Antibacterial 2H-indazole derivatives
09802901 · 2017-10-31
Assignee
Inventors
- Jean-Christophe Gauvin (Allschwil, CH)
- Azely Mirre (Allschwil, CH)
- Etienne Ochala (Allschwil, CH)
- Jean-Philippe Surivet (Allschwil, CH)
Cpc classification
C07D405/10
CHEMISTRY; METALLURGY
C07D413/10
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D231/56
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
C07F9/65038
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
International classification
C07D231/56
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D401/06
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D413/10
CHEMISTRY; METALLURGY
Abstract
The invention relates to antibacterial compounds of formula I ##STR00001##
wherein R.sup.1 is H or halogen; R.sup.2 is alkynyloxy or the group M; R.sup.3 is H or halogen; M is one of the groups ##STR00002##
wherein A is a bond, CH.sub.2CH.sub.2, CH═CH or C≡C and R.sup.1A, R.sup.2A, R.sup.3A, R.sup.1B and R.sup.1C are as defined in claim 1;
and salts thereof.
Claims
1. A compound of formula I ##STR00034## wherein R.sup.1 represents H or halogen; R.sup.2 represents (C.sub.3-C.sub.4)alkynyloxy or the group M; R.sup.3 represents H or halogen; M is one of the groups M.sup.A, M.sup.B, M.sup.C and M.sup.D represented hereafter ##STR00035## ##STR00036## wherein A represents a bond, CH.sub.2CH.sub.2, CH═CH or C≡C; R.sup.1A represents H or halogen; R.sup.2A represents H, (C.sub.1-C.sub.3)alkoxy or halogen; R.sup.3A represents H, (C.sub.1-C.sub.3)alkoxy, hydroxy(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.3)alkoxy(C.sub.2-C.sub.3)alkoxy, dihydroxy(C.sub.3-C.sub.4)alkoxy, (C.sub.1-C.sub.3)thioalkoxy, trifluoromethoxy, amino, di(C.sub.1-C.sub.3)alkylamino, 2-hydroxyacetamido, hydroxy(C.sub.1-C.sub.4)alkyl, 1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, 3-(hydroxy(C.sub.1-C.sub.3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl, 3-(di(C.sub.1-C.sub.3)alkylamino)oxetan-3-yl, 3-hydroxythietan-3-yl, morpholin-4-yl(C.sub.2-C.sub.3)alkoxy, morpholin-4-yl-(C.sub.1-C.sub.2)alkyl, oxazol-2-yl or [1,2,3]triazol-2-yl; R.sup.1B represents 3-hydroxyoxetan-3-yl, 3-aminooxetan-3-yl, 3-hydroxythietan-3-yl, hydroxy(C.sub.1-C.sub.3)alkyl, dihydroxy(C.sub.2-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl, (dimethylamino)methyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-(1,2-dihydroxyethyl)cycloprop-1-yl, 1-((phosphonooxy)methyl)cyclopropyl, 1-(((dimethylglycyl)oxy)methyl)cyclopropyl, 1-methyl-2-hydroxymethyl-cycloprop-1-yl, 2-(hydroxymethyl)-2-methylcyclopropyl, 1-aminocyclopropyl, trans-2-hydroxymethyl-cycloprop-1-yl, trans-2-aminomethyl-cycloprop-1-yl, 1-fluoro-2-(hydroxymethyl)cyclopropyl, 2-fluoro-2-(hydroxymethyl)cyclopropyl, 1-(hydroxymethyl)cyclobutyl, 3-hydroxy-oxetan-3-yl, 3-hydroxymethyl-oxetan-3-yl, 1-(2-hydroxyacetyl)azetidin-3-yl, 1-(2-aminoacetyl)azetidin-3-yl, 1-glycylazetidin-3-yl, 1-(2-amino-2-methylpropanoyl)azetidin-3-yl, 3-(2-aminoacetamido)cyclopentyl, trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 3-hydroxymethylbicyclo[1,1,1]pentan-1-yl, piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 1-(2-aminoacetyl)piperidin-4-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, 5-aminotetrahydro-2H-pyran-2-yl, (1s,3r)-(1-hydroxy-3-(hydroxymethyl)cyclobutyl)methyl or 3-hydroxyoxetan-3-ylmethyl; and R.sup.1C represents 1-hydroxymethyl-cycloprop-1-yl, trans-2-(1,2-dihydroxyethyl)cycloprop-1-yl, 1-methyl-2-hydroxymethyl-cycloprop-1-yl, 2-(hydroxymethyl)-2-methylcyclopropyl, 1-aminocyclopropyl, trans-2-hydroxymethyl-cycloprop-1-yl, 1-fluoro-2-(hydroxymethyl)cyclopropyl or 2-fluoro-2-(hydroxymethyl)cyclopropyl; or a salt of the compound.
2. The compound of formula I according to claim 1, which is a compound of formula I.sub.CE ##STR00037## wherein R.sup.1 represents H or halogen; R.sup.2 represents the group M; R.sup.3 represents H or halogen; M is the one of the groups M.sup.A, M.sup.B, M.sup.c and M.sup.D represented hereafter ##STR00038## wherein A represents a bond, CH═CH or CE-C; R.sup.1A represents H or halogen; R.sup.2A represents H or halogen; R.sup.3A represents H, (C.sub.1-C.sub.3)alkoxy, hydroxy(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.3)alkoxy(C.sub.2-C.sub.3)alkoxy, (C.sub.1-C.sub.3)thioalkoxy, trifluoromethoxy, amino, di(C.sub.1-C.sub.3)alkylamino, 2-hydroxyacetamido, hydroxy(C.sub.1-C.sub.4)alkyl, 1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, 3-(hydroxy(C.sub.1-C.sub.3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl, 3-(di(C.sub.1-C.sub.3)alkylamino)oxetan-3-yl, morpholin-4-yl-(C.sub.1-C.sub.2)alkyl or [1,2,3]triazol-2-yl; R.sup.1B represents 3-hydroxyoxetan-3-yl, 3-aminooxetan-3-yl, 3-hydroxythietan-3-yl, hydroxy(C.sub.1-C.sub.3)alkyl, 1,2-dihydroxyethyl, 1,2-dihydroxy-2-methylethyl, amino(C.sub.1-C.sub.4)alkyl, (dimethylamino)methyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-(1,2-dihydroxyethyl)cycloprop-1-yl, 1-((phosphonooxy)methyl)cyclopropyl, 1-(((dimethylglycyl)oxy)methyl)cyclopropyl, 1-methyl-2-hydroxymethyl-cycloprop-1-yl, 2-(hydroxymethyl)-2-methylcyclopropyl, 1-aminocyclopropyl, trans-2-hydroxymethyl-cycloprop-1-yl, trans-2-aminomethyl-cycloprop-1-yl, 1-fluoro-2-(hydroxymethyl)cyclopropyl, 2-fluoro-2-(hydroxymethyl)cyclopropyl, 1-(hydroxymethyl)cyclobutyl, 3-hydroxymethyl-oxetan-3-yl, 1-(2-hydroxyacetyl)azetidin-3-yl, 1-(2-aminoacetyl)azetidin-3-yl, 1-glycylazetidin-3-yl, 1-(2-amino-2-methylpropanoyl)azetidin-3-yl, 3-(2-aminoacetamido)cyclopentyl, trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 3-hydroxymethylbicyclo[1,1,1]pentan-1-yl, piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 1-(2-aminoacetyl)piperidin-4-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, 5-aminotetrahydro-2H-pyran-2-yl, (1s,3r)-(1-hydroxy-3-(hydroxymethyl)cyclobutyl)methyl or 3-hydroxyoxetan-3-ylmethyl; and R.sup.1C represents trans-2-hydroxymethyl-cycloprop-1-yl; or a salt of the compound.
3. The compound of formula I according to claim 1, which is a compound of formula I.sub.P ##STR00039## wherein R.sup.1 represents H or halogen; R.sup.2 represents (C.sub.3-C.sub.4)alkynyloxy or the group M; R.sup.3 represents H or halogen; M is one of the groups M.sup.A and M.sup.B represented below ##STR00040## wherein A represents a bond, CH.sub.2CH.sub.2, CH═CH or C≡C; R.sup.1A represents H or halogen; R.sup.2A represents H, (C.sub.1-C.sub.3)alkoxy or halogen; R.sup.3A represents H, (C.sub.1-C.sub.3)alkoxy, hydroxy(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.3)thioalkoxy, trifluoromethoxy, amino, di(C.sub.1-C.sub.3)alkylamino, hydroxy(C.sub.1-C.sub.4)alkyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, 3-(hydroxy(C.sub.1-C.sub.3)alkyl)oxetan-3-yl, 3-aminooxetan-3-yl, 3-(di(C.sub.1-C.sub.3)alkylamino)oxetan-3-yl, 3-hydroxythietan-3-yl, morpholin-4-yl(C.sub.2-C.sub.3)alkoxy, morpholin-4-yl-(C.sub.1-C.sub.2)alkyl, oxazol-2-yl or [1,2,3]triazol-2-yl; and R.sup.1B represents 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl, hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl, trans-2-hydroxymethyl-cycloprop-1-yl or 4-hydroxytetrahydro-2H-pyran-4-yl; or a salt of the compound.
4. The compound of formula I according to claim 1, wherein R.sup.1 represents H or fluorine, R.sup.3 represents H or fluorine, R.sup.1A, when present, represents H or fluorine and R.sup.2A, when present, represents H or fluorine; or a salt of the compound.
5. The compound of formula I according to claim 1, wherein R.sup.2 represents the group M.sup.A; or a salt of the compound.
6. The compound of formula I according to claim 5, wherein A represents a bond; or a salt of the compound.
7. The compound of formula I according to claim 5, wherein A represents C≡C; or a salt of the compound.
8. The compound of formula I according to claim 7, wherein R.sup.1A represents H or fluorine, R.sup.2A represents H and R.sup.3A represents hydroxy(C.sub.1-C.sub.4)alkoxy, 2-hydroxyacetamido, hydroxy(C.sub.1-C.sub.4)alkyl, 1-aminocyclopropyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-hydroxymethyl-cycloprop-1-yl, 1,2-dihydroxyethyl or 3-hydroxyoxetan-3-yl; or a salt of the compound.
9. The compound of formula I according to claim 1, wherein R.sup.2 represents the group M.sup.B; or a salt of the compound.
10. The compound of formula I according to claim 9, wherein R.sup.1B represents 1,2-dihydroxyethyl, 3-hydroxyoxetan-3-yl, 3-hydroxythietan-3-yl, hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl, (dimethylamino)methyl, 1-hydroxymethyl-cycloprop-1-yl, trans-2-(1,2-dihydroxyethyl)cycloprop-1-yl, 1-methyl-2-hydroxymethyl-cycloprop-1-yl, 2-(hydroxymethyl)-2-methylcyclopropyl, 1-aminocyclopropyl, trans-2-hydroxymethyl-cycloprop-1-yl, 1-fluoro-2-(hydroxymethyl)cyclopropyl, 2-fluoro-2-(hydroxymethyl)cyclopropyl, 1-(hydroxymethyl)cyclobutyl, 3-hydroxymethyl-oxetan-3-yl, 1-(2-hydroxyacetyl)azetidin-3-yl, 1-(2-aminoacetyl)azetidin-3-yl, 1-glycylazetidin-3-yl, 1-(2-amino-2-methylpropanoyl)azetidin-3-yl, 3-(2-aminoacetamido)cyclopentyl, trans-(cis-3,4-dihydroxy)-cyclopent-1-yl, 3-hydroxymethylbicyclo[1,1,1]pentan-1-yl, piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 4-hydroxytetrahydro-2H-pyran-4-yl, 5-aminotetrahydro-2H-pyran-2-yl, (1s,3r)-(1-hydroxy-3-(hydroxymethyl)cyclobutyl)methyl or 3-hydroxyoxetan-3-ylmethyl; or a salt of the compound.
11. The compound of formula I according to claim 1, wherein R.sup.2 represents the group M.sup.C; or a salt of the compound.
12. The compound of formula I according to claim 11, wherein R.sup.1C represents trans-2-hydroxymethyl-cycloprop-1-yl; or a salt of the compound.
13. The compound of formula I according to claim 1, wherein said compound is: (R)-4-[5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-2-methylsulfonyl-4-[5-(4-methoxy-phenyl)-indazol-2-yl]-2-methyl-butanamide; (R)-4-[6-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-[4-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-[6-fluoro-5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-[4-fluoro-5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-morpholin-4-ylmethyl-phenylethynyl)-indazol-2-yl]-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-trifluoromethoxy-phenyl)-indazol-2-yl]-butanamide; (R)-4-[5-(2-fluoro-4-methylsulfanyl-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-{5-[4-(3-amino-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-[5-(4-dimethylamino-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-[1,2,3]triazol-2-yl-phenyl)-indazol-2-yl]-butanamide; (R)—N-hydroxy-4-(5-((3-hydroxythietan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(4-fluoro-5-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-hydroxytetrahydro-2H-pyran-4-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methyl sulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-(1-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-((E)-styryl)-indazol-2-yl]-butanamide; (R)-4-{4-fluoro-5-[4-((1S*,2S*)-2-hydroxymethyl-cyclopropyl)-buta-1,3-diynyl]-indazol-2-yl}-N-hydroxy-2-methyl sulfonyl-2-methyl-butanamide; (R)-4-[5-(4-amino-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-4-{5-[4-(3-hydroxy-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-4-(5-((4-(hydroxymethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-[5-(3-fluoro-4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-[4-fluoro-5-(4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-(5-(5-amino-5-methylhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-{5-[4-(2-hydroxy-ethyl)-phenylethynyl]-indazol-2-yl}-2-methylsulfonyl-2-methyl-butanamide; (2R)-4-{5-[4-((R)-1,2-dihydroxy-ethyl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-4-(5-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-{4-fluoro-5-[4-(3-hydroxy-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-{5-[4-(3-dimethylamino-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-{6-fluoro-5-[4-(3-hydroxy-oxetan-3-yl)-buta-1,3-diynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-4-[5-(5-hydroxy-5-methyl-hexa-1,3-diynyl)-indazol-2-yl]-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-4-(5-((4-((R)-1-hydroxyethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-((S)-1-hydroxyethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-[5-(2-fluoro-4-trifluoromethoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-4-(5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-{4-fluoro-5-[4-(3-hydroxy-oxetan-3-yl)-buta-1,3-diynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-[5-(2-fluoro-4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; -4-(6-fluoro-5-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(54(4-((1R,2R)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-((1S,2S)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methyl sulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-(3-(hydroxymethyl)oxetan-3-yl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-(2-hydroxyethoxy)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-{5-[4-(3-morpholin-4-yl-propoxy)-phenyl]-indazol-2-yl}-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-{5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-indazol-2-yl}-butanamide; (R)-4-{5-[2-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)-4-(5-but-2-ynyloxy-indazol-2-yl)-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-(5-phenethyl-indazol-2-yl)-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-oxazol-2-yl-phenyl)-indazol-2-yl]-butanamide; (R)-4-(5-(2-fluoro-3-methoxyphenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((3-fluoro-4-(2-hydroxyacetamido)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((R)-5,6-dihydroxy-5-methylhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((4-(2-hydroxyacetamido)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((3-aminooxetan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-(4-(2-hydroxyacetamido)phenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((4-((S)-1,2-dihydroxyethyl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-(4-(2-methoxyethoxy)phenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(6-fluoro-5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(4-fluoro-5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((S)-5,6-dihydroxyhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methyl sulfonyl)butanamide; (R)—N-hydroxy-4-(5-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(4-((R)-2,3-dihydroxypropoxy)-2-fluorophenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(pyrimidin-5-ylethynyl)-2H-indazol-2-yl)butanamide; (R)—N-hydroxy-4-(5-(4-(((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(((2 S*,5 S*)-5-aminotetrahydro-2H-pyran-2-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-(1-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-2H-indazol-5-yl)ethynyl)phenyl)cyclopropyl)methyl dihydrogen phosphate; (R)-(1-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-2H-indazol-5-yl)ethynyl)phenyl)cyclopropyl)methyl dimethylglycinate; (R)-4-(5-(((1S,3R,4S)-3,4-dihydroxycyclopentyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methyl sulfonyl)butanamide; (R)-4-(5-((1-aminocyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-(5-((1S,3R)-1-hydroxy-3-(hydroxymethyl)cyclobutyl)penta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methyl sulfonyl)butanamide; (R)—N-hydroxy-4-(5-(((1R,2R)-2-(hydroxymethyl)-1-methylcyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methyl sulfonyl)butanamide; (R)—N-hydroxy-4-(5-((3-(hydroxymethyl)oxetan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-(((1R,2S)-2-(hydroxymethyl)-2-methylcyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((3-(2-aminoacetamido)cyclopentyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(((1R,2R)-2-((S)-1,2-dihydroxyethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(((1R,2R)-2-(aminomethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(((1R,2R)-1-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(5-(dimethylamino)penta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(piperidin-4-ylbuta-1,3-diyn-1-yl)-2H-indazol-2-yl)butanamide; (R)-4-(5-(((1R,2R)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((1-(2-hydroxyacetyl)piperidin-4-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((4-(1-aminocyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-(5-(3-hydroxyoxetan-3-yl)penta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)—N-hydroxy-4-(5-((1-(2-hydroxyacetyl)azetidin-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-(6-amino-6-methylhepta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((1-glycylpiperidin-4-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (R)-4-(5-((1-glycylazetidin-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; or (R)-4-(5-((1-(2-amino-2-methylpropanoyl)azetidin-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; or a salt of the compound.
14. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is formulated as a medicament.
15. A pharmaceutical composition comprising, as active principle, the compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
16. A method of treating a Gram-negative bacterial infection comprising administering the compound or salt thereof according to claim 1 to a subject in need thereof.
Description
EXAMPLES
(1) All temperatures are stated in ° C. Unless otherwise indicated, the reactions take place at rt.
(2) Analytical TLC characterisations were performed with 0.2 mm plates: Merck, Silica gel 60 F.sub.254. Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection was done with UV or with a solution of KMnO.sub.4 (3 g), K.sub.2CO.sub.3 (20 g), 5% NaOH (3 mL) and H.sub.2O (300 mL) with subsequent heating.
(3) CCs were performed using Brunschwig 60A silica gel (0.032-0.63 mm) or using an ISCO CombiFlash system and prepacked SiO.sub.2 cartridges, elution being carried out with either Hept-EA or DCM-MeOH mixtures with an appropriate gradient. When the compounds contained an acid function, 1% of AcOH was added to the eluent(s). When the compounds contained a basic function, 25% aq. NH.sub.4OH was added to the eluents.
(4) Compounds were characterized by .sup.1H-NMR (300 MHz) (Varian Oxford); or by .sup.1H-NMR (400 MHz) (Bruker Advance 400). Chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, q=quadruplet, p=pentuplet, hex=hexet, hep=heptet, m=multiplet, br.=broad; coupling constants J are given in Hz. Alternatively compounds were characterized by LC-MS (Sciex API 2000 with Agilent 1100 Binary Pump with DAD and ELSD or an Agilent quadrupole MS 6140 with Agilent 1200 Binary Pump, DAD and ELSD); by TLC (TLC plates from Merck, Silica gel 60 F.sub.254); or by melting point.
(5) The analytical LC-MS data have been obtained using the following respective conditions: MS1 data: Column: Zorbax SB-Aq, 3.5 μm, 4.6×50 mm; Injection volume: 1 μL; Column oven temperature: 40° C.; Detection: UV 210 nm, ELSD and MS; MS ionization mode: ESI+; Eluents: A: H.sub.2O+0.04% TFA; and B: MeCN; Flow rate: 4.5 mL/min; Gradient: 5% B to 95% B (0.0 min 1.0 min), 95% B (1.0 min 1.45 min). MS2 data: Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60° C.; Pump: Waters Acquity Binary, Solvent Manager; MS: Waters SQ Detector; DAD: Acquity UPLC PDA Detector; ELSD: Acquity UPLC ELSD; Eluents: A: H.sub.2O+0.05% TFA; and B: MeCN+0.045% TFA; Elution method: gradient: 2% B to 98% B over 2.0 min; Flow rate: 1.0 mL/min; Detection: UV 214 nm and ELSD.
(6) The number of decimals given for the corresponding [M+H.sup.+] peak(s) of each tested compound depends upon the accuracy of the LC-MS device actually used.
(7) The prep-HPLC purifications were performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector, using the following respective conditions: Method 1: Column: Waters Atlantis T3 OBD, 10 μm, 30×75 mm; Flow rate: 75 mL/min; Eluents: A: H.sub.2O+0.1% HCOOH; B: MeCN+0.1% HCOOH; Gradient: 90% A to 5% A (0.0 min 4.0 min), 5% A (4.0 min 6.0 min). Method 2: Column: Waters XBridge C18, 10 μm, 30×75 mm; Flow rate: 75 mL/min; Eluents: A: H.sub.2O+0.1% HCOOH; B: MeCN+0.1% HCOOH; Gradient: 70% A to 5% A (0.0 min 3.5 min), 5% A (3.5 min 6.0 min). Method 3: Column: Waters XBridge C18, 10 μm, 30×75 mm; Flow rate: 75 mL/min; Eluents: A: H.sub.2O+0.5% NH.sub.4OH solution (25%); B: MeCN; Gradient: 90% A to 5% A (0.0 min 4.0 min), 5% A (4.0 min 6.0 min).
(8) Besides, semi-preparative chiral HPLCs were performed using the conditions hereafter.
(9) Semi-Preparative Chiral HPLC Method A:
(10) The semi-preparative chiral HPLC is performed on a Daicel ChiralPak AS-H column (20×250 mm, 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak AS-H column (4.6×250 mm, 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
(11) Semi-Preparative Chiral HPLC Method B: The semi-preparative chiral HPLC is performed on a Daicel ChiralPak AY-H column (20×250 mm, 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak AY-H column (4.6×250 mm, 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
(12) Semi-Preparative Chiral HPLC Method C:
(13) The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OD-H column (20×250 mm; 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples a Daicel ChiralCel OD-H column (4.6×250 mm; 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
(14) Semi-Preparative Chiral HPLC Method D:
(15) The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OJ-H column (20×250 mm; 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel OJ-H column (4.6×250 mm; 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
(16) Semi-Preparative Chiral HPLC Method E:
(17) The semi-preparative chiral HPLC is performed on a Daicel ChiralCel AD-H column (20×250 mm; 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel AD-H column (4.6×250 mm; 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
(18) Semi-Preparative Chiral HPLC Method F:
(19) The semi-preparative chiral HPLC is performed on a Daicel ChiralPak IA column (20×250 mm; 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak IA column (4.6×250 mm; 5 μM) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
(20) Semi-Preparative Chiral HPLC Method G:
(21) The semi-preparative chiral HPLC is performed on a Daicel ChiralPak ASV column (20×250 mm; 5 μM) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol.
PREPARATIONS
Preparation A: (RS)-4-(5-bromo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
A.i. 2-(5-bromo-2H-indazol-2-yl)ethanol
(22) Variant I:
(23) A solution of 5-bromo-1H-indazole (10 g; commercial) in DMF (330 mL) was cooled to 0° C. and treated portionwise with NaH (in 60% mineral oil; 2.41 g). The reaction mixture was allowed to reach rt, further stirred at rt for 1 h, treated with ethylene carbonate (17.9 g) and heated for 3 h at 80° C. The reaction mixture was concentrated under reduced pressure, diluted with 10% aq. NaHSO.sub.4 solution (150 mL) and extracted with EA (2×50 mL). The combined org. layers were washed with brine, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by CC (Hept-EA) to afford the title compound as a yellow oil (5.4 g; 44% yield).
(24) .sup.1H NMR (d6-DMSO) δ: 8.33 (d, J=0.9 Hz, 1H); 7.95 (dd, J=0.9, 1.9 Hz, 1H); 7.57 (td, J=0.9, 9.1 Hz, 1H); 7.29 (dd, J=1.9, 9.1 Hz, 1H); 4.94 (t, J=5.4 Hz, 1H); 4.44 (t, J=5.4 Hz, 2H); 3.85 (q, J=5.4 Hz, 2H).
(25) MS1 (ESI, m/z): 243.0 [M+H.sup.+] for C.sub.9H.sub.9N.sub.2OBr; t.sub.R=0.65 min.
(26) Variant II:
(27) To a solution of 5-bromo-2-nitrobenzaldehyde (4.89 g; 21.3 mmol) in MeOH (53.9 mL) was added ethanolamine (1.3 mL, 21.5 mmol) The mixture was stirred at reflux for 1 h. After cooling, the solvent was evaporated to dryness. The residue was taken up in P(OEt).sub.3 (36.5 mL) and the mixture was immersed in an oil bath heated to 150° C. for 20 min. After cooling and concentration to dryness, the residue was purified by CC (Hept-EA) afford the title indazole as a yellow solid (2.12 g; 41% yield).
(28) NMR data are identical to those reported for the product of Variant I.
A.ii. 3-(5-bromo-2H-indazol-2-yl)ethyl methanesulfonate
(29) A solution of intermediate A.i (5.37 g) in DCM (80 mL) and TEA (4.5 mL) was cooled to 0° C. and treated with MsCl (1.94 mL). The reaction mixture was stirred at 0° C. for 30 min, allowed to reach rt and treated with sat. aq. Na.sub.2CO.sub.3 solution (50 mL). The org. layer was washed with a sat. aq. NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by purified by CC (Hept-EA) to afford the title compound as a yellow oil (3.3 g, 47% yield).
(30) MS1 (ESI, m/z): 320.9 [M+H.sup.+] for C.sub.10H.sub.11N.sub.2O.sub.3BrS; t.sub.R=0.76 min.
A.iii. 5-bromo-2-(3-iodoethyl)-2H-indazole
(31) A solution of intermediate Aii (3.3 g) in 2-butanone (42 mL) and NaI (2.89 mg, 19.3 mmol) was added. The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with water (15 mL) and EA (25 mL). The aq. layer was extracted with EA (4×10 mL). The combined org. layers were washed with a sat. solution of Na.sub.2SO.sub.3 (25 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the desired compound as a yellow solid (3.22 g).
(32) .sup.1H NMR (d6-DMSO) δ: 8.41 (d, J=0.9 Hz, 1H); 7.99 (dd, J=0.9, 1.9 Hz, 1H); 7.59 (td, J=0.9, 9.1 Hz, 1H); 7.31 (dd, J=1.9, 9.1 Hz, 1); 4.76 (t, J=5.4 Hz, 2H); 3.73 (t, J=6.4 Hz, 2H).
(33) MS1 (ESI, m/z): 350.84 [M+H.sup.+] for C.sub.9H.sub.9N.sub.2BrI; t.sub.R=0.86 min.
A.iv. (RS)-ethyl 4-(5-bromo-2H-indazol-2-yl)-2-(methylsulfonyl)butanoate
(34) To a suspension of NaH (0.556 g; 13.9 mmol) in DMF (15 mL) at 0° C. was added slowly ethyl methylsulfonyl acetate (3 mL; 25 mmol). The reaction was allowed to warm to rt and stirred for 30 min. A solution of intermediate A.iii (3.21 g; 9.17 mmol) in DMF (53 mL) was added dropwise and the reaction mixture was stirred at rt overnight. An aq. 20% NaHSO.sub.4 solution (25 mL) was added and the mixture was extracted with EA (3×40 mL). The combined org. layers were washed with brine (25 mL), dried over MgSO.sub.4 and concentrated to dryness. The crude product (6.33 g) was purified by CC (Hept-EA) to afford the title compound as a yellow oil (4.68 g), contaminated with the excess of ethylmethylsulfonyl acetate.
(35) .sup.1H NMR (d6-DMSO) δ: 8.37 (d, J=0.9 Hz, 1H); 7.96 (dd, J=0.9, 1.9 Hz, 1H); 7.57 (td, J=0.9, 9.1 Hz, 1H); 7.30 (dd, J=1.9, 9.1 Hz, 1H); 4.56 (t, J=5.9 Hz, 2H); 4.27 (m, 1H); 3.96-4.08 (m, 2H); 3.11 (s, 3H); 2.55-2.63 (m, 2H); 1.14 (t, J=6.9 Hz, 3H).
A.v. (RS)-ethyl 4-(5-bromo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
(36) Variant I:
(37) Cs.sub.2CO.sub.3 (4.96 g; 15.2 mmol) was added at rt, to a solution of intermediate A.iv (4.68 g; 12 mmol) in DMF (67.1 mL) and the mixture was stirred for 15 min. CH.sub.3I (3 mL; 48.1 mmol) was added and the mixture was stirred overnight. More Cs.sub.2CO.sub.3 (1.96 g, 6.02 mmol) and CH.sub.3I (0.751 mL; 12 mmol) were then added and the reaction mixture was stirred overnight. Water (20 mL) and EA (40 mL) were added. The two layers were separated. The aq. layer was extracted with EA (4×35 mL). The combined org. layers were washed with brine (20 mL), dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude product was purified by CC (Hept-EA) to afford the title compound as a yellow oil (2.91 g, 60% yield).
(38) .sup.1H NMR (d6-DMSO) δ: 8.41 (s, 1H); 7.96 (m, 1H); 7.57 (d, J=9.1 Hz, 1H); 7.30 (dd, J=1.9, 9.1 Hz, 1H); 4.58-4.69 (m, 1H); 4.42-4.54 (m, 1H); 3.88-4.05 (m, 2H); 3.10 (s, 3H), 2.78-2.89 (m, 1H); 2.44 (overlapped m, 1H); 1.58 (s, 3H); 1.12 (t, J=7.1 Hz, 3H).
(39) Variant II:
(40) To a solution of intermediate A.iii (0.537 g; 1.53 mmol) and ethyl 2-(methylsulfonyl)propanoate (0.303 g; 1.68 mmol) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (0.997 g; 3.06 mmol). The reaction was stirred at 80° C. for 2 h. Water (30 mL) was added and the two layers were diluted with EA (40 mL). The aq. layer was extracted with EA (30 mL). The combined org. layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The crude product was purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.171 g, 28% yield).
(41) NMR data are identical to those reported for the product of Variant I.
A.vi. (RS)-4-(5-bromo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(42) To an ice-chilled solution of intermediate A.v (2.91 g; 7.23 mmol) in a THF-MeOH—H.sub.2O (2-2-1, 81 mL) was added LiOH.H.sub.2O (1.19 g; 16 mmol). The reaction mixture was stirred at rt overnight. Solvents were evaporated in vacuo and the residue was dried to a constant weight. The resulting solid was taken up in DMF (70 mL) and HOBT.H.sub.2O (1.96 g, 14.5 mmol), TEA (3.2 mL; 23 mmol), NH.sub.2—OTHP (1.72 g, 14.7 mmol) and EDC (2.72 g, 14.2 mmol) were successively added. The suspension was then stirred at 60° C. for 2 h. More EDC (0.699 g, 3.65 mmol), NH.sub.2—OTHP (0.86 g, 7.36 mmol) were added and the reaction mixture was heated at 60° C. overnight. The reaction mixture was concentrated to dryness. Water (50 mL) and EA (70 mL) were added. The org. layer was washed with water (15 mL), sat. NaHCO.sub.3 (15 mL) and brine (20 mL). The org. layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellowish oil (2.17 g, 63% yield).
(43) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.3 (br. s, 1H); 8.39 (m, 1H); 7.92-7.96 (m, 1H); 7.55-7.60 (m, 1H); 7.30 (dd, J=1.9, 9.1 Hz, 1H); 4.89-4.95 (m, 1H); 4.49-4.59 (m, 1H); 4.32-4.43 (m, 1H); 3.95-4.16 (m, 1H); 3.47-3.53 (m, 1H); 3.05 (s, 1.5H); 3.03 (s, 1.5H); 2.76-2.86 (m, 1H); 2.34-2.46 (m, 1H); 1.61-1.71 (m, 3H); 1.46-1.58 (m, 3H); 1.51 (s, 1.5H); 1.48 (s, 1.5H).
(44) MS1 (ESI, m/z): 474.05 [M+H.sup.+] for C.sub.18H.sub.24N.sub.3O.sub.5BrS; t.sub.R=0.80 min.
Preparation B: (RS)-4-(5-bromo-6-fluoro-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
B.i. 2-(5-bromo-6-fluoro-2H-indazol-2-yl)ethanol
(45) To a solution of 5-bromo-4-fluoro-2-nitrobenzaldehyde (2.0 g; 8.06 mmol; commercial) in MeOH (5 mL) was added ethanolamine (0.61 mL) The mixture was stirred at reflux for 1 h. After cooling, the solvent was evaporated to dryness. The residue was taken up in P(OEt).sub.3 (14 mL) and the mixture was immersed in an oil bath heated to 150° C. for 20 min. After cooling and concentration to dryness, the residue was purified by CC (Hept-EA) to afford the title indazole as a yellow solid (1.17 g, 56% yield).
(46) .sup.1H NMR (CDCl.sub.3) δ: 7.95 (s, 1H); 7.90 (d, J=6.7 Hz, 1H); 7.38 (d, J=6.7 Hz, 1H); 4.49-4.53 (m, 2H); 4.09-4.15 (m, 2H).
(47) MS1 (ESI, m/z): 258.97 [M+H.sup.+] for C.sub.9H.sub.8N.sub.2OBrF; t.sub.R=0.64 min.
B.ii. (RS)-4-(5-bromo-6-fluoro-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(48) Starting from intermediate B.i (1.3 g, 5.02 mmol) and proceeding in analogy to Preparation A, steps A.ii to A.v, the title compound was obtained as a colourless foam (1.2 g; yields: 95% for mesylate formation, 96% for iodide formation, 93% (Variant I) and 86% (Variant II) for alkylation, 60% for saponification, and 95% for amide coupling with THPO—NH.sub.2).
(49) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.4 (br. s, 0.5H); 11.3 (br. s, 0.5H); 8.44 (br. s, 1H); 8.16 (d, J=7.1 Hz, 1H); 7.54-7.60 (m, 1H); 4.92-4.96 (m, 0.5H); 4.87-4.91 (m, 0.5H); 4.47-4.59 (m, 1H); 4.30-4.43 (m, 1H); 3.97-4.16 (m, 1H); 3.72 (m, 0.5H); 3.45-3.55 (m, 1H); 3.05 (s, 1.5H); 3.03 (s, 1.5H); 2.76-2.86 (m, 1H); 2.34-2.46 (m, 1H); 1.61-1.71 (m, 2H); 1.46-1.58 (m, 2H); 1.51 (s, 1.5H); 1.49 (s, 1.5H). MS1 (ESI, m/z): 492.04 [M+H.sup.+] for C.sub.18H.sub.23N.sub.3O.sub.5BrFS; t.sub.R=0.81 min.
Preparation C: (R)-ethyl 4-(5-bromo-4-fluoro-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
(50) To an ice-chilled suspension of NaH (60% in mineral oil, 0.21 g, 5.12 mmol) in DMF (3.2 mL) was slowly added a solution of 5-bromo-4-fluoro-1H-indazole (1 g; 4.65 mmol) in DMF (3.7 mL), keeping IT below 6° C. The reaction mixture was stirred for 1 h at 0° C.; then (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.67 g; 5.81 mmol; prepared as described in WO 2012/137099) in solution in DMF (1.8 mL) was added, keeping IT below 3° C. The mixture was warmed to rt and stirred for 3 h. The reaction mixture was diluted with aq. NaHSO.sub.4 (15%, 5 mL), water (50 mL) and EA (25 mL). The two phases were separated and the aq. layer was extracted with EA (2×25 mL). The combined org. layers were dried over MgSO.sub.4 and filtered and concentrated to dryness. The residue was purified by CC (Hept-EA gradient) to afford first the 1-indazole regioisomer (0.9 g, 46% yield) and then the title regioisomer (0.8 g, 39% yield), still contaminated with 20% of the 1-indazole regioisomer.
(51) .sup.1H NMR (d6-DMSO) δ: 8.68 (s, 1H); 7.35-7.45 (m, 2H); 4.65 (m, 1H); 4.49 (m, 1H); 3.85-4.06 (m, 2H); 3.10 (s, 3H); 2.86 (m, 1H); 2.47 (overlaid with DMSO; m, 1H); 1.60 (s, 3H); 1.11 (t, J=7.1 Hz, 3H).
