SMALL MOLECULE INHIBITORS OF ACETYL COENZYME A SYNTHETASE SHORT CHAIN 2 (ACSS2)
20220298115 · 2022-09-22
Inventors
- Sourav Basu (Uttar Pradesh, IN)
- Dharmendra B. YADAV (Uttar Pradesh, IN)
- Rajib Ghosh (Uttar Pradesh, IN)
- Ritesh Shrivastava (Uttar Pradesh, IN)
- Sandip Middya (Uttar Pradesh, IN)
- David PRYDE (Kent, GB)
- Monali Banerjee (Uttar Pradesh, IN)
- Arjun Surya (Uttar Pradesh, IN)
Cpc classification
C07D405/12
CHEMISTRY; METALLURGY
A61K47/64
HUMAN NECESSITIES
C07D413/04
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
A61K47/62
HUMAN NECESSITIES
C07D401/12
CHEMISTRY; METALLURGY
A61K47/549
HUMAN NECESSITIES
A61K47/6803
HUMAN NECESSITIES
C07D215/48
CHEMISTRY; METALLURGY
A61P1/16
HUMAN NECESSITIES
C07D401/04
CHEMISTRY; METALLURGY
C07D471/02
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D215/233
CHEMISTRY; METALLURGY
A61K47/62
HUMAN NECESSITIES
A61P1/16
HUMAN NECESSITIES
C07D215/48
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
Abstract
The present invention relates to compounds of formula (I). The compounds may be used to modulate the acetyl coenzyme A synthetase short chain.sub.2 (ACSS.sub.2) protein and may thereby treat, ameliorate or prevent a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurodegenerative disease, neurological disorder, cerebrovascular disease, cardiovascular disease, non-alcoholic fatty liver disease and obesity. Alternatively, or additionally, the compounds may be used to promote healthy ageing. (I)
##STR00001##
Claims
1. A compound of formula (I): ##STR00390## wherein X is CR.sup.3 or N; Y is CR.sup.4 or N; Z is CR.sup.5 or N; L is NR.sup.8 or is absent; R and R.sup.1 are each independently selected from the group consisting of H, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkenyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C.sub.1-C.sub.10 alkoxy and NR.sup.9R.sup.10; R.sup.2 is H, halogen, COOR.sup.9, CN, CONR.sup.9R.sup.10, NR.sup.9SO.sub.2R.sup.10, SO.sub.2NR.sup.9R.sup.10, NR.sup.9COR.sup.10, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C.sub.1-C.sub.10 alkylsulfonyl, NR.sup.9R.sup.10, optionally substituted C.sub.1-C.sub.10 alkoxy, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl; R.sup.3 is H, CN, halogen, COOH, CONR.sup.9R.sup.10, NR.sup.9R.sup.10, NO.sub.2, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkenyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C.sub.1-C.sub.10 alkoxy, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl; R.sup.4 and R.sup.5 are each independently selected from the group consisting of H, halogen, OH, CN, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C.sub.1-C.sub.10 alkoxy and optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl; R.sup.6 is H or optionally substituted C.sub.1-C.sub.10 alkyl; R.sup.7 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, or optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R.sup.8 is selected from the group consisting of H, halogen and optionally substituted C.sub.1-C.sub.10 alkyl; and R.sup.9 and R.sup.10 are each independently selected from the group consisting of H, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkenyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, optionally substituted C.sub.1-C.sub.10 alkoxy and NH.sub.2; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
2. The compound according to claim 1, wherein R and R.sup.1 are each independently be selected from the group consisting of H, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkenyl, optionally substituted C.sub.2-C.sub.6 alkenyl and optionally substituted C.sub.2-C.sub.6 alkynyl.
3. The compound according to claim 2, wherein R and R.sup.1 are each independently selected from an optionally substituted phenyl ring, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted C.sub.2-C.sub.6 alkynyl or an optionally substituted 5 or 6 membered heteroaryl.
4. The compound according to claim 3, wherein R and R.sup.1 are each an optionally substituted phenyl ring or methyl.
5. The compound according to any preceding claim, wherein R.sup.2 is H, COOR.sup.9, CONR.sup.9R.sup.10, CN, NR.sup.9COR.sup.10, NR.sup.9R.sup.10, NR.sup.9SO.sub.2R.sup.10, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.
6. The compound according to any preceding claim, wherein X is CR.sup.3, Y is CR.sup.4 and Z is CR.sup.5.
7. The compound according to any one of claims 1 to 5, wherein: X is N, Y is CR.sup.4 and Z is CR.sup.5; X is N, Y is N and Z is CR.sup.5; X is N, Y is CR.sup.4 and Z is N; X is CR.sup.3, Y is N and Z is CR.sup.5; or X is CR.sup.3, Y is CR.sup.4 and Z is N.
8. The compound according to any preceding claim, wherein R.sup.3 is H, CN, halogen, COOH, CONR.sub.2, NR.sub.2, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkenyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 alkoxy, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.
9. The compound according to claim 8, wherein R.sup.3 is H, CN, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.
10. The compound according to any preceding claim, wherein R.sup.4 and R.sup.5 are each independently selected from the group consisting of H, halogen, OH, CN, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkoxy or optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl.
11. The compound according to claim 10, wherein R.sup.4 and R.sup.5 are H, halogen, OH, CN or an optionally substituted C.sub.1-C.sub.6 alkyl.
12. The compound according to claim 11, wherein R.sup.4 and R.sup.5 are H.
13. The compound according to any preceding claim, wherein R.sup.6 is H or optionally substituted C.sub.1-C.sub.6 alkyl.
14. The compound according to any preceding claim, wherein R.sup.7 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, or optionally substituted mono or bicyclic 3 to 8 membered heterocycle.
15. The compound according to claim 14, wherein R.sup.7 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, or optionally substituted 3 to 6 membered heterocycle.
16. The compound according to any preceding claim, wherein L is absent.
17. The compound according to any one of claims 1 to 15, wherein L is NR.sup.8 and R.sup.8 is H or an optionally substituted C.sub.1-C.sub.6 alkyl.
18. The compound according to claim 1, wherein the compound is: 1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-butyl-3-(2,3-diphenylquinolin-6-yl)urea; 1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-butyl-3-(5-(2-hydroxypyridin-3-yl)-2,3-diphenylquinolin-6-yl)urea; 1-(2,3-bis(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-fluorophenyl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(2-methoxypyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(3-(2-methoxyphenyl)-2-phenylquinolin-6-yl)urea; 1-(2,3-bis(6-methoxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(2-(2-methoxyphenyl)-3-phenylquinolin-6-yl)urea; 1-(2,3-bis(2-methoxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-butyl)urea; (R)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-butyl-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea; 1-(2,3-bis(4-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-di(pyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(3-acetylphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-di(1H-pyrazol-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-butyl-3-(3-(2-methoxyphenyl)-2-phenylquinolin-6-yl)urea; 1-(2,3-di(pyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(3-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-fluorophenyl)-3-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(6-oxo-1,6-dihydropyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (S)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(2-hydroxypyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (S)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-(pyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(cyclohex-1-en-1-yl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-(dimethylamino)phenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-(pyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (S)-1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-butyl-3-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)urea; 1-(2-hydroxybutyl)-3-(3-phenyl-2-(pyridin-2-yl)quinolin-6-yl)urea; 1-(2-cyclohexyl-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-cyclopropyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(3-phenyl-2-(pyridin-3-yl)quinolin-6-yl)urea; 1-(2,3-bis(2-hydroxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)urea; 1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-methoxybutyl)urea; 1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea; 1-(3-(2-fluorophenyl)-2-(3-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-(4-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; methyl 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxylate; 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; (E)-1-(2-hydroxybutyl)-3-(3-phenyl-2-styrylquinolin-6-yl)urea; N-(2-(3-(2-fluorophenyl)-6-(3-(2-hydroxybutyl)ureido)quinolin-2-yl)phenyl)acetamide; 1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-(2-cyanophenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-aminophenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-([1,1′-biphenyl]-4-yl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(2-phenethyl-3-phenylquinolin-6-yl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 1-(2-(2-ethoxyphenyl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(2-(2-isobutoxyphenyl)-3-phenylquinolin-6-yl)urea; 1-(2-ethynyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-ethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 6-(3-(2-hydroxybutyl)ureido)-N-methyl-2,3-diphenylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-N,N-dimethyl-2,3-diphenylquinoline-4-carboxamide; N-cyclopropyl-6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxylic acid; 