compound, pharmaceutical composition, and, use of a compound

专利摘要:
COMPOUND, PHARMACEUTICAL COMPOSITION, PRODUCT, AND USE OF A COMPOUND. The invention relates to new compounds derived from naphthyridine, 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.
公开号:BR112014010179B1
申请号:R112014010179-5
申请日:2012-10-26
公开日:2020-12-08
发明作者:Patrick René Angibaud；Michel Obringer；Julien Jérémie Joseph Marin；Matthieu Jeanty
申请人:Astex Therapeutics Limited；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[0001] The invention relates to new compounds derived from naphthyridine, the pharmaceutical compositions comprising said compounds, the processes for preparing said compounds and the uses of said compounds in the treatment of diseases, for example, cancer. SUMMARY OF THE INVENTION
[0002] According to a first aspect of the invention compounds of formula (I) are provided:
which include any tautomeric or stereochemically isomeric form thereof, wherein X1 is N and X2 is CR3a, or X2 is N and X1 is CR3a; each of R2 is independently selected from hydroxyl, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 hydroxy alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 haloalkyl hydroxy, C1-4 haloalkoxy hydroxy, C1-4 alkoxy C1-4 alkyl, C1-4 haloalkoxy C1-4 alkyl, C1-4 alkoxy C1-4 alkyl in each of which C1 alkyl -4 optionally can be substituted with one or two hydroxyl groups, haloalkoxy hydroxy C1.4 alkyl CM, R13, CM alkyl substituted with R13, C1.4 alkyl substituted with -C (= O) -R13, CM alkoxy substituted with R13, CM alkoxy substituted with -C (= O) -Rlj, -C (= O) -R13, CM alkyl substituted with -NR7R8, CM alkyl substituted with -C (= O) -NR7R8, CM alkoxy substituted with -NR'RS, CM alkoxy substituted with - C (= O) -NR7RS, -NR7R8 and -C (= O) -NR'R8; or when two R groups 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; Y- represents -CR18 = N-OR19 or -ED; D represents a 3 to 12 membered monocyclic or bicyclic carbocyclyl in the ring or a 3 to 12 membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl can each one being optionally substituted by one or more (for example, 1, 2 or 3) groups R1; E represents a bond, - (CR "R") n-, C2.4 alkenodiyl optionally substituted with R “, C2-4 alkynodiyl optionally substituted with R22, -CO- (CR22R23) S-, - (CR22R23) S-CO -, -NR22- (CR22R23) S-, - (CR22R23) S-NR22-, -O- (CR22R23) S-, - (CR22R23) SO-, -S (O) m- (CR22R23) s-, - (CR22R23) sS (O) m-, - <CR22R23) S-CO-NR22- (CR22R23) S- OR - (CR22R23) S-NR22- CO- (CR22R23) S-; R1 represents hydrogen, halo, cyano, CM alkyl, CM alkoxy, -C (= O) -O- CM alkyl, C2.4 alkenyl, CM hydroxy alkyl, CM haloalkyl, C1-6 haloalkyl hydroxy, CM cyanoalkyl, CM alkoxy CM each of which CM alkyl can optionally be substituted with one or two hydroxyl groups, -NR4R Cμ6 alkyl substituted with -OC (= O) - Cμ 6 alkyl, Cμ6 alkyl substituted with -NR4R5, -C (-O) -NR4Ri, -C (= O) -CM alkyl- NR4R5, Cμg alkyl substituted with -C (= O) -NR4R5, -S (= O) 2-Cμ6 alkyl, - S (= O) 2-haloalkyl Cμg, -S ( = O) 2-NR14R13, Cμ6 alkyl substituted with - S (= O) 2-Cyl6 alkyl, Cμ6 alkyl substituted with -S (= O) 2-haIoalkyl Cμ6, alkyl substituted with -S (= O) 2-NR14RlD, Cμ6 substituted alkyl with - NH-S (= O) 2-C alkyl] .6, Cμ6 alkyl substituted with —NH-S (= O) 2-halo C1-6 alkyl, Cμ6 alkyl substituted with -NR12-S (= O) 2-NR14R13, R6, Cμβ alkyl substituted with R6, -C (= O) -R6, Cμ6 alkyl substituted with —C (= O) -R6, hydroxy Cμ6 alkyl substituted with R6, Cμ6 alkyl substituted with - Si (CH3) 3, Cμ6 alkyl substituted with -P (= O) (OH) 2 or Cf.6 alkyl substituted with -P (= O) (C6 alkyl O) 6; R'1 represents hydrogen, chlorine, hydroxyl, or Cμ alkoxy; R represents hydroxyl, Cμβ alkoxy, Cμ6 alkoxy hydroxide, Cμ6 alkoxy substituted with -NR10Rn, Cμ6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cμg haloalkyl optionally substituted with -OC (= O) -Cμ6 alkyl, optionally substituted hydroxy alkyl -OC (= O) -Cμ6 alkyl, C2-6 alkenyl hydroxy, C2.6 alkynyl hydroxy, Cμ6 haloalkyl hydroxy, Cμ6 cyanoalkyl, Cμ6 alkyl substituted with carboxyl, Cμ6 alkyl substituted with -C (= O) -Cμ6 alkyl, Cμ alkyl substituted with -C (= O) -O- Cμ6 alkyl, Cμ6 alkyl substituted with Cμ6 alkoxy Cμ6-OC (= O) -, Cμ6 alkyl substituted with Cμ6 alkoxy Cμ6-C (= O) -, Cμ6 alkyl substituted with -OC (= O) - Cμ6 alkyl, Cμ6 alkoxy Cμg alkyl in each of which Cμg alkyl optionally can be substituted with one or two hydroxyl groups or with -OC (= O) -Cμ6 alkyl, C2.6 alkenyl substituted with Cμ6 alkoxy, C2 alkynyl. 6 substituted with Cμ6 alkoxy, Cμg alkyl substituted with R9 and optionally substituted with -OC (= O) -Cμ6 alkyl, substituted Cμg alkyl with -C (= O) -R9, Cμ6 alkyl substituted with hydroxyl and R9, C2.6 alkenyl substituted with R9, C2.e alkynyl substituted with R9, Ci alkyl substituted with -NR10Rn, C2-Ó alkenyl substituted with - NRIOR ' C2.6 alkynyl substituted with -NR! (lRn, C alkyl (_6 substituted with hydroxyl and -NR1 () Rn, Cμ6 alkyl substituted with one or two halogens and - NR'θR11, -CÍ.6-C alkyl (R12) = NO-R12, CM alkyl substituted with -C (= O) - NR10Rn, Cb6 alkyl substituted with -OC (= O) -NR10Rn, -S (= O) 2-Cμ 6 alkyl, -S (= O) 2- Cμ6 haloalkyl, -S (= O) 2-NR14R15, Cμ6 alkylsubstituted with -S (= O) 2-C1 alkyl, Cμg alkyl substituted with -S (= 0) 2-haloalkyl Cμ6, Cp6 alkyl substituted with -S (= O) 2-NRI4RI:>, Cμ6 alkyl substituted with - NRI2-S (= O) 2- Cμ6 alkyl, Cμ6 alkyl substituted with -NH-S (= O) 2- Cμ6 haloalkyl, Ct.6 alkyl substituted with -NRI2-S (= O) 2-NRI4R ':', R13, Cμ6 alkyl substituted with -P (= O) (OH) 2 or Cμ6 alkyl substituted with - P (= O) (O C6 alkyl) 2; R4 and R each independently represent hydrogen, Cμ6 alkyl, Cμ $ alkyl substituted with -NR14R15, hydroxy Cμ6 alkyl, haloalkyl C, hydroxy haloalkyl Cμ6, alkoxy C] .6 alkyl C] .6 in each of which Cμ6 alkyl optionally can be substituted with one or two hydroxyl groups, -S (= O) 2-C1-6 alkyl, -S (= O) 2-haloalkyl Cμ6, -S (= O) 2- NR14R15, -C (= O) -NR '4RI5> -C (= O) -O- Cb6 alkyl, -C (= O) -R13, Cb6 alkyl substituted with -S (= O) 2-C] _6 alkyl, Cμ6 alkyl substituted with -S (= O) 2- Cμ6 haloalkyl, Cμ6 alkyl substituted with -S (= O) 2-NR14Rb, Cμ6 alkyl substituted with -NH-S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -NH- S (= O) 2- C haloalkyl .6, Cμ6 alkyl substituted with -NH-S (= O) 2-NR14R15, R1j or Cμ6 alkyl substituted with R1j; r .... R 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 Cμ6, Cμ6 cyanoalkyl, hydroxyl, carboxyl, Cμ6 hydroxy alkyl, halogen, Cμ6 haloalkyl, Cμe haloalkyl hydroxy, Cμ6 alkoxy, Cμ6 alkoxy CM alkyl, Cμ6-OC alkyl (= O) -, -NR14R15, -C (=) NR14R15, Cμ6 alkyl substituted with -NR14R15, Cμg alkyl substituted with -C (= O) -NRl4Rb, - S (= O) 2-Cμ6 alkyl, -S (~ O) 2-haloalkyl Cμ6, -S (= O) 2-NR14R15, Cμ6 alkyl substituted with -S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -S (= O) 2-haloalkyl Cμ6, Cμ6 alkyl substituted with -S (= O) 2-NRI4R1:!, Cμ6 alkyl substituted with -NH-S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with —NH-S (= O) 2-haloalkyl Cμ6 or Cμ6 alkyl substituted with -NH-S (= O) 2-NRl4Rb; R and R each independently represents hydrogen, CM alkyl, hydroxyl Cμ6 alkyl, haloalkyl Cμ6, hydroxy haloalkyl Cμ6or CM alkoxy alkyl Cμ6; R 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 = O, Cμ4 alkyl, hydroxyl , carboxyl, hydroxy Cμ4 alkyl, cyano, cyanoalkyl Cμ4, Cμ4 alkyl- OC (= O) -, Cμ4 alkylsubstituted with Cμ4-OC (= O) -, CM-C (= O) alkyl -, Cμ4 alkoxy Cμ4 each of which Cμ4 alkyl can optionally be substituted with one or two hydroxyl, halogen, Cμ4 haloalkyl, CM haloalkyl hydroxy, -NR14R15, -C (= O> NR14Rb, CM alkyl substituted with -NR14Rb, Cμ4 alkylsubstituted with - C (= O ) -NR14RI ”, Cμ4 alkoxy, -S (= O) 2-Cμ4 alkyl, -S (= 0) 2-Cμ4 haloalkyl, - S (= O) 2-NR l4Rb, Cμ4 alkyl substituted with —S (= O) 2-NRl4Rb, Cμ4 alkyl substituted with -NH-S (= O) 2-Cμ4 alkyl, CM alkyl substituted with -NH- S (= O) 2-haloalkyl Cμ4, alkyl CM substituted with -NH-S (= O) 2-NRl4Rb, R13, -C (= O) -R13, alkyl CM substituted with Rkl, phenyl optionally substituted with R16, phenylalkyl C6 .6 where 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- to 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; R10 and R11 each independently represent hydrogen, carboxyl, C | .6 alkyl, CM cyanoalkyl, Cμ6 alkylsubstituted with - NR14R Cμ6 alkylsubstituted with -C (= O) -NRI4R3, Cw haloalkyl, CM hydroxy alkyl, CM haloalkyl hydroxy, alkoxy haloalkyl CM, alkoxy CM alkoxyalkoxy. CM, CM alkoxy Cμ 6 alkyl in each of which CM alkyl can optionally be substituted with one or two hydroxyl groups, R6, CM alkyl substituted with R6, -C (= O) -R6, - C (= O) -alkyl CM, -C (= O) -Hydroxy alkyl CM, -C (= O) -haloalkyl CM, - C (= O) -hydroxy haloalkyl CM, CM alkyl substituted with -Si (CHa) 3, - S (= O ) 2-Cμ6 alkyl, -S (= O) 2-Cμ6 haloalkyl, -S (= O) 2-NR14R15, CM alkyl substituted with -S (= O) 2-CM alkyl, CM alkyl replaced with -S (= O) 2- CM haloalkyl, CM alkyl substituted with -S (= O) 2-NR14Rk, CM alkyl substituted with -NH-S (= O) 2-CM alkyl, CM alkyl substituted with -NH- S (= O) 2-halo CM alkyl, CM alkyl substituted with carboxyl, or CM alkyl substituted with -NH-S (= O) 2-NRi4Rb; Ru represents hydrogen or Cμ4 alkyl optionally substituted with Cμ4 alkoxy; R represents C3.8 cycloalkyl or a 4- to 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C3.8 cycloalkyl or monocyclic heterocycly is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxyl, CM alkyl, CM haloalkyl, = 0, cyano, -C (= O)-CM alkyl, CM alkoxy, or -NRI4R15; R14 and Rbcada one independently represents hydrogen, or CM haloalkyl, or C1.4 alkyl optionally substituted with a substituent selected from hydroxyl, CM alkoxy, amino or mono- or di (Camino alkyl; R16 represents hydroxyl, halogen, cyano, CM alkyl, CM alkoxy, -NR14R15 OR -C (= O) NR14R15; R represents hydrogen, CM alkyl, C3.8 cycloalkyl, C] _4 alkyl substituted with C3.8 cycloalkyl; R19 represents hydrogen; CM alkyl; C3.8 cycloalkyl; alkyl Cμ6substituted with -O-R20; - (CH2) r-CN; - (CH2) r-CONR20R21; - (CH2) R'-NR20R21; - (CH2) R'-NR20COR21; - (CH2) R'-NR20- (CH2) S-SO2-R21; - (CH2) R1-NH-SO2-NR20R21; - (CHR'-NRCOSR21 ;-( CH2) r-SO2NR20R21; phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, CM alkyl, CM alkyloxy, cyano or amino; a 5- or 6-membered aromatic monocyclic heterocycle containing at least one heteroatom selected from N, O or S, said heterocycle being optionally substituted with 1 , 2, 3 or 4 substituents each independently selected from halogen, CM alkyl, CM alkyloxy, cyano or amino; wherein said CM alkyl and C3.8 cycloalkyl, may optionally be substituted by one or more groups R "R" and R "independently representing hydrogen, CM alkyl, hydroxy CM alkyl, - (CH2) nO-CM alkyl, OR when attached to a nitrogen atom R20 and R21 can be taken together to form with the nitrogen atom to which they are attached a 4, 5 or 6 membered saturated monocyclic ring that optionally contains another hetero atom selected from O, S or N; R ~ and R ~ independently represent hydrogen, CM alkyl, OR hydroxy CM alkyl! m independently represents an integer equal to 0, 1 or 2; n independently represents an integer equal to 0, 1, 2, 3 or 4; s independently represents an integer equal to 0, 1, 2, 3 or 4; r independently represent an integer equal to 1, 2, 3, or 4; R1 independently represents an integer equal to 2, 3 or 4; the A-oxides thereof, the pharmaceutically acceptable salts thereof or the solvates thereof.
[0003] W02006 / 092430, W02008 / 003702, WOO1 / 68047, W02005 / 007099, W02004 / 098494, WO2009 / 141386, WO 2004/030635, WO 2008/141065, WO 2011/026579, WO 2011/028947, WO 00 / 42026, US2008 / 0116789, WO2010 / 084152, US2009 / 0054304, W02008 / 150827, W02006 / 066361, WO2011064250, W02007 / 125405 and WO2011 / 135376 each of which describes a series of heterocyclic derivatives. DETAILED DESCRIPTION OF THE INVENTION
[0004] Unless the context otherwise indicates, references. to formula (I) in all sections of this document (which include uses, methods and other aspects of the invention) include references to all other sub-formulas, subgroups (eg, IA, IB, IC or ID), preferences, forms of realization and examples as defined herein.
[0005] 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 Cj.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.
[0006] The terms 'halo' or 'halogen' as used herein refer to a fluorine, chlorine, bromine or iodine atom.
[0007] The terms' C6 alkyl .4 or 'C1-6 alkyl' as used herein as a group or part of a group refer to a saturated linear or branched hydrocarbon group containing from 1 to 4 or 1 to 6 carbon atoms. 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.
[0008] The term 'C2-4 alkenyl' or 'C2-6 alkenyl' as used herein as a group or part of a group refers to a straight or branched hydrocarbon group containing from 2 to 4 or 2 to 6 carbon atoms and that contains a carbon carbon double bond.
[0009] The term 'C2-4 alkenodiyl * as used herein as a group or part of a group refers to a linear or branched bivalent hydrocarbon group containing 2 to 4 carbon atoms and containing a double bond of carbon carbon.
[00010] The terms' C2-4 alkynyl 'or' C2-65 alkynyl as used herein as a group or part of a group refer to a linear or branched hydrocarbon group having from 2 to 4 or 2 to 6 atoms of carbon and that contains a carbon carbon triple bond.
[00011] The terms 'CM alkoxy' or 'Ci.6 alkoxy' as used herein as a group or part of a group refer to an O-CM alkyl group or an -O-CM alkyl group in which CM alkyl and alkyl C 6 are as defined herein. Examples of these groups include methoxy, ethoxy, propoxy, butoxy and the like.
[00012] The terms 'CM alkoxy CM alkyl' or 'C alkoxy] .6 CM alkyl' as used herein as a group or part of a group refer to a C 1-4 alkyl group O-CM alkyl OR a group alkyl CM -O-C1-6 alkyl wherein C1-4 alkyl and CM alkyl are as defined herein. Examples of these groups include methoxyethyl, ethoxyethyl, propoxymethyl, butoxypropyl and the like.
[00013] 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.
[00014] 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.
[00015] The terms 'CM hydroxyalkyl' or 'CM hydroxyalkyl' as used herein as a group or part of a group refer to a CM alkyl group or CM alkyl group as defined herein in which one or more than one of the atoms of hydrogen are replaced with a hydroxyl group. The terms ‘hydroxyalkyl CM’ OR ‘hydroxyalkyl Ci.6’ therefore include monohydroxyalkyl CM, monohydroxyalkyl CM and also polyhydroxyalkyl CM θ polyhydroxyalkyl CM. They can have one, two, three or more hydrogen atoms substituted with a hydroxyl group, so the hydroxyalkyl CM OR hydroxyalkyl CM can have one, two, three or more hydroxyl groups. Examples of these groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
[00016] The terms' CM haloalkyl 'OR' CM haloalkyl as used herein as a group or part of a group refer to a CM alkyl OR CM alkyl group as defined herein in which one or more than one of the hydrogen atoms are replaced with a halogen. The terms 'CM haloalkyl' OR 'CM haloalkyl' therefore include CM monoaloalkyl, CM monoaloalkyl and also CM polyaloalkyl and CM polyaloalkyl- There may be one, two, three or more hydrogen atoms replaced with a halogen, thus CM haloalkyl OR CM haloalkyl they can have one, two, three or more halogens. Examples of these groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
[00017] The terms 'C4 hydroxyalkylalkyl' or 'CM hydroxyalkylalkyl' as used herein as a group or part of a group refer to a CM alkyl or alkyl group as defined herein in which one or more than one of the hydrogen atoms they are replaced with a hydroxyl group and one or more than one of the hydrogen atoms are replaced with a halogen. The terms 'hydroxyalkyl CM' or 'hydroxyalkyl Cw' therefore refer to a CM alkyl or Cw alkyl group in which one, two, three or more hydrogen atoms are replaced with a hydroxyl group and one, two, three or more atoms hydrogen are replaced with a halogen.
[00018] The terms 'hydroxyalkoxy CM' OR 'hydroxyalkoxy CM' as used herein as a group or part of a group refer to an O-CM alkyl group OR an -O-C6 alkyl group in which the CM alkyl group and group CM alkyls are as defined above and one or more than one of the hydrogen atoms of the CM alkyl group θu CM alkyl group are replaced with a hydroxyl group. The terms' hydroxyalkoxy CM '' θu '' hydroxyalkoxy CM '' therefore include monohydroxyalkoxy CM, monohydroxy alkoxy CM θ also polyhydroxyalkoxy CM and polyhydroxyalkoxy Cμ6. They can have one, two, three or more hydrogen atoms substituted with a hydroxyl group so the CM hydroxyalkoxy θu CM hydroxyalkoxy can have one, two, three or more hydroxyl groups. Examples of these groups include hydroxymethoxy, hydroxyethoxy, hydroxypropoxy and the like.
[00019] The terms 'haloalkoxy CM' θu 'haloalkoxy CM' as used herein as a group or part of a group refer to an O-CM alkyl group OR an -O-CM alkyl group as defined herein where one or more than one of the hydrogen atoms is replaced with a halogen. The terms' CM haloalkoxy 'θu CM haloalkoxy' therefore include Cμ4 monoaloalkoxy, Cμg monoaloalkoxy and also Cμ4 polyaloyloxy and CM polyaloalkoxy- They can have one, two, three or more hydrogen atoms replaced with a halogen, so that the CM haloalkoxy one, two, three or more halogens. Examples of these groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
[00020] The term 'CM hydroxyalkoxy' as used herein as a group or part of a group refers to an O-Cμ4 alkyl group in which the Cμ alkyl group is as defined herein and in which one or more than one of the atoms of hydrogen are replaced with a hydroxyl group and one or more of the hydrogen atoms are replaced with a halogen. The term 'hydroxyalcoxy CM' therefore refers to a CM O-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.
[00021] The term 'haloalkoxy CM alkyl Cμf as used herein as a group or part of a group refers to a CM alkyl group -O-CM alkyl where C1.4 alkyl is as defined herein and where in one or more both of the Cμ4um alkyl groups or more than one of the hydrogen atoms are replaced with a halogen. The term CM haloalkoxy CM alkyl therefore refers to a CM alkyl group -O-CM alkyl where in one or both of the CM alkyl groups one, two, three or more hydrogen atoms are replaced with a halogen and in which CM alkyl it is as defined here. Preferably, in one of the CM alkyl groups one or more than one of the hydrogen atoms is replaced with a halogen. Preferably, CM haloalkoxy CM alkyl means CM alkyl substituted with CM- haloalkoxy
[00022] The term 'hydroxyalkyl CM CM alkyl alkyl' as used herein refers to a Cμ4-O-CM alkyl group where CM alkyl is as defined herein and where in one or both of the CM alkyl groups one or more of 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 terms 'hydroxy CM CM alkoxyalkyl CM' therefore refer to a Cμ4-O-CM alkyl group where in one or both of the Cμ alkyl groups 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 and where CM alkyl is as defined herein.
[00023] The term 'C2-6 hydroxyalkenyl as used herein refers to a C2 alkenyl group in which one or more of the hydrogen atoms are replaced with a hydroxyl group and in which C2 alkenyl is as defined herein.
[00024] The term 'CM 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 here.
[00025] The term phenylalkyl CM as used herein refers to a C [.6 alkyl group as defined herein which is substituted with a phenyl group.
[00026] The terms cyanoalkyl CM θu cyanoalkyl CM as used herein refer to a CM alkyl group OR C [_6 alkyl group as defined herein which are replaced with a cyano group.
[00027] 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.
[00028] Heterocyclyl groups can be heteroaryl groups having 5 to 12 members in the ring, more usually 5 to 10 members in the ring. 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.
[00029] 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.
[00030] Examples of the five-membered heteroaryl groups include, but are not limited to, the pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.
[00031] Examples of the six-membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
[00032] 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 hetero atoms in the ring; b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1,2 or 3 heteroatoms 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 heteroatoms 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.
[00033] Particular examples of bicyclic heteroaryl groups containing a fused five-membered ring to another five-membered ring include but are not limited to imidazothiazole (eg, imidazo [2, lb] thiazole) and imidazoimidazole (eg, imidazo [1,2-2a] imidazole).
[00034] Particular examples of bicyclic heteroaryl groups containing from a fused six-membered ring to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran , indole, isoindole, indolizine, indoline, isoindoline, purine (e.g. adenine, guanine), indazole, pyrazolpyrimidine (e.g., pyrazole [1,5-a] pyrimidine), triazole-pyrimidine (e.g., [l, 2 , 4] triazolo [1,5-a] pyrimidine), benzodioxol, imidazo-pyridine and pyrazolpyridine (for example, pyrazol [1,5-a] pyridine).
[00035] 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 groups , quinoxaline, quinazoline, cinoline, phthalazine, naphthyridine and pteridine.
[00036] Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include, tetrahydro-isoquinoline, tetrahydroquinoline, dihydrobenzthene, dihydrobenzfurran, 2,3-dihydrobenzo- [1 , 4] dioxin, benzo [1,3] dioxol, 4,5,6,7-tetrahydrobenzo-furan, tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro [1,2, 4] - triazolo- [4,3-a] pyrazine), indoline and indane.
[00037] A heteroaryl ring containing nitrogen 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.
[00038] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanil, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyridinyl , triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, isoindolyl, isolindyl, , purinyl (for example, adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl, benzoxazinyl, benzo-diazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinolmyl, phthalidinin, and naphthyridine.
[00039] Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl and indolinyl.
[00040] The term "non-aromatic group" encompasses, unless the context otherwise indicates, unsaturated ring systems without 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 ie 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 the ring atoms. Saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, piperazine. The partially saturated heterocyclyl groups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.
[00041] 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 example, as in pyrrolidine), cyclic amide moieties (eg, as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (eg, as in imidazolidin-2-a) cyclic ester moieties (eg, as in butyrolactone), cyclic sulfones (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine).
[00042] 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 (for example, 4 -tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, 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.
[00043] In a non-aromatic nitrogen-containing heterocyclyl ring the ring must contain at least one nitrogen atom in the ring. Heterocyclic groups may contain, for example, portions of cyclic amine (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] 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 N-methyl piperazine.
[00044] The heterocyclyl groups can be fused polycyclic ring systems or bridged ring systems such as the oxa and aza analogs of bicycloalkanes, 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.
[00045] 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.
[00046] The term "carbocyclyl" as used herein, unless the context otherwise indicates, should include both aromatic and non-aromatic ring systems. Thus, for example, the term "groupcarbocyclyl" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclyl ring systems. In general, unless the context otherwise indicates, such 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 members in the ring includes 4, 5, 6 or 7 atoms in the ring and reference to 4 to 6 members in the ring includes 4, 5, or 6 atoms in the ring. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7, and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ring members . 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. Where reference is made here to carbocyclyl groups, the carbocyclyl ring, unless the context otherwise indicates, may be optionally substituted (i.e., unsubstituted or substituted) by one or more substituents as discussed herein.
[00047] The term carbocyclyl comprises aryl, C3.8 cycloalkyl, C3.8 cycloalkenyl.
[00048] The term aryl as used herein refers to aromatic carbocyclyl groups that include phenyl, naphthyl, indenyl, and tetrahydronaphyl groups.
[00049] Whenever used here before or hereinafter which substituents can be selected each independently from a list of numerous definitions, all possible combinations are intended to be chemically possible. Whenever used here before or hereinafter a particular substituent is further substituted with two or more groups, such as for example haloalkyl CM hydroxide, CM haloalkoxy hydroxy, all possible combinations are intended to be chemically possible .////
[00050] In one embodiment, the invention relates to a compound of the formula (I-A).
[00051] In one embodiment, the invention relates to a compound of the formula (I-A) in which X1 is N, and X2 is CR a, in particular where R3a represents hydrogen.
[00052] In one embodiment, the invention relates to a compound of the formula (I-A) in which X2 is N and X1 is CR3a; in particular where R, a represents hydrogen.
[00053] In one embodiment, the invention relates to a compound of the formula (I-B), in particular where R3a represents hydrogen.
[00054] In one embodiment, Y represents -CR18 = N-OR'9. In particular, where R1S and R |} represent CM alkyl.
[00055] In one embodiment, Y represents -E-D where E represents a bond.
[00056] In one embodiment, Y represents a 3 to 12 membered monocyclic or bicyclic carbocyclyl in the ring or a 3 to 12 membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl can each optionally be substituted by one or more (for example, 1, 2 or 3) R1 groups.
[00057] In one embodiment, Y represents a 5- to 12-membered monocyclic or bicyclic carbocyclyl or a 5- to 12-membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl can each optionally be substituted by one or more (for example, 1, 2 or 3) R1 groups.
[00058] In one embodiment, Y represents a 3 to 12 aromatic monocyclic or bicyclic carbocyclyl, in particular a 5 to 12 aromatic, ring members or a 3 to 12 aromatic monocyclic or bicyclic heterocyclic, in particular an aromatic from 5 to 12, members in the ring containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) groups R1.
[00059] In one embodiment, Y represents an aromatic monocyclic or bicyclic carbocyclyl of 3 to 12 (for example, 5 to 10) members in the ring, wherein said carbocyclyl can be optionally substituted by one or more (for example , 1, 2 or 3) R1 groups.
[00060] In one embodiment, Y represents phenyl or naphthyl, wherein said phenyl or naphthyl can each be optionally substituted by one or more (for example, 1, 2 or 3) R1 groups.
[00061] In one embodiment, Y represents a 5- to 12-membered monocyclic or bicyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by a or more (for example, 1, 2 or 3) groups R1.
[00062] In one embodiment, Y represents a 5- to 12-membered aromatic monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl group can each optionally be substituted by one or more (for example, 1, 2 or 3) groups R1.
[00063] In one embodiment, Y represents a 5- or 6-membered monocyclic heterocyclyl in the ring that contains at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) groups R1.
[00064] In one embodiment, Y represents a 5- or 6-membered aromatic monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) groups R1.
[00065] In one embodiment, Y represents a 5-membered monocyclic heterocyclyl on the ring that contains at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (by example, 1, 2 or 3) R1 groups.
[00066] In one embodiment, Y represents a 5-membered aromatic monocyclic heterocyclyl in the ring that contains at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more ( for example, 1, 2 or 3) groups R1.
[00067] In one embodiment, Y represents pyrazolyl (for example, pyrazol-4yl), wherein said pyrazolyl can each optionally be substituted by one or more (for example, 1, 2 or 3) R1 groups.
[00068] In one embodiment, Y represents a 6-membered monocyclic heterocyclyl in the ring that contains at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) R1 groups.
[00069] In one embodiment, Y represents a 6-membered aromatic monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more ( for example, 1, 2 or 3) groups R1.
[00070] In one embodiment, Y represents a 12-membered bicyclic heterocyclyl in the ring that contains at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) R1 groups.
[00071] In one embodiment, Y represents a 12-membered aromatic bicyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more ( for example, 1, 2 or 3) groups R1.
[00072] In an embodiment Y represents
where R1 represents hydrogen, Cμ6 alkyl, C2.4 alkenyl, C] _6 hydroxy alkyl, C1-6 haloalkyl, C1-6 haloalkyl hydroxy, CM cyanoalkyl, Cμ6 C1-6 alkoxy in each of which Cj.6 alkyl can optionally be substituted with one or two hydroxyl groups, C1-6 alkyl substituted with - NR4R ', C1-6 alkyl substituted with -C (= O) -NR4R5, -S (= O) 2-C alkyl, - S (= O) 2- haloalkyl CM, -S (= O) 2-NR14Ri3, Cj.6 alkyl substituted with - S (= O) 2-C1-6 alkyl, C1-6 alkyl substituted with -S (= O) 2-C1-6 haloalkyl, alkyl substituted with -S (= O) 2-NR14R15, Cμ6 alkyl substituted with - NH-S (= O) 2-alkyl CÔ, substituted Cμ6 alkyl with -NH-S (= O) 2-haloalkyl Cj-õ, CM substituted with -NRl2-S (-O) 2-N'Rl4Rb, R6, CM alkyl substituted with R6, Cμ6 alkyl substituted with -C (= O) -R6, hydroxy C1-6 alkyl substituted with R6, Cμ6 alkyl substituted with -Si ( CH3) 3, Cμ6 alkyl substituted with -P (= O) (OH) 2 or Cμ6 alkyl substituted with -P (= O) (Oalkyl Cμ6) 2; and each Rla is independently selected from hydrogen, Cμ 4 alkyl, CM alkyl hydroxy, C | .4 alkyl substituted with amino or mono- or di (CM alkyl) amino or -NH (C3.8 cycloalkyl), Cμ4 cyanoalkyl, Cμ4 alkyl Cμ4, and CM alkyl substituted with one or more fluorine atoms. In one embodiment Rla is independently selected from hydrogen and CM alkyl. In an embodiment R, a is hydrogen.
[00073] In one embodiment, Y represents
wherein R1 represents hydrogen, CM alkyl, C2.4 alkenyl, hydroxy C1-6 alkyl, CM haloalkyl, CM haloalkyl hydroxide, CM alkoxy CM alkyl in each of which CM alkyl can optionally be substituted with one or two hydroxyl groups, alkyl CM replaced with -NR4R. CM alkyl substituted with -C (= O) -NR4R -S (= O) 2-CM alkyl, ~ S (= O) 2-CM haloalkyl, -S (= O) 2- NRl4Rb, Cμ6 alkyl substituted with -S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -S (= O) 2-haloalkyl CM, CM alkyl substituted with -S (= O) 2-NR14Rb, Cμ6 alkyl substituted with -NH-S (= O) 2 -CM alkyl, CM alkyl substituted with -NH-S (= O) 2-haloalkyl CM, CM alkyl substituted with -NR12-S (= O) 2-NR14Rb, R6, CM alkyl substituted with R6, CM alkyl substituted with - C (= O) -R6, hydroxy CM alkyl substituted with R6, CM alkyl substituted with -Si (CH3) 3, CM alkyl substituted with -P (= OXOH) 2 or Cμβ alkyl substituted with -P (= O) (Oalkyl Cμ6) 2.
[00074] In one embodiment, E represents a bond, ΠA '70 ti alkenediyl CM optionally substituted with R, -CO- (CR “~ R“) s-, - (CR22R23) S-CO-, -NR22- (CR22R23) S-, - (CR22R23) S-NR22-, -O- (CR22R23) S-, - (CR22R23) S-CO-NR22- (CR22R23) S- OR 4CR22R23) S-NR22-CO- (CR22R23 )S-.
[00075] In one embodiment, E represents a bond, C24 alkenediyl, -CO- (CR22R23) S-, - (CR22R23) S-CO-, -NR22- (CR22R23) S-, - (CR22R23) S- NR22-, - (CR22R23) S-CO-NR22- (CR22R23) S- or - (CR22R23) S-NR22- CO- (CR22R23) S-.
[00076] In one embodiment, E represents C2-4 alkenodiyl, - CO- (CR22R23) S-, - (CR22R23) S-CO-, -NR22- (CR22R23) S-, - (CR22R23) S-NR22 -, - (CR22R23) S-CO-NR22- (CR22R23) S- OR - (CR22R23) S-NR22-CO- (CR22R23) S-,
[00077] In one embodiment, E represents a link.
[00078] In one embodiment, Y represents -E-D, where E is other than a bond.
