Substituted phenyl ethynyl pyridine carboxamides as potent inhibitors of SARS virus

Patent metadata

Field	Value
Publication number	US-11905306-B2
Application number	US-202218086445-A
Country	US
Kind code	B2
Filing date	Dec 21, 2022
Priority date	Dec 21, 2021
Publication date	Feb 20, 2024
Grant date	Feb 20, 2024

Abstract

The present disclosure is concerned with substituted phenyl ethynyl pyridine carboxamide compounds, pharmaceutical compositions comprising the compounds, and methods of treating viral infections due to a Coronavirus such as, for example, Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus disease 2019 (SARS-CoV-2), using the compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein A is selected from —NR 10 C(O)— and —C(O)NR 11 ;
wherein each of R 10 , when present, and R 11 , when present, is selected from hydrogen and C1-C4 alkyl;

wherein each of Z 1 and Z 2 is independently selected from —N═ and —C(R 13 )═;
wherein each occurrence of R 13 , when present, is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

wherein each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein R 3 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyhaloalkyl, —NR 14 C(O)R 15 , —C(O)NR 16a R 16b , —OSO 2 NR 16a R 16b , —NR 17 SO 2 R 18 , —P(O)(OR 19 ) 2 , —CO 2 (C1-C4 alkyl), —CO 2 Cy 1 , —CO 2 (C1-C4 alkyl)Cy 1 , Cy 1 , and —CH 2 Cy 5 ;
wherein R 14 , when present, is selected from hydrogen and C1-C4 alkyl;
wherein R 15 , when present, is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 aminoalkyl, —OR 20 , —NR 21a R 21b , —CH 2 NR 21a R 21b , and Cy 2 ;
wherein R 20 , when present, is selected from hydrogen and C1-C4 alkyl;
wherein each of R 21a and R 21b , when present, is independently selected from hydrogen and C1-C4 alkyl;
or wherein R 21a and R 21b , when present, are covalently bonded, and, together with the intermediate atoms, comprise a 4- to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein Cy 2 , when present, is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

or wherein R 14 and R 15 , when present, are covalently bonded, and, together with the intermediate atoms, comprise a 4- to 9-membered heterocycloalkyl ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
or wherein R 15 , when present, and R 2b are covalently bonded, and, together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein each of R 16a and R 16b , when present, is independently selected from hydrogen, C1-C4 alkyl, and Cy 3 ;
wherein Cy 3 , when present, is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

wherein R 17 , when present, is selected from hydrogen and C1-C4 alkyl;
wherein R 18 , when present is a C1-C4 alkyl;
or wherein R 17 and R 18 , when present, are covalently bonded, and together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein each occurrence of R 19 , when present, is independently selected from hydrogen and C1-C4 alkyl;
wherein Cy 1 , when present, is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and
wherein Cy 5 , when present, is a C3-C6 heterocycloalkyl substituted with at least one ═O group, and substituted with 0, 1, or 2 additional groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

or wherein R 2a is selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl,
and wherein R 2b and R 3 are covalently bonded, and, together with the intermediate atoms, comprise a 5- or 6-membered heteroaryl, and are substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein R 4 is selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, Cy 4 , and —O(C1-C4 alkyl)Cy 4 ; and
wherein Cy 4 , when present, is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl,

provided that when A is —NR 10 C(O)—, then R 3 is —NR 14 C(O)R 15 , —C(O)NR 16a R 16b , —NR 17 SO 2 R 18 , —P(O)(OR 19 ) 2 , —CO 2 (C1-C4 alkyl), —CO 2 Cy 1 , —CO 2 (C1-C4 alkyl)Cy 1 , and Cy 1 , and
provided that when A is —NR 10 C(O)— and R 3 is —NR 14 C(O)R 15 , then R 15 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 aminoalkyl, —NR 21a R 21b , and —CH 2 NR 21a R 21b ,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A is —NR 10 C(O)—.

3. The compound of claim 1 , wherein A is —C(O)NR 11 .

4. The compound of claim 1 , wherein one of Z 1 and Z 2 is —N═.

5. The compound of claim 1 , wherein each of Z 1 and Z 2 is —C(R 13 )═.

6. The compound of claim 1 , wherein each of R 1a , R 1b , R

Assignees

• Southern Res Inst
• Univ North Carolina Chapel Hill
• Univ Vanderbilt
• Univ North Carolina Chapel Hill

Inventors

• Ahmed Syed Kaleem
• Dutta Shilpa
• Tillotson John Phillip
• Augelli-Szafran Corinne E
• Pathak Ashish Kumar
• Moukha-Chafiq Omar
• Sheahan Timothy Patrick
• Baric Ralph S
• Sims Amy Catherine
• Denison Mark R

Classifications

• C07F9/58 Primary

  Pyridine rings · CPC title

• C07D213/56 Primary

  Amides · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title