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:
W is selected from N or C(H);
X is N
Y and Z are independently selected from N or C(R 5 ); and
R 1 is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R 6 , or
(2) 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 , or
(3) 8- to 10-membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 6 ;
R 2 is
(1) phenyl optionally mono-substituted or disubstituted with halogen,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is optionally mono-substituted or disubstituted with halogen, C 1-6 haloalkyl, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)(OH), or OH,
(3) C 1-6 alkyl unsubstituted or optionally mono-substituted, disubstituted or trisubstituted with halogen, OH, CF 3 , —CN, or (C 3-6 )cycloalkyl,
(4) (C 3-6 )cycloalkyl unsubstituted or optionally mono-substituted, disubstituted or trisubstituted with C 1-6 alkyl, halogen, OH, CF 3 , or —CN,
(5) 4- to 6-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 ,
(6) —CH 2 -aryl optionally mono-substituted or disubstituted with halogen,
(7) —CH 2 -tetrahydropyran, or
(8) —C 1-6 alkylC(O)NH 2 ;
R 3 is
(1) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S,
(2) —(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,
(3) —(C 1-6 )alkyl,
(4) —(C 3-6 )cycloalkyl,
(5) —(C 3-6 )cycloalkyl-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 )hydroxyalkyl,
(7) —(C 1-6 )cyanoalkyl,
(8) —(C 1-6 )alkyl-S(O) 2 —(C 1-3 )alkyl,
(9) —(C 1-6 )alkyl-(C 3-6 )cycloalkyl, or
(10) —C( 1-6 )alkyl-N(R 11 ) 2 ,
wherein each cycloalkyl or heterocyclyl is unsubstituted or substituted with 1, 2, 3 or 4 R 9 , and
wherein each alkyl 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 , together with the nitrogen atom to which they are attached, combine to form a mono- or bicyclic heterocyclyl ring containing 1 N and optionally containing 1 additional heteroatom 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 selected from
(1) hydrogen,
(2) (C 1-3 )alkyl,
(3) cyano, or
(4) halogen,
when present, each R 6 is independently selected from
(1) cyano,
(2) halogen,
(3) (C 1-6 )alkyl or OC 1-6 alkyl wherein the alkyl moiety is optionally substituted with cyano,
(4) (C 3-6 )cycloalkyl, optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, OH or OC 1-6 alkyl,
(5) —C(O)NH 2 ,
(6) O(C 3-6 )cycloalkyl wherein the cycloalkyl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, OH, or OC 1-6 alkyl,
(7) hydroxy,
(8) —N(R 11 ) 2 ,
(9) (C 1-6 )haloalkyl-,
(10) OC 1-6 haloalkyl,
(11) —SO 2 (C 1-6 )alkyl, or
(12) —SONH(C 1-6 )alkyl;
when present, each R 7 is independently selected from
(1) (C 1-6 )alkyl,
(2) halo,
(3) (C 1-6 )alkoxy-,
(4) (C 1-6 )haloalkyl-,
(5) (C 3-6 )cycloalkyl,
(6) hydroxy, or
(7) C(O)C 1-6 alkyl;
when present, each R 9 is independently selected from
(1) (C 1-6 )alkyl,
(2) (C 1-3 )haloalkyl-,
(3) oxo,
(4) (C 3-6 )cycloalkyl,
(5) —N(R 11 ) 2
(6) hydroxy,
(7) C 1-6 alkyl(OH),
(8) cyano,
(9) halo, or
(10) morpholinyl;
when present, R 10 is
(1) (C 1-3 )alkyl,
(2) (C 1-3 ) hydroxy alkyl-,
(3) (C 1-3 )alkoxy-,
(4) hydroxy,
(5) halogen,
(6) (C 1-3 )haloalkyl-,
(7) N(R 11 ) 2 , or
(8) C(O)NH 2 ; and
when present, R 11 is independently
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) C(O)C 1-6 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
(a) phenyl unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, N(C 1-3 alkyl) 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 3-6 cycloalkyl, S(O) 2 C 1-6 alkyl, OC 1-6 alkyl-CN, C 1-6 alkyl-CN, or NHC(O)C 1-6 alkyl, and wherein the cycloalkyl is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl; or