(52) MS1 (ESI, m/z): 423.01 [M+H.sup.+] for C.sub.15H.sub.18N.sub.2O.sub.4BrFS; t.sub.R=0.86 min.
Preparation D: 2-(2-fluoro-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(53) A mixture of bis(pinacolato)diboron (1.15 g; 4.5 mmol), Pd(dppf)Cl.sub.2 (0.248 g; 0.3 mmol) and KOAc (1.27 g; 13 mmol) was flushed with nitrogen for 15 min and treated with a solution of 4-bromo-3-fluorothioanisole (1 g; 4.3 mmol; commercial) in dioxane (17 mL). The reaction mixture was heated to reflux for 3 h. After cooling, the reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow oil (0.84 g, 73% yield).
(54) .sup.1H NMR (CDCl.sub.3) δ: 7.61 (dd, J=6.5, 7.9 Hz, 1H); 6.98 (dd, J=1.7, 7.9 Hz, 1H); 6.87 (dd, J=1.7, 10.2 Hz, 1H); 2.47 (s, 3H); 1.34 (s, 12H).
(55) MS1 (ESI, m/z): 269.2 [M+H.sup.+] for C.sub.13H.sub.18O.sub.2BFS; t.sub.R=0.96 min.
Preparation E: (2RS)-4-(5-ethynyl-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
E.i. (RS)-4-(5-Iodo-indazol-2-yl)-2-methylsulfonyl-2-methyl-butyric acid ethyl ester
(56) Into a microwave vial were added a solution of intermediate A.v (0.592 g; 1.47 mmol) in 1,4-dioxane (2.4 mL), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.026 mL: 0.165 mmol; 0.11 eq.), NaI (0.445 g, 2.94 mmol) and then CuI (0.029 g, 0.149 mmol). The reaction mixure was microwaved at 180° C. for 20 min. Water (10 mL) and EA (30 mL) were added. The aq. layer was extracted once with EA (30 mL). The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.55 g; 74% yield).
(57) .sup.1H NMR (d6-DMSO) δ: 8.37 (br. s, 1H); 8.14 (br. s, 1H); 7.43 (br. s, 2H); 4.56-4.68 (m, 1H); 4.40-4.52 (m, 1H); 3.89-4.04 (m, 2H); 3.10 (s, 3H); 2.76-2.89 (m, 1H); 2.39-2.45 (overlapped m, 1H); 1.57 (s, 3H); 1.12 (t, J=7.1 Hz, 3H).
(58) MS1 (ESI, m/z): 451.0 [M+H.sup.+] for C.sub.15H.sub.19N.sub.2O.sub.4IS; t.sub.R=0.85 min.
E.ii. (RS)-ethyl 2-methyl-2-(methylsulfonyl)-4-(5-((trimethylsilyl)ethynyl)-2H-indazol-2-yl)butanoate
(59) CuI (0.04 g, 0.22 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (0.08 g, 0.11 mmol) were introduced in a two-necked round-bottom flask. After flushing with nitrogen for 30 min, a solution of intermediate E.i (0.5 g; 1.11 mmol) in degassed THF (8 mL) was added followed with trimethylsilylacetylene (0.17 mL; 1.22 mmol). Degassed TEA (0.39 mL, 2.78 mmol) was added dropwise and the reaction proceeded at 50° C. for 2 h. The mixture was concentrated to dryness and the residue was purified by CC (Hept-EA) to afford the title compound as a brown gum (0.43 g, 93% yield).
(60) .sup.1H NMR (d6-DMSO) δ: 8.46 (s, 1H); 7.91 (s, 1H); 7.58 (d, J=8.9 Hz, 1H); 7.21 (dd, J=1.2, 8.9 Hz, 1H); 4.58-4.71 (m, 1H); 4.42-4.55 (m, 1H); 3.84-4.07 (m, 2H); 3.12 (s, 3H); 2.79-2.92 (m, 1H); 2.39-2.53 (overlapped m, 1H); 1.61 (s, 3H); 1.11 (t, J=7.2 Hz, 3H); 0.24 (s, 9H).
(61) MS (ESI, m/z): 421.2 [M+H.sup.+] for C.sub.20H.sub.28N.sub.2O.sub.4SSi; t.sub.R=0.96 min.
E.iii. (RS)-ethyl 4-(5-ethynyl-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
(62) To a solution of intermediate E.ii (0.2 g; 0.48 mmol) in THF (1 mL) was added TBAF (1M in THF; 0.37 mL). The mixture was stirred at rt during 2 h. The solvent was removed in vacuo and the residue was purified by CC (Hept-EA gradient) to afford the title compound as a pinkish gum (0.1 g, 61% yield).
(63) .sup.1H NMR (d6-DMSO) δ: 8.46 (s, 1H); 7.92 (s, 1H); 7.59 (d, J=8.9 Hz, 1H); 7.24 (dd, J=1.2, 8.9 Hz, 1H); 4.59-4.71 (m, 1H); 4.42-4.55 (m, 1H); 4.04 (s, 1H); 3.86-4.07 (overlapped m, 2H); 3.11 (s, 3H); 2.78-2.92 (m, 1H); 2.39-2.54 (overlapped m, 1H); 1.60 (s, 3H); 1.12 (t, J=7.1 Hz, 3H).
(64) MS (ESI, m/z): 349.1 [M+H.sup.+] for C.sub.17H.sub.20N.sub.2O.sub.4S; t.sub.R=0.80 min.
E.iv. (2RS)-4-(5-ethynyl-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(65) Starting from intermediate E.iii (0.1 g; 0.28 mmol) and proceeding in analogy to Preparation A, step A.vi (saponification and amide coupling with THPO—NH.sub.2), the title amide was obtained as an off-white foam (0.087 g; 75% yield after the 2 steps).
(66) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.4 (s, 1H); 8.44 (br. s, 1H); 7.91 (s, 1H); 7.56-7.62 (m, 1H); 7.23 (dd, J=1.2, 8.9 Hz, 1H); 4.90-4.97 (m, 1H); 4.48-4.61 (m, 1H); 4.31-4.45 (m, 1H); 4.03-4.14 (overlapped m, 1H); 4.03 (s, 1H); 3.46-3.56 (m, 1H); 3.06 (s, 3×0.5H); 3.04 (s, 3×0.5H); 2.76-2.90 (m, 1H); 2.34-2.48 (overlapped m, 1H); 1.62-1.72 (m, 3H); 1.47-1.58 (m, 6H).
(67) MS (ESI, m/z): 420.2 [M+H.sup.+] for C.sub.20H.sub.25N.sub.3O.sub.5S; t.sub.R=0.77 min.
Preparation F: (R)-ethyl 4-(5-(2-fluoro-4-methoxyphenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
F.i. 5-(2-fluoro-4-methoxyphenyl)-2H-indazole
(68) A mixture of 5-bromo-1H-indazole (9.1 g, 46.2 mmol), 2-fluoro-4-methoxyphenylboronic acid (8.24 g, 48.5 mmol), K.sub.2CO.sub.3 (21 g, 152 mmol) and Pd(PPh.sub.3).sub.4 (3.2 g, 2.77 mmol) was flushed with nitrogen for 15 min. Dioxane (255 mL) and water (70 mL) were added. The mixture was heated at 90° C. for 23 h. After cooling, water (100 mL) and EA (80 mL) were added and the two layers were separated. The aq. layer was extracted with EA (2×100 mL) and the combined org. layers were washed with brine, dried over MgSO.sub.4 and concentrated to dryness. The residue was triturated in DCM (30 mL) to afford the title compound as a white solid (4.08 g, 36% yield). The filtrate was concentrated and the residue was purified by CC (Hept-EA with gradient) to afford more title compound as a light yellow solid (3.65 g, 33% yield).
(69) .sup.1H NMR (d6-DMSO) δ: 13.0 (br. s, 1H); 8.09 (br. s, 1H); 7.83 (br. s, 1H); 7.55-7.60 (m, 1H); 7.41-7.49 (m, 2H); 6.83-6.95 (m, 2H); 3.79 (s, 3H).
(70) MS1 (ESI, m/z): 434.2 [M+H.sup.+] for C.sub.14H.sub.11N.sub.2OF; t.sub.R=0.84 min.
F.ii. (R)-ethyl 4-(5-(2-fluoro-4-methoxyphenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
(71) Starting from intermediate F.i (4.07 g; 15.1 mmol) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (5.22 g; 18.2 mmol, prepared as described in WO 2012/137099), and proceeding in analogy to Preparation C, the title compound was obtained as a colourless gum (2.03 g, 30% yield). The residue was purified by CC (Hept-EA with gradient).
(72) .sup.1H NMR (d6-DMSO) δ: 8.46 (s, 1H); 7.79 (s, 1H); 7.66 (d, J=8.8 Hz, 1H); 7.47 (t, J=8.8 Hz, 1H); 7.34-7.40 (m, 1H); 6.97-6.85 (m, 2H); 4.60-4.71 (m, 1H); 4.44-4.57 (m, 1H); 3.92-4.08 (m, 2H); 3.82 (s, 3H); 3.13 (s, 3H); 2.81-2.93 (m, 1H); 2.37-2.53 (overlapped m, 1H); 1.62 (s, 3H); 1.15 (t, J=7.1 Hz, 3H).
(73) MS1 (ESI, m/z): 449.1 [M+H.sup.+] for C.sub.22H.sub.25N.sub.2O.sub.5FS; t.sub.R=0.90 min.
(74) The e.e. was determined by chiral HPLC using a ChiralPak IA (4.6×250 mm, 5 μM) column at a flow rate of 1.4 mL/min (UV detection at 210 nm), eluting with Hept-EtOH 1-9. The retention times obtained for the racemate produced accordingly from rac-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate were respectively 5.6 and 10.8 min. The title (R)-enantiomer was the second eluting compound. The e.e. was >99%.
Preparation G: 3-(iodoethynyl)oxetan-3-ol
(75) To a solution of 3-ethynyloxetan-3-ol (1.097 g; 11.2 mmol; commercial) in MeOH (50 mL) and 1M aq. KOH (28 mL) was added iodine (3.549 g; 14 mmol). The reaction mixture was stirred for 2 h at rt. Water (150 mL) and DCM (500 mL) were added. The aq. layer was extracted with EA (500 mL). The org. layer were washed with brine, dried over MgSO.sub.4, filtered and concentrated down to afford the desired compound as a light yellow solid (2.21 g, 88% yield).
(76) .sup.1H NMR (d6-DMSO) δ: 4.60 (d, J=6.5 Hz, 2H); 4.45 (d, J=6.5 Hz, 2H).
Preparation H: (R)-4-(5-iodo-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
H.i. (R)-4-(5-bromo-indazol-2-yl)-2-methylsulfonyl-2-methyl-butyric acid ethyl ester
(77) Starting from 5-bromo-1H-indazole (2 g; 10.2 mmol) and proceeding in analogy to Preparation C, the title (R)-enantiomer was obtained, after purification by CC (DCM-EA), as an orange gum (1.71 g, 42% yield).
(78) .sup.1H NMR (d6-DMSO) δ: 8.42 (s, 1H); 7.97 (d, J=1.2 Hz, 1H); 7.59 (d, J=9.1 Hz, 1H); 7.32 (dd, J=9.1, 1.8 Hz, 1H); 4.57-4.70 (m, 1H); 4.42-4.55 (m, 1H); 3.86-4.08 (m, 2H); 3.12 (s, 3H); 2.71-2.91 (m, 1H); 2.40-2.55 (overlapped m, 1H); 1.60 (s, 3H); 1.13 (t, J=7.1 Hz, 3H).
(79) MS (ESI, m/z): 403.0 [M+H+] for C.sub.15H.sub.19N.sub.2O.sub.4BrS; t.sub.R=0.83 min.
H.ii. (R)-4-(5-iodo-indazol-2-yl)-2-methylsulfonyl-2-methyl-butyric acid ethyl ester
(80) Starting from intermediate H.i (1.57 g; 3.91 mmol) and proceeding in analogy to Preparation E, step E.i, the title iodide was obtained as a yellow gum (1.32 g, 75% yield).
(81) MS1 (ESI, m/z): 451.0 [M+H.sup.+] for C.sub.15H.sub.19N.sub.2O.sub.4IS; t.sub.R=0.85 min.
H.iii. (R)-4-(5-iodo-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
(82) Starting from intermediate H.ii (1 g; 2.22 mmol) and proceeding in analogy to Preparation A, step A.vi (saponification and amide coupling with THPO—NH.sub.2), the title compound was obtained as an orange thick oil (0.833 g; 75% yield after the 2 steps).
(83) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.3 (br. s, 1H); 8.35 (s, 1H); 8.14 (d, J=0.6 Hz, 1H); 7.39-7.46 (m, 2H); 4.91 (m, 1H); 4.52 (m, 1H); 4.37 (m, 1H); 4.05 (br. s, 1H); 3.49 (m, 1H); 3.04 (s, 3×0.5H); 3.02 (s, 3×0.5H); 2.82 (m, 1H); 2.41 (overlaid m, 1H); 1.60-1.71 (m, 3H); 1.45-1.57 (m, 3H); 1.49 (s, 3×0.5H); 1.47 (s, 3×0.5H).
(84) MS1 (ESI, m/z): 522.1 [M+H.sup.+] for C.sub.18H.sub.24N.sub.3O.sub.5IS; t.sub.R=0.81 min.
Preparation I: (R)-4-(5-iodo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(2-(trimethylsilyl)ethoxy)butanamide
(85) Starting from intermediate H.ii (0.326 g; 0.72 mmol) and proceeding in analogy to Preparation A, step A.vi (saponification and amide coupling with O-(2-trimethylsilylethyl)hydroxylamine hydrochloride (commercial)), the title compound was obtained as an orange thick oil (0.36 g; 90% yield after the 2 steps).
(86) .sup.1H NMR (d6-DMSO) δ: 11.38 (s, 1H); 8.40 (s, 1H); 8.15 (s, 1H); 7.43-7.48 (m, 2H); 4.52-4.61 (m, 1H); 4.34-4.43 (m, 1H); 3.77-3.84 (m, 2H); 3.06 (s, 3H); 2.82-2.90 (m, 1H); 2.35-2.42 (m, 1H); 1.53 (s, 3H); 0.91-0.97 (m, 2H); 0.02 (s, 9H).
(87) MS1 (ESI, m/z): 538.1 [M+H.sup.+] for C.sub.18H.sub.28N.sub.3O.sub.4ISSi; t.sub.R=0.81 min.
Preparation J: (2R)-4-(5-ethynyl-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(88) Starting from the compound of Preparation H (0.502 g; 0.96 mmol) and trimethysilyl acetylene (0.151 mL, 1.1 eq.), and proceeding in analogy to Preparation E, steps E.ii and E.iii, the title compound was obtained, after purification by CC (DCM-MeOH), as an off-white foam (0.3 g; yields: 97% for Sonogashira coupling; 76% for silyl cleavage).
(89) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.42 (br. s, 1H); 8.45 (s, 1H); 7.92 (s, 1H); 7.61 (d, J=8.9 Hz, 1H); 7.24 (dd, J=1.1, 8.9 Hz, 1H); 4.90-4.97 (m, 1H); 4.50-4.62 (m, 1H); 4.34-4.46 (m, 1H); 4.04 (s, 1H); 3.98-4.15 (overlapped m, 1H); 3.46-3.57 (m, 1H); 3.08 (s, 1.5H); 3.05 (s, 1.5H); 2.72-2.91 (m, 1H); 2.34-2.53 (overlapped m, 1H); 1.63-1.74 (m, 3H); 1.46-1.59 (overlapped m, 3H); 1.53 (s, 1.5H); 1.50 (s, 1.5H).
(90) MS (ESI, m/z): 420.0 [M+H.sup.+] for C.sub.20H.sub.25N.sub.3O.sub.5S; t.sub.R=0.77 min.
Preparation K: (2R)-4-(4-fluoro-5-iodo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—((RS)-(tetrahydro-2H-pyran-2-yl)oxy)butanamide
K.i. (R)-ethyl 4-(4-fluoro-5-iodo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
(91) To a solution of the compound of Preparation C (0.49 g; 1.16 mmol) in 1,4-dioxane (1.9 mL) were added trans-N—N′-dimethylcyclohexane-1,2-diamine (0.07 mL, 0.47 mmol), NaI (0.35 g, 2.4 mmol) and CuI (0.045 g, 0.23 mmol). The reaction mixture was irradiated in a microwave at 180° C. for 20 min. Water (20 mL) and EA (30 mL) were added. The aq. layer was extracted with EA (2×20 mL). The combined org. layers were washed with brine (10 mL), dried over MgSO.sub.4, filtered and concentrated to dryness. The crude product was purified by CC (Hept-EA) to afford the title product as a yellowish solid (0.21 g).
(92) 1H NMR (d6-DMSO) δ: 8.62 (s, 1H); 7.43-7.51 (m, 1H); 7.30 (d, J=9.1 Hz, 1H); 4.57-4.70 (m, 1H); 4.50 (m, 1H); 3.82-4.04 (m, 2H); 3.10 (s, 3H); 2.79-2.92 (m, 1H); 2.42-2.55 (overlapped m, 1H); 1.59 (s, 3H); 1.11 (t, J=7.3 Hz, 3H).
(93) MS1 (ESI, m/z): 469.01 [M+H.sup.+] for C.sub.15H.sub.18N.sub.2O.sub.4FIS; t.sub.R=0.87 min.
K.ii. (2S)-4-(4-fluoro-5-iodo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—((RS)-(tetrahydro-2H-pyran-2-yl)oxy)butanamide
(94) Starting from intermediate K.i (0.197 g, 0.42 mmol) and proceeding in analogy to Preparation A, step A.vi (saponification and amide coupling with THPO—NH.sub.2), the title amide was obtained as a beige foam (0.197 g; 86% yield after the 2 steps).
(95) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.3 (br. s, 1H); 8.58 (s, 1H); 7.44-7.50 (m, 1H); 7.27-7.33 (m, 1H); 4.90-4.94 (m, 0.5H); 4.85-4.88 (m, 0.5H); 4.49-4.60 (m, 1H); 4.33-4.46 (m, 1H); 3.96-4.13 (m, 1H); 3.41-3.54 (m, 1H); 3.05 (s, 1.5H); 3.03 (s, 1.5H); 2.76-2.91 (m, 1H); 2.34-2.44 (m, 1H); 1.61-1.71 (m, 2H); 1.42-1.58 (m, 5H).
(96) MS1 (ESI, m/z): 540.1 [M+H.sup.+] for C.sub.18H.sub.23N.sub.3O.sub.5FIS; t.sub.R=0.84 min.
Preparation L: 3-(4-iodophenyl)oxetan-3-amine hydrochloride
L.i. N-(3-(4-iodophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide
(97) BuLi (1.1M in hexanes, 11.4 mL) was added dropwise to a solution of 1,4-iodobenzene (4.36 g) in THF (50 mL) at −78° C. After stirring for 1 h, a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (1.64 g; commercial) in THF (10 mL) was added dropwise over the course of 30 min at −78° C. The reaction mixture was gradually warmed to rt. After 1 h, sat. NH.sub.4Cl was added and the aq. layer was extracted with EA. The combined org. layer was washed with sat. NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (EA-Hept) to give the title compound as a colourless oil (0.751 g, 21% yield).
(98) .sup.1H NMR (d6-DMSO) δ: 7.77 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 6.35 (s, 1H); 4.98 (d, J=6.3 Hz, 1H); 4.90-4.94 (m, 1H); 4.85-4.88 (m, 1H); 4.67 (d, J=6.3 Hz, 1H); 1.11 (s, 9H).
(99) MS1 (ESI, m/z): 379.97 [M+H.sup.+] for C.sub.13H.sub.18NO.sub.2IS; t.sub.R=0.78 min.
L.ii. 3-(4-iodophenyl)oxetan-3-amine hydrochloride
(100) To a solution of intermediate L.i (0.751 g, 1.98 mmol) in DCM (20 mL) was added a 4M solution of HCl in dioxane (1.06 mL). After stirring for 30 min at rt, the solids were filtered off and washed with Hex (3 mL) to afford the title compound as a white solid (0.624 g, 100% yield).
(101) .sup.1H NMR (d6-DMSO) δ: 9.14-9.30 (m, 3H); 7.82-7.90 (m, 2H); 7.34-7.40 (d, J=8.5 Hz, 2H); 4.80-5.00 (m, 4H).
(102) MS1 (ESI, m/z): 299.89 [M+Na.sup.+] for C.sub.9H.sub.10NOI; t.sub.R=0.50 min.
Preparation M: 3-(4-iodophenyl)-N,N-dimethyloxetan-3-amine
(103) To a solution of the compound of Preparation L (0.2 g; 0.642 mmol) in DCM (8 mL) were added an aq. solution of formaldehyde (37%; 0.15 mL; 1.93 mmol), NaBH(OAc).sub.3 (0.816 g; 3.85 mmol) and sodium sulfate (0.03 g). The reaction mixture was stirred at rt for 2 h. Water (15 mL) and DCM (25 mL) were added. The aq. layer was extracted with DCM (15 mL). The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated to dryness to afford the title compound as a light yellow solid (0.188 g).
(104) .sup.1H NMR (d6-DMSO) δ: 7.73 (d, J=8.4 Hz, 2H); 6.96 (d, J=8.4 Hz, 2H); 4.63-4.67 (m, 4H); 1.87 (s, 6H).
(105) MS1 (ESI, m/z): 304.1 [M+H.sup.+] for C.sub.11H.sub.14NOI; t.sub.R=0.54 min.
Preparation N: ((1S*,2S*)-2-(bromoethynyl)cyclopropyl)methyl acetate
N.i.a ((1S*,2S*)-2-(2,2-dibromovinyl)cyclopropyl)methyl acetate and
N.i.b. rac-[(1S*,2S*)-2-(2,2-dibromo-vinyl)-cyclopropyl]-methanol
(106) To a solution of CBr.sub.4 (30.0 g, 88.9 mmol) in DCM (60 mL) cooled at −20° C., was added dropwise over 45 min a solution of PPh.sub.3 (45.8 g, 175 mmol) in DCM (100 mL). The mixture was kept stirred at this temperature for 30 min and then cooled to −78° C. A solution of ((1S*,2S*)-2-formylcyclopropyl)methyl acetate (6.18 g, 43.5 mmol, prepared as described in WO 2012/154204) in DCM (80 mL) was added dropwise over 45 min, keeping IT below −70° C. The mixture was stirred at this temperature for 30 min and allowed to warm to rt over 1 h. The solvent was removed in vacuo and the residue was purified by CC (EA-Hept) to afford the title acetate as a clear oil (4.84 g, 37% yield), and then the title alcohol as a clear oil (2.2 g, 20% yield).
(107) For intermediate N.i.a:
(108) .sup.1H NMR (CDCl.sub.3) δ: 5.84 (d, J=9.0 Hz, 1H); 3.97 (m, 2H); 2.07 (s, 3H); 1.61 (m, 1H); 1.33 (m, 1H); 0.78-0.92 (m, 2H).
(109) MS1 (ESI, m/z): 295.0 [M+H.sup.+] for C.sub.8H.sub.10O.sub.2Br.sub.2; t.sub.R=0.87 min.
(110) For intermediate N.i.b:
(111) .sup.1H NMR (CDCl.sub.3) δ: 5.86 (d, J=9.0 Hz, 1H); 3.47-3.61 (m, 2H); 1.61-1.53 (m, 1H); 1.43 (m, 1H); 1.22-1.34 (m, 1H); 0.74-0.89 (m, 2H).
N.ii. ((1S*,2S*)-2-(bromoethynyl)cyclopropyl)methyl acetate
(112) To a solution of intermediate N.i.a (0.5 g; 1.68 mmol) in THF (9.5 mL) was added tetrabutylammonium fluoride trihydrate (2.98 g; 9.35 mmol). The reaction mixture was heated at 60° C. for 4 h. The reaction mixture was cooled to rt and diluted with diethyl ether (50 mL). The org. phase was washed with water (20 mL) and brine (20 mL), dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (EA-Hept) to afford the title compound as a yellow oil (0.24 g, 68% yield).
(113) .sup.1H NMR (CDCl.sub.3) δ: 3.97 (dd, J=6.5, 11.7 Hz, 1H); 3.84 (dd, J=7.5, 11.7 Hz, 1H); 2.06 (s, 3H); 1.50 (m, 1H); 1.25 (m, 1H); 0.97 (m, 1H); 0.76 (m, 1H).
Preparation O: (R)-4-(5-bromo-6-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-butyric acid tert-butyl ester
O.i. (RS)-4-bromo-2-methylsulfonyl-2-methyl-butyric acid tert-butyl ester
(114) To a two-necked round-bottom flask containing an ice-chilled suspension of ethyl 2-(methylsulfonyl)propanoate (87.8 g, 0.422 mol) in DMF (0.6 L) was added portionwise NaH (60% in oil dispersion, 21.6 g, 0.54 mol) The mixture was stirred at this temperature for 5 min and at rt for 25 min. 1,2-dibromoethane (0.111 L, 1.28 mol) was added slowly and the reaction mixture was stirred at 70° C. for 19 h. The reaction mixture was partitioned between water (600 mL) and EA (600 mL) and the aq. layer was extracted 3 times with EA (3×200 mL). The combined org. layers were washed with brine (250 mL), dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA with gradient) to afford the title compound as a colourless oil (80.8 g, 60% yield). .sup.1H NMR (CDCl.sub.3) δ: 3.49 (m, 1H); 3.37 (m, 1H); 3.03 (s, 3H); 2.73 (m, 1H); 2.50 (m, 1H); 1.59 (s, 3H); 1.51 (s, 9H).
O.ii. (R)-4-bromo-2-methylsulfonyl-2-methyl-butyric acid tert-butyl ester
(115) Intermediate O.i (4 g) was separated by semi-preparative chiral HPLC Method A (Hept-EtOH 9-1; flow rate: 16 mL/min; UV detection at 220 nM); the respective retention times (flow rate: 0.8 mL/min) were 9.3 and 10.7 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a colourless oil (1.68 g).
O.iii. (R)-4-azido-2-methylsulfonyl-2-methyl-butyric acid tert-butyl ester
(116) A mixture of intermediate O.ii (1.59 g; 5.04 mmol) and NaN.sub.3 (0.83 g; 12.6 mmol) in DMF (45 mL) was heated at 80° C. for 2.5 h. Water (150 mL) and EA (50 mL) were added and the phases were separated. The aq. layer was extracted with EA (2×30 mL). The combined org. layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to afford the title azide as a colourless oil (1.4 g, 100% yield).
(117) .sup.1H NMR (d6-DMSO) δ: 3.58 (m, 1H); 3.29 (overlaid m, 1H); 3.08 (s, 3H); 2.42 (m, overlaid with DMSO, 1H); 1.98 (m, 1H); 1.44 (s, 9H); 1.43 (s, 3H).
(118) An analytical sample was eluted on a Daicel ChiralPak AS-H column (4.6×250 mm, 5 μM) at a flow rate of 0.8 mL/min, using Hept/EtOH/DEA 9:1:0.005 as mobile phase and UV detection at 210 nM. The respective retention times for a racemic sample were 10.6 and 12.1 min. The title (R)-enantiomer was the second eluting compound (e.e.: 98.4%).
O.iv. (R)-4-amino-2-methylsulfonyl-2-methyl-butyric acid tert-butyl ester
(119) To a solution of intermediate O.iii (1.39 g; 5.01 mmol) in THF (50.1 mL) was added PPh.sub.3 (1.99 g; 7.52 mmol). The reaction mixture was heated for 30 min. at 60° C. before water (10.4 mL) was added. The mixture was stirred at 60° C. for 1.5 h. The volatiles were removed under reduced pressure and the aq. residue was diluted with DCM-MeOH (9:1; 25 mL) and water (10 mL). The phases were separated and the aq. layer was extracted with DCM-MeOH (9:1; 2×15 mL). The combined org. layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by CC (DCM-MeOH containing a gradient of aq. NH.sub.4OH) to afford the title compound as a white solid (1.25 g, 99% yield).
(120) .sup.1H NMR (d6-DMSO) δ: 3.06 (s, 3H); 2.63-2.75 (m, 1H); 2.40-2.53 (m, overlaid with DMSO, 1H); 2.16-2.28 (m, 1H); 1.74-1.85 (m, 1H); 1.44 (s, 9H); 1.40 (s, 3H).
(121) MS1 (ESI, m/z): 252.1 [M+H.sup.+] for C.sub.10H.sub.21NO.sub.4S; t.sub.R=0.47 min.
O.v. (R)-4-(5-bromo-6-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-butyric acid tert-butyl ester
(122) Starting from 5-bromo-4-fluoro-2-nitrobenzaldehyde (0.6 g; 2.42 mmol; commercial) and intermediate O.iv (0.64 g; 2.54 mmol) and proceeding in analogy to Preparation A, step A.i, Variant II, the title compound was obtained, after purification by CC (Hept-EA gradient), as a yellowish oil (1.1 g, 100% yield).
(123) .sup.1H NMR (d6-DMSO) δ: 8.51 (s, 1H); 8.17 (d, J=7.1 Hz, 1H); 7.59 (d, J=10.1 Hz, 1H); 4.56-4.68 (m, 1H); 4.37-4.50 (m, 1H); 3.13 (s, 3H); 2.70-2.84 (m, 1H); 2.38-2.58 (m, overlaid with DMSO, 1H); 1.55 (s, 3H); 1.39 (s, 9H).
(124) MS (ESI, m/z): 450.9 [M+H.sup.+] for C.sub.17H.sub.22N.sub.2O.sub.4BrFS; t.sub.R=0.91 min.
Preparation P: rac-tert-butyl-((1R*,2R*)-2-iodoethynyl-cyclopropylmethoxy)-dimethyl-silane
P.i. rac-tert-butyl-[(1S*,2S*)-2-(2, 2-dibromo-vinyl)-cyclopropylmethoxy]-dimethyl-silane
(125) To a mixture of intermediate N.i.b (1.52 g, 5.96 mmol) in THF (14 mL) were added imidazole (0.823 g, 12.1 mmol) and TBDMS-Cl (1.4 g, 9.3 mmol). The mixture was stirred at rt for 1 h. Water (50 mL) and EA (40 mL) were added and the two layers were decanted. The org. layer was extracted with EA (2×30 mL), washed with aq. sat. NaHCO.sub.3 (50 mL), brine (50 mL), dried over MgSO.sub.4, filtered and concentrated to dryness to afford the crude product. The crude was purified by CC (Hept-EA gradient) to afford the title compound as a colourless oil (1.56 g, 71% yield).
(126) .sup.1H NMR (CDCl.sub.3) δ: 5.83 (d, J=9.2 Hz, 1H); 3.58 (d, J=5.5 Hz, 3H); 1.55 (m, 1H); 1.19 (m, 1H); 0.87 (s, 9H); 0.87 (overlapped m, 1H); 0.69 (m, 1H); 0.04 (s, 6H).
P.ii. Rac-tert-butyl-((1R*,2R*)-2-iodoethynyl-cyclopropylmethoxy)-dimethyl-silane
(127) To a solution of intermediate P.i (1.56 g, 4.22 mmol) in THF (20 mL) cooled at −74° C. was added, dropwise over 25 min, BuLi (1.97M in hexanes; 4.29 mL; 8.45 mmol), keeping the IT below −70° C. After stirring for 1 h, the solution was warmed to 0° C. and iodine (1.76 g, 6.97 mmol) in solution in THF (14.2 mL) was added dropwise over 47 min. The reaction mixture was stirred at rt for 18 h. The reaction mixture was quenched with a sat. Na.sub.2S.sub.2O.sub.3 solution (50 mL). The two phases were separated. The aq. layer was extracted with DCM (2×150 mL). The combined org. layers were dried over Mg.sub.2SO.sub.4 and concentrated to dryness to give the desired compound as a yellow oil (1.61 g, quant.).
(128) .sup.1H NMR (CDCl.sub.3) δ: 3.58 (d, J=4.7 Hz, 2H); 1.24-1.44 (m, 2H); 0.86 (s, 9H); 0.86 (overlapped m, 1H); 0.78 (overlapped m, 1H); 0.04 (s, 6H).
Preparation Q: (4-ethynyl-3-fluorophenyl)methanol
(129) Starting from (3-fluoro-4-iodophenyl)methanol (0.510 g; 2.0 mmol; commercial) and trimethysilyl acetylene (0.31 mL, 1.1 eq.), and proceeding in analogy to Preparation E, steps E.ii and E.iii, the title compound was obtained, after purification by CC (DCM-MeOH), as a colourless oil (0.23 g; yields: 96% for Sonogashira coupling and 79% for silyl cleavage).
(130) .sup.1H NMR δ (d6-DMSO): 7.51 (t, J=7.7 Hz, 1H); 7.18-7.24 (m, 1H); 7.12-7.17 (m, 1H); 5.42 (t, J=5.8 Hz, 1H); 4.53 (d, J=5.8 Hz, 2H); 4.45 (s, 1H).
Preparation R: (R)-4-(5-ethynyl-6-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(R)-(tetrahydro-pyran-2-yl)oxy]-butanamide
R.i. (R)-4-(5-bromo-6-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-butyric acid
(131) To a mixture of the compound of Preparation O (0.586 g, 1.3 mmol) with 4N HCl in dioxane (7 mL) was added water (0.26 mL). The resulting mixture was stirred at rt for 16 h. The mixture was concentrated to dryness and co-evaporated with diethyl ether (3×15 mL) to give the title acid as a beige solid (0.52 g; quant.).
(132) .sup.1H NMR (d6-DMSO) δ: 8.50 (s, 1H); 8.17 (d, J=7.1 Hz, 1H); 7.59 (d, J=10.0 Hz, 1H); 4.57-4.70 (m, 1H); 4.41-4.53 (m, 1H); 3.13 (s, 3H); 2.71-2.83 (m, 1H); 2.38-2.56 (overlapped m, 1H); 1.56 (s, 3H).
(133) MS1 (ESI, m/z): 395.01 [M+H.sup.+] for C.sub.13H.sub.14N.sub.2O.sub.4BrFS; t.sub.R=0.73 min.
R.ii. (R)-4-(5-bromo-6-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
(134) To a solution of intermediate R.i (0.52 g, 0.56 mmol) in DMF (12 mL) were added successively HOBT (0.411 g, 3.04 mmol), TEA (0.64 mL, 4.63 mmol), THP—ONH.sub.2 (0.387 g, 3.3 mmol) and EDC (0.583 g, 3.04 mmol). The suspension was then stirred at rt overnight. Water (50 mL) and EA (50 mL) were added. The org. layer was washed with water (50 mL), aq. NaHSO.sub.4 (5% w/w, 30 mL), sat. NaHCO.sub.3 (50 mL) and brine (20 mL). The org. layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to afford the title compound as a yellow gum (0.43 g, 66% yield).
(135) .sup.1H NMR (d6-DMSO) δ (mixture of isomers): 11.41 (br. s, 1H); 8.46 (s, 1H); 8.18 (d, J=7.1 Hz, 1H); 7.59 (d, J=10.2 Hz, 1H); 4.96 (br. s, 0.5H); 4.91 (br. s, 0.5H); 4.48-4.63 (m, 1H); 4.31-4.45 (m, 1H); 3.97-4.16 (m, 1H); 3.40-3.57 (m, 1H); 3.07 (s, 1.5H); 3.05 (s, 1.5H); 2.75-2.91 (m, 1H); 2.34-2.58 (overlapped m, 1H); 1.63-1.77 (m, 3H); 1.53 (s, 1.5H); 1.38-1.62 (overlapped m, 3H); 1.51 (s, 1.5H).
(136) MS1 (ESI, m/z): 491.9 [M+H.sup.+] for C.sub.18H.sub.23N.sub.3O.sub.5BrFS; t.sub.R=0.81 min.
