NEW COMPOUNDS AND METHODS
20230002346 · 2023-01-05
Assignee
Inventors
- Michael J. Rawling (London, GB)
- Edward I. Balmond (London, GB)
- Callum Finn (London, GB)
- Márton Vass (London, GB)
- Mark David Rackham (London, GB)
- Edward D. Savory (London, GB)
- Rebecca Paul (London, GB)
Cpc classification
C07D405/04
CHEMISTRY; METALLURGY
A61P25/28
HUMAN NECESSITIES
C07D401/10
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
C07D491/056
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D401/04
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
Abstract
The present invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and/or prodrug thereof. The present invention also relates to pharmaceutical compositions comprising the compounds of the invention, and to their use in the treatment or prevention of medical conditions in which inhibition of c-Abl is beneficial. (I)
##STR00001##
Claims
1. A compound of formula (I): ##STR00208## or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, N-oxide thereof, and/or prodrug thereof, wherein R.sup.1 is selected from the group consisting of H and halo, preferably H, F, and Cl, more preferably H; R.sup.2 is selected from the group consisting of —OCF.sub.2Cl, —OCF.sub.3, —SCF.sub.3, —SCF.sub.2Cl, —CF.sub.2CF.sub.3, —CF.sub.2CF.sub.2Cl, —OCF.sub.2CF.sub.3, —SF.sub.5, OF.sub.2CH.sub.3, —SOCF.sub.3, —SO.sub.2CF.sub.3, —OCF.sub.2CF.sub.2H, and —SCF.sub.2H, preferably —OCF.sub.2C.sub.1 and —OCF.sub.3; A is ##STR00209## R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently selected from the group consisting of: (i) H, halo, —OH, —C(O)NR.sup.dR.sup.e, —NR.sup.aR.sup.b, cyano, —C(O)OR.sup.c, and —C(O)R.sup.c; (ii) C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, optionally substituted with one or more substituents independently selected from the group consisting of —NR.sup.aR.sup.b, cyano, —OR.sup.c, halo, oxo, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycle, optionally wherein the 5- to 10-membered heteroaryl and 4- to 10-membered heterocycle are independently substituted with one or more substituents selected from halo and C.sub.1-C.sub.7 alkyl, wherein the C.sub.1-C.sub.7 alkyl is optionally substituted with one or more halo atoms; (iii) 6- to 10-membered aryl and 5- to 10 membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo, —C(O)NR.sup.dR.sup.e, —NR.sup.dR.sup.e, —OH, oxo, cyano, —C(O)OR.sup.c, and —C(O)R.sup.c, C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.3 alkyl)-O—(C.sub.1-C.sub.3 alkyl), and 4- to 10-membered heterocycle, wherein the 4- to 10-membered heterocycle is optionally substituted with an oxo group, wherein the alkyl, alkenyl, and alkynyl groups are each optionally independently substituted with one or more halo atoms; and (iv) 4- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, —C(O)NR.sup.dR.sup.e, —NR.sup.dR.sup.e, cyano, —C(O)OR.sup.c, and —C(O)R.sup.c, C.sub.1-C.sub.7 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.3 alkyl)-O—(C.sub.1-C.sub.3 alkyl), 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycle, wherein the alkyl, alkenyl, and alkynyl groups are each optionally independently substituted with one or more halo atoms; each R.sup.7 and R.sup.8 is independently selected from the group consisting of H and halo, preferably H, F and Cl, more preferably H and F, most preferably H; each R.sup.a, R.sup.b, and R.sup.c is independently selected from H and C.sub.1-C.sub.7 alkyl, wherein the C.sub.1-C.sub.7alkyl is optionally substituted with one or more halo atoms; and each R.sup.d and R.sup.e are independently selected from H and C.sub.1-C.sub.7 alkyl, wherein the C.sub.1-C.sub.7 alkyl is optionally substituted with one or more halo atoms, or R.sup.d and R.sup.e can be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered saturated, partially saturated, or unsaturated ring, wherein the ring contains one or more heteroatoms; preferably R.sup.5 and R.sup.3 and/or R.sup.4 are selected from substituents (iii), more preferably R.sup.5 or R.sup.4 is selected from substituents (iii).
2. A compound according to claim 1, wherein the compound is a compound of formula (II): ##STR00210## wherein X is F or C.sub.1; and wherein A is ##STR00211##
3. A compound according to claim 2, wherein X═Cl.
4. A compound according to any preceding claim, wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently selected from the group consisting of: (i) H and cyano; (ii) C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, optionally substituted with one or more substituents independently selected from halo and 5- or 6-membered heterocycle; (iii) 5- or 6-membered heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halo, and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms; and (iv) phenyl optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and 4-membered heterocycle, wherein the 4-membered heterocycle is optionally substituted with an oxo group, wherein the alkyl groups are optionally substituted with one or more halo atoms; (v) 5- to 10-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and (C.sub.1-C.sub.3 alkyl)-O—(C.sub.1-C.sub.3 alkyl), wherein the alkyl groups are optionally substituted with one or more halo atoms; preferably R.sup.5 and R.sup.3 and/or R.sup.4 are selected from substituents (iv) and (v), more preferably R.sup.5 or R.sup.4 is selected from substituents (iv) and (v).
5. A compound according to any of claims 2 to 4, wherein the compound is a compound of formula (IIa): ##STR00212## wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of: (i) H and cyano; (ii) C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, optionally substituted with one or more substituents independently selected from halo and 5- or 6-membered heterocycle; (iii) 5- or 6-membered heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halo, and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms; and (iv) phenyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and 4-membered heterocycle, wherein the 4-membered heterocycle is optionally substituted with an oxo group, wherein the alkyl groups are optionally substituted with one or more halo atoms; (v) 5- to 10-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and (C.sub.1-C.sub.3 alkyl)-O—(C.sub.1-C.sub.3 alkyl), wherein the alkyl groups are optionally substituted with one or more halo atoms; preferably R.sup.3 and/or R.sup.4 is selected from substituents (iv) and (v), more preferably R.sup.4 is selected from substituents (iv) and (v).
6. A compound according to claim 5, wherein R.sup.3 is selected from the group consisting of: (i) H, C.sub.1-C.sub.6 alkoxy, and cyano; (ii) C.sub.1-C.sub.6 alkyl, optionally substituted with one or more halo atoms; (iii) phenyl and 5- or 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms; and (iv) 5- or 6-membered heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halo and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms. preferably R.sup.3 is selected from substituents (iii).
7. A compound according to claim 5 or 6, wherein R.sup.4 is selected from the group consisting of: (i) H; (ii) C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more substituents selected from halo and 5- or 6-membered heterocycle; (iii) phenyl, optionally substituted with one or more substituents independently selected from halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and 4-membered heterocycle, wherein the 4-membered heterocycle is optionally substituted with an oxo group, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms; (iv) 5- or 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and (C.sub.1-C.sub.3 alkyl)-O—(C.sub.1-C.sub.3 alkyl), wherein the alkyl groups are optionally substituted with one or more halo atoms; (v) 5- or 6-membered heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halo, and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms; (vi) group B ##STR00213## wherein each Y and Z is independently selected from C, S, O, and N, at least one Y or Z is S, O or N, each Y and Z is optionally independently substituted with halo, or C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms, n is 0 or 1, m is 0 or 1; (vii) group C ##STR00214## wherein each Y and Z is independently selected from C, S, O, and N, at least one Y or Z is S, O or N, each Y and Z is optionally independently substituted with halo or C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6alkyl is optionally substituted with one or more halo atoms, n is 0 or 1, m is 0 or 1; and (viii) group D ##STR00215## wherein each Y and Z is independently selected from C, S, O, and N, at least one Z is C, each Y and Z is optionally independently substituted with halo or C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6alkyl is optionally substituted with one or more halo atoms, R.sup.9 is selected from halo and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms, n is 0 or 1; preferably R.sup.4 is selected from substituents (iii), (iv), (vi), (vii), and (viii).
8. A compound according to any of claims 2 to 4, wherein the compound is a compound of formula (IIb): ##STR00216## wherein R.sup.5 and R.sup.6 are independently selected from the group consisting of: (i) H and cyano; (ii) C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, optionally substituted with one or more substituents independently selected from halo and 5- or 6-membered heterocycle; and (iii) 5- or 6-membered heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halo, and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms; and (iv) phenyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and 4-membered heterocycle, wherein the 4-membered heterocycle is optionally substituted with an oxo group, wherein the alkyl groups are optionally substituted with one or more halo atoms; (v) 5- to 10-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.3 alkyl)-O—(C.sub.1-C.sub.3 alkyl), wherein the alkyl groups are optionally substituted with one or more halo atoms; preferably R.sup.5 is selected from substituents (iv) and (v).
9. A compound according to claim 8, wherein R.sup.5 is a 5- or 6-membered heteroaryl group, optionally substituted with one or more substituents independently selected from the group consisting of halo and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms.
10. A compound according to claim 8 or 9, wherein R.sup.6 is selected from the group consisting of H and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with one or more halo atoms.