[00079] In one embodiment, Y represents -ED, where E is other than a bond and D represents any of the following: - a 3- to 12-membered monocyclic or bicyclic carbocyclyl in the ring or a monocyclic heterocyclyl or 3 to 12-membered bicyclic ring containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) groups R1; - a 5- to 12-membered monocyclic or bicyclic carbocyclyl in the ring or a 5- to 12-membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) groups R1; - phenyl or naphthyl, wherein said phenyl or naphthyl can each optionally be substituted by one or more (for example, 1, 2 or 3) R1 groups; - a 5- to 12-membered monocyclic or bicyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (for example, 1, 2 or 3) R1 groups; - a 5- or 6-membered monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each be optionally substituted by one or more (for example, 1, 2 or 3) groups R1; - a 5-membered monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be replaced by one or more (e.g. 1, 2 or 3) R1 groups ; - a 5-membered aromatic monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl group can each optionally be replaced by one or more (for example, 1,2 or 3) groups R1; - a 6-membered monocyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each optionally be substituted by one or more (for example, 1, 2 or 3) R1 groups ; - a 6-membered aromatic monocyclic heterocyclyl on the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each be optionally substituted by one or more (for example, 1, 2 or 3) groups R1; - a 12-membered bicyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each be optionally substituted by one or more (for example, 1, 2 or 3) R1 groups ; - a 12-membered aromatic bicyclic heterocyclyl in the ring containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl can each be optionally substituted by one or more (for example, 1,2 or 3) groups R1;
where R1 represents hydrogen, Cμg alkyl, C2-4 alkenyl, hydroxy Cμ6 alkyl, haloalkyl C. hydroxy haloalkyl Cμe, cyanoalkyl Cμ 4, C1-6 alkoxy Cμg alkyl in each of which Cμg alkyl can optionally be replaced with one or two hydroxyl groups, Cμ6 alkylsubstituted with -NR4R5, Cμ6 alkylsubstituted with -C (= O) -NR4R , -S (= O) 2-Cμ 6 alkyl, -S (= O) 2-haloalkyl Cμ6, -S (= O ) 2-NR14Ri: i, Cμ6 alkyl substituted with - S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -S (= O) 2-haIoalkyl Cμ6, Cμ6 alkyl substituted with -S (= O) 2-NR14RI: ', alkyl Cμ6 substituted with - NH-S (= O) 2-alkyl Cμ6, Cμ6 alkyl substituted with -NH-S (= O) 2-haloalkyl Cμ6, Cμ6 alkyl substituted with -NR12-S (= O) 2-NRi4R15, R6, Cμ6 alkyl substituted with R, Cμ6 alkyl substituted with -C (-O) -R, hydroxy Cμ6 alkyl substituted with R6, Cμg alkyl substituted with -Si (CH3) 3, Cμ6 alkyl substituted with -P (= O) (OH) 2 or Cμ6 alkyl substituted with -P (= O) (O C6 alkyl) 2; and each Rla is independently selected from hydrogen, Cμ 4 alkyl, CM hydroxy alkyl, Cμ4 alkyl substituted with amino or mono- or di (Cμ4 alkyl) amino or -NH (C3.s cycloalkyl), Cμ4 cyanoalkyl, CM alkyl CM, and CM alkyl substituted with one or more fluorine atoms;
- where R1 represents hydrogen, Cμ6 alkyl, C2.4 alkenyl, Cμ6 hydroxy alkyl, Cμ6 haloalkyl, Cμg haloalkyl hydroxy, Cμ alkoxy and Cμ6 alkyl, each of which Cμ6 alkyl can optionally be substituted with one or two hydroxyl groups, Cμ alkyl substituted with -NR4R5, Cμg alkyl substituted with -C (= O) -NR4R , -S (= O) 2-Cμe alkyl, - S (= O) 2-haloalkyl Cμg, -S (= O) 2-NRi4Rb, alkyl Cμ6substituted with - S (= O) 2-Cμ6 alkyl, Cμ6 alkylsubstituted with -S (=: O) 2-haloalkyl Cμg, Cμ6 alkylsubstituted with -S (= O) 2-NR14Rb, Cμ6 alkylsubstituted with - NH-S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -NH-S (= O) 2-haloalkyl C], Cμ6 alkyl substituted with -NRi2-S (= O) 2-NR14Rb, R6, Cμ $ alkyl substituted with R6, alkyl substituted with -C (= O) -R6, hydroxy C1-6 alkyl substituted with R, Cμ6 alkyl substituted with -Si (CH2) 3, substituted C1 alkyl with -P (= O) (OH) 2or substituted C | _6 alkyl with -P (= O) (Oalkyl C) 2.
[00080] In one embodiment, D is other than pyrazolyl, in particular D is piperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl, pyrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionally substituted. Said optional substituents may represent halo, cyano, Cμg alkyl, Cμ6 alkoxy, -C (= O) -O-Cμ alkyl, Cμg hydroxy alkyl, -NR4R2>, Cμ.6 alkyl substituted with -OC (= O) - alkyl Cμ6, Cμ6 alkyl substituted with - NR4R5, -C (= O) -NR4R5, -C (= O) -Cμ6-NR4R5 alkyl, R6, Cμ6 alkyl substituted with R6.
[00081] In one embodiment, E is other than a bond and D is other than pyrazolyl, in particular D is piperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, pyrrolopyridinyl, 1,3-benzo-dioxolyl, indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, oxadiazolyl, these being optional .
[00082] In one embodiment E is a bond and D is an optionally substituted 5- or 6-membered aromatic heterocycle. In one embodiment E is a bond and D is an optionally substituted 5-membered aromatic heterocycle, such as, for example, pyrazolyl, optionally substituted with Cμ6 alkyl. In one embodiment E is a bond and D is an optionally substituted 6-membered aromatic heterocycle, such as, for example, substituted pyridyl or unsubstituted pyridyl.
[00083] In one embodiment, E is a bond and D is optionally substituted 4-pyrazolyl. In one embodiment, E is a bond and D is 4-pyrazolyl substituted in position 1 with Cμ6 alkyl, for example methyl.
[00084] In one embodiment, E is a bond and D is 1-pyrazolyl or 2-pyrazolyl, both of which can optionally be substituted.
[00085] In one embodiment, E is other than a bond and D is 1-pyrazolyl or 2-pyrazolyl, both of which can optionally be substituted.
[00086] In one embodiment, E is other than a bond and D is optionally substituted pyrazolyl.
[00087] In one embodiment, E is a bond and D is optionally substituted pyrazolyl.
[00088] In one embodiment R1 represents hydrogen, Cμ6 alkyl, C2.4 alkenyl, Cμ6 hydroxy alkyl, Cμ6 haloalkyl, Cμ6 haloalkyl hydroxy, Cμ4 cyanoalkyl, Cμ6 alkoxyCμ6 alkoxy each of which Cμ6 alkyl can optionally be substituted with or two hydroxyl groups, Cμ6 alkyl substituted with -NR4R ', Cμ6 alkyl substituted with -C (= O) - NR4R5, -S (= O) 2-Cw alkyl, -S (= O) 2-haloalkyl Cμ6, -S (= O ) 2-NR, 4R15, Cμg alkyl substituted with -S (= O) 2-Cμ6 alkyl, Ci alkyl substituted with -S (= O) 2-haloalkyl Cμ6, Cμ6 alkyl substituted with -S (= O) 2-NR14RI :>, Cμ6 alkylsubstituted with -NH-S (= O) 2-Cμ6 alkyl, Cμ6 alkylsubstituted with -NH-S (= O) 2-haloalkyl Cμ6, Cμ6 alkylsubstituted with -NR - S (—O) 2-NR14R13, R6, Cμ alkyl substituted with R6, Cμ6 alkyl substituted with -C (= O) -R6, hydroxy Cμ6 alkyl substituted with R6, Cμ6 alkyl substituted with —Si (CH3) 3, Cμg alkyl substituted with -P (= O) (OH ) 2 or Cμ6 alkyl substituted with -P (= O) (O C6 alkyl) 2.
[00089] In an embodiment R1 represents hydrogen, C | .6 alkyl, C2-4 alkenyl, C-hydroxy alkyl, Cμ haloalkyl, Cμ6 alkoxy] -6 alkoxy in each of which Cμ6 alkyl optionally can be substituted with one or two groups hydroxyl, Cμβ alkyl substituted with -NR4R , C1-6 alkyl substituted with -C (= O) -NR4R3, -S (= O) 2-Cμ alkyl, -S (= O) 2-NRI4R15, Cμ6 substituted with - S (= O) 2-C 6 alkyl, C 6 alkyl substituted with z. z -NH-S (= O) 2-C1-6 alkyl, R, Cμ6 alkyl substituted with R, Cμ alkyl substituted with —C (= O) -R6, hydroxy Cμ6 alkyl substituted with R6, or Cμ6 alkyl substituted with -Si (CH3 ) 3.
[00090] In one embodiment R1 represents hydrogen.
[00091] In one embodiment R1 represents Cμ alkyl, such as, for example, methyl, ethyl or isopropyl. In one embodiment R1 represents methyl.
[00092] In one embodiment each R "is independently selected from hydroxyl, halogen, cyano, CM alkyl, C2.4 alkenyl, Cμ4 alkoxy, Cμ4 hydroxyl, Cμ4 hydroxyl, Cμ4 haloalkyl, Cb4 haloalkyl, Cμ4 alkoxy alkoxy, R, CM alkoxy substituted with R, -C (= O) -R, Cμ4 alkyl substituted with NR7RS, Cμ4 alkoxy substituted with NR R8, - NR7R8 and -C (= O) -NR RS; or when two R2 groups are attached to the atoms of adjacent carbon they can be taken together to form a radical of the formula -O- (C (R) 2) PO- where R represents hydrogen or fluorine and p represents 1 or 2.
[00093] In one embodiment each R "is independently selected from hydroxyl, halogen, cyano, Cμ alkyl, C2-4 alkenyl, C14 alkoxy> Cμ hydroxy, CM alkoxy hydroxide, CM haloalkoxy, CM4 R, alkoxy alkoxy, CM alkoxy substituted with R, -C (= O) -R, CM alkyl substituted with NR7R8, CM alkoxy substituted with NR7R8, -NR7R8 or -C (= O) -NR7R8.
[00094] In one embodiment one or more R represents C1-4 alkoxy, for example CHjO-, or halogen, for example fluorine or chlorine.
[00095] In one embodiment one or more R represents CH3O- or fluorine.
[00096] In one embodiment one or more R "represents C] _4 alkoxy, for example CH3O-.
[00097] In one embodiment n is equal to 0. In one embodiment n is equal to 1. In one embodiment n is equal to 2. In one embodiment n is equal to 3. In one embodiment of realization n is equal to 4.
[00098] In one embodiment, n is equal to 2, 3 or 4.
[00099] In one embodiment n is equal to 2 and an R “is present in position 3 and the other is present in position 5.
[000100] In one embodiment n equals 2 and one R2 is present at position 3 and the other is present at position 5 and each R2 represents C1-4 alkoxy, for example each R "represents CH3O-.
[000101] In one embodiment n is equal to 3 and an R2 is present in position 2, an R "is present in position 3 and an R ~ is present in position 5.
[000102] In one embodiment n is equal to 3 and an R2 is present in position 3 and represents C1.4 alkoxy, for example CH3O-; an R "is present at position 5 and represents C1.4 alkoxy, for example CH30-; an R" is present at position 2 and represents halogen, for example fluorine.
[000103] In one embodiment n is equal to 4 and an R2 is present in position 2, an R2 is present in position 3, an R2 is present in position 5 and an R2 is present in position 6.
[000104] In one embodiment n is equal to 4 and an R2 is present in position 3 and represents C1.4 alkoxy, for example CH3O-; an R "is present at position 5 and represents CM alkoxy, for example CH3O-; a 2 * 1 • R 'is present at position 2 and represents halogen, for example fluorine, and an R" is present at position 6 and represents halogen , for example fluorine.
[000105] In one embodiment, R3 represents Cré alkyl, Cré hydroxy alkyl, Cre haloalkyl hydroxy, C2-6 hydroxy alkynyl, C1-6 haloalkyl, Cre haloalkyl optionally substituted (for example, substituted) with -OC (= O) -Cryl Cre, Cré alkyl substituted with -C (= O) -Cryl Cré, Cré alkoxy Cré alkyl in each of which Cré alkyl can optionally be substituted with one or two hydroxyl groups, Cré alkoxy Cré alkyl in each of which alkyl Cré can optionally be substituted with one or two hydroxyl groups or with -OC (= O) -Alkyl Cré, Cré alkyl substituted with R9, Cré alkyl substituted with -NRIOR11, Cré alkyl substituted with hydroxyl and -NRH) R ", Cré alkyl substituted with one or two halogens and - NR'0RU, Cré alkyl substituted with -C (= O) -O-alkyl Cré, Cre alkyl substituted with -C (= O) -NR10R '', Cré alkyl substituted with carboxyl, alkyl Cre substituted with -OC (= O) -NRl0R ", Cré alkyl substituted with -NRl2-S (= O) 2-Cré alkyl, Cré subs alkyl substituted with -NRI2-S (= O) 2- NRI4R1:>, Cré alkyl substituted with R9e optionally substituted with -O- C (= O)-Cre alkyl, Cré alkyl substituted with hydroxyl and R9, -Cré- C alkyl ( R12) = NO-R12, -S (= O) 2-NR14R15, Cré alkyl substituted with -S (= O) 2- Cré alkyl, Cré alkyl substituted with -C (= O) -NR10R ", Cre alkyl substituted with -C (= O) -R9, C2.6 alkenyl substituted with R9, C2.6 alkynyl substituted with R9, hydroxy Cre alkoxy, C2.6 alkenyl, alkynyl C2.6, Rb, alkyl Cré substituted with alkoxy Cre alkyl Cró- C (= O) - or Cré alkyl substituted with -P (= O) (O1 alkyl C1.0) 2-
[000106] In an embodiment R3 represents Cre alkyl, hydroxy C1-alkyl, hydroxy haloalkyl Cré, haloalkyl Cré, alkyl alkyl substituted with -C (“O) -alkyl Cré, alkoxy Cré alkyl Cré in each of which alkyl Cré can optionally be substituted with one or two hydroxyl groups, Cré alkyl substituted with R9, Cre alkyl substituted with - NRI () R ", Cμ6 alkyl substituted with hydroxyl and -NR'θR11, Ci alkyl substituted with one or two halogens and -NRl (1Rπ 'Cμe alkyl substituted with -C (= O) -O-Cμ6 alkyl> Cμ6 alkyl substituted with -CC-NR'θR11, Cμ6 alkyl substituted with carboxyl, Cμ6 alkyl substituted with -O- C (= O) -NRl0R11, alkyl Cμg substituted with -NRl2-S (= O) 2-C6 alkyl, Cμ6 alkyl substituted with -NR12-S (= O) 2-NR14R13, Cμg alkyl substituted with hydroxyl and R, -Cμ6-C (R) alkyl = NOR, Cμ6 alkyl substituted with -C (= O) -NR10R11, Cμ6 alkyl substituted with -C (= O) -R9, C2.6 alkynyl substituted with R9, Cμ6 hydroxy alkoxy, C2.6 alkenyl, C2.6 alkynyl, R13 or Cμ6 alkylsubstituted with Cμ6 alkoxyCμ6-C alkyl (= O) -.
[000107] In an RJ embodimentrepresents Cμ6 alkyl, Cμ6 hydroxy alkyl, Cμ6 haloalkyl, Cμ6 haloalkyl optionally substituted with -OC (= O) -Cμ6 alkyl, Cj-6 haloalkyl hydroxy, C2-6 alkyl alkoxy, substituted C-6 alkyl with -C (= O) -Cμ6 alkyl, Cμ6 alkoxy Cμ6 alkyl in each of which Cμg alkyl can optionally be substituted with one or two hydroxyl groups or with -OC (= O) -Cμβ alkyl, Cμ6 alkyl substituted with R9, cyanoalkyl Cμ6, Cμ6 alkyl substituted with -NR10Rn, Cμ6 alkyl substituted with hydroxyl and -NR10Rn, Cμ $ alkyl substituted with one or two halo atoms and -NR10R ”. Cμ6 alkyl substituted with -C (= O) -O-C alkyl (.6, Cμ6 alkyl substituted with Cμ6 alkoxy Cμ6-C (= O) -, Cμ6 alkyl substituted with -C (= O) -NRl0R'Cμ6 alkyl substituted with - C (= O) - NRl4Rl3, Cμ6 alkyl substituted with carboxyl, Cμ6 alkyl substituted with - OC (= O) -NRl0R11, Cμ6 alkyl substituted with -NRl2-S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -NR12-S ( = O) 2-NR'4Rb, Cμ6 alkyl substituted with R9 and substituted with -OC (= O) -Cμ6 alkyl, Cμ6 alkyl substituted with hydroxyl and R9,-CC alkyl (R12) = NO-R12, -S (= O) 2-NR14R15, Cμ6 alkyl substituted with -S (= O) 2-Cμ6 alkyl, Cμ6 alkyl substituted with -C (= O) -R9, C2.6 alkenyl substituted with R9 alkynyl C2.6 substituted with R9, Cμ alkyl and alkyl Cμ6 in each of which C6 alkyl may optionally be substituted with one or two hydroxyl groups, C2.6 alkenyl, C2.6 alkynyl, R13, or Cμ6 alkyl substituted with -P (= O) (Oalkyl Cμe) 2.
[000108] In one embodiment, R3 represents Cμ6 alkyl, C1-6 hydroxy alkyl, Cμ6 haloalkyl hydroxy, Cμ6 haloalkyl, Cμ6 substituted alkyl with -C (= O) -C alkyl, Cμ6 alkyl Ct, 6 in each of which Cμ6 alkyl optionally can be substituted with one or two hydroxyl groups, Cμ6 alkyl substituted with R9, Cμg alkyl substituted with - NR10Rn, alkyl substituted with hydroxyl and -NR10R ", Cμ6 alkyl substituted with one or two halogens and -NR'θR11, Cμ6 substituted alkyl with -C (= O) -O-Cμ6 alkyl, alkyl substituted with -OC (= O) -NR, 0R 'Cμ6 alkyl substituted with carboxyl, Cμ6 alkyl substituted with —NR12- S (= O) 2-Cμ6 alkyl, Cμ6 substituted alkyl with -NRl2-S (= O) 2-NR14Rl3, Cμ6 alkyl substituted with hydroxyl and R9, -Cμ6-C alkyl (Rl2) = NO-R12, Cμ6 alkyl substituted with -C (= O) -NR10R11, Cμβ alkyl substituted with - C (= O) -R9, C2.6 alkynyl substituted with R9, Cμβ hydroxy alkoxy, C2.6 alkenyl, C2 or R alkynyl.
[000109] In one embodiment RJ represents C2-6 alkynyl, Cμ6 haloalkyl optionally substituted with -OC (= O) -Cμ6 alkyl, Cμ6 alkyl hydroxy optionally substituted with -OC (-O) -Cμβ alkyl, Cμ6 haloalkyl hydroxy, Cμ6alkyl alkoxy Cμ6 in each of which Cb6 alkyl can optionally be substituted with one or two hydroxyl groups or with -OC (= O) -Cμ6 alkyl, Cμ <5 alkyl substituted with R9, C2.6 alkynyl substituted with R9, Cμ6 alkyl substituted with - NRIORH, or Cμ6 alkyl substituted with -OC (= O) -NRl0Rl
[000110] In one embodiment R3 represents hydroxy Cμe alkyl, hydroxy haloalkyl Cμ6, Cμ6 alkyl substituted with R9, Cμg alkyl substituted with -NR1ORU, C2.6 alkynyl substituted with R9, or C2,6 alkynyl.
[000111] In one embodiment R3 represents hydroxy Cμ6 alkyl, hydroxy haloalkyl Cμ6, Cμ6 alkyl substituted with R9, Cμ6 alkyl substituted with -NR10R ", Cμ6 alkoxy Cμ6alkin each of which Cμ $ alkyl can optionally be substituted with one or two hydroxyl groups or with -OC (= O) -Cμ6 alkyl, or C2.6 alkynyl substituted with R9, C2.6 alkynyl. • 3
[000112] In one embodiment RJ represents hydroxy Cμ6 alkyl, haloalkyl Cj.6, Cμβ alkyl substituted with R9, Cp6 alkyl substituted with - NR10Rn, C alkoxy, .6 alkyl C, .6, or C2-6- alkynyl
[000113] In one embodiment RJ represents hydroxy Cμg alkyl, cyanoalkyl Cμ6, haloalkyl Cμ6, alkyl Cμ6substituted with R9, Cμ6 alkyl substituted with -NR'θR11, Cμ6alkyl Cμ6 alkoxy, Cμ6substituted with -N (O =) alkynyl C2.6 or R13.
[000114] In one embodiment R 'represents C 9 alkyl substituted with R 9, C C 6 alkyl substituted with -NR'θR11OU R13.
[000115] In an embodiment R3 represents C2.g alkynyl. R3 can represent -CH2-C = C-H.
[000116] In an embodiment when R represents Cμ alkyl (for example, CM alkyl) substituted with R9. R9 represents an optionally substituted monocyclic 5- or 6-membered aromatic heterocyclyl, for example optionally substituted imidazolyl.
[000117] In one embodiment when R represents Cμ6 alkyl (e.g., CM alkyl) substituted with R9, where R9 represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl containing one or two nitrogen hetero atoms, for example imidazolyl.
[000118] In an embodiment when R3 represents CM alkyl (for example, methyl) substituted with R9, where R9 represents unsubstituted imidazolyl (for example, imidazol-2-yl) or imidazolyl substituted with -S (O) 2 -N (CH3) 2.
[000119] In an embodiment R represents Cμ6 alkyl substituted with hydroxyl, halo and / or -NR’θR11. In one embodiment RJ represents hydroxyl-substituted CM alkyl, halo or -NR10R ”, where the CM alkyl group is a straight chain alkyl group for example, 2-ethyl, n-propyl, n-butyl. In another embodiment R represents hydroxyl-substituted CM alkyl or -NR10Rn.
[000120] In one embodiment R3 represents hydroxy Cμg alkyl. R3 can represent -CH2CH2OH or -CH2CH2CH2OH.
[000121] In one embodiment RJ represents CM alkyloxy Cμ6 alkyl. R3 can represent -CH2CH2OCH3.
[000122] In another embodiment R 'represents CM alkyl substituted with -NRlüRli. In one embodiment RJ represents C1-4 alkyl substituted with -NR’θR11. In one embodiment RJ represents C1.4 alkyl substituted with -NR1,> R11, where the Cμ4 alkyl group is a straight chain alkyl group for example, 2-ethyl, n-propyl. In one embodiment RJ represents CM alkyl substituted with -NR1OR ”, where the Cl-4 alkyl group is an ethyl group (-CH2CH2-).
[000123] In an embodiment when R represents C 1.6 alkyl (e.g., 2-ethyl, n-propyl) substituted with -NR, 0R ”, where R10 and R11 are independently selected from hydrogen, CM alkyl and Ci haloalkyl -6 (for example, hydrogen, iso-propyl or -CH2CF3).
[000124] In one embodiment when R represents alkyl (for example, 2-ethyl, n-propyl) substituted with -NR10Rn, where Rlüe R11 are independently selected from hydrogen, CM alkyl and Cμ6 alkyl substituted with -NR14R! In an embodiment R14 and R13 each independently represents hydrogen, or CM alkyl.
[000125] In an embodiment when RJ represents CM alkyl (for example, 2-ethyl, n-propyl) substituted with -NR'θR11, where Ri0 and R11 are independently selected from hydrogen, and CM alkyl (for example, hydrogen or iso-propyl).
[000126] In one embodiment when R3 represents CM alkyl substituted with -NR10Rn, and one of R10 and R11 represents hydrogen and the other represents C] .6 substituted with -NRI4R15 (for example, -NRMR '"represents - NHCH (CH3) 2) .R3 can represent -CH2CH2N- (CH (CH3) 2) CH2CH2NHCH (CH3) 2 or -CH2CH2NHCH (CH3) 2.
[000127] In one embodiment when R3 represents C1-6 alkyl substituted with -NR1 () Rn, and one of R10 and R11 represents hydrogen and the other represents C1-6 alkyl, for example -CH (CH3) 2. R1 can represent - CH2CH2NHCH (CH3) 2. 3
[000128] In one embodiment R represents - CH2CH2NHCH (CH3) 2. The
[000129] In one embodiment RJ represents haloalkyl Cj.6. In one embodiment R represents haloalkyl Cμ. In a form of ■ 3 embodiment R represents -CH2CH2-Br.
[000130] In one embodiment Rja represents hydrogen.
[000131] In one embodiment R3a represents chlorine.
[000132] In one embodiment, R9 is selected from: an optionally substituted C3.g cycloalkyl, an optionally substituted 5-membered aromatic monocyclic heterocyclyl, an optionally substituted 6-membered saturated monocyclic heterocyclyl, a saturated monocyclic heterocyclyl or an aromatic 3, 4, 5 or 6 members containing one or two oxygen heteroatoms, an optionally substituted 4-membered heterocyclyl containing an oxygen heteroatom, an optionally substituted 6-membered aromatic monocyclic heterocycle containing one or two nitrogen heteroatoms, one partially saturated 6-membered monocyclic heterocyclyl that contains an optionally substituted nitrogen heteroatom, an optionally substituted 4-membered saturated monocyclic heterocyclyl containing a nitrogen heteroatom, a 5-membered saturated monocyclic heterocyclic that contains a nitrogen heteroatom, one saturated monocyclic heterocyclyl the 6-membered one containing a nitrogen heteroatom, a bicyclic heterocyclyl containing a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms, a 4, 5 or 6 saturated monocyclic heterocycle members substituted with two substituents that are attached to the same atom and which are taken together to form a 4- to 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, an optionally substituted aromatic monocyclic heterocyclyl containing a sulfur heteroatom, an optionally substituted 5-membered aromatic monocyclic heterocyclyl containing one sulfur and one nitrogen heteroatyl, one 6-membered saturated monocyclic heterocyclyl containing two nitrogen heteroatoms, one 5-membered aromatic monocyclic heterocyclyl four nitrogen heteroatoms, a 5-membered aromatic monocyclic heterocyclyl containing an oxygen heteroatoms io and two of nitrogen, an optionally substituted 5-membered aromatic monocyclic heterocyclyl containing two nitrogen heteroatoms, an optionally substituted 5-membered aromatic monocyclic heterocyclyl containing three nitrogen heteroatoms, a 5-membered saturated monocyclic heterocyclyl containing a heteroatome of 5 nitrogen and one oxygen, a 6-membered saturated monocyclic heterocyclic containing one nitrogen and one sulfur, one 7-membered saturated heterocyclic containing two nitrogen heteroatoms, a 7-membered saturated monocyclic heterocycly containing nitrogen and oxygen, and phenyl or naphthyl, in particular phenyl.
[000133] In one embodiment, R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, imidazolyl, or an optionally substituted 6-membered aromatic heterocycle, such as, for example, pyridyl, pyrimidinyl or pyrazinyl. Optional substituents may represent CM alkoxy OU -S (= O) 2-NRI4R ':'.
[000134] In one embodiment, R9 represents C3.6 cycloalkyl, such as, for example, cyclopropyl, a 3-membered saturated heterocyclyl, such as, for example, oxiranyl, an optionally substituted 5-membered saturated heterocycle, such as , for example, pyrolidinonyl, an optionally substituted 6-membered aromatic or saturated heterocycle, such as, for example, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, or morpholinyl, an optionally substituted bicyclic heterocycle, such as, for example, lH-isoindole- 1,3-dione. Optional substituents can represent = 0, CM alkoxy, CM alkyl substituted with -NR14R15, hydroxy CM alkyl, θu alkyl CM-C (= O) - ..
[000135] In one embodiment, R9 represents an optionally substituted 6-membered aromatic heterocycle, such as, for example, pyridinyl or pyrimidinyl. Optional substituents may represent CM alkoxy.
[000136] In one embodiment, R represents an optionally substituted aromatic or saturated 5-membered heterocycle, such as, for example, imidazolyl, pyrolidinyl, oxazolidinyl. Optional substituents may represent = 0, 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 -S (= O) 2- NR14R15.
[000137] In one embodiment, R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, imidazolyl. Optional substituents can represent -S (= O) 2-NRI4RI .
[000138] In one embodiment, R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, imidazolyl, pyrazolyl, oxazolyl or triazolyl; or an optionally substituted 5-membered saturated heterocycle, such as, for example, pyrrolidinonyl or tetrahydrofuranoyl; or an optionally substituted 6-membered aromatic heterocycle, such as, for example, pyrimidinyl. Optional substituents can represent CN alkyl. oxo, benzyl or - S (= O) 2-NR14R'5.
[000139] In one embodiment, R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, imidazolyl or triazolyl; or an optionally substituted 5-membered saturated heterocycle, such as, for example, pyrrolidinonyl.
[000140] In an embodiment R10 represents hydrogen or Cμ6 alkyl.
[000141] In an embodiment R10 is hydrogen.
[000142] In one embodiment Rn represents hydrogen, C1-6 alkyl, Cμ6 haloalkyl, -C (= O) -C1 alkyl, -S (= O) 2-Cμβ alkyl, -S (= O) 2- NRI4RH , Cμ6 alkyl hydroxy, -C (= O) -Cμ6 haloalkyl hydroxy, -C (= O) -R6, Cμg cyanoalkyl, R6, -C (= O) -R6, Cμg alkyl substituted with R6, -C (= O ) - halo-C] .6 alkyl, C] _6 alkyl substituted with -Si (CH3) 3, C] _6 substituted with —NRI4R | 3, C] alkyl substituted with —C (= O) -NR14R15, C alkoxy [ .6, Ci.6 haloalkyl hydroxy, carboxyl, or Ci.6 alkoxy Cμβ.
[000143] In an embodiment R1 () and R11 represent hydrogen or C1-6 alkyl, such as, for example, methyl or isopropyl.
[000144] In one embodiment, R represents a 6-membered saturated monocyclic heterocyclyl that is optionally substituted. For example piperazinyl or morpholinyl or tetrahydropyranyl, optionally substituted with halogen, C1-6 alkyl, or C1-6-O-C (= O) - alkyl.
[000145] In one embodiment, R6 represents a 6-membered aromatic monocyclic heterocyclyl which is optionally substituted. For example pyridinyl, optionally substituted with halogen, C-alkyl, or C-alkyl] .6-O-C (= O) -.
[000146] In one embodiment, R "represents hydrogen or CM alkyl optionally substituted with C 1-4 alkyloxy.
[000147] In one embodiment, R1 'represents a 4- to 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N or O.
[000148] In one embodiment, R represents a 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N or O, such as, for example, piperidinyl.
[000149] In one embodiment, each of R14 and Rl independently represents hydrogen or C1.4 alkyl.
[000150] In one embodiment, each of R14 and R15 independently represents C1.4 alkyl, such as, for example, methyl.
[000151] In one embodiment, each of R and R ~ independently represents hydrogen.
[000152] In an embodiment of the invention, X1 represents N and X represents CH; n represents an integer equal to 2; and each of R ~ represents CM alkoxy, for example CH3O-; R 'represents hydroxy CM alkyl, haloalkyl Ct.6, Cμ6 alkyl substituted with R9, CM alkyl substituted with - NR10RH, CM alkoxy C i-o alkyl, C2-6a alkynyl; Y represents -E-D where E represents a bond and D represents optionally substituted pyrazolyl.
[000153] In an embodiment of the invention, X1 represents N and X represents CH or X represents CH and X ~ represents N; n represents an integer equal to 2, 3 or 4; and each R2 represents CM alkoxy, for example CH3O-, or halo, for example fluorine or chlorine; R3a represents hydrogen or chlorine; R3 represents hydroxy CM alkyl, cyanoalkyl CM »haloalkyl CM, CM alkyl substituted with R9, CM alkyl substituted with -NR10R", CM alkoxy CM alkyl, CM alkyl substituted with -C (= 0) -NR10R ”, C2.6 alkynyl or R13; Y represents -ED where E represents a bond and D represents an optionally substituted 5- or 6-membered aromatic heterocycle.
[000154] In an embodiment of the invention, X! represents N and X ~ represents CH or X represents CH and X "represents N; n represents an integer equal to 2, 3 or 4; and each R" represents CM alkoxy, for example CH3O-, or halo, for example fluorine or chlorine; R3a represents hydrogen or chlorine; R3 represents hydroxy alkyl Cμ6, cyanoalkyl CM, haloalkyl Cμ6, alkyl alkyl substituted with R9, Cμ6 alkyl substituted with -NR10RH, Cμ6alkyl Cμ6 alkoxy, Cμ6 alkyl substituted with -N (O2) = -6 or R; Y represents -ED where E represents a bond and D represents an optionally substituted 5- or 6-membered aromatic heterocycle, such as, for example, optionally substituted pyrazolyl or pyridyl; R1 represents hydrogen or Cμ6 alkyl, for example methyl, ethyl or isopropyl; R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, imidazolyl, pyrazolyl, oxazolyl or triazolyl; or an optionally substituted 5-membered saturated heterocycle, such as, for example, pi rrolidinonyl or tetrahydrofuranoyl; or an optionally substituted 6-membered aromatic heterocycle, such as, for example, pyrimidinyl; R10 and R11 represent hydrogen or C1-6 alkyl, such as, for example, methyl or isopropyl; R represents a 6-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N or O. In particular, the optional substituents for R9 are selected from C] .4, oxo, benzyl or -S (= O) 2- NR14RI:>, where R14 and R13, for example, each independently represents CM alkyl, such as, for example, methyl.
[000155] In an embodiment of the invention, X1 represents N and X represents CH, n represents an integer equal to 2; and each R "represents C1.4 alkoxy, for example CH3O-; R 'represents hydroxy Cμ6 alkyl, CJ-Ô haloalkyl, Cμ6 alkyl substituted with R, CM alkyl substituted with - NR'R", C1-6 alkoxy C1-6 alkyl , C2.6 alkynyl; Y represents -ED where E represents a bond and D represents C1-6 alkyl substituted pyrazolyl; R10 and R11 represent hydrogen or C1-10 alkyl R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, optionally substituted imidazolyl.
[000156] In one embodiment, Y is -ED, where E is a bond and D is a 5- or 6-membered aromatic monocyclic heterocyclyl, wherein said heterocyclyl can optionally be replaced by one or more (for example, 1, 2 or 3) R1 groups, where one or more of the following apply: n is 2; R2 is Cpôl R "alkyloxy is placed in positions 3 and 5.
[000157] In one embodiment, Y is -ED, where E is a bond and D is piperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl, azetidinyl , morpholinyl, tetrazolyl, oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionally substituted, more in particular D is piperidinyl , pyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5,3,6-tetrahydropyridinyl -dihydropyrolyl, pyrimidinyl, pyrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionally substituted and en is 2, even more in particular D is piperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzol , tiazolila, cic lopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl, pyrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionally substituted; n is 2, R “is C1-6 alkyloxy, furthermore in particular D is piperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazol , oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl, pyrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionally substituted; n is 2, R ~ is C 1 .6 alkyloxy and said R "is placed in positions 3 and 5.
[000158] In one embodiment, compounds of the formula (I-A) or (I-B) are provided which include any tautomeric or stereochemically isomeric form thereof, wherein X1 is N and X2 is CR3a; each of R2 represents CM alkoxy, for example CH3O-; Y represents -E-D; D represents a 3 to 12 membered monocyclic or bicyclic carbocyclyl in the ring or a 3 to 12 membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, for example pyrazolyl, wherein said carbocyclyl and heterocyclyl can each be optionally substituted by one or more (for example, 1, 2 or 3) R1 groups; E represents a bond; R1 represents C1-6 alkyl, for example -CH3; Rja represents hydrogen or chlorine; R represents hydroxy Cj.6 alkyl for example -CH2CH2OH or -CH2CH2CH2OH, C1-6 haloalkyl, for example -CH2CH2Br, R9-substituted C1-6 alkyl for example -CH2-substituted with Imidazole-2-yl or substituted imidazole-2-yl in position 3 with -S (O) 2-N (CH3) 2, C1-6 alkyl substituted with -NRIOR "eg -CH2CH2N (CH (CH3) 2) CH2CH2NHCH (CH3) 2OU -CH2CH2NHCH (CH3) 2, alkoxy C1-6 alkyl for example -CH2CH2OCH3, or C2-6 alkynyl; for example - CH2-C = CH; n independently represents an integer equal to 2; the // - oxides thereof, the pharmaceutically acceptable salts thereof or solvates thereof.
[000159] In one embodiment the compound of the formula (IA) is a compound of the formula (IC):
where n, X, X ", R, R, RJ and R are as defined herein. In one embodiment the compound of the formula (IA) is a compound of the formula (IC) where R3a is hydrogen.
[000160] In one embodiment the compound of the formula (IA) is a compound of the formula (ID):
where n, R1, R2, R3 and R3 are as defined herein. In one embodiment the compound of the formula (IA) is a compound of the formula (ID) in which R3a is hydrogen.
[000161] In one embodiment the compound of the formula (IB) is a compound of the formula (IE):
as defined herein. In one embodiment the compound of the formula (IB) is a compound of the formula (ID) in which Rja is hydrogen.
[000162] In one embodiment, the present invention relates to any of the compounds that follow
an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
[000163] In one embodiment, the present invention relates to any of the compounds that follow

