Preparation of oxindole derivatives as novel diacylglyceride O-acyltransferase 2 inhibitors
Invented are compounds of formula I and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases and heart failure and related diseases and conditions, comprising administering a compound of Formula I to a patient in need thereof.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof wherein:
X, Y, and Z are independently selected from N and C(R 5 );
R 1 is a 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 6 ;
R 2a and R 2b are independently selected from
(1) hydrogen,
(2) halogen,
(3) hydroxy,
(4) (C 1-6 )alkyl,
(5) (C 1-6 )haloalkyl,
(6) R 2a and R 2b join to form spiro(C 3-8 )cycloalkyl wherein the spiro(C 3-8 )cycloalkyl is unsubstituted or mono or di-substituted with substituents independently selected from C 1-3 alkyl, halogen, and OH, and
(7) R 2a and R 2b join to form spiro 4- to 8-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S wherein the heterocyclyl is unsubstituted or substituted by 1, 2, or 3 R 7 ;
R 3 is
(1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S,
(3) —(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O and S,
(4) —(C 1-6 )alkyl-aryl,
(5) —(C 1-6 )alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,
(6) (C 1-6 )alkyl,
(7) (C 3-6 )cycloalkyl,
(8) (C 1-6 )hydroxyalkyl,
(9) —(C 1-6 )alkyl-S(O) 2 —NR 8a R 8b , or
(10) —(C 1-6 )alkyl-S(O) 2 —(C 1-3 )alkyl,
wherein each cycloalkyl, or heterocyclyl is unsubstituted or substituted with 1, 2, or 3 R 9 , and wherein each alkyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 10 ;
R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl,
or R 3 and R 4 combine together with the nitrogen atom to which they are attached to form a mono- or bicyclic heterocyclyl ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocyclyl ring is unsubstituted or substituted by 1, 2, or 3 R 11 ,
when present, each R 5 is independently selected from
(1) hydrogen,
(2) (C 1-3 )alkyl,
(3) (C 1-3 )haloalkyl,
(4) cyano, and
(5) halogen,
when present, each R 6 is independently selected from
(1) cyano,
(2) halogen,
(3) —OC 1-6 alkyl
(4) (C 3-6 )cycloalkyl, unsubstituted or substituted with halogen, and OH,
(5) —(C═O)NH 2 ,
(6) (C 3-6 )cycloalkyloxy wherein the cycloalkyl is unsubstituted or substituted with halogen or OH,
(7) hydroxy,
(8) —NR 11 R 11 ,
(9) —NH(C═O)(C 1-6 )alkyl,
(10) (C 2-6 ) cyclic amine, unsubstituted or substituted with one or two halogen substituents,
(11) —(C 1-6 )haloalkyl
(12) —O(C 1-6 )haloalkyl unsubstituted or substituted with OH,
(13) —O(C 0-3 )alkyl-(C 3-6 )cycloalkyl optionally unsubstituted or substituted with one or two halogen substituents,
(14) —SO 2 (C 1-6 )alkyl,
(15) —SO 2 NH(C 1-6 )alkyl,
(16) —SC 1-6 alkyl,
(17) —SC 1-6 haloalkyl, and
(18) (C 1-6 )alkyl,
when present, each R 7 is independently selected from
(1) (C 1-3 )alkyl,
(2) halogen,
(3) (C 1-3 )alkoxy-,
(4) —(C 1-3 )haloalkyl, and
(5) hydroxy,
when present, R 8a and R 8b are independently selected from
(1) hydrogen,
(2) (C 1-3 )alkyl, and
(3) (C 3-7 )cycloalkyl;
when present, each R 9 is independently selected from
(1) (C 1-3 )alkyl,
(2) —(C 1-3 )haloalkyl,
(3) OXO,
(4) (C 3-6 )cycloalkyl,
(5) —N(R 11 ) 2 ,
(6) hydroxy,
(7) (C 1-3 )alkoxyl,
(8) cyano,
(9) halogen,
(10) —SO 2 (C 1-6 )alkyl,
(11) —(C 1-6 )alkyl SO 2 (C 1-6 )alkyl,
(12) —C(O)(C 1-3 )alkyl, and
(13) —O(C 1-3 )alkyl,
when present, R 10 is independently selected from
(1) hydrogen,
(2) (C 1-3 )alkyl,
(3) (C 1-3 )alkoxy-,
(4) hydroxy,
(5) halogen,
(6) (C 1-3 )alkyl-S—,
(7) —(C 1-3 )haloalkyl, and
(8) N(R 11 ) 2 , and
R 11 , when present, is independently
(1) hydrogen, or
