Compounds and compositions for the inhibition of NAMPT
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:
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 cycloalkyl,
wherein:
(i) said cycloalkyl 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 z 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 cycloalkyl 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 are 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 C 3 -C 10 cycloalkyl.
7. The compound of claim 6 , wherein R 1 is cyclohexyl.
8. The compound of claim 1 , wherein R 1 is unsubstituted cycloalkyl or cycloalkyl 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 or alkoxy.
9. The compound of claim 1 , wherein the compound is N-{[4-(cyclohexanesulfonyl)phenyl]methyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.