradient of 0.2% NH4OH, 98% DCM, 2% MeOH to 1, 2% NH4OH, 88% DCM, 12% MeOH)], yield of 21 mg (2.4%) of compound 6. * means relative stereochemistry Example B7

Preparation of compound 7 Sodium hydride (60% in oil) (60 mg; 1.5 mmol) was added portionwise to a solution of 2-Pyrrolidinone (0.12 ml; 1.5 mmol) in N, N- dimethylformamide (5 ml) at 5 ° C under N2 flow. The reaction mixture was stirred at 5 ° C for 1 hour, then a solution of intermediate 6 (0.5 mmol; 250 mg) in dry DMF (3 ml) was added to the drops at 5 ° C. The reaction mixture was stirred at 5 ° C for 1 hour, then overnight at room temperature. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried, (MgSÜ4), filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel [(Spherical SiOH, 10 pm, 60 g), mobile phase (0.1% NH4OH, 97% DCM, 3% MeOH)] to give 63 mg of residue. This residue was purified by chiral SFC [(AMINO, 6 pm, 150 x 21.2 mm); mobile phase (0.3% ISOPROPYLAMINE, 20% MeOH, 80% CO2)]. The residue (43 mg, 8.7%) was dissolved in MeOH and converted to hydrochloric acid salt with HCl / 2-propanol. Et20 was added, then the solvent was evaporated to dryness, yield 32 mg (6.2%) of compound 7. Example B8
b) Preparation of compound 8 HCl 3 M (8 ml) was added to a solution of intermediate 9 (0.75 g; 1.38 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was heated to 60 ° C for 6 hours. After cooling to room temperature, the crude mixture was made basic with the 10% aqueous solution of K2CO3 and extracted twice with DCM. The combined organic layers were dried, (MgSOd), filtered and evaporated. The residue (0.58 g) was purified by silica gel chromatography [(Spherical SiOH, 10 pm, 60 g), mobile phase (0.5% NH4OH, 95% DCM, 5% MeOH)] to give 0.55 g of residue that was crystallized from ACN to give 373 mg (61%) of compound 8. b) Preparation of compound 9
3 M HCI (8 ml) was added to a solution of intermediate 10 (0.64 g; 1.17 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was heated to 60 ° C for 6 hours. After cooling to room temperature, the crude mixture was made basic with 10% aqueous K2CO3 solution extracted twice with DCM. The combined organic layers were dried, (MgSO4), filtered and dried. The fraction (0.45 g) was purified by chromatography on silica gel [(Spherical SiOH, 10 pm, 60 g), mobile phase (0.5% NH4OH, 95% DCM, 5% MeOH)] for give 240 mg (46%) of the product fraction. The hydrochloric salt of the fraction was prepared in MeOH and crystallized from MeOH / EfeO, yielding 193 mg (32%) of compound 9. Example B9

Preparation of compound 10 (Z)
compound 34 (E)
In a sealed tube, under N2, a suspension of X-Phos (67 mg; 0.142 mmol), Pd2 (dba) 3 (16.3 mg; 0.018 mmol), lithium tert-butoxide (1 g; 10.7 mmol ) and intermediate 12 (1.44 g; 3.6 mmol) in 1,4-dioxane (28 ml) was stirred at room temperature for less than 2 minutes. Then 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (1 g; 3.6 mmol) was added. The reaction mixture was stirred at 110 ° C for 12 hours. The mixture was diluted with water and EtOAc. The organic layer was dried, (MgSOO, 10 filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.4% NH4OH gradient, 98% DCM, 2% MeOH to 0.7% NH4OH, 94% DCM, 6% MeOH)]. The product fraction (0.75 g) was purified by chiral SFC [(AMINO, 6 pm , 150 x 21.2 mm), mobile phase (85% CO2, 15% 15 EtOH)]. The desired fractions were collected and the solvent was evaporated to give 270 mg of the primary fraction and 180 mg of the second fraction.
The first fraction (270 mg) was crystallized from Et2Ü and ACN to give 170 mg (11%) of compound 10 (Z). mp 164 ° C
The second fraction (180 mg) was crystallized from Et2O and ACN to give 115 mg (7.5%) of compound 34 (E). mp 177 ° C Example B10 Preparation of compound 11

Diisobutylaluminum hydride (20% toluene solution) (6.75 ml; 1 mmol) was added dropwise to a solution of intermediate 13 (4 g; 9 mmol) in dry THf (48 ml) at 0 ° C under N2. The reaction mixture was stirred at room temperature for 2 hours. Diisobutylaluminum hydride (6.75 ml; 8.1 mmol) was added to the drops at 0 ° C to the mixture. The reaction mixture was stirred at room temperature for 2 hours. Diisobutylaluminum hydride (6.75 ml; 8.1 mmol) was added to the drops at 0 ° C to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was cooled to -10 ° C and MeOH (20 ml) was added to the drops. Then, a 10% NH4 Cl solution (25 ml) was added to the drops. The mixture was diluted with EtOAc. The mixture was extracted with EtOAc. The organic layer was dried, (MgSO4), filtered and the solvent was evaporated. The residue (3.83 g) was purified by silica gel chromatography [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.1% NH4OH, 97% DCM, 3% MeOH) ], yield of 2.1 g of compound 11 (58%, yellow solid). Example B 11

Preparation of compound 12 Potassium cyanide (2.7 g; 41.5 mmol) in DMF (15 ml) was stirred for 20 minutes at room temperature. A solution of intermediate 6 (2 g; 4.1 mmol) in DMF (10 ml) was added to the suspension. The mixture was stirred at room temperature for 18 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried, (MgSOzQ, filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (20% HEPTANE gradient , 80% EtOAc to 10 10% HEPTANE, 90% EtOAc)], 345 mg (20%) yield of compound 12. Example B 12

