Compounds and compositions for the inhibition of NAMPT

Patent metadata

Field	Value
Publication number	US-11279687-B2
Application number	US-202016824885-A
Country	US
Kind code	B2
Filing date	Mar 20, 2020
Priority date	Sep 3, 2010
Publication date	Mar 22, 2022
Grant date	Mar 22, 2022

Abstract

The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications and antidotes. An embodiment of the invention is the provision of a compound of Formula IIIA.

First claim

We claim:

1. A compound of Formula IIIA:

or a pharmaceutically acceptable salt thereof,
wherein:
R a is present 4 times, and each R a is independently selected from the group consisting of hydrogen, amino, oxo, halo, alkoxy, alkyl, haloalkyl, —N(alkyl) 2 , —NH(CO)O-alkyl, 1H-pyrazole, 1H-imidazole, and —C(O)NH 2 ;
the pyridine to which R a is attached can comprise a N-oxide formed with its N atom member;
R 1 is —NR 3 R 4 ;
R 3 is H, alkyl or —S(O) 2 alkyl;
R 4 is hydroxyalkyl, —S(O) 2 alkyl, —(CH 2 ) q cycloalkyl, —(CH 2 ) q heterocycloalkyl, or phenyl;
wherein each of said cycloalkyl, phenyl, or heterocycloalkyl of R 4 is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of:
cyano, hydroxyl, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkylalkoxy, haloalkoxy, arylalkenyl-, aryloxy, benzyloxy, oxo, —(CH 2 ) q —NR b R c , —(CH 2 ) q —CONR b R c , —S(O) 2 -alkyl, —S(O) 2 NH-alkyl, —S(O) 2 -heterocycloalkyl, —S(O) 2 —CF 3 , —C(O)alkyl, —C(O)aryl, —C(O)alkylenylaryl, —C(O)O-alkyl, —(CH 2 ) q cycloalkyl, cycloalkylalkoxy-, arylalkyl-, —(CH 2 ) q heteroaryl, and —(CH 2 ) q heterocycloalkyl;
wherein each of said cycloalkyl, heterocycloalkyl, or aryl may be substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, haloalkyl, or alkoxy;

R b and R c are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxy, aryl, alkoxyalkyl, —S(O) 2 alkyl and cycloalkyl; or R b and R c can form a 5 or 6 membered heterocycloalkyl group together with the nitrogen atom to which they are attached, wherein said heterocycloalkyl group may contain one or more additional heteroatom(s) selected from the group consisting of N, S and O; and
q is 0 or 1.

2. The compound of claim 1 , wherein R 3 is H or —S(O) 2 alkyl.

3. The compound of claim 1 , wherein R 4 is hydroxyalkyl, —S(O) 2 alkyl, —(CH 2 ) q cycloalkyl, or —(CH 2 ) q heterocycloalkyl.

