Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use

Patent metadata

Field	Value
Publication number	US-11084832-B2
Application number	US-202016825142-A
Country	US
Kind code	B2
Filing date	Mar 20, 2020
Priority date	Mar 22, 2019
Publication date	Aug 10, 2021
Grant date	Aug 10, 2021

Abstract

Compounds for use in treating or preventing human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following formula (I):including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2, L, W1, W2, X, Y, and Z are as defined herein. Methods associated with the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is H or C 6-10 aryl, wherein C 6-10 aryl is optionally substituted with one to four R A1 , wherein each R A1 is independently halo, C 1-6 alkyl, C 1-4 haloalkyl, cyano, —O—C 1-4 alkyl, or C 1-4 alkyl-O—C 1-4 alkyl;
R 2 is H, C 1-6 alkyl, or C 1-4 haloalkyl;
L is —CR 3a R 3b —, —C(O)—, —SO 2 —, —CH 2 —CH 2 —, or —N(R a )—;
W 1 is a bond or —CR 4a R 4b —;
W 2 is —CR 5a R 5b —, —CR 5a R 5b CR 5c R 5d —, —CR 6a ═CR 6b —, —N(R 7 )—, —O—, —S(O) n —, —C(O)—, —C(O)O—, —C(O)NH—, —CR 5a R 5b —N(R 7 )—, —CR 5a R 5b —O—, —CR 5a R 5b —S(O) n —, —CR 5a R 5b —C(O)—, —CR 5a R 5b —C(O)O—, —CR 5a R 5b —OC(O)—, —CR 5a R 5b —C(O)NH—, or —CR 5a R 5b —NHC(O)—;
X is a bond or —CR 8a R 8b —;
Y is —C(O)NH— or Q, wherein Q is

Z is —CR 9a R 9b —, —CR 9a R 9b CR 9c R 9d —, or —CR 10a ═CR 10b —;
R 3a and R 3b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or —O—C 1-4 alkyl; or optionally:
R 3a and R 3b together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with one to three R A2 , wherein each R A2 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl;
R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo;
R 5a , R 5b , R 5c , and R 5d are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, cyano, —O—C 1-4 alkyl, or C 1-4 alkylene-O—C 1-4 alkyl; or optionally:
R 5a and R 5b or R 5c and R 5d together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with one to three R A3 , wherein each R A3 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or
R 5a and R 5c or R 5b and R 5d together with the carbon atoms to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, wherein the fused ring is optionally substituted with one to three R A3 , wherein each R A3 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl;

each R 6a and R 6b is independently H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; optionally:
R 6a and R 6b together with the carbon atoms to which each is attached form a 5- to 10-membered partially unsaturated fused ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally substituted with one to four R A4 , wherein each R A4 is independently halo or C 1-4 alkyl;

R 7 is H, C 1-6 alkyl, C 1-4 haloalkyl, C(O)R c , or SO 2 R c ;
R 8a and R 8b are each independently H, hydroxyl, —O—C 1-4 alkyl, C 1-4 alkylene-O—C 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, cyano, or halo; or optionally:
R 8a and R 8b together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with one to four R A5 , wherein each R A5 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or optionally:
R 8a is H, hydroxyl, —O—C 1-4 alkyl, C 1-4 alkylene-O—C 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, cyano, or halo; and
R 8b and one of R 5a , R 5b , R 5c , R 5d , and R 7 together with the atoms to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally substituted with one to four R A5 , wherein each R A5 is independently halo or C 1-4 alkyl; or
R 8b and R 2 together with the carbon atoms to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally substituted with one to four R A5 , wherein each R A5 is independently halo or C 1-4 alkyl;

R 9a , R 9b , R 9c , and R 9d are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo; or optionally:
R 9a and R 9b or R 9c and R 9d together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with one to three R A6 , wherein each R A6 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or
R 9a and R 9c or R 9b and R 9d together with the carbon atoms to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, wherein the fused ring is optionally substituted with one to three R A6 , wherein each R A6 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl; or
one of R 9a , R 9b , R 9c , and R 9d and one of R 4a , R 4b , R 5a , R 5b , and R 7 together with the atoms to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally substituted with one to four R A6 , wherein each R A6 is independently halo or C 1-4 alkyl;

R 10a and R 10b are independently H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; or optionally:
R 10a and R 10b together with the carbon atoms to which each is attached form a 5- to 10-membered partially unsaturated fused ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally substituted with one to four R A7 , wherein each R A7 is independently halo or C 1-4 alkyl;

R a is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R c , or SO 2 R c ;
R b is H or C 1-4 alkyl;
R c is C 1-4 alkyl or —O—C 1-4 alkyl; and
each n is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , and —CH 2 F, or R 2 and R 8b together with the carbon to which they are attached form a 3-membered fused carbocyclic ring.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , and —CH 2 F.

4. The compound of claim 1 , or a pharmaceutic ally acceptable salt thereof, wherein Y is —C(O)NH—.

5. The compound of claim 1 , or a pharmaceutic ally acceptable salt thereof, having a the formula (II):

6. The compound of claim 1 , or a pharmaceutic ally acceptable salt thereof, wherein R 1 is phenyl, optionally substituted with one to four R A1 , wherein each R A1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, —O—C 1-4 alkyl, or C 1-4 alkyl-O—C 1-4 alkyl.

7. Th

Assignees

• Gilead Sciences Inc

Inventors

• Chu Hang
• Gonzalez Buenrostro Ana Z
• Guo Hongyan
• Han Xiaochun
• Jiang Lan
• Li Jiayao
• Mitchell Michael L
• Pyun Hyung-Jung
• Schroeder Scott D
• Schwarzwalder Gregg M
• Shapiro Nathan D
• Shivakumar Devleena M
• Wu Qiaoyin
• Yang Hong
• Zhang Jennifer R

Classifications

• C07D498/08

  Bridged systems · CPC title

• C07D487/08

  Bridged systems · CPC title

• A61P31/18 Primary

  for HIV · CPC title

• C07D513/18

  Bridged systems · CPC title

• C07D495/22

  in which the condensed system contains four or more hetero rings · CPC title