Oxadiazole amine derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same

Patent metadata

Field	Value
Publication number	US-10494355-B2
Application number	US-201615763972-A
Country	US
Kind code	B2
Filing date	Oct 11, 2016
Priority date	Oct 12, 2015
Publication date	Dec 3, 2019
Grant date	Dec 3, 2019

Abstract

The present disclosure relates to novel compounds having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel compounds. The novel compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure have histone deacetylase (HDAC) inhibitory activity and are effective for the prevention or treatment of HDAC6-mediated diseases, including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; diseases of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities.

First claim

The invention claimed is:

1. An oxadiazole amine derivative compound represented by the following Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein R 1 is —CF 2 H or CF 3 ;
L 1 and L 2 are each independently —(C 1 -C 2 alkyl)- or null;
Z 1 to Z 4 are each independently N or CR Z {wherein three or more of Z 1 to Z 4 cannot be N at the same time}, wherein R Z is H, —F, —Cl, —Br, —I or —O(C 1 -C 4 alkyl);
R 2 is —H or —(C 1 -C 4 alkyl);
Y 1 is —CH 2 —, —NR C —, —O—, —C(═O)— or —S(═O) 2 —, wherein R C is —H, —(C 1 -C 6 alkyl), —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(═O)—(C 1 -C 4 alkyl), —C(═O)—O(C 1 -C 4 alkyl), —C(═O)—O(C 1 -C 4 alkyl)-aryl, —(C 1 -C 4 alkyl)-C(═O)—O(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl)-NR A R B , —S(═O) 2 —(C 1 -C 4 alkyl), aryl, —(C 1 -C 4 alkyl)-aryl, —(C 2 -C 4 alkenyl)-aryl, heteroaryl, —(C 1 -C 4 alkyl)-heteroaryl, —C(═O)—(C 3 -C 7 cycloalkyl), —(C 2 -C 6 heterocycloalkyl) or —(C 1 -C 4 alkyl)-C(═O)—(C 2 -C 6 heterocycloalkyl), {wherein at least one H of the —(C 1 -C 6 alkyl), —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C(═O)—(C 1 -C 4 alkyl), —C(═O)—O(C 1 -C 4 alkyl), —C(═O)—O(C 1 -C 4 alkyl)-aryl, —(C 1 -C 4 alkyl)-C(═O)—O(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl)-NR A R B , —S(═O) 2 —(C 1 -C 4 alkyl), aryl, —(C 1 -C 4 alkyl)-aryl, (C 2 -C 4 alkenyl)-aryl, heteroaryl, —(C 1 -C 4 alkyl)-heteroaryl, —C(═O)—(C 3 -C 7 cycloalkyl), —C 2 -C 6 heterocycloaklyl or —(C 1 -C 4 alkyl)-C(═O)—(C 2 -C 6 heterocycloalkyl) may be substituted with —X, wherein X is a halogen};
a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein the a and b cannot all be 0};
L 3 is —(C 1 -C 2 alkyl)-, —SO 2 —, —(C 1 -C 2 alkyl)-SO 2 —, or null;

is -aryl, -heteroaryl,

or heterocycloalkyl, wherein Z 5 and Z 6 are each independently —CH 2 — or —O—; and
R 4 to R 6 are each independently —H, —F, —Cl, —Br, —I, —OH, —O(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl), —CF 3 , —OCF 3 , heterocycloalkyl {wherein the heterocycloalkyl may be unsubstituted or substituted with C 1 -C 4 alkyl or heterocycloalkyl},

—O-aryl, —CF 2 H, —C(═O)—(C 1 -C 4 alkyl), —C(═O)—O(C 1 -C 4 alkyl), —NR A R B , —C(═O)—NR A R B or —S(═O) 2 —(C 1 -C 4 alkyl), wherein Y 2 is —CH 2 —, —NR C —, —O—, —C(═O)— or —S(═O) 2 —, Y 3 to Y 5 are each independently —CH— or —N—, and c to f are each independently an integer of 0, 1, 2, 3 or 4 {wherein c and e cannot all be 0, and d and f cannot all be 0}, wherein R A and R B are each independently —H or —(C 1 -C 4 alkyl) {wherein at least one H of the —(C 1 -C 4 alkyl) may be substituted with —X or —OH}.