(b) 5- or 6-membered heteroaryl containing 1 or 2 N atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, O—C 3-6 cycloalkyl, OC 1-6 alkyl-CN, or CN, and when the cycloalkyl is cyclopropyl, the cyclopropyl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
(a) phenyl optionally substituted with one to three substituents independently selected from halogen, hydroxy, N(C 1-3 alkyl) 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 3-6 cycloalkyl, S(O) 2 C 1-6 alkyl, OC 1-6 alkyl-CN, C 1-6 alkyl-CN, or NHC(O)C 1-6 alkyl, and wherein the cycloalkyl is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl;
(b) 6 membered heteroaryl containing one nitrogen atom optionally substituted with one to three substituents independently selected from halogen C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, O—C 3-6 cycloalkyl, OC 1-6 alkyl-CN or CN, and when the cycloalkyl is cyclopropyl, the cyclopropyl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl; or
(c) 5 membered heteroaryl containing 2 N atoms optionally substituted with C 1-6 alkyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from halogen, OH, CN, CH 3 , CHF 2 , CF 3 , OC 1-6 alkyl, OC 1-6 alkylF 2 , cyclopropyl, O-cyclopropyl, O-cyclobutyl, C(F) 2 CH 3 , S(O) 2 CH 3 , OCH 2 CN, NHC(O)CH 3 , and wherein the cyclopropyl is optionally substituted with CH 3 , CF 3 , CN, OH, or OCH 3 .
5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6 membered heteroaryl containing one nitrogen atom optionally substituted with one to three substituents independently selected from halogen, CN, CH 3 , cyclopropyl, OCHF 2 , OCF 3 , OCH 2 CH 3 , OCH 2 CHF 2 , OCH 2 CF 3 , O-cyclobutyl, O-cyclopropyl, or wherein the O-cyclopropyl is optionally substituted with halogen, CH 3 , CF 3 , CN, OH, or OCH 3 .
6. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5 membered heteroaryl containing 2 N atoms optionally substituted with CH 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
(a) 5- or 6-membered heteroaryl containing zero or one oxygen atoms and/or zero, one or two nitrogen atoms optionally mono-substituted or disubstituted with halogen, C 1-6 haloalkyl, C 1-6 alkyl, C(O)C 1-6 alkyl, or OH,
(b) C 1-6 alkyl unsubstituted or optionally mono-substituted, disubstituted or trisubstituted with halogen, OH, CF 3 , or CN,
(c) C 3-6 cycloalkyl optionally mono-substituted, disubstituted or trisubstituted with C 1-6 alkyl, halogen, OH, CF 3 , or CN,
(d) 4 to 6 membered heterocycle having one or two heteroatoms independently selected from oxygen and nitrogen, optionally mono-substituted or disubstituted with halogen, C 1-6 haloalkyl, C 1-6 alkyl, C(O)C 1-6 alkyl, or OH,
(e) CH 2 -aryl substituted with halogen,
(f) CH 2 -tetrahydropyran,
(g) C 1-6 alkyl-C(O)NH 2 , or
(h) phenyl substituted with halogen.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
(a) 5 or 6-membered heteroaryl containing 2 N atoms optionally substituted with C 1-6 alkyl or halogen,
(b) phenyl substituted with halogen,
(c) C 1-6 alkyl optionally mono-substituted, disubstituted or trisubstituted with halogen, OH, CF 3 , or CN,
(d) C 3-6 cycloalkyl optionally mono-substituted, disubstituted or trisubstituted with C 1-6 alkyl, halogen, OH, CF 3 , or CN,
(e) 4 membered saturated heterocycle containing one oxygen atom or one nitrogen atom optionally substituted with C(O)CH 3 ,
(f) 5 membered saturated heterocycle containing one oxygen atom, optionally substituted with OH,
(g) 6 membered saturated heterocycle containing zero or one oxygen atom and zero or one nitrogen atoms optionally mono-substituted or disubstituted with halogen, C 1-6 haloalkyl, or C 1-6 alkyl,
(h) CH 2 -aryl substituted with halogen,
(i) CH 2 -tetrahydropyran, or
(j) C 1-6 alkyl-C(O)NH 2 .