6-(3-(2-hydroxybutyl)ureido)-2-methyl-3-phenylquinoline-4-carboxamide; (S)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (S)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 6-(3-(2-hydroxybutyl)ureido)-2,3-dimethylquinoline-4-carboxamide; 1-(4-cyano-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 6-(3-(2-hydroxybutyl)ureido)-3-phenylquinoline-4-carboxamide; (R)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 3-(2-fluorophenyl)-6-(3-(2-hydroxybutyl)ureido)-2-methylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-2-methylquinoline-4-carboxamide; 1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-butyl-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-methoxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-methoxyethyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-hydroxybutyl)-3-(2-methyl-3-(pyridin-3-yl)quinolin-6-yl)urea; 1-(2-hydroxybutyl)-3-(2-methyl-3-(o-tolyl)quinolin-6-yl)urea; 1-(3-(2-chlorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(2-methyl-3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(2-methyl-3-(o-tolyl)quinolin-6-yl)urea; N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)acetamide; 1-(2,5-dimethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(5-cyclopropyl-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(5-bromo-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-hydroxybutyl)-3-(3-phenyl-2-(trifluoromethyl)quinolin-6-yl)urea; (S)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; (R)-1-(7-fluoro-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(4-(dimethylamino)-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)—N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)cyclopropanecarboxamide; N-(6-(3-(2-hydroxybutyl)ureido)-2-methyl-3-phenylquinolin-4-yl)acetamide; N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide; 1-(4-amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2-hydroxybutyl)-3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)urea; 1-(2-hydroxybutyl)-3-(4-(oxazol-2-yl)-2,3-diphenylquinolin-6-yl)urea; 1-(4-cyano-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; N-(1-(3-(2-methyl-3-phenylquinolin-6-yl)ureido)butan-2-yl)acetamide; (R)-1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2-hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(4-methoxy-2-methyl-3-phenylquinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(4-methyl-2,3-diphenylquinolin-6-yl)urea; (R)—N-benzyl-6-(3-(2-hydroxybutyl)ureido)-3-methyl-2-phenylquinoline-4-carboxamide; 1-(2,2-difluorobutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 6-(3-(2,2-difluorobutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 1-(2,2-difluorobutyl)-3-(2,3-diphenylquinolin-6-yl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-N,3-dimethyl-2-phenylquinoline-4-carboxamide; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-2-phenylquinoline-4-carboxamide; 1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)urea; (R)-1-(3-(2-fluorophenyl)-2-methyl-5-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-N-(1-methyl-1H-pyrazol-3-yl)-2,3-diphenylquinoline-4-carboxamide; (R)-1-(2,4-dimethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-2-phenylquinoline-4-carboxamide; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide; 1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-methoxyethyl)urea; (R)-1-(3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)ureido)butan-2-yl dihydrogen phosphate; N-(2,3-diphenylquinolin-6-yl)hexanamide; N-(2,3-bis(2-methoxyphenyl)quinolin-6-yl)hexanamide; N-(2-(2-methoxyphenyl)-3-phenylquinolin-6-yl)-4-oxohexanamide; N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)hexanamide; N-(2,3-diphenylquinolin-6-yl)-2,2-difluorohexanamide; N-(2-(2-fluorophenyl)-3-phenylquinolin-6-yl)-4-oxohexanamide; N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide; N-(2,3-diphenylquinolin-6-yl)-4-oxohexanamide; N-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-4-oxohexanamide; N-(2,3-diphenylquinolin-6-yl)-4-hydroxyhexanamide; N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide; N-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-4-hydroxyhexanamide; 4-hydroxy-N-(2-methyl-3-phenylquinolin-6-yl)hexanamide; 1-cyclohexyl-3-(2,3-diphenylquinolin-6-yl)urea; N-(2,3-diphenylquinolin-6-yl)-4-methylpiperazine-1-carboxamide; 4-acetyl-N-(2,3-diphenylquinolin-6-yl)piperazine-1-carboxamide; 1-allyl-3-(2,3-diphenylquinolin-6-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(prop-2-yn-1-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxycyclopentyl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(tetrahydro-2H-pyran-4-yl)urea; N-(2,3-diphenylquinolin-6-yl)-3-methoxypyrrolidine-1-carboxamide; 1-(2,3-diphenylquinolin-6-yl)-3-(pyridin-2-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-phenyl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(1-methylpyrrolidin-3-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(pyridin-4-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(1-(hydroxymethyl)cyclopentyl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(1-methyl-1H-pyrazol-4-yl)urea; 1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea; 1-(6,7-diphenyl-1,5-naphthyridin-2-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-diphenyl-1,7-naphthyridin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea; (R)-1-(6,7-diphenyl-1,5-naphthyridin-2-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2,3-diphenyl-1,7-naphthyridin-6-yl)-3-(2-hydroxybutyl)urea; N-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxamide; N-(6,7-diphenyl-1,5-naphthyridin-2-yl)-3-methoxypyrrolidine-1-carboxamide; or N-(2,3-diphenyl-1,7-naphthyridin-6-yl)-3-methoxypyrrolidine-1-carboxamide.
19. A conjugate of formula (II): ##STR00391## wherein, C is a compound of formula (I), as defined by any one of claims 1 to 18; L.sup.1 and L.sup.2 are linkers; T is a targeting moiety; and a is an integer between 1 and 5; b is an integer between 1 and 10; and z is an integer between 1 and 5.
20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, or a conjugate according to claim 19, and a pharmaceutically acceptable vehicle.
21. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, a conjugate according to claim 19, or a pharmaceutical composition according to claim 20, for use in therapy.
22. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, a conjugate according to claim 19, or a pharmaceutical composition according to claim 20, for use in modulating the acetyl coenzyme A synthetase short chain 2 (ACSS2) protein.
23. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, a conjugate according to claim 19, or a pharmaceutical composition according to claim 20, for use in treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurodegenerative disease, neurological disorder, cerebrovascular disease, cardiovascular disease, non-alcoholic fatty liver disease and obesity or for use in promoting healthy ageing.
24. A compound, conjugate or pharmaceutical composition for use according to claim 23, wherein the disease is cancer, and the cancer is selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, gastrointestinal stromal tumors, lung cancer, brain cancer, neuroblastoma, glial tumors, astrocytoma, glioblastoma, liver cancer, stomach cancer, sarcoma, leukaemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic carcinoma or renal carcinoma.
25. A compound, conjugate or pharmaceutical composition for use according to claim 23, wherein the disease is a viral infection, and the viral infection is a hepatitis C virus (HCV) infection or a human cytomegalovirus (HCMV) infection.
Description
EXAMPLES
[0484] Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (S) are given in parts-per-million downfield from tetramethylsilane (for .sup.1H-NMR) and upfield from trichloro-fluoro-methane (for .sup.19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl.sub.3, deuterochloroform; d.sub.6-DMSO, deuterodimethylsulphoxide; and CD.sub.3OD, deuteromethanol.
[0485] Mass spectra, MS (m/z), were recorded using electrospray ionisation (ESI). Where relevant and unless otherwise stated the m/z data provided are for isotopes .sup.19F, .sup.35Cl, .sup.79Br and .sup.127I.
[0486] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were performed under an atmosphere of nitrogen unless otherwise noted.
[0487] Flash column chromatography was carried out using pre-packed silica gel cartridges in a Combi-Flash platform. Prep-HPLC purification was carried out according to the General purification and analytical methods described above. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). All final compounds were >95% pure as judged by the LCMS or UPLC analysis methods described in the General purification and analytical methods above unless otherwise stated.
Example 45: 1-(2,2-Difluorobutyl)-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea
[0488] ##STR00169##
[0489] Example 45 was prepared according to the methods described in General Procedures 1, 3, 13, 14 and the methods described below.
Preparation 1: 3-(2-Fluorophenyl)-2-phenylquinolin-6-amine
[0490] ##STR00170##
Step 1: 2-(2-Fluorophenyl)-1-phenylethanone
[0491] ##STR00171##
[0492] To a stirred solution of commercially available 2-(2-fluorophenyl)acetic acid (35.0 g, 222.93 mmol) in benzene (350 mL) was added thionyl chloride (105 mL) at 0-5° C. and the resulting reaction mixture was allowed to slowly warmup to RT and was then refluxed for 4 h. The solvent was removed under high vacuum and the leftover residue was diluted with benzene (105 mL). AlCl.sub.3 (32.615 g, 245.22 mmol) was then added carefully portionwise at 0-5° C., and the reaction mixture then allowed to slowly warm to RT and stir at this temperature for 3 h. The reaction was monitored by TLC/LCMS and after completion the reaction mixture was poured into crushed ice, extracted with EtOAc and then washed with water followed by brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (35 g, yield 73.3%) as a white solid. LCMS m/z: 215 [M+H].
