Oxo-tetrahydro-isoquinoline carboxylic acids as STING inhibitors

Patent metadata

Field	Value
Publication number	US-11311528-B2
Application number	US-201916980594-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Mar 20, 2018
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

The instant invention provides compounds of formula I which are STING inhibitors, and as such are useful for the treatment of STING-mediated diseases such as inflammation, asthma, COPD and cancer.

First claim

What is claimed is:

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein: A is a 5- to 7-membered unsaturated non-aromatic ring having 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur;
R 1 is selected from —OH amino, —NHOH, —N(C 1-6 alky) 2 , and —N(C 1-6 alkyl);
n is 0, 1, 2, or 3;
z is 0, 1, 2, or 3;
y is 0, 1, 2, or 3;
each R 3 is independently selected from C 1-10 alkyl, C 1-10 haloalkyl, C 3-7 cycloalkylC 0-6 alkyl, and C 3-7 heterocycloalkylC 0-6 alkyl,
R 2 is phenyl or pyridyl, wherein R 2 is substituted by 0, 1, 2, or 3 R 5 substituents and wherein two R 5 may join together with the ring atoms to which they are attached to form a 3- to 6-membered ring;
each R 4 is independently selected from halogen, —(C 1-6 alkyl)OH, hydroxy, C 1-10 haloalkyl, C 2-10 alkenyl, C 1-6 alkyl, and aryl(C 0-10 alkyl)oxy(C 0-10 alkyl);
each R 5 is independently selected from:
halogen,
C 1-10 alkyl(oxy) 0-1 C 0-10 alkyl,
C 1-10 heteroalkyl(oxy) 0-1 C 0-10 alkyl,
C 2-10 alkenyl(oxy) 0-1 C 0-10 alkyl,
aryl C 0-10 alkyl(oxy) 0-1 C 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkyl(oxy) 0-1 C 0-10 alkyl,
heteroaryl C 0-10 alkyl(oxy) 0-1 C 0-10 alkyl,
(C 3-12 )heterocycloalkyl C 0-10 alkyl(oxy) 0-1 C 0-10 alkyl,
amino,
C 1-10 alkylaminoC 0-10 alkyl,
(C 1-10 )heteroalkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
aryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
heteroaryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
(C 3-12 )heterocycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
C 0-10 alkylamino (carbonyl) 0-1 C 0-10 alkyl,
(C 1-10 )heteroalkylamino (carbonyl) 0-1 C 0-10 alkyl,
C 3-12 cycloalkylamino (carbonyl) 0-1 C 0-10 alkyl,
aryl C 0-10 alkylamino (carbonyl)C 0-10 alkyl,
heteroaryl C 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl,
(C 3-12 )heterocycloalkylamino(carbonyl) 0-1 C 0-10 alkyl,
C 1-10 alkylsulfonylC 0-10 alkyl,
C 1-10 heteroalkylsulfonylC 1-10 alkyl,
(C 3-12 )cycloalkylC 0-10 alkylsulfonylC 0-10 alkyl,
(C 3-12 )cycloheteroalkylC 0-10 alkylsulfonylC 0-10 alkyl,
heteroarylC 0-10 alkylsulfonylC 0-10 alkyl,
arylC 0-10 alkylsulfonylC 0-10 alkyl,
C 1-10 alkylsulfonylaminoC 0-10 alkyl,
(C 1-10 alkyl) 1-2 amino,
—SO 2 NH 2 ,
SO 2 NH(C 1-10 alkyl),
—SO 2 N(C 1-10 alkyl) 2 ,
—SO 2 CF 3 ,
—SO 2 CF 2 H,
—SH,
—S(C 1-10 alkyl),
—NH═CH 2 ,
hydroxy,
—(C 1-10 alkyl)OH,
—C 0-10 alkylalkoxy,
cyano,
—(C 1-6 alkyl)cyano, and
C 1-6 haloalkyl(oxy) 0-1 ; wherein each R 5 is substituted with 0, 1, 2 or 3 R 6 substituents each independently selected by halogen, cyano, oxo, C 1-10 alkylcarbonylC 0-10 alkyl, C 1-10 alkyl, C 1-10 alkylcarbonylaminoC 0-10 alkyl, and —(C 1-10 alkyl)OH.