Preparation of compound 13 Magnesium (3.1 g; 129 mmol) was added in one portion to a suspension of intermediate 13 (5.2 g; 11.7 mmol) in MeOH (180 ml) and THF (19 ml) at temperature environment. The reaction mixture was stirred for 45 minutes. The temperature was raised to 35 ° C. The reaction mixture was cooled to 10 ° C and stirred for 1 hour. Ice and 10% aqueous NH4 Cl solution were added. The reaction mixture was extracted with DCM, dried over MgSCU, filtered and evaporated.
The residue (5.3 g) was purified by silica gel chromatography [(Irregular SiOH, 15 to 40 pm, 90 g), mobile phase (gradient of 0% NH4OH, 100% DCM, 0% MeOH to 0.1% NH4OH, 97% DCM, 3% MeOH)]. The pure fractions were collected and evaporated to dryness to give 3.9 g (74%) of compound 13. Example B13

Preparation of compound 14 2,2,2-Trifluoroethylamine (0.76 ml; 9.5 mmol) was added to a solution of intermediate 14 (200 mg, 0.475 mmol) in ACN (2 ml). The mixture was heated to 90 ° C in a sealed tube for 3 hours. The reaction mixture was cooled to room temperature and poured into ice water and EtOAc. The mixture was extracted with EtOAc. The organic layer was dried, (MgSO4), filtered and the solvent was evaporated. The residue (325 mg) was purified by silica gel chromatography [(Sunfire Silica, 5 pm, 150 x 30.0 mm), mobile phase (0% NH4OH gradient, 100% DCM, 0% MeOH a 0.5% NH4OH, 95% DCM, 5% MeOH)], producing 145 mg of the product fraction (63%) which was crystallized with ACN / Et2O. The precipitate was filtered, washed with Et2O and dried to give 118 mg of compound 14 (51%, white solid), mp = 145 ° C. Example B 14

Preparation of compound 15 (Z) HCl 3 M (5 ml) was added to a solution of intermediate 18 (0.375 g; 0.69 mmol) in MeOH (12 ml) at room temperature. The reaction mixture was heated to 60 ° C for 6 hours. After cooling to room temperature, the crude mixture was made basic with 10% aqueous K2CO3 solution and extracted twice with DCM. The combined organic layers were dried, (MgSÜ4), filtered and evaporated. The residue (340 mg) was purified by silica gel chromatography [(Stability Silica, 5 pm, 150 x 30.0 mm), mobile phase (0.2% NH4OH gradient, 98% DCM, 10 2% MeOH 1% NH4OH, 90% DCM, 10% MeOH)] to give 46 mg of a fraction that was absorbed in DCM and evaporated to give 45 mg (15%, Z isomer, mp = 124 ° C gum ) of compound 15 and 77 mg of a second fraction which was absorbed in DCM and evaporated to give 70 mg (23%, E isomer, mp = 130 ° C, gum) of compound 41. Example B 15
Preparation of compound 27 '
(Mixture of E + Z) 7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) -quinoxaline (8.76 g; 30.3 mmol), (3E) -4- (3.5 -dimethoxyphenyl) -3-buten-2-one (5 g; 24.2 mmol), palladium (II) acetate (47% Pd) (272 mg; 1.2 mmol), tri-o-tolylphosphine (738 mg; 2.4 mmol) and TEA (10 ml; 72.7 mmol) in ACN (35 ml) were stirred at reflux (80 ° C) for 48 hours. After cooling to room temperature, water was added. The reaction mixture was filtered through a pad of Celite®. Celite® was washed with DCM. The organic layer was separated, dried, (MgSCU), filtered and evaporated. The residue (13.8 g) was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.1% NH4OH, 98% DCM. 2% iPrOH) ], yield of 3.4 g of residue. This residue was purified by chiral SFC [(CHIRALPAK IC, 5 pm, 250 x 20 mm), mobile phase (50% CO2, 25% EtOH, 25% iPrOH)], yield of 2.1 g of compound 27 (21%, a yellow oil). C. Conversion reactions Example C1

Preparation of compound 17 Sodium borohydride (414 mg; 10.95 mmol) was added portionwise to a solution of compound 2 (2.05 g, 5.5 mmol) in MeOH (15 ml) and THF (5 ml) at 5o C. The reaction mixture was allowed to stir at room temperature for 40 minutes. The water was added. The reaction mixture was stirred for 10 minutes. The precipitate was filtered off yielding 1.74 g (84%) of compound 17. Example C2

Preparation of compound 18 Magnesium (1.7 g; 71.3 mmol) was added to a suspension of compound B3 (2.7 g; 6.8 mmol) in MeOH (70 ml) and THF (40 ml). The reaction mixture was stirred for 3.5 hours. The temperature was raised to 35 ° C. The reaction mixture was cooled to 10 ° C and stirred for 1 hour. Ice and 10% aqueous NH4 Cl solution were added. The reaction mixture was extracted with DCM, dried, (MgSOzQ, filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 300 g), mobile phase (0.1% NH4OH, 98% DCM, 2% MeOH)] to give 2.6 g of the product fraction that was crystallized from ACN, filtered and dried to give 1.51 g (56%) of compound 18, mp = 165 ° C. Example C2a

Preparation of compound 16 Magnesium shavings (1.36 g, 55.7 mmol) were added in one portion to a solution of compound 27 (2.1 g, 5.1 mmol) in MeOH (80 ml) at room temperature. The reaction mixture was stirred overnight. Ice and 10% aqueous NH4 Cl solution were added. The reaction mixture was extracted with DCM, dried, (MgSCU), filtered and the solvent was partially evaporated. Air was bubbled into the solution. Pd / C 10% (0.4 g) was added and air was bubbled through for 1 day. The mixture was filtered through a pad of Celite®. Celite® was washed with CH2Cl2. The filtrate was evaporated. The residue (2.07 g) was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 300 g), mobile phase (0.1% NH4OH, 97.5% DCM, 2.5 % MeOH)], yielding 1 g of compound 16 (47%, orange solid, mp = 154 ° C). Example C3 Preparation of

