Compounds and compositions for the inhibition of NAMPT

Patent metadata

Field	Value
Publication number	US-10456382-B2
Application number	US-201816212360-A
Country	US
Kind code	B2
Filing date	Dec 6, 2018
Priority date	Sep 3, 2010
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications and antidotes. An illustrative compound of the invention is shown below:

First claim

We claimed:

1. A compound of formula IIB or a pharmaceutically acceptable salt thereof:

wherein:
R is bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatom(s) independently selected from N, S, and O, wherein said heteroaryl may be substituted by one or more substituents selected from the group consisting of amino, oxo, and halo; and wherein said heteroaryl can comprise one or more N-oxide(s) formed with a N atom member of said heteroaryl;
R 1 is heteroaryl,
wherein:
(i) said heteroaryl 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:
deuterium, halo, hydroxy, hydroxyalkyl, cyano, —(CH 2 ) m NR a R b , oxo, alkyl, cyanoalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl-, alkenyl, alkynyl, alkynylalkoxy, —CONH 2 , —S-alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(cycloalkyl), —C(O)NH(aryl), —C(O)N(aryl) 2 , arylalkyl-, arylalkoxy-, aryloxy-, cycloalkyl, heterocycloalkyl, aryl, (heterocycloalkyl)alkyl-, (heterocycloalkyl)alkoxy, —C(O)heterocycloalkyl, heteroaryl, (heteroaryl)alkyl-, —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 —CH,F 3-z , —C(O)alkyl, —N(R 5 )—C(O)-alkyl, —N(R 5 )—C(O)-aryl, —S(O) 2 NH 2 , —S(O) 2 NH(alkyl), —S(O) 2 N(alkyl) 2 , —N(H)S(O) 2 (alkyl), and methylenedioxy, wherein each of said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted by one or more halo, cyano, alkyl, and alkoxy; and

(ii) said heteroaryl may optionally additionally be fused with independently selected heterocycloalkyl or cycloalkyl to form a bicyclic or tricyclic group that may be substituted by one or more halo, cyano, alkyl, and alkoxy;

R 2 and R 3 can be independently selected from the group consisting of H and deuterium;
R 5 is H, alkyl, or arylalkyl;
R a and R b are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkyl, and haloalkyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
z is 0, 1, or 2.

2. The compound of claim 1 , wherein R is selected from 9- to 10-membered bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O.

3. The compound of claim 1 , wherein R is selected from the group consisting of:
benzothiazole, dihydronaphthyridine, dihydropyridopyrimidine, dihydropyrrolopyridine, furopyridine, imidazopyrazine, imidazopyrazole, imidazopyridine, imidazopyrimidine, indazole, indole, isoquinoline, naphthyridine, pyrazolopyridine, pyrrolopyridine, tetrazolopyridine, tetrahydroimidazopyridine, tetrahydropyrazolopyridine, thiazolopyridine, and thienopyridine.

4. The compound of claim 1 , wherein R is selected from the group consisting of: 1H-pyrazolo[3,4-b]pyridine; 1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine; 7,8-Dihydro-5H-pyrido[4,3-d]pyrimidine; 5,7-Dihydro-pyrrolo[3,4-b]pyridine; 7,8-Dihydro-5H-[1,6]naphthyridine; 1,4,6,7-Tetrahydro-imidazo[4,5-c]pyridine; 1,8a-dihydroimidazo[1,2-a]pyridine; thieno[3,2-c]pyridine; 1H-imidazo[1,2-b]pyrazole; furo[2,3-c]pyridine; 1H-pyrrolo[3,2-c]pyridine; thieno[2,3-b]pyridine; imidazo[1,2-a]pyrimidine; furo[2,3-c]pyridine; isoquinoline; 1H-indazole; imidazo[1,2-a]pyridine; thieno[2,3-c]pyridine; furo[2,3-c]pyridine; 1H-pyrrolo[2,3-c]pyridine; imidazo[1,2-a]pyrazine; 1,3-benzothiazole; benzo[d]thiazole; 1H-pyrrolo[2,3-b]pyridine; [1,3]thiazolo[5,4-c]pyridine; [1,2,3,4]tetrazolo[1,5-a]pyridine; 1,5-naphthyridine; 1H-indole; 1H-imidazo[4,5-c]pyridine; and 1,6-naphthyridine.

5. The compound of claim 1 , wherein R is substituted at a position adjacent to a nitrogen atom on its cycle.

6. The compound of claim 1 , wherein R 1 is unsubstituted or substituted 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatom(s) selected from N, S, or O.

