Spiro[benzo[d]thiazole-6 ,4′-piperidine as ACC inhibitors
The invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt; to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly acne.
1 . A compound of formula (I) having the structure:
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R is selected from the group consisting of H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl and —(CH 2 ) m -W, where Wis C 3 -C 8 cycloalkyl, bicyclo alkyl, bridged bicycloalkyl, phenyl, 5- or 6-membered heteroaryl or heterocyclic containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted or substituted by phenyl, halo, cyano, deuterium, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —SO 2 —R′, —CONR′R″, NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —(CH 2 ) n —SO 2 —R′, —NHSO 2 —R′, —NR″SO 2 —R′, —SO 2 NR′R″, NR′R″ or SR′ where R′ and R″ are independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
R 1 is selected from the group consisting of phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms; and, a 9- or 10-membered bicyclic aryl, heteroaryl or heterocyclic containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said phenyl, naphthyl, aryl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, deuterium, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, —SO 2 —R′, —CONR′R″, NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —(CH 2 ) n —SO 2 —R′, —NHSO 2 —R′, —NR″SO 2 —R′, —SO 2 NR′R″, NR′R″, —P(O)R′R″,
or SR′ where R′ and R″ are independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; and,
m and n are independently 0, 1, 2 or 3.
2 . The compound of claim 1 wherein R is selected from the group consisting of H, C 1 -C 6 alkyl and —(CH 2 ) m -W, where W is C 3 -C 8 cycloalkyl, wherein each of said alkyl, and cycloalkyl may be unsubstituted or substituted by halo, cyano, deuterium, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; and,
m and n are independently 0, 1, 2 or 3.
3 . The compound of claim 1 wherein R is t-butyl.
4 . A compound according to claim 1 wherein R 1 is phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl or naphthyl; wherein each of said phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl or naphthyl may be unsubstituted or substituted by halo, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, —CONR′R″, NR′R″ or SR′ where R′ and R″ are independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; and, m and n are independently 0, 1, 2 or 3.
5 . The compound of claim 1 selected from the group consisting of:
2-(tert-butyl)-1′-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one;
2-(tert-butyl)-1′-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4 (7H)-one;
2-(tert-butyl)-1′-(8-methyl-3-(methylamino) quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one;
2-(tert-butyl)-1′-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one; and,
2-(tert-butyl)-1′-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one;
or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
6 . The compound of claim 1 wherein the compound is 2-(tert-butyl)-1′-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4 (7H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
7 . The compound of claim 1 wherein the compound is 2-(tert-butyl)-1′-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
8 . The compound of claim 1 wherein the compound is 2-(tert-butyl)-1′-(8-methyl-3-(methylamino) quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
9 . The compound of claim 1 wherein the compound is 2-(tert-butyl)-1′-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
10 . The compound of claim 1 wherein the compound is 2-(tert-butyl)-1′-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4′-piperidin]-4(7H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
11 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.
12 . A method of treating acne, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.
13 . The method of claim 12 wherein the compound is administered topically.
14 . The method of claim 12 , wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.