R.iii. (R)-4-(5-ethynyl-6-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
(137) In a 7 mL flask, intermediate R.ii (0.42 g; 0.85 mmol), bis(tri-tert-butylphosphine)palladium (0.037 g; 0.07 mmol), cesium fluoride (0.258 g; 1.71 mmol), degassed dioxane (0.77 mL) and ethynyltri-n-butyltin (0.52 mL; 1.71 mmol) were introduced successively. The solution was stirred at 80° C. for 2.5 h. The mixture was concentrated to dryness and purified by CC (Hept-EA with gradient) to afford the title compound as a yellowish foam (0.106 g, 28% yield),
(138) .sup.1H NMR (d6-DMSO) δ (mixture of isomers): 11.37-11.45 (m, 1H); 8.50 (br. s, 1H); 8.05 (d, J=7.1 Hz, 1H); 7.40-7.49 (m, 1H); 4.90-4.97 (m, 1H); 4.48-4.62 (m, 1H); 4.31-4.45 (overlapped m, 1H); 4.33 (s, 1H); 3.98-4.15 (m, 1H); 3.47-3.57 (m, 1H); 3.07 (s, 1.5H); 3.05 (s, 1.5H); 2.73-2.92 (m, 1H); 2.34-2.54 (overlapped m, 1H); 1.62-1.74 (m, 3H); 1.46-1.60 (overlapped m, 3H); 1.54 (s, 1.5H); 1.52 (s, 1.5H).
(139) MS1 (ESI, m/z): 438.0 [M+H.sup.+] for C.sub.20H.sub.24N.sub.3O.sub.5FS; t.sub.R=0.79 min.
Preparation S: 3-(iodoethynyl)thietan-3-ol
S.i. 3-((trimethylsilyl)ethynyl)thietan-3-ol
(140) To a solution of TMS-acetylene (2.1 mL; 14.8 mmol) in THF (33 mL), cooled at −78° C., was added dropwise BuLi (1.97M; 8.5 mL; 16.7 mmol) over 20 min, keeping IT below −68° C. The reaction mixture was stirred at the same temperature for 5 min, then allowed to warm to −20° C. and cooled again at −76° C. A solution of 3-thietanone (1.02 g; 11.3 mmol, commercial) in THF (4.2 mL) was then added dropwise over 10 min (IT below −69° C.) and the reaction mixture was stirred for 80 min before warming to rt. The reaction mixture was quenched by addition of brine (30 mL) and extracted twice with EA (2×40 mL). The combined org. layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give a brown solid (1.91 g, 91% yield).
(141) .sup.1H NMR (CDCl.sub.3) δ: 3.50 (s, 4H); 2.67 (br. s, 1H); 0.19 (s, 9H).
S.ii. 3-ethynylthietan-3-ol
(142) Starting from intermediate S.i (1.91 g, 10.3 mmol) and proceeding in analogy to Preparation E, step E.iii, the title alkyne was obtained as a yellowish oil (1.07 g; 91% yield).
(143) .sup.1H NMR (CDCl.sub.3) δ: 3.44-3.58 (m, 4H); 2.71 (br. s, 1H); 2.64 (s, 1H).
S.iii. 3-(iodoethynyl)thietan-3-ol
(144) Starting from intermediate S.ii (1.07 g; 9.38 mmol) and proceeding in analogy to Preparation G, the title compound was obtained as a brown solid (1.83 g; 81% yield).
(145) .sup.1H NMR (CDCl.sub.3) δ: 3.43-3.57 (m, 4H); 2.71 (br. s, 1H).
Preparation T: (1-(4-ethynylphenyl)cyclopropyl)methanol
(146) Starting from (1-(4-iodophenyl)cyclopropyl)methanol (0.660 g; 2.4 mmol; commercial) and TMS-acetylene (0.51 mL; 1.5 eq.), and proceeding in analogy to Preparation E, steps E.ii and E.iii (Sonogashira coupling: 96% yield; silyl cleavage: 39% yield), the title compound was obtained, after purification by CC (Hept-EA), as yellowish needles (0.167 g).
(147) .sup.1H NMR (d6-DMSO) δ: 7.37 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 4.68 (t, J=5.7 Hz, 1H), 4.08 (s, 1H), 3.53 (d, J=5.6 Hz, 2H), 0.81-0.92 (m, 2H), 0.67-0.79 (m, 2H).
Preparation U: ((1S,2S)-2-(bromoethynyl)cyclopropyl)methyl acetate and ((1R,2R)-2-(bromoethynyl)cyclopropyl)methyl acetate
(148) The racemic product of Preparation N (1.75 g) was separated by semi-preparative chiral HPLC Method B (Hept-EtOH 9-1; flow rate: 20 mL/min, UV detection at 223 nM); the respective retention times (flow rate: 0.8 mL/min) were 5.9 and 8.7 min. The title enantiomers were obtained as clear oils (0.64 g each).
(149) First-Eluting Enantiomer, (1S,2S)-Configurated:
(150) .sup.1H NMR (CDCl.sub.3) δ: 3.97 (dd, J=6.5, 11.7 Hz, 1H); 3.84 (dd, J=7.5, 11.7 Hz, 1H); 2.06 (s, 3H); 1.50 (m, 1H); 1.25 (m, 1H); 0.97 (m, 1H); 0.76 (m, 1H). [α].sub.D=+96° (c=1.03; MeOH).
(151) Second-Eluting Enantiomer, (1R,2R)-Configurated:
(152) .sup.1H NMR (CDCl.sub.3) δ: 3.97 (dd, J=6.5, 11.7 Hz, 1H); 3.84 (dd, J=7.5, 11.7 Hz, 1H); 2.06 (s, 3H); 1.50 (m, 1H); 1.25 (m, 1H); 0.97 (m, 1H); 0.76 (m, 1H).
(153) [α].sub.D=−94° (c=1.01; MeOH).
(154) The respective absolute configurations of these compounds have been determined though transformation of the second-eluting enantiomer into the corresponding (S) and (R) α-methoxy-α-trifluoromethylphenylacetyl esters and the subsequent analysis of their NMR spectra as described by Tsuda et al. in Chem. Pharm. Bull. (2003), 51, 448-451.
Preparation V: tert-butyl (4-iodo-2-methylbut-3-yn-2-yl)carbamate
(155) Starting from tert-butyl (2-methylbut-3-yn-2-yl)carbamate (1.02 g; 5.6 mmol; commercial) and proceeding in analogy to Preparation G, the title compound was obtained as a yellow solid (1.49 g; 86% yield).
(156) .sup.1H NMR (CDCl.sub.3) δ: 4.64 (s, 1H); 1.55 (s, 6H); 1.46 (s, 9H).
Preparation W: ((1R,2R)-2-(4-iodophenyl)cyclopropyl)methanol and ((1S,2S)-2-(4-iodophenyl)cyclopropyl)methanol
(157) Rac-(trans-2-(4-iodophenyl)cyclopropyl)methanol (0.956 g; prepared as described in WO 2005/103032) was separated by semi-preparative chiral HPLC Method F (Hept-EtOH 3-1; flow rate: 16 mL/min, UV detection at 210 nM); the respective retention times (flow rate: 0.8 mL/min) were 5.7 and 7.1 min. The title enantiomers were obtained as white powders (0.45 g each).
(158) First-Eluting Enantiomer, (1R,2R)-Configurated:
(159) .sup.1H NMR (CDCl.sub.3) δ: 7.54 (d, J=8.0 Hz, 2H); 6.86 (d, J=8.0 Hz, 2H); 4.56 (br. s, 1H); 3.43 (m, 1H); 3.32 (m, 1H); 1.73 (m, 1H); 1.23 (m, 1H); 0.75-0.90 (m, 2H). [α].sub.D=−61° (c=1.04, MeOH).
(160) Second-Eluting Enantiomer, (1S,2S)-Configurated:
(161) .sup.1H NMR (CDCl.sub.3) δ: 7.54 (d, J=8.0 Hz, 2H); 6.86 (d, J=8.0 Hz, 2H); 4.56 (br. s, 1H); 3.43 (m, 1H); 3.32 (m, 1H); 1.73 (m, 1H); 1.23 (m, 1H); 0.75-0.90 (m, 2H).
(162) [α].sub.D=+62° (c=1.04, MeOH).
(163) The respective absolute configurations of these compounds have been determined though transformation of the second-eluting enantiomer into the corresponding (S) and (R) α-methoxy-α-trifluoromethylphenylacetyl esters and the subsequent analysis of their NMR spectra as described by Tsuda et al. in Chem. Pharm. Bull. (2003), 51, 448-451.
Preparation X: (3-(4-iodophenyl)oxetan-3-yl)methanol
(164) Starting from (3-(4-bromophenyl)oxetan-3-yl)methanol (0.24 g; 0.98 mmol; commercial) and proceeding in analogy to Preparation E, step E.i, the title iodide was obtained, after purification by CC (Hept-EA), as an off-white solid (0.27 g, 94% yield).
(165) .sup.1H NMR (d6-DMSO) δ: 7.69 (d, J=7.1 Hz, 2H); 6.96 (d, J=7.1 Hz, 2H); 5.10 (t, J=5.6 Hz, 1H); 4.60.4.73 (m, 4H); 3.69 (d, J=5.3 Hz, 2H).
Preparation Y: N-(2-fluoro-4-iodophenyl)-2-hydroxyacetamide
(166) Starting from 2-((4-bromo-2-fluorophenyl)amino)-2-oxoethyl acetate (1.0 g; 3.45 mmol; commercial) and proceeding in analogy to Preparation E, step E.i, the title iodide was obtained in mixture with the corresponding acetate. The mixture was dissolved in MeOH (20 mL) and K.sub.2CO.sub.3 (2.5 g; 17.2 mmol) was added. The reaction mixture was stirred at rt for 10 min. EA (100 mL) and water (60 mL) were added. The aq. phase was extracted with EA (100 mL). The combined org. phases were washed with brine, dried over MgSO.sub.4 and filtered. The filtrate concentrated to dryness to afford the title compound as a brown solid (0.8 g; 79% yield).
(167) .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ: 7.66-7.78 (m, 2H); 7.51-7.57 (m, 1H); 5.85 (t, J=5.9 Hz, 1H); 4.02 (d, J=5.9 Hz, 2H).
Preparation Z: (RS)-1-((tert-butyldiphenylsilyl)oxy)-4-iodo-2-methylbut-3-yn-2-ol
(168) Starting from (RS)-2-methylbut-3-yne-1,2-diol (1.031 g; 10.3 mmol; prepared as reported by Knight and Qing in Tetrahedron Lett. (2009), 50(26), 3534-3537) and TBDPS-Cl (3.95 mL; 15.4 mmol) and proceeding successively in analogy to Preparation P, step P.i. (adding a catalytic amount of DMAP; 90% yield) and Preparation G (100% yield), the title compound was obtained, after purification by CC (DCM), as a colourless oil (0.77 g).
(169) .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ: 7.62-7.71 (m, 4H); 7.36-7.50 (m, 6H); 5.52 (s, 1H); 3.56 (d, J=8.6 Hz, 1H); 3.43 (d, J=8.6 Hz, 1H); 1.39 (s, 3H); 1.02 (s, 9H).
Preparation AA: tert-butyl (3-(iodoethynyl)oxetan-3-yl)carbamate
AA.i. Tert-butyl (3-((trimethylsilyl)ethynyl)oxetan-3-yl)carbamate
(170) To a solution of 3-((trimethylsilyl)ethynyl)oxetan-3-amine hydrochloride (0.123 g; 0.6 mmol; commercial) in DCM (3 mL) were added TEA (0.18 mL; 1.29 mmol) and Boc.sub.2O (0.272 g; 1.25 mmol). The reaction mixture was stirred at rt for 6 h. Boc.sub.2O (0.272 g; 1.25 mmol) was added again and the reaction was stirred overnight. The reaction mixture was diluted with DCM (5 mL) and sat. aq. NaHCO.sub.3 (5 mL) was added. The phases were separated and the aq. layer was extracted twice with DCM (2×5 mL). The combined org. layers were washed with brine (5 mL), dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness to afford the title compound, slightly contaminated by Boc.sub.2O, as a white gum (0.312 g).
(171) .sup.1H NMR (CDCl.sub.3) δ: 4.72-4.81 (m, 4H); 3.05 (br. s, 1H); 1.47 (s, 9H); 0.18 (s, 9H).
AA.ii. Tert-butyl (3-ethynyloxetan-3-yl)carbamate
(172) To a solution of intermediate AA.i (0.211 g; 0.783 mmol) in MeOH (1.6 mL) was added K.sub.2CO.sub.3 (0.162 g; 1.17 mmol). The mixture was stirred at rt for 30 min. Water (5 mL) was added. The mixture was extracted twice with DCM (2×10 mL) and the org. layer was dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness. The crude was purified by CC (PE-EA) to afford the title compound as white solid (0.173 g).
(173) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 5.02 (br. s, 1H); 4.84 (d, J=6.2 Hz, 2H); 4.73 (d, J=6.2 Hz, 2H); 2.57 (s, 1H); 1.47 (s, 9H).
AA.iii. Tert-butyl (3-(iodoethynyl)oxetan-3-yl)carbamate
(174) Starting from intermediate AA.ii (crude; 0.154 g; 0.783 mmol) and proceeding in analogy to Preparation P, step P.ii, the title compound was obtained as a yellow oil (0.234 g; 92% yield).
(175) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 5.02 (br. s, 1H); 4.81-4.85 (m, 2H); 4.70-4.75 (m, 2H); 1.47 (s, 9H).
Preparation AB: 2-oxo-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl acetate
AB.i. 2((4-iodophenyl)amino)-2-oxoethyl acetate
(176) To a solution of 4-iodoaniline (2.15 g; 9.82 mmol; commercial) in DCM (25 mL) was added dropwise acetoxyacetylchloride (1.16 mL; 10.8 mmol) over 15 min. The mixture was stirred for 1.5 h at rt. Water (30 mL) was added. The org. layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to afford the title compound as a light purple solid (3.12 g, 100% yield).
(177) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.18 (s, 1H); 7.66 (d, J=8.8 Hz, 2H); 7.42 (d, J=8.8 Hz, 2H); 4.64 (s, 2H); 2.12 (s, 3H).
(178) MS1 (ESI, m/z): 318.8 [M+H.sup.+] for C.sub.10H.sub.10NO.sub.3I; t.sub.R=0.76 min.
AB.ii. 2-oxo-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl acetate
(179) Starting from intermediate AB.i (1.0 g; 3.15 mmol) and proceeding in analogy to Preparation D, the title compound was obtained, after purification by CC (Hept-EA), as a brown oil (0.43 g; 43% yield).
(180) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.20 (s, 1H); 7.57-7.64 (m, 4H); 4.63-4.68 (m, 2H);
(181) 2.13 (s, 3H); 1.29 (s, 12H).
(182) MS1 (ESI, m/z): 320.0 [M+H.sup.+] for C.sub.16H.sub.22NO.sub.5B; t.sub.R=0.82 min.
Preparation AC: 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-ol
AC.i. Ethyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate
(183) Starting from ethyl 2-(4-bromo-3-fluorophenoxy)acetate (1.0 g; 3.61 mmol; commercial) and proceeding in analogy to Preparation D, the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.816 g, 70% yield).
(184) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.53-7.57 (m, 1H); 6.75-6.81 (m, 2H); 4.86 (s, 2H); 4.17 (q, J=7.1 Hz, 2H); 1.28 (s, 12H); 1.21 (t, J=7.1 Hz, 3H).
(185) MS1 (ESI, m/z): 324.9 [M+H.sup.+] for C.sub.16H.sub.22NO.sub.5BF; t.sub.R=0.93 min.
AC.ii. 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-ol
(186) NaBH.sub.4 (0.14 g; 3.76 mmol) was added portionwise to an ice chilled ethanol (4.5 mL) solution of intermediate AC.i (0.81 g; 2.5 mmol). The mixture was stirred for 2 h. Acetone (0.37 mL), EA (5 mL) and water (10 mL) were added sequentially at rt. Solvents were distilled off under reduced pressure. EA (20 mL) was added to the resulting residue. This org. phase was washed with water (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, filtered then concentrated to dryness. The residue was purified by CC (DCM-MeOH gradient) to afford the title compound as a colourless oil (0.48 g; 68% yield).
(187) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.52-7.57 (m, 1H); 6.79 (dd, J=2.3, 8.4 Hz, 1H); 6.74 (dd, J=2.2, 11.5 Hz, 1H); 4.90 (t, J=5.5 Hz, 1H); 4.00-4.05 (m, 2H); 3.68-3.73 (m, 2H); 1.28 (s, 12H).
Preparation AD: ((1-(bromoethynyl)cyclopropyl)methoxy)(tert-butyl)diphenylsilane
(188) To a mixture of (dibromomethyl)triphenylphosphonium bromide (8.527 g; 16.6 mmol, prepared as described in Fuerst et al., J. Org. Chem. (2013), 78(17), 8748-8758) and THF (40 mL) was added a solution of tBuOK (1M in THF; 16.6 mL; 16.6 mmol). The solution was stirred for 3 min at rt, then cooled to 0° C. A solution of 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarbaldehyde (2.2 g; 6.62 mmol; prepared as described in WO 2010/135536) in THF (23 mL) was added dropwise. The reaction was stirred at 0° C. for 40 min. The reaction mixture was cooled to −78° C. and tBuOK (1M in THF; 29.1 mL; 29.1 mmol) was added rapidly and stirred at −78° C. for 30 min. The reaction mixture was quenched with brine (150 mL). The aq. layer was extracted with Et.sub.2O (3×150 mL). The combined org. phases were washed with brine, dried over MgSO.sub.4, filtered, and concentrated to dryness. The residue was purified by CC (Hept/EA) to afford the title compound as a colourless oil (2.052 g, 75% yield). .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.59-7.70 (m, 4H); 7.37-7.53 (m, 6H); 3.56 (s, 2H); 1.01 (s, 9H); 0.82-0.89 (m, 2H); 0.71-0.76 (m, 2H).
Preparation AE: ((3-(bromoethynyl)bicyclo[1.1.1]pentan-1-yl)methoxy)(tert-butyl)diphenylsilane
AE.i. Bicyclo[1.1.1]pentane-1,3-diyldimethanol
(189) To a solution of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (1.74 g; 9.45 mmol; commercial) in THF (12 mL), cooled at 0° C. was added dropwise LiAlH.sub.4 (2.4M in THF; 5.29 mL; 12.7 mmol) over 45 min keeping IT below 15° C. The suspension was stirred at rt for 3 h. The crude mixture was cooled to 0° C. and carefully quenched successively with water (0.48 mL), a 15% NaOH solution (0.48 mL) and water (1.44 mL). The mixture was stirred at rt for 35 min. THF (17 mL) and MgSO.sub.4 were then added and the mixture was stirred at rt for 10 min before being filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.2 g; 99% yield).
(190) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 4.40 (t, J=5.5 Hz, 2H); 3.35 (d, J=5.6 Hz, 4H); 1.46 (s, 6H).
AE.ii. (3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol
(191) To a suspension of NaH (60% in mineral oil; 0.23 g; 5.67 mmol) in THF (4.5 mL) was added slowly at rt a solution of intermediate AE.i (0.66 g; 5.16 mmol) in THF (3.3 mL) keeping IT below 27° C. After 1 h stirring, a solution of TBDPS-Cl (1.36 mL; 5.16 mmol) in THF (2.8 mL) was added dropwise over 15 min. The solution was stirred for 4 h then diluted in Et.sub.2O (20 mL). The org. phase was washed with brine (2×20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.49 g; 26% yield).
(192) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.56-7.64 (m, 4H); 7.39-7.50 (m, 6H); 4.43 (t, J=5.6 Hz, 1H); 3.64 (s, 2H); 3.36 (d, J=5.5 Hz, 2H); 1.49 (s, 6H); 1.01 (s, 9H).
AE.iii. 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carbaldehyde
(193) To a solution of intermediate AE.ii (1.09 g; 2.98 mmol) in DCM (6.9 mL) cooled to −10° C., was added DIPEA (1.59 mL; 9.31 mmol) over 15 min. A solution of Pyr.SO.sub.3 complex (45%; 1.44 g; 4.07 mmol) in DMSO (4.03 mL) was then dropwise added over 10 min. The reaction mixture was stirred for 1.5 h at 0° C. and 1 h at rt. The reaction mixture was partitioned between water (35 mL) and DCM (20 mL). The two layers were separated and the aq. layer was extracted with DCM (15 mL). The combined org. layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was co-evaporated with toluene (2×10 mL) and then purified by CC (Hept-EA) to afford the title compound as a colourless oil (0.94 g, 87% yield).
(194) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.53 (s, 1H); 7.57-7.62 (m, 4H); 7.41-7.49 (m, 6H); 3.68 (s, 2H); 1.86 (s, 6H); 1.01 (s, 9H).
AE.iv. Tert-butyl((3-(2,2-dibromovinyl)bicyclo[1.1.1]pentan-1-yl)methoxy)diphenylsilane
(195) Starting from intermediate AE.iii (0.94 g; 2.58 mmol) and proceeding in analogy to Preparation N, step N.i, the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (1.2 g; 89% yield).
(196) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.57-7.61 (m, 4H); 7.41-7.49 (m, 6H); 6.74 (s, 1H); 3.64 (s, 2H); 1.90 (s, 6H); 1.01 (s, 9H).
AE.v. ((3-(bromoethynyl)bicyclo[1.1.1]pentan-1-yl)methoxy)(tert-butyl)diphenylsilane
(197) A solution of intermediate AE.iv (0.45 g; 0.86 mmol) in THF (2 mL) cooled at −78° C. was treated with a solution of tBuOK (1M; 3.8 mL; 3.8 mmol). The reaction mixture was stirred for 30 min at −78° C. then was diluted with brine (8 mL) and was allowed to reach rt. Et.sub.2O (15 mL) was added. The aq. phase was extracted with Et.sub.2O (15 mL). The combined org. layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to afford the title compound as a yellow oil (0.37 g, 97% yield).
(198) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.55-7.60 (m, 4H); 7.41-7.49 (m, 6H); 3.60 (s, 2H); 1.91 (s, 6H); 1.00 (s, 9H).
Preparation AF: (S)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(199) A suspension of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.5 g; 2.1 mmol; commercial), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (0.6 g; 2.1 mmol; commercial) and K.sub.2CO.sub.3 (0.58 g; 4.2 mmol) in DMF (4 mL) was stirred at 100° C. overnight. The mixture was cooled to rt and diluted with water (40 mL). The mixture was extracted with EA (3×20 mL). The combined org. layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow oil which crystallized on standing (0.38 g; 51% yield).
(200) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.52-7.58 (m, 1H); 6.75-6.83 (m, 2H); 4.37-4.44 (m, 1H); 4.06-4.11 (m, 2H); 3.99-4.04 (m, 1H); 3.74 (dd, J=6.4, 8.4 Hz, 1H); 1.35 (s, 3H); 1.31 (s, 3H); 1.28 (s, 12H).
(201) MS1 (ESI, m/z): 353.1 [M+H.sup.+] for C.sub.18H.sub.26O.sub.5BF; t.sub.R=0.95 min.
Preparation AG: (4-(((1S*,2S*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)ethynyl)phenyl)boronic acid
AG.i. (1S*,2S*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropane-1-carbaldehyde
(202) Starting from diethyl trans-1,2-cyclopropane-1,2-dicarboxylate (24.96 g; 130 mmol; commercial) and proceeding successively in analogy to Preparation AE, steps AE.i to AE.iii (reduction: 100% yield; silyl protection: 67% yield; and Swern oxidation: 76% yield), the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil.
(203) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 9.07 (s, 0.5H), 9.06 (s, 0.5H); 7.65-7.69 (m, 4H); 7.40-7.49 (m, 6H); 3.76-3.81 (m, 1H); 3.64-3.69 (m, 1H); 1.83-1.89 (m, 1H); 1.73-1.80 (m, 1H); 1.25-1.30 (m, 1H); 1.10-1.15 (m, 1H); 1.06-1.08 (m, 9H).
AG.ii. Ter t-butyl(((1S*,2S*)-2-ethenylcyclopropyl)methoxy)diphenylsilane
(204) A suspension of intermediate AG.i (1.890 g; 5.58 mmol) and K.sub.2CO.sub.3 (1.543 g; 11.2 mmol) in MeOH (50 mL) was treated dropwise with dimethyl 1-diazo-2-oxopropylphosphonate (1.180 g; 6.14 mmol; commercial). The reaction mixture was stirred at rt for 24 h before being concentrated to dryness. The residue was dissolved in DCM (50 mL) and washed with water (40 mL) and brine. The org. layer was dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.65 g; 88% yield).
(205) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.65-7.70 (m, 4H); 7.39-7.47 (m, 6H); 3.65-3.73 (m, 1H); 3.58-3.64 (m, 1H); 1.79-1.85 (m, 1H); 1.39-1.47 (m, 1H); 1.20-1.27 (m, 1H); 1.04-1.10 (m, 9H); 0.84-0.89 (m, 1H); 0.78-0.84 (m, 1H).
AG.iii. (4-(((1S*,2S*)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)ethynyl)phenyl)boronic acid
(206) A mixture of 4-iodophenylboronic acid (1.214 g; 4.9 mmol; commercial) and Pd(PPh.sub.3).sub.4 (0.085 g; 0.0735 mmol) in pyrrolidine (10.1 mL; 123 mmol) was degassed. The mixture was cooled to 0° C. and treated with intermediate AG.ii (1.64 g; 4.9 mmol). The reaction was stirred at rt overnight and concentrated to dryness. The residue was diluted with water (80 mL) and EA (100 mL). The aq. phase was acidified with 1N HCl to pH=3 and extracted with EA (100 mL). The org. layer was washed with water (80 mL) and brine, dried over MgSO.sub.4, filtered and the filtrate concentrated to dryness. The residue was purified by CC (Hept-EA) to afford the title compound as a yellow foam (1.1 g; 49% yield).
(207) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 8.11-8.18 (m, 2H); 7.68-7.74 (m, 4H); 7.49-7.55 (m, 2H); 7.39-7.49 (m, 6H); 3.63-3.82 (m, 2H); 1.53-1.60 (m, 1H); 1.44-1.52 (m, 1H); 1.09 (s, 9H); 0.91-1.04 (m, 2H).
Preparation AH: tert-butyl ((3R,6S)-6-(bromoethynyl)tetrahydro-2H-pyran-3-yl)carbamate
(208) Starting from tert-butyl ((3R,6S)-6-formyltetrahydro-2H-pyran-3-yl)carbamate (3.1 g; 13.6 mmol, prepared as described in Surivet et al., J. Med. Chem. (2013), 56, 7396-7415) and proceeding successively in analogy to Preparation N, step N.i (68% yield) and Preparation AE, step AE.v (97% yield), the title compound was obtained, after purification by CC (Hept-EA), as a white solid (2.7 g).
(209) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 6.84 (d, J=7.6 Hz, 1H); 4.13 (dd, J=2.7, 10.1 Hz, 1H); 3.76 (dd, J=3.0, 10.5 Hz, 1H); 3.59-3.63 (m, 1H); 3.00-3.05 (m, 1H); 1.87-1.93 (m, 1H); 1.80-1.86 (m, 1H); 1.75-1.79 (m, 1H); 1.52-1.61 (m, 1H); 1.38 (s, 9H).
Preparation AI: di-tert-butyl ((1-(4-ethynylphenyl)cyclopropyl)methyl)phosphate
(210) To a solution of the compound of Preparation T (0.051 g; 0.3 mmol) in THF (1.8 mL) at 0° C. were added tetrazole (0.45M in MeCN; 0.12 mL; 1.38 mmol) and di-tert-butyl diisopropylphosphoramidite (0.36 mL; 1.14 mmol; commercial). The reaction mixture was stirred at 0° C. overnight. Tetrazole (0.45M in MeCN; 0.04 mL; 0.46 mmol) and di-tert-butyl diisopropylphosphoramidite (0.12 mL; 0.38 mmol) were added and stirring was pursued at rt overnight. Tetrazole (0.45M in MeCN; 0.08 mL; 0.92 mmol) and di-tert-butyl diisopropylphosphoramidite (0.24 mL; 0.76 mmol) was added at 0° C. and the mixture was stirred at 40° C. for 2 days. Then tetrazole (0.45M in MeCN; 0.04 mL; 0.46 mmol) and di-tert-butyl diisopropylphosphoramidite (0.12 mL; 0.38 mmol) was added at 0° C. and the reaction mixture was stirred at 40° C. over a weekend. The mixture was cooled to 0° C. and H.sub.2O.sub.2 (35%; 3.2 mL) was added slowly over 30 min. The reaction was stirred for 30 min at 0° C. Water (5 mL) was added. The aq. layer was extracted with EA (2×15 mL). The combined org. layers were washed with brine (10 mL), dried over MgSO.sub.4 and filtered. The filtrate concentrated to dryness. After purification of the residue by CC (Hept-EA), the title compound was obtained as a white solid (0.067 g; 62% yield).
(211) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.39-7.43 (m, 2H); 7.29-7.32 (m, 2H); 4.02 (d, J=5.5 Hz, 2H); 3.04 (s, 1H); 1.40 (s, 18H); 0.98-1.01 (m, 2H); 0.91-0.94 (m, 2H).
Preparation AJ: (1-(4-ethynylphenyl)cyclopropyl)methyl dimethylglycinate
(212) To a solution of the compound of Preparation T (0.20 g; 1.18 mmol) in DCM (13 mL) were added N,N-dimethylglycine (0.13 g; 1.18 mmol), EDC (0.31 g; 1.6 mmol) and DMAP (0.19 g; 1.53 mmol). The reaction was stirred at rt for 27 h. A solution of aq. NaHCO.sub.3 (5%; 5 mL) was added to the reaction mixture. The aq. layer was extracted with DCM (2×20 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellow oil (0.23 g; 76% yield).
(213) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.37-7.41 (m, 2H); 7.26-7.30 (m, 2H); 4.21 (s, 2H); 4.13 (s, 1H); 3.10 (s, 2H); 2.17 (s, 6H); 0.97-1.01 (m, 2H); 0.90-0.94 (m, 2H).
(214) MS (ESI, m/z): 258.07 [M+H.sup.+] for C.sub.16H.sub.19NO.sub.2; t.sub.R=0.63 min.
Preparation AK: (3aR,5S,6aS)-5-(bromoethynyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole
(215) Starting from (3aR,5S,6aS)-5-(2,2-dibromoyinyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole (2.06 g; 6.32 mmol; prepared as described in WO 2013/170030) and proceeding in analogy to Preparation AE, step AE.v, the title compound was obtained as a yellow oil (1.37 g, 88% yield).
(216) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.60-4.63 (m, 2H); 2.85-2.93 (m, 1H); 2.12-2.17 (m, 2H); 1.51-1.60 (overlapped m, 2H); 1.41 (s, 3H); 1.26 (s, 3H).
Preparation AL: tert-butyl (1-(iodoethynyl)cyclopropyl)carbamate
(217) Starting from tert-butyl 1-ethynylcyclopropylcarbamate (0.855 g; 4.88 mmol; commercial) and proceeding in analogy to Preparation G (91% yield), the title compound was obtained as a yellow solid (1.36 g).
(218) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.85-5.16 (br. s, 1H); 1.49 (s, 9H); 1.18-1.24 (m, 2H); 1.05-1.11 (m, 2H).
Preparation AM: (1S,3R)-3-(hydroxymethyl)-1-(3-iodoprop-2-yn-1-yl)cyclobutan-1-ol
AM.i. (1S,3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3-(trimethylsilyl)prop-2-yn-1-yl)cyclobutan-1-ol
(219) To a solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-one (2 g; 3.54 mmol; prepared as described in WO 2006/063281) in dry THF (5.9 mL) at rt under nitrogen atmosphere, was added a solution of trimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-yn-1-yl)silane (1.27 g; 5.32 mmol; commercial) in dry THF (5.9 mL) followed by ZnEt.sub.2 (15% in toluene; 0.73 mL; 1.06 mmol). The reaction was stirred at rt for 4 h. Water (10 mL) was added, carefully followed by aq. HCl (6M; 0.3 mL) and the reaction mixture was stirred for 15 min. The mixture was extracted with EA (3×15 mL). The combined org. layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by CC (Hept.-EA) to afford the dirty desired product as a colourless oil (2 g; quant.).
(220) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.59-7.63 (m, 4H); 7.41-7.49 (m, 6H); 5.09 (s, 1H); 3.62 (d, J=6.8 Hz, 2H); 2.31 (s, 2H); 1.88-1.99 (m, 3H); 1.22-1.31 (m, 2H); 1.00 (s, 9H); 0.07 (s, 9H).
(221) MS1 (ESI, m/z): 451.0 [M+H.sup.+] for C.sub.27H.sub.38O.sub.2Si.sub.2, t.sub.R=1.14 min.
AM.ii. (1S,3R)-3-(hydroxymethyl)-1-(3-iodoprop-2-yn-1-yl)cyclobutan-1-ol
(222) Starting from intermediate AM.i (crude; 2 g; 1.77 mmol) and proceeding successively in analogy to Preparation E, step E.iii (72% yield) and Preparation G (48% yield), the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.4 g) which crystallized.
(223) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 3.69 (d, J=5.5 Hz, 2H); 2.71 (s, 2H); 2.29-2.35 (m, 2H); 2.15 (m, 1H); 1.89-1.95 (m, 2H).
(224) MS1 (ESI, m/z): 266.95 [M+H.sup.+] for C.sub.8H.sub.11O.sub.2I; t.sub.R=0.52 min.
Preparation AN: (41S,2S)-2-(bromoethynyl)-2-methylcyclopropyl)methoxy)(tert-butyl)diphenylsilane
AN.i. ((1R,2R)-2-(hydroxymethyl)-1-methylcyclopropyl)methyl acetate
(225) To a solution of ((1R,2R)-2-formyl-1-methylcyclopropyl)methyl acetate (0.925 g; 5.92 mmol, prepared as described in WO 2012/154204) in MeOH (10 mL) was added NaBH.sub.4 (0.297 g; 7.7 mmol) portion wise at 0° C. The reaction was stirred for 80 min at 0° C. then for 30 min at rt. Water (10 mL) and DCM (40 mL) were added and the phases were separated. The aq. layer was extracted with DCM-MeOH 9-1 (2×15 mL) and the combined org. layers were dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated to dryness to yield the title compound as a colourless oil (0.968 g; quant.).
(226) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 3.89 (d, J=11.3 Hz, 1H); 3.82 (d, J=11.3 Hz, 1H); 3.74-3.80 (m, 1H); 3.49-3.56 (m, 1H); 2.08 (s, 3H); 1.19 (s, 3H); 1.09-1.15 (m, 1H); 0.70-0.76 (m, 1H); 0.27-0.31 (m, 1H).
AN.ii. ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylcyclopropyl)methyl acetate
(227) Starting from intermediate AN.i (0.94 g; 5.92 mmol) and TBDPSC1 (1.6 mL; 6.03 mmol) and proceeding in analogy to Preparation P, step P.i, the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (2.29 g; 97% yield).
(228) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.66-7.70 (m, 4H); 7.35-7.45 (m, 6H); 3.84 (s, 2H); 3.82-3.88 (overlapped m, 1H); 3.46-3.55 (m, 1H); 2.07 (s, 3H); 1.14 (s, 3H); 1.05 (s, 9H), 1.03-1.11 (overlapped m, 1H); 0.59-0.65 (m, 1H); 0.14-0.19 (m, 1H).
(229) MS1 (ESI, m/z): 397.01 [M+H.sup.+] for C.sub.24H.sub.32O.sub.3Si; t.sub.R=1.13 min.
AN.iii. ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylcyclopropyl)methanol
(230) To a solution of intermediate AN.ii (2.29 g; 5.77 mmol) in MeOH (50 mL) was added K.sub.2CO.sub.3 (1.59 g; 11.5 mmol). The suspension was stirred at rt for 4 h. The reaction mixture was filtered and the solid was washed with DCM. The filtrate was evaporated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (40 mL). The aq. layer was extracted with DCM-MeOH 9-1 (40 mL) and EA-MeOH 9-1 (40 mL). The combined org. layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title compound as a colourless oil (1.59 g; 78% yield).
(231) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.66-7.72 (m, 4H); 7.36-7.45 (m, 6H); 3.86 (dd, J=5.8, 11.1 Hz, 1H); 3.49 (dd, J=8.7, 11.1 Hz, 1H); 3.38 (d, J=11.0 Hz, 1H); 3.30 (d, J=11.0 Hz, 1H); 1.16 (s, 3H); 1.05 (s, 9H); 0.95-1.02 (m, 1H); 0.55 (dd, J=4.8, 9.0 Hz, 1H); 0.12-0.16 (m, 1H).