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
(a) 5 or 6-membered heteroaryl containing 2 N atoms optionally substituted with CH 3 or fluoro,
(b) phenyl substituted with halogen,
(c) CH 3 , CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH 2 C(CH 3 ) 3 , CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(OH)(CH 3 ), CH 2 C(OH)(CH 3 ) 2 , CH(CH 3 )CH(OH)(CH 3 ), (CH 3 ) 2 C(CH 3 ) 2 (OH), CH(CH 3 )C(CH 3 ) 2 OH, CH 2 CH(OH)(CF 3 ), cyclobutyl, or cyclopropyl wherein the cyclobutyl is optionally mono-substituted or disubstituted selected from OH, fluoro, CH 3 , or CN,
(d) 4 membered saturated heterocycle containing one oxygen atom or one nitrogen atom optionally substituted with C(O)CH 3 ,
(e) 5 membered saturated heterocycle containing one oxygen atom, optionally substituted with OH,
(f) 6 membered saturated heterocycle containing zero or one oxygen atom and zero or one nitrogen atoms optionally mono-substituted or disubstituted with F, CF 3 , or CH 3 ,
(g) CH 2 -phenyl substituted with halogen, or
(h) C 1-6 alkyl-C(O)NH 2 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:
(a) 4 to 6 membered cycloalkyl optionally substituted with halogen, C 1-6 alkyl, C 1-6 alkyl(OH), OH, NH 2 , or morpholinyl;
(b) 4, 5, or 6 membered heterocyclyl containing 1 sulfur atom or 1 oxygen atom optionally mono-substituted, disubstituted, trisubstituted, or quad-substituted with C 1-6 alkyl, C 1-3 alkyl (OH), OH, NH 2 , N(CH 3 ) 2 , CN, or oxo;
(c) C 1-6 alkyl(OH) wherein the alkyl moiety is optionally mono-substituted, disubstituted, or trisubstituted with halogen, CF 3 , C 1-3 alkyl, or OH;
(d) C 1-6 alkyl-N(CH 3 ) 2 , or
(e) C 1-6 alkyl-C(O)NH 2 .
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:
(a) 4 to 6 membered cycloalkyl optionally substituted with F, CH 2 (OH), OH, NH 2 , or morpholinyl,
(b) 4 or 5 membered heterocyclyl containing 1 sulfur atom optionally mono-substituted, disubstituted, trisubstituted, or quad-substituted with oxo, or CH 3 , or OH,
(c) 5 or 6 membered heterocyclyl containing 1 oxygen atom optionally mono-substituted, disubstituted, trisubstituted, or quad-substituted with CH 3 , NH 2 , CN, CH 2 OH, N(CH 3 )(CH 3 ), CH(CH 3 )(OH), or C(CH 3 )(CH 3 )(OH),
(d) C 1-6 alkyl(OH), wherein the alkyl moiety is optionally mono-substituted, disubstituted, or trisubstituted with halogen, CF 3 , CH 3 , OH,
(e) C 1-6 alkyl-N(CH 3 ) 2 , or
(f) C 1-6 alkyl-C(O)NH 2 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is
15. The compound of claim 1 , of Formula Ia,
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , of Formula Ib,
or a pharmaceutically acceptable salt thereof, wherein
R 1 is
R 2 is
and
R 3 is
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is N.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is C(H).
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X, Y, and Z are selected from:
(i) X is N, Y is C(R 5 ), and Z is C(R 5 ),
(ii) X is N, Y is N and Z is C(R 5 ), or
(iii) X is N, Y is C(R 5 ) and Z is N.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 , when present, is selected from hydrogen, halogen, cyano, or (C 1-3 )alkyl.
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 5 , when present, is selected from H, CN, CH 3 , or F.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
27. 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.
28. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
29. 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 compound of claim 1 , or a pharmaceutically acceptable salt thereof.