Methanesulfonyl chloride (574 pl; 7.4 mmol) was added to a solution of compound 22 (1 g; 2.5 mmol) and TEA (1.4 ml, 9.9 mmol) in ACN (3 ml) at 5o C under N2- The reaction mixture was stirred for 1 hour at room temperature. Isopropylamine (16.8 ml) was added. The mixture heated to 90 ° C in a sealed tube using a single mode microwave (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W for 60 minutes. The reaction mixture was evaporated. The residue was taken up in DCM and water. The organic layer was dried, (MgSOzQ, filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.5% NH4OH, 92% DCM, 8% MeOH)]. The fractions were collected and evaporated producing 1.26 g of a residue that was further purified by chiral SFC [(CHIRALPAK AD-H, 5 pm, 250 x 20 mm), mobile phase (0 , 3% ISOPROPYLAMINE, 40% iPrOH, 60% CO2)] to give 439 mg of one enantiomer (compound 19) and 470 mg of another enantiomer (compound 32).
The first fraction (439 mg) was converted to HCI salt in MeOH. Et2O was added. The precipitate was filtered off and dried to give 410 mg of a solid product. Because of some degradation, this product was basified with a mixture of ice water and the aqueous solution of 10% K2CO3. DCM was added and the organic layer was separated, dried, (MgSCU) and the solvent was evaporated, yielding 440 mg of residue. The residue was purified by chromatography on silica gel [(Sunfire Silica, 5 pm, 150 x 30.0 mm), mobile phase (gradient of 0.2% NH4OH, 98% DCM, 2% MeOH to 1, 3% NH4OH, 87% DCM, 13% MeOH)]. The pure fractions were collected and the solvent was evaporated to give 315 mg of compound 19 (optical rotation = +20.7 (589 nm, c = 0.28, DMF, 20 ° C) .This compound was converted to its salt oxalic acid in EtOH The precipitate was filtered off and dried to give 255 mg (18%) of compound 19a, mp = 162 ° C.
The second fraction (470 mg) was converted to HCI salt in MeOH. Et2O was added. The precipitate was filtered off and dried to give 400 mg of a solid product. Because of some degradation, this product and its filtrate were combined and basified with a mixture of ice water and 10% aqueous K2CO3 solution. DCM was added and the organic layer was separated, dried, (MgSCU) and the solvent was evaporated, yielding 440 mg of residue. The residue was purified by chromatography on silica gel [(Sunfire Silica, 5 pm, 150 x 30.0 mm), mobile phase (gradient of 0.2% NH4OH, 98% DCM, 2% MeOH to 1, 3% NH4OH, 87% DCM, 13% MeOH)] The pure fractions were collected and the solvent was evaporated to give 276 mg of compound 32 (optical rotation = -22.7 (589 nm, c 0.26, DMF, 20 ° C) which was converted to its oxalic acid salt in EtOH The precipitate was filtered off and dried to give 217 mg (16%) of compound 32a. Mp = 172 ° C. * means relative stereochemistry Example C4 a) Preparation of compound 20

A solution of compound 18 (1.1 g; 2.75 mmol) was hydrogenated at room temperature in 7 N ammonia in MeOH (250 ml) and THF (50 ml) with Raney Nickel (1.13 g) as a catalyst in a pressure vessel reactor (Parr®) (2 bar). Air was bubbled into the mixture for 4 hours. The catalyst was separated by filtration on a Celite® pad. The filtrate was evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, (15 to 40 pm, (90 g), mobile phase (Gradient of 100% DCM, 0% MeOH to 85% DCM, 15% MeOH )]. The pure fractions were collected and evaporated to dryness The desired fractions combined (790 mg), dissolved in MeOH and converted to hydrochloric acid salt with HCl / 2-propanol. The compound was crystallized from MeOH. precipitate was stirred for 30 minutes, filtered off, washed with Et2O and dried, yield of 792 mg (61%) of compound 20. Example C5 Preparation of compound 21
Compound 36 (
) prepared according to protocol B13 mmol) was hydrogenated at room temperature in MeOH (4 ml) with Pd (10% dry carbon) (50 mg, 0.471 mmol) as a catalyst at atmospheric pressure. After 2 hours, the catalyst was filtered off on a pad of Celite® and washed with CH2 Cl2 / MeOH. The filtrate was evaporated. The residue (180 mg) was purified by chromatography on silica gel [(Sunfire Silica, 5 pm, 150 x 30.0 mm), mobile phase (Gradient 0.2% NH4OH, 98% DCM, 2% 1.2% MeOH NH4OH, 88% DCM, 12% MeOH)], yielding 56 mg of the product fraction that was converted to the HCI salt (5 eq.) In MeOH. Et2O was added. The precipitate was filtered and dried to give 50 mg of compound 21 (21%). Example C6
a) Preparation of compound 22 L1AIH4 (434 mg; 11.4 mmol) was added to a solution of compound 13 (3.4 g; 7.6 mmol) in THF (55 ml) at 0 to 5 ° C under Nitrogen. The reaction mixture was stirred for 1 hour at 05 ° C. EtOAc was carefully added, followed by water. The mixture was filtered through a pad of Celite®. The organic layer was dried, (MgSOO, filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 15 to 40 pm, 300 g), mobile phase (0.1% NH4OH, 3% MeOH, 97% DCM)], yielding 1.79 g (58%) of compound 22. Example C7
a) Preparation of compound 23 Compound 13 (400 mg; 0.9 mmol) and isopropylamine (3.4 ml; 40.3 mmol) in a sealed tube were heated to 135 ° C using a single-mode microwave (Biotage Initiator EXP 60) with an output power ranging from 0 to 400 W for 5 hours (12 bars). Then the reaction was stirred at 135 ° C for 12 hours in an oil bath. After cooling to room temperature, the solvent was evaporated. The residue was purified by chromatography on silica gel [(Sunfire Silica, 5 pm, 150 x 30.0 mm), mobile phase (0% NH4OH gradient, 100% DCM, 0% 0.5% MeOH NH4OH, 95% DCM, 5% MeOH)]. The desired product fraction (91 mg, 22%) was crystallized from Et2O and filtered to give 52 mg (12%) of compound 23. mp = 186 ° C Example C8 Preparation of