Step 2: 3-Chloro-2-(2-fluorophenyl)-3-phenylacrylaldehyde
[0493] ##STR00172##
[0494] To a stirred DMF (55 mL, 700.93 mmol) was added POCl.sub.3 (65.4 mL, 700.93 mmol) dropwise at 0-5° C. and the whole was stirred at RT for 1 h, before 2-(2-fluorophenyl)-1-phenylethanone (Preparation 1, Step 1) (50.0 g, 233.65 mmol) was added slowly at RT. The resulting reaction mixture was stirred at 60° C. for overnight. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was poured into crushed ice and stirred at RT for 1 h. The obtained solid precipitate was collected by filtration, dissolved in EtOAc, dried over anhydrous Na.sub.2SO.sub.4 and the solvent removed in vacuo to afford the title compound (55.0 g, yield 90%) as a crude off white solid which was used in the next step without any further purification. LCMS m/z: 261 [M+H].
Step 3: 3-(2-Fluorophenyl)-6-nitro-2-phenylquinoline
[0495] ##STR00173##
[0496] A stirred solution of commercially available p-nitroaniline (26.54 g, 192.307 mmol) and 3-chloro-2-(2-fluorophenyl)-3-phenylacrylaldehyde (Preparation 1, Step 2) (50.0 g, 192.307 mmol) in AcOH (70 mL) was refluxed for 16 h. TLC showed formation of new polar spot. The mass of the product was confirmed by LCMS. The reaction mixture was diluted with cold water and the product was extracted with EtOAc. The organics were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography to afford the titled compound (21 g, yield 31.7%) as a yellow solid. LCMS m/z: 245 [M+H].
Step 4: 3-(2-Fluorophenyl)-2-phenylquinolin-6-amine
[0497] ##STR00174##
[0498] To a stirred solution of 3-(2-fluorophenyl)-6-nitro-2-phenylquinoline (Preparation 1, Step 3) (500 mg, 1.453 mmol) in MeOH (10 mL) was added 10% Pd—C (100 mg, 50% w/w in water) under an inert atmosphere and the resulting reaction mixture was stirred under H.sub.2 gas balloon pressure at RT for 2 h. Progress of the reaction was monitored by TLC and UPLC-MS which showed complete conversion of the nitro group into its corresponding amino group. The H2 gas balloon was removed and the reaction mixture filtered under an inert atmosphere. The obtained filtrate was evaporated in vacuo to give the title compound (450 mg) as crude which was used in the next step without any further purification. LCMS m/z: 315 [M+H].
Preparation 2: 1-(2,2-Difluorobutyl)-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea (Example 45)
[0499] ##STR00175##
[0500] To a stirred solution of 3-(2-fluorophenyl)-2-phenylquinolin-6-amine (Preparation 1, Step 4) (404 mg, 1.286 mmol) in THF (10 mL) was added p-nitrophenyl chloroformate (285 mg, 1.415) at 0-5° C. and the whole stirred for 1 h at RT. TEA (781 mg, 7.718 mmol) and 2,2-difluorobutan-1-amine (280.06 mg, 2.573 mmol) were then added dropwise and further stirred for 3 h at RT. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mas was diluted with EtOAc and washed with 1N NaOH solution and finally with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to give a residue which was purified by prep-HPLC to afford the title compound (25 mg, yield 4%) as a white solid. LCMS m/z: 450.21 [M+H]; Purity 99.86%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.99 (t, J=7.5 Hz. 3H), 1.86-1.97 (m, 2H), 3.59-3.66 (m, 2H), 6.71 (t, J=6.2 Hz, 1H), 7.09-7.13 (m, 1H), 7.25-7.30 (m 4H), 7.35-7.42 (m 3H), 7.46-7.49 (m, 1H), 7.76-7.78 (m, 1H), 7.99 (d, J=9.05 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.28 (s, 1H), 9.08 (s, 1H).
Example 15: (R)-1-(3-(2-Fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea
[0501] ##STR00176##
[0502] Example 15 was prepared according to the methods described for the preparation of Example 45 and the method described below.
[0503] To a stirred solution of 3-(2-fluorophenyl)-2-phenylquinolin-6-amine (Preparation 1, Step 4) (9.0 g, 28.66 mmol) in THF (90 mL) was added p-nitrophenyl chloroformate (6.4 g, 31.526 mmol) at 0-5° C. and the whole stirred at RT for 3 h. TEA (11.58 g, 114.64 mmol) and (R)-1-aminobutan-2-ol (2.55 g, 28.66 mmol) were then added dropwise and further stirred for 2 h at RT. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N NaOH solution to remove any p-nitrophenol and with 1N HCl to remove unreacted amine, and finally with brine solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by trituration with acetone and hexane to afford the title compound (7.0 g, yield 57%) as a white solid. LCMS m/z: 430.34 [M+H]; Purity 99.46%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.90 (t, J=7.4 Hz, 3H), 1.34-1.46 (m 2H), 2.99-3.03 (m, 1H), 3.23-3.28 (m, 1H), 3.44 (t, J=6.5 Hz, 1H), 4.80 (d, J=5.15 Hz, 1H), 6.34 (t, J=5.55 Hz, 1H), 7.11 (t, J=8.95 Hz, 1H), 7.25-7.29 (m, 4H), 7.35-7.46 (m, 3H), 7.46-7.49 (m, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.97 (d, J=9.05 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 9.06 (s, 1H).
Example 72: (R)-1-(2-Hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea
[0504] ##STR00177##
[0505] Example 72 was prepared according to the methods described in General Procedures 1, 4, 11, 14, 15 and the methods described below.
[0506] Preparation 3: 2-Methyl-3-phenylquinolin-6-amine
##STR00178##
Step 1: N-Methoxy-N-methyl-2-phenylacetamide
[0507] ##STR00179##
[0508] To a stirred solution of commercially available phenyl acetic acid (4.18 g, 30.753 mmol) in DCM (40 mL) was added a catalytic amount of DMF (2 drops) and oxalyl chloride (5.855 g, 46.135 mmol) dropwise at 0-5° C. The resulting reaction mixture was stirred at RT for 2 h and then commercially available N,O-dimethylhydroxylamine hydrochloride (3.0 g, 30.75 mmol) added, followed by TEA (12.45 g, 123.03 mmol) at 0-5° C. and the mixture was further stirred at RT for 30 min. Progress of the reaction was monitored by TLC and LCMS, and after completion the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (4.0 g, yield 72.7%) as an off white solid. LCMS m/z: 180 [M+H].
Step 2: 1-Phenylpropan-2-one
[0509] ##STR00180##
[0510] To a stirred solution of N-methoxy-N-methyl-2-phenylacetamide (Preparation 3, Step 1) (1.0 g, 5.586 mmol) in dry THF (18 mL) was added methyl magnesium bromide (1.332 g, 3.72 mL, 3M solution in diethyl ether) at −78° C. under an inert atmosphere and the reaction mixture was maintained at the same temperature for 1 h. LCMS indicated that the reaction was 60% complete. The mixture was warmed to RT and stirred at RT for 2 h. The reaction was monitored by TLC and LCMS which now showed completion of the reaction. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (0.7 g, yield 93%) as a white solid. LCMS m/z: 135 [M+H].
Step 3: 6-Bromo-2-methyl-3-phenylquinoline
[0511] ##STR00181##
[0512] To a stirred solution of 1-phenylpropan-2-one (Preparation 3, Step 2) (1.098 g, 8.146 mmol) and commercially available 2-amino-5-bromobenzaldehyde (1.646 g, 8.146 mmol) in ethanol (65 mL) was added a 33% aq. KOH solution (6.584 mL) at RT. The resulting reaction mixture was refluxed at 70° C. for 1 h. The reaction was monitored by TLC and LCMS and after completion the solvents were evaporated to give a residue which was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (0.94 g, yield 38%) as a white solid. LCMS m/z: 298 [M+H].
Step 4: N-(4-Methoxybenzyl)-2-methyl-3-phenylquinolin-6-amine
[0513] ##STR00182##
[0514] To a stirred solution of 6-bromo-2-methyl-3-phenylquinoline (Preparation 3, Step 3) (921 mg, 3.099 mmol) in DMSO (12 mL) was added p-methoxy benzyl amine (2.44 mL, 18.594 mmol) followed by K.sub.2CO.sub.3 (1070 mg, 7.747 mmol) under an inert atmosphere, then CuI (590 mg, 3.099 mmol) and L-proline (178.68 mg, 1.549 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90° C. for 12 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was poured into ice-water. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give a crude product which was purified by column chromatography to afford the title compound (951 mg, yield 87%) as a yellow solid. LCMS m/z: 355 [M+H].