an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
[000164] To avoid doubts, it should be understood that each general and specific preference, embodiment and example for a substituent can be combined, whenever possible, 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)
[000165] 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 examples thereof as defined herein.
[000166] In general, the compounds of the formula (IA) in which X is N, and X "is CR3a; R3a is hydrogen, Y is D (E is a bond), said compounds being represented by the formula (I-Aa ), can be prepared according to Reaction Scheme 1 below.

[000167] In scheme 1, an intermediate of formula (IV) wherein W2 represents a suitable starting group, such as, for example, halo, for example, chlorine and the like, or -O-SO2-CF3, is reacted with an intermediate of formula (V) in the presence of a suitable catalyst, such as, for example, palladium (II) acetate or Pd2dba3, a suitable base, such as sodium tert-butoxide or Cs2CO3, a suitable ligand, such as , for example, l, r- [l, l'-binaphthalene] -2,2'-di-ylbis [1,1, l-diphenylphosphine] or xantphos, and a suitable solvent or mixture of solvents, such as for example dioxane or dimethyl ethylene glycol ether and water or N-methylpyrrolidone, or tetrahydrofuran or toluene or a mixture of Dioxane and toluene, which results in an intermediate of formula (VI). This reaction can also be carried out in the presence of a suitable deprotonating agent, such as, for example, potassium bis (trimethylsilyl) amide, and a suitable solvent, such as, for example, tetrahydrofuran. Or alternatively an intermediate of formula (IV) is reacted with an intermediate of formula (V) in the presence of a suitable solvent, such as, for example, an alcohol, for example, n-propanol. Said intermediate of formula (VI) can then be reacted with an intermediate of formula (VI-I) in which W3 represents a suitable starting group, such as, for example, halo, for example, bromine and in which Rx and Ry represent CM alkyl, and Rz represent C1-4 alkyl or phenyl, for example Rx and R> represent CH3 and R7 represents C (CH3) 3 or phenyl, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, N, N-dimethylformamide or N, N-dimethylacetamide, which results in an intermediate of the formula (VI-II). Intermediates of formula (VI-II) or intermediates of formula (VI-II) in which the R1 substituent carries a suitable protecting group can also be prepared by reacting an intermediate of formula (IV) or an intermediate of formula (IV ) in which the substituent R1 carries a suitable protecting group with an intermediate of the formula (XXI-II ') in which R3d represent -C1-6 alkyl (O) (Rx) (Ry) (Rz) in the presence of a catalyst suitable, such as, for example, palladium (II) acetate, a suitable ligand, such as, for example, racemic -2,2'-bis (diphenylphosphmo) -l J'-binaftyl, a suitable base, such as, for example, CS2CO3, and a suitable solvent, such as, for example, 1,2-dimethoxyethane. The intermediates of the formula (VI-II) can be converted into a compound of the formula (I) in which R represents - CI.6-OH alkyl, said compounds being represented by the formula (I-Aa-a) or compounds of the formula (I-Aa) in which the substituent R1 carries a suitable protecting group, by reaction with tetrabutylammonium fluoride in the presence of a suitable solvent, such as, for example, tetrahydrofuran. This type of reaction can also be carried out in the presence of a suitable acid, such as, for example, acetic acid or HCl, and a suitable solvent, such as, for example, tetrahydrofuran or dioxane. Alternatively, an intermediate of formula (VI) can react with an intermediate of formula (VI-I ') in which W3 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, and a suitable solvent, such as, for example, N, N-dimethylformamide or N, N-dimethylacetamide, which results in an intermediate of formula (XXV) that can then be deprotected 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 or isopropanol, to give a compound of the formula (I-Aa- The). The compounds of the formula (I-Aa-a) or the compounds of the formula (I-Aa-a) in which the substituent R1 carries a suitable protecting group can be reacted with methanesulfonyl chloride in the presence of a suitable base, such as , for example, triethylamine, diisopropylethanamine or N, N-dimethyl-4-aminopyridine, and a suitable solvent, such as, for example, dichloromethane or tetrahydrofuran, to result in an intermediate of formula (IX) (derivative mesylate) or an intermediate of formula (IX ') (chloride derivative) or intermediates of formula (IX) or (IX') in which the substituent R1 carries a suitable protecting group. In particular, this type of reaction is used to prepare intermediates of the formula (IX) or (IX ') in which C1-6 alkyl represents Ca-ealalkyl. For some variants of the intermediates of the formula (IX) or (IX '), for example, where C 1 alkyl represents C 2 alkyl, it would be preferred to carry out the reaction under non-basic conditions. The intermediates of formula (IX) or (IX ') can then be reacted with an intermediate of formula (X) to obtain a compound of formula (Ia) in which RJ represents Cμ6 alkyl substituted with NR1ORU, said compounds being represented by the formula (I-Aa-b) or compounds of the formula (I-Aa-b) in which the substituent R1 carries a suitable protecting group. This reaction can optionally be carried out in the presence of a suitable base, such as, for example, triethylamine, K2CO3, Na2CO3 or sodium hydride and optionally a suitable solvent, such as, for example, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, 1-methyl-pyrrolidinone, a suitable alcohol, for example, 1-butanol and the like. This type of reaction can also be carried out with a suitable salt of the intermediate of formula (X), for example, HCl salt of the intermediate of formula (X), or can be carried out in the presence of potassium iodide. In this way, compounds in which R represents Cμ6 iodoalkyl can be obtained. The compounds of the formula (la-b) in which the substituent R1 carries a suitable protecting group can be converted to a compound of the formula (I-Aa- b) by reaction with a suitable acid, such as, for example, trifluoroacetic acid , in the presence of a suitable solvent, such as, for example, dichloromethane.
[000168] Intermediates of formula (IX) can also react with a ring that contains suitable nitrogen within the definition of R9, said ring that is represented by formula (XXI) or a suitable salt of an intermediate of formula (XXI), in the presence of a suitable solvent, such as, for example, acetonitrile, 1-methyl-2-pyrrolidinone, or an alcohol, for example, 1-butanol, optionally in the presence of potassium iodide or a suitable base, such as example, Na2CO3, K2CO3 or triethylamine, which results in a compound of the formula (I-Aa-d). Intermediates of formula (IX) can also react with an intermediate of formula (Xa) where P represents a suitable protecting group, such as, for example, -C (= O) - OC (CH3) 3, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, dimethylacetamide, which results in an intermediate of formula (XXX) that can be deprotected to a compound of formula (I-Aa -b-1) in the presence of a suitable acid, such as, for example, HCl or trifluoroacetic acid, and a suitable solvent, such as, for example, dichloromethane or an alcohol, for example, methanol. The intermediates of the formula (XXX) can also be prepared by reacting an intermediate of the formula (VI) with an intermediate of the formula W6 -C6 alkyl .6-NR10P where W6 represents a suitable starting group, such as, for example , halo, for example, bromine and the like, or -OS (= O) 2-CH3, and P is as defined above, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent , for example, N, N-dimethylformamide or N, N-dimethylacetamide. Alternatively, the compounds of the formula (I-Aa-d) or (I-Aa-b-1) can also be prepared respectively by reacting an intermediate of the formula (VI) with an intermediate of the formula W6-alkyl CVô-N- cycle or W6-C-alkyl] .6-NHR10 where W6 is as defined above. n J
[000169] Intermediates of formula (VI) can react with Wó-R where W6 represents a suitable starting group, such as, for example, halo, for example, bromine and the like, or -OS (= O) 2 -CH3 or p- • ju toluenesulfonate, and RJ represents optionally substituted Cpo alkyl, such as, for example, -CH2-C3H5, in the presence of a suitable base, such as, for example, sodium hydride, Cs2CO3 or potassium hydroxy and a suitable phase transfer agent, such as, for example, tetrabutylammonium bromide or and a suitable solvent, such as, for example, N, N-dimethylformamide, N, N-dimethylacetamide, 2-methyltetrahydrofuran, water or acetonitrile, which results in a compound of the formula (I-Aa-c). W6-R can also be used in an appropriate salt form, for example, a hydrochloric acid salt of W6-RJJ. Thus, compounds of the formula (I-Aa-c) in which R represents -S (= O) 2-N (CH3) 2 can also be prepared by reacting an intermediate of the formula (VI) with dimethylsulfamoyl chloride, in the presence of a suitable base, such as, for example, NaH, and a suitable solvent, such as, for example, N, N-dimethylformamide. This type of reaction can also be used to prepare an intermediate in which the R'd portion is protected by an appropriate protecting group, such as, for example, triphenylmethyl or -CH2-O-CH2-CH2-Si (CH3) 3 , which can then be deprotected to a compound of the formula (I-Aa-c) in the presence of a suitable acid, such as, for example, HCl or trifluoroacetic acid, in a suitable solvent, such as, for example, dichloromethane or acetonitrile , or by reaction with a suitable desilylation agent, such as, for example, tetrabutylammonium fluoride in the presence of a suitable solvent, such as, for example, tetrahydrofuran. This type of reaction can also be used to prepare a compound of the formula (I-Ba) (see hereinafter). The compounds of the formula (I-Aa-c) in which the Cμg alkyl chain within the definition of R3d represents -CH2- (C0-5alkyl) can also be prepared by reacting an intermediate of the formula (VI) with HC (= O) -R3d 'in the presence of sodium cyanoborohydride, and a suitable solvent, such as, for example, an alcohol, for example, methanol, and dichloromethane.
[000170] The compounds of the formula (I-Aa-c) in which R3d represents - CH2-C (OH) (R ') (R ”) in which R' represents optionally substituted alkyl and R” represents hydrogen or CM alkyl optionally substituted, said compounds being represented by the formula (I-Aa-c-1), can be prepared by reacting the intermediate of the formula (VI) with an intermediate of the formula (XXI-I) in the presence of a suitable base, such as , for example, sodium hydride, Cs2CC> 3, or potassium hydroxy, and a suitable solvent, such as, for example, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile or water.
[000171] Intermediates of formula (IV) can also react with an intermediate of formula (XXI-II) in the presence of a suitable catalyst, such as, for example, palladium (II) acetate or tris (dibenzylideneacetone) dipaladium (0 ), a suitable base, such as, for example, sodium tert-butoxide or Cs2CO3, a suitable ligand, such as, for example, l, r- [l, r-binaphthalene] -2,2'-di-ilbis [1,1-diphenylphosphmo] or 2-dicyclohexylphosphmo-2 '- (N, N-dimethylamino) biphenyl or dicyclohexyl (2', 6'-diisopropoxy-2-biphenylyl) phosphine, and a suitable solvent, such as, for example, dioxane, which results in a compound of the formula (I-Aa-c). The intermediates of the formula (XXI-II) can also react in a • 2 J form that the R portion is in the protected form, for example, protected with - C (= O) -O-C | 6 alkyl. The resulting product can then be deprotected, for example in the presence of a suitable acid, such as, for example, HCl, and a suitable solvent, such as, for example, dichloromethane.
[000172] The compounds of the formula (I-Aa-b) in which R11 is amino substituted Cj.6 alkyl, said compounds being represented by the formula (I-Aa-b-2), can also be prepared according to o Reaction scheme 1A that follows. Scheme IA

[000173] In scheme IA, a compound of the formula (I-Aa-b-1) is reacted with N- (C1-6 haloalkyl) phthalimide in the presence of a suitable base, such as, for example, potassium carbonate, and a solvent suitable, such as, for example, acetonitrile, which results in an intermediate of the formula (XXXVI) which can be converted into a compound of the formula (I-Aa-b-2) by reaction with hydrazine in the presence of a suitable solvent, such as, for example, an alcohol, for example, ethanol.
[000174] The compounds of the formula (I-Aa) in which R 'represents optionally substituted C2-6 alkynyl, said compounds being represented by the formula (I-Aa-k), can be prepared according to the Scheme 1B reaction. Scheme 1B

[000175] In scheme 1B, an intermediate of formula (VI) is reacted with an intermediate of formula Wn-Rje in which R3e represents C2 alkynyl. 6 optionally substituted and Wn represents a suitable leaving group such as, for example, halo, for example, chlorine, or -OS (= O) 2-CH3, in the presence of a suitable base, such as, for example, NaH, and a suitable solvent, such as, for example, N, N-dimethylformamide. The intermediate Wn-R3e in which Wn represents -OS (= O) 2-CH3, can be prepared by reacting the corresponding alcohol derivative with methanesulfonyl chloride in the presence of a suitable base, such as, for example, triethylamine or 4- dimethylamino-pyridine, and a suitable solvent, such as, for example, dichloromethane.
[000176] The compounds of the formula (I-Aa-k), in which R3e represents hydroxyl-substituted C2.6 alkynyl, said compounds being represented by the formula (I-Aa-k-1), can be prepared according to o 1C reaction scheme that follows. Scheme 1C

[000177] In scheme 1C, an intermediate of formula (VI) is reacted with an intermediate of formula (XXXVI-II) in the presence of a suitable base, such as, for example, NaH, and a suitable solvent, such as, for example, example, N, N-dimethylformamide, which results in an intermediate of the formula (VI-TI '), which is converted into a compound of the formula (I-Aa-k-1) by reaction with a suitable acid, such as, for example, example, trifluoroacetic acid, in the presence of a suitable solvent, such as, for example, tetrahydrofuran. This reaction can also be carried out with tetrabutyl ammonium fluoride in the presence of a suitable solvent such as, for example, tetrahydrofuran.
[000178] Alternatively, instead of an intermediate of the formula (XXXVI-II), haloalkynyl C2-6-O-Si (Rx) (Ry) (Rz) can also be used.
[000179] The compounds of the formula (I-Aa-k), where R3e represents C2-6 alkynyl, said compounds being represented by the formula (I-Aa-k-2), can be prepared according to the Scheme of 1D reaction that follows. ID scheme

[000180] In scheme 1D, a compound of the formula (I-Aa-k-2) is prepared by deprotecting an intermediate of the formula (XXXXI-I) in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, an alcohol, for example, methanol and the like. Said intermediate of formula (XXXXI-I) can be prepared by the reaction of an intermediate of formula (VI) with W] 3-C2-6-Si (CH3) 3 alkynyl where W13 is a suitable starting group, such as , for example, halogen, in the presence of a suitable base, such as, for example, NaH, and a suitable solvent, such as, for example, N, N-dimethylformamide.
[000181] The compounds of the formula (I-Aa), where RJ represents ethyl substituted with -P (= O) (Oalkyl C 1-0) 2, said compounds being represented by the formula (I-Aa-1), can be prepared according to Reaction Scheme 1E below. IE scheme

[000182] In the IE scheme, an intermediate of formula (VI) is reacted with di (C alkyl) phosphonate in the presence of a suitable catalyst, such as, for example, tri-N-butylphosphine, and a suitable solvent, such as, for example, acetonitrile which results in a compound of the formula (Ia-1).
[000183] The intermediates of formula (IV) can be prepared according to Reaction Scheme 2 which follows. Layout 2
In scheme 2, the following reaction conditions apply: 1: in the presence of a Meldrum acid and triethyl orthoformate, and a suitable solvent, such as, for example, an alcohol, for example, ethanol; 2: in the presence of diphenyl ether or dowtherm A; 3: in the presence of N-bromo-succinimide, and acetic acid; 4: in the presence of phosphoryl chloride, and a suitable solvent, such as, for example, chloroform; 5: in the presence of a suitable base, such as, for example, sodium carbonate, a suitable catalyst, such as, for example, PdCbÍpddfyClHbCb, and a suitable solvent, such as, for example, dioxane and water; 6: in the presence of catalyst, such as, for example, Raney nickel, and H2, a suitable base, such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example , ethanol, and tetrahydrofuran; 7: In the presence of a suitable acid, such as, for example, HCl, and a suitable solvent, such as, for example, dioxane; 8: in the presence of a suitable starting group introducing agent, such as, for example, chloride and phosphoryl, and a suitable solvent, such as, for example, chloroform.
[000184] Some naphthyridines are described in R. Morgentin et a /./ Tetrahedron 64 (2008) 2772e2782.
[000185] The compounds of the formula (IA) wherein X2 is N and X1 is CH; and Y is D (E is a bond) can be prepared according to the reaction schemes described above starting from the corresponding intermediate (1,7-naphthyridine analog of the intermediate of formula (IV)) that can be prepared according to reactions that follow in scheme 2A. Scheme 2A
In scheme 2A, the following reaction conditions apply: 1: in the presence of di-tert-butyl bicarbonate, and a suitable solvent, for example, dioxane; 2: in the presence of N-methoxy-N-methylacetamide, and tetramethylene 'diamine used as a base in the presence of BuLi 3: in the presence of N, N-dimethylformamide and N, N-dimethylacetamide 4: in the presence of a suitable acid, such as, for example, trifluoroacetic acid, and a suitable solvent, such as, for example, toluene. 5: in the presence of N-bromosuccinimide, and a suitable acid, such as, for example, acetic acid 6: in the presence of POC13 and a suitable solvent, such as, for example, CHC13 7: in the presence of a suitable base, such as as, for example, sodium carbonate, a suitable catalyst, such as, for example, PdC12 (pddf) .CH2C12, and a suitable solvent, such as, for example, dioxane and water; 8: in the presence of catalyst, such as, for example, Raney nickel, and H2, a suitable base, such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example , ethanol, and tetrahydrofuran; 9: in the presence of A1C13, and a suitable solvent, such as, for example, dichloroethane 10: in the presence of an agent that introduces a leaving group, such as, for example, SOC12 or N-phenyl-bis (trifluoromethanesulfonimide), optionally a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, toluene, dichloromethane and N, N-dimethylformamide.
[000186] Some of the intermediaries are described in R. Morgentin et «/./Tetrahedron 64 (2008) 2772e2782.
[000187] In general, the compounds of the formula (IB) in which R3a is hydrogen and Y is D (E is a bond), said compounds being represented by the formula (I-Ba), can be prepared according to the reactions that follow in scheme 3. Scheme 3

[000188] In scheme 3, an intermediate of formula (VI) can react with W6-Rjdem which W6 represents a suitable starting group, such as, for example, halo, for example, bromine and the like, or -OS (= O ) 2-CH3, in the presence of a suitable base, such as, for example, potassium hydroxy and a suitable phase transfer agent, such as, for example, tetrabutylammonium bromide, and, and a suitable solvent, such as example, 2-methyltetrahydrofuran and water, which results in a compound of the formula (I-Ba).
[000189] The intermediates of the formula (VI-I1-B) can react with tetrabutylammonium fluoride, in the presence of a suitable solvent, such as, for example, tetrahydrofuran, which results in a compound of the formula (I-Ba- The).
[000190] In general, the compounds of the formula (IA) in which X is N, and X is CRja; Y is D (E is a bond), said compounds being represented by the formula (I-Ab), can be prepared according to Reaction Scheme 4 which follows. Layout 4
In scheme 4, the following reaction conditions apply: 1: the starting material is prepared according to the reactions described in scheme 2. Said starting material is reacted in the presence of a suitable acid, such as, for example, HCl, and a suitable solvent, such as, for example, dioxane. 2: in the presence of POC13, and a suitable solvent, such as, for example, chloroform; 3: in the presence of intermediate (V) (see Scheme 1), a suitable base, such as, for example, diisopropylethylamine, and a suitable solvent, such as, for example, an alcohol, for example, 1-propanol ; 4: according to the reactions described above. The intermediates of the formula (VI-II-a) or (VI-II-b) can be prepared according to the reaction scheme that follows 4 '. Layout 4 '

[000191] In scheme 4 ', an intermediate of the formula (XVI-I) is reacted with an intermediate of the formula (VI-I) in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent , such as, for example, N, N-dimethylformamide, which results in an intermediate of the formula (XVI-II). The intermediate of the formula (XVI-II) can then be reacted with an intermediate of the formulas (I-II) or (I-II-a) in the presence of a suitable catalyst, such as, for example, Pd2 (dba) 3, a suitable base, such as, for example, K3PO4, a suitable ligand, such as, for example, 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-biphenyl or S-Phos, and a suitable solvent, such as, for example , dioxane or water or mixtures thereof.
[000192] The intermediates of the formula (Vl-II-a) can be transformed into an intermediate of the formula (VI-II-b) in the presence of catalyst, such as, for example, Raney nickel, and H2, a suitable base , such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example, ethanol.
[000193] The intermediates of the formulas (Vl-II-a) or (VI-II-b) can also be prepared according to the Reaction Scheme that follows 4A. Scheme 4A

[000194] In scheme 4A, an intermediate of formula (XVI-II) is reacted with an intermediate of formula (XXXVI-I) in the presence of a suitable catalyst, such as, for example, tetracis (triphenylphosphmo) palladium (0), and a suitable solvent, such as, for example, toluene.
[000195] The intermediates of the formula (VI-II-a) can be transformed into an intermediate of the formula (VI-II-b) in the presence of catalyst, such as, for example, Raney nickel, and H2, a suitable base , such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example, ethanol.
[000196] The intermediates of the formula (XVI-I) can be prepared according to Reaction Schemes 5 and 6 that follow. Layout 5
In scheme 5: the following reaction conditions apply: 1: in the presence of a Meldrum acid and triethyl orthoformate, and a suitable solvent, such as, for example, an alcohol, for example, ethanol; 2: in the presence of diphenyl ether; 3: in the presence of N-bromo-succinimide, and acetic acid; 4: in the presence of phosphoryl chloride, and a suitable solvent, such as, for example, chloroform; 5: in the presence of a suitable aniline of formula (V) as defined above, in a suitable solvent, such as, for example, 1-propanol. Layout 6
In scheme 6, the following reaction conditions apply: 1: in the presence of di-tert-butyl bicarbonate, and a suitable solvent, for example, dioxane; 2: in the presence of N-methoxy-N-methylacetamide, and tetramethylene diamine used as a base and in the presence of BuLi 3: in the presence of N, N-dimethylformamide and NNn-dimethylacetamide 4: in the presence of a suitable acid, such as , for example, trifluoroacetic acid, and a suitable solvent, such as, for example, toluene. 5: in the presence of N-bromosuccinimide, and a suitable acid, such as, for example, acetic acid 6: in the presence of POC13 and a suitable solvent, such as, for example, CHCl3 7: in the presence of a suitable aniline of the formula (V) as defined above, and a suitable solvent, such as, for example, 1-propanol, which results in an intermediate of the formula (XVI-lb)
[000197] The intermediates of the formula (VI-II) in which D is a ring portion containing a nitrogen atom, can be further reacted according to Reaction Scheme 7 below, represented for the 1.5 skeleton - naphthyridine and for R3a being hydrogen (intermediates of the formula (VI-IT-b)). It is considered to be within the knowledge of the qualified technician to adopt these reactions for the other intermediaries of the formula (VI-II) described above. Layout 7

[000198] In Scheme 7, the D'N portion represents a -D portion where the D ring portion contains a nitrogen atom. The intermediates of the formula (VI-II'-b) in which D represents D'NH, can be converted into an intermediate of the formula (VI-II'-b-2) by reaction with W12-C] .6-halo wherein W12 represents a suitable starting group, such as, for example, halo, for example, chlorine, in the presence of a suitable base, such as, for example, NaH, and a suitable solvent, such as, for example, N , N-dimethylformamide. Said intermediates of the formula (VI-II'-b-1) can be converted into an intermediate of the formula (VI-II'-b-2) by reaction with R6 in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, acetonitrile. When in an intermediate of the formula (VI-II'-b-2) R6 carries a hydroxyl group as in an intermediate of the formula (VI-II'-b-3), then said hydroxyl group can be protected by a group of adequate protection P, such as, for example, -OC (= O) -C1-6 alkyl, by reaction with C | _6-C (= O) -Wi2 alkyl, in the presence of a suitable base, such as, for example, example, triethylamine, 4-dimethylaminopyridine, and a suitable solvent, such as, for example, dichloromethane, which results in an intermediate of the formula (VI-II'-b-4) which can be converted into an intermediate of the formula (XXXIX) by reaction with tetrabutylammonium fluoride in the presence of a suitable solvent, such as, for example, tetrahydrofuran. Said intermediate of the formula (XXXIX) can be converted into an intermediate of the formula (XXXX) in which Ru represents —SO2CH3, by reaction with methane sulfonyl chloride in the presence of a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, dichloromethane. In particular, this type of reaction is used to prepare the intermediates of the formula (XXXX) in which Cμ6 alkyl represents C3.6 alkyl. For some variants of the intermediates of the formula (XXXX), for example, in which Cμ6 alkyl represents C1.2 alkyl, it would be preferable to carry out the reaction under non-basic conditions. Intermediates of formula (XXXX) can be converted to an intermediate of formula (XXXXI) by reaction with an intermediate of formula (X) in a suitable solvent, such as, for example, acetonitrile. Said intermediate of the formula (XXXXI) can then be deprotected into a compound of the formula (I-Aa-b-4) in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, for example, an alcohol, for example, methanol and the like. It is considered within the skill of the person skilled in the art to recognize that other portions of the D-ring the described reactions also apply. The intermediates of the formula (VI-II'-b) can also be reacted to prepare the compounds of the present invention according to with the reaction schemes as presented in scheme 1. It is considered to be within the knowledge of the qualified person to recognize in which condition and for which definitions of R1 the D-ring portion a protecting group may be appropriate for the reactions to be carried out. For example, a hydroxyl group within the definition of R1 can be protected with a tert-butyldimethylsilyl moiety; an NH group within the definition of R1 can be protected with a group -C (= O) -O- C (CH3) 3. It is also considered to be within the knowledge of the qualified person to recognize appropriate deprotection reactions.
[000199] The compounds of the formula (IA) in which R 'represents optionally substituted C] -6 alkyl, said compounds being represented by the formula (I-Aa-c), can also be prepared according to Reaction Scheme 8 below. Layout 8

[000200] In scheme 8, an intermediate of the formula (XVI-I) is reacted with Wg-R'0 where Wg represents a suitable starting group, such as, for example, halo, for example, bromine and the like, and R3d represents optionally substituted C1-6 alkyl, such as, for example, -CH2-C3H5, in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, N , N-dimethylformamide, which results in an intermediate of the formula (XIX). In a next step, the intermediate of formula (XIX) is reacted with an intermediate of formula (I-II) or (I-II-a) in the presence of a suitable catalyst, such as, for example, phosphine tetracis (triphenyl) palladium or Pd2 (dba) 3 (tris (dibenzylidenoacetone) dipaladium (0)), optionally a suitable ligand, such as 2-dicyclohexylphosphmo-2 ', 6'-dimethoxybiphenyl, a suitable base, such as, for example, Na2CO3 or IQPO4 , and a suitable solvent, such as, for example, ethylene glycol or dioxane dimethyl ether or water. Or the intermediate of formula (XIX) is reacted with an intermediate of formula (XXXVI-I) in the presence of a suitable catalyst, such as, for example, tetracis (triphenyl) phosphine palladium, and a suitable solvent, such as, for example , N, N-dimethylformamide or toluene. Or the intermediate of formula (XIX) is reacted with DW, where W represents a suitable starting group, such as, for example, halo, for example, bromine, iodine and the like, in the presence of a suitable catalyst, such as , for example, tetracis (triphenyl) phosphine palladium, zinc chloride and ethylmagnesium chloride to prepare species that react with organozinc, and a suitable solvent, such as, for example, tetrahydrofuran. An intermediate of formula (XIX) can also react with a suitable portion of the ring represented by D, for example, imidazole or 4-methylimidazole or 3-methylpyrazole or 2-methylimidazole, in the presence of a suitable catalyst, such as, for example, tris (dibenzylidenoacetone) dipaladium (0), a suitable ligand, such as, for example, Rac-bis (diphenylphosphino) -!,! '- binaftyl, in the presence of a suitable base, such as, for example, tert-butoxide sodium, and a suitable solvent, such as, for example, toluene to obtain the corresponding final compound. Or an intermediate of formula (XIX) can react with, for example, ethyl 4- (aminomethyl) piperidine, morpholine, 1,2,4-triazole, 4-methyl-5-imidazolcarboxylate, piperazine or a derivative thereof, for example , 1- (2-hydroxy ethyl) piperazine or 1-methyl-piperazine, in the presence of a suitable base, such as, for example, triethylamine or sodium hydride or cesium carbonate, in the presence of a suitable catalyst, such as, for example, palladium (II) acetate, a suitable ligand, such as, for example, Rac-bis (diphenylphosphino) -1, l'-binaftyl and a suitable solvent, such as, for example, tetrahydrofuran, N, N-dimethylformamide, or an alcohol, for example, 1-butanol, to obtain the corresponding final compound.
[000201] An intermediate of the formula (XIX) can also react with l- (triisopropylsilyl) pyrrole-3-boronic acid, in the presence of a suitable catalyst, such as, for example, tetracis (triphenyl) phosphine palladium, a suitable base, such as, for example, sodium carbonate and tetrabutylammonium fluoride, and a suitable solvent, such as, for example, ethylene glycol dimethyl ether, to obtain a compound of the formula (I-Aa-c-2) . An intermediate of formula (XIX) can react with zinc cyanide in the presence of a suitable catalyst, such as, for example, tetracis (triphenyl) phosphine palladium, a suitable ligand, such as, for example, triphenylphosphine, and a suitable solvent, such as, for example, acetonitrile. The intermediate resulting from formula (IXL) can be reacted with sodium azide and ammonium chloride in the presence of a suitable solvent, such as, for example, N, N-dimethylformamide, to obtain a compound of the formula (I-Aa-c -3).
[000202] The compounds of the formula (I-Aa-c), (I-Aa-c-2) or compounds of the formula (I-Aa-c-3) can be transformed into the corresponding compounds in which R3a is hydrogen, in the presence of catalyst, such as, for example, Raney nickel, and H2, a suitable base, such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example, ethanol
[000203] The compounds of the formula (I-Aa-c) alternatively can also be prepared according to the reaction scheme below 9. Scheme 9

