Thienopyrimidine derivatives having stereo configurations and use thereof in medicine
Thienopyrimidine derivative having stereo configurations and use thereof in medicine. Also included are pharmaceutical compositions of the compounds. The compounds or pharmaceutical compositions may be used to inhibit acetyl-CoA carboxylase (ACC). A method for preparing the compounds and the pharmaceutical compositions, and use thereof in treatment or prevention of diseases associated with ACC regulation of mammals, in particular, humans.
1. A compound having Formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
Z has the following structures:
Het is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, the 3-10 membered heterocyclyl and 5-10 membered heteroaryl can be optionally substituted by 1, 2, 3 or 4 substituents independently selected from H, D, oxo (═O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and carboxyl;
R 1 is H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
R 2 is —OR or —NR a R b ,
each R 3 and R 4 is independently H, D, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 haloalkyl;
each R 5 is independently C 6-10 aryl or 5-10 membered heteroaryl, the C 6-10 aryl and 5-10 membered heteroaryl can be optionally substituted by 1, 2 or 3 R 6 ; wherein, each R 6 is independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 cyanoalkyl or C 1-6 hydroxyalkyl;
each X is independently O or NR 7 ;
each R 7 is independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, —C(═O)OH, —SO 2 R c , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 cyanoalkyl or C 1-6 hydroxyalkyl;
each R, R a , R b and R c is independently H, D, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
or, R a and R b , together with the N atom to which they are attached, form 4-6 membered heterocyclyl, and the 4-6 membered heterocyclyl can be optionally substituted by 1, 2, 3 or 4 substituents independently selected from oxo (═O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 haloalkyl.
2. The compound of claim 1 , wherein the X is O, NH or N—SO 2 R c ; R c is H, D, methyl, ethyl, isopropyl, methoxy or ethoxy.
3. The compound of claim 1 , wherein the Het is
wherein, the Het can be optionally substituted by 1, 2, 3 or 4 substituents independently selected from H, D, oxo (═O), F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, trifluoromethyl, difluoromethyl and carboxyl.
4. The compound of claim 1 , wherein the R 1 is H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropyloxy or trifluoromethyl;
R 2 is —OR or —NR a R b ;
each R, R a and R b is independently H, D, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or, R a and R b , together with the N atom to which they are attached, form 4-6 membered heterocyclyl, and the 4-6 membered heterocyclyl is selected from:
the 4-6 membered heterocyclyl can be optionally substituted by 1, 2, 3 or 4 substituents independently selected from oxo (═O), D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl and difluoromethyl;
each R 3 and R 4 is independently H, D, methyl, ethyl, n-propyl, hydroxymethyl, difluoromethyl, trifluoromethyl or 2-hydroxyethyl;
each R 5 is independently phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl or pyridazinyl; wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl and pyridazinyl can be optionally substituted by 1, 2 or 3 R 6 ; wherein each R 6 is independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl or 2-hydroxyethyl.
5. The compound of claim 1 having one of the following structures:
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising the compound of claim 1 .
7. The composition of claim 6 , further comprising a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle or any combination thereof.
8. A method of treating diseases regulated by Acetyl-CoA carboxylase in a patient comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .
9. The method of claim 8 , wherein the diseases regulated by Acetyl-CoA carboxylase are metabolic disorders.
10. The method of claim 8 , wherein the diseases regulated by ACC Acetyl-CoA carboxylase comprise metabolic disorders, the metabolic disorders comprise insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver steatosis, bullous steatosis, advanced fibrosis or cirrhosis.
11. A method of treating diseases regulated by Acetyl-CoA carboxylase in a patient comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 6 .
12. The method of claim 11 , wherein the diseases regulated by Acetyl-CoA carboxylase are metabolic disorders.
13. The method of claim 11 , wherein the diseases regulated by ACC Acetyl-CoA carboxylase comprise metabolic disorders, the metabolic disorders comprise insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver steatosis, bullous steatosis, advanced fibrosis or cirrhosis.