11. A compound according to any preceding claim, wherein the compound is N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(3-ethoxy-1-methyl-pyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; 1-(2-Morpholinoethyl)-6-oxo-N-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1-methyl-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-[(3S)-tetrahydrofuran-3-yl]pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-(1H-pyrazol-5-yl)pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-[(3R)-tetrahydrofuran-3-yl]pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-thiazol-2-yl-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(2-methyl-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(2,4-dimethoxypyrimidin-5-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-thiazol-5-yl-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(2-methoxypyrimidin-5-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(6-methoxy-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(1-isopropylpyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(1-cyclopropylpyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-[(3R)-1-methylpyrrolidin-3-yl]-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-[(3S)-1-methylpyrrolidin-3-yl]-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(1,5-dimethylpyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(3-cyclopropyl-1-methyl-pyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3-cyanophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-[1-(cyclopropylmethyl)pyrazol-4-yl]-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-[1-(2-methoxyethyl)pyrazol-4-yl]-6-oxo-pyridine-3-carboxamide; 1-(1-tert-Butylpyrazol-4-yl)-N-[4-[chloro(difluoro)methoxy]phenyl]-6-oxo-pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,4-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1-methyl-1H-pyrazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-Methyl-6-oxo-N-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxamide N-[4-(Chlorodifluoromethoxy)phenyl]-1-[1-(difluoromethyl)-1H-pyrazol-4-yl]-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-6-oxo-1-(quinoxalin-5-yl)-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(4-methoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-(5-Chloro-1-methyl-1H-pyrazol-4-yl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(2,3-dimethoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,4-dihydro-1H-2-benzopyran-6-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1,3-dihydro-2-benzofuran-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3-methoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-6-oxo-1-(quinoxalin-6-yl)-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,4-dihydro-1H-2-benzopyran-7-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,4-dihydro-1H-2-benzopyran-8-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,4-dihydro-1H-2-benzopyran-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,4-dimethoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1-methyl-1H-1,2,3-benzotriazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3,5-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-(1,3-Benzoxazol-4-yl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-[4-(2-oxoazetidin-1-yl)phenyl]pyridine-3-carboxamide; 6-Oxo-1-(pyrimidin-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1.6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-6-oxo-1-(pyrimidin-5-yl)-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(1-methylpyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-(3-pyridyl)pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(5-fluoro-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(5-cyano-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-phenyl-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(5-methyl-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-5-methoxy-6-oxo-1-pyrimidin-5-yl-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-5-methyl-6-oxo-1-pyrimidin-5-yl-pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-5-(morpholin-4-yl)-6-oxo-1-(pyrimidin-5-yl)-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(5-methoxy-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-6-oxo-1-[5-(trifluoromethyl)-3-pyridyl]pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(5-chloro-3-pyridyl)-6-oxo-pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-{imidazo[1,2-b]pyridazin-3-yl}-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-6′-methyl-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-5′-(difluoromethyl)-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1,5-naphthyridin-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-{2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-{1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl}-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-{2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl}-6-oxo-1,6-dihydropyridine-3-carboxamide; 6′-Chloro-N-[4-(chlorodifluoromethoxy)phenyl]-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-{2H,3H-furo[2,3-b]pyridin-5-yl}-6-oxo-1,6-dihydropyridine-3-carboxamide; 2′-Chloro-N-[4-(chlorodifluoromethoxy)phenyl]-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-2-oxo-6′-(trifluoromethyl)-2H-[1.3′-bipyridine]-5-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 5-{[4-(Chlorodifluoromethoxy)phenyl]carbamoyl}-2-oxo-2H-[1.3′-bipyridin]-1′-ium-t-olate; N-[4-(Chlorodifluoromethoxy)phenyl]-5-cyano-1-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1.6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-6-oxo-5-(1H-pyrazol-3-yl)-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-5-(3-pyridyl)pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-6-oxo-5-(pyrimidin-5-yl)-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-5-(1-ethyl-1H-pyrazol-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-5-(1-methyl-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-methyl-5-(1-methylpyrazol-4-yl)-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-5-(5-fluoro-3-pyridyl)-1-methyl-6-oxo-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-5-phenyl-pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-[3,3′-bipyridine]-5-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-5-pyrazol-1-yl-pyridine-3-carboxamide; N-[4-[Chloro(difluoro)methoxy]phenyl]-5-imidazol-1-yl-1-methyl-6-oxo-pyridine-3-carboxamide; N-[4-(Chlorodifluoromethoxy)phenyl]-2-oxo-6-(1H-pyrazol-5-yl)-1,2-dihydropyridine-4-carboxamide; 2-Oxo-6-(pyrimidin-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1,2-dihydropyridine-4-carboxamide; or N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide; or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, N-oxide thereof, and/or prodrug thereof.
12. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutically acceptable carrier, excipient, and/or diluent.
13. The compound according to any one of claims 1 to 11, or the pharmaceutical composition of claim 12, for use in therapy.
14. The compound according to any one of claims 1 to 11, or the pharmaceutical composition of claim 12, for use in the treatment or prevention of a neurodegenerative disorder, a cancer, a prion disease, a viral infection, diabetes, an inflammatory disease, acute pancreatitis (preferably severe acute pancreatitis), pulmonary arterial hypertension, or a skeletal or muscular dystrophy, preferably a neurodegenerative disorder or a cancer.
15. Use of the compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder, a cancer, a prion disease, a viral infection, diabetes, an inflammatory disease, acute pancreatitis (preferably severe acute pancreatitis), pulmonary arterial hypertension, or a skeletal or muscular dystrophy, preferably a neurodegenerative disorder or a cancer.
16. A method for the treatment or prevention of a disease or condition responsive to c-Abl inhibition comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 11, or the pharmaceutical composition of claim 12, to a subject.
17. The method of claim 16, wherein the disease or condition is a neurodegenerative disorder, a cancer, a prion disease, a viral infection, diabetes, an inflammatory disease, acute pancreatitis (preferably severe acute pancreatitis), pulmonary arterial hypertension, or a skeletal or muscular dystrophy, preferably a neurodegenerative disorder or a cancer.
18. The compound or pharmaceutical composition for use according to claim 14, the use of the compound according to claim 15, or the method of claim 16, wherein the neurodegenerative disorder is selected from Alzheimer disease, Down's syndrome, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, Niemann-Pick disease, Parkinson's disease, Huntington's disease (HD), dentatorubropallidoluysian atrophy, Kennedy's disease, and spinocerebellar ataxia, fragile X (Rett's) syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12, Alexander disease, Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, Steele-Richardson-Olszewski disease, and Tabes dorsalis.
19. The compound for use, use of the compound, or method, of claim 18, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS) or Parkinson's disease, preferably ALS.
20. The compound or pharmaceutical composition for use according to claim 14, the use of the compound according to claim 15, or the method of claim 16, wherein the cancer is leukaemia, preferably chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), or mixed-phenotype acute leukaemia (MPAL), or any central nervous system (CNS) metastases thereof, preferably CML or ALL.
Description
EXAMPLES AND INTERMEDIATE COMPOUNDS
[0238] All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Reagent grade solvents were used, unless otherwise specified. The reactions facilitated by microwave heating were performed on a Biotage Initiator system using process vials fitted with aluminum caps and septa. Preparative low pressure chromatography was performed using a CombiFlash Companion or Combiflash RF systems equipped with RediSep or GraceResolv silica and C18 RP columns. Preparative RP HPLC was performed on either a Gilson system with a UV detector, a Teledyne Isco ACCQPrep HP125 system with 200-400 nm UV variable wavelength detector and a Purlon mass spectrometer, or an Agilent 1260 Infinity system equipped with DAD and mass-detectors. The RP HPLC systems were equipped with at least one of the following columns: an ACE-5AQ, 100×21.2 mm, 5 μm column; a Phenomenex Synergi Hydro-RP 80A AXIA, 100×21.2 mm, 4 μm column; an ACE SuperC18, 100×21.2 mm, 5 μm column; a RediSep C18Prep, 250 mm×50.0 mm, 5 μm column; or a Waters Sunfire C18 OBD Prep Column, 100A, 5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100A, 10 μm, 19 mm×10 mm. The purest fractions were collected, concentrated and dried under vacuum. Compounds were typically dried in a vacuum oven between 40° C. and 60° C. prior to purity analysis. Quoted yields include purity factoring when marked with a superscript $. Reactions were performed at RT unless otherwise stated. The compounds were automatically named using OpenEye rules.
[0239] Compound analysis was performed by LCMS, HPLC and UPLC. LCMS data was collected using an Agilent 1100 HPLC system with a Waters ZQ mass spectrometer connected, a Waters ACQUITY H-class UPLC with ACQUITY QDa mass detector connected, an Agilent 1100 Series LC/MSD system with DAD\ELSD and Agilent LC\MSD VL (G1956A), SL (G1956B) mass-spectrometer; or an Agilent 1200 Series LC/MSD system with DAD\ELSD and Agilent LC\MSD SL (G6130A), SL (G6140A) mass-spectrometer. The mass values reported correspond to the parent molecule with a hydrogen added [MH].sup.+ or a sodium added [MNa].sup.+. The HPLC and UPLC data was collected on either an Agilent 1100 system with DAD, an Agilent 1200 system with DAD, or an Agilent 1290 Infinity system with DAD. The analytical HPLC or UPLC systems utilised the following columns and methods: a Phenomenex Kinetex XB-C18 column (1.7 μm, 2.1×100 mm) at 40° C. and 0.5 mL/min with a gradient of 5% MeCN (.sup.+0.085% TFA) in water (.sup.+0.1% TFA) for 1.0 min, 5-100% over 8.0 min, holding for 0.2 min, then reequilibration for 0.8 min with a collection wavelength of 200-300 nm; a Phenomenex Kinetex XB-C18 column (1.7 μm, 2.1×50 mm) at 40° C. and 0.8 mL/min with a gradient of 5% MeCN (.sup.+0.085% TFA) in water (.sup.+0.1% TFA) for 1.0 min, 5-100% over 3.0 min, holding for 0.2 min, then reequilibration for 0.8 min with a collection wavelength of 200-300 nm; a Zorbax SB-C18 column (1.8 μm, 4.6×15 mm Rapid Resolution cartridge) at 3.0 mL/min with a gradient of 0% MeCN (0.1% formic acid) in water (0.1% formic acid) for 0.01 min, 0-100% over 1.5 min, holding for 0.3 min then reequilibration for 0.2 min, or a Phenomenex Kinetex XB-C18 column (1.7 μm, 2.1×50 mm) at 40° C. and 0.8 mL/min with a gradient of 0-20% MeCN (.sup.+0.085% TFA) in water (.sup.+0.1% TFA) over 0.9 min, ramping up to 100% in 0.1 min, holding for 0.2 min, then reequilibrate for 0.8 min with a collection wavelength of 200-300 nm.