[000204] In scheme 9, an intermediate of formula (IV) is reacted with R3d-NH2 in the presence of a suitable catalyst, such as, for example, palladium (II) acetate or Pd2dba3, a suitable base, such as, for example, example, sodium tert-butoxide, and a suitable ligand, such as, for example, 1,1 '- [1,1' -baphthalene] -2,2'-di-ylbis [1,1-diphenyl-phosphine] or xantphos, which results in an intermediate of the formula (XX). This type of reaction can also be carried out with Rd-NH2 in the presence of a suitable solvent, such as, for example, an alcohol, for example, n-propanol. An intermediate of formula (IV) can also react with Rjd-NH2 in the presence of a suitable deprotonating agent such as, for example, potassium bis (trimethylsilyl) amide, in a suitable solvent such as, for example, tetrahydrofuran. The intermediates of formula (XX) are reacted in a next step with an intermediate of formula (XIV) in the presence of a suitable catalyst, such as, for example, palladium (II) acetate or Pd2 (dba) 3 (tris (dibenzylidene) acetone) dipaladium (0)), a suitable ligand such as, for example, 2-dicyclohexylphosphene-tris-isopropyl-biphenyl or 1,1'- [1,1 '-binaphthalene] -2,2'-di-ylbis [ 1,1-diphenylphosphine], a suitable base, such as, for example, sodium tert-butoxide, and a suitable solvent, such as, for example, ethylene glycol dimethyl ether. ■ 2
[000205] The compounds of formula (I) in which R represents optionally substituted Cμg alkyl, and in which Y is ED and E is other than a bond, said compounds being represented by the formula (I-Ab) can be prepared in accordance with according to Reaction Scheme 10 below. Layout 10

[000206] In scheme 10, an intermediate of formula (XIX) prepared according to the methods described above, is reacted with D-NHR in the presence of a suitable catalyst, such as, for example, Pd2 (dba) 3 (tris ( dibenzylidenoacetone) dipaladium (0)), a suitable ligand, such as, for example, 9,9-dimethyl-4,5-bis (diphenylphosphmo) -xanthenes, a suitable base, such as, for example, cesium carbonate, and a suitable solvent, such as, for example, dioxane, which results in a compound of the formula (I-Ab-1). Or an intermediate of formula (XIX) is reacted with D CH, in the presence of a suitable catalyst, such as, for example, dichlorobis (triphenylphosphmo) palladium (II) and copper iodide, a suitable ligand, such as, for example, triphenylphosphine, a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, N, N-dimethylformamide to obtain a compound of the formula (I-Ab-2). A compound of the formula (I-Ab-2) can also be prepared by reacting an intermediate of the formula (XLI) with DW as defined above, in the presence of a suitable catalyst, such as, for example, dichlorobis (triphenylphosphmo) palladium ( II) and copper iodide, a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, N, N-dimethylformamide and acetonitrile. The intermediate of the formula (XLI) can be prepared by reacting an (XIX) intermediate with (trimethylsilyl) acetylene in the presence of a suitable catalyst, such as, for example, dichlorobis (triphenylphosphmo) palladium (II) and copper iodide, a suitable ligand, such as, for example, triphenylphosphine, a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, dimethyl sulfoxide, followed by the reaction of the intermediate resulting from formula (XL) with potassium carbonate in a suitable solvent, such as, for example, an alcohol, for example, methanol. The intermediate of the formula (XLI) can also react with 2- (4-morpholino) ethylazide, in the presence of a suitable catalyst, such as, for example, copper iodide, a suitable base, such as, for example, N, N - diisopropylethylamine, and a suitable solvent, such as, for example, tetrahydrofuran, to obtain a compound in which E is a bond and D is 2- (4-morpholino) ethyl-1-triazolyl. An intermediate of the formula (XLI) can also react with sodium azide and formaldehyde in the presence of a suitable catalyst, such as, for example, copper sulfate and L sodium ascorbate, and a suitable solvent, such as, for example, dioxane and acetic acid, to obtain a compound of the formula (IAa-c-5).
[000207] The compounds of the formula (I-Ab-1), (I-Ab-2) and (I-Aa-5) can be transformed into the corresponding compounds in which R'a is hydrogen, in the presence of a catalyst, such as such as, for example, Raney nickel, and H2, a suitable base, such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example, ethanol.
[000208] The compounds of the formula (I-Ab) can also be prepared according to the Reaction Scheme below 10 A. Scheme 10A

[000209] In scheme 10A, an intermediate of formula (XIX) is reacted with CO gas, potassium acetate, in the presence of a suitable catalyst, such as, for example, tetracis (triphenyl) phosphine palladium, and a suitable solvent, such as, for example, dioxane which results in an intermediate of the formula (XLI-I) which can be transformed into an intermediate of the formula (XLI-I ') in the presence of catalyst, such as, for example, Raney nickel, and H2 , a suitable base, such as, for example, sodium hydroxide, and a suitable solvent, such as, for example, an alcohol, for example, ethanol. The intermediate of the formula (XLI-I ') is reacted with D- (CR "R') S-NHR in the presence of suitable peptide-binding reagents such as for example 1- (3-dimethylaminopropyl) -3-ethylcarbodi hydrochloride -imide and 1-hydroxy benzotriazole, a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, methylene chloride, to obtain a compound of the formula (I-Ab-3). The intermediate of the formula (XLI-I ') can also react with DH in the presence of suitable peptide-binding reagents such as for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxy benzotriazole, a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, methylene chloride to obtain a compound of the formula (I-Ab-4). An intermediate of formula (XIX) can also react with 1,1-diphenylmethylonimine in the presence of a suitable catalyst such as tris (dibenzylidenoacetone) dipaladium, in the presence of a suitable ligand such as, for example, 9,9-dimethyl-4, 5- bis (diphenylphosphmo) xanthenes, in the presence of a suitable base, such as, for example, sodium tert-butylate and in the presence of a suitable solvent, such as, for example, ethylene glycol dimethyl ether to obtain an intermediate of the formula (XLI-II-a). Said intermediate can be converted to an amine of the formula (XLI-II) by hydrolysis in an acidic medium, which can react with D-COOH, in the presence of suitable peptide-binding reagents such as, for example, l- (3) hydrochloride -dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxy benzotriazole, a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, methylene chloride to obtain a compound of the formula (I -Ab-5). Said compound can be transformed into a compound of the formula (I-Ab-5) in the presence of catalyst, such as, for example, Raney nickel, and H2, and a suitable solvent, such as, for example, an alcohol, for example, ethanol. Alternatively, the amine of the formula (XLI-II) can first be converted to an intermediate of the formula (XLI-II ') according to the method described for (I-Ab-5') and then reacted with D-COOH with a compound of the formula (I-Ab-5 ').
[000210] The compounds of formula (I) in which R is C] _6 alkyl substituted with 5-amino-1,3,4-oxadiazoyl can be prepared according to Reaction Scheme 11 below. Layout 11

[000211] In scheme 11, a compound of the formula (I-Ac-1) is reacted with NH2-NH2 in the presence of a suitable solvent, such as, for example, an alcohol, for example, ethanol that results in an intermediate of formula (XXXI) which is then reacted in a next step with Wg-CN, where Wg represents a suitable starting group, such as, for example, halo, for example, bromine, in the presence of a suitable base, such as, for example, NaHCO3, and a suitable solvent, such as, for example, water or dioxane.
[000212] The compounds of formula (I) in which R is C] _6 alkyl substituted with 3,3-dimethyl-morpholine can be prepared according to the reaction scheme below 1 IA Scheme 11A

[000213] In Scheme 1 IA, a compound of the formula (I-Ac-3) is reacted with 2-amino-2-methyl-1-propanol in the presence of a suitable base, such as, for example, NaH and in the presence of a suitable solvent, such as, for example, N, N-dimethylformamide which results in an intermediate of the formula (XXXI-I) the NH2 portion of which is protected by a suitable protecting group P, such as, for example, - C (= O) -OC (CH3) 3, by reaction with, for example, di-tert-butyl bicarbonate in the presence of a suitable solvent, such as, for example, dioxane, and a suitable base, such as, for example, NaHCO3, which results in an intermediate of the formula (XXXIII). In a next step, said intermediate is reacted with methanesulfonyl chloride in the presence of a suitable solvent, such as, for example, dichloromethane, and a suitable base, such as, for example, triethylamine which results in an intermediate of the formula (XXXIV ). In particular, this type of reaction is used to prepare intermediates of the formula (XXXIV) in which Cμg alkyl represents C3.6 alkyl. For some variants of the intermediates of the formula (XXXIV), for example, where alkyl represents C1-2 alkyl it would be preferable to carry out the reaction under non-basic conditions. The intermediates of the formula (XXXIV) are converted to an intermediate of the formula (XXXV) by reaction with a suitable acid, such as, for example, trifluoroacetic acid, in the presence of a suitable solvent, such as, for example, dichloromethane. The intermediate of the formula (XXXV) is converted into a compound of the formula (I-Ac-4) by reaction with a suitable base, such as, for example, A / A-diisopropylethylamine and triethylamine in the presence of a suitable solvent, such as, for example, an alcohol, for example, methanol.
[000214] In general, the compounds of the formula (I) in which Y represents - CCH3 = N-ORr>, The said compounds being represented by the formula (I-Ad), can be prepared as in scheme 12. Scheme 12

[000215] In scheme 12, the following reaction conditions apply: 1: reaction with tributyl (l-ethoxyvinyl) tin, in the presence of a suitable catalyst, such as, for example, dichlorobis (triphenylphosphmo) palladium (II) and copper iodide, a suitable ligand, such as, for example, triphenylphosphmo, and a suitable solvent, such as, for example, N, N-dimethylformamide 2: in the presence of a suitable acid, such as, for example, hydrochloric acid , and a suitable solvent, such as, for example, acetone. The obtained intermediate can also be converted into a compound of the formula (I-Aa) in which E is a direct bond and D is 3-methyl-oxazole or oxazole, by reaction with 1-methyl-1-tosylmethyl isocyanide or isocyanide of tosylmethyl, in the presence of a suitable base, such as, for example, potassium bicarbonate, and a suitable solvent, such as, for example, an alcohol, for example, methanol. 3: reaction with ethylene glycol in the presence of an acid to obtain a ketal such as CPD. 4: in the presence of catalyst, such as, for example, Raney nickel, and H2, in a suitable solvent, such as, for example, an alcohol, for example, ethanol. 5: the protection with ketal can be removed by reaction with an acid such as, for example, acetic acid in a solvent such as dichloromethane or tetrahydrofuran. 6: reaction with Rt9-O-NH2 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.
[000216] As already shown above, the present compounds or some of the intermediates described above can be prepared by deprotecting the corresponding protected compounds. Other protection-deprotection reactions are shown in Reaction Scheme 13 below. Layout 13

[000217] In scheme 13, the Y'N portion represents an -ED portion where the D ring portion contains a nitrogen atom. Compounds of formula (IA) in which R1 represents hydroxy Cμ alkyl can be prepared by deprotecting an intermediate of formula (XXVI) in the presence of a suitable acid, such as, for example, HCl or trifluoroacetic acid, or a desilylation agent suitable, such as, for example, tetrabutyl ammonium fluoride, and a suitable solvent, such as an alcohol, for example, methanol, or tetrahydrofuran (step 2). Intermediates of formula (XXVI) can be prepared by reacting a compound of formula (IA) in which R1 is hydrogen with an intermediate of formula (XXIV) in which W9 represents a suitable starting group, such as, for example, halo , for example, bromine and the like, and P represents a suitable protecting group, such as —Si (CH3) 2 (C (CH3) 3) or
, in the presence of a suitable base, such as, for example, sodium hydride or K2CO3, and a suitable solvent, such as, for example, N, N-dimethylformamide or acetonitrile (step 1).
[000218] The compounds of the formula (IA) in which R1 represents C1-6 alkyl substituted with -C (= O) -R6 in which R6 is a ring containing appropriate nitrogen attached to the C (= O) moiety via the atom nitrogen compounds can be prepared by reacting an intermediate of the formula (XXIX) with an intermediate of the formula (XXI) in the presence of suitable peptide-binding reagents such as, 1-hydroxy-benzotriazole and l- (3-dimethylaminopropyl) -3 -ethyl carbodiimide HCl (step 5). Intermediates of formula (XXIX) can be prepared by reacting an intermediate of formula (XXVI-II) with LiOH in the presence of a suitable solvent, such as, for example, tetrahydrofuran or water (step 4). formula (XXVI-II) can be prepared as represented in step 3 with an intermediate of formula (XXVI-I) where W9 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.
[000219] Step 6 represents the preparation of compounds of the formula (IA) starting from an intermediate of the formula (XXIX) by reaction with NHR4R5 in the presence of suitable peptide binding reagents such as 1-hydroxy-benzotriazole and l- (3 -dimethylaminopropyl) -3-ethyl carbodiimide HCl and a suitable base, such as triethylamine, and a suitable solvent, such as, for example, dichloromethane.
[000220] Other protection-deprotection reactions can also be used as outlined in Reaction Scheme 14 below. Layout 14

[000221] In Scheme 14, the following reaction conditions apply: 1: in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, N, N - dimethylformamide. 2: in the presence of a suitable catalyst, such as, for example, palladium (II) acetate, a suitable base, such as, for example, sodium tert-butoxide, a suitable ligand, such as, for example, 1, 1'- [1,1'-baphthalene] -2,2'-di-ylbis [1,1-diphenylphosphmo], and a suitable solvent, such as, for example, dioxane or dimethyl ethylene glycol. Alternatively, this type of reaction can also be carried out in the presence of a suitable deprotonating agent, such as, for example, potassium bis (trimethylsilyl) amide, in a suitable solvent, such as, for example, tetrahydrofuran. Alternatively, this type of reaction can also be carried out in the presence of a suitable solvent, such as, for example, an alcohol, for example, n-propanol. 3:: in the presence of a suitable catalyst, such as, for example, palladium (II) acetate, a suitable base, such as, for example, sodium tert-butoxide, a suitable ligand, such as, for example, 1 , 1'- [1, r-binaphthalene] -2,2'-di-ylbis [1,1, 1-diphenylphosphine], and a suitable solvent, such as, for example, dioxane or dimethyl ethylene glycol. 4: in the presence of a suitable base, such as, for example, triethylamine, and a suitable solvent, such as, for example, dichloromethane. 5: in the presence of a suitable base, such as, for example, K2COS, and a suitable solvent, such as, for example, 1-methyl-2-pyrrolidinone. 6: in the presence of hydrazine monohydrate, and a suitable solvent, such as, for example, an alcohol, for example, ethanol. 7: in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, tetrahydrofuran.
[000222] It should be considered to be within the knowledge of the person skilled in the art to recognize that the reactions described above for the compounds of (I-A) are also applicable for the compounds of the formula (I-B).
[000223] It is considered to be within the knowledge of the person skilled in the art to recognize in which condition and in which part of the molecule a protecting group may be appropriate. For example, protecting group on substituent R1 or on portion D, or protecting group on substituent R or substituent R- 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
or -O-Si (CH3) 2 (C (CH3) 3) or -CH2-O-CH2CH2-O-CH3OU -CH2- O-CH2-CH2-Si (CH3) 3. The skilled person is also considered to be able to recognize the most practicable deprotection reaction conditions, such as, for example, suitable acids, for example, trifluoroacetic acid, hydrochloric acid, or suitable salts, such as, for example, tetrabutylammonium fluoride . Therefore, reference is also made to the examples described in the Experimental Part that will follow.
[000224] The qualified person is also considered to be able to recognize that when R1 represents C (= O) -morpholinyl, said R1 can be prepared from -C (= O) -NH-CH2-CH2-O-CH2 -CH2-O-SO2-4- methylphenyl, in the presence of sodium hydride, and a suitable solvent, such as, for example, N, N-dimethylformamide. Or that when R1 represents - NH-C (= O) -morpholinyl, said R1 can be prepared from -NH- C (= O) -OC (CH3) 3 in the presence of morpholine, and a suitable solvent, such as such as, for example, 1-methyl-2-pyrrolidinone. Or that when R1 represents hydroxylalkyl Cμ6, for example -CH2-CH2-OH, said R1 can be prepared from the corresponding alkoxycarbonyl intermediate, for example, -CH2-C (= O) -O-CH2-CH3, in the presence of Dibal-H 1M in hexane, and a suitable solvent, such as, for example, tetrahydrofuran.
[000225] The present invention 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 (IV-a)
can be converted into an intermediate of the formula (IV-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.
[000226] The compounds of formula (I) can also be converted to one another through reactions known in the art or functional group transformations.
[000227] For example, 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, HCl or trifluoroacetic acid, in the presence of a suitable solvent, such as, for example, dichloromethane, dioxane, or an alcohol, for example, methanol, isopropanol and the like.
[000228] The compounds of formula (I) in which R1 or RJ represent monohaloalkyl, can be converted to a compound of formula (I) in which R or R represents Cμ $ alkyl substituted with a ring moiety as defined herein above by the intermediate of the formula (XXI) and attached to the Cμ6 alkyl moiety by the nitrogen atom, by reaction with an intermediate of the formula (XXI) optionally in the presence of a suitable base, such as, for example, triethylamine or K.2CO3 or sodium hydride, and optionally in the presence of a suitable solvent, such as, for example, acetonitrile, N, N-dimethylformamide or 1-methyl-2-pyrrolidinone. For the R3 portion, this type of reaction is in particular used to prepare compounds in which Cμ alkyl represents C3 alkyl. For some variants of the compounds, for example, in which Cμ6 alkyl represents Cμ2 alkyl, it would be preferred to carry out the reaction under non-basic conditions .
[000229] The compounds of formula (I) in which R1 or R1 represents Cμ6-OH alkyl, can be converted into a compound of formula (I) in which R1 or R3 represents CF 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 formula (I) in which R or R represents Cμ6 alkyl substituted with R or R9 in which said R6 or R9 is replaced with OH, can be converted into a compound of formula (I) in which R1 or R 'represent C 6 alkyl substituted with R 6 or R 9 wherein said R 6 or R 9 is substituted with F, by reaction with diethylamino sulfur trifluoride in the presence of a suitable solvent, such as, for example, dichloromethane.
[000230] The compounds of the formula (I) in which R1 or RJ represent Q-6 alkyl substituted with Rô or R9 in which said R6 or R9 is substituted with -C (= O) ~ O-alkyl C, can be converted in a compound of the formula (I) in which R1 or R represents Ct_6 alkyl substituted with R or R in which said R or R is substituted with CH2-OH, by reaction with LiAlH4 in the presence of a suitable solvent, such as, for example, example, tetrahydrofuran.
[000231] The compounds of the formula (I) in which RJ represents C] .6 alkyl substituted with 1,3-dioxo-2H-isoindol-2-yl, can be converted into a compound of the formula (I) in which R represents C] .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.
[000232] The compounds of the formula (I) in which R or R represents amino substituted C1.6 alkyl, can be converted to a compound of the formula (I) in which R or R represents -NH- substituted C1-6 alkyl S (= O) 2-C 1-6 alkyl, by reaction with Cl-S (= O) 2-alkyl CI-Ó in the presence of a suitable base, such as, for example, triethylamine, and a suitable solvent, such as such as dichloromethane.
[000233] The compounds of formula (I) in which R1 or R1 represents halo-substituted Cμ6 alkyl, can be converted into a compound of formula (I) in which R1 or R 'represents NR'R or NR'θR11-substituted Cb6 alkyl , by reaction with NHR4R: I or NHRIOR ", 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. For the R portion, this type of reaction is in particular used to prepare compounds in which alkyl represents C3.6 alkyl. For some variants of the compounds, for example, in which Cμ6 alkyl represents Cμ2 alkyl, it would be preferred to perform the reaction in non-basic conditions.
[000234] The compounds of formula (I) in which R1 represents hydrogen, can be converted into a compound of formula (I) in which R1 represents polyhaloalkyl Cμ6or polyhydroxy alkyl Cμ6or alkyl Cμ6or -S (= O) 2- NRI4R'3 or -S (= O) 2-Cμ6 alkyl, by reaction with polyhaloalkyl C1.6-W or polyhydroxy Cμ6-W alkyl or Cμ6-W alkyl or WS (= O) 2-NR14R15 or W- S (= O) 2- Cμ6 alkyl, where W represents a suitable starting group, such as, for example, halo, for example, bromine, iodine 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.
[000235] The compounds of formula (I) in which R1 represents hydrogen can also be converted into a compound of formula (I) in which R represents Q.6-OH alkyl, by reaction with W-alkyl Cμ6-O-Si ( CH3) 2 (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 and then followed by a reaction with a suitable desilylation agent such as tetrabutyl ammonium fluoride.
[000236] The compounds of formula (I) in which R1 represents hydrogen, can also be converted into the compound of formula (I) in which R1 represents ethyl substituted with -S (= O) 2-Cμg alkyl, by reaction with C1 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 C] alkyl. bromoethylsulfone in the presence of a suitable deprotonating agent, such as, for example, NaH, and a suitable solvent, such as, for example, dimethylformamide.
[000237] Compounds of formula (I) in which R1 represents hydrogen can also be converted into a compound of formula (I) in which R1 represents -CH2-CHOH-CH2
, by the reaction with
in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, N, N-dimethylformamide, where
- represents a ring that contains adequate nitrogen within the definition of R6.
[000238] The compounds of formula (I) in which R represents alkyl substituted with R6 in which said R6 is substituted with -C (= O) -O-alkyl C] .6 or -S (= O) 2-NRI4R '21 or where R3 represents alkyl substituted with R9 where said R9 is substituted with -C (= O) -O-alkyl C] .6 or —S (= O) 2-NRl4Rb, can be converted into a compound of formula (I) in which Ró or R9 is unsubstituted, by reaction with a suitable acid, such as, for example, HCl 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 Cμg alkyl substituted with R6 in which said R6 is a ring moiety comprising a nitrogen atom which is substituted with -CH2-OH or in which R 'represents Cf.6 alkyl substituted 9 9 with R in which said R is a ring portion comprising a nitrogen atom which is substituted with -CH2-OH, can be converted into a compound of formula (I) in which R6 or R9 is unsubstituted , by reaction with sodium hydroxide, in the presence of a suitable solvent, such as, for example, tetrahydrofuran.
[000239] The compounds of formula (I) in which R1 represents R6-substituted Cμ6 alkyl or R3 represents R9-substituted Cμ6 alkyl, in which said R6 or said R9 is unsubstituted, can be converted into a compound of the formula ( I) in which said R6 or said R9 are substituted with Cμ6 alkyl, by the reaction with W-Cμ6 alkyl in which 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.
[000240] The compounds of formula (I) in which R1 or R 'represent hydroxy Cμg alkyl, 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, example, dichloromethane.
[000241] The compounds of formula (I) in which R1 represents Cμ6 alkyl substituted with R or R represents Cμ6 alkyl substituted with R, in which said R6 or said R9 are substituted with Cμ6-halo alkyl, can be converted into a compound of formula (I) in which said R6 or said R9 are replaced with Cμ6-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 .
[000242] The compounds of formula (I) in which R1 represents C6 alkyl substituted with R6 in which said R6 is unsubstituted or in which R3 represents C9 alkyl substituted by R9 in which said R9 is unsubstituted, can be converted into a compound of formula (I) in which R6 or R9 is replaced with -CH3 or -CH (CH3) 2, by reaction with formaldehyde or acetone and NaBH3CN, in the presence of a suitable solvent, such as, for example, tetrahydrofuran or an alcohol, for example, methanol.
[000243] Compounds of formula (I) in which R1 contains an OH-substituted R6 substituent or in which RJ contains an OH-substituted R9 substituent can be converted into a compound of the formula (I) in which the R6 or R9 substituents are replaced with C1-6 alkyloxy by reaction with W-C1-6 alkyl in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, N, N-dimethyl 1 formamide.
[000244] Compounds of formula (I) in which R1 contains a Cμ6 alkyloxy substituted R substituent, or in which R contains a C1 alkyloxy substituted R9 substituent, can be converted to a compound of formula (I) in which R6 or R9 are replaced with -OH by reaction with a suitable acid, such as, for example, hydrochloric acid.
[000245] Compounds of formula (I) in which R1 contains a halo-substituted R substituent or in which R contains a halo-substituted R substituent can be converted to a compound of formula (I) in which the R6 or R9 substituents are replaced with -NR! 4R,:> by reaction with NHR14R13 in a suitable solvent, such as, for example, 1-methylpyrrolidinone. The ,
[000246] Compounds of formula (I) in which R represents C 1 alkyl substituted with -C (= O) -O-Cμg alkyl, can be converted into a compound of formula (I) in which RJ represents C | -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) in which R3 represents Cμs alkyl substituted with COOH, can be converted into a compound of formula (I) in which R represents C-6 alkyl substituted with -C (= O) -NH2 or -C (= O) -NHCH3 or -C (= O) NR10R11, by reaction with NH (Si (CH3) 3) 2 or MeNH3 + Cf or NHR10Rn in the presence of suitable peptide binding reagents such as for example l- (3 - dimethylaminopropyl) -3-ethylcarbodiimide HCl and 1-hydroxy benzotriazole, a suitable base, such as, for example, triethylamine and a suitable solvent such as, for example, dichloromethane or N, N-dimethylformamide. The compounds of formula (I) in which R3 represents Cμ6 alkyl substituted with - C (= O) -O-C C alkyl, can also be converted into a compound of formula (I) in which R3 represents Cμ6 alkyl substituted with 4,5-di -hydro- imidazol-2-yl, 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 RJ represents Cμ6 alkyl substituted with 4,5-dihydro-imidazol-2-yl, can be converted into a compound of formula (I) in which R3 represents Cμg alkyl substituted with -C ( = O) -NH- (CH2) 2-NH2 by reaction with sodium hydroxide. The compounds of formula (I) in which R3 represents COOH-substituted Cμ6 alkyl, can also be converted into a compound of formula (I) in which R represents -C (= O) -N (CH3) -C (alkyl) CH3) (OCH3 ) by reaction with dimethylhydroxylamine, in the presence of carbonyldiimidazole and a suitable solvent, such as, for example, dichloromethane.
[000247] The compounds of formula (I) in which R3 represents Cμ6 alkyl substituted with
, can be converted into a compound of the formula (I) in which R 'represents Cμ6 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 R represents Cμ6 alkyl substituted with
, can also be converted into a compound of the formula (I) in which R represents Cμ6 alkyl substituted with OH and NR10R ", by reaction with NH2RIOR" optionally in the form of salt, such as, for example, NHR10Rll + Cr, optionally in the presence of a suitable base, such as, for example, sodium hydride or Na2CO3 or triethylamine, a suitable additive such as, for example, Kl, and in the presence of a suitable solvent, such as, for example, N, N-dimethylfomiamide or a alcohol, for example, 1-butanol or ethanol.
[000248] The compounds of formula (I) in which R represents C] alkyl .3 substituted with -C (= O) -O-C alkyl, can be converted to a compound of formula (I) in which R 'represents alkyl C1.3 replaced 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.
[000249] The compounds of formula (I) in which R ~ represents Cμ5 alkyl substituted with -C (= O) -O-C alkyl, can be converted into a compound of formula (I) in which RJ represents Cμ6 alkyl substituted with - OH, by reaction with LiAlH4 in a suitable solvent, such as, for example, tetrahydrofuran.
[000250] The compounds of formula (I) in which R 'represents C1.5 alkyl substituted with -OH, can be converted into a compound of formula (I) in which R represents Cμ5 alkyl substituted with -OC (= O) -alkyl Cμ6 by reaction with Cl-C (= O) -Cμ6 alkyl in the presence of a suitable base, such as, for example, NaH, and a suitable solvent, such as, for example, tetrahydrofuran.
[000251] The compounds of formula (I) in which R represents -CH2- CH = CH2, can be converted into a compound of formula (I) in which R3 represents -CH2-CHOH-CH2-OH, by reaction with permanganate of potassium, and a suitable solvent, such as, for example, acetone or water.
[000252] The compounds of formula (I) in which R1 represents Cμ alkyl substituted with -C (= O) -Cμ4 alkyl, can be converted into a compound of formula (I) in which R represents Cμ $ alkyl substituted with -C (Cb4 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.
[000253] The compounds of formula (I) where R3 represents Cμ6 alkyl substituted with NH2, can be converted to a compound of formula (I) in which R represents alkyl substituted with -NH-C (=: O) -R or with - NH-C (= O) -C1-6 alkyl or with -NH-C (= O) -polyhydroxy C1-6 alkyl or with - NH-C (=: O) -polyhaloalkyl C [.6 or with -NH- C (= O) -C1-6 polyhaloalkyl polyhydroxy, by reaction with the corresponding COOH analog, for example, R6-COOH or CF3-C (CH3) (OH) -COOH and the like, in the presence of suitable peptide binding reagents such 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 R 'represents Cμg alkyl substituted with NH2, can also be converted into a compound of formula (I) in which R represents C] .6 alkyl substituted with NH-C (= 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, tetrahydrofuran. Said compounds of formula (I) in which R3 represents C1-6 alkyl substituted with NH2, can also be converted into a compound of formula (I) in which R3 represents C6 alkyl substituted with -NH- polyhaloalkyl C6 .6, for example , -NH-CH2-CH2-F, by reaction with polyhaloalkyl Cμ6-W, 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. Said compounds of the formula (I) in which R 'represents Cμ6 alkyl substituted with NH2 can also be converted to a compound of the formula (I) in which R represents C1-6 alkyl substituted with -NH-R6 or -N (R6) 2 wherein R6 represents, for example, oxetane, by reaction with the appropriate R6 in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride, a suitable acid, such as, for example, acetic acid, and a suitable solvent , such as, for example, 1,2-dichloroethane.
[000254] The compounds of the formula (I) in which R represents Cμe alkyl substituted with cyano, can be converted into a compound of the formula (I) in which R represents C] alkyl .6 substituted with tetrazolyl by reaction with sodium azide, and NH4 + C1 'in the presence of a suitable solvent, such as, for example, N, N-dimethylformamide.
[000255] The compounds of formula (I) in which R3 represents -CH2- C = CH, can be converted into a compound of formula (I) in which R'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.
[000256] Compounds of formula (I) in which R 'represents -CH2- C = CH, can be converted into a compound of formula (I) in which R 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.
[000257] The compounds of the formula (I) in which RJ represent C2-6 alkynyl, can be converted into a compound of the formula (I) in which R1 represents C2-Ó alkynyl substituted with R9, by reaction with W-R9 in which W is as defined above, in the presence of a suitable catalyst, such as, for example, dichlorobis (triphenylphosphmo) 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.
[000258] The compounds of formula (I) in which R comprises halo-substituted R9, can be converted to a compound of formula (I) in which R comprises -NR substituted R by reaction with 14 IS NHR R in the presence of a suitable solvent, such as, for example, 1-methyl-2-pyrrolidinone.
[000259] The compounds of formula (I) in which R comprises C2-6 alkynyl can be hydrogenated to a compound of formula (I) in which R comprises C2-6 alkyl in the presence of a suitable catalyst, such as, for example, palladium on charcoal, and a suitable solvent, such as, for example, ethyl acetate.
[000260] The compounds of formula (I) in which R comprises alkynyl and C2-6 can be hydrogenated to a compound of formula (I) in which R comprises C2-6 alkenyl in the presence of a suitable catalyst, such as, for example, Lindlar catalyst, and a suitable solvent, such as, for example, ethyl acetate.
[000261] The compounds of formula (I) in which R3 represents Cμ6 alkyl substituted with -P (= O) (Oalkyl C [.6) 2 can be converted to a compound of formula (I) in which R represents Cj alkyl. 6 replaced with - P (= O) (OH) 2 by reaction with bromotrimethylsilane in the presence of a suitable solvent, such as, for example, dichloromethane.
[000262] The compounds of formula (I) in which the substituent R is replaced with = 0, can be converted to the corresponding reduced R9 substituent by reaction with a suitable reducing agent, such as, for example, LiAlH * in a suitable solvent , such as, for example, tetrahydrofuran.
[000263] The compounds of formula (I) in which R3 represents C | _6 alkyl substituted with -C (= O) -R9 can be converted into a compound of formula (I) in which RJ represents Cμ6 alkyl substituted with hydroxyl and R by reaction with a suitable reducing agent, such as, for example, sodium borohydride, in the presence of a suitable solvent, such as, for example, an alcohol, for example, methanol.
[000264] The compounds of the formula (I) in which R comprises -NHR can be converted into a compound of the formula (I) in which RJ 10 • • • comprises -NR - (C = O) -C1-6 alkyl optionally substituted by reaction with the corresponding optionally substituted W- (C = O) -C1-6 alkyl where W represents a suitable starting group, such as, for example, halo, for example, chlorine and the like, in the presence of a suitable base , such as, for example, triethylamine, and a suitable solvent, such as, for example, acetonitrile. The
[000265] The compounds of formula (I) in which R represents NR.6 substituted C1-6 alkyl (benzyl) can be converted to a compound of formula (I) in which R represents NHR substituted C1-6 alkyl by reaction with 1-chloroethylchloroformate in the presence of a suitable solvent, such as, for example, dichloromethane.
[000266] The compounds of formula (I) in which R1 represents unsubstituted piperidine, can be converted into a compound of formula (I) in which R1 represents 1-methyl-piperidine, by reaction with iodomethane in the presence of a suitable base, such as, for example, potassium carbonate, and a suitable solvent, such as, for example, acetonitrile.
[000267] The compounds of formula (I) in which R1 represents hydrogen can be converted into a compound of formula (I) in which R! represents optionally substituted C | _6 alkyl by reaction with optionally substituted C | 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, potassium carbonate, and a suitable solvent, such as, for example, acetonitrile.
[000268] The compounds of the formula (I) in which R2 represents halo, for example, bromine, can be converted into a compound of the formula (I) in which R "represents cyan, by reaction with zinc cyanide, in the presence of a suitable catalyst, such as, for example, Pd2 (dba) 3 and a suitable ligand, such as, for example, 1,1-bis (diphenylphosphmo) ferrocene, in the presence of a suitable solvent, such as, for example, N, N-dimethylformamide.
[000269] Said substituent R "being cyan can be converted to - CH2-NH2 by hydrogenation in the presence of NH3 and Nickel.
[000270] The compounds of formula (I) in which R2 represents -OCH3 can be converted into a compound of formula (I) in which R ~ represents -OH by reaction with boron tribromide in the presence of a suitable solvent, such as, for example, dichloromethane.
[000271] The compounds of the formula (I) in which R2 represents -OH can be converted into a compound of the formula (I) in which R represents -OCH3 by reaction with methyl iodide in the presence of a suitable base, such as, for example, example, potassium carbonate, and a suitable solvent, such as, for example, N, N-dimethylformamide.
[000272] The compounds of formula (I) in which R "represents hydrogen, can be converted into a compound of formula (I) in which R2 represents -CHOH-CF3 by reaction with methyl hemicetal trifluoroacetaldehyde.
[000273] For conversion reactions, reference is also made to the examples described in the Experimental Part that will follow.
[000274] Another aspect of the invention is a process for the preparation of a compound of formula (I) as defined herein, a process which comprises: (i) deprotecting a compound of formula (XXX) in which P represents a protecting group suitable, such as, for example, a butyloxycarbonyl group (-CO2C (CH3) 3) in the presence of a suitable acid, such as, for example, HCl or trifluoroacetic acid;
(ii) the reaction of a compound of the formula (IX) or (IX '):
(IX): Rué -O- (S = O), - CH3 (IX '): Rué Cl or a protected form thereof, with an appropriately substituted amine or reactive derivative thereof, such as, for example, NHRR11 ( X), NHR10P (Xa) or ll— (XXI), for example in a sealed vessel, in the presence of a suitable base, such as, for example, sodium hydride and / or in the presence or absence of a solvent such as acetonitrile , N, N-dimethylformamide or N, N-dimethylacetamide; or (i-ii) the reaction of a compound of formula (VI):