Step 5: 2-Methyl-3-phenylquinolin-6-amine
[0515] ##STR00183##
[0516] A solution of N-(4-methoxybenzyl)-2-methyl-3-phenylquinolin-6-amine (Preparation 3, Step 4) (920 mg, 2.137 mmol) in TFA (10 mL) was stirred at RT for 12 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was neutralized with an aqueous solution of NaHCO.sub.3, extracted with EtOAc and washed with a saturated solution of NaHCO.sub.3 followed by brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (644 mg, purity 90%) as a crude solid which was used in the next step without any further purification. LCMS m/z: 235 [M+H].
Preparation 4: (R)-1-(2-Hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea (Example 72)
[0517] ##STR00184##
[0518] To a stirred solution of 2-methyl-3-phenylquinolin-6-amine (Preparation 3, Step 5) (644 mg, 2.751 mmol) in THF (6 mL) was added p-nitrophenyl chloroformate (609.8 mg, 3.026 mmol) and the whole stirred at RT for 1 h. After complete consumption of the amine by TLC, TEA (1.535 mL, 11.00 mmol) and (R)-1-aminobutan-2-ol (269.68 mg, 3.025 mmol) were added dropwise and the combined mixture was further stirred at RT for 3 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc, washed with 1N NaOH solution thrice followed by brine and 1N HCl solution and again with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by crystallization with acetone and hexane to afford the title compound (393 mg, yield 41%) as a white solid. LCMS m/z: 350.22 [M+H]; Purity 99.71%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 0.88 (t, J=7.44 Hz, 3H), 1.28-1.44 (m, 2H), 2.50 (s, 3H), 2.93-2.99 (m, 1H), 3.18-3.32 (m, 1H), 3.40 (d, J=4.84 Hz, 1H), 4.76 (d, J=4.96 Hz, 1H), 6.25 (t, J=5.72 Hz, 1H), 7.40-7.50 (m, 5H), 7.61-7.64 (m, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.95 (s, 1H), 7.99 (s, 1H), 8.90 (s, 1H).
Example 101: (R)-1-(2-Hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea
[0519] ##STR00185##
[0520] Example 101 was prepared according to the methods described in General Procedures 1, 3, 17, 18 and the method described below.
Preparation s: 4-Methoxy-2,3-diphenylquinolin-6-amine
[0521] ##STR00186##
Step 1: 2-Azido-5-nitrobenzaldehyde
[0522] ##STR00187##
[0523] To a stirred solution of commercially available 2-bromo-5-nitrobenzaldehyde (2.0 g, 8.684 mmol) in DMF was added NaN.sub.3 (0.869 g, 13.378 mmol) at 50° C. and the reaction mixture maintained at this temperature for 30 min. The reaction was monitored by TLC and after complete consumption of the starting material; the reaction mixture was quenched with ice-water and stirred for another 30 min. to give a solid precipitate which was filtered off. The filtrate was then extracted with MTBE, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (1.35 g, yield 80.8%) as a yellow solid. LCMS m/z: 193 [M+H].
Step 2: 4-Methoxy-6-nitro-2,3-diphenylquinoline
[0524] ##STR00188##
[0525] To a stirred solution of 2-azido-5-nitrobenzaldehyde (Preparation 5, Step 1) (1.35 g, 5.862 mmol) in dry DCM was added MeOH (0.94 mL, 23.44 mmol) followed by diphenyl acetylene (1.044 g, 5.86 mmol) at RT. The reaction mixture was cooled to 0-5° C. and TMSOTf (5.22 g, 23.44 mmol) then added dropwise. The resulting reaction mixture was stirred at RT for 12 h. Progress of the reaction mixture was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to give the title compound (2.2 g, yield 88%) as a yellow solid. LCMS m/z: 357.25 [M+H].
Step 3: 4-Methoxy-2,3-diphenylquinolin-6-amine
[0526] ##STR00189##
[0527] To a stirred solution of 4-methoxy-6-nitro-2,3-diphenylquinoline (Preparation 5, Step 2) (832 mg, 2.335 mmol) in THF (10 mL) was added aq. HCl (0.3 mL) followed by SnCl.sub.2 (1742 mg, 9.338 mmol) at RT and the resulting reaction mixture was refluxed at 60° C. for 2 h. Progress of the reaction mixture was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc and washed with 0.5N NaOH and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to give the title compound (605 mg, yield 79.5%) as a yellow solid. LCMS m/z: 327 [M+H].
Preparation 6: (R)-1-(2-Hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea (Example 101)
[0528] ##STR00190##
[0529] To a stirred solution of 4-methoxy-2,3-diphenylquinolin-6-amine (Preparation 5, Step 3) (605 mg, 1.855 mmol) in THF (6 mL) was added p-nitrophenyl chloroformate (411.29 mg, 2.041 mmol) and the whole stirred at RT for 1 h. After complete consumption of the amine by TLC, TEA (1.035 mL, 7.42 mmol) and (R)-1-aminobutan-2-01 (181.87 mg, 2.0405 mmol) were added dropwise and the combined mixture was further stirred at RT for 3 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc, washed with 1N NaOH solution thrice followed by brine and 0.02N HCl solution and again with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by crystallization with acetone and hexane to afford the title compound (400 mg, yield 49%) as a white solid. LCMS m/z: 442.27 [M+H]; Purity 99.51%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 0.88 (t, J=7.4 Hz, 3H), 1.32-1.42 (m, 2H), 2.96-3.01 (m, 1H), 3.21-3.25 (m, 1H), 3.42 (d, J=4.76 Hz, 1H). 3.49 (s, 3H), 4.75 (d, J=5.16 Hz, 1H), 6.26 (t, J=5.48 Hz, 1H), 7.16-7.33 (m, 10H), 7.67 (dd, J′=2.36 Hz, J″=9.04 Hz, 1H), 7.93 (d, J=9.08 Hz, 1H), 8.29 (d, J=2.44 Hz, 1H), 9.04 (s, 1H).
Example 20: (R)-1-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea
[0530] ##STR00191##
[0531] Example 20 was prepared according to the methods described in General Procedures 1, 3, 7, 8, 9, 10 and the method described below.
Preparation 7: 2,3-Bis(2-fluorophenyl)quinolin-6-amine
[0532] ##STR00192##
Step 1: 6-Nitroquinolin-2(1H)-one
[0533] ##STR00193##
[0534] To a stirred solution of commercially available quinolin-2(1H)-one (5.0 g, 34.44 mmol) in H.sub.2SO.sub.4 (100 mL, 1.876 mmol) was added KNO.sub.3 (3.83 g, 37.884 mmol) portionwise at −10 to 0° C. The whole was stirred at 0-5° C. for 30 min. Completion of the reaction was confirmed by TLC/LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (7.4 g, crude) as a yellow solid. LCMS m/z: 188.97 [M−H].
Step 2: 3-Bromo-6-nitroquinolin-2(1H)-one
[0535] ##STR00194##
[0536] To a stirred solution of 6-nitroquinolin-2(1H)-one (Preparation 7, Step 1) (7.315 g, 38.46 mmol) in water (25.15 mL) was added NaBrO.sub.3 (6.965 g, 46.16 mmol) at -10 to 5° C., then aq. 48% HBr (133.8 mL) was added dropwise at the same temperature. The whole was then refluxed at 100° C. for 4 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was quenched in ice-water and stirred at 0-5° C. for 1 h. The resulting solid precipitate was filtered off and washed with water to give a solid material which was slurry washed with hexane (500 mL) to afford the title compound (8.0 g, yield 77.3%) as a yellow solid. LCMS m/z: 266.98 [M−H].
Step 3: 2,3-Dibromo-6-nitroquinoline
[0537] ##STR00195##
[0538] A solution of 3-bromo-6-nitroquinolin-2(1H)-one (Preparation 7, Step 2) (2.0 g, 7.435 mmol) in POBr.sub.3 (4.263 g, 14.869 mmol) was heated at 140° C. for 12 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was quenched with cold water and basified with aqueous NaHCO.sub.3 to pH 7-8. The aqueous mixture was extracted with EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (1.6 g crude) as a crude brown solid. LCMS m/z: 231 [M+H].