Intermediate 1
Methyl 1-(2-morpholinoethyl)-6-oxo-pyridine-3-carboxylate
[0240] ##STR00023##
[0241] Methyl 6-oxo-1,6-dihydro-3-pyridinecarboxylate (123 mg, 0.80 mmol), 4-(2-chloroethyl)morpholine. HCl (223 mg, 1.20 mmol), TBAI (29.6 mg, 0.08 mmol), and K.sub.2CO.sub.3 (332 mg, 2.40 mmol) in MeCN (4.0 mL) were heated at 110° C. using a microwave reactor for 60 min, filtered then concentrated in vacuo. Purification by RP column chromatography gave the title compound (162 mg, 76.0%) as a colourless gum. LCMS (ES.sup.+): 267.1 [MH].sup.+. HPLC: Rt 0.64 min, 100% purity.
Intermediate 2
Methyl 1-(1-methylpyrazol-3-yl)-6-oxo-pyridine-3-carboxylate
[0242] ##STR00024##
[0243] 1-Methyl-1H-pyrazol-3-amine (2.19 g, 22.5 mmol) and methyl coumalate (2.16 g, 20.5 mmol) in MeOH (20 mL) were stirred for 20 minutes, then the precipitate was collected by filtration and dried for 4 h under vacuum at 45° C. The crude solid was dissolved in 15% aq Na.sub.2CO.sub.3 (40 mL), heated to 40-45° C., stirred for 15 min, cooled to RT, and the solid material was collected by filtration then recrystallised from IPA to give the title compound (2.62 g, 57.3%) as an off-white solid. LCMS (ES.sup.+): 234.1 [MH].sup.+.
Intermediates 3-25
[0244] Intermediates 3-25 were prepared similarly to Intermediate 2, by ring-opening of methyl coumalate with the appropriate primary amine, followed by condensation-cyclisation; see Table 1 below.
TABLE-US-00002 TABLE 1 Reaction of methyl coumalate with the appropriate primary amine
Intermediate 26
1-(3,4-Dimethoxyphenyl)-6-oxo-pyridine-3-carboxylic acid
[0245] ##STR00050##
[0246] Methyl coumalate (503 mg, 3.25 mmol) and 3,4-dimethoxyaniline (510 mg, 3.24 mmol) in dry MeOH (10 mL) was refluxed for 2 h, cooled to RT then NaOH (264 mg, 6.50 mmol) was added and the RM stirred for an additional 12 h. The RM was treated with water (40 mL), washed with EtOAc (20 mL) and CHCl.sub.3 (20 mL). The aqueous layer was acidified to pH 2 using 10% HCl and extracted by EtOAc (2×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and the solvent was evaporated. The crude product was purified by RP HPLC to give the title compound (54.0 mg, 6.2%) as a white solid. LCMS (ES.sup.+): 276.0 [MH].sup.+.
Intermediates 27-47
[0247] Intermediates 27-47 were prepared similarly to Intermediate 26, by ring-opening of methyl coumalate with the appropriate primary amine, followed by condensation-cyclisation and subsequent ester hydrolysis; see Table 2 below.
TABLE-US-00003 TABLE 2 Reaction of methyl coumalate with the appropriate primary amine, then ester hydrolysis
Intermediate 48
5-Bromo-1-(1-methylpyrazol-4-yl)-6-oxo-pyridine-3-carboxylic acid
[0248] ##STR00074##
[0249] Intermediate 48 was prepared similarly to Intermediate 26, using methyl 3-bromo-2-oxo-2H-pyran-5-carboxylate instead of methyl coumalate and 1-methyl-1H-pyrazol-4-amine instead of 3,4-dimethoxyaniline, to give the title compound (9.54 g, 78.3%) as a yellow solid. LCMS (ES.sup.+): 298.0 [MH].sup.+.
Intermediate 49
Lithium 1-(1,3-benzoxazol-4-yl)-6-oxo-pyridine-3-carboxylate
[0250] ##STR00075##
[0251] Intermediate 25 (312 mg, 1.12 mmol) and LiOH (442 mg, 1.12 mmol) were stirred in 1:1 EtOH:water (10 mL) at RT until TLC analysis (EtOAc/10% MeOH) showed full consumption of the starting material. Solvent was removed under reduced pressure and the residue was dried under vacuum giving the title compound (244 mg, 78.4%) as a yellow solid, which was used in the next step without purification or characterisation.
Intermediate 50
Methyl 6-methoxy-5-morpholino-pyridine-3-carboxylate
[0252] ##STR00076##
[0253] Methyl 5-bromo-6-methoxynicotinate (3.04 g, 12.2 mmol) and morpholine (2.13 g, 24.4 mmol) in dry dioxane (30 mL) were treated with Cs.sub.2CO.sub.3 (11.9 g, 36.6 mmol), Pd.sub.2(dba).sub.3 (331 mg, 366 μmol) and XantPhos (421 mg, 732 μmol) then heated to 100° C. overnight. The RM was mixed with water (50 mL), extracted with EtOAc (3×50 mL), the combined organic extracts concentrated under vacuum to give the title compound which was used in the next step without further purification or characterisation.
Intermediate 51
5-Morpholino-6-oxo-1H-pyridine-3-carboxylic acid
[0254] ##STR00077##
[0255] Intermediate 50 (1.03 g, 3.97 mmol) and conc aq HCl (5.0 mL) was heated under reflux for 12 h, then concentrated under vacuum to give the title compound which was used in the next step without further purification or characterisation.
Intermediate 52
6-Oxo-5-(1H-pyrazol-5-yl)-1H-pyridine-3-carboxylic acid
[0256] ##STR00078##
[0257] Methyl 5-bromo-6-methoxynicotinate (3.04 g, 12.2 mmol), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.08 g, 15.9 mmol), K.sub.2CO.sub.3 (6.73 g, 48.8 mmol) and Pd(dppf)Cl.sub.2.DCM (500 mg, 0.61 mmol) in dioxane-water (100 mL, 1:1, v/v) was heated to 90° C. for 12 h. The RM was diluted with water (50 mL), extracted with EtOAc (2×30 mL) and the combined organic layers concentrated in vacuo.
[0258] The residue was treated with conc HCl solution (10 mL) and THF (10 mL), stirred at 35-40° C. for 1 h then the precipitated solid was filtered and dried to give the title product (922 mg, 36.7%) as a grey powder. LCMS (ES.sup.+): 206.0 [MH].sup.+.
General Amidation Procedures A, B, C, D and E
[0259] ##STR00079##
[0260] Several amidation procedures were used throughout this invention to prepare various intermediates and exemplified compounds, through reaction of the appropriate aniline with the appropriate carboxylic acid. R.sup.1 and R.sup.2 are as defined in formula (I) and Z is either A as defined in formula (I), or Z is an intermediate used in the preparation of A. General, representative amidation protocols A-E are outlined below.
General Amidation Procedure A:
[0261] The appropriate carboxylic acid (25.8 mmol) was suspended in dry DCM (100 mL) and dry DMF (200 μL) at 0° C. then COCl.sub.2 (2.22 mL, 25.8 mmol) was added dropwise and the mixture stirred at RT for 2 h. DIPEA (9.00 mL, 51.7 mmol) and the appropriate aniline (25.8 mmol) were added and the reaction stirred at RT for 18 h. Sat aq NaHCO.sub.3 (50 mL) was carefully added and the mixture extracted with DCM or EtOAc (3×50 mL). The combined organic extracts were concentrated in vacuo and typically purified by column chromatography, RP HPLC, trituration or crystallisation.
General Amidation Procedure B:
[0262] The appropriate carboxylic acid (5.91 mmol), the appropriate aniline (8.87 mmol), EDCI.HCl (2.27 g, 11.8 mmol), DMAP (72.2 mg, 591 μmol) and DIPEA (3.09 mL, 17.7 mmol) in dioxane (20 mL) was stirred under reflux until reaction completion by LCMS then concentrated in vacuo and typically purified by column chromatography, RP HPLC, trituration or crystallisation.
General Amidation Procedure C:
[0263] The appropriate carboxylic acid was suspended in dioxane (12 mL) then HATU (466 mg, 1.22 mmol) and DIPEA (213 μL, 1.22 mmol) were added and the RM stirred at 80° C. for 15 min. The appropriate aniline (284 mg, 1.47 mmol) in dioxane (1.0 mL) was added and the RM stirred at 80° C. overnight, then concentrated in vacuo and typically purified by column chromatography, RP HPLC, trituration or crystallisation.
General Amidation Procedure D:
[0264] The appropriate carboxylic acid (14.3 mmol, 1 equiv.) and CDI (17.2 mmol, 1.2 equiv.) in DMF (10 mL) was stirred at 80° C. for 2 h, then the required aniline (15.7 mmol, 1.1 equiv.) was added and the RM was stirred at 80° C. overnight. The RM was cooled to RT, DMF was removed under vacuum, the residue mixed with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum then typically purified by column chromatography, RP HPLC, trituration or crystallisation.