AN.iv. (((1R,2R)-2-(bromoethynyl)-2-methylcyclopropyl)methoxy)(tert-butyl)diphenylsilane
(232) Starting from intermediate AN.iii (1.59 g; 4.5 mmol) and proceeding successively in analogy to Preparation AE, step AE.iii (92% yield), Preparation N, step N.i (85% yield) and Preparation AE, step AE.v (98% yield), the title compound was obtained as a yellow oil (1.48 g).
(233) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.65-7.72 (m, 4H); 7.36-7.46 (m, 6H); 3.79 (dd, J=5.6, 11.5 Hz, 1H); 3.49 (dd, J=8.4, 11.5 Hz, 1H); 1.43-1.51 (m, 1H); 1.25 (s, 3H); 1.05 (s, 9H); 1.02 (dd, J=4.7, 9.1 Hz, 1H); 0.37 (dd, J=4.7, 6.4 Hz, 1H).
Preparation AO: tert-butyl((3-(iodoethynyl)oxetan-3-yl)methoxy)diphenylsilane
AO.i. 3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetane-3-carbaldehyde
(234) Starting from oxetane-3,3-diyldimethanol (5 g; 42.3 mmol; commercial) and proceeding successively in analogy to Preparation AE, steps AE.i (95% yield) and AE.ii (90% yield), the title compound was obtained, after purification by CC (Hept-EA), as a colourless oil (12.87 g).
(235) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.82 (s, 1H); 7.59-7.62 (m, 4H); 7.44-7.50 (m, 6H); 4.66 (d, J=6.3 Hz, 2H); 4.43 (d, J=6.3 Hz, 2H); 4.15 (s, 2H); 0.98 (s, 9H).
AO.ii. Tert-butyl((3-(iodoethynyl)oxetan-3-yl)methoxy)diphenylsilane
(236) Starting from intermediate AO.i (2 g; 5.64 mmol) and proceeding successively in analogy to Preparation AG, step AG.ii (87% yield) and Preparation G (41% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a colourless oil (0.94 g).
(237) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.64-7.72 (m, 4H); 7.42-7.54 (m, 6H); 4.58 (d, J=5.8 Hz, 2H); 4.48 (d, J=5.8 Hz, 2H); 3.90 (s, 2H); 1.03 (s, 9H).
Preparation AP: 01S,2S)-2-(bromoethynyl)-1-methylcyclopropyl)methyl acetate
AP.i. (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylallyl acetate
(238) To a solution of (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylprop-2-en-1-ol (1.4 g; 8.1 mmol; prepared as reported in Smith III et al., Tetrahedron (2009), 65(33), 6470-6488) in THF (48 mL) was added TEA (2.8 mL; 20.1 mmol). Then AcCl (1.2 mL; 16.5 mmol) was added dropwise over 10 min at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into water (80 mL) and extracted with EA (3×50 mL). The combined org. layers were dried over MgSO.sub.4, filtered and the filtrate removed under reduce pressure. The crude product was purified by CC (PE-EA) to afford the title compound as a colourless oil (1.64 g; 94% yield).
(239) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 5.48-5.51 (m, 1H); 4.79-4.84 (m, 1H); 4.44-4.52 (m, 2H); 4.07-4.11 (m, 1H); 3.55 (t, J=8.0 Hz, 1H); 2.09 (s, 3H); 1.75 (d, J=1.3 Hz, 3H); 1.43 (s, 3H); 1.40 (s, 3H).
AP.ii. ((1S,2S)-24(R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-methylcyclopropyl)methyl acetate
(240) To a mechanically stirred solution of intermediate AP.i (1.64 g; 7.65 mmol) in toluene (102 mL), cooled to −25° C., was added dropwise ZnEt.sub.2 (15% in toluene; 34.5 mL; 38.3 mmol) over 20 min, keeping IT below −20° C. Then diiodomethane (6.5 mL; 79.9 mmol) was added dropwise over 10 min, keeping IT below −20° C. The reaction mixture was stirred at −20° C. for 2 h, then allowed to slowly warm up to rt and stirred overnight. The reaction mixture was quenched with sat. aq. NH.sub.4Cl (33 mL) and extracted with Et.sub.2O (4×30 mL). The combined org. layers were washed with sat. aq. Na.sub.2S.sub.2O.sub.3 (30 mL), water (30 mL) and brine (30 mL), then dried over MgSO.sub.4 and filtered. After evaporation of the filtrate under reduced pressure, a yellow oil (22.4 g) was obtained. The crude product was purified by CC (PE-EA) to afford the title compound as a colourless oil (1.4 g; 80% yield).
(241) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.09 (dd, J=5.9, 7.9 Hz, 1H); 3.89 (d, J=11.3 Hz, 1H); 3.77 (d, J=11.3 Hz, 1H); 3.70-3.76 (overlapped m, 1H); 3.61-3.66 (m, 1H); 2.07 (s, 3H); 1.45 (s, 3H); 1.36 (s, 3H); 1.13 (s, 3H); 0.85-0.95 (m, 2H); 0.56 (t, J=5.0 Hz, 1H).
AP.iii. ((1S,2S)-24(R)-1, 2-dihydroxyethyl)-1-methylcyclopropyl)methyl acetate
(242) A mixture of intermediate AP.ii (1.4 g; 6.1 mmol) in AcOH (80%; 14 mL) was stirred at rt for 23 h. The mixture was added to sat. aq. NaHCO.sub.3 (100 mL; pH 6-7) and the aq. layer was extracted with DCM (3×60 mL). The combined org. layers were washed with water (10 mL) and brine (20 mL), dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was co-evaporated with cyclohexane. The crude was purified by CC (DCM-MeOH) to afford the title compound as a colourless oil (1 g: 87% yield).
(243) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 3.89 (d, J=11.3 Hz, 1H); 3.74 (d, J=11.3 Hz, 1H); 3.68 (dd, J=3.4, 11.2 Hz, 1H); 3.57 (dd, J=7.4, 11.2 Hz, 1H); 3.33-3.39 (m, 1H); 2.07 (s, 3H); 1.16 (s, 3H); 0.89 (td, J=5.7, 9.0 Hz, 1H); 0.80 (dd, J=4.9, 8.8 Hz, 1H); 0.48 (t, J=5.3 Hz, 1H).
AP.iv. ((1S,2S)-2-formyl-1-methylcyclopropyl)methyl acetate
(244) To a solution of intermediate AP.iii (1 g; 5.3 mmol) in THF (16.5 mL), water (3.4 mL) and sat. aq. NaHCO.sub.3 (1.6 mL), cooled to 0° C., was added NaIO.sub.4 (1.48 g; 6.9 mmol). The reaction mixture was stirred at 0° C. for 30 min, then filtered and washed with Et.sub.2O. The aq. layer was extracted with Et.sub.2O (3×40 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated to dryness. The title compound was obtained as a colourless oil (0.81 g; 98% yield).
(245) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 9.47 (d, J=4.7 Hz, 1H); 4.00 (d, J=11.4 Hz, 1H); 3.85 (d, J=11.4 Hz, 1H); 2.09 (s, 3H); 1.92-1.97 (m, 1H); 1.39 (t, J=5.3 Hz, 1H); 1.32 (s, 3H); 1.21 (dd, J=5.0, 8.3 Hz, 1H).
AP.v. ((1S,2S)-2-(bromoethynyl)-1-methylcyclopropyl)methyl acetate
(246) Starting from intermediate AP.iv (0.81 g; 5.19 mmol) and proceeding successively in analogy to Preparation N, steps N.i (81% yield) and N.ii (62% yield), the title compound was obtained, after purification by CC (PE/TBME), as a colourless oil (0.6 g).
(247) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 3.89 (d, J=11.4 Hz, 1H); 3.80 (d, J=11.4 Hz, 1H); 2.07 (s, 3H); 1.39 (dd, J=5.5, 8.9 Hz, 1H); 1.27 (s, 3H); 0.94 (dd, J=4.8, 8.9 Hz, 1H); 0.65 (t, J=5.1 Hz, 1H).
Preparation AQ: tert-butyl (2-((3-(iodoethynyl)cyclopentyl)amino)-2-oxoethyl)carbamate
AQ.i. Methyl 3-(2-((tert-butoxycarbonyl)amino)acetamido)cyclopentane-1-carboxylate
(248) To a solution of methyl 3-aminocyclopentane carboxylate hydrochloride (0.87 g; 4.58 mmol; commercial) in DMF (17 mL) were added successively HOBT (1.29 g; 9.26 mmol), TEA (2.2 mL; 15.8 mmol); Boc-Gly-OH (0.845 g; 4.82 mmol; commercial) and EDC (1.58 g; 8.14 mmol). The reaction mixture was diluted with DMF (6 mL) and the suspension was stirred at rt for 3 days. The reaction mixture was concentrated in vacuo and partitioned between water (20 mL) and EA (40 mL). The org. layer was washed with water (20 mL), aq. NaHSO.sub.4 (15%; 20 mL), sat. aq. NaHCO.sub.3 (20 mL) and brine (20 mL), dried over MgSO.sub.4 and filtered. The filtrate was concentrated to dryness to give the title compound as a colourless oil (1.41 g; quant.).
(249) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.78 (d, J=7.3 Hz, 1H); 6.86 (t, J=6.0 Hz, 1H); 3.60 (s, 3H); 3.47 (d, J=6.1 Hz, 2H); 2.76-2.85 (m, 1H); 2.08-2.16 (m, 1H); 1.77-1.87 (m, 3H); 1.54-1.62 (m, 1H); 1.41-1.48 (m, 1H); 1.33-1.39 (overlapped m, 1H); 1.37 (s, 9H).
(250) MS1 (ESI, m/z): 301.05 [M+H.sup.+] for C.sub.14H.sub.24N.sub.2O.sub.5; t.sub.R=0.67 min.
AQ.ii. Tert-butyl (2((3-(hydrozymethyl)cyclopentyl)amino)-2-oxoethyl)carbamate
(251) To a solution of intermediate AQ.i (1.38 g; 4.58 mmol) in THF (9 mL) was added DIBAH (1M in toluene; 19 mL) at 0° C. over 1.5 h, keeping IT below 5° C. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with the slow addition of water (11 mL) over 10 min. After 2 h stirring, the mixture was filtered through a Celite bed and the filtrate was evaporated under reduced pressure. The crude was purified by CC (DCM-MeOH) to afford the title compound as a white foam (0.604 g; 48% yield).
(252) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.68 (d, J=7.4 Hz, 1H); 6.82 (t, J=5.9 Hz, 1H); 4.50 (t, J=5.2 Hz, 1H); 3.91-4.06 (m, 1H); 3.46 (d, J=6.1 Hz, 2H); 3.28-3.32 (m, 2H); 1.90-2.02 (m, 2H); 1.72-1.81 (m, 1H); 1.56-1.64 (m, 1H); 1.31-1.44 (overlapped m, 2H); 1.37 (s, 9H); 1.01-1.11 (m, 1H).
(253) MS1 (ESI, m/z): 273.07 [M+H.sup.+] for C.sub.13H.sub.24N.sub.2O.sub.4; t.sub.R=0.56 min.
AQ.iii. Tert-butyl (24(3-formylcyclopentyl)amino)-2-oxoethyl)carbamate
(254) Starting from intermediate AQ.ii (0.604 g; 2.22 mmol) and proceeding in analogy to Preparation AE, step AE.iii, the title compound was obtained, after purification by CC (DCM-MeOH), as a yellow oil (0.483 g; 81% yield).
(255) MS1 (ESI, m/z): 271.09 [M+H.sup.+] for C.sub.13H.sub.22N.sub.2O.sub.4; t.sub.R=0.59 min.
AQ.iv. Tert-butyl (2-((3-(iodoethynyl)cyclopentyl)amino)-2-oxoethyl)carbamate
(256) Starting from intermediate AQ.iii (0.483 g; 1.79 mmol) and proceeding successively in analogy to Preparation AG, step AG.ii (87% yield) and Preparation G (90% yield), the title compound was obtained, after purification by CC (DCM-MeOH), as a yellow foam (0.55 g; 1-1 cis-trans mixture).
(257) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 6.13-6.20 (m, 0.5H); 6.01-6.08 (m, 0.5H); 5.08 (br. s, 1H); 4.26-4.41 (m, 1H); 3.75 (d, J=5.3 Hz, 1H); 3.72 (d, J=5.9 Hz, 1H); 2.88-3.00 (m, 1H); 2.26-2.33 (m, 0.5H); 2.16-2.24 (m, 0.5H); 1.99-2.12 (m, 0.5H); 1.90-1.98 (m, 0.5H); 1.67-1.88 (m, 2H); 1.54-1.66 (overlapped m, 1H); 1.36-1.49 (overlapped m, 1H); 1.47 (s, 4.5H); 1.45 (s, 4.5H).
(258) MS1 (ESI, m/z): 392.88 [M+H.sup.+] for C.sub.14H.sub.21N.sub.2O.sub.3I; t.sub.R=0.80 min.
Preparation AR: (S)-4-((1R,2R)-2-(bromoethynyl)cyclopropyl)-2,2-dimethyl-1,3-dioxolane
(259) Starting from (1R,2R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)cyclopropane-1-carbaldehyde (1 g; 5.88 mmol; prepared as described in Mohapatra et al., Tetrahedron Lett. (2012), 53(49), 6718-6720) and proceeding successively in analogy to Preparation N, step N.i (79% yield) and Preparation AE, step AE.v (92% yield), the title compound was obtained, after purification by CC (PE-TBME), as a yellow oil (1.05 g).
(260) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.08-4.13 (m, 1H); 3.72-3.77 (m, 1H); 3.63-3.68 (m, 1H); 1.41 (s, 3H); 1.20-1.35 (overlapped m, 2H); 1.32 (s, 3H); 0.83-1.00 (m, 2H).
Preparation AS: tert-butyl a/R,2R)-2-(iodoethynyl)cyclopropyl)methyl)carbamate
(261) Starting from tert-butyl (((1R,2R)-2-formylcyclopropyl)methyl)carbamate (0.56 g; 2.81 mmol; commercial) and proceeding successively in analogy to Preparation AG, step AG.ii (quant.) and Preparation G (87% yield), the title compound was obtained as a yellow oil (0.746 g).
(262) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.64 (br. s, 1H); 3.08-3.17 (m, 1H); 2.90-2.97 (m, 1H); 1.44 (s, 9H); 1.30-1.38 (m, 1H); 1.24-1.30 (m, 1H); 0.90-0.95 (m, 1H); 0.68-0.74 (m, 1H).
Preparation AT: ((1-(bromoethynyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane
(263) Starting from cyclobutane-1,1-diyldimethanol (3.03 g; 24.8 mmol; commercial) and proceeding successively in analogy to Preparation AE, steps AE.ii (98% yield) and AE.iii (86% yield), Preparation N, step N.i (93% yield) and Preparation AE, step AE.v (quant.), the title compound was obtained as a colourless oil (4.79 g).
(264) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.70-7.74 (m 4H); 7.40-7.48 (m, 6H); 3.67 (s, 2H); 2.18-2.29 (m, 4H); 2.00-2.08 (m, 1H); 1.86-1.95 (m, 1H); 1.11 (s, 9H).
Preparation AU: (4/R,2R)-2-(bromoethynyl)-2-fluorocyclopropyl)methoxy)(tert-butyl)diphenylsilane
AU.i. ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methanol
(265) To a solution of ethyl (1R,2R)-2-0(tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropane-1-carboxylate (0.5 g; 1.25 mmol; prepared as described in Sakagami et al., Bioorg. Med. Chem. (2008), 16(8), 4359-4366) in THF (9 mL), cooled to −78° C., was added dropwise LiBH.sub.4 (2M in THF; 2.2 mL; 4.4 mmol). The reaction mixture was allowed to reach rt and stirred at rt for 24 h. MeOH (2 mL) was carefully added, the reaction mixture was stirred for 20 min, concentrated to dryness and partitioned between water (10 mL) and DCM (15 mL). The aq. layer was extracted with DCM (2×10 mL). The combined org. layers were dried over Na.sub.2SO.sub.4 and filtered. After concentration of the filtrate to dryness, the title compound was obtained as a colourless oil (0.429 g; 96% yield).
(266) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.66-7.72 (m, 4H); 7.36-7.45 (m, 6H); 3.89 (ddd, J=1.6, 6.0, 11.0 Hz, 1H); 3.80-3.83 (m, 1H); 3.70-3.78 (m, 2H); 1.74 (t, J=6.4 Hz, 1H); 1.24-1.33 (m, 1H); 1.05 (s, 9H); 0.79-0.88 (m, 2H).
(267) MS1 (ESI, m/z): 358.95 [M+H.sup.+] for C.sub.21H.sub.27O.sub.2FSi; t.sub.R=1.01 min.
AU.ii. (((1R,2R)-2-(bromoethynyl)-2-fluorocyclopropyl)methoxy)(tert-butyl)diphenylsilane
(268) Starting from intermediate AU.i (2.04 g; 5.7 mmol) and proceeding successively in analogy to Preparation AE, step AE.iii (83% yield), Preparation N, step N.i (17% yield) and Preparation AE, step AE.v (99% yield), the title compound was obtained as a brown oil (0.351 g).
(269) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.66-7.70 (m 4H); 7.36-7.45 (m, 6H); 3.84 (ddd, J=1.6, 5.8, 11.3 Hz, 1H); 3.71 (ddd, J=1.1, 8.0, 11.3 Hz, 1H); 1.56-1.64 (m, 1H); 1.14-1.20 (m, 1H); 1.06 (s, 9H); 0.98-1.04 (m, 1H).
Preparation AV: 3-iodo-N,N-dimethylprop-2-yn-1-amine
(270) Starting from N,N-dimethylprop-2-yn-1-amine (1 g; 12 mmol; commercial) and proceeding in analogy to Preparation G, the title compound was obtained as a yellow solid (0.746 g; 56% yield).
(271) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 3.45 (s, 2H); 2.33 (s, 6H).
Preparation AW: tert-butyl 4-(iodoethynyl)piperidine-1-carboxylate
(272) Starting from tert-butyl 4-ethynylpiperidine-1-carboxylate (0.952 g; 4.55 mmol; commercial) and proceeding in analogy to Preparation G, the title compound was obtained as a yellow solid (1.51 g; 99% yield).
(273) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 3.62-3.74 (m, 2H); 3.14-3.23 (m, 2H); 2.70-2.78 (m, 1H); 1.72-1.80 (m, 2H); 1.55-1.63 (m, 2H); 1.45 (s, 9H).
(274) MS1 (ESI, m/z): 335.85 [M+H.sup.+] for C.sub.12H.sub.18NO.sub.2I; t.sub.R=0.93 min.
Preparation AX: ((1R,2R)-2-(bromoethynyl)-1-fluorocyclopropyl)methyl acetate
AX.i. ((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-fluorocyclopropyl)methyl acetate
(275) Starting from intermediate AU.i (2.12 g; 5.91 mmol) and proceeding in analogy to Preparation AP, step AP.i, the crude product was obtained as a yellow oil (2.3 g).
(276) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 7.66-7.71 (m, 4H); 7.36-7.45 (m, 6H); 4.27-4.35 (m, 2H); 3.90 (ddd, J=1.6, 5.8, 11.0 Hz, 1H); 3.69 (ddd, J=1.2, 8.3, 11.0 Hz, 1H); 2.11 (s, 3H); 1.31-1.40 (m, 1H); 1.06 (s, 9H); 0.80-0.94 (m, 2H).
(277) MS1 (ESI, m/z): 400.98 [M+H.sup.+] for C.sub.12H.sub.18NO.sub.2; t.sub.R=1.09 min.
AX.ii. ((JR, 2R)-1-fluoro-2-(hydroxymethyl)cyclopropyl)methyl acetate
(278) To a solution of intermediate AX.i (2.16 g; 5.39 mmol) in THF (10 mL) was added TBAF (1M in THF; 7 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and purified by CC (DCM-MeOH) to afford the title alcohol as a yellow oil (0.726 g; 83% yield).
(279) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.27-4.41 (m, 2H); 3.94 (m, 1H); 3.64 (m, 1H); 2.13 (s, 3H); 1.51 (m, 1H); 1.41 (m, 1H); 0.98-1.06 (m, 2H).
AX.iii. ((1R,2R)-2-(bromoethynyl)-1-fluorocyclopropyl)methyl acetate
(280) Starting from intermediate AX.ii (0.725 g; 4.46 mmol) and proceeding successively in analogy to Preparation AE, step AE.iii (100% yield), Preparation N, step N.i (52% yield) and Preparation AE, step AE.v (57% yield), the title compound was obtained as a colourless oil (0.351 g).
(281) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 6.21 (dd, J=1.3, 8.8 Hz, 1H); 4.32-4.38 (m, 2H); 2.14 (s, 3H); 1.90-1.98 (m, 1H); 1.22-1.35 (m, 2H).
Preparation AY: 2-hydroxy-1-(4-(iodoethynyl)piperidin-1-yl)ethan-1-one
AY.i. 1-(4-ethynylpiperidin-1-yl)-2-hydroxyethan-1-one
(282) To a solution of 4-ethynylpiperidine hydrochloride (0.720 g; 4.94 mmol; commercial) in MeCN (9.5 mL) and DMF (4.5 mL) was added TEA (3 mL; 21.5 mmol), EDC (1.17 g; 5.97 mmol), HOBT (0.935 g, 6.71 mmol) and glycolic acid (0.425 g; 5.54 mmol). The reaction mixture was stirred at rt for 20 h. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL) and EA (15 mL). The two phases were separated and the aq. layer was extracted with EA (3×15 mL). The combined org. layers were washed with NaHCO.sub.3 (30 mL) and brine (30 mL), dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a white solid (0.569 g).
(283) .sup.1H NMR (300 MHz, DMSO-d6) δ: 4.44 (t, J=5.4 Hz, 1H); 4.05 (d, J=5.3 Hz, 2H); 3.80 (m, 1H); 3.47 (m, 1H); 3.05-3.18 (m, 2H); 2.95 (d, J=2.4 Hz, 1H); 2.65 (m, 1H); 1.66-1.81 (m, 2H); 1.31-1.53 (m, 2H).
AY.ii. 2-hydroxy-1-(4-(iodoethynyl)piperidin-1-yl)ethan-1-one
(284) Starting from intermediate AY.i (0.255 g; 1.52 mmol; commercial) and proceeding in analogy to Preparation G, the title compound was obtained as a yellow solid (0.400 g; 90% yield).
(285) MS1 (ESI, m/z): 293.84 [M+H.sup.+] for C.sub.9H.sub.12NO.sub.2I; t.sub.R=0.63 min.
Preparation AZ: 3-(3-iodoprop-2-yn-1-yl)oxetan-3-ol
(286) A flask charged with ZnBr.sub.2 (1.08 g, 4.80 mmol) and Mg turnings (5.85 g) was heated with stirring under vacuum at 150° C. for 2 h and then cooled to rt. Et.sub.2O (90 mL) and a few drops of 1,2-dibromoethane were added. Propargyl bromide (9 mL; 118.78 mmol) in Et.sub.2O (70 mL) was then added dropwise. The mixture was stirred at the same temperature for 1 h. In a separate flask were introduced 3-oxetanone (3.15 g; 43.71 mmol) and THF (420 mL). The Grignard reagent solution (127 mL; 65.56 mmol), cannulated in a graduated addition funnel, was added dropwise. The solution was stirred at the same temperature for 1 h and diluted with sat. aq. NH.sub.4Cl and Hex (100 mL). The two layers were separated and the aq. layer was extracted with Hex (100 mL). The combined org. layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. Starting from the crude intermediate thus obtained (4.33 g; 38.63 mmol) and proceeding in analogy to Preparation G, the title compound was obtained as a yellow solid (3.01 g; 33% yield).
(287) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.51 (d, J=7.4 Hz, 2H); 4.66 (d, J=7.1 Hz, 2H); 2.98 (s, 2H); 2.55 (s, 1H).
Preparation BA: 2-hydroxy-1-(3-(iodoethynyl)azetidin-1-yl)ethan-1-one
BA.i. 3-ethynylazetidine hydrochloride
(288) A solution of tert-butyl 3-ethynylazetidine-1-carboxylate (1.34 g; 7.37 mmol) in 4N HCl in dioxane (19 mL) was stirred at rt for 1.5 h. The reaction mixture was concentrated to dryness to give the title compound as a white solid (0.865 g; quant.).
(289) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 10.09 (br. s, 1H); 9.80 (br. s, 1H); 4.13-4.28 (m, 4H); 3.77 (m, 1H); 2.42 (d, J=2.4 Hz, 1H).
BA.ii. 2-hydroxy-1-(3-(iodoethynyl)azetidin-1-yl)ethan-1-one
(290) Starting from intermediate BA.i (0.865 g; 7.37 mmol) and proceeding in analogy to Preparation AY, the title compound was obtained as a brown solid (0.142 g; 31% yield).
(291) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.26-4.38 (m, 2H); 4.07-4.18 (m, 2H); 3.97-4.06 (m, 2H); 3.67 (m, 1H); 3.02 (br. s, 1H).
(292) MS1 (ESI, m/z): 265.86 [M+H.sup.+] for C.sub.7H.sub.8NO.sub.2I; t.sub.R=0.71 min.
Preparation BB: tert-butyl (5-iodo-2-methylpent-4-yn-2-yl)carbamate
(293) Starting from tert-butyl (2-methyl-4-oxobutan-2-yl)carbamate (0.51 g; 2.57 mmol) and proceeding successively in analogy to Preparation AG, step AG.ii (93% yield) and Preparation G (96% yield), the title compound was obtained as a crude yellowish oil (0.74 g).
(294) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.59 (s, 1H); 2.80 (s, 2H); 1.48 (s, 9H); 1.35 (s, 6H).
Preparation BC: tert-butyl (2-(4-(iodoethynyl)piperidin-1-yl)-2-oxoethyl)carbamate
(295) Starting from tert-butyl (2-(4-ethynylpiperidin-1-yl)-2-oxoethyl)carbamate (1.14 g; 4.29 mmol, prepared as described in WO 03/051797) and proceeding in analogy to Preparation G, the title compound was obtained as a crude yellowish oil (1.56 g; 93% yield).
(296) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 6.70 (M, 1H); 3.80 (m, 1H); 3.74-3.76 (m, 2H); 3.55 (m, 1H); 3.15 (m, 1H); 3.03 (m, 1H); 2.80 (m, 1H); 1.68-1.80 (m, 2H); 1.38-1.50 (m, 2H); 1.37 (s, 9H).
(297) MS1 (ESI, m/z): 392.87 [M+H.sup.+] for C.sub.14H.sub.21N.sub.2O.sub.3I; t.sub.R=0.82 min.
Preparation BD: tert-butyl (2-(3-(bromoethynyl)azetidin-1-yl)-2-oxoethyl)carbamate
BD.i. Tert-butyl (2-(3-ethynylazetidin-1-yl)-2-oxoethyl)carbamate
(298) Starting from intermediate BA.i (0.406 g; 3.45 mmol) and Boc-Gly-OH (0.641 g; 3.66 mmol) and proceeding in analogy to Preparation AY, step AY.i, the title compound was obtained as a yellowish oil which crystallized on standing (0.535 g; 65% yield).
(299) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 5.24 (s, 1H); 4.36 (t, J=8.5 Hz, 1H); 4.29 (t, J=9.1 Hz, 1H); 4.13 (m, 1H); 4.05 (dd, J=6.4, 9.3 Hz, 1H); 3.71-3.75 (m, 2H); 3.45 (m, 1H); 2.33 (d, J=2.5 Hz, 1H); 1.44 (s, 9H).
(300) MS1 (ESI, m/z): 239.13 [M+H.sup.+] for C.sub.12H.sub.18N.sub.2O.sub.3; t.sub.R=0.63 min.
BD.ii. Tert-butyl (2-(3-(bromoethynyl)azetidin-1-yl)-2-oxoethyl)carbamate
(301) To a stirring solution of intermediate BD.i (0.206 g; 0.87 mmol) and NBS (0.185 g; 1.04 mmol) in acetone (3.4 mL) was added AgNO.sub.3 (0.15 g; 0.09 mmol). The mixture was stirred at rt for 2 h. After filtration and evaporation of solvent under reduced pressure, the crude (0.44 g) was purified by CC (Hept-EA) to give the title compound as a white solid (0.214 g; 78% yield).
(302) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 5.24 (br. s, 1H); 4.34 (t, J=8.5 Hz, 1H); 4.27 (t, J=9.2 Hz, 1H); 4.14 (m, 1H); 4.04 (dd, J=6.3, 9.3 Hz, 1H); 3.72 (t, J=5.2 Hz, 2H); 3.47 (m, 1H); 1.44 (s, 9H).
(303) MS1 (ESI, m/z): 318.89 [M+H.sup.+] for C.sub.12H.sub.17N.sub.2O.sub.3Br; t.sub.R=0.73 min.
Preparation BE: tert-butyl (1-(3-(iodoethynyl)azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate
BE.i. Tert-butyl (1-(3-ethynylazetidin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate
(304) Starting from intermediate BA.i (0.235 g; 2 mmol) and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (0.429 g; 2.11 mmol), and proceeding in analogy to Preparation AY, step AY.i, the title compound was obtained as a white solid (0.29 g; 54% yield).
(305) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.93 (br. s, 1H); 3.94-4.60 (m, 4H); 3.32-3.40 (m, 1H); 2.29 (d, J=2.4 Hz, 1H); 1.58 (s, 3H); 1.40-1.52 (m, 12H). MS1 (ESI, m/z): 267.1 [M+H.sup.+] for C.sub.14H.sub.22N.sub.2O.sub.3; t.sub.R=0.67 min.
BE.ii. Tert-butyl (1-(3-(iodoethynyl)azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate
(306) Starting from intermediate BE.i (0.288 g; 1.05 mmol) and proceeding in analogy to Preparation G, the title compound was obtained as a white solid (0.367 g; 88% yield).
(307) .sup.1H NMR (500 MHz, CDCl.sub.3) δ: 4.84-5.01 (br. s, 1H); 3.94-4.55 (m, 4H); 3.46-3.53 (m, 1H); 1.40-1.51 (m, 15H).
(308) MS1 (ESI, m/z): 392.7 [M+H.sup.+] for C.sub.14H.sub.21N.sub.2O.sub.3I; t.sub.R=0.76 min.
REFERENCE EXAMPLES
Reference Example 1: (RS)—N-hydroxy-2-methylsulfonyl-2-methyl-4-{5-[4-(3-morpholin-4-yl-propoxy)-phenyl]-indazol-2-yl}-butanamide formic acid salt
(309) Starting from the compound of Preparation A (0.088 g; 0.19 mmol) and 4-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxyl]propyl]morpholine (0.068 g; 0.19 mmol; commercial), and proceeding in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling: 33% yield; deprotection using aq. TFA (50%, 0.5 mL) instead of PPTS/MeOH: 39% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as an off-white foam (0.013 g).
(310) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.61 (br. s, 1H); 9.24 (br. s, 1H); 8.41 (s, 1H); 7.86 (s, 1H); 7.58-7.67 (m, 3H); 7.52 (dd, J=1.7, 9.1 Hz, 1H); 7.02 (d, J=8.8 Hz, 2H); 4.48-4.60 (m, 1H); 4.29-4.40 (m, 1H); 4.06-4.13 (m, 2H); 3.94-4.03 (m, 2H); 3.57-3.69 (m, 2H); 3.35-3.52 (m, 4H); 3.05-3.17 (overlapped m, 2H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 2.08-2.19 (m, 2H); 1.50 (s, 3H).
(311) MS1 (ESI, m/z): 531.2 [M+H.sup.+] for C.sub.27H.sub.36N.sub.4O.sub.8S; t.sub.R=0.55 min.
Reference Example 2: (RS)—N-hydroxy-2-methylsulfonyl-2-methyl-4-{5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-indazol-2-yl}-butanamide formic acid salt
(312) Starting from the compound of Preparation A (0.087 g, 0.18 mmol) and 4-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]morpholine (0.064 g, 0.19 mmol; commercial), and proceeding in analogy to Example 1, steps 1.i and 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 1), as an off-white foam (0.025 g; Suzuki coupling: 35% yield; deprotection using aq. TFA (50%, 0.5 mL) instead of PPTS/MeOH: 77% yield).
(313) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.96 (br. s, 1H); 9.25 (br. s, 1H); 8.42 (s, 1H); 7.87 (s, 1H); 7.62-7.68 (m, 3H); 7.52 (dd, J=1.7, 9.1 Hz, 1H); 7.09 (d, J=8.8 Hz, 2H); 4.48-4.60 (m, 1H); 4.29-4.40 (m, 3H); 3.33-3.77 (m, 8H); 3.05-3.17 (overlapped m, 2H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(314) MS1 (ESI, m/z): 517.2 [M+H.sup.+] for C.sub.26H.sub.34N.sub.4O.sub.8S; t.sub.R=0.53 min.
Reference Example 3: (RS)-4-{5-[2-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide formic acid salt
(315) Starting from the compound of Preparation A (0.097 g, 0.2 mmol) and 4-[2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy] ethyl]-morpholine (0.075 g, 0.21 mmol; commercial), and proceeding in analogy to Example 1, steps 1.i and 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 1), as an off-white foam (0.025 g; Suzuki coupling: 63% yield; deprotection using aq. TFA (50%, 0.5 mL) instead of PPTS/MeOH: 42% yield).
(316) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.96 (br. s, 1H); 9.28 (br. s, 1H); 8.42 (s, 1H); 7.78 (s, 1H); 7.66 (d, J=8.9 Hz, 1H); 7.51 (t, J=8.9 Hz, 1H); 7.33-7.38 (m, 1H); 6.91-7.06 (m, 2H); 4.48-4.61 (m, 1H); 4.31-4.45 (m, 3H); 3.35-3.82 (m, 8H); 3.06-3.18 (overlapped m, 2H); 3.05 (s, 3H); 2.78-2.89 (m, 1H); 2.35-2.45 (overlapped m, 1H); 1.50 (s, 3H).
(317) MS1 (ESI, m/z): 535.1 [M+H.sup.+] for C.sub.26H.sub.33N.sub.4O.sub.8FS; t.sub.R=0.55 min.
Reference Example 4: (RS)-4-(5-but-2-ynyloxy-indazol-2-yl)-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
RE4.i. Rac-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol
(318) To a solution of 1H-indazol-5-ol (2.0 g; commercial) in THF (20 mL) and DCM (20 mL) were added 3,4-dihydro-2H-pyran (1.4 mL) in DCM (4 mL) and MsOH (0.1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with aq. 10% NaHSO.sub.4. The aq. layer was extracted with DCM. The combined org. layers were dried over MgSO.sub.4, filtered, concentrated under reduced pressure. After purification by CC (DCM-MeOH), the title compound was obtained as a non pure reddish oil (2.74 g, 84% yield), still contained with an unknown compound.
(319) .sup.1H NMR (d6-DMSO) δ: 9.11 (s, 1H); 8.15 (s, 1H); 7.42-7.46 (m, 1H); 6.78-6.87 (m, 2H); 5.61 (dd, J=2.5, 9.5 Hz, 1H); 3.89-3.97 (m, 1H); 3.61-3.74 (m, 1H); 1.86-2.04 (m, 2H); 1.63-1.80 (m, 2H); 1.50-1.60 (m, 2H).
RE4.ii. (RS)-5-but-2-ynyloxy-2-(tetrahydro-pyran-2-yl)-2H-indazole and (RS)-5-but-2-ynyloxy-1-(tetrahydro-pyran-2-yl)-1H-indazole
(320) A suspension of intermediate RE4.i (2.7 g, 12.6 mmol), K.sub.2CO.sub.3 (2.1 g, 15.3 mmol) and 1-bromo-2-butyne (1.1 mL, 12.6 mmol) in acetone (10 mL) was refluxed overnight. The reaction mixture was filtered off, the filtrate was evaporated under reduced pressure and purified by CC (Hept-EA) to afford the title compound as a yellow oil (1.95 g, 57% yield).
(321) MS1 (ESI, m/z): 271.1 [M+H.sup.+] for C.sub.16H.sub.18N.sub.2O.sub.2; t.sub.R=0.87 min.