[000275] or a protected form thereof, with a compound of the formula W6-alkyl CI.6-NR10P where P represents a suitable protecting group and W6 represents a suitable starting group, such as, for example, halo, for example bromine and the like, or -OS (= O) 2-CH3, in the presence of a suitable base, such as, for example, sodium hydride or potassium hydroxide, and optionally in the presence of a phase transfer agent suitable, such as, for example, tetrabutylammonium bromide, and a suitable solvent, for example, N, N-dimethylformamide, N, N-dimethylacetamide, 2-methyltetrahydro furan, water, followed by the removal of P and optionally removal of any other protection group present; or (iv) the reaction of a compound of the formula (VI):

[000276] or a protected one thereof, with a compound of the formula W6-C-NHR10 alkyl wherein W6 represents a suitable starting group, such as, for example, halo, for example, bromine and the like, or -O- S (= O) 2-CH3, in the presence of a suitable base, such as, for example, sodium hydride or potassium hydroxide, and, optionally, a suitable phase transfer agent, such as, for example, bromide tetrabutylammonium, and a suitable solvent, for example, N, N-dimethylformamide, N, N-dimethylacetamide or 2-methyltetrahydrofuran, water; (v) the reaction of a compound of the formula (XXXVI)
with hydrazine in the presence of a suitable solvent, such as, for example, an alcohol, for example, ethanol; (vi) the reaction of a compound of the formula (IX-1) in which Ru represents -OS (~ O) 2-CH3,
with an intermediate of formula (X) in the presence of a suitable solvent, such as, for example, acetonitrile; (vi-i) the reaction of a compound of the formula (VI)
with an intermediate of the formula WirRJ where RJ represents optionally substituted C2-6 alkynyl and Wn represents a suitable starting group such as, for example, halo, for example chlorine, or -OS (O-CHβ, in the presence of a base suitable, such as, for example, NaH, and a suitable solvent, such as, for example, N, N-dimethylformamide; (vi-ii) the reaction of a compound of the formula (VI-II ') in which Rx and Ry represent CM alkyl, and Rz represents CM alkyl or phenyl,
with a suitable acid, such as, for example, trifluoroacetic acid, in the presence of a suitable solvent, such as, for example, tetrahydrofuran; (ix) unprotecting a compound of the formula (XXXXI-I)
in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, an alcohol, for example, methanol and the like; (x) the reaction of a compound of the formula (VI)
with di (C] .6 alkyl) vinyl phosphonate in the presence of a suitable catalyst, such as, for example, tri-N-butylphosphine, and a suitable solvent, such as, for example, acetonitrile; (xi) deprotecting a compound of the formula (XXXXI) in which the D'N portion represents a D portion in which the D portion contains a nitrogen atom
in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, an alcohol, for example, methanol and the like; (xi-i) the reaction of a compound of the formula (XXXI)

[000277] with W8-CN, where W8 represents a suitable starting group, such as, for example, halo, for example, bromine, in the presence of a suitable base, such as, for example, NaHCCh, and a suitable solvent , such as, for example, water or dioxane;
[000278] (xi-ii) the reaction of a compound of the formula (XXXV)
with a suitable base, such as, for example, A / JV-diisopropylethylamine and triethylamine, in the presence of a suitable solvent, such as, for example, an alcohol, for example, methanol; (xiv) deprotecting a compound of the formula (XXVI) where P represents a suitable protecting group such as, for example, - Si (CH3) 2 (C (CH3) 3) or,
where Y'N represents an -ED portion where the D-ring portion contains a nitrogen atom
in the presence of a suitable acid, such as, for example, HCl or trifluoroacetic acid, or a suitable desilylation agent, such as, for example, tetrabutyl ammonium fluoride, and a suitable solvent, such as an alcohol, for example, methanol , or tetrahydrofuran;
[000279] (xv) the reaction of a compound of the formula (XXIX) in which Y'N represents an -ED portion in which the portion of the D ring contains a nitrogen atom, with a compound of the formula (XXI)
in the presence of suitable peptide binding reagents such as, 1-hydroxy-benzotriazole and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide HCl; (xvi) the reaction of a compound of the formula (XXIX) in which Y'N represents an -ED portion in which the D-ring portion contains a nitrogen atom
with NHR4R5 in the presence of suitable peptide binding reagents such as 1-hydroxy-benzotriazole and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide HCl and a suitable base, such as triethylamine, and a suitable solvent, such as , for example, dichloromethane; (xvi-i) react the compound below
with NHR7R8 in the presence of a suitable base, such as, for example, K2CO3, and a suitable solvent, such as, for example, tetrahydrofuran; (xvi-ii) unprotect the compound below
in the presence of hydrazine monohydrate, and a suitable solvent, such as, for example, an alcohol, for example, ethanol; wherein the variables are as defined herein; and optionally thereafter converting a compound of formula (I) into another compound of formula (I).
[000280] Another embodiment is a process for the synthesis of a compound of the formula (VI) in which:
a compound of formula (IV) is reacted with an intermediate of formula (V) in the presence of a suitable catalyst, such as, for example, palladium (II) acetate, a suitable base, such as sodium tert-butoxide or Cs2CO3 , a suitable ligand, such as, for example, 1,1 '- [1,1 binaphthalene] -2,2 "-di-ylbis [I, 1-diphenylphosphine], and a suitable solvent or mixture of solvents, such as for example dioxane or dimethyl ethylene glycol and water.
[000281] Alternatively a compound of formula (IV) is reacted with an intermediate of formula (V) in the presence of a suitable solvent such as, for example, an alcohol, for example, isopropanol, and optionally in the presence of a suitable acid such such as hydrochloric acid.
[000282] Alternatively a compound of formula (IV) is reacted with an intermediate of formula (V) in the presence of a suitable deprotonating agent such as, for example, potassium bis (trimethylsilyl) amide, in the presence of a suitable solvent such such as, for example, tetrahydrofuran.
[000283] In another embodiment the invention provides a new intermediate. In one embodiment, the invention provides a new intermediate as described herein. In another embodiment, the invention provides a new intermediate of formula (VI) or formula (IX).
[000284] In one embodiment, the present invention also relates to a compound having the following formula:
where E 'represents - (CR R ") n-, C2.4 alkenodiyl optionally substituted with R", C2-4 alkynodiyl optionally substituted with R22, -CO- (CR22R23) s-> - (CR22R23) S-CO- , -NR22- (CR22R23) S-, - (CR22R23) S-NR22-, -O- (CR22R23) S-> - (CR22R23) SO-, -S (O) m- (CR22R23) s-, - ( CR22R23) sS (O) m-, - (CR22R23) S-CO-NR22- (CR22R23) S- or - (CR22R23) S-NR22- CO- (CR22R23) S-; wherein Y, D, R, X, X, X and n are as defined for a compound of the formula (IA) above. Pharmaceutically Acceptable Salts, Solvates or Derivatives
[000285] 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 examples of the same as here defined.
[000286] Unless otherwise specified, a reference to a particular compound also includes ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the ionic forms, or salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the ionic forms, or salts or tautomers or solvates or protected forms thereof, even more preferably the salts or tautomers or solvates thereof. 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 protected forms thereof.
[000287] According to one aspect of the invention, a compound as defined herein or a salt, tautomer, N-oxide or solvate thereof is provided. According to another aspect of the invention, a compound as defined herein or a salt or solvate thereof is provided. References to the compounds of the formula (I) and subgroups thereof as defined herein include within their scope the salts or solvates or tautomers or N-oxides of the compounds.
[000288] 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.
[000289] The salts of the present invention can be synthesized from the precursor compound containing 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 base or appropriate acids in water or 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 disalts depending on the pKa of the acid from which the salt is formed.
[000290] 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, (+) - (! S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclical, dodecylsulfuric, ethane-l, 2 -disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactarian, gentisic, glycoheptonic, D-glyconic, glycuronic (eg, D-glucuronic), glutamic (eg, L-glutamic), glycolic, hypuric, a-oxoglutaric hydrobromic, hydrochloric, hydroiodic, isethionic, lactic (for example, (+) - 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, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, pyruvic, salicylic, 4-amino-salicylic, sebaceous, stearic, succinic, sulfuric, tannic, (+) - Thiocyanic L-tartaric, toluenesulfonic (by example, p-toluenesulfonic), undecylenic and valeric, as well as acylated amino acids and cation exchange resins.
[000291] A particular group of salts consists of salts formed from acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (meshanesulfonic) (methanesulfonic). , ethanesulfonic, 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.
[000292] 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 Alj +. Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4) and substituted ammonium ions (for example, NH3R +, NH2R2 +, NHR3 +, NR /).
[000293] 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 amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N (CH3) 4+.
[000294] 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
[000295] various 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.
[000296] 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.
[000297] 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 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.
[000298] 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.

[000299] Where the compounds of the formula (I) contain one or more chiral centers and may exist in the form of two or more optical isomers, references to compounds of the 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 forming 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.
[000300] The invention includes all isomeric forms of the compounds of the invention, pure isomeric forms or as a mixture of two or more isomeric forms.
[000301] Where the compounds of the formula (I) exist as two or more optical isomeric forms, an enantiomer in a pair of enantiomers may 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).
[000302] When a specific isomeric form is identified (for example, S configuration, or E isomer), this means that said isomeric form is substantially free of the other isomer (s), i.e., said isomeric form is present in at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more (for example, substantially all) of the total amount of the compound of the invention.
[000303] 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 'H, 2H (D) and (T). Similarly, references to carbon and oxygen include within their scope respectively 12O, 1JC 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.
[000304] Esters such as carboxylic acid esters and acyloxy esters of the compounds of the formula (I) which carry a carboxylic acid group or a hydroxyl group are also covered by the 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 - C (-O) OR group, where R is a substituent ester, for example, a Cj.6 alkyl group, a heterocyclyl group, or a C5.2o 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 C3.2o heterocyclyl group, θu 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 ) Ph and -OC (= O) CH2Ph.
[000305] 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.
[000306] Such esters can be formed by esterification, for example, of any of the carboxylic acid groups (-C (= O) OH) in the parent compound, with, where appropriate, prior to protection of any of the other reactive groups present in the precursor compound, followed by deprotection if required.
[000307] Examples of such metabolically unstable esters include those of the formula -C (= O) OR where R is: Cμ6 alkyl (for example, -Me, - Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); Cr6 aminoalkyl [e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) -ethyl); and C1-7 acyloxy-alkyl [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)
[000308] 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
[000309] 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)).
[000310] 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).
[000311] 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. Overexpression and activation of FGFR1 in the tumor-associated vasculature has suggested a role for these molecules in tumor angiogenesis.
[000312] A recent study has shown a link between FGFR1 expression and tumorigenicity in Classical 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-pll.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.
[000313] The fibroblast growth factor 2 receptor has 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 FGFR2 mutations include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2.
[000314] 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 a new gene mutation in the fibroblast growth factor 2 receptor and it has recently been shown that mutations in the fibroblast growth factor 2 receptor disrupt one of the cardinal rules that control ligand specificity. 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.
[000315] 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.
[000316] 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 frequently activated by the 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 included many invasive muscle tumors. FGFR3 is also linked to endometrial and thyroid cancer.
[000317] FGFR4 overexpression has been linked to 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 FGF19 ligand is often elevated. FGFR4 is also linked to astrocytomas, rhabdomyosarcoma.
[000318] 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.
[000319] Several preclinical studies have demonstrated the overloading 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 antifibrotic 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.
[000320] 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-activating mutants or receptor tyrosine kinase overload 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)
[000321] 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 the destruction of tissue through the invasive proliferation of blood vessels.
[000322] 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 was linked to angiogenesis. Tumor growth and metastasis has been found to be dependent on angiogenesis.
[000323] 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.
[000324] There are publications that describe that angiogenesis inhibitors, which work by different mechanisms, are beneficial in diseases such as cancer and metastasis, eye diseases, arthritis and hemangioma.
[000325] Vascular endothelial growth factor (VEGF), a polypeptide, is mitogenic for endothelial cells in vitroe stimulates angiogenic responses in vivo. VEGF has also been linked to inadequate angiogenesis. 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.
[000326] 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 overloaded 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.
[000327] Inhibition at the binding site of the VEGFR-2 kinase domain would block the tyrosine residue phosphorylation and serve to disrupt the onset of angiogenesis.
[000328] 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.
[000329] 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 antiangiogenic 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.
[000330] 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.
[000331] There is evidence regarding the 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 combination with circulating biomarkers provides an effective means of assessing the response to antiangiogenic agents. PDGFR
[000332] 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 platelet-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 which include growth, - proliferation and differentiation. Advantages of a selective inhibitor
[000333] 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
[000334] 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 activity platelet-derived growth factor receptor (PDGFR) inhibitor or modulator and which will be useful in the prevention or treatment of 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.
[000335] 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 the elevated / suppressed or overexpression or underexpression of a kinase, which includes gene amplification (i.e., multiple gene copies) and / or expression increased or decreased by a transcriptional effect, as well 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.
[000336] 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 restrictively 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, states or kinase-mediated 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.
[000337] Thus, for example, the compounds of the invention may be useful in alleviating or reducing the incidence of cancer.
[000338] 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.
[000339] 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 µM.
[000340] The compounds of the invention also have activity against VEGFR.
[000341] Furthermore many of the compounds of the invention exhibit selectivity for FGFR 1, 2, and / or 3, and / or 4 compared to 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.
[000342] 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 apoptosis of neoplasms, 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.
[000343] In particular tumors with VEGFR-activating mutants or VEGFR-supra-stamping and patients with elevated 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 activation or overloading mutants or overexpression 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.
[000344] 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 adenoma of the colon) colon), 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 ( for example, exocrine pancreatic carcinoma), stomach, gastrointestinal cancer (also known as gastric cancer) (eg, gastrointestinal stromal tumors), cervix, endometrium, thyroid, prostate, or skin (eg, 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's 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.
[000345] 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.
[000346] 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.
[000347] In addition, the compounds of the invention can be used for gastrointestinal cancer (also known as gastric) for example, stromal gastrointestinal tumors. Gastrointestinal cancer refers to the malignant conditions of the gastrointestinal tract, which include the esophagus, stomach, liver, biliary system, pancreas, intestines and anus.
[000348] Thus, in the pharmaceutical compositions, uses or methods of this invention for the treatment of a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is a cancer.
[000349] Private subsets of cancers include multiple myeloma, bladder, cervical, prostate and thyroid carcinomas, lung, breast and colonic cancers.
[000350] Another subset of cancers includes multiple, bladder, hepatocellular myeloma, oral squamous cell carcinoma and cervical carcinomas.
[000351] 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).
[000352] 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.
[000353] 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 oral squamous cell carcinoma.
[000354] Other subsets of cancer are multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer and thyroid carcinomas.
[000355] In particular the compounds of the invention are useful in the treatment of multiple myeloma (in particular multiple myeloma with t (4; 14) translocation or FGFR3 overexpression), prostate cancer (hormone-refractory prostate carcinomas), endometrial cancer ( in particular endometrial tumors with activating mutations in FGFR2) and breast cancer (in particular lobular breast cancer).
[000356] In particular the compounds are useful in the treatment of lobular carcinomas such as CLC (classic lobular carcinoma).
[000357] Since the compounds have activity against FGFR3 they will be useful in the treatment of multiple myeloma and bladder cancer.
[000358] In particular the compounds are useful for the treatment of positive multiple myeloma in t (4; 14) translocation.
[000359] 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.
[000360] 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.
[000361] 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.
[000362] 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).
[000363] 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, therefore the compounds of the invention may be useful in the treatment of VEGFR2 resistant thyroid and renal cell carcinomas.
[000364] 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.
[000365] 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 “Methods of Diagnosis".
[000366] The compounds of the invention and in particular those compounds having FGFR inhibitory activity, or VEGFR, may 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 example the cancers alluded to in this context in the introductory section of this application.
[000367] 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.
[000368] It has been discovered 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.
[000369] The compounds of the invention may be useful in the treatment of other conditions that result from disorders in proliferation such as diabetes mellitus type II or non-insulin dependent, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as that of Alzheimer's, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease for example autoimmune diseases and neurodegenerative diseases.
[000370] 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.
[000371] FGFR and VEGFR are also known to play a role in apoptosis, angiogenesis, proliferation, differentiation and transcription and therefore the compounds of the invention can 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.
[000372] Furthermore, 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), syndrome Apert (AP) syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyratee syndrome, Pfeiffer syndrome.
[000373] 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).
[000374] The compound of the invention, having FGFR inhibitory activity such as FGFR1, FGFR2 or FGFR3, can be particularly useful in the treatment or prevention in 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.
[000375] 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.
[000376] The activity of the compounds of the invention as inhibitors of FGFR 1-4, 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 IC50 values. Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 μM, more preferably less than 0.1 μM.
[000377] The invention provides compounds that have FGFR inhibitory or modulating activity and which may be useful in preventing or treating disease states or conditions mediated by FGFR kinases.
[000378] 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.
[000379] 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.
[000380] Consequently, the invention provides inter alia: - A method for the prophylaxis or treatment 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 the formula (I ) as defined here. - 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 (for example 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 the formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition characterized by the overloading of a FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4) . - The use of a compound of the formula (I) as defined herein for the manufacture of a medicine for the prophylaxis or treatment of a cancer, the cancer being one that is characterized by the overfilling of a FGFR kinase (eg 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 over-labeling of a 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 alleviating or reducing the incidence of a disease or condition characterized by the over-stamping of a 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 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 (i-i) 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 overloading of a FGFR kinase (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4); a method which comprises (i) subjecting a patient to a diagnostic test to detect a characteristic marker of FGFR kinase overloading (for example, FGFR1 or FGFR2 or FGFR3 or FGFR4) and (ii) where the diagnostic test is indicative of overloading a FGFR kinase, thereafter administering to the patient a compound of formula (I) as defined herein having FGFR kinase inhibitory activity.
[000381] 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 described 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 gyrato syndrome, Pfeiffer syndrome, achondroplasia and Thanatophoric dwarfism (also known as thanatophoric dysplasia). Mutated Kinases
[000382] 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.
[000383] A study on samples from a patient with gastric cancer showed the presence of two mutations in FGFR2, Serl67Pro in exon I-Ila 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.
[000384] 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.
[000385] 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.
[000386] It has been suggested that mutations of a threonine residue conserved at the FGPR ATP binding site 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
[000387] 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.
[000388] 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 which leads to the overloading of FGFR levels or activity, and / or VEGFR or the sensitization of a path to normal FGFR activity, and / or VEGFR or to the overloading of these growth factor signaling pathways such as ligand levels of the growth factor or growth factor ligand activity or for the overloading of a biochemical pathway downstream of FGFR, and / or activation of VEGFR.
[000389] Examples of such abnormalities that result in activation or sensitization of the FGFR signal, and / or VEGFR include the loss of, or inhibition of apoptotic pathways, receptor or ligand overloading, or the presence of mutant variants of receptors or ligands by example, PTK variants. Tumors with mutants of FGFR1, FGFR2 or FGFR3 or FGFR4 or overloading, in particular overexpression of FGFR1, or FGFR2 or FGFR3 function gain mutants may be particularly sensitive to FGFR inhibitors.
[000390] For example, point mutations that engender function gain in FGFR2 have been identified under various conditions. In particular activating mutations in FGFR2 have been identified in 10% of endometrial tumors.
[000391] 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, carcinomas of the bladder and cervical. 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.
[000392] 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.
[000393] The term overload includes high expression or overexpression, which includes gene amplification (ie, multiple gene copies) 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 overloading 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.
[000394] 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.
[000395] The methods of identifying and analyzing mutations and protein overloading 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).
[000396] The identification of an individual who 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.
[000397] Furthermore, mutant forms, for example of FGFR or VEGFR2, can be identified by direct sequencing of, 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.
[000398] In RT-PCR triage, 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).
[000399] 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.
[000400] 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 strand 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.
[000401] Alternatively, protein products expressed from mRNAs can be assayed by tumor sample immunohistochemistry, solid phase immunoassay with microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, cytometry flow 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 overloading, or detection of FGFR variants and mutants, and / or VEGFR could be applicable in the present case.
[000402] 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.
[000403] Alternative methods for measuring the overexpression or activation of FGFR or VEGFR that include their isoforms, include measuring the microweaker 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 CD 105.
[000404] Therefore, all of these techniques can also be used to identify tumors particularly suitable for treatment with the compounds of the invention.
[000405] The compounds of the invention are particularly useful in the treatment of 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.
[000406] 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 at risk of suffering from, a disease or condition that would be susceptible to treatment with a compound having activity against FGFR.
[000407] The particular mutations of a patient are screened to include G697C, R248C, S249C, G372C, S373C, Y375C, K652Q mutations in the FGFR3 and Gly388Arg polymorphism in FGFR4.
[000408] 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).
[000409] MRI determination of vessel normalization (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 (progenitor cells Circulating (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
[000410] In view of their useful pharmacological properties, the object compounds can be formulated in various dosage forms for administration purposes.
[000411] 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.
[000412] To prepare the pharmaceutical compositions of this invention, an effective amount of a compound of the present invention, as the active ingredient is combined in intimate mixture with a pharmaceutically acceptable carrier, which carrier can take a wide variety of forms depending on the form of desired preparation for 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 oral liquid 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.
[000413] 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.
[000414] 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.
[000415] The compound of the invention is administered in an amount sufficient to exert its anti-tumor activity.
[000416] 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 at appropriate intervals throughout the day. Said underdoses 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 per unit dosage form .
[000417] 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 the total weight of the composition.
[000418] 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 remedy, more specifically for use in the treatment of cancer or related diseases.
[000419] 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 I-I 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 the same, pipobrozine, estrobazone, estrob , uracil; - antitumor anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxyl, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin; - molecules that target the IGF-1 receptor, for example picropodophyllin; - tetracarcine derivatives for example tetrocarcin A; '- glucocorticoiden eg 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 selective 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 BcI-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; - famesyltransferase inhibitors for example tipifamib; - 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 such as dromone propionate, acetone propionate of megestrol, nandrolone (decanoate, fenpropionate), dexamethasone - agonists of the hormone that releases gonadotropin or antagonists for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate - thalidomide, lenalidomide - mercaptopurine, pegotamine, pegotamine, pegotamine, pegotamine, pegotamine, rasburicase - BH3 mimetics eg ABT-737 - MEK inhibitors eg PD98059, AZD6244, CI1040 - 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.
[000420] The compounds of the present invention also have therapeutic applications in cells that sensitize tumors to radiotherapy and chemotherapy.
[000421] 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".
[000422] 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 treatment of diseases that are treatable with ionizing radiation.
[000423] 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.
[000424] Several mechanisms for the mode of action of radiosensitizers have been suggested in the literature that 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.
[000425] 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 (ÍUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin and therapeutically effective analogs and derivatives thereof.
[000426] 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, nafitalocyanins, phthalocyanines, phthalocyanine zinc and therapeutically effective derivatives same.
[000427] 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.
[000428] 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.
[000429] 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 pharmaceutical forms for purposes of administration. The compounds can be formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition that contains all compounds.
[000430] 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.
[000431] 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.
[000432] 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 treatment of cancer patients.
[000433] 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 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, through its administration, on the particular tumor. that 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.
[000434] 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.
[000435] The platinum coordination compound is advantageously administered in a dosage of 1 to 500 mg per square meter (mg / m2) of body surface area, for example 50 to 400 mg / m2,
[000436] particularly for cisplatin at a dosage of about 75 mg / m and for carboplatin at about 300 mg / m "per course of treatment.
[000437] The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg / m) of body surface area, for example from 75 to 250 mg / m2, particularly parafor paclitaxel at a dosage of about 175 to 250 mg / m2 and for docetaxel at about 75 to 150 mg / m2 per course of treatment.
[000438] The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg / m ") of body surface area, for example from 1 to 300 mg / m2, particularly for irinotecan in a dosage of about 100 to 350 mg / nT and for topotecan at about 1 to 2 mg / m "per course of treatment.
[000439] The antitumor podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg / m ") of body surface area, for example 50 to 250 mg / m2, particularly for etoposide in a dosage from about 35 to 100 mg / m2 and for teniposide at about 50 to 250 mg / m2 per course of treatment.
[000440] The anti-tumor vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg / m) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg / m, for vincristine at a dosage of about 1 to 2 mg / m "and for vinorelbine at a dosage of about 10 to 30 mg / m" per course of treatment.
[000441] The antitumor nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg / m) of body surface area, for example from 700 to 1500 mg / m, particularly for 5-FU in a dosage of 200 to 500 mg / m2, for gemcitabine at a dosage of about 800 to 1200 mg / m and for capecitabine at about 1000 to 2500 mg / m2 per course of treatment.
[000442] 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 from 120 to 200 mg / m ", particularly for cyclophosphamide in a dosage of about 100 to 500 mg / m, 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 / m "and for lomustine at a dosage of about 100 to 150 mg / m per course of treatment.
[000443] 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 / m ", particularly for doxorubicin in a dosage from about 40 to 75 mg / m2, for daunorubicin in a dosage of about 25 to 45 mg / m and for idarubicin in a dosage of about 10 to 15 mg / m "per course of treatment.
[000444] 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.
[000445] Antibodies are advantageously administered at a dosage of about 1 to 5 mg per square meter (mg / m) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg / m ") of body surface area, particularly 2 to 4 mg / m2 per course of treatment.
[000446] 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.
[000447] The compounds of the formula (I), the pharmaceutically acceptable addition salts, in particular the 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.
[000448] 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, 'H 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.
[000449] 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
[000450] The following examples illustrate the present invention but are only examples and are not intended to limit the scope of the claims in any way. Experimental Part
[000451] Hereinafter, the term 'ACN' or CH3CN means acetonitrile, 'DCM' means dichloromethane, 'K2CO3' means potassium carbonate, 'Cs2CO3' means cesium carbonate, 'Na2CO3' means sodium carbonate, 'MgSOf magnesium sulfate, 'Na2SO4' means sodium sulfate, 'MeOH' or 'CH3OH' means methanol, 'EtOH' means ethanol, 'EtOAc' means ethyl acetate, 'Et3N' means triethylamine, 'TE1F' means tetrahydrofuran, 'NH4CI' means ammonium chloride, 'NaF means sodium iodide,' NaOH 'means sodium hydroxide,' NaCT means sodium chloride, 'DMF' means N, N-dimethylformamide, 'NaH' means sodium hydride, dispersion at 60% in mineral oil, 'Pd (OAc) 2' means palladium (II) acetate (47% Pd), 'PdC12 (dppf) .CH2Cl2' means l, r-Bis (diphenylphosphine) ferrocene-dichloride complex palladium (II) and dichloromethane, 'KOH' means potassium hydroxy, 'CO2' means carbon dioxide, 'Et2O' means diethyl ether, 'DMSO' itself gnifies dimethyl sulfoxide, 'HCl' means hydrochloric acid, 'SiO2' or 'SiOH' means silica, 'N2' means nitrogen, 'MP' means melting point 'rf means room temperature,' CHC13 'means chloroform,' POC13 ' means phosphorus oxychloride, 'DiPEA' means N, N-diisopropylethylamine, 'Ni' means Raney Nickel, 50% slurry in water, 'NaHCO3' means sodium hydrogen carbonate, 'TFA' means trifluoroacetic acid, ' DMAP 'means 4-dimethylamino-pyridine,' NaBHf means sodium borohydride, 'LiCl' means lithium chloride, 'Ruphos' means 2- Dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl,' pH 'means potential hydrogen,' H2 'means hydrogen,' A1C13 'means aluminum trichloride,' h 'means hour; 'Mn' means minute; 'Xantphos' means 4,5- Bis (diphenylphosphine) -9,9-dimethylxanthene, 'P.F.' means melting point; 'DSC' means differential scanning calorimetry.
[000452] Some compounds of the present invention have been obtained as salt forms or hydrates or contain some amount of solvent. Hereinafter, these compounds are reported as determined based on elementary analysis. A. Preparation of the intermediates Example Al
a) Preparation of intermediary 1
[000453] Under an argon atmosphere, meldrum acid (108 g, 752 mmol) and triethyl orthoformate (108 ml, 651 mmol) were added to a solution of 5-amino-2-methoxypyridine (62.2 g, 501 mmol ) in Ethanol (210 ml). The mixture was stirred at 80 ° C for 3 hours and then cooled to room temperature and stirred overnight. The precipitate was filtered off, washed with ethanol (2 x 200 ml) and then dried to produce 138 g (99%) of intermediate 1, which was used without further purification for the next step.
b) Preparation of intermediary 2
[000454] Intermediate 1 (13.6 g, 49.6 mmol) was added portionwise to diphenyl ether (100 ml, 630 mmol) at 220 ° C. The solution was stirred at reflux for 10 minutes and then cooled to room temperature. The combined precipitated solid was filtered off and washed with diethyl ether (2 x 500 ml) to give 45.6 g of a light brown solid. The solid was triturated in diethyl ether (2 x 500 ml), filtered off and dried in vacuo to give 44g (50%) of intermediate 2, which was used without further purification for the next step.
c) Preparation of the intermediary 3
[000455] A-bromosuccinimide (57.8 g, 325 mmol) was added to a solution of intermediate 2 (44 g, 250 mmol) in acetic acid (800 ml) at room temperature. The mixture was stirred for 2 hours, separated by filtration and washed successively with acetic acid (100 ml) and diethyl ether (2 x 500 ml), then dried to give 58.2 g (91%, beige solid) of intermediate 3 , which was used without further purification for the next step.
d) Preparation of intermediate 4 N
[000456] Phosphoryl chloride (213 ml, 2282 mmol) was added to a mixture of intermediate 3 (58.2 g, 228 mmol) in chloroform (213 ml). The solution was refluxed for 3 hours, concentrated to dryness and dried under vacuum. The residual solid was carefully basified with an aqueous 1 M sodium hydroxide solution (300 ml), diluted with water (300 ml) and extracted with ethyl acetate (6 x 500 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated, yielding 54.0 g (87%) of intermediate 4 which was used without further purification for the next step.
e) Preparation of the intermediary 5
[000457] A solution of intermediate 4 (31.4 g, 115 mmol), 1-methylpyrazole-4-boronic acid pinacolic ester (25.1 g, 121 mmol), sodium carbonate (36.5 g, 344 mmol ) in a mixture of 1,4-dioxane (400 ml) and water (120 ml) was degassed and filled with argon (operation repeated 3 times). PdCl2 (dppf). CH2C12 (4.68 g, 5.74 mmol) was added and the resulting mixture was degassed and filled with argon (repeated operation twice) and stirred at 110 ° C for 16 hours. After cooling to room temperature, ethyl acetate (500 ml) and water (500 ml) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 400 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness. The residue was sonified in diethyl ether (500 ml), filtered on the glass frit, washed with diethyl ether (2 x 200 ml) and dried under vacuum, yielding 29.2 g (93%) of the intermediate 5. Analogous preparation of the intermediate 22 from the middleman 24
Analogous preparation of intermediate 27 starting from intermediate 4
Analogue preparation of intermediate 50 starting from intermediate 4
Analogous preparation of intermediate 56 from intermediate 4
Analogous preparation of intermediate 70 starting from intermediate 4

f) Preparation of the intermediary 6
[000458] A catalytic amount of Raney Nickel (50% slurry in water, 1.68 g, 28.6 mmol) was washed twice with ethanol and collected after decanting. This catalytic amount was added to a solution of intermediate 5 (26.2 g, 95.4 mmol) in a mixture of ethanol (700 ml), tetrahydrofuran (500 ml) and 1 M in NaOH (114 ml, 114 mmol ). The mixture was purged and stirred under a hydrogen atmosphere (1 bar) at 50 ° C for 16 hours. An additional amount of Raney Nickel (50% slurry in water, 1.68 g, 28.6 mmol) was added and the reaction mixture was purged and stirred under a hydrogen atmosphere (1 bar) at 50 ° C for 24 hours. The mixture was cooled to room temperature, filtered through celite, washed with tetrahydrofuran (500 ml) and concentrated. The residue was triturated in diethyl ether (500 ml), the precipitate was filtered off and washed with diethyl ether (100 ml). The product obtained was absorbed on silica gel and purified by chromatography on silica gel (mobile phase, gradient 96% DCM, 4% MeOH to 94% DCM, 6% MeOH). The product fractions were collected and the solvent was evaporated, yielding 9.05 g (39%) of intermediate 6. Analogous preparation of intermediate 21 starting from intermediate 22
Analogous preparation of intermediate 26 starting from intermediate 27
Analogous preparation of intermediate 49 starting from intermediate 50
Analogue preparation of intermediate 55 starting from intermediate 56
Analogue preparation of intermediate 69 starting from intermediate 70
Intermediate 6 was also prepared as follows:
The reaction was carried out in parallel in 3 batches (3 x 21.2 g).
[000459] A catalytic amount of Raney Nickel, 50% slurry in water (2.72 g, 46.3 mmol) was washed twice with ethanol and collected after decanting. This catalytic amount was added to a solution of intermediate 5 (21.2 g; 77.3 mmol) in a mixture of EtOH (400 ml), THF (400 ml) and 1 M NaOH (81.3 ml; 81.3 mmol). The mixture was purged and stirred under a hydrogen atmosphere (1 bar) at 50 ° C for 90 hours. The 3 reactions were combined and the resulting mixture was cooled to room temperature, filtered through a pad of celite®, washed with EtOH (1000 ml), then with THF (300 ml) and concentrated. The residue (63.9 g, brown solid) was purified several times by column chromatography on silica gel (eluent: Petroleum Ether / ethyl acetate 50/50 to 0/100). The product fractions were collected and the solvent was evaporated to give 31.2 g (56%, beige solid) of intermediate 6.
g) Preparation of the intermediary 7
[000460] Aqueous 6M HCl (94 ml, 564 mmol) was added to a solution of intermediate 6 (9.0 g, 37.6 mmol) in 1,4-dioxane (200 ml). The mixture was stirred at 80 ° C for 3 hours, cooled to room temperature and concentrated. The residue was suspended in a mixture of water, dichloromethane and methanol (300 ml; 3/2/1). The mixture was basified with a 3 N aqueous NaOH solution until pH = 9 and the resulting solution was concentrated, producing 13.7 g (161%) of intermediate 7, which was used without further purification for the next step. Analogous preparation of intermediate 20 starting from intermediate 21
Analogous preparation of intermediate 25 starting from intermediate 26
Analogue preparation of intermediate 48 from intermediate 49
Analogous preparation of intermediate 54 from intermediate 55
Analogue preparation of intermediate 68 starting from intermediate 69
Intermediate 7 was also prepared as follows:

[000461] 6M aqueous HCl (44 ml; 266 mmol) was added to a solution of intermediate 6 (4.26 g, 17.7 mmol) in dioxane (85 ml). The mixture was stirred at 80 ° C for 3 hours, cooled to room temperature and quenched with an aqueous saturated solution of potassium carbonate (300 ml). The precipitated solid was separated by filtration, washed with water (400 ml) and Et2O (200 ml) yielding fraction A (intermediate 7 hydrated). The filtrate was extracted with a 9/1 mixture of CH2Cl2 / MeOH (4 x 1 liter). Fraction A was added to the combined organic layers. The resulting mixture was evaporated. The residual solid was suspended in methanol and concentrated to produce 5.22 g of intermediate 7 which was used as such in the next step.
h) Preparation of intermediate 8 The reaction was carried out under argon.
[000462] Phosphoryl chloride (200 ml, 2146 mmol) was added to a suspension of intermediate 7 (crude 13.7 g, maximum 37.6 mmol) in chloroform (200 ml). The reaction mixture was refluxed for 16 hours, cooled to room temperature and concentrated. The residual solid was collected in a 95/5 dichloromethane / methanol mixture (300 ml), slowly basified at 0 ° C with an aqueous 3 M sodium hydroxide solution (60 ml) and diluted with water (100 ml). The aqueous layer was extracted with a 95/5 dichloromethane / methanol mixture (2 x 150 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was dissolved in a mixture of dichloromethane and methanol (400 ml; 3/1), absorbed on silica gel and purified by silica gel chromatography (mobile phase, gradient 97% DCM, 3% MeOH to 95% DCM, 5% MeOH). The product fractions were collected and the solvent was evaporated, producing 6.15 g (67%) of intermediate 8, which was used without further purification for the next step. Analogous preparation of intermediate 19 starting from intermediate 20
Analogous preparation of intermediate 24 from intermediate 25
Analogue preparation of intermediate 47 from intermediate 48
Analogous preparation of intermediate 53 starting from intermediate 54
Analogue preparation of intermediate 67 starting from intermediate 68
Intermediate 8 was also prepared as follows:

[000463] POCI3 (18.5 ml; 199 mmol) was added to a suspension of intermediate 7 (4.5 g; 19.9 mmol) in CHCl3 (19 ml). The reaction mixture was refluxed for 3 hours, cooled to room temperature and concentrated. The residual solid was collected in a 97/3 DCM / MeOH mixture (500 ml) and washed with an aqueous 1 M sodium hydroxide solution (500 ml). The aqueous layer was extracted with a 97/3 DCM / MeOH mixture (2 x 250 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 3.61 g (74%, yellow solid) of intermediate 8.
i) Preparation of the intermediary 9
[000464] 3,5-Dimethoxyaniline (1.25 g, 8.2 mmol) was added to a solution of intermediate 8 (1.0 g, 4.1 mmol) in 1-propanol (70 ml). The reaction mixture was refluxed for 16 hours. The resulting precipitate was filtered off, rinsed with 1-propanol (15 ml), diethyl ether (20 ml) and dried in vacuo, yielding 1.02 g (69%) of intermediate 9.
[000465] The filtrate was concentrated under reduced pressure to dryness. The residue was dissolved in a mixture of dichloromethane and methanol (50 ml; 4/1) and purified by silica gel chromatography (mobile phase, gradient 96% DCM, 4% MeOH to 94% DCM, 6% MeOH). The product fractions were collected and the solvent was evaporated yielding 0.456 g (31%) of intermediate 9. Analogous preparation of intermediate 18 starting from intermediate 19
Analogue preparation of intermediate 23 starting from intermediate 24
Analogue preparation of intermediate 32 from intermediate 8
Analogue preparation of intermediate 33 starting from intermediate 8
Analogue preparation of intermediate 46 starting from intermediate 47
Analogous preparation of intermediate 52 from intermediate 53
Analogous preparation of intermediate 66 starting from intermediate 67
Alternative preparation of the intermediate 9
[000466] The reaction was carried out 5 times in the same quantities in parallel.
[000467] Palladium (II) acetate (0.069 g, 0.1 mmol) was added to a mixture of intermediate 8 (0.72 g, 2.9 mmol), 3.5-dimethoxyaniline (0.9 g, 5.9 mmol), cesium carbonate (4.8 g, 14.7 mmol) and 2,2'-bis (diphenylphosphino) -1,1'-binaftyl (0.366 g, 0.59 mmol) in a mixture 50 / 50 (v / v) of NMP and 1,4-dioxane (15.0 ml). The mixture was stirred at 150 ° C for 30 minutes under microwave irradiation and was concentrated. The combined residues from 5 experiments were purified by silica gel chromatography (mobile phase, gradient from 100% DCM to 96% DCM, 4% MeOH). The product fractions were collected and the solvent was evaporated yielding 4.57 g (86%) of crude intermediate 9. A sample (0.4 g) was purified by silica gel chromatography (mobile phase, gradient from 100% DCM to 98% DCM, 2% MeOH). The desired fractions were collected and the solvent was evaporated to produce 0.187 g green solid (PF: 229 at 230 ° C) Example A2
Preparation of the intermediary 10
[000468] The reaction was carried out under anhydrous conditions under an argon atmosphere. NaH (60% in mineral oil, 0.332 g, 8.30 mmol) was added to a solution of intermediate 9 (2.0 g, 5.5 mmol) in dimethylformamide (50 ml) at 0 ° C. The mixture was stirred at 0 ° C for 40 minutes, then (2-bromoethoxy) - tert-butyl-dimethylsilane (1.78 ml, 8.3 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. Ice water (800 g) was added and the mixture was extracted with ethyl acetate (1 x 800 ml and 2 x 400 ml). The combined organic layers were washed with brine (3 x 400 ml), dried over sodium sulfate, filtered and concentrated, yielding 3.17 g (110%) of intermediate 10, which was used without further purification for the next step.
Analog preparation of intermediate 11 Analog preparation of intermediate 31 starting from intermediate 28
Example A2a
Preparation of the intermediary 51
[000469] NaH (11.2 mg; 0.279 mmol) was added to a mixture of intermediate 52 (0.050 g; 0.140 mmol) in DMF (2 ml) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes, then (2-bromoethoxy) -tert-butyldimethylsilane (6 μl; 0.279 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 72 hours. More NaH (11.2 mg; 0.279 mmol) was added at 0 ° C, the mixture was stirred at 0 ° C for 30 minutes and (2-bromoethoxy) -tert-butyldimethylsilane (6 μl; 0.279 mmol) was added. The mixture was stirred at 0 ° C for 30 minutes and 65 hours at room temperature. Ice water (5 ml) was added and the mixture was extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine (3 x 10 ml), dried over Na2SO4, filtered and concentrated. The residue (0.118g) was purified by column chromatography on silica gel (eluent: DCM / MeOH: 99/1 to 98/2). Product fractions were collected and the solvent was evaporated to give 0.04 g (56%, yellow solid) of intermediate 51. Example A3
Preparation of the intermediate 12 x
[000470] The reaction was carried out under anhydrous conditions under an argon atmosphere.
[000471] Methanesulfonyl chloride (0.04 ml, 0.51 mmol) was added dropwise to a mixture of compound 1 (0.104 g, 0.26 mmol), triethylamine (0.083 ml, 0.59 mmol) and 4 -dimethylaminopyridine (0.004 g, 0.031 mmol) in dichloromethane (2.10 ml) at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes and at room temperature overnight. Ice water (25 ml) was added and the mixture was extracted with dichloromethane (4 x 25 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The aqueous layer was concentrated to dryness, producing 0.153 g (123%) of intermediate 12, which was used without further purification for the next step. Example A4
Preparation of the intermediary 13
[000472] The reaction was carried out under anhydrous conditions under an argon atmosphere. NaH (60% in mineral oil, 0.355 g, 8.86 mmol) was added portionwise to a solution of intermediate 9 (1.60 g, 4.43 mmol) in N, N-dimethylformamide (12.7 ml) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes and 3-bromo-1-trimethylsilyl-1-propine (2.03 ml, 12.4 mmol) was added to the drops. The mixture was stirred at 0 ° C for 3 hours. Water (450 ml) was added and the mixture was extracted with ethyl acetate (4 x 200 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue (6.12 g) was purified by silica gel chromatography (mobile phase, gradient from 100% DCM to 95% DCM, 5% MeOH). The product fractions were collected and the solvent was evaporated, producing 1.60 g (77%) of intermediate 13. Example A5
a) Preparation of the intermediary 14
[000473] A 6 M solution of HCl (16.4 ml, 98.3 mmol) was added to a solution of intermediate 5 (1.8 g, 6.55 mmol) in 1,4-dioxane (30 ml) in the room temperature. The reaction mixture was heated to 80 ° C for 16 hours. The reaction mixture was basified (pH = 8) with a 3 M NaOH solution (35 ml) and extracted with a 9/1 mixture of DCM and MeOH. The organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (40 to 63 μm, mobile phase, gradient from 100% DCM to 85% DCM, 15% MeOH). The product fractions were evaporated to dryness, producing 1.17 g (68%) of intermediate 14.
b) Preparation of the intermediary 15
[000474] Phosphoryl chloride (16 ml, 172 mmol) was added to a solution of intermediate 14 (1.2 g, 4.6 mmol) in chloroform (16 ml) at room temperature. The reaction mixture was refluxed for 16 hours, cooled to room temperature and concentrated to dryness. The residue was collected in a 95/5 mixture of DCM and MeOH (30 ml), cooled to 0 ° C and carefully basified with a 3 M NaOH solution (10 ml). The mixture was diluted with water (10 ml) and extracted twice with a 95/5 mixture of DCM and MeOH. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residual solid was triturated in Et2O (50 ml), filtered, rinsed with Et2O and dried in vacuo yielding 1.15 g (89%) of the intermediate shown.
c) Preparation of the 16 OMe intermediary
[000475] 3,5-Dimethoxyaniline (587 mg, 3.83 mmol) and AV-diisopropylethylamine (1.34 ml, 7.67 mmol) were added to a suspension of 2,8-dichloro-7- (1-methyl-177-pyrazol-4-yl) -1,5-naphthyridine (1.07 g, 3.83 mmol) in 1-propanol (30 ml). The mixture was subjected to reflux for 16 hours. 3.5- Dimethoxyaniline (176 mg, 1.15 mmol) and A, / - diisopropylethylamine (1.34 ml, 7.67 mmol) were added again and the mixture was refluxed for 4 hours. 3,5-Dimethoxyaniline (176 mg, 1.15 mmol) was added, the mixture was refluxed for 16 hours and cooled to room temperature. The precipitate was filtered off, washed with EtOH and dried in vacuo. The solid was collected with a saturated aqueous solution of NaHCO3 (100 ml) and extracted with a 9/1 mixture of DCM and MeOH. The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and dried under vacuum for 16 hours yielding 840 mg (55%) of intermediate 16 which was used without further purification for the next step.
d) Preparation of the 17 OMe intermediary
[000476] Sodium hydride (60% in mineral oil, 91 mg, 2.3 mmol) was added to a solution of intermediate 16 (300 mg, 0.76 mmol) in DMF (7.5 ml) at 0 ° Ç. The mixture was stirred at 0 ° C for 45 minutes and (3-bromopropoxy) -erc-butyldimethylsilane (0.264 ml, 1.14 mmol) was added. The mixture was stirred at 0 ° C for 2 hours and at room temperature overnight. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness yielding 616 mg of intermediate 17 which was used without further purification for the next step.
[000477] Analogue preparation of intermediate 29 starting from intermediate 16
Example A6
Preparation of the intermediary 30
[000478] 1 M potassium bis (trimethylsilyl) amide in THF (6.29 ml; 6.29 mmol) was added to a solution of 2,6-difluoroaniline (0.369 ml; 3.43 mmol) in THF (8 ml ) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and intermediate 8 (0.700 g; 2.86 mmol) was added. The mixture was stirred at 0 ° C for 2 hours and at room temperature overnight. Water (200 ml) was added and the mixture was extracted with EtOAc (3 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residue (1 g, brown solid) was purified by column chromatography on silica gel (eluent: from 100% DCM to 99% DCM, 1% MeOH). The product fractions were collected and the solvent was evaporated to give 0.901 g (93%) of intermediate 30. PF: 209 ° C (DSC). Analogous preparation of intermediate 28 from intermediate 8
Analogue preparation of intermediate 36 from intermediate 8
Example A7
a) Preparation of the intermediary 35
[000479] Sodium triacetoxyborohydrite (6.82 g; 32.2 mmol) and acetic acid (0.6 ml) were added to a mixture of 3,5-dimethoxyaniline (3.08 g, 20.1 mmol) and 1 -boc-4-piperidone (4.00 g, 20.1 mmol) in dichloroethane (150 ml) at 0 ° C. The mixture was stirred at room temperature for 65 hours. Ice water (150 ml) and a saturated aqueous solution of K2CO3 (400 ml) were added and the mixture was extracted with DCM (4 x 200 ml). The combined organic layers were dried over Na2SC> 4, filtered and concentrated to give 6.80 g (100%, white solid) of intermediate 35.0. The product was used as such in the next step.
b) Preparation of the intermediary 34
[000480] Pd (OAc) 2 (0.02 g; 0.08 mmol) was added to a mixture of intermediate 8 (0.40 g; 1.63 mmol), intermediate 35 (0.77 g; 2 , 28 mmol), Cs2CO3 (1.59 g, 4.89 mmol) and Rufuses (0.01 g; 0.02 mmol) in dioxane (6 ml). The mixture was heated to 100 ° C overnight. Water (200 ml) was added and the mixture was extracted with DCM (4 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 to 95/5). The product fractions were collected and concentrated to give 0.30 g of intermediate 34 (12% purity, contaminated by 88% of intermediate 8). Example A8
a) Preparation of intermediate 38 0H
[000481] Sodium borohydride (0.994 g; 26.28 mmol) was added in portions to a solution of 4-formyl-A, A-dimethyl-1H-imidazole-1-sulfonamide (CAS 140174-48-7) ( 4.45 g, 21.9 mmol) in MeOH (45 ml) at 5 ° C under N2 flow. The reaction mixture was then stirred at room temperature for 2 hours, poured into ice water, extracted with DCM, dried over MgSÜ4, filtered and evaporated to dryness. The residue was crystallized from Et2O. The precipitate was filtered and evaporated yielding 2.5 g (56%) of intermediate 38 PF: 99 ° C (Kofler).
b) Preparation of the intermediary 37
[000482] Methanesulfonyl chloride (0.249 ml; 3.22 mmol) and LiCl (0.341 g; 8.04 mmol) were added to a solution of intermediate 38 (0.550 g; 2.68 mmol) and Et3N (0.747 ml; 5.36 mmol) in THF (6 ml) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 3 hours. Water (100 ml) was added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (75 ml), dried over Na2SO4, filtered and concentrated to give 0.597 g (100%, yellow oil with a tendency to crystallize) (stored at 4 ° C) of intermediate 37. The product was used as such in the next step. Example A9
Preparation of the intermediary 39
[000483] Et3N (7.46 ml; 52.11 mmol), p-toluenesulfonyl chloride (9.94 g; 52.11 mmol) and DMAP (531 mg; 4.34 mmol) were added successively to a solution of (R) - (-) 5- (hydroxymethyl) -2-pyrrolidinone (CAS 66673-40-3) (5 g; 43.43 mmol) in DCM (75 ml) at 5 ° C under a flow of N . The reaction mixture was stirred at room temperature for 2 hours. A 1N aqueous HCl solution was added. The mixture was extracted with DCM (3 times). The organic layer was dried over MgSO4, filtered and the solvent was evaporated to dryness. The residue was collected in ACN, filtered, washed with Et2O and dried yielding 8.44 g (72%) of intermediate 39. Example AIO
Preparation of the intermediary 41
[000484] NaH (0.105 g; 2.64 mmol) was added to a solution of intermediate 33 (0.5 g; 1.32 mmol) in DMF (13 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and 1H-1,2,4-Triazol-3-methanol, 1- (triphenylmethyl) -, 3-methanesulfonate (CAS: 163009-16-3) (1.11 g 2.64 mmol) was added to the portions. The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 16 hours. EtOAc (100 ml) was added and the mixture was washed with brine (3 x 100 ml). The organic layer was dried over NajSCE, filtered and concentrated. The residue (1.54 g, orange foam) was purified by column chromatography on silica gel (eluent: DCM / MeOH 99/1 to 95/5). The product fractions were collected and the solvent was evaporated to give 0.785 g (85%, yellow foam) of intermediate 41. Analogous preparation of intermediate 40 starting from intermediate 9
Analogous preparation of intermediate 42 from intermediate 28
Example Al 1
a) Preparation of the intermediary 43 0
[000485] Dimethylsulfonyl chloride (3.09 ml; 28.62 mmol) was added to a solution of l-77-pyraz ° l-3-carbaldehyde (2.5 g; 26.02 mmol) and triethylamine (5 , 96 ml; 41.63 mmol) in ACN (25 ml) and the reaction mixture was stirred at 50 ° C overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 15 to 45 μm, 80 g; mobile phase: 99% DCM, 1% MeOH). The product fractions were collected and evaporated to dryness producing 4.42 g of intermediate 43 (84%).
b) Preparation of the intermediary 44
[000486] Sodium borohydride (987.41 mg; 26.1 mmol) was added portionwise to a solution of intermediate 43 (4.42 g; 21.75 mmol) in MeOH (50 ml) at 5 ° C. The reaction mixture was then stirred at room temperature for 2 hours, poured into ice water, extracted with DCM, dried over MgSO4, filtered and evaporated to dryness. The crude product was collected with Et2O. The precipitate was filtered and evaporated yielding 3.04 g of intermediate 44 (73%).
c) Preparation of intermediate 45 Cl
[000487] Triethylamine (4.24 ml; 29.63 mmol), methanesulfonyl chloride (1.38 ml; 17.78 mmol) and lithium chloride (1.88 g; 44.45 mmol) were added successively to a solution of intermediate 44 (3.04 g; 14.82 mmol) in THF (75 ml) at 5 ° C under N2 flow and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness yielding 3.82 g of intermediate 45 which was used in the next step without further purification. Example A12
a) Preparation of the intermediary 57
[000488] 6-Methoxy-1,7-naphthyridin-4 (l //) -one (CAS 952059-64-2) (19.2 g; 66.2 mmol) was solubilized by heating in acetic acid (300 ml) and A-bromosuccinimide (17.7 g; 99.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. The resulting yellow precipitate was filtered off and successively washed with acetic acid (2 x 100 ml) and Et2O (2 x 200 ml) to give 16.3 g (96%, light yellow solid) of intermediate 57 which was used as such. in the next step.
b) Preparation of intermediate 58 N
[000489] The reaction was carried out in 2 batches of intermediate 57 (16.3 g; 63.9 mmol) and (10.1 g; 39.6 mmol):
[000490] POCI3 (160 ml; 1.72 mol) was added to a mixture of intermediate 57 (16.3 g; 63.9 mmol) in chloroform (160 ml). The solution was stirred at reflux for 2 hours, concentrated and dried in vacuo. The residual solid was collected with EtOAc (300 ml), cooled to 0 ° C and carefully basified with an aqueous 3 M NaOH solution (250 ml). Then, the resulting mixture was diluted with water (200 ml) and extracted with EtOAc (3 x 400 ml). The combined organic layers were dried over Na2SO4, filtered, combined with the other batch (10.1 g of intermediate 57) and concentrated to give 26.5 g (94% overall yield, light yellow solid) of intermediate 58 which was used as such in the next step.
c) Preparation of the intermediary 59
[000491] The reaction was carried out in 2 batches of intermediate 58 (21.5 g; 78.6 mmol) and (9.8 g; 358 mmol):
[000492] A solution of intermediate 58 (21.5 g; 78.6 mmol), 1-methylpyrazole-4-boronic acid pinacolic ester (17.2 g, 82.5 mmol), Na2CO3 (25 g; 236 mmol ) in a mixture of dioxane (510 ml) and water (210 ml) was degassed and backfilled with argon (operation repeated 3 times). PdCl2 (dppf) .CH2Cl2 (3.21 g; 3.93 mmol) was added and the resulting mixture was degassed and backfilled with argon (repeated twice) and stirred at 110 ° C for 16 hours. After cooling to room temperature and concentration of the solution, the residue was combined with the other batch (9.8 g). A mixture of EtOAc (800 ml) and MeOH (100 ml) was added. The organic layer was washed with a saturated aqueous solution of NaHCO3 (500 ml) and water (300 ml). The layers were separated and the aqueous layer was extracted with a mixture of EtOAc and MeOH (9/1; 3 x 300 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The resulting solid was triturated in Et2O (500 ml), filtered off and rinsed with Et2O (200 ml) to give 29.3 g (93% of the overall yield, reddish brown solid) of intermediate 59 PF: 180 ° C (DSC ).
d) Preparation of the intermediary 60
[000493] A catalytic amount of Raney Nickel, 50% slurry in water (1.88 g, 32.0 mmol) was washed twice with EtOH and collected after decanting. This catalytic amount was added to a solution of intermediate 59 (29.3 g; 107 mmol) in a mixture of EtOH (500 ml), THF (500 ml) and 1 N NaOH (112 ml; 112 mmol). The mixture was purged and stirred under a hydrogen atmosphere (1 bar) at 50 ° C for 65 hours. The mixture was cooled to room temperature, filtered through a pad of celite® which was washed with a mixture of TFIF and EtOH (1/1; 400 ml) and concentrated. The residue (brown solid) was absorbed on the silica gel and purified by column chromatography on silica gel (eluent: from 98% DCM, 2% MeOH to 95% DCM, 5% MeOH). The product fractions were collected and the solvent was evaporated. The resulting solid (16.5 g, orange solid) was triturated in Et2O (300 ml), filtered off and washed with Et2O (100 ml) to give 13.15 g (51%, beige solid) of intermediate 60. PF : 61 ° C (DSC).
e) Preparation of the intermediary 61
[000494] AICI3 (16.6 g, 125 mmol) was added in one portion to a solution of intermediate 60 (5 g; 20.8 mmol) in 1,2-dichloroethane (300 ml) at room temperature. The reaction mixture was stirred at reflux for 1 hour and cooled to room temperature. MeOH (500 ml) was added. The mixture was concentrated under reduced pressure, collected in a mixture of MeOH and DCM (8/2; 1 liter), absorbed on silica gel and purified by column chromatography on silica gel (eluent: 95% DCM, 5% MeOH to 80% DCM, 20% MeOH). The product fractions were collected and the solvent was evaporated to give 13.8 g (brown solid) of intermediate 61 which was used as such in the next step.
f) Preparation of the intermediary 62
[000495] A-Phenyl-bis (trifluoromethanesulfonimide) (14.9 g; 41.6 mmol) was added to the portions to a suspension of intermediate 61 (13.8 g; 20.8 mmol) and Et3N (43.5) ml; 312 mmol) in a mixture of DCM (400 ml) and DMF (100 ml) at room temperature. The reaction mixture was stirred at room temperature for 65 hours and concentrated under reduced pressure. The residue was collected in a mixture of EtOAc (500 ml) and brine (500 ml), filtered through a pad of celite® that was rinsed with EtOAc (200 ml) and brine (200 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (25.2 g, brown oil) was purified by column chromatography on silica gel (eluent: from 100% DCM to 96% DCM, 4% MeOH). The fractions containing the product were collected and the solvent was evaporated. The resulting residue (3.5 g, light brown oil) was purified by column chromatography on silica gel (eluent: from 100% DCM to 98% DCM, 2% MeOH). The product fractions were collected and the solvent was evaporated to give 1.02 g (14% in 2 steps of intermediate 60, beige solid) of intermediate 62.
g) Preparation of the intermediary 63
[000496] The reaction was carried out in 2 batches of intermediate 62 (0.57 g; 1.58 mmol) and (0.42 g; 1.17 mmol):
[000497] A solution of intermediate 62 (0.57 g; 1.58 mmol), 3,5-dimethoxyaniline (0.29 g, 1.89 mmol), Cs2CO3 (1.54 g, 4.73 mmol) and xantphos (0.05 g; 0.08 mmol) in toluene (40 ml) was degassed and backfilled with argon (operation repeated 3 times). Pd2dba3 (0.04 g; 0.047 mmol) was added. The resulting mixture was degassed and backfilled with argon (operation repeated twice), stirred at 0 ° C for 16 hours and concentrated under reduced pressure. The residue was collected in a mixture of water (100 ml) and DCM (100 ml). The layers were separated and the aqueous layer was extracted with DCM (2 x 50 ml). The combined organic layers were dried over Na2SO4 and concentrated. The residues originating from the 2 lots were combined and the resulting residue was purified by column chromatography on silica gel (eluent: DCM / MeOH 99/1 to 97/3). The product fractions were collected and concentrated. The resulting solid was triturated in Et2O (30 ml), filtered off, rinsed with Et2O (10 ml) and dried under vacuum to give 0.66 g (of overall yield 63%) of intermediate 63 (PF: 208 ° C ( DSC) Example Al3
a) Preparation of the intermediary 64
[000498] The two reactions, carried out on intermediate 62 respectively at 0.938 g and 0.100 g, were combined for the job. The synthesis is described below:
[000499] A solution of intermediate 62 (0.938 g; 2.62 mmol), 2,6-difluoro-3,5-dimethoxyaniline (0.990 g; 5.24 mmol), Cs2CO3 (4.26 g; 13.1 mmol ) and xantphos (0.151 g; 0.26 mmol) in a mixture of toluene (65 ml) and dioxane (20 ml) was degassed and backfilled with argon (operation repeated 3 times). Pd2dba3 (0.144 g, 0.16 mmol) was added. The resulting mixture was degassed and backfilled with argon (repeated twice), stirred at 110 ° C for 65 hours and concentrated under reduced pressure. The residue was combined with the reaction mixture carried out on 0.1 g of intermediate 62 in a mixture of DCM (200 ml) and MeOH (50 ml), absorbed on silica gel and purified by column chromatography on silica gel ( eluent: DCM / MeOH 99/1 to 97/3). The fractions containing the product were collected and the solvent was evaporated. The residue (0.578 g, orange solid) was triturated in Et2O (30 ml), filtered off, rinsed with Et2O (10 ml) and dried under vacuum at 80 ° C overnight to give 0.431 g (37%, yellow solid) ) of intermediate 64. PF: 228 ° C (DSC). Analogous preparation of intermediate 65 starting from intermediate 62
B. Preparation of compounds Example BI
Preparation of compound 1 7
[000500] The reaction was carried out under anhydrous conditions under an argon atmosphere. Tetrabutylammonium fluoride (1 M in THF; 7.3 ml, 7.3 mmol) was added to a solution of intermediate 10 (crude 3.17 g, maximum 5.53 mmol) in THF (120 ml) and the mixture it was stirred at room temperature overnight. Ice water (400 ml) and a saturated aqueous solution of potassium carbonate (600 ml) were added. The mixture was extracted with ethyl acetate (1 x 800 ml and 2 x 300 ml). The combined organic layers were washed with brine (400 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase, gradient from 100% DCM to 98% DCM, 2% MeOH). The desired fractions were collected and the solvent was evaporated, yielding 1.51 g (67% in 2 steps) of compound 1. Analogous preparation of compound 2
starting from intermediate 11 Analogous preparation of compound 22 starting from intermediate 31
Example Bl-a
Preparation of compound 61
[000501] Intermediate 51 (0.04 g; 0.077 mmol) was dissolved in a mixture of aqueous 3 N HCl (2 ml) and THF (3 ml). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with a 3 M NaOH solution (4 ml) and extracted with EtOAc (3x10 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residue (yellow gum) was purified by column chromatography on silica gel (eluent: DCM / MeOH 98/2). The product fractions were collected and the solvent was evaporated. The yellow solid was triturated in Et2O (15 ml). The supernatant liquid was removed and the resulting solid was dried in vacuo (70 ° C, 5 hours) to give 0.022 g (71%, light yellow solid) of compound 61. PF: 209 ° C (Buchi M-560). Example B2
Preparation of compound 3 z
[000502] The reaction was carried out under anhydrous conditions under an argon atmosphere. NaH (60% mineral oil, 0.1 g, 2.5 mmol) was added to a mixture of intermediate 9 (0.3 g, 0.83 mmol) in N, N-dimethylformamide (7 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and bromo-ethyl methyl ether (0.31 ml, 3.32 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. Ice water (100 ml) was added and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase, gradient from 100% DCM to 90% DCM, 10% MeOH). The product fractions were collected and the solvent was evaporated. The residue was dissolved in ethyl acetate (100 ml) and washed with water (3 x 60 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated in diethyl ether (4x5 ml) and dried in vacuo, yielding 0.222 g (64%) of compound 3 (PF: 138 ° C (DSC)). Analogous preparation of compound 35 starting from intermediate 28
Analogous preparation of compound 36 starting from intermediate 33
Analogous preparation of compound 45 starting from intermediate 28
Analogous preparation of compound 50 starting from intermediate 9
Analogous preparation of compound 51 starting from intermediate 33
Analogous preparation of compound 54 starting from intermediate 33
Analogous preparation of compound 57 starting from intermediate 33
Analogous preparation of compound 69 starting from intermediate 63
Example B2a-1
Preparation of compound 40
[000503] NaH (0.380 g; 9.49 mmol) was added to a solution of intermediate 33 (0.900 g; 2.37 mmol) in DMF (18 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and intermediate 39 (0.958 g; 3.56 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. Water (100 ml) and brine (150 ml) were added and the mixture was extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (1.96 g, brown oil) was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. The resulting solid was triturated in Et2O and dried in vacuo to give 0.354 g (31%, yellow solid) of the expected compound which was purified again by column chromatography on silica gel (eluent: DCM / MeOH 98/2 to 96 / 4). The product fractions were collected and the solvent was evaporated producing 2 fractions which were ground in Et2O. The precipitates were filtered and evaporated in vacuo to give 0.071 g (6%, yellow solid) of compound 40 and 0.207 g (18%, yellow solid) of compound 40 PF: decomposition from 21 TC, DSC). Example B2a-2
Preparation of compound 41
[000504] NaH (0.443 g, 11.1 mmol) was added to a solution of intermediate 9 (1.00 g; 2.77 mmol) in DMF (20 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and intermediate 39 (CAS 128899-31-0) (1.12 g; 4.16 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. Water (250 ml) and brine (100 ml) were added and the mixture was extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (2.47 g, brown oil) was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 to 95/5). The product fractions were collected and the solvent was evaporated to give 0.289 g (yellow solid) of the expected compound which was purified again by silica gel column chromatography (eluent: DCM / methanol 98/2 to 95/5) . The product fractions were collected and the solvent was evaporated to give 0.235 g (19%, beige solid) of compound 41. PF: decomposition starting at 276 ° C, DSC). Example B2a-3
Preparation of compound 42
[000505] NaH (0.362 g, 9.04 mmol) was added to a solution of intermediate 28 (0.900 g; 2.26 mmol) in DMF (20 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and intermediate 39 (0.913 g; 3.39 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 72 hours. Water (100 ml) and brine (150 ml) were added and the mixture was extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (2.42 g, brown oil) was purified by column chromatography on silica gel (eluent: EtOAc / MeOH 100/0 to 98/2). The product fractions were collected and the solvent was evaporated to give 0.502 g (yellow gum) of the expected product which was purified once again by column chromatography on silica gel (15 to 40 μm, eluent: DCM / MeOH 99/1 to 97/3). The product fractions were collected and the solvent was evaporated. The resulting residue was triturated in Et2O. The precipitate was filtered and evaporated in vacuo to give 0.239 g (21%, yellow solid) of compound 42. PF: decomposition starting at 233 ° C (DSC). Example B2a-4
Preparation of compound 43
[000506] NaEI (0.380 g; 9.49 mmol) was added to a solution of intermediate 33 (0.900 g; 2.37 mmol) in DMF (18 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and the (S) - (+) - 5- (hydroxymethyl) -2-pyrrolidinone p-toluenesulfonate (CAS 51693-17-5) (0.958 g; 3, 56 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. Water (100 ml) and brine (150 ml) were added and the mixture was extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (3.34 g, brown oil) was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 to 96/4). The product fractions were collected and the solvent was evaporated. The resulting residue was triturated in Et2O and dried in vacuo to give 0.277 g (25%, brown solid) of compound 43. PF: decomposition starting at 221 ° C (DSC). Analogous preparation of compound 37 starting from intermediate 9
Analogous preparation of compound 44 starting from intermediate 28
Example B2a-5
Preparation of compound 70
[000507] NaH (0.160 g; 4.00 mmol) was added to a solution of intermediate 64 (0.397 g; 1.00 mmol) in DMF (10 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 45 minutes and (2-chloroethyl) methylamine hydrochloride (CAS 4535-90-4) (0.195 g, 1.50 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour later, at room temperature for 65 hours. Water (30 ml) and brine (70 ml) were added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (3 x 50 ml), dried over Na2SO4, filtered and the solvent was evaporated. The residue (0.85 g, reddish brown solid) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH4OH: from 95/5/0 to 90/10/0 to 90/10/1) . The product fractions were collected and the solvent was evaporated to give 230 mg of an intermediate residue that was triturated in Et2O (20 ml). The precipitate was filtered off, washed with Et2O and dried under vacuum at 80 ° C for 16 hours to give 210 mg (47%) of compound 70. PF: 148 ° C (DSC). Example B2a-6
Preparation of compound 46
[000508] The two reactions at 1.00 g and 0.050 g respectively were combined for the job. The synthesis is described below:
[000509] NaH (0.403 g; 10.1 mmol) was added to a solution of intermediate 28 (1.00 g; 2.52 mmol) in DMF (25 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and methylaminoethyl chloride hydrochloride (0.491 g; 3.78 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. The reaction mixture and the reaction mixture (0.05 g of intermediate 28) were combined. Water (100 ml) and brine (150 ml) were added. The mixture was extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (4.43 g, brown oil) was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 to 93/7). The product fractions were collected and the solvent was evaporated. The resulting fraction was triturated in Et2O (4x5 ml) and dried under vacuum to give 0.208 g (18%, yellow solid) of compound 46. 0.184 g of this fraction was purified by chiral SFC in (AMINO 6 μm 150 x 21.2 mm ; mobile phase: 0.3% isopropylamine, 75% CO2, 25% MeOH). The product fractions were collected and the solvent was evaporated. The residue (145 mg) was crystallized from Et2O to give, after filtration, 124 mg (11%) of compound 46. PF: 157 ° C (DSC). Analogous preparation of compound 52 starting from intermediate 36
Analogous preparation of compound 73 starting from intermediate 65
Example B3 Preparation of the
Compound 4 (2.69 HCl 2.91 EGO) Compound 5 Compound 6
[000510] A mixture of intermediate 9 (0.5 g, 1.4 mmol), tetrabutylammonium bromide (0.11 g, 0.35 mmol) and potassium hydroxide (1.16 g, 20.8 mmol) in 2-methyltetrahydrofuran (7.5 ml) and water (0.6 ml) was heated to 50 ° C for 1 hour. Isopropylaminoethyl chlorine hydrochloride (0.39 g, 2.5 mmol) was added and the mixture was heated to 50 ° C overnight. Water (25 ml) was added and the mixture was extracted with a 95/5 dichloromethane / methanol mixture (3 x 25 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase, gradient 98% DCM, 2% MeOH to 90% DCM, 10% MeOH). The desired fractions were collected and the solvent was evaporated, producing 0.233 g of a residue that was further subjected to purification by silica gel chromatography (mobile phase, gradient of 95% DCM, 5% MeOH to 95% DCM, 5% MeOH, 0.1% NH4OH). The desired fractions were collected and the solvent was evaporated, yielding 0.13 g of fraction 1 which consists of a mixture of compound 4 and compound 5.
[000511] Alternatively a mixture of compounds 4 and can be obtained using the following conditions:
[000512] Under anhydrous conditions under an argon atmosphere, NaH (60% in mineral oil, 0.232 g, 5.8 mmol) was added slowly to a suspension of intermediate 9 (0.35 g, 0.97 mmol) in N, N-dimethylformamide (10 ml) at 0 ° C and the mixture was stirred at 0 ° C for 10 minutes. Isopropylaminoethyl chlorine hydrochloride (0.459 g, 2.9 mmol) was added to the portions and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was quenched with a saturated solution of ammonium chloride (15 ml) and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with a saturated sodium chloride solution (2 x 50 ml), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (mobile phase, gradient of 95% DCM, 5% MeOH to 90% DCM, 10%). The fractions were collected and the solvent was evaporated producing 0.22 g of fraction 2 composed of a mixture of compound 4 and compound 6.
[000513] Fraction 1 and fraction 2 were combined and purified by chiral SFC (mobile phase, 0.3% isopropylamine, 86% CO2, 14% MeOH). The desired fractions were collected and concentrated, yielding 17 mg of compound 5, 168 mg of compound 4 and 60 mg of the fraction of product 3 containing compound 4 and compound 6.
[000514] Compound 4 was converted to the HCl salt (3 eq. Of 1 M solution in water) in Et2O and ground. The precipitate was filtered off, washed with Et2O and dried in vacuo, yielding 153 mg of compound 4 (mp = 175 ° C Kofler).
[000515] The fraction of product 3 was purified by chiral SFC in (5 μm mobile phase, 0.3% isopropylamine, 85% CO2, 15% MeOH), producing 22 mg of compound 6. Example B3a
Preparation of compound 30
[000516] A mixture of intermediate 33 (0.56 g; 1.46 mmol), tetrabutylammonium bromide (0.12 g; 0.37 mmol) and KOH (1.23 g; 21.9 mmol) in 2- methyltetrahydrofuran (8.5 ml) and water (1 ml) was heated to 50 ° C for 1 hour. Methylaminoethyl chloride hydrochloride (0.34 g; 2.63 mmol) was added and the mixture was heated to 50 ° C overnight. Water (200 ml) was added and the mixture was extracted with DCM (3 x 150 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH 98/2 to 85/15). The product containing fractions were collected and concentrated to produce etching in Et O and dried under vacuum to give 0.408 g of the expected compound. This solid was purified by chiral SFC in (AMINO 6 μm 150 x 21.2 mm; mobile phase: 0.3% isopropylamine, 75% CO2, 25% MeOH) to give 308 mg of an intermediate residue that was crystallized from Et2O to produce 256 mg (40%) of compound 30. PF: 120 ° C (gum) (Kofler). Analogous preparation of compound 12 starting from intermediate 18
Analogous preparation of compound 13 starting from intermediate 23
Analogous preparation of compound 23 starting from intermediate 32
Analogous preparation of compound 26 starting from intermediate 28
Analogous preparation of compound 68 starting from intermediate 63
Example B3b
Preparation of compound 21
and compound 20
[000517] A mixture of intermediate 30 (0.66 g; 1.94 mmol), tetrabutylammonium bromide (0.16 g; 0.49 mmol) and KOH (1.63 g; 29.1 mmol) in 2- methyltetrahydrofuran (11 ml) and water (1.6 ml) was heated to 50 ° C for 1 hour. Isopropylaminoethyl chlorine hydrochloride (0.55 g; 3.49 mmol) was added and the mixture was heated to 50 ° C overnight. Water (400 ml) was added and the mixture was extracted with DCM (3 x 200 ml). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 to 85/15). The fractions containing the product were collected and concentrated to give 0.485 g of a mixture of compounds 20 and 21. This solid was purified by chiral SFC in (CIANO 6 μm 150 x 21.2 mm; mobile phase: 0.3% of isopropylamine, 80% CO2, 20% MeOH) to give 40 mg of compound 20 (5%), PF: 130 to 134 ° C (Kofler) and 360 mg of an intermediate compound that was crystallized from Et2O to give 330 mg (40%) of compound 21. PF: 78 ° C (DSC). Analogous preparation of compound 29
and compound 28
starting from intermediary 33 Example B4
Preparation of compound 7 z
[000518] The reaction was carried out under anhydrous conditions under argon. NaH (60% in mineral oil; 0.083 g, 2.1 mmol) was added portionwise to a solution of intermediate 9 (0.5 g, 1.4 mmol) in DMF (7 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 minutes and 2- (chloromethyl) -A, A-dimethyl-1H-imidazole-1-sulfonamide, (0.371 g, 1.7 mmol) was added. The mixture was warmed to room temperature overnight. The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layers were washed with a saturated aqueous solution of NaCl (3 x 40 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase, gradient 99% DCM, 1% MeOH to 95% DCM, 5% MeOH). The desired fractions were collected and the solvent was evaporated to give 0.55 g (72%) of compound 7 which was used without further purification for the next step. Analogous preparation of compound 17 starting from intermediate 16
Analogous preparation of compound 18 starting from intermediate 30
Analogous preparation of compound 25 starting from intermediate 32
Analogous preparation of compound 27 starting from intermediate 33
Analogous preparation of compound 32 starting from intermediate 9
Analogous preparation of compound 33 starting from intermediate 36
Analogous preparation of compound 38 starting from intermediate 9 and intermediate 37
Analogous preparation of compound 56 starting from intermediate 33 and intermediate 45
Analogous preparation of compound 58 starting from intermediate 33 el, 3-oxazol-2-ylmethylmethanesulfonate (CAS 916810-51-0)
Analogous preparation of compound 60 starting from intermediate 46
Analogous preparation of compound 63 starting from intermediate 52
Analogous preparation of compound 64 starting from intermediate 28
Analogous preparation of compound 66 starting from intermediate 63
Analogous preparation of compound 71 starting from intermediate 64
Analogous preparation of compound 76 starting from intermediate 65
Example B4a
Preparation of compound 14
[000519] The reaction was carried out in 2 batches of intermediate 28 (0.057 g; 0.14 mmol) and (0.23 g; 0.58 mmol):
[000520] NaH (0.07 g; 1.74 mmol) was added to a solution of intermediate 28 (0.230 g; 0.58 mmol) in DMF (8 ml) at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes and 2- (chloromethyl) -pyrimidine hydrochloride (0.143 g; 0.87 mmol) was added. The mixture was stirred at 0 ° C for 3 hours. Water (200 ml) was added and the reaction mixture (0.057 g of intermediate 28) was combined with the mixture. The mixture was extracted with EtOAc (3 x 200 ml). The combined organic layers were dried over Na2SÜ4, filtered and concentrated. The residue (1.73 g, brown oil) was purified by column chromatography on silica gel (eluent: DCM / MeOH from 100/0 to 95/5). The product fractions were collected and the solvent was evaporated to give 0.295 g which was triturated in Et2O (4x5 ml). The solid was filtered and evaporated in vacuo to give 0.286 g (of overall yield 81%, yellow solid) of compound 14 PF: 183 ° C (DSC). Example B5
Preparation of compound 8
[000521] Potassium carbonate (0.45 g, 3.4 mmol) was added to a mixture of intermediate 13 (1.6 g, 3.4 mmol) in MeOH (34 ml) and the mixture was stirred at temperature environment at night. The mixture was concentrated to dryness and purified by silica gel chromatography (mobile phase, 98% DCM, 2%). The desired fractions were collected and the solvent was evaporated, yielding 0.665 g (49%) of compound 8. Example B6
Preparation of compound 11 ° "
[000522] A 1 M solution of tetrabutylammonium in THF (1.13 ml, 1.13 mmol) was added to a solution of intermediate 17 (0.76 mmol) in THF (38 ml). The reaction mixture was stirred at room temperature for 2 hours. Water and a saturated K2CO3 solution were added and the mixture was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel (40 to 63 μm, mobile phase, gradient of 98% DCM,% MeOH to 96% DCM, 4% MeOH). The product fractions were collected and evaporated to dryness, yielding 190 mg (55%) of compound 11 (PF: 167 ° C, DSC). Analogous preparation of compound 15 starting from intermediate 29
Example B7
Preparation of compound 48
[000523] The two reactions performed on 0.735 g and 0.05 g respectively were combined for the job. The synthesis is described below:
[000524] 12 M HCl (0.436 ml; 5.23 mmol) was added to a solution of intermediate 41 (0.735 g; 1.05 mmol) in MeOH (15 ml) at 0 ° C. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture and the reaction mixture (0.05 g of intermediate 41) were poured into a mixture of ice water (100 ml) and solid NaHCO3 (about 20 g). The aqueous layer was extracted with an EtOAc / MeOH mixture (9/1; 3 x 40 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (1.32 g, yellow solid) was absorbed on the silica gel and purified by silica gel column chromatography (eluent: DCM / MeOH 97/3 to 93/7). The product fractions were collected and the solvent was evaporated. The residue (0.500 g) was ground in Et2O (30 ml). The precipitate was filtered off, washed with Et2O (10 ml) and dried under vacuum at 80 ° C for 16 hours to give 0.420 g (82% overall yield, yellow solid) of compound 48. PF: 216 ° C (DSC ). Analogous preparation of compound 47 starting from intermediate 40
Analogous preparation of compound 49 starting from intermediate 42
Example B8
Preparation of compound 31
[000525] 4 M HCl in dioxane (6.9 ml; 27.7 mmol) was added to a mixture of intermediate 34 (0.30 g; 0.55 mmol) in DCM (1.5 ml) and the mixture it was stirred at room temperature overnight. A 2 M aqueous solution of NaOH (15 ml) and water (130 ml) were added (pH = 14). The mixture was extracted with DCM (3 x 100 ml). The combined organic layers were washed with brine (150 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH 95/5 to 90/10, then DCM / MeOH / NH4OH 90/10 / 0.1 to 90/10 / 0.4).
[000526] The fractions containing the product were collected and concentrated to give 0.084 g of the expected compound. This solid was purified by preparative TLC (SiOH, eluent: DCM / MeOEI / NH4OH 90/10 / 0.1) to give an intermediate residue which was triturated in Et2O and dried under vacuum to give 68 mg of the expected compound. This fraction was purified by reverse phase chromatography (Luna Cl8 10 μm, eluent: MeOH / water / trifluoroacetic acid 40/60 / 0.1). The resulting fraction was triturated in Et2O. The precipitate was filtered and evaporated in vacuo to give 0.025 g (10%) of compound 31. PF: 150 ° C (DSC). Example B9
Preparation of compound 74
[000527] NaH (8 mg; 0.198 mmol) was added to a mixture of intermediate 65 (50 mg; 0.132 mmol) in DMF (2 ml) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes, then (2-bromoethoxy) -ether-butyldimethylsilane (CAS 86864-60-1) (0.042 ml; 0.198 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 65 hours. The reaction mixture was cooled to 0 ° C and more NaH (8 mg; 0.198 mmol) was added. The mixture was stirred at 0 ° C for 30 minutes, then (2-bromoethoxy) -erc-butyldimethylsilane (CAS 86864-60- 1) (0.042 ml; 0.198 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 2 hours.
[000528] Ice water (5 ml) was added and the mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (3 x 10 ml), dried over Na2SO4, filtered and concentrated. The residue was collected with THF (2 ml) and aqueous 3 M HCl (2 ml) and stirred at room temperature for 16 hours. The reaction mixture was basified with a 3 M aqueous NaOH solution (2.5 ml), diluted with water (20 ml) and extracted with a DCM / MeOH mixture (9/1; 3 x 15 ml). The organic layers were dried over Na2SO4, filtered and the solvent was evaporated. The residue (0.067 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH /: 98/2 to 97/3). The product fractions were collected and the solvent was evaporated to give 24 mg of an intermediate residue that was triturated in Et2O (2 ml). The precipitate was filtered off rinsed with Et2O (10 ml) and dried under vacuum at 80 ° C for 16 hours to give 20 mg (36%, yellow solid) of compound 74. PF: 200 ° C (DSC). Analogous preparation of compound 75 starting from intermediate 65
Analogous preparation of compound 78 starting from intermediate 66
C. Conversion of compounds Example C1
Preparation of compound 9
[000529] Compound 1 (1.0 g, 2.5 mmol) was added to a mixture of triphenyl phosphine (0.776 g, 3.0 mmol), 2,3-dichloro-5,6-diciano-benzoquinone (0.682 g, 3.0 mmol) and tetrabutylammonium bromide (0.954 g, 3.0 mmol) in dichloromethane (22 ml). The mixture was stirred at room temperature for 30 minutes and concentrated to dryness. The residual brown solid was purified by silica gel chromatography (mobile phase, gradient from 100% DCM to 80% DCM, 20%). The product fractions were collected and the solvent was evaporated, yielding 0.720 g (62%) of compound 9. Example C2
Preparation of compound 10 z
[000530] A 4 N solution of hydrochloric acid in dioxane (2.5 ml, 10 mmol) was added to a solution of compound 7 (0.55 g, 1.0 mmol) in acetonitrile (10 ml). The reaction mixture was heated at 50 ° C for 16 hours. After cooling to room temperature, the mixture was basified with an aqueous 1 M sodium hydroxide solution (20 ml), diluted with water (100 ml) and extracted with dichloromethane (3 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The desired residue was purified by chromatography on silica gel (mobile phase, gradient of 97% DCM, 3% MeOH to 85% DCM, 15% MeOH). Two product fractions were collected and the solvent was evaporated, producing 0.233 g (42%) of unreacted starting material (compound 7) and 0.204 g of fraction 2.
[000531] Fraction 2 was purified again by chromatography on silica gel (mobile phase, gradient 98% DCM, 2% MeOH to 90% DCM, 10% MeOH). The desired fractions were collected and the solvent was evaporated. The residue was triturated in diethyl ether, filtered off and dried in vacuo, yielding 0.137 g of compound 10 (PF: 195 ° C, DSC). Analogous preparation of compound 16 starting from compound 17
Analogous preparation of compound 19 starting from compound 18
Analogous preparation of compound 24 starting from compound 25
Analogous preparation of compound 34 starting from compound 33
Analogous preparation of compound 55 starting from compound 56
Analogous preparation of compound 59 starting from compound 60
Analogous preparation of compound 62 starting from compound 63
Analogous preparation of compound 65 starting from compound 64
Analogous preparation of compound 67 starting from compound 66
Analogous preparation of compound 72 starting from compound 71
Analogous preparation of compound 77 starting from compound 76
Example C2a
Preparation of compound 39
[000532] 4 M HCl in dioxane (4.3 ml; 17.2 mmol) was added dropwise to a solution of compound 38 (0.473 g, 0.86 mmol) in ACN (8.6 ml). The mixture was stirred at room temperature for 1 hour, at 50 ° C overnight and was allowed to cool to room temperature. A 1 M aqueous solution of NaOH (80 ml) and water (80 ml) were added (pH = 14). The mixture was extracted with DCM (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na.SO4, filtered and concentrated. The residue (0.410 g, yellow gum) was purified by column chromatography on silica gel (eluent: EtOAc / MeOH 95/5 to 90/10). The product fractions were collected and the solvent was evaporated. The resulting residue was triturated in Et20 (4 x 5 ml) and dried in vacuo to give 0.254 g (67%, yellow solid) of compound 39 PF: 188 ° C (DSC). Example C3
Preparation of compound 53
[000533] NaH (0.038 g; 0.94 mmol) was added to a suspension of compound 40 (0.287 g, 0.63 mmol) in DMF (3 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, then iodomethane (0.058 ml; 0.94 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. Water (50 ml) and brine (50 ml) were added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue (0.600 g, yellow oil) was purified by column chromatography on silica gel (eluent: DCM / MeOH from 100/0 to 95/5). Fractions containing product were collected and the solvent was evaporated. The residue was triturated in Et2O. The precipitate was filtered and evaporated in vacuo to give 41 mg (14%, yellow solid) of compound 53. M.P .: 192 ° C (DSC).
[000534] The following compounds were prepared according to the reaction protocols of one of the Examples above using alternative starting materials as appropriate.
[000535] In tables Al and Ala = CX (ou = BX) indicates that the preparation of this compound is described in Conversion X (or Method BX).
[000536] In tables Al and Ala ~ CX (or ~ BX) indicates that this compound was prepared according to Conversion X (or Method BX).
[000537] As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may exist as a solvate for example, hydrate, and / or contain residual solvent or minor impurities. The compounds isolated as a salt form, can be stoichiometric integers that is, mono or di salts, or the stoichiometric intermediate. Table Al: compounds and physico-chemical data