General Amidation Procedure E:
[0265] PyBop (253 mg, 1.12 mmol, 1.0 equiv.) was added to a solution of the appropriate carboxylic acid (1.12 mmol, 1.0 equiv.), the appropriate aniline (1.12 mmol, 1.0 equiv.) and DIPEA (213 mg, 1.65 mmol, 1.5 equiv.) in dry DMF (10 mL). The RM was stirred at RT overnight, then treated with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried under Na.sub.2SO.sub.4, concentrated under vacuum and typically purified by column chromatography, RP HPLC, trituration or crystallisation.
Intermediates 53-63
[0266] Intermediates 53-63 were prepared by similar procedures to General Amidation Procedures A-E between the appropriate carboxylic acid and the appropriate aniline; see Table 3 below. If no intermediates are specified, then the appropriate reactants were sourced commercially.
TABLE-US-00004 TABLE 3 Amidation reactions Intermediate(s) used, Amidation procedure, Form, Yield, LCMS, Int. Structure Name UPLC 53
Intermediate 64
5-Bromo-N-[4-[chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-pyridine-3-carboxamide
[0267] ##STR00091##
[0268] Intermediate 55 (1.70 g, 89.6% purity, 3.87 mmol), iodomethane (241 μL, 3.87 mmol) and K.sub.2CO.sub.3 (535 mg, 3.87 mmol) were stirred in DMSO (25 mL) for 18 h. Water (30 mL) was added to the rapidly stirring reaction mixture, which was then cooled to 0-5° C. and stirred for 10 min. The solid material was collected by filtration, washed with water (3×20 mL), then dried in the vacuum oven at 50° C. for 4 h to give the title compound (1.58 g, 94.4%.sup.$) as an off-white solid. LCMS (ES.sup.+): 407.1 [MH].sup.+. HPLC: Rt 5.71 min, 94.2% purity.
Intermediate 65
2-Chloro-6-pyrimidin-5-yl-N-[4-(trifluoromethoxy)phenyl]pyridine-4-carboxamide
[0269] ##STR00092##
[0270] Intermediate 62 (4.64 g, 13.0 mmol), (pyrimidin-5-yl)boronic acid (813 mg, 6.53 mmol), 25% aq K.sub.2CO.sub.3 (4.10 g, 29.5 mmol) and Pd(dppf)Cl.sub.2DCM (114 mg, 0.13 mmol) in dioxane (20 mL) under argon were stirred at 90° C. for 4 h. The RM was cooled to RT, mixed with water (100 mL) and EtOAc (100 mL) and the separated organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. Purification by column chromatography (Hex/TBME) gave the title compound (1.10 g, 35.4%) as a yellow solid. LCMS (ES.sup.+): 394.0 [MH].sup.+.
Intermediate 66
2-Methoxy-6-pyrimidin-5-yl-N-[4-(trifluoromethoxy)phenyl]pyridine-4-carboxamide
[0271] ##STR00093##
[0272] MeOH (0.12 mL, 3.00 mmol) was dissolved in dry DMF (5.0 mL) followed by addition of NaH (60% in mineral oil, 61.0 mg, 1.50 mmol) then the resulting mixture stirred for 30 min at RT and 30 min at 60° C. Intermediate 65 (203 mg, 0.51 mmol) was added and the RM was left under stirring at 60° C. overnight. The RM was neutralized with few drops of AcOH, concentrated under vacuum then purified by HPLC to give the title compound (113 mg, 55.4%) as a white solid. LCMS (ES.sup.+): 390.0 [MH].sup.+.
Intermediate 67
2-Chloro-N-[4-[chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-pyridine-4-carboxamide
[0273] ##STR00094##
[0274] Intermediate 63 (1.52 g, 4.30 mmol) was dissolved in DMF (4.0 mL) and NaH (60% in mineral oil, 213 mg, 4.70 mmol) was added. The RM was stirred for 15 min at RT then iodomethane (904 mg, 6.45 mmol) was added. The RM was heated overnight at 70° C., diluted with water (10 mL) and the precipitate was collected by filtration. Recrystallisation (1:2 EtOAc:Hex) gave the title compound (484 mg, 31.5%) as a light brown solid. LCMS (ES.sup.+): 364.0 [MH].sup.+.
Intermediate 68
N-[4-[Chloro(difluoro)methoxy]phenyl]-3-iodo-benzamide
[0275] ##STR00095##
[0276] Intermediate 68 was synthesised similarly to General Amidation Procedure C, using 3-iodobenzoic acid as the acid reactant, to give the title compound (3.56 g, 98.7%) as a light brown solid. LCMS (ES.sup.+): 423.9 [MH].sup.+. UPLC: Rt 3.25 min, 98.1% purity.
Intermediate 69
3-Iodo-4-methyl-N-[4-(trifluoromethoxy)phenyl]benzamide
[0277] ##STR00096##
[0278] Intermediate 69 was synthesised similarly to General Amidation Procedure C, using 3-iodo-4-methyl-benzoic acid as the acid reactant, to give the title compound (3.21 g, 74.7%.sup.$) as a white solid. LCMS (ES.sup.+): 421.9 [MH].sup.+. UPLC: Rt 3.29 min, 97.2% purity.
Intermediate 70
Methyl 5-(3-pyridyl)pyridine-3-carboxylate
[0279] ##STR00097##
[0280] Methyl 5-bromopyridine-3-carboxylate (2.08 g, 9.61 mmol) in 1,4-dioxane (20 mL) and water (1.5 mL) was degassed with N.sub.2 for 5 min. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.07 g, 10.1 mmol), Pd(PPh3)4 (1.11 g, 0.96 mmol), and K2CO3 (1.99 g, 14.4 mmol) were added, and heated at 80° C. for 20 h. The mixture was allowed to cool to RT, filtered, and concentrated in vacuo. The crude material was treated with 2M HCl (40 mL) and EtOAc (160 mL), the aqueous layer was separated, and added to EtOAc (200 mL). The mixture was neutralised with Na2CO3 to ˜pH 7, and the phases separated. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (1.78 g, 86.4%.sup.$) as an off-white solid. LCMS (ES.sup.+): 215.1 [MH].sup.+. UPLC: Rt 1.99 min, 98.3% purity.
Intermediate 71
5-(3-Pyridyl)pyridine-3-carboxylic acid
[0281] ##STR00098##
[0282] Intermediate 70 (1.78 g, 8.30 mmol) was dissolved in THF (10 mL) and water (10 mL), cooled to 0° C., LiOH (522 mg, 12.5 mmol) was added, and stirred for 30 min. The organics were evaporated, the aqueous phase was diluted with water (20 mL), and washed with EtOAc (20 mL). The aqueous phase was acidified with aq KHSO4 (1M) until pH-4, the precipitate was collected by filtration, and washed
with water to give the title compound (929 mg, 55.9%.sup.$) as a white solid. LCMS (ES.sup.+): 201.1 [MH].sup.+. UPLC: Rt 1.20 min, 100% purity.
Example 1
N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(3-ethoxy-1-methyl-pyrazol-4-yl)-6-oxo-pyridine-3-carboxamide
[0283] ##STR00099##
[0284] Intermediate 3 (144 mg, 99.4% purity, 516 μmol) and 1M aq NaOH (568 μL, 568 μmol) was stirred in THF:water (1:1, 4.0 mL) for 1 h. 1M aq HCl (568 μL, 568 μmol) was added then the mixture was concentrated in vacuo and dried in a vacuum oven at 60° C. overnight. The residue was reacted with 4-[chloro(difluoro)methoxy]aniline (120 mg, 620 μmol) similarly to General
[0285] Amidation Procedure C. Purification by RP HPLC and trituration (MeOH:water) gave the title compound (62.1 mg, 27.3%.sup.$) as a white solid. LCMS (ES.sup.+): 439.0 [MH].sup.+. UPLC: Rt 5.80 min, 99.4% purity.
Examples 2-24
[0286] Examples 2-24 were prepared similarly to Example 1, by ester hydrolysis of Intermediates 1, 2 and 4-24 then amide coupling with the appropriate aniline similarly to General Amidation Procedures A-E; see Table 4 below.
TABLE-US-00005 TABLE 4 Ester hydrolysis then amide coupling reactions
Example 25
N-[4-(Chlorodifluoromethoxy)phenyl]-1-(1-methyl-1H-pyrazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide
[0287] ##STR00125##
[0288] Intermediate 27 (248 mg, 1.14 mmol) was reacted with 4-[chloro(difluoro)methoxy]aniline (263 mg, 1.14 mmol) similarly to General Amidation Procedure D. Purification by RP HPLC gave the title compound (132 mg, 29.2%) as a white solid. LCMS (ES.sup.+): 395.2 [MH].sup.+. UPLC: Rt 5.38 min, 99.9% purity.
Examples 26-49
[0289] Examples 26-49 were prepared similarly to Example 25, by amide coupling of the appropriate carboxylic acid with the appropriate aniline using procedures similar to General Amidation Procedure A-E, see Table 5 below. If no intermediates are specified, then commercial reactants were used.
TABLE-US-00006 TABLE 5 Amidation reactions
Example 50
6-Oxo-1-(pyrimidin-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1.6-dihydropyridine-3-carboxamide
[0290] ##STR00152##
[0291] To (pyrimidin-5-yl)boronic acid (398 mg, 3.22 mmol) in MeOH (10 mL), Cu(OTf).sub.2 (1.17 g, 3.22 mmol) and Intermediate 54 were added sequentially, followed by pyridine (551 μL, 5.15 mmol). The RM was stirred at 25° C. for 16 h in a sealed vessel equipped with a bubble counter then the precipitate was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (20 mL), washed with aq ammonia (2×50 mL) and the organic layer was concentrated under vacuum. Purification by HPLC gave the title compound (253 mg, 20.9%) as a brown solid. LCMS (ES.sup.+): 377.0 [MH].sup.+. HPLC: Rt 4.95 min, 99.7% purity.
