US2019060291A1PendingUtilityA1
Azetidine derivative, preparation method therefor, and use thereof
Assignee: SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTDPriority: Dec 11, 2015Filed: Oct 24, 2018Published: Feb 28, 2019
Est. expiryDec 11, 2035(~9.4 yrs left)· nominal 20-yr term from priority
Inventors:Yinong XieZejin YouZhiwen DengJun ZhuAo WangYan FengDong LongHong ZengHongmei SongQijun YeWei QiDonghai SuLichun WangJingyi Wang
A61K 31/437A61P 29/00A61K 31/343A61K 2300/00A61K 31/519A61P 37/00A61P 19/02A61P 35/00C07D 487/04A61K 2039/505A61K 38/1793C07D 471/04
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Claims
Abstract
The present invention relates to an azetidine derivative for use as a Janus kinase (JAK) inhibitor, a drug composition comprising same, a preparation method therefor, and a use thereof in the treatment of JAK-related diseases comprising, for example, inflammatory diseases, autoimmune diseases, and cancers.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for preparing a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:
wherein:
R 1 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, C(O)R 10 , and S(O) 2 R 11 ;
R 2 and R 3 are each independently selected from the group consisting of H, CN, halogen, and C 1-6 alkyl;
R 4 and R 5 are each independently selected from the group consisting of H, halogen, and CN;
X is CR 6 ;
Y is selected from the group consisting of N and CR 9 ;
Z is selected from the group consisting of N and CR 7 ;
W is selected from the group consisting of N and CR 8 ;
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxyl, and C(O)NR 12 R 13 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 ;
R 12 and R 13 are each independently selected from the group consisting of H and C 1-6 alkyl;
wherein the above alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl;
the method comprising:
reacting compound a as shown with SEMCl in the presence of a base in a polar aprotic solvent, to afford compound b, wherein Hal is selected from the group consisting of fluorine, chlorine, bromine, and iodine;
reacting compound b with a suitable reagent in the presence of a base, under the catalysis of a palladium catalyst, to afford compound c;
reacting compound c with a suitable reagent in the presence of a base, to afford compound d; and
treating compound d under the catalysis of a Lewis acid, to afford the compound of Formula I; alternatively, first reacting compound d under the catalysis of an acid, and then reacting the resulting product, after treatment, in the presence of a base, to afford the compound of Formula I;
alternatively, the method comprising:
reacting compound a as shown with SEMCl in the presence of a base in a polar aprotic solvent, to afford compound b, wherein Hal is selected from the group consisting of fluorine, chlorine, bromine, and iodine;
reacting compound b with a suitable reagent in the presence of a base, under the catalysis of a palladium catalyst, to afford compound c′, wherein R 14 and R 15 are each independently selected from the group consisting of H and C 1-6 alkyl, or alternatively, R 14 and R 15 together with the atoms to which they are attached form a 5- or 6-membered ring system; and
reacting compound c′ with a suitable reagent in the presence of a base, under the catalysis of a palladium catalyst, to afford compound d′;
reacting compound d′ with a suitable reagent in the presence of a base, to afford compound e′; and
reacting compound e′ under the catalysis of a Lewis acid, to afford the compound of Formula I;
49 alternatively, first reacting compound e′ is first reacted under the catalysis of an acid, and then reacting the resulting product is then reacted, after treatment, in the presence of a base, to afford the compound of Formula I.
2 . The method according to claim 1 , wherein the compound is a compound of Formula II:
3 . The method according to claim 1 , wherein the compound is a compound of Formula IV:
wherein:
R 1 is selected from the group consisting of C(O)R 10 and S(O) 2 R 11 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl.