Compound 2 (814 mg; 2.17 mmol) and N-isopropylethylene diamine (98%) (3.6 ml; 28.3 mmol) were stirred at 140 ° C for 7 hours, then at 60 ° C during night. After cooling to 5 ° C, MeOH (15 ml) was added, then sodium borohydride (329 mg; 8.7 mmol) was added and the reaction mixture was stirred for 1 hour at 5 ° C then at room temperature for 4 hours . Water was added and the crude mixture was extracted twice with DCM. The combined organic layers were washed with water, dried, (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel [(Irregular SiOH, 20 to 45 pm, 450 g), mobile phase (0.5% NH4OH, 95% DCM, 5% MeOH)] to give 675 mg of fraction of the product. The product fraction was purified by chiral SFC [(CHIRALPAK AD-H, 5 pm, 250 x 20 mm), mobile phase (0.3% ISOPROPYLAMINE, 70% CO2, 15% EtOH, 15% iPrOH) ]. The pure fractions were collected and the solvent was evaporated to give 240 mg of an enantiomer (first fraction) and 237 mg of another enantiomer (second fraction).
The first fraction (240 mg) was converted to its salt in HCI with HCI in iPrOH (5-6N) in ACN. The solvent was evaporated and the residue was taken up in Et2O, filtered and dried to give 267 mg (22%) of compound 24.
The second fraction (237 mg) was converted to its salt in HCI with HCI in iPrOH (5-6N) in ACN. The solvent was evaporated and the residue was taken up in Et2O, filtered and dried to give 269 mg (22%) of compound 39. * means relative stereochemistry Example C9
Preparation of compound 25 A mixture of compound 26 (180 mg; 0.418 mmol) (see Example CIO) and isopropylamine (178 pl; 2.1 mmol) in DMF (3.5 ml) was heated to 100 ° C for 20 hours. Isopropylamine (178 pl; 2.1 mmol) was added to the mixture. The reaction mixture was heated to 120 ° C overnight. Isopropylamine (1 ml; 11.7 mmol) and ethanol (1 ml) were added. The mixture was heated to reflux overnight and then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The organic layer was dried, (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel [(Sunfire Silica, 5 pm, 150 x 30.0 mm), mobile phase (gradient of 0.2% NH4OH, 98% DCM, 2% MeOH to 1, 3% NH4OH, 87% DCM, 13% MeOH)], producing, after the evaporation of the collected fractions, 200 mg of a yellow oil which was converted into the HCI salt (5 eq.) In MeOH / Et2O. The solvent was evaporated to give 200 mg (87%) of compound 25. Example CIO
Preparation of compound 26
Potassium tert-butoxide (182 mg; 1.6 mmol) was added portionwise to a solution of trimethylsulfoxonium iodide (357 mg; 1.6 mmol) in dimethoxymethane (15 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and the solution was added dropwise to a solution of compound 16 (450 mg; 1.08 mmol) in DMSO (6 ml) at 5 ° C under a flow of N2. The reaction mixture was stirred at 5 ° C for 1 hour afterwards at room temperature for 48 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried, (MgSO4), filtered and the solvent was evaporated. The residue (473 mg) was purified by chiral SFC [(CYANO, 6 pm, 150 x 21.2 mm), mobile phase (90% CO2, 10% MeOH)], yield of two fractions 140 mg (28% ) and 180 mg (39%) of compound 26.
The following compounds were prepared according to the reaction protocols of one of the Examples above using alternative starting materials as appropriate.
In Table Al = CoX or = BX indicate that the preparation of this compound is described in Conversion X or Method BX.
In Table A1 -CoX or -BX indicates that this compound is prepared according to Conversion X or Method BX.
In Table Al * means relative stereochemistry Table Al Method - or - Melting Point 0o C - minute - and - oxalic acid