2. The oxadiazole amine derivative compound represented by Formula I, stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1 ,
wherein R 1 is —CF 2 H or —CF 3 ;
L 1 and L 2 are null;
Z 1 and Z 3 are N;
Z 2 and Z 4 are CR Z , wherein R Z is —H, —F, —Cl, —Br, —I or —O(C 1 -C 4 alkyl);
R 2 is —H or —(C 1 -C 4 alkyl);
Y 1 is —CH 2 — or —NR c —, wherein R C is —H, or —C(═O)—O(C 1 -C 4 alkyl)-aryl {wherein at least one H of the —C(═O)—O(C 1 -C 4 alkyl)-aryl may be substituted with —X, wherein X is a halogen};
a and b are each independently an integer of 0, 1, 2 or 3 {wherein the a and b cannot all be 0};
L 3 is —(C 1 -C 2 (C 1 -C 2 alkyl)-SO 2 —, or null;

is phenyl, pyridine, benzo[d][1,3]dioxol, thiophene, pyrimidine, pyrazine or pyridazine; and
R 4 to R 6 are each independently —H, —F, —Cl, —Br, —I, —OH, —O(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl), —CF 3 , —OCF 3 , piperidine, morpholino, piperazine or pyrrolidine {wherein the piperidine, morpholino, piperazine or pyrrolidine may be unsubstituted or substituted with C 1 -C 4 alkyl}, or

wherein Y 2 is —O—, Y 3 and Y 5 are —CH—, Y 4 is —N—, c and e are each independently an integer of 0, 1 or 2 {wherein c and e cannot all be 0}, and d and f are each independently an integer of 0, 1, 2 or 3 {wherein d and f cannot all be 0}.

3. The oxadiazole amine derivative compound represented by Formula I, stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1 ,
wherein the compound represented by the above Formula I is a compound represented by the following Formula II:

wherein R 1 is —CF 2 H or —CF 3 ;
R 2 is —H;
Y 1 is —CH 2 — or —NR C —, wherein R C is —H, or —C(═O)—O(C 1 -C 4 alkyl)-aryl;
a and b are each independently an integer of 0, 1, 2 or 3 {wherein a and b cannot all be 0};
L 3 is —(C 1 -C 2 alkyl)-, (C 1 -C 2 alkyl)-SO 2 —, or null;

is phenyl, pyridine, benzo[d][1,3]dioxol and thiophene; and
R 4 to R 6 are each independently —H, —F, —Cl, —Br, —I, —OH, —O(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl), —CF 3 , —OCF 3 , piperidine morpholino {wherein the piperidine may be unsubstituted or substituted with C 1 -C 4 alkyl}, or

4. The oxadiazole amine derivative compound represented by Formula II, stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 3 ,
wherein R 1 is —CF 2 H or —CF 3 ;
R 2 is —H;
Y 1 is —CH 2 — or —NR c —, wherein R C is —H, or

a and b are each independently an integer of 0, 1, 2 or 3 {wherein the a and b cannot all be 0, a ring formed by Y 1 , a and b is a 3- to 7-membered saturated cycloalkyl when Y 1 is —CH 2 — or a ring formed by Y 1 , a and b is a 3- to 7-membered saturated heterocycloalkyl containing one N when Y1 is —NR c —};
L 3 is —CH 2 —, —CH 2 —SO 2 —, or null;

is phenyl, pyridine, benzo[d][1,3]dioxol and thiophene; and
R 4 to R 6 are each independently —H, —F, —Cl, —Br, —I, —OH, —O(C 1 -C 4 alkyl), —(C 1 -C 4 alkyl), —CF 3 , —OCF 3 , morpholino,

or

wherein R 7 is —H or —(C 1 -C 4 alkyl).

5. The oxadiazole amine derivative compound represented by formula I, stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of Formula I is selected from the group consisting of the following compounds:
5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylcyclopropyl)pyrimidin-2-amine;
N-(1-phenylcyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine;
5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylcyclobutyl)pyrimidin-2-amine;
5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenyl

Assignees

• Chong Kun Dang Pharmaceutical Corp

Inventors

• Kim Yuntae
• Lee Chang Sik
• Oh Jung Taek
• Song Hyeseung
• Choi Jin
• Lee Jaeyoung

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title