Pyrrolopyrimidine nucleosides and analogs thereof

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Quick Facts

Patent No.: US 10,407,457
App. No.: 15/599,056
Granted: Sep 10, 2019
Kind: B2

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Abstract

The present disclosure provides pyrrolopyrimidine nucleoside analogs of the Formula I, Formula IA, Formula IB, or Formula II and phospholipid conjugates and pharmaceutical compositions thereof wherein R c and A are defined herein. Also presented are methods of treating and/or preventing viral infection and/or viral infection-associated disease or disorder with one or more compounds of Formula I, Formula IA, Formula IB, or Formula II.

Claims (224)

1. A method of treating a viral infection comprising administering to a subject in need thereof an effective amount of a compound of Formula IB

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

A is:

X 1 is CR 11 R 12 — or —OCH 2 CH 2 — wherein the oxygen atom is distal to the R IB moiety in A;

R 11 and R 12 are independently hydrogen or C 1 -C 4 alkyl, wherein the alkyl is optionally substituted with one or more halogen, —OH, —SH, or —NH 2 ;

X 2 is absent, —O—, —C(O)O—, or —OCH 2 — wherein the oxygen atom is distal to the R IB moiety in A;

each R IB independently is hydrogen, —C 1 -C 6 alkyl,

or R IB is an amino acid residue bound via the carbonyl group, wherein the alkyl is optionally substituted with one or more halogen, —OH, —SH, or —NH 2 ;

v is 0 or 1;

n is 0, 1, 2, or 3 and when X 2 is —C(O)O—, n is 0;

p is 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18;

R z is hydrogen, halogen, —C 1 -C 4 alkylthio, —C 1 -C 4 alkoxy, —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —C 2 -C 4 alkynyl, aryl, heteroaryl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, or 3- to 5-membered nonaromatic heterocycle, wherein each alkylthio, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle is optionally substituted with one or more halogen, —OH, —SH, or —NH 2 ;

R a , R b , R x , and R y are each independently selected from the group consisting of hydrogen, halogen, —OH, —SH, —C 1 -C 6 alkoxy, aryloxy, —C 1 -C 6 alkylthio, arylthio, —OC(O)C 1 -C 6 alkyl, —OC(O)aryl, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, aryl, heteroaryl, —C 3 -C 8 cycloalkyl, and —C 4 -C 8 cycloalkenyl, wherein each alkoxy, aryloxy, alkylthio, arylthio, alkyl, aryl, alkenyl, alkynyl, heteroaryl, cycloalkyl, or cycloalkenyl is optionally substituted with one or more halogen, —OH, —SH, or —NH 2 ;

or any two R a or R b , together with the atom to which they are both attached, can combine to form a C 3 -C 8 spirocycloalkyl or 3- to 8-membered spiroheterocycle;

or any two R a or R b , when on adjacent atoms, can combine to form a cis- or trans-carbon-carbon double bond or a carbon-carbon triple bond;

or any two R a or R b , when on adjacent atoms, can combine to form an aryl, heteroaryl, —C 3 -C 10 cycloalkyl, —C 4 -C 10 cycloalkenyl, or 5- to 10-membered ring heterocycle;

or any CR a R b can be replaced by —O—, —S—, —S(O)—, or —SO 2 —;

or any two R x or R y , together with the atom to which they are both attached, can combine to form a —C 3 -C 8 spirocycloalkyl or 3- to 8-membered spiroheterocycle;

or any two R x or R y , when on adjacent atoms, can combine to form a cis- or trans-carbon-carbon double bond or a carbon-carbon triple bond;

or any two R x or R y , when on adjacent atoms, can combine to form an aryl, heteroaryl, —C 3 -C 10 cycloalkyl, —C 4 -C 10 cycloalkenyl, or 5- to 10-membered ring heterocycle;

or any CR x R y can be replaced by —O—, —S—, —S(O)—, or —SO 2 —;

R 1 and R 45 are each independently hydrogen, halogen, —N 3 , —OH, —NH 2 , —SH, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 8 -C 11 cycloalkynyl, —C 1 -C 6 alkoxy, or —C 1 -C 6 alkylthio wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, alkoxy or alkylthio is independently substituted with one or more halogen, —N 3 , —OH, —NH 2 , or —SH;

R 2 , R 3 , R 4 and R 44 are each independently hydrogen, halogen, —N 3 , —OH, —NH 2 , —SH, C 1 -C 6 alkoxy, or —C 1 -C 6 alkylthio, wherein each alkyl, alkoxy, or alkylthio is optionally substituted with one or more halogen, —N 3 , —OH, —NH 2 , or —SH;

or R 3 and one of R 4 and R 44 , together with the atoms to which they are attached can form a carbon-carbon double bond;

R 5 is independently hydrogen, —R IB , M + , aryl, aralkyl, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, cycloalkyl, non-aromatic heterocyclic ring, or heteroaryl, wherein M + is a cation and wherein each aryl, aralkyl, alkyl, heteroalkyl, cycloalkyl, heterocycle, or heteroaryl is optionally substituted with one or more halogen, —N 3 , —OH, —NH 2 , or —SH, and wherein R 5 is not an amino acid; and

R c is —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 8 -C 12 cycloalkynyl, or aryl, wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl, or aryl is optionally substituted with one or more halogen, —N 3 , —OH, —NH 2 , or —SH;

wherein the subject exhibits early signs of the infection.

2. The method of claim 1 , wherein the viral infection is norovirus infection.

3. The method of claim 1 , wherein the subject is dosed for five weeks or less.

4. A method of preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of Formula IB

or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

A is:

X 1 is —CR 11 R 12 — or —OCH 2 CH 2 — wherein the oxygen atom is distal to the R IB moiety in A;