(2) (C 1-3 )alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6 membered heteroaryl containing one or two nitrogen atoms substituted with one or two substituents independently selected from halogen, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, —OC 1-3 haloalkyl unsubstituted or substituted with OH, —OC 0-3 alkyl-C 3-6 cycloalkyl unsubstituted or substituted with 1-2 halogens, azetidinyl unsubstituted or substituted with 1-2 halogens, CN, —SC 1-3 alkyl, and —SC 1-3 haloalkyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6 membered heteroaryl containing one or two nitrogen atoms substituted with one or two substituents independently selected from: C 1-3 alkyl; C 1-3 haloalkyl-OC 1-6 alkyl; —OC 1-3 haloalkyl unsubstituted or substituted with —OH; —O-cyclopropyl unsubstituted or substituted with halogen; —O—C 1-3 alkyl-C 3-6 cycloalkyl unsubstituted or substituted with one or two fluoro substituents; —SC 1-3 alkyl; —SC 1-3 haloalkyl; azetidinyl unsubstituted or substituted with one or two fluoro substituents; and halogen.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is a pyridinyl, substituted with one or two substituents independently selected from F; —CH 3 ; —CF 2 CH 3 ; —OCH(CH 3 ) 2 ; —OCHF 2 ; —OCH 2 CH 3 ; —OCF 2 CH 3 ; —OCF 2 CHF 2 , —OCH 2 CH(CH 3 ) 2 ; —OCH 2 CHF 2 ; —OCH 2 CF 3 ; —OCF 3 ; O-cyclopropyl; —O—CH 2 -cyclopropyl unsubstituted or substituted with 1 or 2 F; —O—CH 2 -cyclobutyl unsubstituted or substituted with 2 F; —OCH 2 CF 2 CH 3 ; —OCH 2 CF 2 CHF 2 ; —OCF 2 CH 2 OH; azetidinyl; 3,3-difluoroazetidinyl; and —SCHF 2 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are selected from one of the following:
(1) R 2a and R 2b are hydrogen,
(2) R 2a is hydrogen and R 2b is (C 1-6 )alkyl, or R 2a is (C 1-6 )alkyl and R 2b is hydrogen,
(3) R 2a is halogen and R 2b is (C 1-6 )alkyl, or R 2a is (C 1-6 )alkyl and R 2b is halogen,
(4) R 2a is hydroxy and R 2b is (C 1-6 )alkyl, or R 2a is (C 1-6 )alkyl and R 2b is hydroxy,
(5) R 2a is hydroxy and R 2b is (C 1-6 )haloalkyl, or R 2a is (C 1-6 )haloalkyl and R 2b is hydroxy,
(6) R 2a and R 2b are each independently selected from (C 1-6 )alkyl,
(7) R 2a and R 2b join to form spiro 4- to 8-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S wherein the spiroheterocyclyl is unsubstituted or substituted by 1, 2, or 3 R 7 , or
(8) R 2a and R 2b join to form spiro(C 3-8 )cycloalkyl unsubstituted or optionally mono-substituted, or di-substituted with C 1-63 alkyl, halogen, or OH.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected from H, and C 1-3 alkyl, or together form a spiro C 3-8 cycloalkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
(1) 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
(2) (C 3-6 )cycloalkyl,
(3) (C 1-6 ) hydroxyalkyl,
(4) —(C 1-6 )alkyl-S(O) 2 —NR 8a R 8b ,
(5) —(C 1-6 )alkyl-S(O) 2 —(C 1-3 )alkyl,
(6) —(C 1-6 )alkyl-heterocyclyl, wherein the heterocyclyl is a 5-membered heterocyclyl containing one oxygen,
(7) 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O and S, or
(8) —(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl containing 2 N heteroatoms,
wherein each cycloalkyl, or heterocyclyl is unsubstituted or substituted with 1, 2, or 3 R 9 , and wherein each alkyl or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 10 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, F, Cl, or CN.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen; hydroxy; —CN; —C 1-6 alkyl; —C 1-6 haloalkyl; —C 3-6 cycloalkyl unsubstituted or substituted with halogen or OH; —OC 1-6 alkyl; —OC 1-6 haloalkyl unsubstituted or substituted with OH; —O(C 1-3 )alkyl-(C 3-6 )cycloalkyl unsubstituted or substituted with one or two halogen substituents; —OC 3-6 cycloalkyl; —SO 2 NH(C 1-6 )alkyl; —S(O) 2 C 1-6 alkyl; —S—C 1-6 alkyl; —SC 1-6 haloalkyl; —NH(C—O)C 1-3 alkyl; (C 2-6 ) cyclic amine unsubstituted or substituted with one or two halogen substituents; or —N((C 1-3 )alkyl) 2 .