Step 4: 2,3-Bis(2-fluorophenyl)-6-nitroquinoline
[0539] ##STR00196##
[0540] A solution of 2,3-dibromo-6-nitroquinoline (Preparation 7, Step 3) (1.6 g, 4.805 mmol), (2-fluorophenyl)boronic acid (1.7 g, 12.151 mmol) and K.sub.3PO.sub.4 (4.118 g, 19.399 mmol) in a mixture of solvents 1,4-dioxane (20 mL) and water (2 mL) was degassed with argon for 30 min. then Pd.sub.2(dba).sub.3 (444 mg, 0.485 mmol) and PCy.sub.3 (272 mg, 0.969 mmol) were added. The resulting reaction mixture was stirred at 100° C. for 16 h under an inert atmosphere. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc, filtered and the filtrate was partitioned with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to give the title compound (1.2 g, yield 68.73%) as a pale yellow solid. LCMS m/z: 363 [M+H].
Step.: 2,3-Bis(2-fluorophenyl)quinolin-6-amine
[0541] ##STR00197##
[0542] To a stirred solution of 2,3-bis(2-fluorophenyl)-6-nitroquinoline (Preparation 7, Step 4) (1.2 g, 3.312 mmol) in THF (15 mL) was added aq. HCl (0.2 mL) followed by SnCl.sub.2.H.sub.2O (2.98 g, 13.22 mmol) at RT and the resulting reaction mixture was then refluxed at 60° C. for 2 h. Progress of the reaction mixture was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO.sub.3 and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to give the title compound (1.0 g, yield 91%) as a light yellow solid. LCMS m/z: 333 [M+H].
Preparation 8: (R)-1-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea (Example 20)
[0543] ##STR00198##
[0544] To a stirred solution of 2,3-bis(2-fluorophenyl)quinolin-6-amine (Preparation 7, Step 5) (1.0 g, 3.008 mmol) in THF (15 mL) was added p-nitrophenyl chloroformate (758 mg, 3.761 mmol) and the whole stirred at RT for 2 h. After complete consumption of the amine by TLC, TEA (1.257 g, 12.445 mmol) and (R)-1-aminobutan-2-ol (0.335 g, 3.764 mmol) were added dropwise and the combined mixture was further stirred at RT for 2 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc, washed with saturated solution of NaHCO.sub.3 thrice followed by brine and 0.02N HCl solution and again with brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (0.6 g, yield 45%) as a white solid. LCMS m/z: 448.37 [M+H]; Purity 98.05%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.90 (t, J=7.4 Hz, 3H), 1.34-1.45 (m, 2H), 2.99-3.03 (m, 1H), 3.24-3.27 (m, 1H), 3.44 (d, J=4.9 Hz, 1H), 4.81 (d, J=5.1 Hz, 1H), 6.39 (t, J=5.45 Hz, 1H), 7.04-7.20 (m, 4H), 7.30-7.36 (m, 3H), 7.44 (t, J=7.35 Hz, 1H), 7.75-7.77 (m, 1H), 7.97 (d, J=9.1 Hz, 1H), 8.17 (d, J=2.05 Hz, 1H), 8.29 (s, 1H), 9.15 (s, 1H)
Example 11s: (R)-6-(3-(2-Hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide
[0545] ##STR00199##
[0546] Example 115 was prepared according to the methods described in General Procedures 1, 4, 19, 23 and the method described below.
Preparation 9: 6-Amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide
[0547] ##STR00200##
Step 1: 6-Bromo-3-methyl-2-phenylquinoline-4-carboxylic acid
[0548] ##STR00201##
[0549] A stirred solution of commercially available 5-bromoisatin (3.0 g, 13.272 mmol) in 2N NaOH (60 mL) solution was refluxed at 90° C. for 30 min. The reaction mixture was then cooled to RT and commercially available propiophenone (1.959 g, 14.60 mmol) was added at RT. The whole was refluxed at 85-90° C. for 16 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was filtered and the obtained solid was dissolved in water and acidified with 2N HCl solution to give a solid precipitate which was filtered and washed with water to afford the title compound (1.3 g, yield 28.6%) as a white solid. LCMS m/z: 342 [M+H].
Step 2: 6-Bromo-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide
[0550] ##STR00202##
[0551] To a stirred solution of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (Preparation 9, Step 1) (600 mg, 1.753 mmol) in a mixture of solvents DCM (10 mL) and DMF (10 mL) was added oxalyl chloride (0.229 mL, 2.63 mmol) dropwise at 0-5° C. The whole was stirred at RT for 1 h under an inert atmosphere. After formation of the corresponding acid chloride (a small aliquot was quenched in MeOH and checked by LCMS), excess oxalyl chloride was evaporated in vacuo to give a residue. A pre-prepared mixture of 1-methyl-1H-pyrazol-3-amine (340 mg, 3.506 mmol) and TEA (0.977 mL, 7.01 mmol) in DCM (5 mL) was added dropwise into the concentrated acid chloride residue at low temperature and the resulting reaction mixture was further stirred at RT for 16 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with DCM, washed with brine solution and dried over anhydrous Na.sub.2SO.sub.4. The organic layer was concentrated under reduced pressure to give the crude compound which was purified by combi-flash to afford the title compound (603 mg, yield 79.0%) as a yellow solid. LCMS m/z: 421.30 [M+H].
Step 3: 6-((4-Methoxybenzyl)amino)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide
[0552] ##STR00203##
[0553] To a stirred solution of 6-bromo-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Preparation 9, Step 2) (550 mg, 1.306 mmol) in DMSO (10 mL) was added p-methoxy benzyl amine (899 mg, 6.527 mmol) followed by K.sub.2CO.sub.3 (451 g, 2.263 mmol) under an inert atmosphere, then CuI (497 mg, 2.611 mmol) and L-proline (171 mg, 1.305 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90° C. for 14 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was poured into ice-water. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give a crude product which was purified by column chromatography to afford the title compound (484 mg, yield 77.5%) as a yellow solid. LCMS m/z: 478 [M+H].
Step 4: 6-Amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide
[0554] ##STR00204##
[0555] A solution of 6-((4-methoxybenzyl)amino)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Preparation 9, Step 3) (484 mg, 1.014 mmol) in TFA (5 mL) was stirred at RT for 14 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was neutralized with an aqueous solution of NaHCO.sub.3, extracted with 5% MeOH in DCM and washed with a saturated solution of NaHCO.sub.3 followed by brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (450 mg, purity 91.69%) as a crude solid which was used in the next step without any further purification. LCMS m/z: 358.34 [M+H].
Preparation 10: (R)-6-(3-(2-Hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Example 115)
[0556] ##STR00205##
[0557] To a stirred solution of 6-amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Preparation 9, Step 4) (212 mg, 0.593 mmol) in THF (5 mL) was added p-nitrophenyl chloroformate (132 mg, 0.653 mmol) and the whole stirred at RT for 1 h. After complete consumption of the amine by TLC, TEA (0.33 mL, 2.374 mmol) and (R)-1-aminobutan-2-ol (63.47 mg, 0.712 mmol) were added dropwise and the combined mixture was further stirred at RT for 3 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc, washed with a saturated solution of NaHCO.sub.3 thrice followed by brine and 0.02N HCl solution and again with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (89.6 mg, yield 32%) as a white solid. LCMS m/z: 473.5 [M+H]; Purity 98.83%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.88 (bs, 3H), 1.33-1.41 (m, 2H), 2.31 (s, 3H), 2.95 (bs, 1H), 3.20 (bs, 1H), 3.41 (s, 1H), 3.79 (s, 3H), 4.77 (s, 1H), 6.20 (s, 1H), 6.72 (s, 1H), 7.49-7.57 (m, 5H), 7.68 (s, 1H), 7.79-7.82 (m, 2H), 7.91 (d, J=10.1 Hz, 1H), 9.07 (s, 1H) 11.12 (s, 1H).
Example 95: 1-(4-Amino-2,3-diphenylquinolin-6-yl)-1-(2-hydroxybutyl)urea
[0558] ##STR00206##
[0559] Example 95 was prepared according to the methods described in General Procedures 1, 4, 19, 22 and the method described below.
Preparation 11: 2,3-Diphenylquinoline-4,6-diamine
[0560] ##STR00207##
Step 1: 6-Bromo-2,3-diphenylquinolin-4-amine
[0561] ##STR00208##
[0562] To a stirred solution of 6-bromo-2,3-diphenylquinoline-4-carboxylic acid (Synthesized according to method described in preparation 9, Step 1) (2.0 g, 4.948 mmol) in DMF (30 mL) was added TEA (1.03 mL, 7.42 mmol) at 0-5° C. under a N.sub.2 atmosphere, and diphenyl phosphorazide (2.126 mL, 9.896 mmol) was added. The whole was stirred at RT for 2 h then water (30 mL) was added and refluxed at 100° C. for 4 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was diluted with water to give a solid precipitate which was filtered and washed with water followed by hexane. The obtained solid was dried in a vacuum oven to afford the title compound (1.5 g, yield 81%) as a pale yellow solid. LCMS m/z: 375.40/377.35 [M+H].