Analytical Part LC / GC / NMR General procedure A
The LC measurement was performed using an UPLC (Ultra Performance Liquid Chromatography) Acquity (Waters) system comprising a binary pump with degasser, a self-sampler, a diode array detector (DAD) and a column as specified in the respective methods below, the column is maintained at a temperature of 40 ° C. Flow of the column was taken to an MS detector. The MS detector was configured with an electrospray ionization source. The capillary needle voltage was 3 kV and the source temperature was maintained at 130 ° C in the Quattro (Waters triple quadripolar mass spectrometer). Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system. Method 1
In addition to general procedure A: reverse phase UPLC was performed on a Cl8 Waters Acquity BEH (bridged ethyl siloxane / silica hybrid) column (1.7 pm, 2.1 x 100 mm) with a flow rate of 0 , 35 ml / min. Two mobile phases (mobile phase A: 95% ammonium acetate 7 mM / 5% acetonitrile; mobile phase B: 100% acetonitrile) were used to drive a gradient condition of 90% A and 10% B (maintaining for 0.5 minutes) to 8% A and 92% B in 3.5 minutes, holding for 2 min and back to initial conditions in 0.5 min, holding for 1.5 minutes. An injection volume of 2 pl was used. The cone voltage was 20 V by positive and negative ionization mode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2 seconds using a 0.1 second inter-scan delay. General procedure B
The UPLC measurement was performed using an Alliance HT 2795 (Waters) system that comprises a quaternary pump with degasser, an auto-sampler, a diode array detector (DAD) and a column as specified in the respective methods below, the column is kept in a temperature of 30 ° C. The column flow was divided into an MS spectrometer. The MS detector was configured with an electrospray ionization source. The capillary needle voltage was 3 kV and the source temperature was maintained at 100 ° C in the LCT (Waters Flight Time Z Spray Mass Spectrophotometer). Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynxOpenlynx data system. Method 2
In addition to general procedure B: the reverse phase UPLC was performed on a Supelco Ascentis Express Cl8 column (2.7 pm, 3.0 x 50 mm) with a flow rate of 0.7 ml / min. Two mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile) were used to drive a gradient condition of 80% A and 20% B (maintained for 0.5 minute) to 5% A and 95% B in 2.5 minutes, maintained for 4.5 minutes and back to initial conditions in 1.5 minutes and maintained for 1 min. An injection volume of 5 pl was used. The cone voltage was 20 V for both positive and negative ionization modes. Mass spectra were acquired by scanning from 100 to 1000 in 0.4 seconds using an inter-scan delay of 0.3 seconds. NMR data
The NMR experiments below were performed using a Bruker Avance 500 spectrometer and a Bruker Avance DRX 400 at room temperature, using an internal deuterium lock and equipped with a reverse triple resonance probe tip (1H, 13O, 15N TXI) for the 500 MHz and with a double reverse resonance probe tip (1H, 13O, SEI) for 400 MHz. Chemical changes (δ) are reported in parts per million (ppm). Compound 19a
NMR (DMSO-de) 8: 9.24 (s, 1H), 8.55 - 8.82 (m, 3H), 8.26 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.68 (dd, J = 8.6.1.5 Hz, 1H), 6.57 (d, J = 2.0 Hz, 2H), 6.36 - 6.40 (m, 1H), 4.28 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H), 3.72 (s, 6H), 3.24 - 3.37 (m, 1H), 2.84 (br. S „2H), 2.38 - 2.47 (m, 2H), 1.17 (d, J = 6.1 Hz, 6H) Compound 10
'H NMR (DMSO-do) 6: 9.23 (s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 8.8, 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 6.57 (t, J = 2.2 Hz, 1H), 6.47 (t, J = 6.6 Hz, 1H), 6.35 (d, J = 2.2 Hz, 2H), 3.92 (s, 3H), 3.75 ( s, 6H), 2.96 (d, J = 6.6 Hz, 2H), 2.16 (s, 6H) Compound 14
'H NMR (DMSO-de) 6: 9.23 (s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 8.8, 1.9 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 6.56 (t, J = 2.0 Hz, 1H), 6.45 (t, J = 6.6 Hz, 1H), 6.38 (d, J = 2.0 Hz, 2H), 3.92 (s, 3H), 3.75 ( s, 6H), 3.17 - 3.32 (m, 4H), 2.65 - 2.75 (m, 1 H) Compound 8
'H NMR (DMSO-de) 6: 9.22 (s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.80 (dd, J = 8.8, 1.3 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 6.56 (br. S, 1H), 6.46 (t, J = 6.6 Hz, 1H), 6.38 (d, J = 1.9 Hz, 2H), 3.92 (s, 3H), 3.75 (s, 6H), 3.21 (d, J = 6.6 Hz, 2H), 2.69 - 2.78 (m, 1H), 1.76 (br. S, 1H), 0.93 (d, J = 6, 3 Hz, 6H) Compound 29
! H NMR (DMSO-de) 6: 9.25 (s, 1H), 8.72 - 9.00 (m, 2H), 8.62 (s, 1H), 8.27 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.92 (br. S., 1H), 7.68 (d, J = 8.5 Hz, 1H), 6.58 (br. s „2H), 6.38 (br., 1H), 4.33 (t, J = 7.3 Hz, 1H), 3.95 (s, 3H), 3.72 (s, 6H) , 3.24 - 3.34 (m, 1H), 2.74 -2.89 (m, 2H), 2.53 - 2.59 (m, 2H), 1.19 (d, J = 4, 1 Hz, 6H) Pharmacological Part Biological tests A FGFR 1 (enzymatic assay)
In a final reaction volume of 30 pl, FGFR1 (h) (25 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCE, 1 mM DTT, 0.1 mM NaaVCb, 0 , 01% Triton-X-100, 500 nM Btn-Flt3 and 5 pM ATP in the presence of the compound (1% final DMSO). After incubation for 60 minutes at room temperature, the reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nM SA-XL-665 and 0.02% BS A which was present for 60 minutes at room temperature. The Time Solved Fluorescence Resonance Energy Transfer (TR-FRET) signal (ex340 nm. At 620 nm, at 655 nm) was subsequently measured and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range from 10 pM to 0.1 nM) was determined and used to calculate an IC50 (M) and pICo (-logICgo) value. FGFR2 (enzymatic assay)
In a final reaction volume of 30 pl, FGFR2 (h) (150 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCE, 1 mM DTT, 0.1 mM Na3VO4, 0 , 01% Triton-X-100, 500 nM Btn-Flt3 and 0.4 pM ATP in the presence of the compound (1% final DMSO). After incubation for 60 minutes at room temperature, the reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA which was present for 60 minutes at room temperature. The Time Solved Fluorescence Resonance Energy Transfer (TR-FRET) signal (ex340 nm. At 620 nm, at 655 nm) was measured subsequently and the results are expressed in (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range of 10 pM to 0.1 nM) was determined and used to calculate an IC50 (M) and pICso (- logICso) value. FGFR3 (enzymatic assay)
In a final reaction volume of 30 pl, FGFR3 (h) (40 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCE, 1 mM DTT, 0.1 mM Na3VO4, 0 , 01% Triton-X-100, 500 nM Btn-Flt3 and 25 pM ATP in the presence of the compound (1% final DMSO). After incubation for 60 minutes at room temperature, the reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA which was present for 60 minutes at room temperature. The Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) signal (ex340 nm. At 620 nm, at 655 nm) was subsequently measured and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range from 10 pM to 0.1 nM) was determined and used to calculate an IC50 (M) and ^ iCso (- logICso) value. FGFR4 (enzymatic assay)
In a final reaction volume of 30 pl, FGFR4 (h) (60 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCE, 1 mM DTT, 0.1 mM NaaVCh, 0 , 01% Triton-X-100, 500 nM Btn-Flt3 and 5 pM ATP in the presence of the compound (1% final DMSO). After incubation for 60 minutes at room temperature, the reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA which was present for 60 minutes at room temperature. The Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) signal (ex340 nm. At 620 nm, at 655 nm) was subsequently measured and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (10 pM to 0.1 nM range) was determined and used to calculate an IC50 (M) and pICso (-logICso) value. KDR (VEGFR2) (enzymatic assay)
In a final reaction volume of 30 pl, KDR (h) (150 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCE, 1 mM DTT, 0.1 mM Ne / VOd , 0.01% Triton-X-100, 500 nM Btn-Flt3 and 3 pM ATP in the presence of the compound (1% final DMSO). After incubation for 120 minutes at room temperature, the reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nM SA-XL-665 and 0.02% BS A which was present for 60 minutes at room temperature. The Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) signal (ex340 nm. At 620 nm, at 655 nm) was subsequently measured and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (10 pM to 0.1 nM range) was determined and used to calculate an IC50 (M) and PIC93 (- logICeo) value. Ba / F3-FGFR1 (less IL3 or more IL3) (cell proliferation assay)
In a 384 well plate, 100 nl of compound dilution in DMSO was sprayed before adding 50 µl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM L-Glutamine and 50 pg / ml Gentamicin) containing 20,000 cells per cell pool transfected with Ba / F3-FGFR1. The cells were placed in an incubator at 37 ° C and 5% CO2. After 24 hours, 10 µl Alamar Blue solution (0.5 mM K3Fe (CN) 6, 0.5 mM K4Fe (CN) 6, 0.15 mM Resazurin and 100 mM phosphate buffer) was added to the reservoirs, incubated for 4 hours at 37 ° C and 5% CO2 before RFU's (Relative Fluorescence Units) (eg. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader.
In this assay, the inhibitory effect of different compound concentrations (range of 10 pM to 0.1 nM) was determined and used to calculate an IC 50 (M) and pICso (-logIC) value.
As a counterscreen the same experiment was carried out in the presence of 10 ng / ml of murine 1L3. Ba / F3-FGFR3 (less IL3 or more IE3) (cell proliferation assay)
In a plate of 384 reservoirs, 100 nl of dilution of the compound in DMSO was sprayed before adding 50 µl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM L-Glutamine and 50 pg / ml of Gentamycin) containing 20,000 cells per cell pool transfected with Ba / F3-FGFR3. The cells were placed in an incubator at 37 ° C and 5% CO2. After 24 hours, 10 µl Alamar Blue solution (0.5 mM K3Fe (CN) 6, 0.5 mM K4Fe (CN) 6, 0.15 mM Resazurin and 100 mM phosphate buffer) were added to the reservoirs, incubated for 4 hours at 37 ° C and 5% CO2 before RFU's (Relative Fluorescence Units) (eg. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader.
In this assay, the inhibitory effect of different compound concentrations (range from 10 pM to 0.1 nM) was determined and used to calculate an IC50 (M) and pICso (-logICso) value.
As a counterscreen the same experiment was carried out in the presence of 10 ng / ml of murine IE3. Ba / F3-KDR (less IE3 or more IE3) (cell proliferation assay)
In a plate of 384 reservoirs, 100 nl of dilution of the compound in DMSO was sprayed before adding 50 µl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM E-Glutamine and 50 pg / ml Gentamicin) containing 20,000 cells per cell pool transfected with Ba / F3-KDR. The cells were placed in an incubator at 37 ° C and 5% CO2. After 24 hours, 10 µl Alamar Blue solution (0.5 mM KaFefCNX 0.5 mM K4Fe (CN) ó, 0.15 mM Resazurin and 100 mM phosphate buffer) were added to the reservoirs, incubated for 4 hours at 37 ° C and 5% CO2 before RFU's (Relative Fluorescence Units) (eg. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader.
In this assay, the inhibitory effect of different compound concentrations (range from 10 pM to 0.1 nM) was determined and used to calculate an IC50 (M) and pICso (-logICso) value.
As a counterscreen the same experiment was performed in the presence of 10 ng / ml of murine IL3. Ba / F3-Flt3 (less IL3 or more IL3) (cell proliferation assay)
In a plate of 384 reservoirs, 100 nl of dilution of the compound in DMSO was sprayed before adding 50 µl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM L-Glutamine and 50 pg / ml Gentamicin) containing 20,000 cells per cell pool transfected with Ba / F3-Flt3. The cells were placed in an incubator at 37 ° C and 5% CO2. After 24 hours, 10 µl of Alamar Blue solution (0.5 mM KaFe (CN) 6, 0.5 mM K4Fe (CN) ó, 0.15 mM Resazurin and 100 mM phosphate buffer) were added to the reservoirs, incubated for 4 hours at 37 ° C and 5% CO2 before RFU's (Relative Fluorescence Units) (eg. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader.
In this assay, the inhibitory effect of different compound concentrations (range from 10 pM to 0.1 nM) was determined and used to calculate an IC50 (M) and pICso (-logICso) value.
As a counterscreen the same experiment was performed in the presence of 10 ng / ml of murine IL3.
The pICso data for the compounds of the invention in the above tests are provided in Table A2. Table A2