4 . The method according to claim 1 , wherein the compound is a compound of Formula V:
5 . The method according to claim 1 , wherein the compound is a compound of Formula VI:
6 . The method according to claim 1 , wherein the compound of Formula I is selected from the group consisting of:
7 . A method for preparing a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:
wherein:
R 1 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, C(O)R 10 , and S(O) 2 R 11 ;
R 2 and R 3 are each independently selected from the group consisting of H, CN, halogen, and C 1-6 alkyl;
R 4 and R 5 are each independently selected from the group consisting of H, halogen, and CN;
X is selected from the group consisting of N and CR 6 ;
Y is selected from the group consisting of N and CR 9 ;
Z is selected from the group consisting of N and CR 7 ;
W is selected from the group consisting of N and CR 8 ;
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxyl, and C(O)NR 12 R 13 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 ;
R 12 and R 13 are each independently selected from the group consisting of H and C 1-6 alkyl;
wherein the above alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl;
the method comprising:
reacting compound a as shown with SEMCl in the presence of a base in a polar aprotic solvent, to afford compound b, wherein Hal is selected from the group consisting of fluorine, chlorine, bromine, and iodine;
reacting compound b with a suitable reagent in the presence of a base, under the catalysis of a palladium catalyst, to afford compound c;
reacting compound c with a suitable reagent in the presence of a base, to afford compound d; and
treating compound d under the catalysis of a Lewis acid, to afford the compound of Formula I;
alternatively, first reacting compound d under the catalysis of an acid, and then reacting the resulting product, after treatment, in the presence of a base, to afford the compound of Formula I;
alternatively, the method comprising:
reacting compound a as shown with SEMCl in the presence of a base in a polar aprotic solvent, to afford compound b, wherein Hal is selected from the group consisting of fluorine, chlorine, bromine, andiodine;
reacting compound b with a suitable reagent in the presence of a base, under the catalysis of a palladium catalyst, to afford compound c′, wherein R 14 and R 15 are each independently selected from the group consisting of H and C 1-6 alkyl, or alternatively, R 14 and R 15 together with the atoms to which they are attached form a 5- or 6-membered ring system; and
reacting compound c′ with a suitable reagent in the presence of a base, under the catalysis of a palladium catalyst, to afford compound d′;
reacting compound d′ with a suitable reagent in the presence of a base, to afford compound e′; and
reacting compound e′ under the catalysis of a Lewis acid, to afford the compound of Formula I; alternatively, first reacting compound e′ under the catalysis of an acid, and then reacting the resulting product, after treatment, in the presence of a base, to afford the compound of Formula I;
wherein the compound of Formula I is selected from the group consisting of:
8 . A method for treating a JAK-related disease, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound having Formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:
wherein:
R 1 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, C(O)R 10 , and S(O) 2 R 11 ;
R 2 and R 3 are each independently selected from the group consisting of H, CN, halogen, and C 1-6 alkyl;
R 4 and R 5 are each independently selected from the group consisting of H, halogen, and CN;
X is CR 6 ;
Y is selected from the group consisting of N and CR 9 ;
Z is selected from the group consisting of N and CR 7 ;
W is selected from the group consisting of N and CR 8 ;
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxyl, and C(O)NR 12 R 13 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 ;
R 12 and R 13 are each independently selected from the group consisting of H and C 1-6 alkyl;
wherein the above alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl.
9 . The method according to claim 8 , wherein the compound is a compound of Formula II:
10 . The method according to claim 8 , wherein the compound is a compound of Formula IV:
wherein:
R 1 is selected from the group consisting of C(O)R 10 and S(O) 2 R 11 ;
R 10 and R 11 are each independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, C 7-20 aralkyl, and NR 12 R 13 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, CN, and C 1-4 alkyl.
11 . The method according to claim 8 , wherein the compound is a compound of Formula V:
12 . The method according to claim 8 , wherein the compound is a compound of Formula VI:
13 . A method for treating a JAK-related disease, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof.
14 . The method according to claim 8 , wherein the JAK-related disease is selected from the group consisting of an inflammatory disease, autoimmune disease, and cancer.
15 . The method according to claim 8 , wherein the JAK-related disease is selected from the group consisting of an inflammatory bowel disease, lupus, and psoriasis.
16 . The method according to claim 13 , wherein the JAK-related disease is selected from the group consisting of an inflammatory disease, autoimmune disease, and cancer.
17 . The method according to claim 13 , wherein the JAK-related disease is selected from the group consisting of an inflammatory bowel disease, lupus, and psoriasis.
18 . The method according to claim 8 , wherein the therapeutically effective amount is selected from the group consisting of about 0.01 mg to about 1000 mg, 0.1-500 mg, 0.5-300 mg, 1-150 mg, 1-50 mg, or 25 mg.
19 . The method according to claim 8 , wherein the therapeutically effective amount is selected from the group consisting of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg, or 10 mg.
20 . The method according to claim 8 , wherein the therapeutically effective amount is selected from the group consisting of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, or 6 mg.
21 . The method according to claim 13 , wherein the therapeutically effective amount is selected from the group consisting of about 0.01 mg to about 1000 mg, 0.1-500 mg, 0.5-300 mg, 1-150 mg, 1-50 mg, or 25 mg.
22 . The method according to claim 13 , wherein the therapeutically effective amount is selected from the group consisting of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg, or 10 mg.
23 . The method according to claim 13 , wherein the therapeutically effective amount is selected from the group consisting of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, or 6 mg.Cited by (0)
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