7. The compound of claim 1 , wherein R 1 is selected from the group consisting of: 6-methoxypyridine; 1-(3-chlorophenyl)-1H-pyrazole; 1-(4-fluorophenyl)-1H-pyrazole; 1-(propan-2-yl)-1H-pyrazole; 1,3-thiazole; 1,4-dimethyl-1H-imidazole; 1,5-dimethyl-1H-imidazole; 1-benzothiophene; 1H-indole; 1-methyl-1H-1,3-benzodiazole; 1-methyl-1H-indazole; 1-methyl-1H-indole; 1-methyl-1H-pyrazole; 1-methyl-3-(trifluoromethyl)-1H-pyrazole; 1-methyl-5-(trifluoromethyl)-1H-pyrazole; 1-propyl-1H-pyrazole; 2-(3-fluorophenyl)-1,3-thiazole; 2-(dimethylamino)pyrimidine; 2-(morpholin-4-yl)pyridine; 2-(morpholin-4-yl)pyridine; 2-(pyrrolidin-1-yl)-1,3-thiazole; 2-(trifluoromethyl)imidazo[1,2-a]pyridine; 2-(trifluoromethyl)pyridine; 2,6-dimethoxypyridine; 2-[ethyl(methyl)amino]-1,3-thiazole; 2-methyl-1,3-thiazole; 2-methyl-2H-indazole; 2-methylpyridine; 3-chloro-2-(morpholin-4-yl)pyridine; 4-(trifluoromethyl)pyridine; 4-methylpyridine; 4-methylthiophene; 5-(dimethylamino)pyrazine; 5-(pyrrolidin-l-yl)pyridine; 5-(trifluoromethyl)pyridine; 5-chloropyridine; 5-fluoro-6-methylpyridine; 5-fluoropyridine; 5H,6H,7H,8H,9H-imidazo[1,2-a]azepine; 5-hydroxy-l-methyl-1H-indazole; 5-methoxypyridine; 5-methylpyridine; 5-methylthiophene; 6-(1H-pyrazol-1-yl)pyridine; 6-(3,4-difluorophenyl)pyridine; 6-(4-methylpiperazin-1-yl)pyridine; 6-(dimethylamino)pyridine; 6-(morpholin-4-yl)pyridine; 6-(trifluoromethyl)pyridine; 6-chloroimidazo[1,2-a]pyridine; 6-methoxypyridine; 6-methylpyrazine; 6-methylpyridine; b6-chloroimidazo[1,2-a]pyridine; dimethyl-1,3-thiazole; furan; isoquinoline; and pyridine.

8. The compound of claim 1 wherein R 1 is heteroaryl, wherein said heteroaryl 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:
halo, hydroxy, hydroxyalkyl, cyano, alkyl, alkynyl, alkynylalkoxy, alkoxyalkyl, alkoxy, haloalkyl, haloalkoxy, —C(O)NH(alkyl), —C(O)NH(cycloalkyl), —C(O)N(alkyl) 2 , arylalkoxy-, aryloxy-, cycloalkyl, heterocycloalkyl, aryl, (heterocycloalkyl)alkyl-, (heterocycloalkyl)alkoxy-, —C(O)heterocycloalkyl, heteroaryl, (heteroaryl)alkyl-, —S(O) 2 -alkyl, —S-alkyl, —C(O)alkyl, —S(O 2 )NH 2 , —S(O 2 )NH(alkyl), —S(O 2 )N(alkyl) 2 , and —N(H)(SO 2 )(alkyl), wherein each of said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted by one or more halo, cyano, alkyl, and alkoxy.

9. The compound of claim 1 , wherein R 1 is heteroaryl, wherein said heteroaryl 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: halo, haloalkyl, and haloalkoxy.

10. The compound of claim 9 , wherein haloalkyl is —CH z F 3-z , or —CH 2 CH z F 3-z , and z is 0, 1 or 2.

11. The compound of claim 9 , wherein haloalkoxy is —OCH z F 3-z , and z is 0, 1 or 2.

12. The compound of claim 9 , wherein halo is F.

13. A compound selected from the group consisting of:
N-({4-[1-(3-chlorophenyl)-1H-pyrazole-4-sulfonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
N-{[4-(dimethyl-1,3-thiazole-5-sulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
N-({4-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-sulfonyl]phenyl}methyl)imidazo[1,2-a]pyrimidine-6-carboxamide
N-({4-[6-(trifluoromethyl)pyridine-3-sulfonyl]phenyl}methyl)thieno[2,3-c]pyridine-2-carboxamide
N-{[4-(2-methyl-2H-indazole-6-sulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
N-({4-[6-(trifluoromethyl)pyridine-2-sulfonyl]phenyl}methyl)furo[2,3-c]pyridine-2-carboxamide
N-({4-[6-(trifluoromethyl)pyridine-2-sulfonyl]phenyl}methyl)-1H-pyrazolo[3 ,4-b]pyridine-5 -carboxamide
N-{[4-(1 -methyl-1H-indazole-7-sulfonyl)phenyl]methyl}furo[2,3-c]pyridine-2-ca

Assignees

• Forma Tm Llc
• Genentech Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · 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