Biological Assays B In vitro Assays of FGFR3, VEGFR2 and PDGFR Kinase Inhibitory Activity
Enzymes (from Upstate), prepared at 2x final concentration, were incubated with test compounds, biotinylated Flt3 substrate (biotin-VASSDNEYFYVDF) (Cell Signalling Technology Inc.) and ATP in the appropriate Assay Buffer (Table 1). The reaction was allowed to proceed for 3 hours (FGFR3), 1 hour (VEGFR2, PDGFR-beta) at room temperature on a plate shaker at 700 rpm before being stopped with 35 mM EDTA, pH 8 (FGFR3, VEGFR2) or 55 mM EDTA, pH 8 (PDGFR-beta). 5x detection mixture (50 mm HEPES pH 7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20) (PerkinElmer) 74 nM SA-XL665 (Cisbio) for FGFR3, 50 mM HEPES, pH 7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20), 187.5 nM SA-XL665 for VEGFR2 and 50 mM HEPES, pH 7.5 , 0.1% BSA, 11.34 nM Eu-anti-pY (PT66) (PerkinElmer), 375 nM SA-XL665 (Cisbio) for PDGFR-beta) were then added to each reservoir and the plate sealed and incubated at room temperature for one hour on a plate shaker at 700 rpm. The plate was then read in a Packard Fusion plate reader or a BMG Pherastar both in TRF mode. Table 1: Final test conditions for FGFR3, VEGFR2 and PDGFR beta tests

