US 12,440,484 B2
1,3,4-oxadiazole homophthalimide derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
Chang Sik Lee, Gyeonggi-do (KR); Jung Taek Oh, Gyeonggi-do (KR); Hokeun Yun, Gyeonggi-do (KR); Hyeseung Song, Gyeonggi-do (KR); and Hyunjin Michael Kim, Gyeonggi-do (KR)
Assigned to Chong Kun Dang Pharmaceutical Corporation, (KR)
Appl. No. 17/615,363
Filed by Chong Kun Dang Pharmaceutical Corp., Seoul (KR)
PCT Filed May 29, 2020, PCT No. PCT/IB2020/055110
§ 371(c)(1), (2) Date Nov. 30, 2021,
PCT Pub. No. WO2020/240493, PCT Pub. Date Dec. 3, 2020.
Claims priority of application No. 10-2019-0064666 (KR), filed on May 31, 2019.
Prior Publication US 2023/0079386 A1, Mar. 16, 2023
Int. Cl. A61K 31/4439 (2006.01); A61K 31/4245 (2006.01); A61K 31/437 (2006.01); A61K 31/4725 (2006.01); A61K 31/496 (2006.01); A61K 31/506 (2006.01); A61K 31/517 (2006.01); A61K 31/5377 (2006.01)
CPC A61K 31/4439 (2013.01) [A61K 31/4245 (2013.01); A61K 31/437 (2013.01); A61K 31/4725 (2013.01); A61K 31/496 (2013.01); A61K 31/506 (2013.01); A61K 31/517 (2013.01); A61K 31/5377 (2013.01)] 9 Claims
 
1. A compound represented by a following chemical formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof:

OG Complex Work Unit Chemistry
wherein,
X1 to X4 are each independently CR0 or N, wherein at least two of X1 to X4 are CR0,
in which each R0 is independently hydrogen, halogen, straight or branched —C1-7 alkyl, or straight or branched —O—C1-7 alkyl,
R1 is straight or branched —C1-5 haloalkyl,
R2 and R3 are each independently H, halogen,

OG Complex Work Unit Chemistry
 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from group comprising N, O or S, 3- to 7-membered heterocycloalkenyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S,

OG Complex Work Unit Chemistry
 —C1-7 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkenyl, cyclopenta-1,3-diene, phenyl, indolyl,

OG Complex Work Unit Chemistry
wherein at least one hydrogen of said 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered heterocycloalkenyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S,

OG Complex Work Unit Chemistry
 —C1-7 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkenyl, cyclopenta-1,3-diene, phenyl, indolyl,

OG Complex Work Unit Chemistry
 can be substituted with R4,
R4 is halogen, —C1-7 alkyl, —C1-7 haloalkyl, —O—C1-7 alkyl, —C(═O)—C1-7 alkyl, —C(═O)—C1-7 alkyl-OH, —C(═O)—O—C1-7 alkyl, —S(═O)2—C1-7 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered halocycloalkyl, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S,

OG Complex Work Unit Chemistry
 —C1-7 alkyl-C(═O)—R5, —C1-7 alkyl-C(═O)—O—R6, —C1-7 alkyl-R7, —C1-7 alkyl-O—R8, —NR9R10, —C(═O)—NR11R12 or —C1-7 alkyl-NR13R14,
in which R5 is —C1-7 alkyl, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, cyclopenta-1,3-diene or phenyl,
R6 is —C1-7 alkyl, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, cyclopenta-1,3-diene or phenyl,
R7 is 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, cyclopenta-1,3-diene or phenyl,
R8 is —C1-7 alkyl, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, cyclopenta-1,3-diene or phenyl,
R9 and R10 are each independently H or —C1-7 alkyl,
R11 and R12 are each independently H or —C1-7 alkyl, and
R13 and R14 are each independently H or —C1-7 alkyl,
Rx and Ry are each independently —C1-7 alkyl, —C1-7 alkyl-NR15R16, H, —C1-7 alkyl-O-C1-7 alkyl, —C(═O)—C1-7 alkyl, heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O)-heterocycloalkyl wherein the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O) cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl, —C1-7 alkyl-O-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S or —C1-7 alkyl-cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl wherein at least one hydrogen of —C1-7 alkyl, —C1-7 alkyl-O—C1-7 alkyl, —C(═O)—C1-7 alkyl, —C(═O)-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O)-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O) cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl, —C1-7 alkyl-O-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S or —C1-7 alkyl-cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl can be substituted with —C1-7 alkyl, halogen, —O—C1-7 alkyl, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, —S(═O)2—C1-7 alkyl, —CF3,