Examples 51-60
[0292] Examples 51-60 were prepared similarly to Example 50, by Chan-Lam coupling of Intermediates 53, 56, 57 and 60 with the appropriate aryl or heteroaryl boronate ester or boronic acid; see Table 6 below.
TABLE-US-00007 TABLE 6 Chan-Lam reactions
Example 61
N-[4-[Chloro(difluoro)methoxy]phenyl]-1-(5-methoxy-3-pyridyl)-6-oxo-pyridine-3-carboxamide
[0293] ##STR00165##
[0294] Intermediate 53 (200 mg, 97.8% pure, 622 μmol), Cs.sub.2CO.sub.2 (621 mg, 1.91 mmol), DMEDA (137 μL, 1.27 mmol), and 3-bromo-5-methoxypyridine (239 mg, 1.27 mmol) in 1,4-dioxane (3.0 mL) was degassed with N.sub.2 for 5 min. CuI (60.5 mg, 318 μmol) was added, the vial was sealed and heated at 120° C. for 15 h. The RM was added to water (30 mL) and extracted with DCM (30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by RP column chromatography to give the title compound (53.5 mg, 20.4%.sup.$) as an off-white solid. LCMS (ES.sup.+): 422.0 [MH].sup.+. HPLC: Rt 5.40 min, 99.8% purity.
Examples 62-75
[0295] Examples 62-75 were prepared similarly to Example 61, by Ullmann reaction of Intermediate 53 with the appropriate aryl or heteroaryl halide; see Table 7 below.
TABLE-US-00008 TABLE 7 Ullmann reactions
Example 76
N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide
[0296] ##STR00182##
[0297] Example 76 was isolated as a byproduct from an attempted Ullman coupling between Intermediate 53 and 3-bromo-5-fluoro-4-methoxypyridine, following a procedure similar to that used in the synthesis of Example 61. Example 76 was isolated (16.0 mg, 16.3%) as a white solid. LCMS (ES.sup.+): 329.1 [MH].sup.+. HPLC: Rt 2.55 min, 100% purity.
[0298] It is expected that Example 76 could be made similarly to Example 26 using 4-[chloro(difluoro)methoxy]aniline instead of 4-(trifluoromethoxy)aniline, following General Amidation Procedure C.
Example 77
N-[4-(Chlorodifluoromethoxy)phenyl]-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide
[0299] ##STR00183##
[0300] Intermediate 53 (223 mg, 0.63 mmol), Na.sub.2CO.sub.3 (134 mg, 1.26 mmol) and 4-iodotetrahydro-2H-pyran (164 mg, 0.76 mmol) in DMF (5.0 mL) were stirred at RT overnight then partitioned between EtOAc (30 mL) and water (10 mL). The EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by preparative HPLC to give the title compound (12.0 mg, 5.3%) as a white solid. LCMS (ES.sup.+): 399.0 [MH].sup.+. HPLC: Rt 6.24 min, 99.4% purity.
Example 78
5-{[4-(Chlorodifluoromethoxy)phenyl]carbamoyl}-2-oxo-2H-[1.3′-bipyridin]-1′-ium-1′-olate
[0301] ##STR00184##
[0302] Example 53 (213 mg, 0.54 mmol) was dissolved in DCM (5.0 mL) and mCPBA (284 mg, 1.60 mmol) was added. The resulting mixture was stirred at RT for 24 h, washed with 1M aq NaOH (2×10 mL) then the organic layer was dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by prep HPLC to provide the title compound (27.0 mg, 12.3%) as a yellow solid. LCMS (ES.sup.+): 408.0 [MH].sup.+. HPLC: Rt 2.45 min, 95.8% purity.
Example 79
N-[4-(Chlorodifluoromethoxy)phenyl]-5-cyano-1-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1.6-dihydropyridine-3-carboxamide
[0303] ##STR00185##
[0304] CuCN (94.0 mg, 1.05 mmol) was added to Intermediate 61 (335 mg, 0.70 mmol) then the mixture was heated under reflux for 10 h, cooled to 80° C. and poured into a solution of NaCN (214 mg, 4.37 mmol) in water (10 mL). After stirring for 1 h at RT, the mixture was extracted with EtOAc (2×25 mL) and the organic phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by RP HPLC to give the title compound (104 mg, 34.1%) as a beige solid. LCMS (ES.sup.+): 420.0 [MH].sup.+. UPLC: Rt 2.75 min, 99.6% purity.
Example 80
N-[4-(Chlorodifluoromethoxy)phenyl]-6-oxo-5-(1H-pyrazol-3-yl)-1,6-dihydropyridine-3-carboxamide
[0305] ##STR00186##
[0306] Example 80 was prepared similarly to Example 25 using Intermediate 52 instead of Intermediate 27 and following General Amidation Procedure D to give the title compound (63.0 mg, 6.6%) as a white solid. LCMS (ES.sup.+): 381.0 [MH].sup.+. HPLC: Rt 2.51 min, 99.2% purity.
Example 81
N-[4-[Chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-5-(3-pyridyl)pyridine-3-carboxamide
[0307] ##STR00187##
[0308] Intermediate 64 (100 mg, 94.2% purity, 231 μmol), pyridin-3-ylboronic acid (56.8 mg, 462 μmol), K.sub.2CO.sub.3 (95.8 mg, 693 μmol), Pd(OAc).sub.2 (10.4 mg, 46.2 μmol) and PPh.sub.3 (30.3 mg, 116 μmol) in dioxane (1.0 mL) were heated in a sealed tube at 110° C. under N.sub.2 for 18 h, then the RM was purified by column chromatography to give the title compound (48.3 mg, 50.8%.sup.$) as a beige solid. LCMS (ES.sup.+): 406.0 [MH].sup.+. UPLC: Rt 4.54 min, 98.7% purity.
Examples 82-89
[0309] Examples 82-89 were prepared similarly to Example 81, by Suzuki reaction of Intermediates 61 and 64 with the appropriate aryl or heteroaryl boronic acid or boronate ester; see Table 8 below.
TABLE-US-00009 TABLE 8 Suzuki reactions
Example 90
N-[4-[Chloro(difluoro)methoxy]phenyl]-1-methyl-6-oxo-5-pyrazol-1-yl-pyridine-3-carboxamide
[0310] ##STR00198##
[0311] To a mixture of Intermediate 64 (100 mg, 94.2% purity, 231 μmol), CuI (8.80 mg, 46.2 μmol) and K.sub.2CO.sub.3 (95.8 mg, 693 μmol) in toluene (4.0 mL) was added trans N,N-dimethylcyclohexane-1,2-diamine (7.29 μL, 46.2 μmol) and pyrazole (31.5 mg, 462 μmol), then the RM heated at 110° C. under nitrogen for 66 h. The RM was diluted with DCM (5.0 mL), filtered, then purified by column chromatography and RP HPLC to give the title compound (21.6 mg, 23.5%.sup.$) as a white solid. LCMS (ES.sup.+): 394.8 [MH].sup.+. UPLC: Rt 5.81 min, 99.4% purity.
Example 91
N-[4-[Chloro(difluoro)methoxy]phenyl]-5-imidazol-1-yl-1-methyl-6-oxo-pyridine-3-carboxamide
[0312] ##STR00199##
[0313] Example 91 was prepared similarly to Example 90 from Intermediate 64, using imidazole instead of pyrazole, to give the title compound (8.25 mg, 5.9%.sup.$) as a beige solid. LCMS (ES.sup.+): 395.0 [MH].sup.+. UPLC: Rt 4.53 min, 97.7% purity.
Example 92
N-[4-(Chlorodifluoromethoxy)phenyl]-2-oxo-6-(1H-pyrazol-5-yl)-1,2-dihydropyridine-4-carboxamide
[0314] ##STR00200##
[0315] Intermediate 59 (201 mg, 554 μmol), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (140 mg, 720 μmol), K.sub.2CO.sub.3 (305 mg, 2.22 mmol) and Pd(dppf)Cl.sub.2.DCM (23.0 mg, 28.0 μmol) in dioxane-water (10 mL, 1:1, v/v) was heated to 90° C. for 12 h. The RM was mixed with water (5.0 mL), extracted with EtOAc (2×10 mL) and concentrated in vacuo. The residue was treated with conc HCl (5.0 mL) and THF (5.0 mL) and stirred at 35-40° C. for 1 h. After cooling to RT the RM was extracted with EtOAc (2×10 mL) and the combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by RP HPLC to give the title compound (12.0 mg, 5.7%) as a white solid. LCMS (ES.sup.+): 381.2 [MH].sup.+. UPLC: Rt 2.56 min, 99.2% purity.
Example 93
2-Oxo-6-(pyrimidin-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1,2-dihydropyridine-4-carboxamide
[0316] ##STR00201##
[0317] Intermediate 66 (313 mg, 0.77 mmol) was dissolved in AcOH (2.0 mL), conc HCl (2.0 mL) was added and the RM was stirred for 12 h at 50° C. then concentrated in vacuo and purified by RP HPLC to give the title compound (14.0 mg, 3.1%) as an off-white solid. LCMS (ES.sup.+): 377.2 [MH].sup.+. HPLC: Rt 1.26 min, 100% purity.
