Sars-cov-2 inhibitors for treating coronavirus infections
AssigneeInsilico Medicine IP Limited
InventorsXiao DING, Jingjing PENG, Feng REN, Xiaoyu DING, Bogdan ZAGRIBELNYY, Yan A. IVANENKOV
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Abstract
Provided herein are compounds, pharmaceutical compositions, and methods for treating a SARS-CoV-2 infection.
Claims62
A compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
- wherein:
- R1 is halogen;
- R2 is halogen;
- Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R3 is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)NRcRd, —SH, —SRa, —SF5, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R3a;
- or two R3 on the same atom are taken together to form an oxo;
- each R3a is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or two R3a on the same atom are taken together to form an oxo;
- n is 0-4;
- L is —(CR4R4)p—;
- each R4 is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
- or two R4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R4a;
- each R4a is independently halogen, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
- p is 0-4;
- R5 is deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
- Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R6 is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R6a;
- or two R6 on the same atom are taken together to form an oxo;
- each R6a is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or two R6a on the same atom are taken together to form an oxo;
- m is 0-4;
- R7 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R8 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl);
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R8a;
- each R8a is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or two R8a on the same atom are taken together to form an oxo;
- or R7 and R8 are taken together to form a heterocycloalkyl optionally and independently substituted with one or more R8a;
- each R8a is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or two R7a on the same atom are taken together to form an oxo;
- each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl);
- wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl);
- wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl);
- wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
- and
- each R is independently halogen, —CN, —OH, —OC1-C6alkyl, —S(═O)C1-C6alkyl, —S(═O)2C1-C6alkyl, —S(═O)2NH2, —S(═O)2NHC1-C6alkyl, —S(═O)2N(C1-C6alkyl)2, —NH2, —NHC1-C6alkyl, —N(C1-C6alkyl)2, —NHC(═O)OC1-C6alkyl, —C(═O) C1-C6alkyl, —C(═O)OH, —C(═O)OC1-C6alkyl, —C(═O)NH2, —C(═O)N(C1-C6alkyl)2, —C(═O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
- or two R on the same atom are taken together to form an oxo.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the abundance of deuterium in each of R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc, Rd, and/or R is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one or more of R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc, Rd, and/or R groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc, Rd, and/or R.
A compound selected from a compound of table 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
Dependencies are inferred from the claim text.