Wing Table: compounds and physicochemical data








Analytical part LC / GC / NMR
[000538] The LC / GC data reported in Table A1 was determined as follows. General procedure A
[000539] LC measurement was performed using a UPLC (Ultra Performance Liquid Chromatography) Acquity system (Waters) comprising a binary pump with degasser, an auto-sampler, a diode array detector (DAD) and a column as specified in respective methods below, the column is maintained at a temperature of 40 ° C. The column flow 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
[000540] In addition to general procedure A: The reverse phase UPLC was performed on a C18 column (ethyl siloxane / silica bridged hybrid) Waters Acquity BEH (1.7 μm, 2.1 x 100 mm) with a rate of flow of 0.343 ml / min. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate / 5% acetonitrile; mobile phase B: 100% acetonitrile) were used to drive a gradient condition of 84.2% A and 15.8 % B (maintained for 0.49 minutes) to 10.5% A and 89.5% B in 2.18 minutes, maintained for 1.94 min and back to initial conditions in 0.73 min, maintained for 0.73 minutes. An injection volume of 2 μl was used. The cone voltage was 20V for positive and negative ionization mode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2 seconds using a 0.1 second scan delay. Oral procedure B
[000541] HPLC measurement was performed using an HPLC System 1100/1200 (Agilent) comprising 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 at room temperature. The MS detector (MS-Agilent quadripolar single) was configured with an electrospray APCI ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Chemstation data system. Method 2
[000542] In addition to general procedure B: Reverse phase HPLC was performed on a Cl8 Nucleosil column (3 μm, 3 x 150 mm) with a flow rate of 0.42 ml / min. Two mobile phases (mobile phase A: 0.1% TFA water; mobile phase B: 100% acetonitrile) were used to drive a gradient condition of 98% A for 3 minutes, to 100% B in 12 minutes, 100% B for 5 minutes, then back to 98% A in 2 minutes and 1 rebalanced with 98% A for 6 minutes. An injection volume of 2 μl was used. The capillary voltage was 2 kV, the corona discharge was maintained at 1 μA and the source temperature was maintained at 250 ° C. A varying voltage was used for the shredder. The mass spectra were acquired by electrospray ionization and APCI in positive mode, by scanning from 100 to 1100 amu. Method 3
[000543] In addition to general procedure B: Reverse phase HPLC was performed on an Agilent Cl8 Eclipse Column (5 μm, 4.6 x 150 mm) with a flow rate of 1 ml / min. Two mobile phases (mobile phase A: 0.1% TFA water; mobile phase B: 100% acetonitrile) were used to drive a gradient condition of 98% A for 3 minutes, to 100% B in 12 minutes, 100% B for 5 minutes, then back to 98% A in 2 minutes and 1 rebalanced with 98% A for 6 minutes. An injection volume of 2 μl was used. The capillary voltage was 2 kV, the corona discharge was maintained at 1 μA and the source temperature was maintained at 250 ° C. A varying voltage was used for the shredder. The mass spectra were acquired by electrospray ionization and APCI in positive mode, by scanning from 80 to 1000 amu. Method 4
[000544] In addition to the general NOVA procedure: Reverse phase HPLC was performed on an Agilent C18 eclipse Column (5 μm, 4.6 x 150 mm) with a flow rate of 1.0 ml / min. Two mobile phases (mobile phase A: Water with 0.1% TFA; mobile phase B: 100% methanol) were used to conduct a gradient condition of 98% A maintained for 3 minutes at 100% B in 12 minutes. , 100% B for 5 minutes, then back to 98% A in 2 minutes and 1 rebalanced with 98% A for 5 minutes. An injection volume of 2 μl was used. The capillary voltage was 2 kV, the corona discharge was maintained at 1 μA and the source temperature was maintained at 250 ° C. A varying voltage was used for the shredder. The mass spectra were acquired by electrospray ionization and APCI in positive mode, by scanning from 100 to 1000 amu.
[000545] Melting point (P.F.) was determined with a Kofler hot bar or a Büchi M-560 melting point but also, for various compounds, they were determined with a DSC1 Stare System (Mettler-Toledo). In this case, the melting points were measured with a temperature gradient of 5 or 10 ° C / minute. The maximum temperature was 350 ° C. The values are peak values. ” NMR data
[000546] The NMR experiments below were performed using a Bruker Avance 500 spectrometer and a Bruker Avance DRX 400 spectrometer at room temperature, using internal deuterium lock and equipped with reverse triple resonance ('H, I3C, I5N TXI) tip probe for 500 MHz and with double reverse resonance ('H, 13C, SEI) probe tip for 400 MHz. Chemical changes (δ) are reported in parts per million (ppm). Compound 11 1 H NMR (400 MHz, DMSO-d6): δ 8.80 (1H, s), 8.47 (1H, s), 8.13 (1H, s), 7.95 (1H, d, J = 9.4 Hz), 6.87 (d, 1 hour, J = 9.4 Hz), 6.55 - 6.53 (3H, m), 4.50 (1H, t, J = 5.2 Hz), 4.17 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 3.77 (6H, s), 3.53 (2H, q, J = 6.0 Hz), 1.87 (2H, qt, J = 6.7 Hz). Compound 4 'H NMR (500 MHz, DMSO-d6) δ 9.07 (br.s, 1H), 8.91 (br.s, 2H), 8.48 (s, 1H), 8.43 (br .s, 1H), 8.15 (s, 1H), 8.10 (d, J = 9.4 Hz, 1H), 6.92 (d, J = 9.4 Hz, 1H), 6.72 (d, J = 2.2 Hz, 2H), 6.59 (t, J = 2.2 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 3.94 (s , 3H), 3.78 (s, 6H), 3.45 (spt, J = 6.2 Hz, 1H), 3.26 (quin, J = 6.6 Hz, 2H), 1.28 (d , J = 6.2 Hz, 6H). Compound 30 * H NMR (500 MHz, DMSO-d6) δ (ppm) 8.91 (d, J = 1.9 Hz, 1H), 8.46 (s, 1H), 8.15 (s, 1H) , 8.11 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 6.76 - 6.82 (m, 1H), 6.66 - 6.72 (m, 2H), 4.09 (t, J = 6.8 Hz, 2H), 3.90 (s, 1H), 3.88 (s, 1H), 3.78 (s, 3H ), 2.78 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H) Compound 31 'H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8 , 47 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.85 (d, J = 9.3 Hz, 1H), 6.64 (br. S. , 1H), 6.32 - 6.45 (m, 3H), 5.01 -5.21 (m, 1H), 3.91 (s, 3H), 3.78 (s, 6H), 3, 01 (d, J = 11.9 Hz, 2H), 2.66 (d, J = 13.4 Hz, 2H), 1.90 (d, J = 11.9 Hz, 2H), 1.20 - 1.39 (m, 3H) Compound 39 'H NMR (400 MHz, DMSO-d6) δ 11.46 - 11.97 (m, 1H), 8.80 - 9.04 (m, 1H), 8, 47 (s, 1H), 8.07 - 8.29 (m, 2H), 7.78 - 8.00 (m, 1H), 7.43 - 7.60 (m, 1H), 7.05 ( s, 1H), 6.80 - 6.99 (m, 1H), 6.60 - 6.79 (m, 2H), 6.34 - 6.52 (m, 1H), 5.09 - 5, 30 (m, 2H), 3.91 (s, 3H), 3.74 (s, 6H) Compound 40! H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.47 (s, 1H), 8.16 (br., 2H), 7.98 (d, J = 9.1 Hz, 1H), 7.7 8 (s, 1H), 6.81 (br. s „2H), 6.69 (d, 9.1 Hz, 1H), 4.11 (br. s., 2H), 3.85 - 3.96 (m, 7H), 3.79 (s, 3H), 2.21 - 2.32 (m, 1H), 2.03 - 2.17 (m, 2H), 1.85 (br. S., 1H) Compound 41 * H NMR (400 MHz, DMSO -d6) δ 8.90 (s, 1H), 8.45 (s, 1H), 8.19 - 8.08 (m, 2H), 7.92 (d, J = 9.3 Hz, 1H) , 7.81 (s, 1H), 6.77 (d, J = 9.3 Hz, 1H), 6.66 (s, 2H), 6.53 (br. S, 1H), 4.17 - 4.29 (m, 1H), 4.06 - 4.16 (m, 1H), 3.87 - 3.98 (m, 4H), 3.78 (s, 6H), 2.21 - 2, 32 (m, 1H), 2.04 - 2.18 (m, 2H), 1.73 - 1.89 (m, 1H) Compound 42 'H NMR (400 MHz, DMSO-d6) δ 8.98 ( s, IH), 8.48 (s, 1H), 8.17 (s, 2H), 8.05 (d, 9.1 Hz, IH), 7.56 (s, IH), 7.07 - 7.20 (m, IH), 6.51 - 6.91 (m, IH), 4.11 - 4.26 (m, IH), 3.99 - 4.06 (m, IH), 3, 88 - 3.97 (m, 9H), 3.79 - 3.87 (m, IH), 2.20 - 2.32 (m, IH), 2.01 - 2.18 (m, 2H), 1.84 - 1.99 (m, IH) Compound 43! H NMR (400 MHz, DMSO-d6) δ 8.94 (s, IH), 8.47 (s, IH), 8.16 (s, 2H), 7.98 (d, J = 9.1 Hz, IH), 7.78 (s, IH), 6.81 (br. S „2H), 6.69 (d, J = 9.1 Hz, IH), 4.04 - 4.25 (m, 2H), 3.85 - 3.97 (m, 7H), 3.79 (s, 3H), 2.19 - 2.31 (m, IH), 2.03 - 2.16 (m, 2H), 1.76 - 1.93 (m, IH) Compound 48 * H NMR (400 MHz, DMSO-d6) δ 13 , 82 (br. s., IH), 8.95 (s, IH), 8.46 (s, IH), 8.21 - 8.34 (m, IH), 8.15 (s, 2H), 8.02 ( d, J = 9.3 Hz, IH), 6.82 (d, J = 9.3 Hz, IH), 6.68 - 6.78 (m, 2H), 5.35 (br. s., 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.73 (s, 3H) Compound 70 'H NMR (400 MHz, DMSO-d6) δ 9.03 - 8.87 (m, 2H), 8.43 (br. s., IH), 8.24 (br. s., IH), 8.10 (br. s., IH), 6.93 - 7.17 ( m, IH), 6.67 (br. s., IH), 3.71 - 4.06 (m, 12H), 2.84 (br., 2H), 2.37 (s, 3H) Pharmacological Part Biological Assay A FGFR1 (enzymatic assay)
[000547] In a final reaction volume of 30 μl, FGFR1 (h) (25 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.1 mM Na3VO4, 0.01% Triton-X-100, 500 nM Btn-Flt3 and 5 μM 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 Resonance Energy Transfer signal in Time-Resolved Fluorescence (TR-FRET) (ex340 nm. At 620 nm, at 655 nm) was measured after that and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range of 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value. FGFR2 (enzymatic assay)
[000548] In a final reaction volume of 30 μL, FGFR2 (h) (150 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.1 mM Na3VO4, 0.01% Triton-X-100, 500 nM Btn-Flt3 and 0.4 μM 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 Resonance Energy Transfer signal in Time-Resolved Fluorescence (TR-FRET) (ex340 nm. At 620 nm, at 655 nm) was measured after that and the results are expressed in (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range from 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value. FGFR3 (enzymatic assay)
[000549] In a final reaction volume of 30 μL, FGFR3 (h) (40 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCL, 1 mM DTT, 0.1 mM Na3VO4, 0.01% Triton-X-100, 500 nM Btn-Flt3 and 25 μM ATP in the presence of 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 Resonance Energy Transfer signal in Time-Resolved Fluorescence (TR-FRET) (ex340 nm. At 620 nm, at 655 nm) was measured after that and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range from 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC5o (-logIC5o) value. FGFR4 (enzymatic assay)
[000550] In a final reaction volume of 30 μL, FGFR4 (h) (60 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCb, 1 mM DTT, 0.1 mM Na3VO4, 0.01% Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of 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 Resonance Energy Transfer signal in Time-Resolved Fluorescence (TR-FRET) (ex340 nm. At 620 nm, at 655 nm) was measured after that and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range from 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value. KDR (VEGFR2) (enzyme assay)
[000551] In a final reaction volume of 30 μL, KDR (h) (150 ng / ml) was incubated with 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.1 mM Na3VO4, 0.01% Triton-X-100, 500 nM Btn-Flt3 and 3 μM ATP in the presence of 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% BSA which was present for 60 minutes at room temperature. The Resonance Energy Transfer signal in Time-Resolved Fluorescence (TR-FRET) (ex340 nm. At 620 nm, at 655 nm) was measured after that and the results are expressed in RFU (Relative Fluorescence Units). In this assay, the inhibitory effect of different compound concentrations (range from 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC5o) value. Ba / Fβ-FGFR1 (less IL3 or more IL3) (cell proliferation assay)
[000552] In a 384 well plate, 100 nl of the compound dilution in DMSO was sprayed before adding 50 μl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM of L-Glutamine and 50 μg / ml Gentamicin) containing 20,000 cells per cell reservoir transfected with Ba / FS-FGFR1. 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 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 the RFU's (Relative Fluorescence Units) (ex. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader .
[000553] In this assay, the inhibitory effect of different compound concentrations (range 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value. Ba / F3-FGFR3 (less IL3 or more IL3) (cell proliferation assay)
[000554] In a 384 well plate, 100 nl of the compound dilution in DMSO was sprayed before adding 50 μl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM of L-Glutamine and 50 μg / ml Gentamicin) containing 20,000 cells per cell reservoir transfected with Ba / F3-FGFR3. 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 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 the RFU's (Relative Fluorescence Units) (ex. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader .
[000555] In this assay, the inhibitory effect of different compound concentrations (range 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value.
[000556] As an inverse selection the same experiment was carried out in the presence of 10 ng / ml of murine IL3. Ba / F3-KDR (less IL3 or more IL3) (cell proliferation assay)
[000557] In a 384 well plate, 100 nl of the compound dilution in DMSO was sprayed before adding 50 μl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM of L-Glutamine and 50 μg / ml Gentamicin) containing 20,000 cells per cell reservoir transfected with Ba / F3-KDR. 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 K3Fe (CN) 6, 0.5 mM K4Fe (CN) is 0.15 mM Resazurin and 100 mM phosphate buffer) were added to the reservoirs, incubated for 4 hours at 37 ° C and 5% CO before RFU’s (Relative Fluorescence Units) (eg. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader.
[000558] In this assay, the inhibitory effect of different compound concentrations (range from 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value.
[000559] As an inverse selection 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)
[000560] In a 384 well plate, 100 nl of the compound dilution in DMSO was sprayed before adding 50 μl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM of L-Glutamine and 50 μg / ml Gentamicin) containing 20,000 cells per cell reservoir 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 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 the RFU's (Relative Fluorescence Units) (ex. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader .
[000561] In this assay, the inhibitory effect of different compound concentrations (range 10 μM to 0.1 nM) was determined and used to calculate a value of 1C5O (M) and pIC50 (-logIC50). Ba / F3-FGFR4 (cell proliferation assay)
[000562] In a 384 well plate, 100 nl of the compound dilution in DMSO was sprayed before adding 50 μl of cell culture medium (RPMI-1640 free of phenol red, 10% FBS, 2 mM of L-Glutamine and 50 μg / ml Gentamicin) containing 20,000 cells per transfected cell pool. 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 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 the RFU's (Relative Fluorescence Units) (ex. 540 nm., at. 590 nm.) were measured in a fluorescence plate reader .
[000563] In this assay, the inhibitory effect of different compound concentrations (range of 10 μM to 0.1 nM) was determined and used to calculate an IC50 (M) and pIC50 (-logIC50) value.
[000564] The data for the compounds of the invention in the above tests are provided in Tables A2 and A2a. Table A2ÇIf data were generated multiple times for a different compound or batches were tested, average values are reported)
Table A2 (If data was generated multiple times for a different compound or batches were tested, average values are reported)