Example 94
N-[4-(Chlorodifluoromethoxy)phenyl]-1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide
[0318] ##STR00202##
[0319] A mixture of Intermediate 67 (152 mg, 0.41 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (134 mg, 0.62 mmol), 30% aq K.sub.2CO.sub.3 (284 mg, 2.07 mmol) and Pd(dppf)Cl.sub.2DCM (9.1 mg, 12.4 μmol) was evacuated and backfilled with argon three times. Dioxane (2.0 mL) was added and the RM was stirred at 100° C. overnight then cooled to RT, the organic layer was separated, dried under Na2SO.sub.4 and evaporated. The crude product was purified by RP HPLC (water/MeCN) to give the title compound (25.0 mg, 15.2%) as a white solid. LCMS (ES.sup.+): 409.2 [MH]+, Rt 5.40 min, 99.4% purity.
REFERENCE COMPOUNDS
Reference Example 1
N-[4-[Chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide
[0320] ##STR00203##
[0321] Asciminib was purchased from Med Chem Express (CAS: 1492952-76-7) and used as received.
Reference Example 2
N-[4-[Chloro(difluoro)methoxy]phenyl]-3-pyrimidin-5-ylbenzamide
[0322] ##STR00204##
[0323] Intermediate 68 (250 mg, 0.59 mmol), pyrimidine-5-boronic acid pinacol ester (304 mg, 1.48 mmol) and Pd(dppf)Cl.sub.2.DCM (48.2 mg, 0.06 mmol) in a mixture of 1,4-dioxane (15 mL) and 2M aq Na.sub.2CO.sub.3 (5.0 mL, 10.0 mmol) were heated by microwave at 130° C. for 30 min. The RM was partitioned between EtOAc (20 mL) and water (20 mL), and the separated aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography to give the title compound (174 mg, 78.5%) as a grey solid. LCMS (ES.sup.+): 376.0 [MH].sup.+. Rt 5.96 min, 100% purity.
Reference Example 3
4-Methyl-3-(3-pyridyl)-N-[4-(trifluoromethoxy)phenyl]benzamide
[0324] ##STR00205##
[0325] Intermediate 69 (2.40 g, 5.70 mmol), pyridin-3-ylboronic acid (1.05 g, 8.55 mmol),
[0326] Na2CO3 (1.81 g, 17.1 mmol) and Pd(PPh3).sub.4 (400 mg, 570 μmol) were dissolved in EtOH/DME/water (13.5 mL, 1.5:10:2). The reaction was heated using a microwave reactor to 130° C. for 30 min. The solvents were removed in vacuo and the residue purified by column chromatography and RP HPLC to give the title compound (320 mg, 15.1%.sup.$) as a white solid. LCMS (ES.sup.+): 373.1 [MH].sup.+. UPLC:
[0327] Rt 4.93 min, 99.1% purity.
Reference Example 4
5-(3-Pyridyl)-N-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxamide
[0328] ##STR00206##
[0329] Reference Example 4 was synthesised similarly to General Amidation Procedure C, using Intermediate 71 and 4-(trifluoromethoxy)aniline, to give the title compound (104 mg, 58.1%.sup.$) as a white solid. LCMS (ES.sup.+): 360.1 [MH].sup.+. UPLC: Rt 4.44 min, 100% purity.
Reference Example 5
2-Oxo-1-(pyrimidin-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide
[0330] ##STR00207##
[0331] To Intermediate 58 (483 mg, 1.62 mmol), (pyrimidin-5-yl)boronic acid (206 mg, 1.62 mmol) and Cu(OTf).sub.2 (604 mg, 1.62 mmol) in MeOH (10 mL) was added pyridine (0.27 mL, 2.56 mmol), then the mixture stirred at 25° C. for 16 h in a sealed vessel with a bubble counter. The precipitate was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (20 mL), washed with aq ammonia (2×50 mL) then then organic layer was dried over Na2SO.sub.4, concentrated under vacuum and purified by HPLC to give the title compound (33.0 mg, 5.2%) as a beige solid. LCMS (ES.sup.+): 377.0 [MH].sup.+. Rt 2.67 min, 99.6% purity.
TABLE-US-00010 High Resolution Mass Spectrometry Data MIM MIM calculated calculated positive negative from from Example MWt MIM ion m/z ion m/z positive ion* negative ion* 1 438.81 438.09 439.097 437.0827 438.0897 438.09 2 411.38 411.14 412.147 410.3127 411.1397 411.32 3 394.76 394.06 395.071 393.057 394.0637 394.0643 4 384.76 384.07 385.0755 383.0614 384.0682 384.0687 5 380.73 380.05 381.0554 379.0412 380.0481 380.0485 6 384.76 384.07 385.0755 383.0612 384.0682 384.0685 7 430.74 430.05 431.0522 429.0378 430.0449 430.0451 8 397.78 397.01 398.0169 396.0024 397.0096 397.0097 9 405.78 405.07 406.0756 404.0613 405.0683 405.0686 10 452.8 452.07 453.0762 451.0621 452.0689 452.0694 11 397.78 397.01 398.0164 396.0022 397.0091 397.0095 12 422.77 422.06 423.0657 421.0517 422.0584 422.059 13 421.78 421.06 422.0707 420.0565 421.0634 421.0638 14 422.81 422.1 423.1035 421.0887 422.0962 422.096 15 420.8 420.08 421.0862 419.0723 420.0789 420.0796 16 397.8 397.1 398.1076 396.093 397.1003 397.1003 17 397.8 397.1 398.1072 396.0928 397.0999 397.1001 18 408.79 408.08 409.0867 407.0725 408.0794 408.0798 19 434.82 434.1 435.102 433.0878 434.0947 434.0951 20 415.78 415.05 416.06 414.0459 415.0527 415.0532 21 434.82 434.1 435.1024 433.0878 434.0951 434.0951 22 438.81 438.09 439.0973 437.0828 438.09 438.0901 23 436.84 436.11 437.1181 435.1034 436.1108 436.1107 24 426.75 426.04 427.0462 425.0318 426.0389 426.0391 25 394.76 394.06 395.0711 393.057 394.0638 394.0643 27 430.74 430.05 431.0525 429.0378 430.0452 430.0451 28 442.8 442.06 443.071 441.0566 442.0637 442.0639 29 420.79 420.07 421.0751 419.0613 420.0678 420.0686 30 429.2 428.03 429.0324 427.0176 428.0251 428.0249 32 450.82 450.08 451.0871 449.0723 450.0798 450.0796 33 446.83 446.08 447.0911 445.0767 446.0838 446.084 34 432.8 432.07 433.0754 431.061 432.0681 432.0683 35 420.79 420.07 421.0754 419.0613 420.0681 420.0686 36 448.8 448.06 449.0703 447.056 448.063 448.0633 40 446.83 446.08 447.0912 445.0766 446.0839 446.0839 41 446.83 446.08 447.0926 455.0769 446.0853 456.0842 42 408.76 408.05 409.0557 407.0412 408.0484 408.0485 43 450.82 450.08 451.0859 449.0715 450.0786 450.0788 45 429.2 428.02 429.0323 427.0178 428.025 428.0251 46 426.74 426.03 427.0459 425.032 426.0386 426.0393 47 408.76 408.05 409.0558 407.0413 408.0485 408.0486 48 431.78 431.05 432.0552 430.0408 431.0479 431.0481 49 459.83 459.08 460.0863 458.0721 459.079 459.0794 50 376.29 376.08 377.0849 375.0708 376.0776 376.0781 51 392.74 392.05 393.0554 391.0414 392.0481 392.0487 52 394.76 394.06 395.0714 393.0571 394.0641 394.0644 53 391.76 391.05 392.0599 390.0461 391.0526 391.0534 54 409.75 409.04 410.0508 408.0364 409.0435 409.0437 55 416.77 416.05 417.0554 415.0412 416.0481 416.0485 56 390.77 390.06 391.0648 389.0509 390.0575 390.0582 57 405.78 405.07 406.0756 404.0613 405.0683 405.0686 58 422.77 422.06 423.0658 421.0517 422.0585 422.059 59 406.77 406.06 407.0712 405.0566 406.0639 406.0639 60 477.85 477.1 478.1082 476.0936 477.1009 477.1009 61 421.78 421.06 422.0706 420.0564 421.0633 421.0637 62 459.75 459.04 460.0474 458.0333 459.0401 459.0406 63 426.2 425.01 426.0212 424.0071 425.0139 425.0144 64 431.78 431.06 432.0663 430.0519 431.059 431.0592 65 405.78 405.07 406.0758 404.0614 405.0685 405.0687 66 441.76 441.05 442.0582 440.043 441.0509 441.0503 67 442.8 442.06 443.071 441.0566 442.0637 442.0639 68 472.83 472.07 473.0816 471.0671 472.0743 472.0744 69 449.79 449.05 450.0655 448.0513 449.0582 449.0586 70 445.81 445.07 446.082 444.0675 445.0747 445.0748 71 445.81 445.07 446.082 444.0677 445.0747 445.075 72 426.2 425.01 426.0209 424.0069 425.0136 425.0142 73 433.79 433.06 434.0707 432.0563 433.0634 433.0636 74 392.4 392.14 393.152 391.139 392.1447 392.1463 75 459.75 459.04 460.0476 458.0332 459.0403 459.0405 76 328.69 328.04 329.0494 327.0353 328.0421 328.0426 77 398.79 398.08 399.0912 397.0769 398.0839 398.0842 78 407.76 407.05 408.0549 406.0407 407.0476 407.048 79 419.77 419.06 420.066 418.0518 419.0587 419.0591 80 380.73 380.05 381.0553 379.0411 380.048 380.0484 81 405.78 405.07 406.0759 404.0616 405.0686 405.0689 82 406.77 406.06 407.0708 405.0568 406.0635 406.0641 83 408.79 408.08 409.0868 407.0725 408.0795 408.0798 84 422.81 422.1 423.1021 421.0883 422.0948 422.0956 85 408.79 408.08 409.0866 407.0724 408.0793 408.0797 86 408.79 408.08 409.0872 407.0734 408.0799 408.0807 87 423.77 423.06 424.0662 422.0522 423.0589 423.0595 88 404.79 404.07 405.0804 403.0663 404.0731 404.0736 89 471.84 471.09 472.0977 470.0831 471.0904 471.0904 90 394.76 394.06 395.0712 393.0571 394.0639 394.0644 91 394.76 394.06 395.0712 393.0571 394.0639 394.0644 92 380.73 380.05 381.0555 379.0412 380.0482 380.0485 93 376.29 376.08 377.0851 357.0708 376.0778 358.0781 94 408.79 408.08 409.0867 407.0725 408.0794 408.0798 Reference 449.84 449.11 450.1137 448.0992 449.1064 449.1065 Example 1 Reference 375.76 375.06 376.0654 374.0511 375.0581 375.0584 Example 2 Reference 372.34 372.11 373.1149 371.1011 372.1076 372.1084 Example 3 Reference 359.3 359.09 360.0947 358.0808 359.0874 359.0881 Example 4 Reference 376.29 376.08 377.0852 375.0714 376.0779 376.0787 Example 5
Biological Data
Ba/F3 CellTiter-Glo Assay
[0332] The CellTiter-Glo luminescent cell viability assay is a homogeneous method of determining the number of viable cells in culture based on quantification of the ATP present. Briefly, IL-3 dependent Ba/F3 cells are modified to express BCR-ABL. Activity of the transformed kinase overrides IL3 dependency for cellular proliferation and survival. Test compounds that specifically inhibit kinase activity lead to programmed cell death which can be measured through the addition of CellTiter-Glo reagent. In this assay Ba/F3 cells expressing BCR-ABL (Advanced Cellular Dynamics) or parental Ba/F3 (control) cells were prepared at 5×104/mL in RPMI 1640 containing 10% FBS, 1× Glutamax and 750 ng/mL puromycin. Test compounds were dispensed into 384 well plates using the Tecan D300e at a top final assay concentration of 10 μM with dosing normalised to 0.1% DMSO in 50 μL volume. 50 μL cells were added to each well of the prepared 384 well plates and the plates spun at 1000 rpm for 1 min prior to incubation at 37° C., 5% CO.sub.2 for 48 h. After 48 h 15 μL CellTiterGlo reagent was added to each well in the plate. Following a 60 min incubation at RT luminescence was read on the Pherastar FS reader.