The kinase assay buffers were: A: 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.01% Triton X-100 B: 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.01% TritonX-100, 0.1 mM sodium orthovanadate C: 20 mM HEPES pH 7.5, 10 mM MnCE, 0.01% Triton X- 100, 1 mM DTT, 0.1 mM sodium orthovanadate
The FGFR3 and VEGFR2 data for the compounds of the invention in the above assays are provided in Table A3. Ba / F3-TEL-FGFR3 & Ba / F3 (WT) cell proliferation assays
Stable transfected Ba / F3-TEL-FGFR3 cells were plated on tissue culture plates of 96 black wells with clear bottoms in RPMI medium containing 10% FBS and 0.25 mg / ml G418 at a density of 5 x 103 cells / reservoir (200 pl per reservoir). The precursor wild-type Ba / F3 cells (DSMZ no .: ACC 300) were plated on 96-well black tissue culture plates with clear bottoms in RPMI medium containing 10% FBS and 2 ng / ml IL-3 mouse (R&D Systems) at a density of 2.5 x 103 cells / reservoir (200 pl per reservoir). The plates were plated in an incubator overnight before adding the compounds the next day. Dilutions of the compounds were made in DMSO starting at 10 mM and were diluted in the reservoirs to give a final concentration of 0.1% DMSO in the assay. The compounds were left on the cells for 72 hours before the plates were removed from the incubator and 20 µl of Alamar ® Blue (Biosource) was added to each reservoir. The plates were plated in the incubator for 4 to 6 hours before reading the plates at 535 nm (excitation) / 590 nm (emission) in a Fusion plate reader (Packard). Where inhibition is high, an IC 50 can be determined.
The data for the compounds of the invention in the above tests are provided in Table A3.