RE4.iii. 5-but-2-ynyloxy-1H-indazole
(322) A solution of intermediate RE4.ii (1.95 g) in DCM (56 mL) and TFA (14 mL) was stirred at rt for 2 h. The reaction mixture was evaporated to dryness and the residue was taken up in DCM and washed with sat. aq. NaHCO.sub.3 (to adjust pH at 7). The aq. layer was extracted with DCM. The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title compound as a brown oil (2.20 g).
(323) MS1 (ESI, m/z): 187.3 [M+H.sup.+] for C.sub.11H.sub.10N.sub.2O; t.sub.R=0.73 min.
RE4.iv. 2-(5-but-2-ynyloxy-indazol-1-yl)-ethanol
(324) Starting from intermediate RE4.iii (2.25 g) and ethylene carbonate (2.13 g), and proceeding in analogy to Preparation A, step A.i, Variant I, the title compound was obtained, after purification by CC (Hept-EA), in 1-1 mixture with the 1-indazole regioisomer (brown oil; 1.11 g; 40% yield).
(325) MS1 (ESI, m/z): 231.2 [M+H.sup.+] for C.sub.13H.sub.14N.sub.2O.sub.2; t.sub.R=0.66 min and 0.69 min (2 regioisomers).
RE4.v. Methanesulfonic acid 2-(5-but-2-ynyloxy-indazol-2-yl)-ethyl ester
(326) Starting from intermediate RE4.iv (1.11 g) and MsCl (0.49 mL), and proceeding in analogy to Preparation A, step A.ii, the title compound was obtained, after purification by CC (Hept-EA), in mixture with some 1-indazole derivative (yellow oil; 0.37 g; 25% yield).
(327) MS1 (ESI, m/z): 308.9 [M+H.sup.+] for C.sub.14H.sub.16N.sub.2O.sub.4S; t.sub.R=0.76 min.
RE4.vi. 5-but-2-ynyloxy-2-(2-iodo-ethyl)-2H-indazole
(328) Starting from intermediate RE4.v (0.37 g) and Nat (0.32 g), and proceeding in analogy to Preparation A, step A.iii, the title compound was obtained, after purification by CC (Hept-EA), in mixture with some 1-indazole regioisomer (yellow oil; 0.24 g; 58% yield).
(329) MS1 (ESI, m/z): 340.8 [M+H.sup.+] for C.sub.13H.sub.13N.sub.2OI; t.sub.R=0.85 min.
RE4.vii. (RS)-4-(5-but-2-ynyloxy-indazol-2-yl)-2-methylsulfonyl-2-methyl-butanoic acid ethyl ester
(330) Starting from intermediate RE4.vi (0.24 g) and 2-(methylsulfonyl)-propanoic acid ethyl ester (0.14 g; commercial), and proceeding in analogy to Preparation A, step A.v, the title compound was obtained, after purification by CC (Hept-EA), in mixture with some 1-indazole derivative (yellow oil; 0.137 g; 50% yield).
(331) MS1 (ESI, m/z): 393.2 [M+H.sup.+] for C.sub.19H.sub.24N.sub.2O.sub.5S; t.sub.R=0.82 min.
RE4.viii. (RS)-4-(5-but-2-ynyloxy-indazol-2-yl)-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(332) Starting from intermediate RE4.vii (0.137 g), and proceeding successively in analogy to Preparation A, step A.vi (35% yield) and Example 1, step 1.ii (62% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a colourless solid (0.03 g).
(333) .sup.1H NMR (d6-DMSO) δ: 11.0 (br. s, 1H); 9.24 (s, 1H); 8.23 (s, 1H); 7.50 (d, J=9.3 Hz, 1H); 7.04 (d, J=2.3 Hz, 1H); 6.90 (dd, J=2.4 Hz, 1H); 4.67-4.71 (m, 2H); 4.40-4.52 (m, 1H); 4.22-4.33 (m, 1H); 3.04 (s, 3H); 2.74-2.85 (m, 1H); 2.30-2.40 (m, 1H); 1.82 (t, J=2.3 Hz, 3H); 1.48 (s, 3H).
(334) MS1 (ESI, m/z): 380.0 [M+H.sup.+] for C.sub.17H.sub.21N.sub.3O.sub.5S; t.sub.R=0.66 min.
Reference Example 5: (RS)—N-hydroxy-2-methylsulfonyl-2-methyl-4-(5-phenethyl-indazol-2-yl)-butanamide
RE5.i. (RS)-(E)-3-methyl-3-(methylsulfonyl)-5-(5-styryl-2H-indazol-2-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(335) Starting from the compound of Preparation A (0.107 g, 0.205 mmol) and trans-2-phenylvinylboronic acid (0.035 g; commercial), and proceeding in analogy to Example 1, step 1.i, the title compound was obtained, after purification by CC (Hept-EA), as a white foam (0.086 g, 85% yield).
(336) MS1 (ESI, m/z): 498.2 [M+H.sup.+] for C.sub.26H.sub.31N.sub.3O.sub.5S; t.sub.R=0.90 min.
RE5.ii. (RS)-3-methyl-3-(methylsulfonyl)-5-(5-phenethyl-2H-indazol-2-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(337) A suspension of intermediate RE5.i (0.102 g) and 10% Pd/C (0.030 g) in EtOH (2 mL) and THF (3 mL) was stirred under hydrogen atmosphere for 14 h at rt. The catalyst was filtered off, thoroughly washed with EA (2×) and the filtrate was evaporated under reduced pressure to give the title compound as a grey gum (0.095 g; 93% yield).
(338) MS1 (ESI, m/z): 500.2 [M+H.sup.+] for C.sub.26H.sub.33N.sub.3O.sub.5S; t.sub.R=0.90 min.
RE5.iii. (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-(5-phenethyl-indazol-2-yl)-butanamide
(339) Starting form intermediate RE5.ii (0.095 g) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 1), as a colourless solid (0.031 g, 41% yield).
(340) MS1 (ESI, m/z): 416.1 [M+H.sup.+] for C.sub.21H.sub.25N.sub.3O.sub.4S; t.sub.R=0.78 min.
Reference Example 6: (RS)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-oxazol-2-yl-phenyl)-indazol-2-yl]-butanamide formic acid salt
(341) Starting from the compound of Preparation A (0.090 g, 0.19 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (0.055 g; 0.21 mmol; commercial), and proceeding in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling: 32% yield; deprotection 27% yield), the title compound was obtained as an off-white solid (0.009 g).
(342) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.49 (s, 1H); 8.00-8.11 (m, 3H); 7.81-7.88 (m, 2H); 7.60-7.73 (m, 2H); 7.38 (s, 1H); 4.48-4.60 (m, 1H); 4.30-4.44 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(343) MS1 (ESI, m/z): 455.2 [M+H.sup.+] for C.sub.22H.sub.22N.sub.4O.sub.5S; t.sub.R=0.73 min.
Reference Example 7: (RS)-4-(5-(2-fluoro-3-methoxyphenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(344) Starting from the compound of Preparation A (0.090 g, 0.2 mmol) and (2-fluoro-3-methoxyphenyl)boronic acid (0.045 g; 0.26 mmol; commercial), and proceeding in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling: 45% yield; deprotection: 51% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as an off-white solid (0.017 g).
(345) .sup.1H NMR (d6-DMSO) δ: 11.02 (s, 1H); 9.24 (s, 1H); 8.46 (s, 1H); 7.82 (s, 1H), 7.66 (d, J=8.9 Hz, 1H); 7.38 (m, 1H); 6.99-7.21 (m, 3H); 4.48-4.60 (m, 1H); 4.30-4.44 (m, 1H); 3.86 (s, 3H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(346) MS1 (ESI, m/z): 436.1 [M+H.sup.+] for C.sub.20H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.73 min.
EXAMPLES OF COMPOUNDS ACCORDING TO THE INVENTION
Example 1: (R)-4-[5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
1.i. (RS)-4-(5-(2-fluoro-4-methoxyphenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(347) A mixture of 2-fluoro-4-methoxyphenylboronic acid (0.8 g, 4.61 mmol), Pd(PPh.sub.3).sub.4 (0.203 g, 0.176 mmol), Na.sub.2CO.sub.3 (1.63 g, 15.1 mmol) was flushed under N.sub.2 for 15 min. A solution of the compound of Preparation A (1.47 g, 3.1 mmol) in DME (21.1 mL) and water (8.6 mL) was added. The mixture was stirred at rt for 5 min and then heated at 90° C. overnight. Water (40 mL) and EA (40 mL) were added. The two layers were separated and the aq. layer was extracted with EA (5×10 mL). The combined org. layers were washed with brine, dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by CC (Hept-EA) afford the title product as a white foam (1.15 g, 72% yield).
(348) .sup.1H NMR (d6-DMSO) δ (mixture of stereoisomers): 11.4 (br. s, 1H); 8.45 (s, 1H); 7.80 (br. s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.45 (t, J=8.9 Hz, 1H); 7.35 (d, J=8.9 Hz, 1H); 6.83-6.94 (m, 2H); 4.89-4.97 (m, 1H); 4.48-4.60 (m, 1H); 4.30-4.45 (m, 1H); 3.79 (s, 3H); 3.51 (m, 1H); 3.09-3.17 (m, 1H); 3.06 (s, 1.5H); 3.04 (s, 1.5H); 2.77-2.93 (m, 1H); 2.46 (overlapped m, 1H); 1.64-1.76 (m, 2H); 1.47-1.57 (m, 2H); 1.52 (s, 1.5H); 1.49 (s, 1.5H).
(349) MS1 (ESI, m/z): 520.2 [M+H.sup.+] for C.sub.25H.sub.30N.sub.3O.sub.6FS; t.sub.R=0.87 min.
1.ii. Rac-4-[5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(350) To a solution of intermediate 1.i (1.15 g, 2.22 mmol) in EtOH (22.1 mL) was added PPTS (0.35 g, 1.38 mmol). The reaction mixture was stirred at 75° C. overnight. Water (50 mL) was added and the mixture was stirred at rt for 1.5 h. The solid that precipitated was filtered and washed with water. The latter was purified with prep-HPLC (Method 2) to afford the title product as a white solid (0.42 g, 44% yield).
(351) .sup.1H NMR (d6-DMSO) δ: 9.25 (br. s, 1H); 8.43 (s, 1H); 7.77 (br. s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.45 (t, J=8.9 Hz, 1H); 7.35 (d, J=8.9 Hz, 1H); 6.83-6.94 (m, 2H); 4.48-4.60 (m, 1H); 4.29-4.41 (m, 1H); 3.79 (s, 3H); 3.05 (s, 3H); 2.78-2.89 (m, 1H); 2.38-2.48 (m, 1H); 1.50 (s, 3H).
(352) MS1 (ESI, m/z): 436.1 [M+H.sup.+] for C.sub.20H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.88 min.
1.iii. (R)-4-[5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(353) Variant I:
(354) Intermediate 1.ii (0.265 g) was separated by semi-preparative chiral HPLC Method C (Hept-EtOH-TFA 1-1-0.002; flow rate: 20 mL/min; UV detection at 210 nM); the respective retention times of analytical samples (flow rate: 0.8 mL/min) were 6.7 and 8.7 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a beige solid (0.089 g).
(355) MS1 (ESI, m/z): 436.1 [M+H.sup.+] for C.sub.20H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.88 min.
(356) Variant II:
(357) Starting from the compound of Preparation F (2 g, 4.46 mmol) and proceeding successively in analogy to Preparation A, step A.vi (82% yield) and Example 1, step 1.ii (92% yield), the title compound was obtained, after filtration of the solid that formed during the course of the deprotection step, as a white solid (1.36 g).
(358) MS data equivalent to those obtained regarding Variant I. The e.e., determined using the analytical chiral HPLC conditions mentioned for Variant I, was >99%.
Example 2: (R)—N-hydroxy-2-methylsulfonyl-4-[5-(4-methoxy-phenyl)-indazol-2-yl]-2-methyl-butanamide
2.i. (RS)-2-methylsulfonyl-4-[5-(4-methoxy-phenyl)-indazol-2-yl]-2-methyl-butanoic acid ethyl ester
(359) Starting from intermediate A.v (0.171 g, 0.425 mmol) and 4-methoxybenzene boronic acid (0.101 g; 0.65 mmol; commercial), and proceeding in analogy to Example 1, step 1.i, the title compound was obtained, after purification by CC (eluent: Hept-EA mixture with gradient), as a colourless oil (0.156 g, 86% yield).
(360) .sup.1H NMR (d6-DMSO) δ: 8.39 (d, J=0.9 Hz, 1H); 7.96 (dd, J=0.9, 1.9 Hz, 1H); 7.57 (td, J=0.9, 9.1 Hz, 1H); 7.30 (dd, J=1.9, 9.1 Hz, 1); 4.63 (m, 1H); 4.47 (m, 1H); 3.88-4.02 (m, 2H); 3.1 (s, 3H); 2.84 (m, 1H); 2.44 (m, 1H); 1.58 (s, 3H); 1.12 (t, J=7.1 Hz, 3H).
(361) MS1 (ESI, m/z): 431.1 [M+H.sup.+] for C.sub.22H.sub.26N.sub.2O.sub.5S; t.sub.R=0.88 min.
2.ii. (RS)-4-(5-(4-methoxyphenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(362) To a solution of intermediate 2.i (0.157 g; 0.364 mmol) in a THF-MeOH—H.sub.2O mixture (2-2-1; 5 mL) was added in one portion LiOH (0.059 g; 0.79 mmol). The reaction mixture was stirred at rt for 1 h. Solvents were evaporated under vacuum. The residue was taken up in water and directly purified by prep-HPLC (Method 2) to afford the desired product as a beige solid (0.056 g, 0.14 mmol). The latter was taken up in a DCM (2 mL). TEA (0.06 mL, 0.427 mmol), THPO—NH.sub.2 (0.034 g, 0.291 mmol), EDC (0.053 g, 0.277 mmol) and HOBT.H.sub.2O (0.038 g, 0.279 mmol) were added. The mixture was stirred at rt overnight. The mixture was concentrated to dryness. The residue was taken up in DCM (20 mL). The org. layer was washed with sat. NaHCO.sub.3 (10 mL) and brine (20 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by CC (eluent: DCM-MeOH mixture with gradient) to afford the desired product as a colourless oil (0.08 g).
(363) MS1 (ESI, m/z): 502.12 [M+H.sup.+] for C.sub.25H.sub.31N.sub.3O.sub.6S; t.sub.R=0.85 min.
2.ii (RS)—N-hydroxy-2-methylsulfonyl-4-[5-(4-methoxy-phenyl)-indazol-2-yl]-2-methyl-butanamide
(364) Starting from intermediate 2.ii (0.08 g; 0.159 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.041 g; 62% yield).
(365) .sup.1H NMR (d6-DMSO) δ: 11.0 (br. s, 1H); 9.27 (br. s, 1H); 8.41 (s, 1H); 7.86 (s, 1H); 7.56-7.67 (m, 3H); 7.52 (dd, J=1.5, 9.1 Hz, 1H); 7.00 (d, J=8.8 Hz, 2H); 4.47-4.59 (m, 1H); 4.29-4.44 (m, 1H); 3.77 (s, 3H); 3.06 (s, 3H); 2.79-2.90 (m, 1H); 2.35-2.40 (m, 1H); 1.50 (s, 3H).
(366) MS1 (ESI, m/z): 418.07 [M+H.sup.+] for C.sub.20H.sub.23N.sub.3O.sub.5S; t.sub.R=0.65 min.
2.iv. (R)—N-hydroxy-2-methylsulfonyl-4-[5-(4-methoxy-phenyl)-indazol-2-yl]-2-methyl-butanamide
(367) Intermediate 2.iii (0.08 g) was separated by semi-preparative chiral HPLC Method D (MeCN-EtOH-TFA 3-17-0.02; flow rate: 16 mL/min; UV detection at 257 nM); the respective retention times (flow rate: 0.8 mL/min) were 11.2 and 13.3 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a beige solid (0.017 g).
(368) MS2 (ESI, m/z): 418.1 [M+H.sup.+] for C.sub.20H.sub.23N.sub.3O.sub.5S; t.sub.R=0.85 min.
Example 3: (R)-4-[6-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
3.i. (R)-4-[6-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-2-methylsulfonyl-2-methyl-butanoic acid tert-butyl ester
(369) Starting from the compound of Preparation O (0.1 g, 0.22 mmol) and 4-methoxyphenylboronic acid (0.025 g, 0.17 mmol), and proceeding in analogy to Example 1, step 1.i, the title compound was obtained, after purification by CC (eluent: Hept-EA mixture with gradient), as a beige gum (0.089 g; 84% yield).
(370) .sup.1H NMR (d6-DMSO) δ: 8.48 (s, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.37-7.48 (m, 3H); 7.01 (d, J=8.7 Hz, 2H); 4.59 (m, 1H); 4.42 (m, 1H); 3.78 (s, 3H); 2.74 (m, 1H); 2.43 (m, overlaid with DMSO, 1H); 1.53 (s, 3H); 1.39 (m, 9H).
(371) MS1 (ESI, m/z): 477.1 [M+H.sup.+] for C.sub.24H.sub.29N.sub.2O.sub.5FS; t.sub.R=0.96 min.
3.ii. (R)-4-[6-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-2-methylsulfonyl-2-methyl-butanoic acid
(372) To intermediate 3.i (0.08 g, 0.18 mmol) in 4N HCl in dioxane (1.1 mL) was added water (0.04 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated to dryness. The crude residue was co-evaporated twice with Et.sub.2O (4 mL) to give the title acid as an off-white solid (0.08 g; quant.).
(373) .sup.1H NMR (d6-DMSO) δ: 8.50 (s, 1H); 7.77 (d, J=7.9 Hz, 1H); 7.40-7.50 (m, 3H); 7.03 (d, J=8.7 Hz, 2H); 4.38-4.70 (m, 2H); 3.80 (s, 3H); 3.14 (s, 3H); 2.68-2.86 (m, 1H); 2.39-2.58 (overlapped m, 1H); 1.57 (s, 3H) MS1 (ESI, m/z): 421.0 [M+H.sup.+] for C.sub.20H.sub.21N.sub.2O.sub.5FS; t.sub.R=0.79 min.
3.iii. (R)-4-[6-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(374) Starting from intermediate 3.ii (0.072 g, 0.17 mmol), and proceeding successively in analogy to Example 2, step ii (only the coupling reaction using THPO—NH.sub.2 and EDC; 100% yield) and Example 1, step 1.ii (56% yield), the title compound was obtained as a white solid (0.04 g).
(375) .sup.1H NMR (d6-DMSO) δ: 11.0 (d, J=1.7 Hz, 1H); 9.24 (d, J=1.7 Hz, 1H); 8.46 (s, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.39-7.48 (m, 3H); 7.01 (d, J=8.8 Hz, 2H); 4.46-4.57 (m, 1H); 4.26-4.38 (m, 1H); 3.78 (s, 3H); 3.05 (s, 3H); 2.78-2.89 (m, 1H); 2.33-2.46 (m, 1H); 1.50 (s, 3H).
(376) MS1 (ESI, m/z): 436.1 [M+H.sup.+] for C.sub.25H.sub.30N.sub.3O.sub.6PS; t.sub.R=0.74 min.
Example 4: (R)-4-[4-fluoro-5-(4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(377) Starting from the compound of Preparation C (0.11 g, 0.26 mmol) and 4-methoxyphenylboronic acid (0.049 g, 0.32 mmol), and proceeding successively in analogy to Example 1, step 1.i (61% yield), Example 2, step 2.ii (90% yield) and Example 1, step 1.ii (80% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.043 g).
(378) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.62 (s, 1H); 7.50 (d, J=8.8 Hz, 2H); 7.38 (t, J=8.7 Hz, 1H); 7.03 (d, J=8.8 Hz, 2H); 4.50-4.61 (m, 1H); 4.30-4.43 (m, 1H); 3.78 (s, 3H); 3.06 (s, 3H); 2.80-2.90 (m, 1H); 2.35-2.45 (overlapped m, 1H); 1.53 (s, 3H).
(379) MS1 (ESI, m/z): 436.2 [M+H.sup.+] for C.sub.25H.sub.30N.sub.3O.sub.6FS; t.sub.R=0.75 min.
Example 5: (R)-4-[6-fluoro-5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
5.i. (RS)-5-(6-fluoro-5-(2-fluoro-4-methoxyphenyl)-2H-indazol-2-yl)-N-hydroxy-3-methyl-3-(methylsulfonyl)butanamide
(380) Starting from the compound of Preparation B (0.3 g, 0.61 mmol) and 2-fluoro-4-methoxyphenylboronic acid (0.137 g, 0.79 mmol), and proceeding in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling 70% yield, deprotection 49% yield), the title compound was obtained as a white foam (0.095 g).
(381) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.48 (s, 1H); 7.73 (d, J=7.5 Hz, 1H); 7.43 (d, J=11.4 Hz, 1H); 7.35 (t, J=8.8 Hz, 1H); 6.84-6.95 (m, 2H); 4.48-4.59 (m, 1H); 4.28-4.39 (m, 1H); 3.81 (s, 3H); 3.05 (s, 3H); 2.77-2.89 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(382) MS1 (ESI, m/z): 454.1 [M+H.sup.+] for C.sub.20H.sub.21N.sub.3O.sub.5F.sub.2S; t.sub.R=0.75 min.
5.ii. (R)-4-[6-fluoro-5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(383) Intermediate 5.i (0.095 g) was separated by semi-preparative chiral HPLC Method C (Hept-EtOH-TFA 1-1-0.002; flow rate: 23 mL/min; UV detection at 210 nM); the respective retention times (flow rate: 1.2 mL/min) were 4.4 and 6.9 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a white solid (0.031 g).
(384) MS2 (ESI, m/z): 454.3 [M+H.sup.+] for C.sub.20H.sub.21N.sub.3O.sub.5F.sub.2S; t.sub.R=0.9 min.
Example 6: (R)-4-[4-fluoro-5-(2-fluoro-4-methoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(385) Starting from the compound of Preparation C (0.16 g; 0.38 mmol) and (2-fluoro-4-methoxy)phenylboronic acid (0.085 g, 0.49 mmol), and proceeding successively in analogy to Example 1, step 1.i (66% yield), Example 2, step 2.ii (96% yield) and Example 1, step 1.ii (74% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white solid (0.069 g).
(386) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.23 (s, 1H); 8.65 (s, 1H); 7.51 (d, J=8.8 Hz, 1H); 7.38 (t, J=8.7 Hz, 1H); 7.18-7.24 (m, 1H); 6.85-6.95 (m, 2H); 4.50-4.62 (m, 1H); 4.31-4.43 (m, 1H); 3.81 (s, 3H); 3.07 (s, 3H); 2.79-2.92 (m, 1H); 2.35-2.45 (overlapped m, 1H); 1.53 (s, 3H).
(387) MS1 (ESI, m/z): 454.1 [M+H.sup.+] for C.sub.20H.sub.21N.sub.3O.sub.5F.sub.2S; t.sub.R=0.77 min.
Example 7: (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-morpholin-4-ylmethyl-phenylethynyl)-indazol-2-yl]-butanamide formate
7.i. (R)-2-methylsulfonyl-2-methyl-4-[5-(4-morpholin-4-ylmethyl-phenylethynyl)-indazol-2-yl]-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
(388) CuI (0.01 g; 0.04 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.01 g, 0.02 mmol), the compound of Preparation H (0.1 g; 0.19 mmol) and 4-(4-ethynylbenzyl)morpholine (0.05 g; 0.23 mmol; prepared as described in WO 2008/154642) were introduced in a two-necked round flask. The atmosphere was flushed with nitrogen during 30 min then degassed THF (1.3 mL) and degassed TEA (0.07 mL, 0.48 mmol) were added. The suspension was stirred under nitrogen atmosphere at 50° C. for 45 min. After concentration to dryness, the residue was purified by CC (DCM-MeOH+NH.sub.4OH gradient) to afford the title compound, slightly contaminated with a bis-alkyne residue, as a yellow foam (0.1 g; 91% yield).
(389) .sup.1H NMR (d6-DMSO) δ (mixture of isomers): 11.39-11.48 (m, 1H); 8.45-8.49 (m, 1H); 7.98 (s, 1H); 7.65 (d, J=9.0 Hz, 1H); 7.47-7.54 (m, 2H); 7.32-7.39 (m, 3H); 4.92-5.00 (m, 1H); 4.51-4.64 (m, 1H); 4.32-4.47 (m, 1H); 3.98-4.18 (m, 1H); 3.44-3.65 (overlapped m, 5H); 3.49 (s, 2H); 3.08 (s, 1.5H); 3.06 (s, 1.5H); 2.77-2.95 (m, 1H); 2.30-2.59 (overlapped m, 5H); 1.65-1.74 (m, 3H); 1.55 (s, 1.5H); 1.49-1.59 (overlapped m, 3H); 1.53 (s, 1.5H).
(390) MS1 (ESI, m/z): 595.2 [M+H.sup.+] for C.sub.31H.sub.38N.sub.4O.sub.6S; t.sub.R=0.66 min.
7.ii. (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-morpholin-4-ylmethyl-phenylethynyl)-indazol-2-yl]-butanamide formate
(391) Starting from intermediate 7.i (0.1 g, 0.16 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellowish foam (0.085 g; 92% yield).
(392) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.94 (br. s, 1H); 9.24 (br. s, 1H); 8.50 (s, 1H); 8.11 (br. s, 1H); 7.99 (s, 1H); 7.59-7.65 (m, 3H); 7.47-7.55 (m, 2H); 7.32 (m, 1H); 4.55 (m, 1H); 4.26-4.42 (m, 2H); 3.84-4.08 (m, 2H); 3.05-3.68 (multiple m, 5H); 3.15 (s, 2H); 3.05 (s, 3H); 2.85 (m, 1H); 2.46 (m, 1H); 1.60 (s, 3H).
(393) MS1 (ESI, m/z): 511.2 [M+H.sup.+] for C.sub.26H.sub.30N.sub.4O.sub.5S; t.sub.R=0.57 min.
Example 8: (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-trifluoromethoxy-phenyl)-indazol-2-yl]-butanamide
(394) Starting from the compound of Preparation H (0.103 g, 0.19 mmol) and (4-(trifluoromethoxy)phenyl)boronic acid (0.043 g, 0.21 mmol), and proceeding in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling: 41% yield; deprotection: 11% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a white foam (0.011 g).
(395) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.47 (s, 1H); 7.98 (s, 1H); 7.79 (d, J=8.2 Hz, 2H); 7.69 (d, J=9.0 Hz, 1H); 7.55 (dd, J=1.5, 9.0 Hz, 1H); 7.42 (d, J=8.2 Hz, 2H); 4.49-4.60 (m, 1H); 4.29-4.41 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(396) MS1 (ESI, m/z): 472.1 [M+H.sup.+] for C.sub.20H.sub.20N.sub.3O.sub.5F.sub.3S; t.sub.R=0.81 min.
Example 9: (R)-4-[5-(2-fluoro-4-methylsulfanyl-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(397) Starting from the compound of Preparation H (0.1 g, 0.192 mmol) and the compound of Preparation D (0.062 g, 0.23 mmol), and proceeding in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling: 59% yield; deprotection: 51% yield), the title compound was obtained, after purification by trituration in diethyl ether, as a white solid (0.024 g).
(398) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.47 (s, 1H); 7.83 (s, 1H); 7.66 (d, J=8.4 Hz, 1H); 7.38 (dd, J=1.4, 7.5 Hz, 1H); 7.13-7.23 (m, 2H); 4.48-4.60 (m, 1H); 4.30-4.41 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(399) MS1 (ESI, m/z): 452.2 [M+H.sup.+] for C.sub.2OH.sub.22N.sub.3O.sub.4FS.sub.2; t.sub.R=0.81 min.
Example 10: (R)-4-{5-[4-(3-amino-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide toluene-4-sulfonate
(400) Starting from the compound of Preparation L (0.072 g; 0.23 mmol) and the compound of Preparation J (0.081 g; 0.2 mmol), and proceeding successively in analogy to Example 7, step 7.i (69% yield) and Example 1, step 1.ii (44% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellowish solid (0.04 g).
(401) .sup.1H NMR (d6-DMSO δ: 9.24 (br. s, 1H); 8.49 (s, 1H); 8.11 (s, 1H); 7.99 (s, 1H); 7.61 (m, 5H); 7.45 (d, J=8.0 Hz, 2H); 7.33 (dd, J=1.2, 8.9 Hz, 1H); 7.08 (d, J=8.0 Hz, 2H); 4.76-4.85 (m, 4H); 4.55 (m, 1H); 4.34 (m, 1H); 3.25 (br. s, 3H); 2.84 (m, 1H); 2.48 (m, overlaid with DMSO, 1H); 2.26 (s, 3H); 1.53 (s, 3H).
(402) MS1 (ESI, m/z): 483.1 [M+H.sup.+] for C.sub.24H.sub.26N.sub.4O.sub.5S; t.sub.R=0.54 min.
Example 11: (R)-4-[5-(4-dimethylamino-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
11.i. (R)-4-[5-(4-dimethylamino-phenyl)-indazol-2-yl]-2-methylsulfonyl-2-methyl-N-(2-trimethylsilanyl-ethoxy)-butanamide
(403) Starting from the compound of Preparation I (0.103 g, 0.192 mmol) and [4-(dimethylamino)phenyl]boronic acid (0.038 g; commercial), and proceeding in analogy to Example 1, step 1.i, the title compound was obtained as a yellowish oil (0.095 g; 94% yield).
(404) MS1 (ESI, m/z): 531.1 [M+H.sup.+] for C.sub.26H.sub.38N.sub.4O.sub.4SSi; t.sub.R=0.76 min.
11.ii. (R)-4-[5-(4-dimethylamino-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(405) An ice-chilled solution of intermediate 11.i (0.095 g, 0.18 mmol) in MeCN (3 mL) was treated with BF.sub.3.OEt.sub.2 (0.205 mL) and the mixture stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by prep-HPLC (Method 2) to afford the title compound as an off-white solid (0.033 g; 45% yield).
(406) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.36 (s, 1H); 7.79 (s, 1H); 7.61 (d, J=8.1 Hz, 1H); 7.47-7.53 (m, 3H); 6.79 (d, J=8.9 Hz, 2H); 4.45-4.57 (m, 1H); 4.38-4.27 (m, 1H); 3.05 (s, 3H); 2.91 (s, 6H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(407) MS1 (ESI, m/z): 431.2 [M+H.sup.+] for C.sub.21H.sub.26N.sub.4O.sub.4S; t.sub.R=0.56 min.
Example 12: (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-[1,2,3]triazol-2-yl-phenyl)-indazol-2-yl]-butanamide
(408) Starting from intermediate H.i (0.11 g, 0.27 mmol) and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (0.077 g; 0.28 mmol; commercial), and proceeding successively in analogy to Example 1, step 1.i (76% yield), Preparation A, step A.vi (78% yield) and Example 1, step 1.ii (82% yield), the title compound was obtained as an off-white solid (0.052 g).
(409) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.47 (s, 1H); 8.11 (s, 2H); 8.01-8.09 (m, 3H); 7.85-7.89 (m, 2H); 7.67-7.71 (m, 1H); 7.58-7.63 (m, 1H); 4.48-4.60 (m, 1H); 4.29-4.40 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(410) MS1 (ESI, m/z): 455.1 [M+H.sup.+] for C.sub.21H.sub.22N.sub.6O.sub.4S; t.sub.R=0.75 min.
Example 13: (R)—N-hydroxy-4-(5-((3-hydroxythietan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
13.i. (R)-4-(5-((3-hydroxythietan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(411) Starting from the compound of Preparation J (0.103 g, 0.246 mmol) and the compound of Preparation S (0.063 g, 0.26 mmol), and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (DCM-MeOH), as a yellow gum (0.123 g; 94% yield).
(412) .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ (mixture of stereoisomers): 11.38-11.44 (m, 1H); 8.52 (s, 1H); 8.10 (s, 1H); 7.61-7.68 (m, 1H); 7.29-7.37 (m, 1H); 6.80 (s, 1H); 4.91-4.98 (m, 1H); 4.5-4.64 (m, 1H); 4.33-4.48 (m, 1H); 3.99-4.16 (m, 1H); 3.44-3.57 (m, 3H); 3.38 (d, J=10.3 Hz, 2H), 3.08 (s, 1.5H); 3.05 (s, 1.5H); 2.78-2.92 (m, 1H); 2.36-2.55 (overlapped m, 1H); 1.63-1.74 (m, 3H); 1.48-1.60 (overlapped m, 3H); 1.54 (s, 1.5H); 1.52 (s, 1.5H).
(413) MS1 (ESI, m/z): 532.00 [M+H.sup.+] for C.sub.25H.sub.29N.sub.3O.sub.6S.sub.2; t.sub.R=0.82 min.
13.ii. (R)—N-hydroxy-4-(5((3-hydroxythietan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(414) A solution of intermediate 13.i (0.123 g; 0.23 mmol) in water (0.42 mL) and TFA (0.68 mL) was stirred at rt for 15 min. The reaction mixture was purified by prep-HPLC (Method 1) to afford the title compound as an off-white solid (0.012 g; 11% yield).
(415) .sup.1H NMR (d6-DMSO) δ: 11.02 (s, 1H); 9.25 (s, 1H); 8.54 (s, 1H); 8.10 (s, 1H); 7.65 (d, J=8.9 Hz, 1H); 7.33 (d, J=9.2 Hz, 1H); 6.80 (s, 1H); 4.50-4.63 (m, 1H); 4.30-4.43 (m, 1H); 3.50 (d, J=9.4 Hz, 2H); 3.38 (d, J=9.4 Hz, 2H); 3.07 (s, 3H); 2.79-2.91 (m, 1H); 2.35-2.55 (overlapped m, 1H); 1.52 (s, 3H).
(416) MS1 (ESI, m/z): 448.0 [M+H.sup.+] for C.sub.20H.sub.21N.sub.3O.sub.5S.sub.2; t.sub.R=0.70 min.
Example 14: (R)-4-(4-fluoro-5-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(417) Starting from 2-(4-ethynylphenyl)propan-2-ol (0.028 g; 0.17 mmol; prepared as described in WO 2006/099972) and the compound of Preparation K (0.086 g; 0.16 mmol), and proceeding successively in analogy to Example 7, step 7.i (64% yield) and Example 1, step 1.ii (35% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as an orange solid (0.016 g).
(418) .sup.1H NMR (d6-DMSO) δ: 11.02 (br. s, 1H); 9.25 (br. s, 1H); 8.74 (s, 1H); 7.45-7.56 (m, 5H); 7.29-7.38 (m, 1H); 5.10 (s, 1H); 4.52-4.65 (m, 1H); 4.33-4.44 (s, 1H); 3.08 (s, 3H); 2.82-2.94 (m, 1H); 2.40-2.60 (overlapped m, 1H); 1.54 (s, 3H); 1.44 (s, 6H).
(419) MS1 (ESI, m/z): 488.0 [M+H.sup.+] for C.sub.24H.sub.26N.sub.3O.sub.5FS; t.sub.R=0.75 min.
Example 15: (R)—N-hydroxy-4-(5-((4-hydroxytetrahydro-2H-pyran-4-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
15.i. 4-(iodoethynyl)tetrahydro-2H-pyran-4-ol
(420) Starting from 4-ethynyltetrahydro-2H-pyran-4-ol (1.17 g; 9.33 mmol; commercial) and proceeding in analogy to Preparation G, the title iodide was obtained, after purification by CC (Hept-EA), as a yellowish solid (1.57 g, 67% yield).
(421) .sup.1H NMR (d6-DMSO) δ: 5.64 (s, 1H); 3.64-3.74 (m, 2H); 3.40-3.51 (m, 2H); 1.68-1.79 (m, 2H); 1.51-1.62 (m, 2H).
15.ii. (R)—N-hydroxy-4-(5((4-hydroxytetrahydro-2H-pyran-4-yl)buta-1, 3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(422) Starting from the compound of Preparation J (0.100 g; 0.24 mmol) and intermediate 15.i (0.078 g; 0.31 mmol), and proceeding successively in analogy to Example 7, step 7.i (74% yield) and Example 1, step 1.ii (62% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as an orange solid (0.048 g).