[0333] The exemplified compounds of the invention were tested in the Ba/F3 CellTiter-Glo Assay and the IC.sub.50 data is shown in Table 9. All of the exemplified compounds of the invention had an IC.sub.50 value of 1000 nM or less. This data shows that the compounds of the invention can inhibit c-Abl.
[0334] Reference Example 5 had an IC.sub.50 value of >10 μM and is therefore inactive against c-Abl. Without wishing to be bound by theory, the pyridone C═O bond in Reference Example 5 may sterically clash with the amide group, inducing an unfavourable twist in the amide-pyridone bond so that the two moieties are no longer co-planar. This may disrupt the edge-to-face pi-stacking interaction between the pyridone ring and the Tyr454 residue of c-Abl. Furthermore, the pyridone C═O bond may form a 6-membered ring through a intramolecular hydrogen bond with the NH of the amide group, which prevents the NH from forming a potentially crucial hydrogen bond to a water molecule within the active site of c-Abl, and may even displace said water molecule. The pyridone regioisomers in the compounds of the invention do not suffer these drawbacks and therefore exhibit much improved inhibition of c-Abl.
TABLE-US-00011 TABLE 9 Bcr-Abl IC.sub.50 (A: 1000-151 nM, B: 150-31 nM, C: ≤30 nM) Ex. IC.sub.50 Ref. ex. 1 C Ref. ex. 2 C Ref. ex. 3 B Ref. ex. 4 B Ref. ex. 5 >10 μM 1 A 2 A 3 B 4 A 5 B 6 A 7 A 8 A 9 B 10 B 11 C 12 B 13 B 14 A 15 B 16 A 17 A 18 C 19 A 20 B 21 A 22 A 23 A 24 C 25 B 26 A 27 B 28 A 29 B 30 C 31 B 32 A 33 B 34 B 35 C 36 B 37 C 38 C 39 B 40 B 41 A 42 C 43 A 44 C 45 A 46 C 47 C 48 B 49 B 50 B 51 C 52 B 53 C 54 C 55 B 56 C 57 B 58 B 59 B 60 B 61 C 62 A 63 C 64 B 65 C 66 B 67 C 68 C 69 C 70 B 71 C 72 C 73 C 74 A 75 B 76 A 77 A 78 A 79 A 80 A 81 B 82 B 83 B 84 A 85 A 86 B 87 C 88 B 89 C 90 A 91 B 92 A 93 A 94 B
Determination of Pharmacokinetic Profile and Brain Penetrance in Rat
[0335] Male Sprague Dawley Rats 300-350 g (Charles River, UK) were group housed, n=3, under a 12 h light/dark cycle with food and water available ad libitum. At 17:00 on the day prior to dosing all food was removed. On the day of dosing animals were weighed, tail marked and dosed via oral gavage with compound at 3 mg/kg in a volume of 5 mL/kg. Animals were culled at 30 min, 1 h and 4 h post dose via intra-peritoneal administration of pentobarbital. Post mortem blood was withdrawn via cardiac puncture, and briefly stored in K2 EDTA blood tubes on ice before being spun at 14,000 g for 4 min at 4° C. Plasma was withdrawn into a 96 well plate, placed on dry ice and stored at −80° C. Brains were quickly dissected and placed on dry ice before storage at −80° C. Bioanalysis of plasma and brain samples is performed as detailed below. Methods were prepared with guidance from industry standard documents..sup.i,ii
Plasma Bioanalysis
[0336] A 10 mM DMSO stock is used to prepare spiking solutions of test compound in the range of 10-100,000 ng/mL in diluent (MeCN:water, 1;1). Calibration lines are prepared in control male Sprague-Dawley Rat plasma at known concentrations in the range of 1-10000 ng/mL by spiking 2.5 μL of calibration spiking solution into 25 μL control plasma. Experimental samples are thawed to RT and 25 μL aliquots are extracted alongside the calibration lines using protein precipitation (agitation for at least 5 min at RT with 400 μL of MeCN containing 25 ng/mL tolbutamide as an internal standard). Protein precipitates are separated from the extracted test compound by centrifugation at 4000 rpm for 5 min, 4° C. The resulting supernatants are diluted in a ratio of 1:2 with a relevant diluent (e.g. 0.1% formic acid in water or 1:1 MeOH:water). Samples are analysed by UPLC-MS/MS on either an API6500 QTrap or Waters 30 TQS mass spectrometer using previously optimised analytical MRM (multiple reaction monitoring) methods, specific to the test compound. The concentration of test compound in isolated samples is determined following analysis of the samples against the two replicates of the calibration line, injected before and after the sample set with an appropriate regression and weighting used. Only samples within 20% of the expected test concentration are included in the calibration line and any samples that fall outside of the limits of the calibration line will be deemed to be less than or above the limit of quantification (LLoQ/ALoQ).
Brain Bioanalysis
[0337] A 10 mM DMSO stock is used to prepare spiking solutions of test compound in the range of 10-100,000 ng/mL in diluent (1:1 MeCN:water). Calibration lines are prepared in control male Sprague-Dawley Rat brain homogenate at known concentrations in the range of 3-30000 ng/g by spiking 2.5 μL of calibration spiking solution into 25 μL control homogenate. To prepare control and experimental brain homogenates, brains are thawed, weighed and a volume of diluent added (water) in the ratio of 2 mL per gram of brain. Homogenisation of brains is performed by bead-beater homogenisation using Precellys Evolution and CK14 7 mL small ceramic bead homogenisation tubes. Aliquots of 25 μL experimental sample are extracted alongside the calibration lines using protein precipitation (agitation for at least 5 min at RT with 400 μL of MeCN containing 25 ng/mL tolbutamide as an internal standard). Protein precipitates are separated from the extracted test compound by centrifugation at 4000 rpm for 5 min, 4° C. The resulting supernatants are diluted in a ratio of 1:2 with a relevant diluent (e.g. 0.1% formic acid in water or 1:1 MeOH:water). Samples are analysed by UPLC-MS/MS on either an API6500 QTrap or Waters TQS mass spectrometer using previously optimised analytical MRM (multiple reaction monitoring) methods, specific to the test compound. The concentration of test compound in isolated samples is determined following analysis of the samples against the two replicates of the calibration line, injected before and after the sample set with an appropriate regression and weighting used. Only samples within 20% of the expected test concentration are included in the calibration line and any samples that fall outside of the limits of the calibration line will be deemed to be less than or above the limit of quantification (LLoQ/ALoQ).
Determination of Brain to Plasma (B:P) Ratio
[0338] Total brain to plasma (B:P) ratios were calculated by dividing the concentration in the brain by the concentration in plasma for each timepoint. The mean brain to plasma ratio is calculated by averaging these brain to plasma ratios across certain timepoints. Table 10 shows the brain to plasma (B:P) ratios for compounds of the invention and reference examples. The examples of the invention have much improved brain to plasma (B:P) ratios compared to the reference examples. Therefore, compounds of the invention are particularly useful in the treatment of certain diseases and conditions in which blood-brain barrier penetration is important. It is noted that blood-brain barrier penetration is unpredictable and is established empirically. Overcoming the challenges associated with delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders.