Step 2: N6-(4-Methoxybenzyl)-2,3-diphenylquinoline-4,6-diamine
[0563] ##STR00209##
[0564] To a stirred solution of 6-bromo-2,3-diphenylquinolin-4-amine (Preparation 11, Step 1) (500 mg, 1.06 mmol) in DMSO (15 mL) was added p-methoxy benzyl amine (0.83 mL, 6.39 mmol) followed by K.sub.2CO.sub.3 (365.7 mg, 2.65 mmol) under an inert atmosphere, then CuI (100.9 mg, 0.53 mmol) and L-proline (48.8 mg, 0.424 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90° C. for 16 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was poured into ice-water. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give a crude product which was purified by column chromatography to afford the title compound (329 mg, yield 71.5%) as a yellow solid.
[0565] LCMS m/z: 432.35 [M+H].
Step 3: 2,3-Diphenylquinoline-4,6-diamine
[0566] ##STR00210##
[0567] A solution of N6-(4-methoxybenzyl)-2,3-diphenylquinoline-4,6-diamine (Preparation 11, Step 2) (320 mg, 0.742 mmol) in TFA (7 mL) was stirred at RT for 16 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with water and neutralized with solid NaHCO.sub.3, extracted with EtOAc and washed with a saturated solution of NaHCO.sub.3 followed by brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (400 mg, purity 88%) as a crude solid which was used in the next step without any further purification. LCMS m/z: 312.19 [M+H].
Preparation 12: 1-(4-Amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea (Example 95)
[0568] ##STR00211##
[0569] To a stirred solution of 2,3-diphenylquinoline-4,6-diamine (Preparation 11, Step 3) (80 mg, 0.257 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (64.78 mg, 0.321 mmol) and the whole stirred at RT for 1 h. After complete consumption of the amine by TLC, TEA (0.14 mL, 1.06 mmol) and 1-aminobutan-2-ol (0.03 mL, 0.312 mmol) were added dropwise and the combined mixture was further stirred at RT for 3 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc and washed with 0.5N NaOH solution followed by brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (20 mg, yield 18.3%) as a white solid. LCMS m/z: 427.37 [M+H]; Purity 98.19%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.90 (t, J=7.4 Hz, 3H), 1.42-1.47 (m, 2H), 2.98-3.03 (m, 1H), 3.24-3.28 (m, 1H), 3.44-3.45 (m, 1H), 4.82 (d, J=4.95 Hz, 1H), 6.53 (s, 1H), 7.21 (d, J=7.05 Hz, 2H), 7.36-7.39 (m, 10H), 7.87-7.92 (m, 2H), 8.34 (s, 1H), 8.99 (s, 1H).
Example 94: N-(6-(R-(2-Hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide
[0570] ##STR00212##
[0571] Example 94 was prepared according to the methods described in General Procedures 1, 4, 19, 22 and the method described below.
Preparation 13: N-(6-Amino-2,3-diphenylquinolin-4-yl)methanesulfonamide
[0572] ##STR00213##
Step 1: N-(6-Bromo-2,3-diphenylquinolin-4-yl)-N-(methylsulfonyl)methanesulfonamide
[0573] ##STR00214##
[0574] To a stirred solution of 6-bromo-2,3-diphenylquinolin-4-amine (Preparation 11, Step 1) (800 mg, 2.12 mmol) in dry DMF (10 mL) was added NaH (153 mg, 6.38 mmol, 60% suspension in mineral oil) at 0-5° C. and the whole stirred at RT for 20 min. Then MeSO.sub.2Cl (0.5 mL, 6.36 mmol) was added dropwise at 0-5° C. and the whole stirred at RT for a further 2 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was quenched with a saturated solution of NH.sub.4Cl and extracted with MTBE and washed with water followed by brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (1.132 g crude) as a yellow gummy solid. LCMS m/z: 531.25 [M+H].
Step 2: N-(6-Bromo-2,3-diphenylquinolin-4-yl)methanesulfonamide
[0575] ##STR00215##
[0576] To a stirred solution of N-(6-bromo-2,3-diphenylquinolin-4-yl)-N-(methylsulfonyl)methane-sulfonamide (Preparation 13, Step 1) (1.132 g, 2.13 mmol) in DMSO (10 mL) was added Cs.sub.2CO.sub.3 (2.776 g, 8.5 mmol) and the mixture heated in a sealed tube at 120° C. for 16 h. The reaction was checked by TLC/LCMS and after completion the reaction mixture was quenched with ice-water and extracted with EtOAc, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by combi-flash to afford the title compound (900 mg, yield 93%) as a brown solid. LCMS m/z: 453.17 [M+H].
Step 3: N-(6-((4-Methoxybenzyl)amino)-2,3-diphenylquinolin-4-yl)methanesulfonamide
[0577] ##STR00216##
[0578] To a stirred solution of N-(6-bromo-2,3-diphenylquinolin-4-yl)methanesulfonamide (Preparation 13, Step 2) (383 mg, 0.84 mmol) in DMSO (15 mL) was added p-methoxy benzyl amine (0.667 mL, 5.06 mmol) followed by K.sub.2CO.sub.3 (289.8 mg, 2.1 mmol) under an inert atmosphere, then CuI (80 mg, 0.50 mmol) and L-proline (39 mg, 0.336 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90° C. for 16 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was poured into ice-water. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give a crude product which was purified by column chromatography to afford the title compound (300 mg, yield 69.7%) as a yellow solid. LCMS m/z: 510.37 [M+H].
Step 4: N-(6-Amino-2,3-diphenylquinolin-4-yl)methanesulfonamide
[0579] ##STR00217##
[0580] A solution of N-(6-((4-methoxybenzyl)amino)-2,3-diphenylquinolin-4-yl)methanesulfonamide (Preparation 13, Step 3) (293 mg, 0.575 mmol) in TFA (4 mL) was stirred at RT for 16 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with water and neutralized with solid NaHCO.sub.3, extracted with EtOAc and washed with a saturated solution of NaHCO.sub.3 followed by brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (400 mg, crude) as a yellow gummy semisolid which was used in the next step without any further purification. LCMS m/z: 390.31 [M+H].
Preparation 14: N-(6-(3-(2-Hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide (Example 94)
[0581] ##STR00218##
[0582] To a stirred solution of N-(6-amino-2,3-diphenylquinolin-4-yl)methanesulfonamide (Preparation 13, Step 4) (400 mg, 1.02 mmol) in THF (5 mL) was added p-nitrophenyl chloroformate (258.86 mg, 1.28 mmol) and the whole stirred at RT for 1 h. After complete consumption of the amine by TLC, TEA (0.58 mL, 4.207 mmol) and 1-aminobutan-2-ol (0.12 mL, 1.28 mmol) were added dropwise and the combined mixture was further stirred at RT for 3 h. Progress of the reaction was monitored by TLC/LCMS and after completion the reaction mixture was diluted with EtOAc and washed with 0.5N NaOH solution followed by brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (150 mg, yield 29%) as a white solid. LCMS m/z: 505.37 [M+H]; Purity 98.16%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.90 (t, J=7.4 Hz, 3H), 1.34-1.46 (m, 2H), 2.24 (s, 3H), 2.98-3.03 (m, 1H), 3.24-3.35 (m, 1H), 3.45 (s, 1H), 4.81 (d, J=5.1 Hz, 1H), 6.36 (d, J=5.1 Hz, 1H), 7.22-7.34 (m, 10H), 7.97 (d, J=9 Hz, 1H), 8.05 (d, J=9.15 Hz, 1H), 8.17 (s, 1H), 9.16 (s, 1H), 9.56 (bs, 1H).
Example 145: 1-(6,7-Diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea
[0583] ##STR00219##
[0584] Example 145 was prepared according to the methods described in General Procedures 1, 4, 15 and the method described below.
Preparation 16: 6,7-Diphenyl-1,8-naphthyridin-3-amine
[0585] ##STR00220##
Step-1:6-Bromo-2,3-diphenyl-1,8-naphthyridine
[0586] ##STR00221##
[0587] To a stirred solution of commercially available 2-amino-5-bromonicotinaldehyde (250 mg, 1.24 mmol) in piperidine (3 mL), 1,2-diphenylethan-1-one (244 mg. 1.24 mmol) was added at room temperature and the resulting reaction mixture was heated at 120° C. for 16 h in a sealed tube. The reaction was monitored by LCMS and after completion of the reaction, it was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (3×50 mL) and washed with water (3×50 mL) followed by brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography on silica gel to give the title compound (200 mg, 45% yield) as an off white solid. LCMS m/z: 361 [M+H].