(423) .sup.1H NMR (d6-DMSO) δ: 11.02 (s, 1H); 9.25 (s, 1H); 8.52 (s, 1H), 8.07 (s, 1H); 7.64 (d, J=9.1 Hz, 1H); 7.30 (d, J=9.1 Hz, 1H); 5.86-5.91 (m, 1H); 4.50-4.63 (m, 1H); 4.29-4.42 (m, 1H); 3.69-3.82 (m, 2H); 3.46-3.57 (m, 2H); 3.07 (s, 3H); 2.78-2.92 (m, 1H); 2.34-2.55 (overlapped m, 1H); 1.79-1.90 (m, 2H); 1.61-1.74 (m, 2H); 1.52 (s, 3H).
(424) MS1 (ESI, m/z): 459.9 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.6S; t.sub.R=0.64 min.
Example 16: (R)—N-hydroxy-4-(5-((4-(1-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(425) Starting from the compound of Preparation T (0.032 g, 0.19 mmol) and the compound of Preparation H (0.097 g; 0.19 mmol), and proceeding successively in analogy to Example 7, step 7.i (69% yield) and Example 1, step 1.ii (44% yield), the title compound was obtained as a beige solid (0.048 g).
(426) .sup.1H NMR (d6-DMSO δ: 11.03 (br. s, 1H); 9.26 (s, 1H); 8.49 (s, 1H); 7.97 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.45 (d, J=8.2 Hz, 2H); 7.29-7.36 (m, 3H); 4.66-4.75 (m, 1H); 4.49-4.62 (m, 1H); 4.29-4.42 (m, 1H); 3.56 (d, J=4.0 Hz, 2H); 3.08 (s, 3H); 2.80-2.92 (m, 1H); 2.34-2.57 (overlapped m, 1H); 1.54 (s, 3H); 0.84-0.93 (m, 2H); 0.73-0.82 (m, 2H)
(427) MS1 (ESI, m/z): 482.0 [M+H.sup.+] for C.sub.25H.sub.27N.sub.3O.sub.5S; t.sub.R=0.74 min.
Example 17: (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-((E)-styryl)-indazol-2-yl]-butanamide
17.i. (RS)-(E)-3-methyl-3-(methylsulfonyl)-5-(5-styryl-2H-indazol-2-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(428) Starting from the compound of Preparation H (0.107 g, 0.205 mmol) and trans-2-phenylvinylboronic acid (0.035 g; commercial), and proceeding in analogy to Example 1, step 1.i, the title compound was obtained, after purification by CC (Hept-EA), as a white foam (0.086 g, 85% yield).
(429) MS1 (ESI, m/z): 498.2 [M+H.sup.+] for C.sub.26H.sub.31N.sub.3O.sub.5S; t.sub.R=0.90 min.
17.ii. (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-((E)-styryl)-indazol-2-yl]-butanamide
(430) Starting from intermediate 17.i (0.086 g, 0.17 mmol), and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by trituration with MeCN and then with diethyl ether, as a white solid (0.018 g; 25% yield).
(431) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.96 (br. s, 1H); 9.28 (br. s, 1H); 8.42 (s, 1H);
(432) 7.78 (s, 1H); 7.66 (d, J=8.9 Hz, 1H); 7.51 (t, J=8.9 Hz, 1H); 7.33-7.38 (m, 1H); 6.91-7.06 (m, 2H); 4.48-4.61 (m, 1H); 4.31-4.45 (m, 3H); 3.35-3.82 (m, 8H); 3.06-3.18 (overlapped m, 2H); 3.05 (s, 3H); 2.78-2.89 (m, 1H); 2.35-2.45 (overlapped m, 1H); 1.50 (s, 3H).
(433) MS1 (ESI, m/z): 414.1 [M+H.sup.+] for C.sub.21H.sub.23N.sub.3O.sub.4S; t.sub.R=0.78 min.
Example 18: (R)-4-{4-fluoro-5-[4-((1S*,2S*)-2-hydroxymethyl-cyclopropyl)-buta-1,3-diynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
18.i. 4-(4-fluoro-5-((trimethylsilyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-methylsulfonyl-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(434) Starting from the compound of Preparation K (0.52 g, 0.96 mmol) and trimethysilyl acetylene (0.16 mL, 1.12 mmol), and proceeding in analogy to Preparation E, step E.ii, the title compound was obtained as an orange solid (0.5 g; 100% yield).
(435) MS1 (ESI, m/z): 510.0 [M+H.sup.+] for C.sub.23H.sub.32N.sub.3O.sub.5FSSi; t.sub.R=0.95 min.
18.ii. (R)-4-(5-ethynyl-4-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
(436) A solution of intermediate 18.i (0.5 g; 0.96 mmol) in MeOH (3.4 mL) was treated with K.sub.2CO.sub.3 (0.240 g, 1.73 mmol). The mixture was stirred at rt for 45 min. The reaction mixture was diluted with DCM (30 mL) and water (20 mL) was added. The two layers were separated. The aq. layer was extracted twice with DCM (2×15 mL) then twice with DCM-MeOH 9-1 (2×15 mL). The combined org. layers were washed with brine (30 mL), dried over MgSO.sub.4, filtered and concentrated to dryness to afford the desired product as a yellowish solid (0.260 g; 62% yield).
(437) .sup.1H NMR (d6-DMSO) δ (mixture of diastereomers): 11.40 (br. s, 1H); 8.70 (s, 1H); 7.47 (d, J=8.8 Hz, 1H); 7.25 (dd, J=6.8, 8.8 Hz, 1H); 4.88-4.97 (m, 1H); 4.52-4.64 (m, 1H); 4.35-4.49 (overlapped m, 1H); 4.38 (s, 1H); 3.96-4.14 (m, 1H); 3.45-3.56 (m, 1H); 3.08 (s, 1.5H); 3.05 (s, 1.5H); 2.79-2.93 (m, 1H); 2.36-2.55 (overlapped m, 1H); 1.62-1.72 (m, 3H); 1.48-1.60 (overlapped m, 3H); 1.53 (s, 1.5H); 1.52 (s, 1.5H).
(438) MS1 (ESI, m/z): 438.0 [M+H.sup.+] for C.sub.20H.sub.24N.sub.3O.sub.5FS; t.sub.R=0.80 min.
18.iii. (R)-4-(5-{4-[(1S*,2S*)-2-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-buta-1, 3-diynyl}-4-fluoro-indazol-2-yl)-2-methylsulfonyl-2-methyl-N—[(RS)-(tetrahydro-pyran-2-yl)oxy]-butanamide
(439) Starting from intermediate 18.ii (0.130 g, 0.30 mmol) and the compound of Preparation P (0.135 g, 0.4 mmol), and proceeding in analogy to Preparation E, step E.ii, the title compound was obtained, after purification by CC (DCM-MeOH gradient) as a brownish gum (0.167 g, 87% yield).
(440) .sup.1H NMR (d6-DMSO) δ (mixture of diastereomers): 11.37-11.44 (m, 1H); 8.69-8.81 (m, 1H); 7.44-7.68 (m, 1H); 7.22-7.42 (m, 1H); 4.86-4.97 (m, 1H); 4.51-4.67 (m, 1H); 4.33-4.50 (m, 1H); 3.97-4.16 (m, 1H); 3.43-3.57 (m, 1H); 3.24-3.31 (overlapped m, 2H); 3.01-3.09 (m, 3H); 2.81-2.93 (m, 1H); 2.35-2.53 (overlapped m, 1H); 1.41-1.73 (m, 12H); 0.94-1.03 (m, 1H); 0.76-0.93 (m, 9H); 0.00-0.10 (m, 6H).
(441) MS1 (ESI, m/z): 646.0 [M+H.sup.+] for C.sub.32H.sub.44N.sub.3O.sub.6FSSi; t.sub.R=1.10 min.
18.iv. (R)-4-{4-fluoro-5-[4-((1S*,2S*)-2-hydroxymethyl-cyclopropyl)-buta-1, 3-diynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(442) A solution of the intermediate 18.iii (0.168 g, 0.26 mmol) in water (0.91 mL) and TFA (0.91 mL) was stirred at rt for 30 min. The reaction mixture was purified by prep-HPLC (Method 1) to afford the title compound as a brown solid (0.022 g, 19% yield).
(443) .sup.1H NMR (d6-DMSO) δ (mixture of diastereomers): 11.01 (s, 1H); 9.24 (br. s, 1H); 8.74 (s, 1H); 7.47 (d, J=8.8 Hz, 1H); 7.22-7.31 (m, 1H); 4.49-4.63 (m, 1H); 4.31-4.44 (m, 1H); 3.20-3.47 (m, 3H); 3.07 (s, 3H); 2.80-2.93 (m, 1H); 2.32-2.58 (overlapped m, 1H); 1.39-1.56 (overlapped m, 2H); 1.52 (s, 3H); 0.84-0.99 (m, 2H).
(444) MS1 (ESI, m/z): 448.0 [M+H.sup.+] for C.sub.21H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.70 min.
Example 19: (R)-4-[5-(4-amino-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
19.i. (R)-4-(5-iodo-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(2-(trimethylsilyl)ethoxy)butanamide
(445) Starting from 4-ethynylaniline (0.039 g, 0.33 mmol; commercial) and the compound of Preparation I (0.153 g, 0.28 mmol), and proceeding in analogy to Example 7, step 7.i, the title alkyne was obtained, after purification by CC (DCM-MeOH), as a brown oil (0.144 g; 97% yield).
(446) .sup.1H NMR (d6-DMSO) δ: 11.3 (s, 1H); 8.46 (s, 1H); 7.86 (s, 1H); 7.60 (d, J=8.9 Hz, 1H); 7.27 (d, J=8.9 Hz, 1H); 7.20 (d, J=8.5 Hz, 2H); 6.57 (d, J=8.5 Hz, 2H); 5.54 (br. s, 2H); 4.49-4.64 (m, 1H); 4.31-4.45 (m, 1H); 3.80-3.86 (m, 2H); 3.07 (s, 3H); 2.81-2.90 (m, 1H); 2.33-2.47 (m, 1H); 1.55 (s, 3H); 0.91-0.99 (m, 2H); 0.03 (s, 9H).
(447) MS1 (ESI, m/z): 527.2 [M+H+] for C.sub.26H.sub.34N.sub.4O.sub.4SSi; t.sub.R=0.95 min.
19.ii. (R)-4-[5-(4-amino-phenylethynyl)-indazol-2-yl]-N-hydroxy-2 methylsulfonyl-2-methyl-butanamide
(448) An ice-chilled solution of intermediate 19.i (0.144 g, 0.28 mmol) in MeCN (5 mL) was treated with BF.sub.3.OEt.sub.2 (0.31 mL) and the mixture stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by prep-HPLC (Method 2) to afford the title compound as a beige solid (0.063 g, 54% yield).
(449) .sup.1H NMR (d6-DMSO) δ: 9.32 (br. s, 1H); 8.41 (s, 1H); 7.82 (s, 1H); 7.24 (dd, J=1.5, 8.9 Hz, 1H); 7.17 (d, J=8.6 Hz, 2H); 6.54 (d, J=8.6 Hz, 2H); 5.48 (br. s, 2H); 4.47-4.59 (m, 1H); 4.26-4.38 (m, 3H); 3.05 (s, 3H); 2.77-2.89 (m, 1H); 2.32-2.44 (m, 1H); 1.50 (s, 3H).
(450) MS1 (ESI, m/z): 427.1 [M+H.sup.+] for C.sub.21H.sub.22N.sub.4O.sub.4S; t.sub.R=0.61 min.
Example 20: (R)—N-hydroxy-4-{5-[4-(3-hydroxy-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-2-methylsulfonyl-2-methyl-butanamide
20.i. 3-(4-iodophenyl)oxetan-3-ol
(451) A solution of 1,4-diiodobenzene (0.800 g, 2.43 mmol) in THF (8 mL) was treated at −78° C. with BuLi (1.68M in Hex; 2.23 mL). After stirring at this temperature for 30 min, the solution was treated with a suspension of 3-oxetanone (0.24 g, 3.34 mmol) in THF (3 mL). The reaction mixture was allowed to reach rt and was further stirred overnight. The reaction mixture was treated with 10% aq. NaHSO.sub.4 solution (4 mL) and diluted water and EA. The aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by CC (Hept-EA) to afford the title alcohol as a colourless solid (0.2 g; 55% yield).
(452) .sup.1H NMR (d6-DMSO) δ: 7.73 (d, J=8.5 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 6.39 (s, 1H); 4.73 (d, J=6.8 Hz, 2H); 4.60 (d, J=6.8 Hz, 2H).
20.ii. 3-(4-ethynylphenyl)oxetan-3-ol
(453) Starting from intermediate 20.i (0.2 g; 0.73 mmol) and proceeding in analogy to Preparation E, step E.ii, the intermediate 3-(4-((trimethylsilyl)ethynyl)phenyl)oxetan-3-ol was obtained, after purification by CC (Hept-EA), as a light brown solid (0.17 g; 94% yield). The latter was dissolved in MeOH (3 mL), treated with K.sub.2CO.sub.3 (0.182 g) and further stirred at rt for 90 min. The reaction mixture was diluted with DCM and washed with water. The aq. layer was extracted with DCM. The combined org. layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford the terminal alkyne as a brown oil (0.13 g; 100% yield).
(454) .sup.1H NMR (d6-DMSO) δ: 7.56-7.61 (m, 2H); 7.45-7.51 (m, 2H); 6.40 (s, 1H); 4.75 (d, J=6.8 Hz, 2H); 4.63 (d, J=6.8 Hz, 2H); 4.13 (s, 1H).
20.iii. (RS)-4-((2R)-5((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide
(455) Starting from intermediate 20.ii (0.239 g, 1.37 mmol) and the compound of Preparation H (0.550 g; 1.05 mmol), and proceeding in analogy to Example 7, step 7.i, the title compound was obtained as a yellowish foam (0.481 g; 80% yield).
(456) MS1 (ESI, m/z): 568.3 [M+H.sup.+] for C.sub.29H.sub.33N.sub.3O.sub.7S; t.sub.R=0.79 min.
20.iv. (R)—N-hydroxy-4-{5-[4-(3-hydroxy-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-2-methylsulfonyl-2-methyl-butanamide
(457) Starting from the intermediate 20.iii (0.477 g; 0.84 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 2), as a brownish foam (0.17 g, 42% yield).
(458) .sup.1H NMR (d6-DMSO) δ: 8.48 (br. s, 1H); 7.97 (br. s, 1H); 7.51-7.66 (m, 6H); 7.32 (dd, J=1.3, 8.8 Hz, 1H); 6.41 (br. s, 1H); 4.77 (d, J=6.6 Hz, 2H); 4.66 (d, J=6.6 Hz, 2H); 4.44-4.62 (m, 1H); 4.29-4.41 (m, 1H); 3.05 (s, 3H); 2.79-2.88 (m, 1H); 2.35-2.45 (m, 1H); 1.50 (s, 3H).
(459) MS1 (ESI, m/z): 484.0 [M+H.sup.+] for C.sub.25H.sub.27N.sub.3O.sub.8S; t.sub.R=0.67 min.
Example 21: (R)—N-hydroxy-4-(5-((4-(hydroxymethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
21.i. (RS)-ethyl 4-(54(4-(hydroxymethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanoate
(460) Starting from (4-ethynylphenyl)methanol (0.031 g; commercial) and intermediate E.i (0.097 g; 0.2 mmol) and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (Hept-EA), as a yellowish solid (0.093 g, 95% yield).
(461) MS1 (ESI, m/z): 455.2 [M+H.sup.+] for C.sub.24H.sub.26N.sub.2O.sub.5S; t.sub.R=0.83 min.
21.ii. (RS)—N-hydroxy-4-(54(4-(hydroxymethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(462) Starting from intermediate 21.i (0.090 g) and proceeding successively in analogy to Preparation A, step A.vi (100% yield) and Example 1, step 1.ii (52% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.044 g).
(463) MS1 (ESI, m/z): 442.1 [M+H.sup.+] for C.sub.22H.sub.23N.sub.3O.sub.5S; t.sub.R=0.67 min.
21.iii. (R)—N-hydroxy-4-(54(4-(hydroxymethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(464) Intermediate 21.ii (0.04 g) was separated by semi-preparative chiral HPLC Method C (Hept-EtOH-TFA 1-3-0.0025; flow rate: 20 mL/min; UV detection at 278 nM); the respective retention times (flow rate: 1 mL/min) were 4.2 and 5.4 min. The title (R)-enantiomer, identified as the second eluting compound, was obtained as a beige solid (0.089 g).
(465) .sup.1H NMR (d6-DMSO) δ: 11.0 (br. s, 1H); 9.23 (br. s, 1H); 8.47 (s, 1H); 7.96 (s, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.49 (d, J=8.4 Hz, 2H); 7.34 (d, J=8.4 Hz, 2H); 7.31 (overlapped m, 1H); 5.24 (t, J=5.8 Hz, 1H); 4.51 (d, J=5.8 Hz, 2H); 4.50-4.60 (overlapped m, 1H); 4.29-4.41 (m, 1H); 3.05 (s, 3H); 2.78-2.89 (m, 1H); 2.33-2.45 (m, 1H); 1.50 (s, 3H).
(466) MS2 (ESI, m/z): 436.1 [M+H.sup.+] for C.sub.20H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.88 min.
Example 22: (R)-4-[5-(3-fluoro-4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
22.i. (RS)-4-[5-(3-fluoro-4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-2-methanesulfonyl-2-methyl-butyric acid ethyl ester
(467) Starting from (4-ethynylphenyl)-2-fluoro-methanol (0.034 g; prepared according to WO 2011/021209) and intermediate E.i (0.097 g) and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (Hept-EA), as a brown gum (0.089 g, 87% yield).
(468) MS1 (ESI, m/z): 473.2 [M+H.sup.+] for C.sub.24H.sub.25N.sub.2O.sub.5FS; t.sub.R=0.85 min.
22.ii. (R)-4-[5-(3-fluoro-4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(469) Starting from intermediate 22.i (0.085 mg) and proceeding successively in analogy to Example 21, steps 21.ii and 21.iii (saponification and amide coupling: 89% yield; deprotection: 66% yield), the title compound was obtained as a mixture of enantiomers. The racemate was separated by semi-preparative chiral HPLC Method C (Hept-EtOH-TFA 1-9-0.01; flow rate: 20 mL/min; UV detection at 277 nM); the respective retention times (flow rate: 1 mL/min) were 4.0 and 5.6 min. The title (R)-enantiomer, identified as the second eluting compound, was collected as a white solid (0.01 g; chiral separation: 44% yield).
(470) .sup.1H NMR (d6-DMSO) δ: 11.0 (br. s, 1H); 9.23 (br. s, 1H); 8.49 (s, 1H); 7.98 (s, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.49 (t, J=7.8 Hz, 1H); 7.29-7.39 (m, 3H); 5.32 (t, J=5.8 Hz, 1H); 4.55 (d, J=5.8 Hz, 2H); 4.50-4.60 (overlapped m, 1H); 4.29-4.41 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.33-2.45 (m, 1H); 1.50 (s, 3H).
(471) MS1 (ESI, m/z): 460.2 [M+H.sup.+] for C.sub.22H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.70 min.
Example 23: (R)-4-[4-fluoro-5-(4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide trifluoro-acetic acid salt
23.i. (RS)-4-(4-fluoro-5-((4-(hydroxymethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(472) Starting from (4-ethynylphenyl)methanol (0.021 g; commercial) and the compound of Preparation C (0.080 g) and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (Hept-EA), as a brownish solid (0.098 g, 100% yield).
(473) MS1 (ESI, m/z): 544.3 [M+H.sup.+] for C.sub.27H.sub.30N.sub.3O.sub.6FS; t.sub.R=0.81 min.
23.ii. (R)-4-[4-fluoro-5-(4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide trifluoro-acetic acid salt
(474) Starting from the intermediate 23.i (0.091 g) and proceeding in analogy to Example 1, step 1.ii, the crude product obtained was triturated with ether to provide a racemate. The racemate was separated by semi-preparative chiral HPLC Method E (Hept-EtOH-TFA 1-1-0.01; flow rate: 23 mL/min; UV detection at 220 nM); the respective retention times (flow rate: 1.4 mL/min) were 8.7 and 11.6 min. The title (R)-enantiomer, identified as the second eluting compound, was collected as a beige solid (0.012 g; 38% yield).
(475) .sup.1H NMR (d6-DMSO) δ: 10.9 (br. s, 1H); 9.23 (br. s, 1H); 8.72 (s, 1H); 7.45-7.53 (m, 3H); 7.28-7.39 (m, 3H); 4.47-4.53 (m, 3H); 4.44-4.22 (m, 1H); 3.92 (br. s, 2H); 3.05 (s, 3H); 2.78-2.92 (m, 1H); 2.35-2.45 (m, 1H); 1.50 (s, 3H).
(476) MS1 (ESI, m/z): 460.1 [M+H.sup.+] for C.sub.22H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.53 min.
Example 24: (R)-4-(5-(5-amino-5-methylhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(477) Starting from intermediate A.vi (0.090 g; 0.19 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (0.055 g; 0.21 mmol; commercial), and proceeding successively in analogy to Example 1, steps 1.i and 1.ii (Suzuki coupling: 32% yield; deprotection: 27% yield), the title compound was obtained as an off-white solid (0.009 g).
(478) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.24 (s, 1H); 8.49 (s, 1H); 8.00-8.11 (m, 3H); 7.81-7.88 (m, 2H); 7.60-7.73 (m, 2H); 7.38 (s, 1H); 4.48-4.60 (m, 1H); 4.30-4.44 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.35-2.44 (overlapped m, 1H); 1.50 (s, 3H).
(479) MS1 (ESI, m/z): 455.2 [M+H.sup.+] for C.sub.22H.sub.22N.sub.4O.sub.5S; t.sub.R=0.73 min.
Example 25: (R)—N-hydroxy-4-{5-[4-(2-hydroxy-ethyl)-phenylethynyl]-indazol-2-yl}-2-methylsulfonyl-2-methyl-butanamide
(480) Starting from the compound of Preparation J (0.081 g; 0.155 mmol) and 2-(4-iodophenyl)ethanol (0.025 g; 0.174 mmol; commercial), and proceeding successively in analogy to Example 7, step 7.i (68% yield) and Example 1, step 1.ii (84% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.037 g).
(481) .sup.1H NMR (d6-DMSO) δ: 8.47 (s, 1H); 7.95 (s, 1H); 7.62 (d, J=8.8 Hz, 1H); 7.44 (d, J=8.2 Hz, 2H); 7.31 (d, J=8.8 Hz, 1H); 7.26 (d, J=8.2 Hz, 2H); 4.63 (t, J=5.2 Hz, 1H); 4.48-4.58 (m, 1H); 4.27-4.41 (m, 1H); 3.60 (q, J=6.7 Hz, 2H); 3.06 (s, 3H); 2.75-2.90 (m, 1H); 2.74 (t, J=7.0 Hz, 2H); 2.33-2.43 (m, 1H); 1.52 (s, 3H).
(482) MS1 (ESI, m/z): 456.1 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.5S; t.sub.R=0.59 min.
Example 26: (2R)-4-{5-[4-((R)-1,2-dihydroxy-ethyl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(483) Starting from the compound of Preparation J (0.082 g; 0.195 mmol) and (R)-1-(4-iodophenyl)-1,2-ethanediol (0.058 g, 0.22 mmol), and proceeding successively in analogy to Example 7, step 7.i (50% yield) and Example 1, step 1.ii (37% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.017 g).
(484) .sup.1H NMR (d6-DMSO) δ: 8.47 (s, 1H); 7.96 (s, 1H); 7.63 (d, J=8.8 Hz, 1H); 7.48 (d, J=8.2 Hz, 2H); 7.37 (d, J=8.2 Hz, 2H); 7.32 (d, J=8.8 Hz, 1H); 5.29 (br. s, 1H); 4.71 (br. s, 1H); 4.48-4.61 (m, 2H); 4.28-4.42 (m, 1H); 3.39-3.47 (m, 2H); 3.06 (s, 3H); 2.78-2.90 (m, 1H); 2.32-2.51 (overlapped m, 1H); 1.52 (s, 3H).
(485) MS1 (ESI, m/z): 472.15 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.6S; t.sub.R=0.61 min.
Example 27: (R)—N-hydroxy-4-(5-((4-(2-hydroxypropan-2-yl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(486) Starting from the compound of Preparation H (0.1 g, 0.19 mmol) and 2-(4-ethynylphenyl)propan-2-ol (0.034 g, 0.21 mmol; prepared as described in WO 2006/099972), and proceeding successively in analogy to Example 7, step 7.i (79% yield) and Example 1, step 1.ii (32% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.022 g).
(487) .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H); 9.26 (s, 1H); 8.49 (s, 1H); 7.98 (s, 1H); 7.65 (d, J=9.1 Hz, 1H); 7.44-7.55 (m, 4H); 7.33 (dd, J=9.1, 1.0 Hz, 1H); 5.08 (br. s, 1H); 4.49-4.63 (m, 1H); 4.28-4.42 (m, 1H); 3.08 (s, 3H); 2.79-2.93 (m, 1H); 2.33-2.54 (overlapped m, 1H); 1.54 (s, 3H); 1.44 (s, 6H).
(488) MS1 (ESI, m/z): 470.2 [M+H.sup.+] for C.sub.24H.sub.27N.sub.3O.sub.5S; t.sub.R=0.72 min.
Example 28: (R)—N-hydroxy-4-(5-((3-hydroxyoxetan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(489) Starting from the compound of Preparation J (0.148 g, 0.35 mmol) and the compound of Preparation G (0.090 g, 0.40 mmol), and proceeding successively in analogy to Example 7, step 7.i (54% yield) and Example 1, step 1.ii (60% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.049 g).
(490) .sup.1H NMR (d6-DMSO) δ: 9.27 (br. s, 1H); 8.51 (s, 1H); 8.07 (s, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.4, 8.9 Hz, 1H); 6.71 (br. s, 1H); 4.70 (d, J=6.7 Hz, 2H); 4.54 (d, J=6.7 Hz, 2H); 4.54 (overlaid m, 1H); 4.34 (m, 1H); 3.04 (s, 3H); 2.82 (m, 1H); 2.39 (overlaid m, 1H); 1.54 (s, 3H).
(491) MS1 (ESI, m/z): 431.7 [M+H+] for C.sub.20H.sub.21N.sub.3O.sub.6S; t.sub.R=0.63 min.
Example 29: (R)-4-{4-fluoro-5-[4-(3-hydroxy-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(492) Starting from intermediate 20.ii (0.04 g, 0.2 mmol) and the compound of Preparation K (0.1 g; 0.185 mmol), and proceeding successively in analogy to Example 7, step 7.i (57% yield) and Example 1, step 1.ii (64% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellowish foam (0.032 g).
(493) .sup.1H NMR (d6-DMSO) δ: 11.0 (br. s, 1H); 9.22 (br. s, 1H); 8.73 (s, 1H); 7.46-7.70 (m, 5H); 7.33 (m, 1H); 6.43 (br. s, 1H); 4.73-4.79 (m, 2H); 4.61-4.68 (m, 2H); 4.55 (m, 1H); 4.37 (m, 1H); 3.05 (s, 3H); 2.79-2.88 (m, 1H); 2.35-2.45 (m, 1H); 1.50 (s, 3H).
(494) MS1 (ESI, m/z): 502.1 [M+H.sup.+] for C.sub.24H.sub.24N.sub.3O.sub.6FS; t.sub.R=0.69 min.
Example 30: (R)-4-{5-[4-(3-dimethylamino-oxetan-3-yl)-phenylethynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide toluene-4-sulfonic acid salt
(495) Starting from the compound of Preparation J (0.1 g, 0.248 mmol) and the compound of Preparation M (0.085 g, 0.28 mmol), and proceeding successively in analogy to Example 7, step 7.i (44% yield) and Example 1, step 1.ii (39% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.030 g).
(496) MS1 (ESI, m/z): 511.1 [M+H.sup.+] for C.sub.33H.sub.38N.sub.4O.sub.8S.sub.2; t.sub.R=0.45 min.
Example 31: (R)-4-{6-fluoro-5-[4-(3-hydroxy-oxetan-3-yl)-buta-1,3-diynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(497) Starting from the compound of Preparation R (0.1 g, 0.23 mmol) and the compound of Preparation G (0.056 g, 0.25 mmol), and proceeding successively in analogy to Preparation E, step E.ii (47% yield) and Example 1, step 1.iii (27% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as an orange foam (0.012 g).
(498) .sup.1H NMR (d6-DMSO) δ: 9.15-9.33 (m, 1H); 8.59 (s, 1H); 8.21 (d, J=7.0 Hz, 1H); 7.51 (d, J=10.9 Hz, 1H); 6.77 (s, 1H); 4.73 (d, J=6.6 Hz, 2H); 4.56 (d, J=6.6 Hz, 2H); 4.49-4.62 (overlapped m, 1H); 4.28-4.41 (m, 1H); 3.06 (s, 3H); 2.77-2.92 (m, 1H); 2.32-2.57 (overlapped m, 1H); 1.52 (s, 3H).
(499) MS1 (ESI, m/z): 449.9 [M+H.sup.+] for C.sub.20H.sub.20N.sub.3O.sub.6FS; t.sub.R=0.64 min.
Example 32: (R)—N-hydroxy-4-[5-(5-hydroxy-5-methyl-hexa-1,3-diynyl)-indazol-2-yl]-2-methylsulfonyl-2-methyl-butanamide
(500) Starting from the compound of Preparation J (0.1 g; 0.248 mmol) and 4-iodo-2-methylbut-3-yn-2-ol (0.060 g; 0.28 mmol; prepared as reported in Rajender Reddy et al., Tetrahedron Lett. (2010), 51, 2170-2173), and proceeding successively in analogy to Example 7, step 7.i (93% yield) and Example 1, step 1.ii (66% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.063 g).
(501) .sup.1H NMR (d6-DMSO): 8.49 (s, 1H); 8.01 (s, 1H); 7.61 (d, J=8.9 Hz, 1H); 7.27 (d, J=8.9 Hz, 1H); 4.46-4.61 (m, 1H); 4.28-4.40 (m, 1H); 2.76-2.90 (m, 3H); 2.31-2.50 (m, overlaid with DMSO, 1H); 1.49 (s, 3H); 1.40 (s, 6H).
(502) MS1 (ESI, m/z): 418.1 [M+H.sup.+] for C.sub.20H.sub.23N.sub.3O.sub.5S; t.sub.R=0.68 min.
Example 33: (R)—N-hydroxy-4-(5-((4-((R)-1-hydroxyethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(503) Starting from the compound of Preparation J (0.1 g, 0.24 mmol) and (R)-1-(4-iodophenyl)ethan-1-ol (0.082 g; 0.33 mmol; commercial), and proceeding successively in analogy to Example 7, step 7.i (73% yield) and Example 1, step 1.ii (71% yield), the title compound was obtained as a beige solid (0.055 g) recovered by filtration from water.
(504) .sup.1H NMR (d6-DMSO) δ: 11.01 (s, 1H); 9.24 (s, 1H); 8.47 (s, 1H); 7.96 (s, 1H); 7.62 (d J=8.9 Hz, 1H); 7.44-7.51 (m, 2H); 7.34-7.40 (m, 2H); 7.31 (dd, J=1.3, 8.9 Hz, 1H); 5.14-5.25 (m, 1H); 4.72 (q, J=6.4 Hz, 1H); 4.48-4.60 (m, 1H); 4.27-4.40 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.32-2.52 (overlapped m, 1H); 1.52 (s, 3H); 1.31 (d, J=6.4 Hz, 3H).
(505) MS1 (ESI, m/z): 456.1 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.5S; t.sub.R=0.70 min.
Example 34: (R)—N-hydroxy-4-(5-4-((4(S)-1-hydroxyethyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(506) Starting from the compound of Preparation J (0.1 g, 0.24 mmol) and (S)-1-(4-iodophenyl)ethan-1-ol (0.082 g; 0.33 mmol; commercial), and proceeding successively in analogy to Example 7, step 7.i (54% yield) and Example 1, step 1.ii (79% yield), the title compound was obtained as a beige solid (0.043 g) recovered by filtration from water.
(507) .sup.1H NMR (d6-DMSO) δ: 11.01 (s, 1H); 9.24 (s, 1H); 8.47 (s, 1H); 7.96 (s, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.44-7.51 (m, 2H); 7.34-7.40 (m, 2H); 7.31 (dd, J=1.3, 8.9 Hz, 1H); 5.14-5.25 (m, 1H); 4.72 (q, J=6.4 Hz, 1H); 4.48-4.60 (m, 1H); 4.27-4.40 (m, 1H); 3.05 (s, 3H); 2.78-2.90 (m, 1H); 2.32-2.52 (overlapped m, 1H); 1.52 (s, 3H); 1.31 (d, J=6.4 Hz, 3H).
(508) MS1 (ESI, m/z): 456.1 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.5S; t.sub.R=0.70 min.
Example 35: (R)-4-[5-(2-fluoro-4-trifluoromethoxy-phenyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(509) Starting from the compound of Preparation H (0.10 g; 0.19 mmol) and 2-fluoro-4-trifluoromethoxyphenylboronic acid (0.052 g; 0.23 mmol; commercial), and proceeding successively in analogy to Example 1, step 1.i (83% yield) and step 1.ii (75% yield), the title compound was obtained as an off-white solid (0.056 g) recovered by filtration from water.
(510) .sup.1H NMR (d6-DMSO) δ: 11.04 (br. s, 1H); 9.27 (br. s, 1H); 8.52 (s, 1H); 7.90 (s, 1H); 7.66-7.74 (m, 2H); 7.46-7.53 (m, 1H); 7.38-7.45 (m, 1H); 7.30-7.37 (m, 1H); 4.51-4.64 (m, 1H); 4.32-4.45 (m, 1H); 3.08 (s, 3H); 2.80-2.94 (m, 1H); 2.36-2.56 (overlapped m, 1H); 1.53 (s, 3H).
(511) MS1 (ESI, m/z): 490.1 [M+H.sup.+] for C.sub.20H.sub.19N.sub.3O.sub.5F.sub.4S; t.sub.R=0.82 min.
Example 36: (R)—N-hydroxy-4-(5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide formate
36.i. ((1S,2S)-24(2-((R)-3-methyl-3-(methylsulfonyl)-4-oxo-4-((((RS)-tetrahydro-2H-pyran-2-yl)oxy)amino)butyl)-2H-indazol-5-yl)buta-1,3-diyn-1-yl)cyclopropyl)methyl acetate
(512) Starting from the compound of Preparation J (0.254 g; 0.605 mmol) and the dextrorotatory compound of Preparation U (0.177 g; 0.81 mmol), and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (Hept-EA), as a yellowish oil (0.077 g, 23% yield).
(513) MS1 (ESI, m/z): 555.97 [M+H.sup.+] for C.sub.28H.sub.33N.sub.3O.sub.7S; t.sub.R=0.90 min.
36.ii. (R)-4-(5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(514) To a solution of intermediate 36.i (0.124 g; 0.223 mmol) in MeOH (1 mL) was added K.sub.2CO.sub.3 (0.062 g; 0.447 mmol). The suspension was stirred at rt for 30 min. The reaction mixture was diluted with DCM (10 mL) and washed with an aq. 15% NaHSO.sub.4 solution (8 mL). The aq. layer was extracted with DCM/MeOH (9/1, 4×10 mL). The combined org. layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure to afford the desired product as a yellow oil (0.108 g).
(515) MS1 (ESI, m/z): 513.91 [M+H.sup.+] for C.sub.26H.sub.31N.sub.3O.sub.6S; t.sub.R=0.80 min.
36.iii. (R)—N-hydroxy-4-(5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide formate
(516) Starting from intermediate 36.ii (0.108 g; 0.24 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.052 g, 57% yield).
(517) .sup.1H NMR (d6-DMSO) δ: 11.98 (s, 1H); 9.22 (br. s, 1H); 8.46 (br. s, 1H); 8.11 (br. s, 1H); 7.97 (br. s, 1H); 7.23 (d, J=8.8 Hz, 1H); 7.58 (d, J=8.8 Hz, 1H); 4.65 (m, 1H); 4.52 (m, 1H); 4.32 (m, 1H); 3.40 (m, 1H); 3.25 (overlapped m, 1H); 3.04 (s, 3H); 2.81 (m, 1H); 2.38 (overlapped m, 1H); 1.49 (s, 3H); 1.34-1.45 (m, 2H); 0.79-0.97 (m, 2H).