TABLE-US-00012 TABLE 10 Brain to plasma ratio in rat Mean Timepoints Dose B:P averaged Ex. Formulation Route (mg/kg) ratio (h) Ref. 30% HPBC in water i.v. 1 <0.01 0.17-1 ex. 1 13 30% HPBC in water p.o. 3.0 0.79 0.5-4 24 30% HPBC in water p.o. 3.0 0.68 0.5-4 35 30% HPBC in water p.o. 3.0 1.11 1 42 30% HPBC in water p.o. 3.0 0.98 0.5-4 47 30% HPBC in water p.o. 3.0 1.54 0.5-4 51 3.3% NMP in 30% HPBC i.v. 1.5 0.67 0.5-1 in water 53 5% NMP in 30% HPBC in p.o. 3.0 0.82 0.5-1 water 54 5% NMP in 30% HPBC in i.v. 0.5 0.53 0.17-1 water 56 30% HPBC in water p.o. 3.0 1.91 0.5-4 61 30% HPBC in water p.o. 3.0 0.45 0.5-4 63 30% HPBC in water p.o. 3.0 0.64 0.5-4 65 30% HPBC in water p.o. 3.0 0.31 0.5-4 88 30% HPBC in water P.o. 3.0 0.69 0.5-4
Determination of Bioavailability, Clearance and Half-Life In Vivo
[0339] Pharmacokinetic parameters such as bioavailability (% F), clearance (CL), half-life (T½) and volume of distribution are calculated by non-compartmental analysis using Phoenix Winnonlin 64 software (build 8.0). The bioavailability was calculated from p.o. dosed rats, whereas the clearance and half-life were calculated from i.v. dosed rats. Briefly, in vivo plasma concentrations, timepoints and dose values are imported into the software in a compatible format. Plasma concentration for each animal is plotted against time, and the elimination phase identified and selected. The area under the curve for each plot is calculated using a linear trapezoidal linear interpolation from which pharmacokinetic parameters can subsequently be determined. Table 11 shows pharmacokinetic parameters for compounds of the invention and reference examples. Compounds of the invention have much improved clearance (CL) and half-life (T½) compared to the reference examples.
TABLE-US-00013 TABLE 11 Rat PK profile i.v. p.o. dose dose CL T½ Ex. Formulation (mg/kg) (mg/kg) % F (mL/min/kg) (h) Ref. 30% HPBC in 1 3 4 22 2.1 ex. 1 water Ref. 20% PEG/24% 1 3 113 12 1.2 ex. 4 HPBC in water 54 5% NMP, 30% 0.5 3 97 4.0 7.6 HPBC in water 56 5% NMP, 30% 1 3 97 1.9 20 HPBC in water 81 5% NMP, 30% 1 3 102 3.0 6.2 HPBC in water
Kinetic Aqueous Solubility Assay
[0340] Using a 10 mM stock solution of test compound in 100% DMSO, test compounds were spiked into 0.05M potassium phosphate buffer (pH 7.4) at a final concentration of 250 μM. Samples in buffer (n=2 aqueous samples, in 96-well plates) were allowed to equilibrate at RT on an orbital shaker for 30 min (300 rpm) to induce precipitation of test compounds. The appearance of each sample was determined by visual examination and noted (clear, cloudy, precipitate observed etc.). The aqueous phosphate buffer samples were filtered using a Multiscreen HTS solubility filter plate (Millipore) and filtrate was analysed by LC-UV alongside calibration standards of the test compounds prepared at 5, 25, 100 and 250 μM in 50:50 acetonitrile:water. The concentration of compound in phosphate buffer filtrate was determined by comparing the UV absorbance peak area of each replicate against that of the calibration standards. Table 12 shows kinetic aqueous solubility values for compounds of the invention and reference examples. Compounds of the invention have much improved solubility compared to the reference examples.
TABLE-US-00014 TABLE 12 Kinetic aqueous solubility Ex. Solubility (μM) Ref. ex. 2 9 Ref. ex. 3 56 Ref. ex. 4 <5 2 215 3 140 4 180 12 140 16 180 18 200 20 100 25 170 27 100 30 140 42 120 51 190 52 160 53 170 54 170 55 150 57 170 58 180 59 190 60 210 61 160 63 120 65 170 71 110 78 150 82 170
hERG Assay
[0341] The human ether-a-go-go related gene (hERG) potassium channel (K.sub.v11.1) contributes to human cardiac action potential repolarisation. Inhibition of hERG channels can prolong the human cardiac action potential, resulting in QTc prolongation and potentially lethal arrhythmias (e.g. Torsade de Pointes).
[0342] Test samples were screened against the hERG channel on a QPatch 48 gigaseal automated patch clamp platform, using a Chinese Hamster Ovary (CHO) cell line stably expressing the human ether-á-go-go related gene, which encodes the hERG channel. All recordings were made in the conventional whole-cell configuration and performed at RT (−21° C.) using standard single hole chips (Rchip 1.5-4M0). Series resistance (4-15Mc) was compensated by >80%. Currents were elicited from a holding potential of −90 mV using the industry standard “.sup.+40/−40” voltage protocol, which was applied at a stimulus frequency of 0.1 Hz. On achieving the whole-cell configuration, vehicle (0.1% DMSO v/v in external recording solution) was applied to each cell in two bolus additions with a 2 min recording period between each addition. Following the vehicle period, eight increasing concentrations of test sample were applied from 0.003 μM to 10 μM as a single bolus addition per test concentration, and the effects on hERG tail current amplitude measured during the 2 min recording period. Each eight-point concentration-response curve was constructed using cumulative single sample additions of each concentration to the same cell. The positive control used in this study was verapamil hydrochloride (Tocris, Cat #0654, Batch #5A/61673) and prepared to a stock concentration of 10 mM in 100% DMSO and kept as frozen aliquots.
[0343] Data analysis: All cells passing the QC parameters (i.e. >200 pA outward current, membrane resistance and rundown) are selected as ‘passed QC’ using the QPatch software, which then calculates the mean peak current for the last three sweeps at the end of each concentration application period from the cursor positions defined. Percent inhibition is calculated for each test concentration application period as the reduction in mean cursor value (peak current or charge) relative to the cursor value measured at the end of the control (i.e. vehicle) period. The percent inhibition values from each cell are used to construct concentration-response curves employing a four parametric logistic fit with 0 and 100% inhibition levels fixed at very low and very high concentrations, respectively, and a free Hill slope factor. The IC.sub.50 (50% inhibitory concentration) and Hill coefficient are then determined, but only data from cells with Hill slopes within 0.5>nH<2.0 are included. The IC.sub.50 data reported below represents the mean (and S.D.) of at least three separate cells (N≥3). If a test sample failed to achieve >50% block at the top concentration it was deemed inactive, and assigned an arbitrary IC.sub.50 value of ′>10 μM. Table 13 shows hERG IC.sub.50 values for compounds of the invention and reference examples. Compounds of the invention show reduced hERG inhibitory activity compared to the reference examples.
TABLE-US-00015 TABLE 13 hERG IC.sub.50 (μM) Ex. hERG IC.sub.50 (μM) Ref. ex. 2 1.9 Ref. ex. 3 2.5 Ref. ex. 4 4.7 18 >10 24 >10 26 >10 35 >10 47 >10 50 >10 51 >10 52 >10 53 >10 56 >10 61 >10 63 >10 82 >10
Ames Assay
[0344] Examples 50, 52 and 54 were tested, in vitro, for their ability to induce mutations in 2 histidine dependent auxotrophic mutants of Salmonella typhimurium, strains TA98 and TA100. The mutation screen was conducted using the plate incorporation method and was performed in both the presence and absence of S-9 mix (a liver post-mitochondrial fraction derived from the livers of Aroclor 1254 treated rats). The bacteria were exposed to the test items dissolved in DMSO, which was also the negative Control. The test items were tested up to the regulatory maximum dose level. The dose levels used were 5, 15, 50, 150, 500, 1500 or 5000 μg/plate, unless the highest treatment level of the test items was limited by solubility, or toxicity against the background bacterial lawn. Dose levels were expressed in terms of the free base.
[0345] There were no increases of 2-fold or greater in revertant numbers compared with negative Control values in either strain at any dose level in the presence or absence of S-9 mix, so Examples 50, 52 and 54 were not mutagenic in the Bacterial Reverse Mutation (i.e. Ames) Test under the conditions of this screen.
Off-Target Selectivity Assays
[0346] Examples 50 and 54 were tested for kinase selectivity against the Eurofins KinaseProfiler™ kinase screen consisting of 430 wild-type and mutant kinases, including a panel of lipid kinases, up to a top concentration of 1 μM. The radiometric kinase activity assays were run at ATP Km. Neither of the compounds showed >50% inhibition against any of the kinases at the top concentration.
[0347] Example 50 was screened against the Eurofins SafetyScreen™ panel of 87 targets across GPCRs, ion channels, and enzymes. Only 2 of 87 targets were inhibited >50% at a top concentration of 10 μM, with a maximum inhibition of 65%.
REFERENCES
[0348] .sup.i Food and Drug Administration. (2018). Bioanalytical Method Validation: Guidance for Industry. [0349] .sup.ii Whitmire M, Ammerman J, de Lisio P, Killmer J, Kyle D (2011) LCMS/MS Bioanalysis Method Development, Validation, and Sample Analysis: Points to Consider When Conducting Nonclinical and Clinical Studies in Accordance with Current Regulatory Guidances. J Anal Bioanal Techniques S4:001. doi:10.4172/2155-9872.S4-001.