Step-2: N-(4-Methoxybenzyl)-6,7-diphenyl-1,8-naphthyridin-3-amine
[0588] ##STR00222##
[0589] To a stirred solution of 6-bromo-2,3-diphenyl-1,8-naphthyridine (Preparation 16, Step 1) (400 mg, 1.108 mmol) in toluene (10 mL), p-methoxy benzyl amine (227.70 mg, 1.66 mmol), K.sub.3PO.sub.4 (704.70 mg, 3.32 mmol) and X-Phos (105.48 mg, 0.222 mmol) were added and the reaction mixture was degassed with N.sub.2 gas for 10 min. After that Pd.sub.2(dba).sub.3 (101.38 mg, 0.111 mmol) was added to the reaction mixture. The whole reaction mixture was capped and stirred at 100° C. for 16 h. The reaction was monitored by LCMS and after completion of the reaction the reaction mixture was quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to give a crude product which was purified by column chromatography (silica gel, eluent: 60% EtOAc in hexane) to afford the title compound (300 mg, 65% yield) as a reddish gummy solid. LCMS m/z: 418.0 [M+H].
Step-3: 6,7-Diphenyl-1,8-naphthyridin-3-amine
[0590] ##STR00223##
[0591] To a stirred solution of N-(4-methoxybenzyl)-6,7-diphenyl-1,8-naphthyridin-3-amine (Preparation 16, Step 2) (190 mg, 0.455 mmol) in DCM (1 mL) was added TFA (1.8 mL) and the whole stirred for 2 h. The reaction was monitored by LCMS and after completion of the reaction it was basified with saturated sodium bicarbonate solution and extracted with EtOAc (3×50 mL), washed with water (3×50 mL) followed by brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel, eluent: 80% EtOAc in hexane) to afford the title compound (100 mg, 73% yield) as a yellowish gum. LCMS m/z: 297.9 [M+H].
Preparation 17: 1-(6,7-Diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea (Example 145)
[0592] ##STR00224##
[0593] To a stirred solution of 6,7-diphenyl-1,8-naphthyridin-3-amine (Preparation 16, Step 3) (150 mg, 0.504 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (152.51 mg, 0.757 mmol) at 0-5° C. and the whole stirred at room temperature for 3 h. To the reaction mixture was added TEA (0.352 mL, 2.52 mmol) and 1-aminobutan-2-ol (0.053 mL, 0.555 mmol) at the same temperature and the whole stirred for another 6 h. The reaction was monitored by LCMS and after completion the solvent was evaporated to give the crude product. The crude was purified by reverse phase prep-HPLC to afford the title compound (23 mg, 11% yield) as an off white solid. LCMS m/z: 413.5 [M+H]; Purity 99.45%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 0.89 (t, J=7.4 Hz, 3H), 1.32-1.39 (m, 1H), 1.41-1.48 (m, 1H), 2.98-3.05 (m, 1H), 3.23-3.28 (m, 1H), 3.45 (d, J=4.8 Hz, 1H), 4.78 (d, J=5.08 Hz, 1H), 6.48 (d, J=5.32 Hz, 1H), 7.26-7.39 (m, 10H), 8.35 (s, 1H), 8.57 (d, J=2.72 Hz, 1H), 8.93 (d, J=2.72 Hz, 1H), 9.28 (s, 1H).
Preparation 18: 6-Chloro-2,3-diphenyl-1,5-naphthyridine
[0594] ##STR00225##
Step-1: 3-Amino-6-chloropicolinamide
[0595] ##STR00226##
[0596] To a stirred solution of commercially available 3-amino-6-chloropicolinonitrile (4.0 g, 26.1 mmol) in EtOH (40.0 mL) was added SnCl.sub.2 (9.92 g, 52.3 mmol) and the reaction mixture was stirred at 90° C. for 16 h. Progress of the reaction was monitored by LCMS and after completion of the reaction, the excess solvent was concentrated under reduced pressure and the reaction mixture was quenched with 2M NaOH solution to make the pH 8-9 and the product was then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (1×30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (3.2 g, 71.2% yield) as a crude light yellow solid which was used in the next step without any further purification. LCMS m/z: 172.0 [M+H].
Step-2: -Amino-6-chloropicolinic acid
[0597] ##STR00227##
[0598] 3-Amino-6-chloropicolinamide (Preparation 18, Step-1) (3.0 g, 17.5 mmol) was taken up in cone. HCl (15 mL) and heated to 110° C. for 5 h. The solvent was removed under reduced pressure to afford the title compound (3.0 g, crude) as a yellow solid. The crude was used in the next step without any further purification. LCMS m/z: 173.09 [M+H].
Step-3: (3-Amino-6-chloropyridin-2-yl)methanol
[0599] ##STR00228##
[0600] To a stirred solution of 3-amino-6-chloropicolinic acid (Preparation 18, Step-2) (3.0 g, 17.4 mmol) in THF (30.0 mL) was added BH.sub.3-THF (1M in THF) (69.5 mL, 69.5 mmol) and the reaction mixture was stirred at room temperature for 48 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was diluted with HCl and H.sub.2O, then neutralized with NaHCO.sub.3 and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated to afford the title compound (2.5 g, crude) as a yellow sticky solid which was used in the next step without any further purification.
Step-4: 3-Amino-6-chloropicolinaldehyde
[0601] ##STR00229##
[0602] To a stirred solution of (3-amino-6-chloropyridin-2-yl)methanol (Preparation 18, Step-3) (2.5 g, 15.8 mmol) in DCM (50 mL) was added MnO.sub.2 (2.75 g, 31.6 mmol). After 24 h another portion of MnO.sub.2 (2 eq.) was added to the mixture and the whole was stirred for a further 24 h at RT. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was filtered through Celite, and the solvent was removed in vacuo to afford the title compound (950 mg, 38.4% yield) as a yellow solid. LCMS m/z: 156.84 [M+H].
Step-5: 6-Chloro-2,3-diphenyl-1,5-naphthyridine
[0603] ##STR00230##
[0604] To a stirred solution of 3-amino-6-chloropicolinaldehyde (Preparation 18, Step-4) (100 mg, 0.64 mmol) in DMF (2.0 mL) was added K.sub.2CO.sub.3 (88.6 mg, 0.64 mmol) and 1,2-diphenylethan-1-one (126 mg, 0.64 mmol) and the reaction mixture was stirred at 90° C. for 16 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was quenched with crushed ice and cold water (20 mL). The product was extracted using EtOAc (3×20 mL) and the combined organic layers were washed with brine solution (1×30 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative-TLC (20% EtOAc-Hexane) to afford the title compound (3 mg, 1.48% yield) as an off white solid. LCMS m/z: 316.9 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 8.53 (d, J=8.8 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.31-7.40 (m, 10H),
Preparation 19: N-(4-Methoxybenzyl)-2,3-diphenyl-1,7-naphthyridin-6-amine
[0605] ##STR00231##
Step-1: 6-Chloro-2,3-diphenyl-1,7-naphthyridine
[0606] ##STR00232##
[0607] To a stirred solution of commercially available 5-amino-2-chloroisonicotinaldehyde (300 mg, 1.92 mmol) in DMF (6.0 mL) were added K.sub.2CO.sub.3 (265.7 mg, 1.92 mmol) and 1,2-diphenylethan-1-one (377 mg, 1.92 mmol) and the reaction mixture was stirred at 90° C. for 16 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was quenched with crushed ice and cold water (20 mL). The product was extracted using EtOAc (3×20 mL) and the combined organic layers were washed with brine solution (3×20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under reduced pressure to afford the crude product which was purified by preparative-TLC (20% EtOAc-Hexane) to afford the title compound (240 mg, 34.9% yield) as an off white solid. LCMS m/z: 316.9 [M+H].
Step-2: N-(4-Methoxybenzyl)-2,3-diphenyl-1,7-naphthyridin-6-amine
[0608] ##STR00233##
[0609] To a degassed solution of 6-chloro-2,3-diphenyl-1,7-naphthyridine (Preparation 19, Step-1) (St mg, 0.32 mmol) in toluene (1 mL) were added p-methoxybenzyl amine (0.08 mL, 0.63 mmol), K.sub.3PO.sub.4 (201 mg, 0.95 mmol), Brett-phos (57.23 mg, 0.063 mmol) and Brettphos-Pd-G.sup.1 (50.43 mg, 0.063 mmol). The whole reaction mixture was capped and stirred at 130° C. for 1 h in the microwave. After completion of the reaction (monitored by LCMS) the reaction mixture was quenched with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine solution (1×10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated to give the crude product which was purified by column chromatography (silica gel, eluent: 5000 EtOAc in hexane) followed by prep-TLC to afford the title compound (10 mg, crude) as a brown solid. LCMS m/z: 418.0 [M+H].
