Compounds and compositions for the inhibition of NAMPT

Patent metadata

Field	Value
Publication number	US-10329275-B2
Application number	US-201816008378-A
Country	US
Kind code	B2
Filing date	Jun 14, 2018
Priority date	Sep 3, 2010
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

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 IIA:

or a pharmaceutically acceptable salt thereof,
wherein:
R a is present 1, 2, 3 or 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; and
R 1 is haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl;
wherein each of said cycloalkyl, heterocycloalkyl, or heteroaryl of R 1 is unsubstituted or substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, or alkoxy;
wherein said aryl of R 1 is substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, or alkoxy.

2. The compound of claim 1 , wherein R 1 is haloalkyl.

3. The compound of claim 1 , wherein R 1 is cycloalkyl that is optionally substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, or alkoxy.

4. The compound of claim 1 , wherein R 1 is aryl that is substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, or alkoxy.

5. The compound of claim 1 , wherein R 1 is heterocycloalkyl that is unsubstituted or substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, or alkoxy.

6. The compound of claim 1 , wherein R 1 is heteroaryl that is unsubstituted or substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, or alkoxy.

7. The compound of claim 1 , wherein each R a is hydrogen.

8. A compound selected from the group consisting of:
1-(pyridin-3-ylmethyl)-3-(4-{[2-(trifluoromethoxy)benzene]sulfonyl}phenyl)urea;
3-{4-[(4-bromobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-methoxy-2-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,4-dimethoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-[(6-aminopyridin-3-yl)methyl]-3-{4-[(4-fluorobenzene)sulfonyl]phenyl}urea;
3-{4-[(3,5-dimethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-bromobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-ethoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(3,4-dimethoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{[4-(trifluoromethyl)benzene]sulfonyl}phenyl)urea;
3-{4-[(2,5-dimethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{[3-(trifluoromethoxy)benzene]sulfonyl}phenyl)urea;
3-{4-[(3-bromobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{[3-(trifluoromethyl)benzene]sulfonyl}phenyl)urea;
3-{4-[(5-fluoro-2-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-chloro-2-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-fluoro-3-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,3-difluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-chloro-6-fluoro-3-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(pyridin-3-ylmethyl)-1-[4-(pyrimidine-5-sulfonyl)phenyl]urea;
3-{4-[(3,5-difluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,4-dichlorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,5-difluoro-4-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-ethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-chlorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-chloro-2-fluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-chlorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(5-fluoro-2-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-fluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-[4-(2-methoxynaphthalene-1-sulfonyl)phenyl]-1-(pyridin-3-ylmethyl)urea;
3-{[({4-[(4-chlorobenzene)sulfonyl]phenyl}carbamoyl)amino]methyl}pyridin-1-ium-1-olate;
3-{4-[(3-fluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(3-chlorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[2-(methoxymethyl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,3-dichlorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-fluoro-2-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[3-(propan-2-yl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,3-dimethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-[4-(cyclopentanesulfonyl)phenyl]-3-(pyridin-3-ylmethyl)urea;
3-{4-[(2-fluoro-6-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,5-dimethoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-[4-(trifluoromethane)sulfonylphenyl]urea;
3-{4-[(2-fluoro-4-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-[4-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)phenyl]-1-(pyridin-3-ylmethyl)urea;
3-{4-[(4-chloro-3-fluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[2-chloro-5-(trifluoromethyl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-fluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{[2-(trifluoromethyl)benzene]sulfonyl}phenyl)urea;
3-(4-{[4-chloro-3-(trifluoromethyl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-fluoro-4-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[2-chloro-6-(propan-2-yl)pyridine-3-sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-methoxy-5-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(pyridin-3-ylmethyl)-1-[4-(pyridine-4-sulfonyl)phenyl]urea;
3-{4-[(2-chloro-4-fluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-ethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(3-fluoro-4-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,5-dichlorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(pyridin-3-ylmethyl)-1-[4-(pyridine-3-sulfonyl)phenyl]urea;
3-{4-[(3-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,4-difluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,6-dimethoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
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;
3-(pyridin-3-ylmethyl)-1-[4-(pyridine-2-sulfonyl)phenyl]urea;
3-{4-[(5-chloro-2-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-(4-{[2-methoxy-5-(propan-2-yl)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
3-(4-{[3-(propan-2-yloxy)benzene]sulfonyl}phenyl)-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-{4-[(2,4,6-trimethylbenzene)sulfonyl]phenyl}urea;
3-{4-[(3-fluoro-4-methoxybenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,4-dimethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,5-difluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2-fluoro-5-methylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
1-(pyridin-3-ylmethyl)-3-(4-{[4-(trifluoromethoxy)benzene]sulfonyl}phenyl)urea;
3-[4-(1-methyl-1H-pyrazole-4-sulfonyl)phenyl]-1-(pyridin-3-ylmethyl)urea;
3-[4-(5-methylthiophene-2-sulfonyl)phenyl]-1-(pyridin-3-ylmethyl)urea;
3-{4-[(3,4-difluorobenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)urea;
3-{4-[(2,6-dimethylbenzene)sulfonyl]phenyl}-1-(pyridin-3-ylmethyl)

Assignees

• Forma Tm Llc
• 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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/02

  specific for leukemia · CPC title