(518) MS1 (ESI, m/z): 429.94 [M+H.sup.+] for C.sub.21H.sub.23N.sub.3O.sub.5S; t.sub.R=0.68 min.
Example 37: (R)—N-hydroxy-4-(5-((((R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide formate
(519) Starting from the compound of Preparation J (0.252 g; 0.602 mmol) and the levorotatory compound of Preparation U (0.177 g; 0.81 mmol); and proceeding in analogy to Example 36, steps 36.i to 36.iii (Sonogashira coupling: 10% yield; acetate cleavage and deprotection: 63% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.056 g).
(520) .sup.1H NMR (d6-DMSO) δ: 11.98 (s, 1H); 9.22 (br. s, 1H); 8.46 (br. s, 1H); 8.11 (br. s, 1H); 7.97 (br. s, 1H); 7.23 (d, J=8.8 Hz, 1H); 7.58 (d, J=8.8 Hz, 1H); 4.65 (m, 1H); 4.52 (m, 1H); 4.32 (m, 1H); 3.23-3.40 (m, 2H); 3.04 (s, 3H); 2.81 (m, 1H); 2.38 (overlapped m, 1H); 1.49 (s, 3H); 1.34-1.45 (m, 2H); 0.79-0.97 (m, 2H).
(521) MS1 (ESI, m/z): 429.95 [M+H.sup.+] for C.sub.21H.sub.23N.sub.3O.sub.5S; t.sub.R=0.68 min.
Example 38: (R)-4-{4-fluoro-5-[4-(3-hydroxy-oxetan-3-yl)-buta-1,3-diynyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(522) Starting from intermediate 36.i (0.130 g; 0.30 mmol) and the compound of Preparation G (0.073 g; 0.32 mmol), and proceeding successively in analogy to Preparation E, step E.ii (50% yield) and Example 1, step 1.ii (45% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.030 g).
(523) .sup.1H NMR (d6-DMSO) δ: 11.01 (s, 1H); 9.24 (br. s, 1H); 8.79 (s, 1H); 7.47-7.54 (m, 1H); 7.28-7.37 (m, 1H); 6.77 (br. s, 1H); 4.73 (d, J=6.3 Hz, 2H); 4.56 (d, J=6.3 Hz, 2H); 4.52-4.61 (overlapped m, 1H); 4.32-4.46 (m, 1H); 3.07 (s, 3H); 2.80-2.94 (m, 1H); 2.33-2.57 (overlapped m, 1H); 1.53 (s, 3H).
(524) MS (ESI, m/z): 449.86 [M+H.sup.+] for C.sub.20H.sub.20N.sub.3O.sub.6FS; t.sub.R=0.65 min.
Example 39: (R)-4-[5-(2-fluoro-4-hydroxymethyl-phenylethynyl)-indazol-2-yl]-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide
(525) Starting from the compound of Preparation H (0.1 g; 0.19 mmol) and the compound of Preparation Q (0.037 g; 0.21 mmol; prepared as described in WO 2006/099972), and proceeding successively in analogy to Example 7, step 7.i (79% yield) and Example 1, step 1.ii (32% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige solid (0.022 g).
(526) 1H NMR (d6-DMSO) δ: 11.03 (br. s, 1H); 9.26 (s, 1H); 8.51 (s, 1H); 8.01 (s, 1H); 7.66 (d, J=8.8 Hz, 1H); 7.58 (t, J=7.8 Hz, 1H); 7.31-7.36 (m, 1H); 7.17-7.27 (m, 2H); 5.36-5.43 (m, 1H); 4.49-4.63 (m, 3H); 4.30-4.42 (m, 1H); 3.08 (s, 3H), 2.79-2.92 (m, 1H); 2.34-2.56 (overlapped m, 1H); 1.54 (s, 3H).
(527) MS1 (ESI, m/z): 460.0 [M+H.sup.+] for C.sub.22H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.69 min.
Example 40: 4-(6-fluoro-5-((4-(3-hydroxyoxetan-3-yl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(528) Starting from the compound of Preparation R (0.1 g, 0.18 mmol) and intermediate 20.ii (0.042 g, 0.24 mmol), and proceeding successively in analogy to Preparation E, step E.ii (67% yield) and Example 1, step 1.iii (76% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellowish foam (0.046 g).
(529) .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H); 9.25 (s, 1H); 8.56 (s, 1H); 8.12 (d, J=7.2 Hz, 1H); 7.67 (d, J=7.6 Hz, 2H); 7.60 (d, J=7.6 Hz, 2H); 7.50 (d, J=10.9 Hz, 1H); 6.46 (s, 1H); 4.79 (d, J=6.0 Hz, 2H); 4.68 (d, J=6.0 Hz, 2H); 4.49-4.62 (m, 1H); 4.28-4.41 (m, 1H); 3.07 (s, 3H); 2.79-2.92 (m, 1H); 2.34-2.55 (overlapped m, 1H); 1.54 (s, 3H).
(530) MS1 (ESI, m/z): 501.9 [M+H.sup.+] for C.sub.24H.sub.24N.sub.3O.sub.6FS; t.sub.R=0.68 min.
Example 41: (R)—N-hydroxy-4-(5-((4-((1R,2R)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(531) Starting from the compound of Preparation J (0.106 g; 0.253 mmol) and the first-eluting enantiomer of Preparation W (0.079 g; 0.288 mmol), and proceeding successively in analogy to Example 7, step 7.i (90% yield) and Example 1, step 1.ii (38% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.041 g).
(532) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H); 9.23 (s, 1H); 8.46 (s, 1H); 7.93 (s, 1H); 7.61 (d, J=8.8 Hz, 1H); 7.39 (d, J=7.0 Hz, 2H); 7.30 (d, J=9.1 Hz, 1H); 7.09 (d, J=7.9 Hz, 2H); 4.46-4.63 (overlapped m, 2H); 4.26-4.40 (m, 1H); 3.40-3.53 (m, 1H); 3.26-3.38 (overlapped m, 1H); 3.05 (s, 3H); 2.75-2.88 (m, 1H); 2.30-2.51 (overlapped m, 1H); 1.75-1.86 (m, 1H); 1.51 (s, 3H); 1.22-1.35 (m, 1H); 0.80-0.95 (m, 2H).
(533) MS1 (ESI, m/z): 481.95 [M+H.sup.+] for C.sub.25H.sub.27N.sub.3O.sub.5S; t.sub.R=0.62 min.
Example 42: (R)—N-hydroxy-4-(5-((4-((1S,2S)-2-(hydroxymethyl)cyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(534) Starting from the compound of Preparation J (0.106 g; 0.253 mmol) and the second-eluting enantiomer of Preparation W (0.079 g; 0.288 mmol), and proceeding successively in analogy to Example 7, step 7.i (71% yield) and Example 1, step 1.ii (46% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.041 g).
(535) .sup.1H NMR (d6-DMSO) δ: 11.0 (s, 1H), 9.23 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.39 (d, J=7.0 Hz, 2H), 7.30 (d, J=9.1 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 4.46-4.63 (overlapped m, 2H), 4.26-4.40 (m, 1H), 3.40-3.53 (m, 1H), 3.26-3.38 (overlapped m, 1H), 3.05 (s, 3H), 2.75-2.88 (m, 1H), 2.30-2.51 (overlapped m, 1H), 1.75-1.86 (m, 1H), 1.51 (s, 3H), 1.22-1.35 (m, 1H), 0.80-0.95 (m, 2H).
(536) MS1 (ESI, m/z): 481.95 [M+H.sup.+] for C.sub.25H.sub.27N.sub.3O.sub.5S; t.sub.R=0.62 min.
Example 43: (R)—N-hydroxy-4-(5-((4-(3-(hydroxymethyl)oxetan-3-yl)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(537) Starting from the compound of Preparation J (0.100 g; 0.24 mmol) and the compound of Preparation X (0.079 g; 0.27 mmol), and proceeding successively in analogy to Example 7, step 7.i (72% yield) and Example 1, step 1.ii (53% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellowish solid (0.041 g).
(538) .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H); 9.26 (s, 1H); 8.50 (s, 1H); 7.99 (s, 1H); 7.63 (s, 1H); 7.53 (d, J=8.1 Hz, 2H); 7.35 (s, 1H); 7.20 (d, J=8.1 Hz, 2H); 5.08-5.20 (m, 1H); 4.72 (br. s, 4H); 4.47-4.65 (s, 1H); 4.29-4.42 (m, 1H); 3.68-3.76 (m, 2H); 3.07 (s, 3H); 2.79-2.93 (m, 1H); 2.36-2.55 (overlapped m, 1H); 1.54 (s, 3H).
(539) MS1 (ESI, m/z): 497.8 [M+H.sup.+] for C.sub.25H.sub.27N.sub.3O.sub.6S; t.sub.R=0.66 min.
Example 44: (R)—N-hydroxy-4-(5-((4-(2-hydroxyethoxy)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(540) Starting from the compound of Preparation J (0.100 g; 0.24 mmol) and 2-(4-iodophenoxy)ethanol (0.06 g; 0.28 mmol; commercial) and proceeding successively in analogy to Example 7, step 7.i (39% yield) and Example 1, step 1.ii (67% yield), the title compound was obtained, after precipitation from the reaction mixture and washing with water, as a beige solid (0.041 g).
(541) .sup.1H NMR (d6-DMSO) δ: 11.03 (s, 1H); 9.24 (s, 1H); 8.45 (s, 1H); 7.92 (s, 1H); 7.62 (d, J=8.0 Hz, 1H); 7.45 (d, J=8.2 Hz, 2H); 7.30 (dd, J=0.9, 8.0 Hz, 1H); 6.96 (d, J=8.1 Hz, 2H); 4.84 (m, 1H); 4.54 (m, 1H); 4.34 (m, 1H); 3.96-4.04 (m, 2H); 3.66-3.74 (m, 2H); 3.05 (s, 3H); 2.83 (m, 1H); 2.39 (overlapped m, 1H); 1.51 (s, 3H).
(542) MS1 (ESI, m/z): 471.9 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.6S; t.sub.R=0.66 min.
Example 45: (R)-4-(5-((3-fluoro-4-(2-hydroxyacetamido)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(543) Starting from the compound of Preparation J (0.100 g; 0.24 mmol) and the compound of Preparation Y (0.084 g; 0.29 mmol), and proceeding successively in analogy to Example 7, step 7.i (42% yield) and Example 1, step 1.ii (64% yield), the title compound was obtained, after filtration from water and trituration in Et.sub.2O, as an orange solid (0.029 g).
(544) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.06 (s, 1H); 9.44 (s, 1H); 9.29 (s, 1H); 8.52 (s, 1H); 8.08 (t, J=8.3 Hz, 1H); 8.01 (s, 1H); 7.66 (d, J=8.9 Hz, 1H); 7.52 (d, J=11.5 Hz, 1H); 7.40 (d, J=8.5 Hz, 1H); 7.35 (d, J=8.9 Hz, 1H); 5.91 (t, J=5.9 Hz, 1H); 4.54-4.61 (m, 1H); 4.32-4.40 (m, 1H); 4.07 (d, J=5.6 Hz, 2H); 3.08 (s, 3H); 2.83-2.90 (m, 1H); 2.35-2.46 (m, 1H); 1.54 (s, 3H).
(545) MS1 (ESI, m/z): 502.9 [M+H.sup.+] for C.sub.23H.sub.23N.sub.4O.sub.6PS; t.sub.R=0.67 min.
Example 46: (R)-4-(5-((R)-5,6-dihydroxy-5-methylhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
46.i. (2R)-4-(5-((R)-6-((tert-butyldiphenylsilyl)oxy)-5-hydroxy-5-methylhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(546) Starting from the compound of Preparation J (0.100 g; 0.24 mmol) and the compound of Preparation Z (0.133 g; 0.29 mmol), and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (DCM-MeOH), as an orange foam (0.103 g, 57% yield).
(547) .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ (mixture of stereoisomers): 11.43 (s, 0.5H); 11.40 (s, 0.5H); 8.50 (br. s, 1H); 8.06 (br. s, 1H); 7.40-7.72 (m, 11H); 7.26-7.32 (m, 1H); 5.77 (s, 1H); 5.75 (s, 1H); 4.89-4.98 (m, 1H); 4.50-4.64 (m, 1H); 4.33-4.47 (m, 1H); 3.62-3.68 (m, 1H); 3.47-3.57 (m, 2H); 3.08 (s, 1.5H); 3.05 (s, 1.5H); 2.78-2.93 (m, 1H); 2.32-2.53 (overlapped m, 1H); 1.63-1.75 (m, 3H); 1.51 (s, 3H); 1.41-1.60 (overlapped m, 6H); 1.04 (s, 9H).
(548) MS1 (ESI, m/z): 755.9 [M+H.sup.+] for C.sub.41H.sub.49N.sub.3O.sub.7SSi; t.sub.R=1.06 min.
46.ii. (2R)-4-(5-((R)-5,6-dihydroxy-5-methylhexa-1, 3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(549) To a stirred solution of intermediate 46.i (0.1 g; 0.13 mmol) in MeOH (2 mL) was added ammonium fluoride (0.04 g: 1.06 mmol) at reflux for 6.5 h. The resulting mixture was concentrated to the dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellowish foam (0.064 g; 93% yield).
(550) .sup.1H NMR (300 MHz, d.sub.6-dmso) δ: 11.34-11.42 (m, 1H); 8.46 (s, 1H); 8.01 (s, 1H); 7.60 (d, J=8.9 Hz, 1H); 7.22-7.29 (m, 1H); 5.72 (s, 1H); 5.52 (s, 1H); 5.00-5.07 (m, 1H); 4.87-4.95 (m, 1H); 4.47-4.60 (m, 1H); 4.30-4.44 (m, 1H); 3.95-4.13 (m, 1H); 3.22-3.54 (overlapped m, 2H); 3.04 (s, 1.5H); 3.02 (s, 1.5H); 2.74-2.88 (m, 1H); 2.32-2.52 (overlapped m, 1H); 1.61-1.71 (m, 3H); 1.44-1.57 (m, 6H); 1.32 (s, 3H).
(551) MS (ESI, m/z): 518.2 [M+H.sup.+] for C.sub.25H.sub.31N.sub.3O.sub.7S; t.sub.R=0.71 min.
46.iii. (R)-4-(5-((R)-5, 6-dihydroxy-5-methylhexa-1, 3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(552) Starting from intermediate 46.ii (0.06 g; 0.116 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 1), as an orange solid (0.025 g; 49% yield).
(553) .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 8.53 (s, 1H); 8.05 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.29 (d, J=9.3 Hz, 1H); 5.50-5.76 (m, 1H); 4.99-5.27 (m, 1H); 4.50-4.62 (m, 1H); 4.29-4.41 (m, 1H); 3.28-3.44 (overlapped m, 2H); 3.07 (s, 3H); 2.78-2.89 (m, 1H); 2.32-2.43 (m, 1H); 1.51 (s, 3H); 1.36 (s, 3H).
(554) MS1 (ESI, m/z): 434.2 [M+H.sup.+] for C.sub.20H.sub.23N.sub.3O.sub.6S; t.sub.R=0.59 min.
Example 47: (R)—N-hydroxy-4-(5-((4-(2-hydroxyacetamido)phenyl)ethynyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(555) Starting from the compound of Preparation J (0.100 g; 0.24 mmol) and 2-hydroxy-N-(4-iodophenyl)acetamide (0.069 g; 0.25 mmol; commercial) and proceeding successively in analogy to Example 7, step 7.i (51% yield) and Example 1, step 1.ii (73% yield), the title compound was obtained, after filtration from water, as a beige solid (0.0411 g).
(556) .sup.1H NMR (500 MHz, d6-DMSO) δ: 11.06 (s, 1H); 9.88 (s, 1H); 9.29 (s, 1H); 8.50 (s, 1H); 7.97 (s, 1H); 7.79 (d, J=8.3 Hz, 2H); 7.65 (d, J=8.9 Hz, 1H); 7.50 (d, J=8.3 Hz, 2H); 7.33 (d, J=8.9 Hz, 1H); 5.62-5.76 (m, 1H); 4.52-4.61 (m, 1H); 4.31-4.40 (m, 1H); 4.02 (d, J=4.1 Hz, 2H); 3.08 (s, 3H); 2.82-2.90 (m, 1H); 2.35-2.45 (m, 1H); 1.54 (s, 3H).
(557) MS1 (ESI, m/z): 484.9 [M+H.sup.+] for C.sub.23H.sub.24N.sub.4O.sub.6S; t.sub.R=0.64 min.
Example 48: (R)-4-(5-((3-aminooxetan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide formate
(558) Starting from the compound of Preparation J (0.124 g; 0.296 mmol) and the compound of Preparation AA (0.177 g; 0.57 mmol) and proceeding successively in analogy to Example 7, step 7.i (quant.) and Example 13, step 13.ii (4% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a yellow solid (0.005 g).
(559) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.00 (br. s, 1H); 9.32 (br. s, 1H); 8.54 (s, 1H); 8.18 (s, 1H); 8.07 (s, 1H); 7.65 (d, J=8.9 Hz, 1H); 7.31 (d, J=8.9 Hz, 1H); 4.67 (d, J=5.8 Hz, 2H); 4.54-4.63 (m, 1H); 4.46 (d, J=5.8 Hz, 2H); 4.33-4.41 (m, 1H); 3.08 (s, 3H); 2.82-2.92 (m, 1H); 2.33-2.60 (overlapped m, 1H); 1.52 (s, 3H).
(560) MS1 (ESI, m/z): 471.91 [M+H.sup.+] for C.sub.21H.sub.24N.sub.4O.sub.7S; t.sub.R=0.49 min.
Example 49: (R)—N-hydroxy-4-(5-(4-(2-hydroxyacetamido)phenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(561) Starting from the compound of Preparation H (0.124 g; 0.296 mmol) and the compound of Preparation AB (0.0735 g; 0.23 mmol) and proceeding in analogy to Example 1, steps 1.i (39% yield) and 1.ii (38% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.012 g).
(562) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.95-11.15 (m, 1H); 9.75 (s, 1H); 9.30 (br. s, 1H); 8.46 (br. s, 1H); 7.94 (dd, J=0.8, 1.4 Hz, 1H); 7.80 (d, J=8.7 Hz, 2H); 7.68 (m, 1H); 7.65 (d, J=8.7 Hz, 2H); 7.58 (dd, J=1.7, 9.0 Hz, 1H); 5.69 (t, J=6.1 Hz, 1H); 4.52-4.60 (m, 1H); 4.33-4.40 (m, 1H); 4.02 (d, J=5.9 Hz, 2H); 3.09 (s, 3H); 2.83-2.91 (m, 1H); 2.39-2.46 (m, 1H); 1.53 (s, 3H).
(563) MS1 (ESI, m/z): 460.9 [M+H.sup.+] for C.sub.21H.sub.24N.sub.4O.sub.6S; t.sub.R=0.57 min.
Example 50: (R)-4-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(564) Starting from the compound of Preparation H (0.1 g; 0.192 mmol) and the compound of Preparation AC (0.065 g; 0.23 mmol) and proceeding in analogy to Example 1, steps 1.i (77% yield) and 1.ii (51% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.034 g).
(565) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.95-11.18 (m, 1H); 9.16-9.41 (m, 1H); 8.47 (s, 1H); 7.80 (s, 1H); 7.67 (d, J=9.0 Hz, 1H); 7.47 (t, J=8.9 Hz, 1H); 7.38 (d, J=9.0 Hz, 1H); 6.85-6.99 (m, 2H); 4.92 (t, J=5.4 Hz, 1H); 4.52-4.61 (m, 1H); 4.33-4.42 (m, 1H); 4.06 (t, J=4.7 Hz, 2H); 3.74 (q, J=4.9 Hz, 2H); 3.09 (s, 3H); 2.82-2.91 (m, 1H); 2.38-2.46 (m, 1H); 1.53 (s, 3H).
(566) MS1 (ESI, m/z): 465.9 [M+H.sup.+] for C.sub.21H.sub.24N.sub.3O.sub.6FS; t.sub.R=0.64 min.
Example 51: (R)-4-(5-((4-((S)-1,2-dihydroxyethyl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(567) Starting from the compound of Preparation J (0.105 g; 0.25 mmol) and (S)-1-(4-iodophenyl)-1,2-ethanediol (0.0743 g; 0.281 mmol; commercial), and proceeding successively in analogy to Example 7, step 7.i (70% yield) and Example 1, step 1.ii (31% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellow solid (0.026 g).
(568) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.0 (s, 1H); 9.28 (s, 1H); 8.50 (s, 1H); 7.99 (s, 1H); 7.65 (d, J=8.8 Hz, 1H); 7.50 (d, J=8.2 Hz, 2H); 7.39 (d, J=8.2 Hz, 2H); 7.34 (d, J=8.8 Hz, 1H); 5.34 (d, J=4.3 Hz, 1H); 4.76 (t, J=6.1 Hz, 1H); 4.53-4.61 (m, 2H); 4.32-4.40 (m, 2H); 3.39-3.48 (m, 1H); 3.08 (s, 3H); 2.85 (m, 1H); 2.35-2.45 (m, 1H); 1.54 (s, 3H).
(569) MS1 (ESI, m/z): 471.93 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.6S; t.sub.R=0.60 min.
Example 52: (R)—N-hydroxy-4-(5-(4-(2-methoxyethoxy)phenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(570) Starting from the compound of Preparation H (0.1 g; 0.192 mmol) and 2-(4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.064 g; 0.23 mmol; commercial), and proceeding in analogy to Example 1, steps 1.i (57% yield) and 1.ii (29% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.013 g).
(571) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.06 (s, 1H); 9.29 (s, 1H); 8.44 (s, 1H); 7.89 (s, 1H); 7.65-7.68 (m, 1H); 7.62 (d, J=8.7 Hz, 2H); 7.55 (dd, J=1.6, 9.0 Hz, 1H); 7.03 (d, J=8.7 Hz, 2H); 4.51-4.60 (m, 1H); 4.32-4.40 (m, 1H); 4.11-4.17 (m, 2H); 3.66-3.71 (m, 2H); 3.33 (overlapped s, 3H); 3.09 (s, 3H); 2.82-2.91 (m, 1H); 2.38-2.46 (m, 1H); 1.53 (s, 3H).
(572) MS1 (ESI, m/z): 462.0 [M+H.sup.+] for C.sub.22H.sub.27N.sub.3O.sub.6S; t.sub.R=0.71 min.
Example 53: (R)-4-(6-fluoro-5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(573) Starting from the compound of Preparation R (0.1 g; 0.229 mmol) and the (1S,2S)-configurated compound of Preparation U (0.0546 g; 0.251 mmol), and proceeding successively in analogy to Example 37, step 37.i (quant.), Example 36, step 36.ii (99% yield) and Example 1, step 1.ii (66% yield), the title compound was obtained, after filtration from water and trituration in Et.sub.2O, as a brown solid (0.065 g).
(574) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.03 (s, 1H); 9.19-9.37 (m, 1H); 8.55 (s, 1H); 8.13 (d, J=7.1 Hz, 1H); 7.48 (d, J=10.7 Hz, 1H); 4.50-4.58 (m, 1H); 4.29-4.38 (m, 1H); 3.41-3.46 (m, 1H); 3.23-3.29 (m, 1H); 3.07 (s, 3H); 2.80-2.88 (m, 1H); 2.34-2.42 (m, 1H); 1.52 (s, 3H); 1.42-1.49 (m, 2H); 0.93-0.98 (m, 1H); 0.85-0.91 (m, 1H).
(575) MS1 (ESI, m/z): 447.9 [M+H.sup.+] for C.sub.21H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.69 min.
Example 54: (R)-4-(4-fluoro-5-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(576) Starting from intermediate 18.ii (0.2 g; 0.459 mmol) and the (1S,2S)-configurated compound of Preparation U, and proceeding successively in analogy to Example 37, step 37.i and Example 36, step 36.ii (91% yield over the two steps) and Example 1, step 1.ii (29% yield), the title compound was obtained, after purification by prep-HPLC (Method 1), as a beige foam (0.054 g).
(577) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.05 (br. s, 1H); 9.28 (br. s, 1H); 8.75 (s, 1H); 7.47 (d, J=8.9 Hz, 1H); 7.24-7.29 (m, 1H); 4.71 (s, 1H); 4.53-4.60 (m, 1H); 4.33-4.41 (m, 1H); 3.39-3.45 (m, 1H); 3.22-3.34 (m, 1H); 3.07 (s, 3H); 2.82-2.89 (m, 1H); 2.35-2.44 (m, 1H); 1.52 (s, 3H); 1.41-1.48 (m, 2H); 0.92-0.97 (m, 1H); 0.85-0.90 (m, 1H).
(578) MS1 (ESI, m/z): 447.97 [M+H.sup.+] for C.sub.21H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.70 min.
Example 55: (R)-4-(5-((S)-5,6-dihydroxyhexa-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(579) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and (S)-4-iodobut-3-yne-1,2-diol (0.061 g; 0.286 mmol; prepared as reported in Wang et al., J. Org. Chem. (2001), 66, 2146-2148), and proceeding successively in analogy to Example 37, step 37.i and Example 13, step 13.ii, the title compound was obtained, after purification by prep-HPLC (Method 2), as a brown foam (0.0213 g; 20% yield over the two steps).
(580) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (s, 1H); 9.22-9.34 (m, 1H); 8.53 (d, J=0.7 Hz, 1H); 8.04-8.08 (m, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.30 (dd, J=1.5, 8.9 Hz, 1H); 4.52-4.62 (m, 1H); 4.32-4.40 (m, 1H); 4.35 (t, J=6.1 Hz, 1H); 3.47 (d, J=6.1 Hz, 2H); 3.08 (s, 3H); 2.81-2.89 (m, 1H); 2.35-2.44 (m, 1H); 1.52 (s, 3H).
(581) MS1 (ESI, m/z): 419.8 [M+H.sup.+] for C.sub.19H.sub.21N.sub.3O.sub.6S; t.sub.R=0.55 min.
Example 56: (R)—N-hydroxy-4-(5-((1-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(582) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AD (0.112 g; 0.262 mmol), and proceeding successively in analogy to Example 37, step 37.i (70% yield), Example 46, step 46.ii (87% yield), and Example 1, step 1.ii (59% yield) the title compound was obtained, after purification by prep-HPLC (Method 2), as a white foam (0.035 g).
(583) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (s, 1H); 9.28 (s, 1H); 8.51 (s, 1H); 7.99-8.02 (m, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.27 (dd, J=1.5, 8.9 Hz, 1H); 5.03 (t, J=6.1 Hz, 1H); 4.52-4.60 (m, 1H); 4.32-4.39 (m, 1H); 3.40 (d, J=6.1 Hz, 2H); 3.07 (s, 3H); 2.81-2.88 (m, 1H); 2.36-2.43 (m, 1H); 1.52 (s, 3H); 0.91-0.95 (m, 2H); 0.86-0.90 (m, 2H).
(584) MS1 (ESI, m/z): 430.0 [M+H.sup.+] for C.sub.21H.sub.23N.sub.3O.sub.5S; t.sub.R=0.68 min.
Example 57: (R)—N-hydroxy-4-(5-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(585) Starting from the compound of Preparation J (0.07 g; 0.167 mmol) and the compound of Preparation AE (0.077 g; 0.167 mmol), and proceeding successively in analogy to Example 37, step 37.i (86% yield) and Example 13, step 13.ii (47% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as an off-white solid (0.03 g).
(586) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (s, 1H); 9.28 (s, 1H); 8.52 (s, 1H); 8.04 (s, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.28 (dd, J=1.5, 8.9 Hz, 1H); 4.59 (t, J=5.6 Hz, 1H); 4.52-4.61 (overlapped m, 1H); 4.32-4.40 (m, 1H); 3.35 (d, J=5.6 Hz, 2H); 3.07 (s, 3H); 2.80-2.89 (m, 1H); 2.36-2.43 (m, 1H); 1.98 (s, 6H); 1.52 (s, 3H).
(587) MS1 (ESI, m/z): 456.0 [M+H.sup.+] for C.sub.23H.sub.25N.sub.3O.sub.5S; t.sub.R=0.72 min.
Example 58: (R)-4-(5-(4-((R)-2,3-dihydroxypropoxy)-2-fluorophenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(588) Starting from the compound of Preparation H (0.12 g; 0.23 mmol) and the compound of Preparation AF (0.097 g; 0.276 mmol), and proceeding successively in analogy to Example 1, step 1.i (80% yield) and Example 13, step 13.ii (50% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white foam (0.044 g).
(589) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.06 (s, 1H); 9.30 (s, 1H); 8.47 (s, 1H); 7.80 (s, 1H); 7.67 (d, J=9.0 Hz, 1H); 7.47 (t, J=8.9 Hz, 1H); 7.39 (dt, J=1.6, 8.9 Hz, 1H); 6.87-6.95 (m, 2H); 4.86-5.14 (m, 1H); 4.50-4.82 (overlapped m, 1H); 4.50-4.63 (m, 1H); 4.31-4.43 (m, 1H); 4.07 (dd, J=4.1, 10.0 Hz, 1H); 3.94 (dd, J=6.2, 10.0 Hz, 1H); 3.78-3.85 (m, 1H); 3.46 (d, J=5.7 Hz, 2H); 3.09 (s, 3H); 2.82-2.91 (m, 1H); 2.38-2.46 (m, 1H); 1.53 (s, 3H).
(590) MS1 (ESI, m/z): 496.0 [M+H.sup.+] for C.sub.22H.sub.26N.sub.3O.sub.7FS; t.sub.R=0.59 min.
Example 59: (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(pyrimidin-5-ylethynyl)-2H-indazol-2-yl)butanamide
(591) Starting from the compound of Preparation H (0.11 g; 0.211 mmol) and 5-ethynylpyrimidine (0.025 g; 0.232 mmol; commercial), and proceeding successively in analogy to Example 7, step 7.i (71% yield) and Example 1, step 1.ii (77% yield), the title compound was obtained, after filtration from water, as a yellow solid (0.045 g).
(592) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.06 (d, J=1.3 Hz, 1H); 9.29 (d, J=1.7 Hz, 1H); 9.20 (s, 1H); 9.03 (s, 2H); 8.57 (s, 1H); 8.10 (s, 1H); 7.70 (d, J=8.9 Hz, 1H); 7.40 (dd, J=1.5, 8.9 Hz, 1H); 4.55-4.63 (m, 1H); 4.33-4.43 (m, 1H); 3.09 (s, 3H); 2.87 (m, 1H); 2.38-2.45 (m, 1H); 1.55 (s, 3H).
(593) MS1 (ESI, m/z): 413.9 [M+H.sup.+] for C.sub.19H.sub.19N.sub.5O.sub.4S; t.sub.R=0.67 min.
Example 60: (R)—N-hydroxy-4-(5-(4-(((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(594) Starting from the compound of Preparation C (0.1 g; 0.248 mmol) and the compound of Preparation AG (0.118 g; 0.26 mmol), and proceeding successively in analogy to Example 1, step 1.i (48% yield), Example 2, step 2.ii (saponification: 94% yield; amide coupling with THPO—NH.sub.2: 77% yield) and Example 13, step 13.ii (36% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as an off-white solid (0.013 g).
(595) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.06 (s, 1H); 9.30 (s, 1H); 8.49 (s, 1H); 8.00 (s, 1H); 7.65-7.74 (m, 3H); 7.59 (dd, J=1.7, 9.1 Hz, 1H); 7.44 (d, J=8.4 Hz, 2H); 4.64-4.79 (m, 1H); 4.53-4.61 (m, 1H); 4.33-4.42 (m, 1H); 3.46 (dd, J=5.4, 11.5 Hz, 1H); 3.29 (dd, J=6.4, 11.5 Hz, 1H); 3.09 (s, 3H); 2.83-2.91 (m, 1H); 2.39-2.46 (m, 1H); 1.53 (s, 3H); 1.36-1.48 (m, 2H); 0.81-0.94 (m, 2H).
(596) MS1 (ESI, m/z): 482.0 [M+H.sup.+] for C.sub.25H.sub.27N.sub.3O.sub.5S; t.sub.R=0.72 min.
Example 61: (R)-4-(5-(((2S*,5S*)-5-aminotetrahydro-2H-pyran-2-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(597) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AH (0.087 g; 0.29 mmol), and proceeding successively in analogy to Example 37, step 37.i (84% yield) and Example 13, step 13.ii (67% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as an off-white solid (0.058 g).
(598) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.54 (d, J=0.6 Hz, 1H); 8.09 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.31 (dd, J=1.5, 8.9 Hz, 1H); 4.53-4.61 (m, 1H); 4.30-4.41 (overlapped m, 1H); 4.33 (dd, J=2.7, 9.9 Hz, 1H); 3.77-3.84 (m, 1H); 3.07 (s, 3H); 3.03 (dd, J=9.1, 10.8 Hz, 1H); 2.81-2.89 (m, 1H); 2.68-2.75 (m, 1H); 2.36-2.44 (m, 1H); 1.88-1.99 (m, 2H); 1.57-1.67 (m, 1H); 1.52 (s, 3H); 1.24-1.35 (m, 1H).
(599) MS1 (ESI, m/z): 459.0 [M+H.sup.+] for C.sub.22H.sub.26N.sub.4O.sub.5S; t.sub.R=0.54 min.
Example 62: (R)-(1-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-2H-indazol-5-yl)ethynyl)phenyl)cyclopropyl)methyl dihydrogen phosphate
62.i. (R)-di-tert-butyl ((1-(4-((2-(3-methyl-3-(methylsulfonyl)-4-oxo-4-((((RS)-tetrahydro-2H-pyran-2-yl)oxy)amino)butyl)-2H-indazol-5-yl)ethynyl)phenyl)cyclopropyl)methyl) phosphate
(600) Starting from the compound of Preparation H (0.16 g; 0.3 mmol) and the compound of Preparation AI (0.067 g; 0.184 mmol), and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (Hept-EA), as a yellow oil (0.06 g; 43% yield).
(601) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.47 (s, 0.5H); 11.44 (s, 0.5H); 8.48 (s, 0.5H); 8.47 (s, 0.5H); 7.98 (s, 1H); 7.59-7.68 (m, 1H); 7.48 (d, J=8.2 Hz, 2H); 7.31-7.38 (overlapped m, 1H); 7.36 (d, J=8.2 Hz, 2H); 4.94-4.98 (m, 1H); 4.53-4.62 (m, 1H); 4.34-4.46 (m, 1H); 3.96-4.16 (m, 3H); 3.49-3.57 (m, 1H); 3.08 (s, 1.5H); 3.06 (s, 1.5H); 2.79-2.91 (m, 1H); 2.39-2.59 (overlapped m, 1H); 1.65-1.74 (m, 3H); 1.47-1.60 (m, 6H); 1.35 (s, 18H); 0.99-1.04 (m, 2H); 0.92-0.97 (m, 2H).
(602) MS1 (ESI, m/z): 757.9 [M+H.sup.+] for C.sub.38H.sub.52N.sub.3O.sub.9PS; t.sub.R=0.99 min.
62.ii. (R)-(1-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-2H-indazol-5-yl)ethynyl)phenyl)cyclopropyl)methyl dihydrogen phosphate
(603) To a solution of intermediate 62.i (0.058 g; 0.077 mmol) in DCM (1.9 mL) was added TFA (0.87 mL; 11 mmol). The reaction was stirred at rt for 20 min and concentrated to dryness. The residue was purified by prep-HPLC (Method 1) to afford the title compound as a white solid (0.005 g; 11% yield).
(604) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.05 (s, 1H); 9.29 (br. s, 1H); 8.49 (s, 1H); 7.98 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.46 (d, J=8.2 Hz, 2H); 7.31-7.35 (m, 3H); 4.51-4.64 (m, 1H); 4.31-4.45 (m, 1H); 3.95 (d, J=5.3 Hz, 2H); 3.07 (s, 3H); 2.82-2.91 (m, 1H); 2.35-2.60 (overlapped m, 1H); 1.53 (s, 3H); 0.98-1.03 (m, 2H); 0.89-0.95 (m, 2H).