TABLE-US-00001 LCMS Purity Ex Structure IUPAC Name 1H-NMR [M + H] (%) 1
TABLE-US-00002 IUPAC Ex. Structure name 146
Example 128: N-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide
[0610] ##STR00374##
[0611] Example 128 was prepared according to the methods described in General Procedures 1, 2, 3, 7, 8, 9, 10 and the method described below.
Preparation 1s: N-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide (Example 124)
[0612] ##STR00375##
[0613] To a stirred solution of 4-oxohexanoic acid (56.2 mg, 0.432 mmol) in DMF (2 mL) was added DIPEA (0.103 mL, 0.602 mmol) and HATU (171.68 mg, 0.452 mmol). Stirring was continued for 10 min., then 2,3-bis(2-fluorophenyl)quinolin-6-amine (Preparation 7 Step 5) (100 mg, 0.301 mmol) was added. The whole was stirred at RT for 2 h. Progress of the reaction was confirmed by TLC/LCMS and after completion the reaction mixture was diluted with water and extracted with MTBE, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (39 mg, yield 29%) as a white solid. LCMS m/z: 445.2 [M+H]; Purity 98.04%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.96 (t, J=7.3 Hz, 3H) 2.52 (t, J=7.35 Hz, 2H), 2.66 (t, J=6.65 Hz, 2H), 2.79 (t, J=6.6 Hz, 2H), 7.03-7.21 (m, 4H), 7.31-7.39 (m, 3H), 7.45 (t, J=7.55 Hz, 1H), 7.89 (dd, J′=2.1 Hz, J″=9.15 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 8.37 (s, 1H), 8.45 (d, J=1.85 Hz, 1H), 10.41 (s, 1H).
Preparation 16: N-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide (Example 128)
[0614] ##STR00376##
[0615] To a stirred solution of N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide (Preparation 15) (50 mg, 0.113 mmol) in MeOH (2 mL) was added NaBH.sub.4 (4.26 mg, 0.113 mmol) at 0-5° C. and the whole stirred at the same temperature for 1 h. After completion of the reaction (monitored by TLC and LCMS) the reaction mixture was quenched with water and extracted with EtOAc, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (15 mg, yield 29.8%) as a white solid. LCMS m/z: 447.22 [M+H]; Purity 98.69%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 0.89 (t, J=7.35 Hz, 3H), 1.23 (s, 1H), 1.36-1.45 (m, 2H), 1.60-1.63 (m, 1H), 1.78-1.81 (m, 1H), 2.46-2.48 (m, 1H), 3.39 (d, J=3.75 Hz, 1H), 4.49 (d, J=5.3 Hz, 1H), 7.05 (t, J=9.4 Hz, 1H), 7.10-7.21 (m, 3H), 7.31-7.37 (m, 3H), 7.45 (t, J=7.25 Hz, 1H), 7.90 (t, J=7.15 Hz, 1H), 7.92-7.05 (m, 1H), 8.38 (s, 1H), 8.49 (s, 1H), 10.34 (s, 1H)
TABLE-US-00003 LCMS IUPAC [M + Purity Ex Structure Name 1H NMR H] (%) 118
[0616] Biological Assays
[0617] ACSS2 Enzyme Assay
[0618] Novel compounds were screened in a human ACSS2 enzyme assay. Briefly, the ACSS2 enzyme reaction was monitored by directly measuring acetyl-CoA formation. The cytosolic fraction of BT474 cells was used as a source of the ACSS2 enzyme. A short protocol for this assay is provided below.
[0619] Preparation of Cytosolic Fraction from BT474 Cells
[0620] 9×10.sup.6 cells were harvested by trypsinization followed by centrifugation. The cell pellet was washed with PBS and dissolved in 500 μl STM buffer (50 mM Tris-HCl pH7.4, 250 mM sucrose, 5 mM MgCl.sub.2 & protease-phosphatase inhibitor cocktail) and homogenized at 600-1000 rpm for 1 min. on ice followed by incubation for 30 min. with intermittent vortexing. Supernatant was collected by centrifugation at 800 g for 15 min. at 4° C. Cytosolic fraction was prepared by further centrifugation of the supernatant at 12000 g for 15 min. at 4° C. Total protein content of the cytosolic fraction was estimated & diluted to 1 mg/ml concentration in storage buffer (25 mM Tris-HCl pH7.4, 1 mM MgCl.sub.2, 1 mM DTT & 10% glycerol) and stored at −80° C. for further use.
[0621] Assay Protocol
[0622] 100 ng of cytosolic fraction in buffer composed of 25 mM Tris-HCl pH7.4 1 mM MgCl.sub.2, 1 mM DTT & 0.05% Tween20 was preincubated with desired concentrations of novel compounds for 5 min. maintaining 1% DMSO. Reaction was started with addition of substrate mix (100 μM of acetate, CoA and ATP) and incubated for 2 h at 25° C. with constant shaking at 500 rpm. Post incubation the reaction was terminated by addition of 10% TCA followed by 5 fold dilution in water. The reaction mixture was centrifuged at 800 g for 10 min. at RT and acetyl-CoA detected in supernatant by LC-MS/MS (QTrap5500 ABSCIEX).
[0623] Cell Based [.sup.14C] Acetate Incorporation Assay
[0624] In the cellular assay, ACSS2 inhibitors were screened against [.sup.14C] acetate incorporation in macromolecules. 4×10.sup.4 BT474 cells were plated in 96 well plates in growth media composed of DMEM & 10% FBS and incubated overnight in a 37° C., 5% CO.sub.2 incubator. The following day the cells were washed in HBSS and the assay was performed in 100 μl of HBSS. 50 μl of 4× compound in 4% DMSO was added to the cells and preincubated for 10 min. at 37° C. 50 μl of acetate solution (0.1 μCi .sup.14C acetate+10 μM .sup.12C acetate) was added to each well of the plate and incubated for 3 h in a 37° C., 5% CO.sub.2 incubator. Following incubation, cells were harvested with water on polyethylene imine (PEI) presoaked GF/C filtermat, air dried and radioactive count were recorded in Trilux micro beta Liquid Scintillation Counter (PerkinElmer).
[0625] In the tables below, IC.sub.50 value ranges for exemplary compounds are given. The IC.sub.50 ranges are indicated as “A” for values less than 100 nM, “B” for values less than or equal to 1 μM, “C” for values less than or equal to 10 μM, and “D” for values greater than 10 μM.
[0626] ACSS2 Activity
TABLE-US-00004 Enzyme Cellular Ex Activity Activity 1 A A 2 A A 3 A A 4 A A 5 A A 6 A A 7 A A 8 A A 9 D C 10 A A n B C 12 A A 13 B B 14 A A 15 A A 16 A A 17 A A 18 A A 19 A C 20 A A 21 C C 22 C D 23 A A 24 B C 25 B B 26 A A 27 B C 28 A A 29 D D 30 A A 31 A A 32 B B 33 A A 34 A A 35 A A 36 A A 37 A A 38 A B 39 D C 40 B C 41 A A 42 D D 43 A B 44 A A 45 A A 46 A A 47 A A 48 A A 49 A A 50 C D 51 A A 52 A A 53 A B 54 A A 55 C D 56 C C 57 A A 58 A A 59 A A 60 A A 61 A A 62 A A 63 A A 64 A A 65 A C 66 A B 67 A A 68 A A 69 C D 70 A A 71 B D 72 A A 73 A B 74 C D 75 A A 76 B A 77 A B 78 B B 79 A B 80 A A 81 A A 82 B D 83 A A 84 A A 85 A A 86 A A 87 A A 88 C D 89 B B 90 B B 91 A A 92 A A 93 A B 94 A A 95 A A 96 A A 97 A A 98 B A 99 B B 100 A A 101 A A 102 A A 103 A A 104 A A 105 A A 106 A A 107 A A 108 A A 109 A B 110 A A 111 A B 112 A A 113 A A 114 A B 115 A B 116 B A 117 A A 118 B B 119 A A 120 A A 121 A B 122 C D 123 A A 124 A A 125 A A 126 A A 127 A A 128 A A 129 A A 130 A B 131 B B 132 C D 133 C D 134 B B 135 B B 136 B B 137 B B 138 A A 139 D D 140 D D 141 C D 142 D D 143 D C 144 B A 145 B B