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 6 is F; —CN; —OH; —CH 3 ; —CF 2 CH 3 ; —OCF 2 CH 3 ; —OCHF 2 ; —OCF 3 ; —OCH 2 CF 3 ; —OCH 2 CH 3 ; —OCH(CH 3 ) 2 ; —OCF 2 CHF 2 ; —OCH 2 CHF 2 ; —OCHF 2 CH 3 ; —OCH 2 CF 2 CH 3 ; OCH 2 CH(CH 3 ) 2 ; OCH 2 CF 2 CHF 2 ; -cyclopropyl; —O-cyclopropyl; OCH 2 -cyclopropyl unsubstituted or substituted with 1 or 2 F; —OCH 2 -cyclobutyl unsubstituted or substituted with 1 or 2 F; azetidine unsubstituted or substituted with 1 or 2 F; —SCHF 2 ; —S(O) 2 CH 3 ; —S(O) 2 NHCH 3 ; —N(CH 3 ) 2 ; —OCF 2 CH 2 OH; or —NH(C═O)C 1-3 alkyl.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b are independently selected from hydrogen and cyclohexyl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is ═O, —OH, halogen, OC 1-3 alkyl, C 1-3 alkyl, C 1-3 haloalky, —SO 2 (C 1-3 )alkyl, —C( 1-3 )alkylSO 2 (C 1-3 )alkyl, or C(O)C 1-3 alkyl.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, —OH, —CH 3 , —CH 2 CH 3 , F, or CF 3 .
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C(R 5 ), and Z is C(R 5 ).
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C(R 5 ), Y is N, and Z is C(R 5 ).
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X, Y, and Z are each C(R 5 ).
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N, Y is N and Z is C(R 5 ).
23. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 which is:
3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,
3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,
3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,
3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,
1-[2-(2,2-difluoroethoxy)pyrimidin-4-yl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide,
1-[5-(difluoromethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-(5-ethoxy-3-pyridyl)-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[5-(2,2-difluoroethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[5-(difluoromethylsulfanyl)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[2-(2,2-difluoroethoxy)-5-fluoro-4-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[6-(2,2-difluoroethoxy) pyrazin-2-yl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[5-(1,1-difluoroethyl)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[5-(1,1-difluoroethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-[5-(2,2-difluoroethoxy)-2-methyl-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,
1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,
7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide,
7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide,
7-fluoro-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide,
1-[6-(2,2-difluoroethoxy)pyridazin-4-yl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-indoline-5-carboxamide,
1-(2-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-4-yl)-3,3-dimethyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxoindoline-5-carboxamide,
1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl) indoline-5-carboxamide,
1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(2-ethoxy-5-fluoropyridin-4-yl)-3,3-dimethyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxoindoline-5-carboxamide,
3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl) indoline-5-carboxamide,
1-(4-(2,2-difluoropropoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl) indoline-5-carboxamide,
1-(4-((2,2-difluorocyclopropyl) methoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-((3,3-difluorocyclobutyl) methoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-cyclopropoxypyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(difluoromethoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl) indoline-5-carboxamide,
1-(5-(difluoromethoxy)pyridin-3-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl) indoline-5-carboxamide,
1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxoindoline-5-carboxamide,
1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl-N-(1-((methylsulfonyl)methyl)cyclobutyl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoroethoxy)-3-fluoropyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(2-(2,2-difluoropropoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(5-(2,2-difluoroethoxy)pyridazin-3-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoroethoxy)pyrimidin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-isopropoxypyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-((1-fluorocyclopropyl) methoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(cyclopropylmethoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-isobutoxypyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(1,1-difluoroethyl) pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(5-fluoro-4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(5-(1,1-difluoro-2-hydroxyethoxy)pyridin-3-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(2-(3,3-difluoroazetidin-1-yl)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoropropoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(difluoromethoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoropropoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
1-(4-(2,2-difluoroethoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide, N-(4-(difluoromethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carboxamide, or
1-(5-fluoro-2-isopropoxypyridin-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
or a pharmaceutically acceptable salt thereof.
25. A compound which is:
or a pharmaceutically acceptable salt thereof.
26. A compound which is:
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 25 which is
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 25 which is
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 25 which is
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 26 which is
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 26 which is
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 26 which is
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 26 which is
or a pharmaceutically acceptable salt thereof.
34. A composition for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.
35. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
36. A method for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising administering to a patient in need thereof of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
37. A compound selected from:
38. The compound of claim 37 which is
39. The compound of claim 37 which is
40. The compound of claim 37 which is
41. The compound of claim 37 which is
42. The compound of claim 37 which is
43. The compound of claim 37 which is
44. The compound of claim 37 which is
45. A method for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 25 or a pharmaceutically acceptable salt thereof.
46. A method for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 26 or a pharmaceutically acceptable salt thereof.
47. A method for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 37 .
48. A compound of Formula I:
or a pharmaceutically acceptable salt thereof wherein:
X, Y, and Z are each C(R 5 );
R 1 is
R 2a and R 2b are each methyl;
R 3 is
R 4 is hydrogen; and
each R 5 is hydrogen or fluoro.