OG Complex Work Unit Chemistry
 and
R15 and R16 are each independently H or —C1-7 alkyl),
K is O or S,
Y is CRaRb or NRc,
Ra and Rb are each independently hydrogen, —C1-7 alkyl, 3- to 7-membered cycloalkyl, —C1-7 alkyl-O—C1-7 alkyl, —C1-7 alkyl-NR17R18, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C1-7 alkyl-C(═O)—C1-7 alkyl or —C1-7 alkyl-C(═O)—O—C1-7 alkyl, or Ra and Rb are linked to each other to form 3- to 7-membered cycloalkyl,
wherein at least one hydrogen of —C1-7 alkyl, 3- to 7-membered cycloalkyl, —C1-7 alkyl-O—C1-7 alkyl, —C1-7 alkyl-NR17R18, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C1-7 alkyl-C(═O)—C1-7 alkyl or —C1-7 alkyl-C(═O)—O—C1-7 alkyl may be substituted with —C1-7 alkyl, halogen, —O—C1-7 alkyl, 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, —S(═O)2—C1-7 alkyl, —CF3,

OG Complex Work Unit Chemistry
 and R17 and R18 are each independently H or —C1-7 alkyl, Rc is hydrogen, —C1-7 alkyl, —C1-7 alkyl-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C1-7 alkyl-phenyl, —C1-7 alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, —C1-7 alkyl-O—C1-7 alkyl, —C1-7 alkyl-NR19R20, —C1-7 alkyl-cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, a 3- to 7-membered cycloalkyl, a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, cyclopenta-1,3-diene, phenyl, —C(═O)—, —C(═O)-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O) cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl, —C(═O)-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O)-phenyl, —C(═O)—C1-7 alkyl, —C(═O)—C1-7 alkyl-O—C1-7 alkyl or —C(═O)—C1-7 alkyl-NR19R20, wherein at least one hydrogen of —C1-7 alkyl, —C1-7 alkyl-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C1-7 alkyl-phenyl, —C1-7 alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, —C1-7 alkyl-O—C1-7 alkyl, —C1-7 alkyl-NR19R20, —C1-7 alkyl-cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, a 3- to 7-membered cycloalkyl, a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, cyclopenta-1,3-diene, phenyl, —C(═O)—, —C(═O)-heterocycloalkyl wherein the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O) cycloalkyl wherein the cycloalkyl is a 3- to 7-membered cycloalkyl, —C(═O)-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O)-phenyl, —C(═O)—C1-7 alkyl, —C(═O)—C1-7 alkyl-O—C1-7 alkyl or —C(═O)—C1-7 alkyl-NR19R20, can be substituted with —C1-7 alkyl, halogen, —O—C1-7 alkyl, a 3- to 7-membered heterocycloalkyl comprising one to three heteroatoms selected from the group comprising N, O or S, —C(═O)—O—C1-7 alkyl, a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, heteroaryl-C1-5 haloalkyl wherein the heteroaryl is a 5- or 6-membered heteroaryl comprising one to three heteroatoms selected from the group comprising N, O or S, 3- to 7-membered cycloalkyl, —S(═O)2—C1-7alkyl, —CF3,

OG Complex Work Unit Chemistry
 and R19 and R20 are each independently H or —C1-7 alkyl,

OG Complex Work Unit Chemistry
 is phenylene or 5- or 6-membered heteroarylene comprising one to three heteroatoms selected from the group comprising N, O or S,
halogen is F, Cl, Br or I, and
n is 1.