权利要求:
Claims (25)
[0001]
1. Compound of formula (I):
[0002]
2. Compound according to claim 1, characterized by the fact that n is 0 or 2.
[0003]
A compound according to claim 1 or 2, characterized by the fact that R1 is -CH3.
[0004]
Compound according to any one of claims 1 to 3, characterized in that R2 is CH3O-.
[0005]
Compound according to any one of claims 1 to 4, characterized in that R3a is C1-6 alkyl substituted with - NR10Rn.
[0006]
A compound according to any one of claims 1 to 4, characterized in that R3a and R3b are taken together to form = 0, to form cyclopropyl together with the carbon atom to which they are attached to form = CH- C0-4 alkyl substituted with R3c.
[0007]
Compound according to any one of claims 1 to 4, characterized in that R9 is a 5- or 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, said monocyclic heterocycly optionally being substituted com = ().
[0008]
A compound according to any one of claims 1 to 5, characterized by the fact that R3b represents hydrogen.
[0009]
9. Compound, characterized by the fact that the compound is selected from {(Z) -3- (3,5-Dimethoxy-phenyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) - quinoxalin-6-yl] -ally} dimethyl-amine; {(Z) -3- (3,5-Dimethoxy-phenyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-6-yl] -alyl} isopropyl-amine; {(Z) -3- (3,5-Dimethoxy-phenyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-6-yl] -alyl} (2,2, 2-trifluoro-ethyl) -amine; {(S) -3- (3,5-Dimethoxy-phenyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-6-yl] -propyl} isopropyl-amine; {3- (3,5-Dimethoxy-phenyl) -3- [3- (1-methyl-1 H-pyrazol-4-yl) -quinoxalin-6-yl] -propyl} isopropyl-amine; or a pharmaceutically acceptable salt thereof.
[0010]
10. Pharmaceutical composition, characterized by the fact that it comprises a compound of the formula (I) as defined in any one of claims 1 to 9.
[0011]
11. Use of a compound as defined in any one of claims 1 to 9, characterized in that it is for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by an FGFR kinase.
[0012]
12. Use of a compound as defined in any one of claims 1 to 9, characterized by the fact that it is for the manufacture of a medicine for the prophylaxis or treatment of cancer.
[0013]
13. Use according to claim 12, characterized by the fact that the cancer is selected from multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, ovarian cancer, breast cancer , gastric cancer, colorectal cancer and oral squamous cell carcinoma.
[0014]
14. Use according to claim 12, characterized by the fact that the cancer is selected from lung cancer, squamous cell carcinoma, liver cancer, kidney cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer.
[0015]
15. Use, according to claim 14, characterized by the fact that the cancer is NSCLC.
[0016]
16. Use, according to claim 12, characterized by the fact that cancer is multiple myeloma.
[0017]
17. Use, according to claim 16, characterized by the fact that cancer is positive multiple myeloma for t translocation (4; 14).
[0018]
18. Use, according to claim 12, characterized by the fact that cancer is a bladder cancer
[0019]
19. Use, according to claim 18, characterized by the fact that the cancer is a bladder cancer with a chromosomal translocation of FGFR3.
[0020]
20. Use, according to claim 18, characterized by the fact that cancer is a bladder cancer with a point mutation in FGFR3.
[0021]
21. Use according to claim 12, characterized by the fact that the cancer is a tumor with a FGFR1, FGFR2, FGFR3 or FGFR4 mutant.
[0022]
22. Use according to claim 12, characterized by the fact that the cancer is a tumor with a FGFR2 or FGFR3 function gain mutant.
[0023]
23. Use, according to claim 12, characterized by the fact that cancer is a tumor with FGFR1 overexpression.
[0024]
24. Use of a compound as defined in any one of claims 1 to 9, characterized in that it is for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition as described herein.
[0025]
25. Process for the preparation of a compound of formula (I) as defined in claim 1, characterized in that the process comprises (I) reacting an intermediate of formula (IV) in which Wire presents a suitable starting group, with a intermediate of formula (V) in the presence of a suitable catalyst, a suitable base and a suitable solvent, with R1, R2 en as defined in claim 1; (Ila) an intermediate of formula (VI) reacts in which W3 represents a suitable starting group, with an intermediate of formula (XIII) in the presence of CO, a suitable catalyst, a suitable ligand, with R1, R2 and as defined in claim 1; (Ilb) reacting an intermediate of formula (VI ') in which W3 represents a suitable starting group, with an intermediate of formula (XIII) in the presence of CO, a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent , with R1, R2, Rla and n as defined in claim 1; (IHa) to react an intermediate of formula (VII) with an intermediate of formula (VIII) where W2 represents an appropriate starting group, in the presence of a catalyst, a suitable base and a suitable solvent, with R1, R2 en as defined in claim 1; (Illb) reacting an intermediate of formula (VII ') with an intermediate of formula (VIII) where W2 represents a suitable starting group, in the presence of a catalyst, a suitable base and a suitable solvent, with R1, R2, Rla and n as defined in claim 1; (IVa) reacting an intermediate of formula (VI), in which W3 represents a suitable starting group, with an intermediate of formula (IX) in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent, with R1, R2, R3 'en as defined in claim 1; (IVb) reacting an intermediate of formula (VI '), in whichWs represents a suitable starting group, with an intermediate of formula (IX) in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent, with R1, R2, Rla, R3C and as defined in claim 1; (Va) to react an intermediate of the formula (XI) with a intermediate of formula (XII) wherein W4 represents a suitable starting group, in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent, with R1, R2, R3c and n as defined in claim 1; (Vb) reacting an intermediate of the formula (XI ') with an intermediate of the formula (XII) where W4 represents a suitable starting group, in the presence of a suitable catalyst, a suitable base, a suitable solid base and a suitable solvent, comR1, R2, Rla, R3c en as defined in claim 1; (Via) deprotect an intermediate of the formula (XIV), in which P represents a suitable protecting group, in the presence of an acid with R1, R2, R11 en as defined in claim 1; (VIb) deprotect an intermediate of the formula (XIV '), in which P represents a suitable protecting group, in the presence of a suitable acid and a suitable solvent, with R1, R2, R1a, R11 en as defined in claim 1; (Vila) to react an intermediate of formula (XIX) with an intermediate of formula (VI), in which W3 represents a suitable starting group, in the presence of a suitable catalyst, a suitable ligand, a suitable base and a suitable solvent, with R1, R2, R10, R11 and n as defined in claim 1; (Vllb) to react an intermediate of formula (XIX) with an intermediate of formula (VI '), in which W3 represents a suitable starting group, in the presence of a suitable catalyst, a suitable ligand, with R1, R2, R1a, R10, R11 and n as defined in claim 1; (IXa) an intermediate of the formula (XXIII) reacts in which W5 represents a suitable starting group, with NHR11 in the presence of a suitable solvent, with R1, R2, R11 en as defined in claim 1; (IXb) an intermediate of the formula (XXIII ') reacts in which Ws represents a suitable starting group, with NHR11 in the presence of a with R1, R2, Rla, R11 and n as defined in claim 1; (Xla) reacting an intermediate of the formula (XXIV) with potassium in the presence of a suitable solvent, with R1, R2 en as defined in claim 1; (Xlb) to react an intermediate of the formula (XXIV ') with potassium cyanide in the presence of a suitable solvent, with R1, R2, Rla and n as defined in claim 1; (Xlla) react an intermediate of the formula (XXIV) with HR9 in the presence of a suitable base and a suitable solvent, with R1, R2, R9 and n as defined in claim 1; (Xllb) to react an intermediate of the formula (XXIV ') with HR9 in the presence of a suitable base and a suitable solvent, with R1, R2, Rla, R9 and n as defined in claim 1; (Xllla) to react an intermediate of the formula (XXV) with NHR10Rπ in the presence of a suitable solvent, with R1, R2, R10, R11 and n as defined in claim 1; (XlIIb) to react an intermediate of the formula (XXV ') with NHR10Rπ in the presence of a suitable solvent, with R1, R2, Rla, R10, R11 en as defined in claim 1; (XVa) react a compound of the formula (Ib-3) with a reducing agent H in the presence of a suitable solvent, with R1, R2 en as defined in claim 1; (XVb) reacting a compound of the formula (I-b'-3) with a reducing agent H in the presence of a suitable solvent, with R1, R2, Rla and n as defined in claim 1; (XVT) convert a compound of formula (I) into another compound of formula (I).

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同族专利:

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公开号 | 公开日

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CN103370314B|2015-10-21|

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KR101914720B1|2018-11-05|

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SMT201500191B|2015-09-07|

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GB201020179D0|2011-01-12|

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BR112013013435A2|2016-10-11|

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JP5868992B2|2016-02-24|

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EP2646432A1|2013-10-09|

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SI2646432T1|2015-08-31|

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US20160031856A1|2016-02-04|

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CN103370314A|2013-10-23|

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RU2602233C2|2016-11-10|

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HRP20150692T1|2015-08-14|

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RU2013129820A|2015-01-10|

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US9856236B2|2018-01-02|

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HRP20150692T8|2015-09-25|

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JP2013543883A|2013-12-09|

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KR20130132509A|2013-12-04|

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AU2011334624A1|2013-06-13|

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ES2541493T3|2015-07-21|

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-05-21| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-01-14| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-06-02| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-10-20| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 29/11/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US41774410P| true| 2010-11-29|2010-11-29|

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GBGB1020179.6A|GB201020179D0|2010-11-29|2010-11-29|New compounds|

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US61/417744|2010-11-29|

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GB1020179.6|2010-11-29|

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PCT/GB2011/052356|WO2012073017A1|2010-11-29|2011-11-29|Substituted benzopyrazin derivatives as fgfr kinase inhibitors for the treatment of cancer diseases|

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