权利要求:
Claims (16)
[0001]
1. Compound, characterized by the fact that it is of the formula (IA) or (IB):
[0002]
Compound according to claim 1, characterized by the fact that the compound is a compound of the formula (I-A).
[0003]
3. Compound according to claim 2, characterized by the fact that X1 is N, X2 is CR3a.
[0004]
4. Compound according to claim 2, characterized by the fact that X2 is N and X1 is CR3a.
[0005]
Compound according to claim 1, characterized by the fact that the compound is a compound of the formula (I-B).
[0006]
6. Compound according to any of the preceding claims, characterized by the fact that Y represents -CR18 = N-OR19.
[0007]
A compound according to any one of claims 1 to 5, characterized in that Y is -E-D.
[0008]
A compound according to claim 7, characterized by the fact that E represents (i) a bond, C2-4 alkenodiyl, -CO- 22 23 22 23 22 22 23 22 23 22 (CR R) s, (CR R ) s CO, NR (CR R) s, (CR R) s NR, 22 23 22 22 23 22 23 22 22 23 (CR R) s — CO-NR - (CR R) s— or - (CR R) s-NR -CO- (CR R) s- or (ii) a bond.
[0009]
Compound according to claim 7 or 8, characterized in that D is optionally substituted pyrazolyl.
[0010]
A compound according to any one of the preceding claims, characterized in that R2 (i) is independently selected from hydroxyl, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1- hydroxy alkyl 4, hydroxy C1-4 alkoxy, halo C1-4 alkoxy, C1-4 alkoxy C1-4 alkyl, R13, C1-4 alkoxy substituted with R13, -C (= O) -R13, C1-4 alkyl substituted with NR7R8, alkoxy C1-4 replaced with NR7R8, -NR7R8 or - C (= O) -NR7R8; or (ii) represents C1-4 alkoxy; or (iii) represents C1-4 alkoxy or fluorine.
[0011]
A compound according to any one of the preceding claims, characterized by the fact that R3 represents (i) C1-6 alkyl, C1-6 hydroxy alkyl, C1-6 haloalkyl hydroxy, C1-6 haloalkyl, C1-6 alkyl substituted with - C (= O) -C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, each of which C1-6 alkyl can optionally be substituted with one or two hydroxyl groups, C1-6 alkyl substituted with R9, C1- alkyl 6 substituted with -NR10R11, C1-6 alkyl substituted with hydroxyl and -NR10R11, C1-6 alkyl substituted with one or two halogens and - NR10R11, C1-6 alkyl substituted with -C (= O) -O-C1-6 alkyl , C1-6 alkyl substituted with -OC (= O) -NR10R11, C1-6 alkyl substituted with carboxyl, C1-6 alkyl substituted with -NR12-S (= O) 2-C1-6 alkyl, substituted C1-6 alkyl with -NR12-S (= O) 2-NR14R15, C1-6 alkyl substituted with hydroxyl and R9, -C1-6 alkyl C (R12) = NO-R12, C1-6 alkyl substituted with -C (= O) -NR10R11, C1-6 alkyl substituted with -C (= O) -R9, C2-6 alkynyl substituted with R9, hydroxy C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl or R13; or (ii) represents hydroxy C1-6 alkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, R9 substituted C1-6 alkyl, C1-6 alkyl substituted with - NR10R11, C1-6 alkoxy, C1-6 alkyl, C1-6 alkyl 6 replaced with -C (= O) - NR10R11, C2-6 alkynyl or R13; or (iii) represents hydroxy C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with R9, C1-6 alkyl substituted with -NR10R11, C1-6 alkoxy C1-6 alkyl, or C2-6 alkynyl.
[0012]
12. Compound according to any one of the preceding claims, characterized by the fact that R3a represents (i) hydrogen or chlorine, or (ii) hydrogen.
[0013]
13. A compound according to claim 1, characterized by the fact that (i) X2 represents N and X1 represents CH, n represents an integer equal to 2; and each R2 represents C1-4 alkoxy, for example CH3O-; R3 represents hydroxy C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with R9, C1-6 alkyl substituted with -NR10R11, C1-6 alkoxy C1-6 alkyl, C2-6a alkynyl; Y represents -E-D where E represents a bond and D represents C1-6 alkyl substituted pyrazolyl; R10 and R11 represent hydrogen or C1-6 alkyl; R9 represents an optionally substituted 5-membered aromatic heterocycle, such as, for example, optionally substituted imidazolyl; or (11) X1 represents N and X2 represents CH or X1 represents CH and X2 represents N; n represents an integer equal to 2, 3 or 4; and each R2 represents C1-4 alkoxy, for example CH3O-, or halo, for example fluorine or chlorine; R3a represents hydrogen or chlorine; R3 represents hydroxy C1-6 alkyl, cyanoalkyl C1-6, haloalkyl C1-6, C1-6 alkyl substituted with R9, C1-6 alkyl substituted with -NR10R11, C1-6 alkoxy C1-6 alkyl, C1-6 alkyl substituted with -C (= O) -NR10R11, C2-6 alkynyl or R13; Y represents -E-D where E represents a bond and D represents an optionally substituted 5- or 6-membered aromatic heterocycle.
[0014]
14. A compound, characterized by the fact that it is in accordance with any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof.
[0015]
15. Pharmaceutical composition, characterized by the fact that it comprises a compound of the formula (I-A) or (I-B) as defined in any one of claims 1 to 14.
[0016]
16. Use of a compound as defined in any of claims 1 to 14, characterized by the fact that it is in the preparation of a medicament for (i) prophylaxis or treatment of a condition or condition of diseases mediated by FGFR kinase; or (ii) cancer prophylaxis or treatment; or (iii) cancer treatment in which the cancer is selected from prostate cancer, bladder cancer, lung cancer such as NSCLC, breast cancer, gastric cancer, and liver cancer; or (iv) cancer treatment in which 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 ; or (v) cancer treatment in which the cancer is selected from lung cancer, in particular NSCLC, oral squamous cell carcinoma, liver cancer, kidney cancer, breast cancer, colonic cancer, colorectal cancer, prostate cancer; or (vi) cancer treatment in which the cancer is multiple myeloma; or (vii) cancer treatment in which the cancer is positive multiple myeloma in t translocation (4; 14); or (viii) cancer treatment where the cancer is bladder cancer; or (ix) cancer treatment in which the cancer is bladder cancer with a chromosomal translocation in FGFR3; or (x) cancer treatment where the cancer is bladder cancer with a point mutation in FGFR3; or (xi) cancer treatment in which the cancer is a tumor with a FGFR1, FGFR2, FGFR3 or FGFR4 mutant; or (xii) cancer treatment in which the cancer is a tumor with a FGFR2 or FGFR3 mutant with gain in function; or (xiii) cancer treatment in which the cancer is a tumor with FGFR1 overexpression.

类似技术:

---

公开号 | 公开日 | 专利标题

---

ES2731216T3|2019-11-14|New compounds

---

ES2739348T3|2020-01-30|Pteridines as FGFR inhibitors

---

ES2688868T3|2018-11-07|Anti-cancer pyridopyrazines through the inhibition of FGFR kinases

---

ES2791179T3|2020-11-03|Pyridopyrazine and naphthyridine derivatives for the treatment of cancer

---

RU2701517C2|2019-09-27|Quinazolinone derivatives applicable as modulators of fgfr kinase

---

ES2765031T3|2020-06-05|Anti-cancer benzopyrazines through inhibition of fgfr kinases

---

RU2625303C2|2017-07-13|Quinolines as fgfr kinase modulators

---

ES2541493T3|2015-07-21|Benzopyrazine derivatives substituted as FGFR kinase inhibitors for the treatment of cancer diseases

---

JP2020525469A|2020-08-27|New quinolinone compound

---

BR112020010012A2|2020-10-13|pyrazolopyridinone compounds

---

BR112021011571A2|2021-08-31|THIENOPYRIDINONE COMPOUNDS

---

BR112020010004A2|2020-10-13|pyrazolopyridinone compounds

同族专利:

---

公开号 | 公开日

---

AU2012328167A1|2014-05-22|

---

HUE044576T2|2019-11-28|

---

EP2776436B1|2019-03-13|

---

MX2014004859A|2014-08-26|

---

KR102027602B1|2019-10-01|

---

US20150057293A1|2015-02-26|

---

US20160108034A1|2016-04-21|

---

US20170105978A1|2017-04-20|

---

KR20140096033A|2014-08-04|

---

US9527844B2|2016-12-27|

---

US9309241B2|2016-04-12|

---

CN104011052A|2014-08-27|

---

US9757364B2|2017-09-12|

---

ES2731216T3|2019-11-14|

---

GB201118675D0|2011-12-14|

---

SI2776436T1|2019-08-30|

---

RU2629194C2|2017-08-25|

---

IN2014MN00987A|2015-04-24|

---

JP2014530897A|2014-11-20|

---

MX349004B|2017-07-06|

---

JP6022588B2|2016-11-09|

---

LT2776436T|2019-06-10|

---

DK2776436T3|2019-06-11|

---

AU2012328167B9|2017-09-28|

---

RU2014121496A|2015-12-10|

---

EP2776436A1|2014-09-17|

---

CN104011052B|2016-06-08|

---

CA2853367A1|2013-05-02|

---

AU2012328167B2|2017-08-24|

---

BR112014010179A8|2018-01-09|

---

CA2853367C|2021-05-25|

---

BR112014010179A2|2017-04-25|

---

WO2013061077A1|2013-05-02|

---

HRP20190994T1|2019-11-29|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2940972A|1957-06-27|1960-06-14|Thomae Gmbh Dr K|Tri-and tetra-substituted pteridine derivatives|

---

US4666828A|1984-08-15|1987-05-19|The General Hospital Corporation|Test for Huntington's disease|

---

US4683202B1|1985-03-28|1990-11-27|Cetus Corp|

---

US4801531A|1985-04-17|1989-01-31|Biotechnology Research Partners, Ltd.|Apo AI/CIII genomic polymorphisms predictive of atherosclerosis|

---

US5272057A|1988-10-14|1993-12-21|Georgetown University|Method of detecting a predisposition to cancer by the use of restriction fragment length polymorphism of the gene for human poly polymerase|

---

US5192659A|1989-08-25|1993-03-09|Genetype Ag|Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes|

---

GB9125001D0|1991-11-25|1992-01-22|Ici Plc|Heterocyclic compounds|

---

US5700823A|1994-01-07|1997-12-23|Sugen, Inc.|Treatment of platelet derived growth factor related disorders such as cancers|

---

US6331555B1|1995-06-01|2001-12-18|University Of California|Treatment of platelet derived growth factor related disorders such as cancers|

---

EP0951541B1|1995-07-31|2005-11-30|Urocor, Inc.|Biomarkers and targets for diagnosis, prognosis and management of prostate disease|

---

US6218529B1|1995-07-31|2001-04-17|Urocor, Inc.|Biomarkers and targets for diagnosis, prognosis and management of prostate, breast and bladder cancer|

---

TW472045B|1996-09-25|2002-01-11|Astra Ab|Protein kinase C inhibitor compounds, method for their preparation, pharmaceutical composition thereof and intermediate used for their preparation|

---

SK158199A3|1997-05-28|2000-06-12|Rhone Poulenc Rorer Pharma|QUINOLINE AND QUINOXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/OR p56lck TYROSINE KINASES|

---

ZA988961B|1997-10-06|1999-10-04|Asta Medica Ag|Methods of modulating serine/threonine protein kinase function with 5-azaquinoxaline-based compounds.|

---

WO2000042026A1|1999-01-15|2000-07-20|Novo Nordisk A/S|Non-peptide glp-1 agonists|

---

KR20020027649A|1999-09-15|2002-04-13|로즈 암스트롱, 크리스틴 에이. 트러트웨인|Pteridinones as Kinase Inhibitors|

---

DE10013318A1|2000-03-17|2001-09-20|Merck Patent Gmbh|Quinoxaline derivatives are used as photo-stable UV filters in cosmetic or pharmaceutical sunscreens for the hair or skin|

---

WO2002076985A1|2001-03-23|2002-10-03|Smithkline Beecham Corporation|Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases|

---

US7569592B2|2001-12-18|2009-08-04|Merck & Co., Inc.|Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5|

---

DK1463506T3|2001-12-24|2010-01-11|Astrazeneca Ab|Substituted quinazoline derivatives as inhibitors of aurora kinases|

---

JP2003213463A|2002-01-17|2003-07-30|Sumitomo Chem Co Ltd|Metal anticorrosive and cleaning solution|

---

US7074534B2|2002-07-10|2006-07-11|E. I. Du Pont De Nemours And Company|Polymeric charge transport compositions and electronic devices made with such compositions|

---

US7825132B2|2002-08-23|2010-11-02|Novartis Vaccines And Diagnostics, Inc.|Inhibition of FGFR3 and treatment of multiple myeloma|

---

EP1549614A4|2002-10-03|2008-04-16|Targegen Inc|Vasculostatic agents and methods of use thereof|

---

AR043059A1|2002-11-12|2005-07-13|Bayer Pharmaceuticals Corp|DERIVATIVES OF INDOLIL PIRAZINONA USEFUL FOR THE TREATMENT OF HYPER-PROLIFERATIVE DISORDERS|

---

US7098332B2|2002-12-20|2006-08-29|Hoffmann-La Roche Inc.|5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones|

---

AT433967T|2003-01-17|2009-07-15|Warner Lambert Co|2-AMINOPYRIDINE SUBSTITUTED HETEROCYCLES AS INHIBITORS OF CELLULAR PROLIFERATION|

---

WO2004098494A2|2003-04-30|2004-11-18|Cytokinetics, Inc.|Compounds, compositions, and methods|

---

BRPI0410348A|2003-05-14|2006-05-30|Torreypines Therapeutics Inc|compounds and uses thereof in amyloid-beta modulation|

---

DE10323345A1|2003-05-23|2004-12-16|Zentaris Gmbh|New pyridopyrazines and their use as kinase inhibitors|

---

PL1636228T3|2003-05-23|2009-04-30|Aeterna Zentaris Gmbh|Novel pyridopyrazines and use thereof as kinase modulators|

---

WO2005007099A2|2003-07-10|2005-01-27|Imclone Systems Incorporated|Pkb inhibitors as anti-tumor agents|

---

US7339065B2|2003-07-21|2008-03-04|Bethesda Pharmaceuticals, Inc.|Design and synthesis of optimized ligands for PPAR|

---

ES2293354T3|2003-10-17|2008-03-16|4 Aza Ip Nv|PTERIDINE DERIVATIVES REPLACED BY HETEROCICLES AND ITS USE IN THERAPY.|

---

EP1692085A4|2003-11-07|2010-10-13|Novartis Vaccines & Diagnostic|Inhibition of fgfr3 and treatment of multiple myeloma|

---

SG150533A1|2003-11-20|2009-03-30|Janssen Pharmaceutica Nv|6-alkenyl and 6-phenylalkyl substituted 2-quinolinones and 2- quinoxalinones as poly polymerase inhibitors|

---

EP1689740A1|2003-11-24|2006-08-16|F.Hoffmann-La Roche Ag|Pyrazolyl and imidazolyl pyrimidines|

---

PL1706385T3|2003-12-23|2011-03-31|Astex Therapeutics Ltd|Pyrazole derivatives as protein kinase modulators|

---

US7205316B2|2004-05-12|2007-04-17|Abbott Laboratories|Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands|

---

US7098222B2|2004-05-12|2006-08-29|Abbott Laboratories|Bicyclic-substituted amines having cyclic-substituted monocyclic substituents|

---

JP2008511599A|2004-08-31|2008-04-17|アストラゼネカアクチボラグ|Quinazolinone derivatives and their use as B-Raf inhibitors|

---

EP1805174A1|2004-10-14|2007-07-11|F.Hoffmann-La Roche Ag|1,5-naphthyridine azolidinones having cdk1 antiproliferative activity|

---

EP2650011A1|2004-12-24|2013-10-16|Spinifex Pharmaceuticals Pty Ltd|Method of treatment or prophylaxis|

---

AU2006212726C1|2005-02-14|2013-05-16|Bionomics Limited|Novel tubulin polymerisation inhibitors|

---

WO2006092430A1|2005-03-03|2006-09-08|Universität des Saarlandes|Selective inhibitors of human corticosteroid synthases|

---

US20090156617A1|2005-05-12|2009-06-18|Northrup Alan B|Tyrosine kinase inhibitors|

---

CA2608362A1|2005-05-18|2006-11-23|Wyeth|4, 6-diamino-[1,7] naphthyridine-3-carbonitrile inhibitors of tpl2 kinase and methods of making and using the same|

---

GB0513692D0|2005-07-04|2005-08-10|Karobio Ab|Novel pharmaceutical compositions|

---

EP1790342A1|2005-11-11|2007-05-30|Zentaris GmbH|Pyridopyrazine derivatives and their use as signal transduction modulators|

---

AU2006313701B2|2005-11-11|2012-05-31|Aeterna Zentaris Gmbh|Novel pyridopyrazines and their use as modulators of kinases|

---

US8217042B2|2005-11-11|2012-07-10|Zentaris Gmbh|Pyridopyrazines and their use as modulators of kinases|

---

NZ568807A|2005-12-21|2011-05-27|Janssen Pharmaceutica Nv|Triazolopyridazines as tyrosine kinase modulators|

---

EP2024342A2|2006-05-01|2009-02-18|Pfizer Products Incorporated|Substituted 2-amino-fused heterocyclic compounds|

---

GB0609621D0|2006-05-16|2006-06-21|Astrazeneca Ab|Novel co-crystal|

---

JP2009537590A|2006-05-24|2009-10-29|ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング|Substituted pteridines substituted with four-membered heterocycles|

---

US20100016293A1|2006-07-03|2010-01-21|Rogier Adriaan Smits|Quinazolines and Related Heterocyclic Compounds, and Their Therapeutic Use|

---

JP2008127446A|2006-11-20|2008-06-05|Canon Inc|1,5-naphthyridine compound and organic light emitting device|

---

WO2008076278A2|2006-12-13|2008-06-26|Schering Corporation|Methods of cancer treatment with igf1r inhibitors|

---

WO2008080015A2|2006-12-21|2008-07-03|Plexxikon, Inc.|Compounds and methods for kinase modulation, and indications therefor|

---

CN101679408B|2006-12-22|2016-04-27|Astex治疗学有限公司|As the bicyclic heterocycles of FGFR inhibitor|

---

MX2009006627A|2006-12-22|2009-08-12|Novartis Ag|Quinazolines for pdk1 inhibition.|

---

KR20080062876A|2006-12-29|2008-07-03|주식회사 대웅제약|Novel antifungal triazole derivatives|

---

US20100234386A1|2007-05-10|2010-09-16|Chaudhari Amita|Quinoxaline derivatives as pi3 kinase inhibitors|

---

EP1990342A1|2007-05-10|2008-11-12|AEterna Zentaris GmbH|Pyridopyrazine Derivatives, Process of Manufacturing and Uses thereof|

---

JP2010529031A|2007-05-29|2010-08-26|グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー|Naphthyridine derivatives as PI3 kinase inhibitors|

---

AR066879A1|2007-06-08|2009-09-16|Novartis Ag|DERIVATIVES OF QUINOXALINE AS INHIBITORS OF THE TYPOSINE CINASA ACTIVITY OF THE JANUS CINASES|

---

WO2008155378A1|2007-06-21|2008-12-24|Janssen Pharmaceutica Nv|Polymorphic and hydrate forms, salts and process for preparing 6-{difluoro[6-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline|

---

WO2009019518A1|2007-08-09|2009-02-12|Astrazeneca Ab|Pyrimidine compounds having a fgfr inhibitory effect|

---

WO2009021083A1|2007-08-09|2009-02-12|Smithkline Beecham Corporation|Quinoxaline derivatives as pi3 kinase inhibitors|

---

US20090054304A1|2007-08-23|2009-02-26|Kalypsys, Inc.|Heterocyclic modulators of tgr5 for treatment of disease|

---

WO2009064835A1|2007-11-16|2009-05-22|Incyte Corporation|4-pyrazolyl-n-arylpyrimidin-2-amines and 4-pyrazolyl-n-heteroarylpyrimidin-2-amines as janus kinase inhibitors|

---

WO2009137378A2|2008-05-05|2009-11-12|Schering Corporation|Sequential administration of chemotherapeutic agents for treatment of cancer|

---

NZ588511A|2008-05-23|2012-04-27|Novartis Ag|Derivatives of quinolines and quinoxalines as protein tyrosine kinase inhibitors|

---

WO2010059771A1|2008-11-20|2010-05-27|Osi Pharmaceuticals, Inc.|Substituted pyrrolo[2,3-b]-pyridines and-pyrazines|

---

EP2389376A1|2009-01-21|2011-11-30|Basilea Pharmaceutica AG|Novel bicyclic antibiotics|

---

US20110288090A1|2009-02-02|2011-11-24|Armstrong Donna J|Inhibitors of AKT Activity|

---

TW201041888A|2009-05-06|2010-12-01|Plexxikon Inc|Compounds and methods for kinase modulation, and indications therefor|

---

JP5905385B2|2009-06-12|2016-04-20|アビバックス|Compounds useful for treating premature aging, especially progeria|

---

CA2772714C|2009-09-03|2017-09-26|Bioenergenix|Heterocyclic compounds for the inhibition of pask|

---

WO2011026579A1|2009-09-04|2011-03-10|Bayer Schering Pharma Aktiengesellschaft|Substituted aminoquinoxalines as tyrosine threonine kinase inhibitors|

---

EP2332939A1|2009-11-26|2011-06-15|Æterna Zentaris GmbH|Novel Naphthyridine derivatives and the use thereof as kinase inhibitors|

---

NZ603156A|2010-03-30|2014-10-31|Verseon Corp|Multisubstituted aromatic compounds as inhibitors of thrombin|

---

GB201007286D0|2010-04-30|2010-06-16|Astex Therapeutics Ltd|New compounds|

---

US8513421B2|2010-05-19|2013-08-20|Millennium Pharmaceuticals, Inc.|Substituted hydroxamic acids and uses thereof|

---

US9096590B2|2010-05-24|2015-08-04|Intellikine Llc|Substituted benzoxazoles as PI3 kinase inhibitors|

---

GB201020179D0|2010-11-29|2011-01-12|Astex Therapeutics Ltd|New compounds|

---

CN102532141A|2010-12-08|2012-07-04|中国科学院上海药物研究所|-triazolo- -triazine compounds, as well as preparation method and use thereof|

---

PE20140293A1|2011-01-31|2014-03-19|Novartis Ag|NEW HETERO CYCLIC DERIVATIVES|

---

TWI592411B|2011-02-23|2017-07-21|英特爾立秦有限責任公司|Combination of kinase inhibitors and uses thereof|

---

WO2012118492A1|2011-03-01|2012-09-07|Array Biopharma Inc.|Heterocyclic sulfonamides as raf inhibitors|

---

WO2013032951A1|2011-08-26|2013-03-07|Neupharma, Inc.|Certain chemical entities, compositions, and methods|

---

CN104080455B|2011-09-14|2018-07-31|润新生物公司|Certain chemical entities, composition and method|

---

WO2013043935A1|2011-09-21|2013-03-28|Neupharma, Inc.|Certain chemical entites, compositions, and methods|

---

CA2850763A1|2011-10-04|2013-04-11|Gilead Calistoga Llc|Novel quinoxaline inhibitors of pi3k|

---

GB201118654D0|2011-10-28|2011-12-07|Astex Therapeutics Ltd|New compounds|

---

GB201118652D0|2011-10-28|2011-12-07|Astex Therapeutics Ltd|New compounds|

---

GB201118675D0|2011-10-28|2011-12-14|Astex Therapeutics Ltd|New compounds|

---

JO3210B1|2011-10-28|2018-03-08|Merck Sharp & Dohme|Fused bicyclic oxazolidinone cetp inhibitor|

---

PT2771342T|2011-10-28|2016-08-17|Novartis Ag|Purine derivatives and their use in the treatment of disease|

---

GB201118656D0|2011-10-28|2011-12-07|Astex Therapeutics Ltd|New compounds|

---

GB201209613D0|2012-05-30|2012-07-11|Astex Therapeutics Ltd|New compounds|

---

GB201209609D0|2012-05-30|2012-07-11|Astex Therapeutics Ltd|New compounds|

---

GB201307577D0|2013-04-26|2013-06-12|Astex Therapeutics Ltd|New compounds|

---

US9221804B2|2013-10-15|2015-12-29|Janssen Pharmaceutica Nv|Secondary alcohol quinolinyl modulators of RORγt|

---

JO3512B1|2014-03-26|2020-07-05|Astex Therapeutics Ltd|Quinoxaline derivatives useful as fgfr kinase modulators|

---

WO2015144808A1|2014-03-26|2015-10-01|Astex Therapeutics Ltd|Combinations of an fgfr inhibitor and an igf1r inhibitor|

---

PL3122358T3|2014-03-26|2021-06-14|Astex Therapeutics Ltd.|Combinations of fgfr- and cmet-inhibitors for the treatment of cancer|

---

JOP20200201A1|2015-02-10|2017-06-16|Astex Therapeutics Ltd|Pharmaceutical compositions comprising n--n'--n-[3-quinoxalin-6-yl]ethane-1,2-diamine|GB201007286D0|2010-04-30|2010-06-16|Astex Therapeutics Ltd|New compounds|

---

GB201020179D0|2010-11-29|2011-01-12|Astex Therapeutics Ltd|New compounds|

---

GB201118656D0|2011-10-28|2011-12-07|Astex Therapeutics Ltd|New compounds|

---

GB201118652D0|2011-10-28|2011-12-07|Astex Therapeutics Ltd|New compounds|

---

GB201118654D0|2011-10-28|2011-12-07|Astex Therapeutics Ltd|New compounds|

---

GB201118675D0|2011-10-28|2011-12-14|Astex Therapeutics Ltd|New compounds|

---

AR090844A1|2012-04-27|2014-12-10|Actelion Pharmaceuticals Ltd|PROCESS TO MANUFACTURE DERIVATIVES OF NAFTIRIDINE|

---

GB201209613D0|2012-05-30|2012-07-11|Astex Therapeutics Ltd|New compounds|

---

GB201209609D0|2012-05-30|2012-07-11|Astex Therapeutics Ltd|New compounds|

---

AR094812A1|2013-02-20|2015-08-26|Eisai R&D Man Co Ltd|DERIVED FROM MONOCYCLIC PYRIDINE AS AN FGFR INHIBITOR|

---

GB201307577D0|2013-04-26|2013-06-12|Astex Therapeutics Ltd|New compounds|

---

JP6112724B2|2013-10-31|2017-04-12|日本化薬株式会社|1,5-naphthyridine derivative and insecticide comprising the same as an active ingredient|

---

JO3512B1|2014-03-26|2020-07-05|Astex Therapeutics Ltd|Quinoxaline derivatives useful as fgfr kinase modulators|

---

WO2015144808A1|2014-03-26|2015-10-01|Astex Therapeutics Ltd|Combinations of an fgfr inhibitor and an igf1r inhibitor|

---

PL3122358T3|2014-03-26|2021-06-14|Astex Therapeutics Ltd.|Combinations of fgfr- and cmet-inhibitors for the treatment of cancer|

---

CA2956270A1|2014-08-18|2016-02-25|Eisai R&D Management Co., Ltd.|Salt of monocyclic pyridine derivative and crystal thereof|

---

JOP20200201A1|2015-02-10|2017-06-16|Astex Therapeutics Ltd|Pharmaceutical compositions comprising n--n'--n-[3-quinoxalin-6-yl]ethane-1,2-diamine|

---

US10478494B2|2015-04-03|2019-11-19|Astex Therapeutics Ltd|FGFR/PD-1 combination therapy for the treatment of cancer|

---

LT3353177T|2015-09-23|2020-08-25|Janssen Pharmaceutica Nv|Tricyclic heterocycles for the treatment of cancer|

---

CN108137546B|2015-09-23|2021-07-27|詹森药业有限公司|Bis-heteroaryl substituted 1, 4-benzodiazepine compounds and their use for the treatment of cancer|

---

US9855255B1|2017-05-26|2018-01-02|King Saud University|Substituted naphthyridinyl hydrazines as anti-liver cancer agents|

---

JPWO2019189241A1|2018-03-28|2021-03-18|エーザイ・アール・アンド・ディー・マネジメント株式会社|Hepatocellular carcinoma therapeutic agent|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2019-08-13| 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 |

---

2019-09-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-02-18| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

---

2020-08-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2020-12-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/10/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201161552883P| true| 2011-10-28|2011-10-28|

---

GB1118675.6|2011-10-28|

---

GBGB1118675.6A|GB201118675D0|2011-10-28|2011-10-28|New compounds|

---

US61/552883|2011-10-28|

---

PCT/GB2012/052669|WO2013061077A1|2011-10-28|2012-10-26|New compounds|

---