2. The compound according to claim 1 , wherein R 1 is selected from —OH, amino, —NHOH, —N(C 1-3 alkyl) 2 , and —N(C 1-3 alkyl) or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 , wherein R 1 is selected from —OH, amino, —NHOH, dimethylamino, and methylamino or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein each R 3 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkylC 0-6 alkyl, and C 3-7 heterocycloalkylC 0-6 alkyl or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein each R 3 is independently selected from methyl, isopropyl, and cyclopropyl or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein each R 4 is independently selected from halogen, hydroxy, C 2-10 alkenyl, and aryl(C 0-10 alkyl)oxy(C 0-10 alkyl) or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein each R 4 is independently selected from halogen, hydroxy, ethenyl, and phenylmethoxy or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein each R 5 is independently selected from: halogen, C 1-6 alkyl(oxy) 0-1 C 0-10 alkyl, C 2-10 alkenyl, aryl C 0-10 alkyl(oxy) 0-1 C 0-10 alkyl, C 3-12 cycloalkyl C 0-10 alkyl, heteroaryl C 0-10 alkyl, (C 3-12 )heterocycloalkyl C 0-10 alkyl, C 1-10 alkylaminoC 0-10 alkyl, aryl C 0-10 alkylamino (carbonyl)C 0-10 alkyl, C 1-10 alkylsulfonylC 0-10 alkyl, C 1-10 alkylsulfonylaminoC 0-10 alkyl, (C 1-10 alkyl) 1-2 amino, —SO 2 NH(C 1-10 alkyl), —SO2N(C 1-10 alkyl) 2 , —SH, —NH═CH 2 , —(C 1-10 alkyl)OH, —C 0-10 alkylalkoxy, cyano, —(C 1-6 alkyl)cyano, and C 1-6 haloalkyl(oxy) 0-1 ; wherein each R 5 is substituted with 0, 1, 2, or 3 R 6 substituents or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 , wherein each R 5 is independently selected from: F, Cl, tert-butyl, isopropyl, methyl, ethyl, morpholinyl, methylsufonyl, dimethysulfamoyl, 1-cyano-1-methylethyl, cyclopropyl, piperazinyl, pyrazolyl, methoxy, —SH, —N═CH 2 , methylamino, cyano, hydroxyethyl, 2,2,2-trifluoroethyloxy, phenylaminocarbonyl, cyclohexyl, propyl, ((methylsulfonyl)amino)methyl, morpholinylmethyl, phenylmethyloxy, Br, prop-2-enyl, hydroxymethyl, phenyl, and piperidinyl, wherein each R 5 is substituted with 0, 1, 2 or 3 R 6 substituents or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 , wherein each R 6 is independently selected from halogen, cyano, oxo, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkylcarbonylamino, and (C 1-10 alkyl)OH or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 , wherein each R 6 is independently selected from halogen, methylcarbonyl, hydroxyethyl, oxo, cyano, hydroxymethyl, methylcarbonyl amino, and methyl or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein R 5 is selected from hydrogen, methyl, methylcarbonyl, ethyl, isopropyl, morpholinoethyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethyl, 1-phenylethyl, benzyl, tetrahydro-2H-pyranylmethyl, 1-cyclopropylethyl, and tetrahydro-2H-pyranyl or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 11 , wherein R 6 is hydrogen or oxo or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein

is selected from:

or a pharmaceutically acceptable salt thereof.

15. The compound or a pharmaceutically acceptable salt, thereof, wherein the compound is selected from:
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(1-methylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic aci

Assignees

• Merck Sharp & Dohme
• Altman Michael D
• Childers Matthew L
• Jewell James P
• Lesburg Charles A
• Siu Tony

Inventors

• Altman Michael D
• Childers Matthew L
• Jewell James P
• Lesburg Charles A
• Siu Tony

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title