(605) MS1 (ESI, m/z): 561.91 [M+H.sup.+] for C.sub.25H.sub.28N.sub.3O.sub.8PS; t.sub.R=0.64 min.
Example 63: (R)-(1-(4-((2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl)-2H-indazol-5-yl)ethynyl)phenyl)cyclopropyl)methyl dimethylglycinate hydrochloride
(606) Starting from the compound of Preparation H (0.25 g; 0.48 mmol) and the compound of Preparation AJ (0.122 g; 0.48 mmol), and proceeding successively in analogy to Example 7, step 7.i (43% yield) and Example 13, step 13.ii (14% yield), the title compound was obtained, after purification by prep-HPLC (Method 1) and lyophilisation from a diluted HCl solution, as a white solid (0.017 g).
(607) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.00-11.13 (br. s, 1H); 10.01-10.17 (br. s, 1H); 8.50 (s, 1H); 7.97 (s, 1H); 7.65 (d, J=8.9 Hz, 1H); 7.49 (d, J=8.2 Hz, 2H); 7.36 (d, J=8.2 Hz, 2H); 7.32 (dd, J=1.2, 8.9 Hz, 1H); 4.53-4.61 (m, 1H); 4.38 (s, 2H); 4.32-4.38 (overlapped m, 1H); 4.19 (d, J=2.1 Hz, 2H); 3.07 (s, 3H); 2.82-2.90 (m, 1H); 2.80 (s, 6H); 2.38-2.50 (overlapped m, 1H); 1.53 (s, 3H); 1.05-1.09 (m, 2H); 0.98-1.02 (m, 2H).
(608) MS1 (ESI, m/z): 567.02 [M+H.sup.+] for C.sub.29H.sub.34N.sub.4O.sub.6S; t.sub.R=0.66 min.
Example 64: (R)-4-(5-(((1S,3R,4S)-3,4-dihydroxycyclopentyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(609) Starting from the compound of Preparation J (0.1 g; 0.24 mmol) and the compound of Preparation AK (0.066 g; 0.27 mmol), and proceeding successively in analogy to Example 37, step 37.i (91% yield) and Example 13, step 13.ii (30% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.029 g).
(610) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (s, 1H); 9.28 (br. s, 1H); 8.51 (d, J=0.6 Hz, 1H); 8.00-8.02 (m, 1H); 7.61-7.64 (m, 1H); 7.27 (dd, J=1.4, 8.7 Hz, 1H); 4.53-4.60 (m, 1H); 4.32-4.39 (m, 1H); 3.94-3.98 (m, 2H); 3.13-3.21 (m, 1H); 3.07 (s, 3H); 2.82-2.89 (m, 1H); 2.37-2.44 (m, 1H); 1.90-1.97 (m, 2H); 1.75-1.82 (m, 2H); 1.52 (s, 3H).
(611) MS1 (ESI, m/z): 459.99 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.6S; t.sub.R=0.62 min.
Example 65: (R)-4-(5-((1-aminocyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(612) Starting from the compound of Preparation J (0.11 g; 0.262 mmol) and the compound of Preparation AL (0.0926 g; 0.302 mmol), and proceeding successively in analogy to Example 7, step 7.i (46% yield) and Example 13, step 13.ii (47% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.023 g).
(613) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.72-11.35 (m, 1H); 9.11-9.53 (m, 1H); 8.51 (d, J=0.7 Hz, 1H); 8.01 (s, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.27 (dd, J=1.5, 8.9 Hz, 1H); 4.52-4.61 (m, 1H); 4.32-4.40 (m, 1H); 3.07 (s, 3H); 2.81-2.89 (m, 1H); 2.36-2.45 (m, 1H); 1.52 (s, 3H); 0.98-1.02 (m, 2H); 0.88-0.92 (m, 2H).
(614) MS1 (ESI, m/z): 415.0 [M+H.sup.+] for C.sub.20H.sub.22N.sub.4O.sub.4S; t.sub.R=0.52 min.
Example 66: (R)—N-hydroxy-4-(5-(5-01S,3R)-1-hydroxy-3-(hydroxymethyl)cyclobutyl)penta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(615) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AM (0.0856 g; 0.322 mmol), and proceeding successively in analogy to Example 7, step 7.i (64% yield) and Example 1, step 1.ii (34% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellow foam (0.023 g). .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.95-11.12 (m, 1H); 9.22-9.34 (m, 1H); 8.51 (s, 1H); 8.03-8.04 (m, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 5.24 (s, 1H); 4.53-4.60 (m, 1H); 4.49 (t, J=5.3 Hz, 1H); 4.32-4.40 (m, 1H); 3.37 (t, J=5.7 Hz, 2H); 3.07 (s, 3H); 2.81-2.89 (m, 1H); 2.63 (s, 2H); 2.36-2.44 (m, 1H); 2.04-2.11 (m, 2H); 1.92-2.00 (m, 1H); 1.70-1.77 (m, 2H); 1.52 (s, 3H).
(616) MS1 (ESI, m/z): 474.0 [M+H.sup.+] for C.sub.23H.sub.27N.sub.3O.sub.6S; t.sub.R=0.62 min.
Example 67: (R)—N-hydroxy-4-(5-(((1R,2R)-2-(hydroxymethyl)-1-methylcyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(617) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AN (0.122 g; 0.286 mmol), and proceeding successively in analogy to Example 37, step 37.i (91% yield) and Example 13, step 13.ii (40% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as an off-white solid (0.037 g).
(618) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (s, 1H); 9.28 (s, 1H); 8.50 (d, J=0.6 Hz, 1H); 8.00-8.01 (m, 1H); 7.60-7.63 (m, 1H); 7.27 (dd, J=1.5, 8.9 Hz, 1H); 4.69 (t, J=5.4 Hz, 1H); 4.52-4.61 (m, 1H); 4.32-4.41 (m, 1H); 3.59-3.65 (m, 1H); 3.23-3.31 (m, 1H); 3.07 (s, 3H); 2.81-2.89 (m, 1H); 2.36-2.44 (m, 1H); 1.52 (s, 3H); 1.40-1.48 (m, 1H); 1.32 (s, 3H); 1.11 (dd, J=4.4, 9.3 Hz, 1H); 0.63 (dd, J=4.6, 6.6 Hz, 1H).
(619) MS1 (ESI, m/z): 444.0 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.5S; t.sub.R=0.70 min.
Example 68: (R)—N-hydroxy-4-(5-((3-(hydroxymethyl)oxetan-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
68.i. (R)-4-(5-((3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)buta-1, 3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(620) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AO (0.129 g; 0.271 mmol), and proceeding in analogy to Example 7, step 7.i, the title compound was obtained, after purification by CC (DCM-MeOH), as a yellow oil (0.064 g; 35% yield).
(621) MS1 (ESI, m/z): 768.01 [M+H.sup.+] for C.sub.42H.sub.49N.sub.3O.sub.7SSi; t.sub.R=1.10 min.
68.ii. (R)-4-(5-((3-(hydroxymethyl)oxetan-3-yl)buta-1, 3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N-(08)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(622) To a stirred solution of intermediate 68.i (0.64 g; 0.836 mmol) in THF (1 mL) was added TBAF.3H.sub.2O (0.109 g; 0.334 mmol). The mixture was stirred at rt for 3 h and then concentrated to dryness. The residue was purified by CC (DCM-MeOH) to afford the title compound as a yellow oil (0.026 g).
(623) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.45 (s, 1H); 8.51 (s, 1H); 8.07 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.31 (d, J=9.0 Hz, 1H); 5.48 (t, J=5.9 Hz, 1H); 4.91-4.98 (m, 1H); 4.61 (d, J=5.7 Hz, 2H); 4.51-4.62 (overlapped m, 1H); 4.53 (d, J=5.7 Hz, 2H); 4.35-4.46 (m, 1H); 4.04-4.15 (m, 1H); 3.73 (d, J=5.8 Hz, 2H); 3.49-3.55 (m, 1H); 3.08 (s, 1.5H); 3.06 (s, 1.5H); 2.79-2.90 (m, 1H); 2.34-2.45 (m, 1H); 1.65-1.77 (m, 3H); 1.47-1.63 (overlapped m, 3H); 1.53 (s, 1.5H); 1.50 (s, 1.5H).
(624) MS1 (ESI, m/z): 530.0 [M+H.sup.+] for C.sub.26H.sub.31N.sub.3O.sub.7S; t.sub.R=0.75 min.
68.iii. (R)—N-hydr oxy-4-(5-((3-(hydr oxymethyl)oxetan-3-yl)buta-1, 3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(625) Starting from intermediate 68.ii (0.026 g; 0.0498 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 2), as a beige solid (0.019 g; 86% yield).
(626) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.00 (s, 1H); 9.28 (s, 1H); 8.53 (s, 1H); 8.06 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.31 (d, J=8.9 Hz, 1H); 5.48 (t, J=5.9 Hz, 1H); 4.61 (d, J=5.7 Hz, 1H); 4.55-4.60 (overlapped m, 1H); 4.53 (d, J=5.7 Hz, 2H); 4.33-4.42 (m, 1H); 3.73 (d, J=5.9 Hz, 2H); 3.08 (s, 3H); 2.81-2.89 (m, 1H); 2.35-2.45 (m, 1H); 2.08 (s, 1H); 1.53 (s, 3H).
(627) MS1 (ESI, m/z): 445.96 [M+H.sup.+] for C.sub.21H.sub.23N.sub.3O.sub.6S; t.sub.R=0.63 min.
Example 69: (R)—N-hydroxy-4-(5-((1R,2S)-2-(hydroxymethyl)-2-methylcyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(628) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AP (0.066 g; 0.286 mmol), and proceeding successively in analogy to Example 37, step 37.i and Example 36, step 36.ii (79% yield over the two steps) and Example 1, step 1.ii (82% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a yellow foam (0.07 g).
(629) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.95-11.12 (m, 1H); 9.22-9.36 (m, 1H); 8.50 (s, 1H); 8.02 (s, 1H); 7.61 (d, J=8.9 Hz, 1H); 7.28 (dd, J=1.5, 8.9 Hz, 1H); 4.75 (t, J=5.8 Hz, 1H); 4.52-4.60 (m, 1H); 4.31-4.40 (m, 1H); 3.31 (dd, J=6.0, 11.3 Hz, 1H); 3.23 (dd, J=5.6, 11.2 Hz, 1H); 3.07 (s, 3H); 2.81-2.90 (m, 1H); 2.36-2.44 (m, 1H); 1.57 (dd, J=5.3, 8.7 Hz, 1H); 1.52 (s, 3H); 1.20 (s, 3H); 1.05 (dd, J=4.1, 8.7 Hz, 1H); 0.63-0.66 (m, 1H).
(630) MS1 (ESI, m/z): 444.0 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.5S; t.sub.R=0.70 min.
Example 70: (R)-4-(5-((3-(2-aminoacetamido)cyclopentyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(631) Starting from the compound of Preparation J (0.08 g; 0.191 mmol) and the compound of Preparation AQ (0.097 g; 0.248 mmol), and proceeding successively in analogy to Example 7, step 7.i (57% yield) and Example 13, step 13.ii (28% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige foam (0.014 g).
(632) MS1 (ESI, m/z): 499.9 [M+H.sup.+] for C.sub.24H.sub.29N.sub.5O.sub.5S; t.sub.R=0.58 min.
Example 71: (R)-4-(5-(((1R,2R)-2-((S)-1,2-dihydroxyethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(633) Starting from the compound of Preparation J (0.08 g; 0.191 mmol) and the compound of Preparation AR (0.14 g; 0.286 mmol), and proceeding successively in analogy to Example 37, step 37.i (84% yield) and Example 13, step 13.ii (41% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.029 g).
(634) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.03 (s, 1H); 9.27 (s, 1H); 8.49 (d, J=0.6 Hz, 1H); 7.99-8.00 (m, 1H); 7.61 (dt, J=0.9, 9.0 Hz, 1H); 7.25 (dd, J=1.5, 9.0 Hz, 1H); 4.70 (d, J=5.1 Hz, 1H); 4.61 (t, J=5.8 Hz, 1H); 4.52-4.59 (m, 1H); 4.31-4.38 (m, 1H); 3.33-3.37 (overlapped m, 2H); 3.26-3.31 (m, 1H); 3.06 (s, 3H); 2.80-2.88 (m, 1H); 2.35-2.43 (m, 1H); 1.51 (s, 3H); 1.48 (dt, J=4.9, 8.5 Hz, 1H); 1.33-1.39 (m, 1H); 0.92-0.96 (m, 1H); 0.81-0.85 (m, 1H).
(635) MS1 (ESI, m/z): 460.0 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.6S; t.sub.R=0.61 min.
Example 72: (R)-4-(5-(((1R,2R)-2-(aminomethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(636) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AS (0.14 g; 0.286 mmol), and proceeding successively in analogy to Example 7, step 7.i (23% yield) and Example 13, step 13.ii (59% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a white solid (0.013 g).
(637) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.49 (s, 1H); 7.99-8.00 (m, 1H); 7.61 (d, J=8.9 Hz, 1H); 7.26 (dd, J=1.5, 8.9 Hz, 1H); 4.50-4.61 (m, 1H); 4.32-4.41 (m, 1H); 3.06 (s, 3H); 2.77-2.90 (m, 1H); 2.58-2.69 (m, 1H); 2.46-2.55 (overlapped m, 1H); 2.33-2.44 (m, 1H); 1.47-1.51 (overlapped m, 1H); 1.50 (s, 3H); 1.33-1.41 (m, 1H); 0.85-0.98 (m, 2H).
(638) MS1 (ESI, m/z): 429.0 [M+H.sup.+] for C.sub.21H.sub.24N.sub.4O.sub.4S; t.sub.R=0.55 min.
Example 73: (R)—N-hydroxy-4-(5-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
73.i. (2R)-4-(5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide
(639) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AT (0.11 g; 0.253 mmol), and proceeding in analogy to Example 37, step 37.i, the title compound was obtained, after purification by CC (Hept-EA/MeOH), as a pink foam (0.16 g; 87% yield).
(640) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.45 (s, 0.5H); 11.43 (s, 0.5H); 8.50 (d, J=0.4 Hz, 0.5H); 8.49 (d, J=0.4 Hz, 0.5H); 8.03-8.04 (m, 1H); 7.66-7.69 (m, 4H); 7.61-7.65 (m, 1H); 7.44-7.49 (m, 6H); 7.28 (dd, J=1.5, 9.0 Hz, 1H); 4.96 (s, 0.5H); 4.92 (s, 0.5H); 4.53-4.61 (m, 1H), 4.36-4.45 (m, 1H); 4.08-4.15 (m, 0.5H); 4.02-4.08 (m, 0.5H); 3.75 (s, 2H); 3.49-3.56 (m, 1H); 3.08 (s, 1.5H); 3.05 (s, 1.5H); 2.79-2.90 (m, 1H); 2.38-2.46 (m, 1H); 2.14-2.25 (m, 4H); 1.95-2.02 (m, 1H); 1.86-1.93 (m, 1H); 1.63-1.73 (m, 3H); 1.54 (s, 1.5H); 1.52 (s, 1.5H); 1.49-1.59 (overlappped m, 3H); 1.05 (s, 9H).
(641) MS1 (ESI, m/z): 765.86 [M+H.sup.+] for C.sub.43H.sub.51N.sub.3O.sub.6SSi; t.sub.R=1.15 min.
73.ii. (2R)-4-(5-((1-(hydr oxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)-N—(((RS)tetrahydro-2H-pyran-2-yl)oxy)butanamide
(642) To a stirred solution of intermediate 73.i (0.15 g; 0.2 mmol) in THF (0.4 mL) was added TBAF (1M; 1 mL; 1 mmol). The mixture was stirred at rt for 6 h and then concentrated to dryness. The residue was purified by CC (Hept-EA/MeOH) to afford the title compound as an off-white foam (0.1 g; 99% yield).
(643) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.45 (s, 0.5H); 11.43 (s, 0.5H); 8.49 (s, 0.5H); 8.48 (s, 0.5H); 8.02 (s, 1H); 7.61-7.64 (m, 1H); 7.28 (dd, J=1.4, 8.8 Hz, 1H); 5.17 (t, J=5.8 Hz, 1H); 4.96 (s, 0.5H); 4.93 (s, 0.5H); 4.52-4.61 (m, 1H); 4.35-4.45 (m, 1H); 4.08-4.15 (m, 0.5H); 3.99-4.07 (m, 0.5H); 3.49-3.57 (overlapped m, 1H); 3.49 (d, J=5.8 Hz, 2H); 3.08 (s, 1.5H); 3.05 (s, 1.5H); 2.78-2.90 (m, 1H); 2.37-2.45 (m, 1H); 2.11-2.17 (m, 4H); 1.84-1.98 (m, 2H); 1.64-1.73 (m, 3H); 1.48-1.60 (overlapped m, 3H), 1.53 (s, 1.5H), 1.51 (s, 1.5H).
(644) MS1 (ESI, m/z): 528.05 [M+H.sup.+] for C.sub.27H.sub.33N.sub.3O.sub.6S; t.sub.R=0.84 min.
73.iii. (R)—N-hydroxy-4-(5-((1-(hydroxymethyl)cyclobutyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(645) Starting from intermediate 73.ii (0.1 g; 0.131 mmol) and proceeding in analogy to Example 1, step 1.ii, the title compound was obtained, after purification by prep-HPLC (Method 2), as an off-white solid (0.056 g; 97% yield).
(646) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.99-11.08 (m, 1H); 9.28 (s, 1H); 8.52 (s, 1H); 8.02-8.03 (m, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 5.18 (t, J=5.8 Hz, 1H); 4.52-4.61 (m, 1H); 4.32-4.41 (m, 1H); 3.50 (d, J=5.8 Hz, 2H); 3.08 (s, 3H); 2.81-2.90 (m, 1H); 2.37-2.45 (m, 1H); 2.12-2.18 (m, 4H); 1.85-2.02 (m, 2H); 1.52 (s, 3H).
(647) MS1 (ESI, m/z): 444 [M+H.sup.+] for C.sub.22H.sub.25N.sub.3O.sub.5S; t.sub.R=0.72 min.
Example 74: (R)-4-(5-(((1R,2R)-1-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(648) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AU (0.12 g; 0.279 mmol), and proceeding successively in analogy to Example 37, step 37.i (87% yield), Example 73, step 73.ii (84% yield) and Example 1, step 1.ii (80% yield), the title compound was obtained, after precipitation in water, as a beige solid (0.06 g).
(649) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.05 (d, J=1.0 Hz, 1H); 9.28 (d, J=1.5 Hz, 1H); 8.56 (s, 1H); 8.12 (s, 1H); 7.66 (d, J=8.9 Hz, 1H); 7.33 (dd, J=1.4, 8.9 Hz, 1H); 4.91 (t, J=4.6 Hz, 1H); 4.54-4.62 (m, 1H); 4.34-4.41 (m, 1H); 3.66-3.72 (m, 1H); 3.35-3.41 (m, 1H); 3.08 (s, 3H); 2.82-2.90 (m, 1H); 2.37-2.44 (m, 1H); 1.64-1.71 (m, 1H); 1.53 (s, 3H); 1.38-1.44 (m, 1H); 1.23-1.31 (m, 1H).
(650) MS1 (ESI, m/z): 448.0 [M+H.sup.+] for C.sub.21H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.69 min.
Example 75: (R)-4-(5-(5-(dimethylamino)penta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(651) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AV (0.075 g; 0.358 mmol), and proceeding successively in analogy to Example 37, step 37.i (quant.) and Example 1, step 1.ii (41% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.042 g).
(652) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.02 (m, 1H); 9.29 (m, 1H); 8.53 (s, 1H); 8.07 (m, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.31 (dd, J=1.5, 8.9 Hz, 1H); 4.57 (m, 1H); 4.37 (m, 1H); 3.48 (s, 2H); 3.08 (s, 3H); 2.86 (m, 1H); 2.40 (m, 1H); 2.23 (s, 6H); 1.53 (s, 3H).
(653) MS1 (ESI, m/z): 458.0 [M+H.sup.+] for C.sub.20H.sub.24N.sub.4O.sub.4S; t.sub.R=0.51 min.
Example 76: (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(5-(piperidin-4-ylbuta-1,3-diyn-1-yl)-2H-indazol-2-yl)butanamide
(654) Starting from the compound of Preparation J (0.08 g; 0.191 mmol) and the compound of Preparation AW (0.096 g; 0.286 mmol), and proceeding successively in analogy to Example 37, step 37.i (79% yield) and Example 13, step 13.ii (66% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.042 g).
(655) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.51 (d, J=0.4 Hz, 1H); 8.03 (m, 1H); 7.62 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 4.56 (m, 1H); 4.38 (m, 1H); 3.07 (s, 3H); 2.88-2.93 (m, 2H); 2.84 (m, 1H); 2.74 (m, 1H); 2.54-2.60 (m, 2H); 2.39 (m, 1H); 1.75-1.82 (m, 2H); 1.44-1.56 (overlapped m, 2H); 1.51 (s, 3H).
(656) MS1 (ESI, m/z): 443.0 [M+H.sup.+] for C.sub.22H.sub.26N.sub.4O.sub.4S; t.sub.R=0.55 min.
Example 77: (R)-4-(5-(((1R,2R)-2-fluoro-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(657) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AX (0.084 g; 0.358 mmol), and proceeding successively in analogy to Example 37, step 37.i (88% yield) and Example 1, step 1.ii (45% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.040 g).
(658) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (d, J=1.0 Hz, 1H); 9.28 (d, J=1.4 Hz, 1H); 8.52 (d, J=0.5 Hz, 1H); 8.04 (m, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 5.25 (t, J=6.1 Hz, 1H); 4.57 (m, 1H); 4.36 (m, 1H); 3.59-3.74 (m, 2H); 3.07 (s, 3H); 2.85 (m, 1H); 2.40 (m, 1H); 1.96 (m, 1H); 1.52 (s, 3H); 1.32-1.43 (m, 2H).
(659) MS1 (ESI, m/z): 448.0 [M+H.sup.+] for C.sub.21H.sub.22N.sub.3O.sub.5FS; t.sub.R=0.55 min.
Example 78: (R)—N-hydroxy-4-(5-41-(2-hydroxyacetyl)piperidin-4-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(660) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation AY (0.110 g; 0.374 mmol), and proceeding successively in analogy to Example 37, step 37.i (100% yield) and Example 1, step 1.ii (35% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.044 g).
(661) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.05 (br. s, 1H); 9.30 (br. s, 1H); 8.52 (d, J=0.6 Hz, 1H); 8.04 (s, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 4.56 (overlapped m, 1H); 4.53 (t, J=5.5 Hz, 1H); 4.36 (m, 1H); 4.09 (dd, J=2.4, 5.3 Hz, 2H); 3.88 (m, 1H); 3.53 (m, 1H); 3.11-3.22 (m, 2H); 3.07 (s, 3H); 2.95 (m, 1H); 2.84 (m, 1H); 2.40 (m, 1H); 1.79-1.90 (m, 2H); 1.45-1.62 (overlapped m, 2H); 1.52 (s, 3H).
(662) MS1 (ESI, m/z): 501.0 [M+H.sup.+] for C.sub.24H.sub.28N.sub.4O.sub.6S; t.sub.R=0.67 min.
Example 79: (R)-4-(5-((4-(1-aminocyclopropyl)phenyl)ethynyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide formate
(663) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and tert-butyl (1-(4-iodophenyl)cyclopropyl)carbamate (0.100 g; 0.27 mmol), and proceeding successively in analogy to Example 7, step 7.i (42% yield) and Example 13, step 13.ii (35% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.044 g).
(664) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.51 (d, J=0.5 Hz, 1H); 7.99 (m, 1H); 7.66 (d, J=8.9 Hz, 1H); 7.54 (d, J=8.5 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 7.34 (dd, J=1.5, 8.9 Hz, 1H); 4.58 (m, 1H); 4.37 (m, 1H); 3.08 (s, 3H); 2.88 (m, 1H); 2.41 (m, 1H); 1.54 (s, 3H); 1.17-1.22 (m, 2H); 1.11-1.17 (m, 2H).
(665) MS1 (ESI, m/z): 467.0 [M+H.sup.+] for C.sub.24H.sub.26N.sub.4O.sub.4S; t.sub.R=0.57 min.
Example 80: (R)—N-hydroxy-4-(5-(5-(3-hydroxyoxetan-3-yl)penta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(666) Starting from the compound of Preparation J (0.082 g; 0.195 mmol) and the compound of Preparation AZ (0.080 g; 0.332 mmol), and proceeding successively in analogy to Example 37, step 37.i (81% yield) and Example 1, step 1.ii (67% yield), the title compound was obtained, after purification by CC (DCM-MeOH gradient), as a beige solid (0.046 g).
(667) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (s, 1H); 9.28 (s, 1H); 8.52 (s, 1H); 8.05 (s, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.30 (dd, J=1.5, 8.9 Hz, 1H); 6.08 (s, 1H); 4.57 (m, 1H); 4.45-4.48 (m, 2H); 4.41-4.44 (m, 2H); 4.36 (m, 1H); 3.07 (s, 3H); 2.86 (overlapped m, 1H); 2.87 (s, 2H); 2.40 (m, 1H); 1.52 (s, 3H).
(668) MS1 (ESI, m/z): 446.0 [M+H.sup.+] for C.sub.21H.sub.23N.sub.3O.sub.6S; t.sub.R=0.62 min.
Example 81: (R)—N-hydroxy-4-(5-((1-(2-hydroxyacetyl)azetidin-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-2-methyl-2-(methylsulfonyl)butanamide
(669) Starting from the compound of Preparation J (0.07 g; 0.167 mmol) and the compound of Preparation BA (0.088 g; 0.334 mmol), and proceeding successively in analogy to Example 37, step 37.i (100% yield) and Example 1, step 1.ii (12% yield), the title compound was obtained, after purification by CC (DCM-MeOH gradient), as a yellowish solid (0.01 g).
(670) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 11.04 (d, J=1.0 Hz, 1H); 9.28 (d, J=1.4 Hz, 1H); 8.53 (s, 1H); 8.07 (s, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.30 (dd, J=1.5, 8.9 Hz, 1H); 5.01 (t, J=6.1 Hz, 1H); 4.58 (m, 1H); 4.48 (m, 1H); 4.37 (m, 1H); 4.17-4.22 (m, 2H); 3.92 (d, J=6.0 Hz, 2H); 3.86 (m, 1H); 3.75 (m, 1H); 3.07 (s, 3H); 2.86 (m, 1H); 2.41 (m, 1H); 1.52 (s, 3H)
(671) MS1 (ESI, m/z): 473.0 [M+H.sup.+] for C.sub.22H.sub.24N.sub.4O.sub.6S; t.sub.R=0.61 min.
Example 82: (R)-4-(5-(6-amino-6-methylhepta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(672) Starting from the compound of Preparation J (0.085 g; 0.203 mmol) and the compound of Preparation BB (0.124 g; 0.384 mmol), and proceeding successively in analogy to Example 37, step 37.i (74% yield) and Example 13, step 13.ii (53% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a white solid (0.03 g).
(673) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.51 (d, J=0.6 Hz, 1H); 8.04 (m, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 4.51-4.61 (m, 1H); 4.37 (m, 1H); 3.07 (s, 3H); 2.84 (m, 1H); 2.48 (s, 2H); 2.39 (m, 1H); 1.52 (s, 3H); 1.14 (s, 6H).
(674) MS1 (ESI, m/z): 431.0 [M+H.sup.+] for C.sub.24H.sub.26N.sub.4O.sub.4S; t.sub.R=0.55 min.
Example 83: (R)-4-(5-((1-glycylpiperidin-4-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide formate
(675) Starting from the compound of Preparation J (0.1 g; 0.238 mmol) and the compound of Preparation BC (0.094 g; 0.239 mmol), and proceeding successively in analogy to Example 7, step 7.i (53% yield) and Example 13, step 13.ii (11% yield), the title compound was obtained, after purification by prep-HPLC (Method 3), as a white solid (0.013 g). MS1 (ESI, m/z): 500.0 [M+H.sup.+] for C.sub.24H.sub.29N.sub.5O.sub.5S; t.sub.R=0.57 min.
Example 84: (R)-4-(5-((1-glycylazetidin-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(676) Starting from the compound of Preparation J (0.09 g; 0.215 mmol) and the compound of Preparation BD (0.074 g; 0.232 mmol), and proceeding successively in analogy to Example 37, step 37.i and Example 13, step 13.ii, the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.037 g; 37% yield over the two steps).
(677) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.52 (s, 1H); 8.06 (s, 1H); 7.63 (d, J=8.9 Hz, 1H); 7.29 (dd, J=1.5, 8.9 Hz, 1H); 4.55 (m, 1H); 4.32-4.43 (m, 2H); 4.11-4.21 (m, 2H); 3.84 (m, 1H); 3.75 (m, 1H); 3.09-3.19 (m, 2H); 3.07 (s, 3H); 2.83 (m, 1H); 2.38 (m, 1H); 1.51 (s, 3H).
(678) MS1 (ESI, m/z): 472.0 [M+H.sup.+] for C.sub.22H.sub.25N.sub.5O.sub.5S; t.sub.R=0.53 min.
Example 85: (R)-4-(5-((1-(2-amino-2-methylpropanoyl)azetidin-3-yl)buta-1,3-diyn-1-yl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
(679) Starting from the compound of Preparation J (0.098 g; 0.233 mmol) and the compound of Preparation BE (0.178 g; 0.455 mmol), and proceeding successively in analogy to Example 37, step 37.i and Example 13, step 13.ii, the title compound was obtained, after purification by prep-HPLC (Method 3), as a beige solid (0.031 g; 27% yield over the two steps).
(680) .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.21 (br. s, 1H); 8.52 (s, 1H); 8.06 (d, J=1.0 Hz, 1H); 7.64 (d, J=8.9 Hz, 1H); 7.30 (dd, J=1.5, 8.9 Hz, 1H); 4.74 (m, 1H); 4.56 (m, 1H); 4.45 (m, 1H); 4.38 (m, 1H); 4.13 (m, 1H); 3.80 (m, 1H); 3.68 (m, 1H); 3.07 (s, 3H); 2.83 (m, 1H); 2.39 (m, 1H); 1.51 (s, 3H); 1.19 (s, 6H).
(681) MS1 (ESI, m/z): 500.0 [M+H.sup.+] for C.sub.24H.sub.29N.sub.5O.sub.5S; t.sub.R=0.55 min.
(682) Besides, the racemic mixtures of Reference Examples 1 to 7 can be separated into their enantiomers using, for example, chiral HPLC. Thus the following further invention compounds or salts would be obtained: (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-{5-[4-(3 morpholin-4-yl-propoxy)-phenyl]-indazol-2-yl}-butanamide formate; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-{5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-indazol-2-yl}-butanamide formate; (R)-4-{5-[2-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-indazol-2-yl}-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide formate; (R)-4-(5-but-2-ynyloxy-indazol-2-yl)-N-hydroxy-2-methylsulfonyl-2-methyl-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-(5-phenethyl-indazol-2-yl)-butanamide; (R)—N-hydroxy-2-methylsulfonyl-2-methyl-4-[5-(4-oxazol-2-yl-phenyl)-indazol-2-yl]-butanamide formate; and (R)-4-(5-(2-fluoro-3-methoxyphenyl)-2H-indazol-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide.
Pharmacological Properties of the Invention Compounds
In Vitro Assays
Bacterial Growth Minimal Inhibitory Concentrations:
Experimental Methods:
(683) Minimal Inhibitory Concentrations (MICs; mg/L) were determined in cation-adjusted Mueller-Hinton Broth by a microdilution method following the description given in “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically”, Approved standard, 7.sup.th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, Pa., USA (2006).
(684) Results:
(685) All Example compounds, except the compound of Example 62, were tested against several Gram-positive and Gram-negative bacteria. Typical antibacterial test results are given in Table 1 hereafter (MICs in mg/L). K. pneumoniae A-651 and Acinetobacter baumannii T6474 are multiply-resistant strains (in particular quinolone-resistant), while E. coli ATCC25922 and P. aeruginosa ATCC27853 are quinolone-sensitive strains.
(686) TABLE-US-00001 TABLE 1 Exam- MIC for MIC for MIC for MIC for ple E. coli P. aeruginosa A. Baumannii K. Pneumoniae No. ATCC25922 ATCC27853 T6474 A-651 RE1 0.5 4 4 1 RE2 1 4 4 1 RE3 1 8 8 2 RE4 4 8 32 8 RE5 0.5 8 0.25 2 RE6 0.125 8 4 0.25 RE7 0.125 2 0.5 0.125 1 0.063 2 1 0.063 2 0.125 4 1 0.5 3 0.063 2 0.5 0.125 4 0.125 4 2 0.5 5 0.063 4 2 0.063 6 0.125 4 2 0.5 7 0.25 2 0.5 0.125 8 0.25 4 0.125 0.5 9 0.063 2 0.25 0.063 10 0.5 2 2 0.5 11 0.063 8 2 0.063 12 0.063 2 1 0.125 13 0.125 0.5 32 0.25 14 0.25 2 16 0.25 15 2 2 >32 2 16 0.125 1 0.5 0.125 17 0.063 16 1 0.063 18 0.125 0.5 4 0.125 19 0.063 2 0.5 0.125 20 0.25 0.5 0.5 0.125 21 0.125 1 0.5 0.25 22 0.125 2 1 0.5 23 0.25 4 1 0.25 24 0.5 0.5 >32 1 25 0.063 0.5 0.5 0.063 26 0.5 1 8 0.5 27 0.063 0.5 0.25 0.125 28 0.5 1 >32 0.5 29 0.25 1 0.5 0.25 30 1 4 2 2 31 1 2 >32 1 32 0.5 1 32 0.5 33 0.063 0.5 2 0.125 34 0.063 0.5 1 0.125 35 0.125 4 0.25 0.5 36 0.063 0.25 2 0.125 37 0.063 0.25 2 0.063 38 0.5 1 >32 1 39 0.125 1 0.25 0.125 40 0.125 1 1 0.25 41 0.125 1 0.125 0.063 42 0.063 0.25 0.125 0.063 43 1 2 2 1 44 0.125 1 0.25 0.25 45 0.25 1 8 1 46 4 4 >32 8 47 0.25 1 1 0.5 48 2 2 >32 4 49 4 4 >32 4 50 0.5 2 2 1 51 1 0.5 1 0.5 52 0.125 2 1 0.5 53 ≦0.063 0.5 2 0.125 54 ≦0.063 0.5 4 ≦0.063 55 2 2 >32 4 56 0.25 0.5 >32 0.5 57 0.125 0.5 8 0.25 58 2 2 8 4 59 4 8 8 8 60 ≦0.063 0.5 ≦0.063 0.125 61 2 1 >8 4 63 2 8 8 4 64 0.125 0.25 4 0.5 65 0.125 0.5 >32 0.125 66 1 2 >32 4 67 0.125 0.25 32 0.125 68 1 1 >32 1 69 ≦0.063 0.25 2 0.125 70 1 2 >32 1 71 0.25 0.25 8 0.5 72 2 2 >8 4 73 0.125 1 32 0.25 74 0.125 0.5 4 0.125 75 0.125 0.5 >32 0.15 76 8 2 >32 32 77 0.125 0.25 4 0.25 78 0.5 1 4 2 79 0.125 1 2 0.25 80 0.5 1 32 1 81 0.5 1 4 1 82 4 4 >32 8 83 2 4 32 8 84 1 0.5 >32 4 85 4 2 >32 8 Cipro 0.5 >32 >8 >32
(687) The compounds of Examples 62 and 63 were tested against wild-type E. coli A-1261 in the absence of alkaline phosphatase or esterase, in the presence of an alkaline phosphatase and in the presence of an esterase. The corresponding antibacterial test results are given in Table 2 hereafter (MICs in mg/L).
(688) TABLE-US-00002 TABLE 2 MIC for E. coli A-1261 In the absence of In the presence of alkaline an alkaline In the presence of Example phosphatase phosphatase an esterase No. or esterase (2 i.U./mL) (10 i.U./mL) 62 >16 1 >16 63 0.25 0.5 0.063