4. The compound of claim 1 , wherein R 3 is H and R 4 is substituted phenyl.

5. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A compound selected from:
3-(4-{[2-methyl-4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
N-[2-(pyridin-3-yl)ethyl]-4-{[3-(trifluoromethoxy)benzene]sulfonyl}benzamide;
1-[(6-aminopyridin-3-yl)methyl]-3-[4-(benzenesulfonyl)phenyl]urea;
3-[4-(benzenesulfonyl)phenyl]-1-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}urea;
3-(4-{[2-fluoro-4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
4-(benzenesulfonyl)-N-{imidazo[1,2-a]pyridin-7-ylmethyl}benzamide;
4-(benzenesulfonyl)-N-(pyridin-3-ylmethyl)benzamide;
3-[4-(benzenesulfonyl)phenyl]-1-{[6-(1H-imidazol-1-yl)pyridin-3-yl]methyl}urea;
3-{[({4-[(4-chlorobenzene)sulfinyl]phenyl}carbamoyl)amino]methyl}pyridin-1-ium-1-olate;
N,N-dimethyl-4-[(4-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzene)sulfonyl]benzamide;
3-(4-{[2-methoxy-4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-[4-(benzenesulfonyl)phenyl]-1-(pyridin-3-ylmethyl)urea;
1-[4-(benzenesulfonyl)phenyl]-3-(1H-pyrazol-3-ylmethyl)urea;
N-{imidazo[1,2-a]pyridin-6-ylmethyl}-4-{[3-(trifluoromethoxy)benzene]sulfonyl}benzamide;
1-{[4-(benzenesulfonyl)phenyl]methyl}-3-(quinolin-6-yl)urea;
3-[4-(benzenesulfonyl)phenyl]-1-{[6-(dimethylamino)pyridin-3-yl]methyl}urea;
1-[6-(benzenesulfonyl)pyridin-3-yl]-3-(pyridin-3-ylmethyl)urea;
1-[(3-aminophenyl)methyl]-3-[4-(benzenesulfonyl)phenyl]urea;
3-{4-[(4-chlorobenzene)sulfinyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-[4-(2H-1,3-benzodioxole-5-sulfonyl)phenyl]-3-(pyridin-3-ylmethyl)urea;
4-[(2-chlorobenzene)sulfonyl]-N-{imidazo[1,2-a]pyridin-6-ylmethyl}benzamide;
4-[(3-chlorobenzene)sulfonyl]-N-{imidazo[1,2-a]pyridin-6-ylmethyl}benzamide;
3-[4-(benzenesulfonyl)phenyl]-1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}urea;
1-{4-[(2-phenoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-ylmethyl)urea;
1-[4-(benzenesulfonyl)phenyl]-3-{5H,6H,7H,8H-imidazo[1,2-a]pyridin-6-ylmethyl}urea;
3-{4-[(2-acetylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-[4-(benzenesulfonyl)phenyl]-3-{imidazo[1,2-a]pyridin-6-ylmethyl}urea;
3-(4-{[3-fluoro-4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-[4-(benzenesulfonyl)phenyl]-1-(quinolin-6-yl)urea;
1-{4-[(4-fluorobenzene)sulfonyl]phenyl}-3-{imidazo[1,2-a]pyridin-6-ylmethyl}urea;
N-{imidazo[1,2-a]pyridin-6-ylmethyl}-4-{[3-(trifluoromethyl)benzene]sulfonyl}benzamide;
4-[(3,5-difluorobenzene)sulfonyl]-N-{imidazo[1,2-a]pyridin-6-ylmethyl}benzamide;
3-{4-[(4-methanesulfonylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
N-{imidazo[1,2-a]pyridin-6-ylmethyl}-4-[(3-methoxybenzene)sulfonyl]benzamide;
1-(4-{8-oxatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaene-6-sulfonyl}phenyl)-3-(pyridin-3-ylmethyl)urea;
N-(1,3-benzothiazol-6-ylmethyl)-4-[(3-chlorobenzene)sulfonyl]benzamide;
1-[4-(benzenesulfonyl)phenyl]-3-{thieno[2,3-c]pyridin-2-ylmethyl}urea;
1-(4-benzoylphenyl)-3-(pyridin-3-ylmethyl)urea;
3-[4-(benzenesulfonyl)phenyl]-1-(pyridin-3-yl)urea;
4-(benzenesulfonyl)-N-(pyridin-3-yl)benzamide;
4-(benzenesulfonyl)-N-(pyridin-4-yl)benzamide;
3-{4-[4-(3-methoxyphenyl)piperazine-1-sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-methoxy-2-methylphenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-[4-(phenylsulfamoyl)phenyl]-3-(pyridin-3-ylmethyl)urea;
3-{4-[(3-chloro-4-fluorophenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{8-methyl-2,8-diazaspiro[5.5]undecane-2-sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{4-[4-(trifluoromethyl)phenyl]piperazine-1-sulfonyl}phenyl)urea;
3-{4-[(3,4-difluorophenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
N-methyl-5-[(4-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzene)sulfonyl]pyridine-2-carboxamide;
3-{4-[(4-chloro-2-methyl phenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[3-(3-methoxyphenyl)pentan-3-yl]sulfamoyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-methoxy-3-methylphenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[4-chloro-3-(trifluoromethyl)phenyl]sulfamoyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[6-(dimethylamino)pyridine-3-sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]sulfamoyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
(2S)—N,N-dimethyl-1-[(4-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzene)sulfonyl]pyrrolidine-2-carboxamide;
methyl 4-[(4-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzene)sulfonyl]piperazine-1-carboxylate;
3-{4-[(2-methoxyethyl)(methyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-{4-[4-(2H-1,3-benzodioxol-5-yl)piperazine-1-sulfonyl]phenyl}-3-(pyridin-3-ylmethyl)urea;
3-{4-[(2-methoxyphenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
N-(propan-2-yl)-3-[(4-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzene)sulfonyl]benzamide;
3-(4-{[(2-methoxyphenyl)methyl]sulfamoyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-fluoro-4-methylphenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-fluorophenyl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-[4-(cycloheptylsulfamoyl)phenyl]-3-(pyridin-3-ylmethyl)urea;
1-{4-[4-(pyrazin-2-yl)piperazine-1-sulfonyl]phenyl}-3-(pyridin-3-ylmethyl)urea;
3-{4-[(5-methylpyridin-3-yl)sulfamoyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[4-(2-methoxyphenyl (piperazine-1-sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan

Assignees

• Valo Health Inc
• Genentech Inc

Inventors

• Bair Kenneth W
• Baumeister Timm R
• Buckmelter Alexandre J
• Clodfelter Karl H
• Han Bingsong
• Lin Jian
• Reynolds Dominic J
• Smith Chase C
• Wang Zhongguo
• Zheng Xiaozhang
• Yuen Po-Wai

Classifications

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P19/10

  for osteoporosis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title