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US 2022/0054512 A1Published application
Cd73 inhibitors
AssigneeOric Pharmaceuticals, Inc.
InventorsXiaohui DU, John EKSTEROWICZ, Valeria R. FANTIN, Erica L. JACKSON, Daqing SUN, Qiuping YE, Jared MOORE
Life of this patent
Estimating the term…
Abstract
Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.
Claims102
A compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
- wherein:
- A —O— or —CH2—;
- R1 and R2 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), —S(═O)2R15, —S(═O)2NR16R17, or —C(═O)2R15;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20a;
- or R1 and R2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20a;
- R3 is halogen, —CN, OR15, SR18, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20b;
- R4 and R7 are each independently hydrogen, halogen, —OH, —OR15, —NR16S(═O)2R15, —NR16C(═O)R15, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20c;
- R5 and R6 are each independently hydrogen, halogen, —OH, —OR15, —NR16S(═O)2R15, —NR16C(═O)R15, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20d;
- R8 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with one, two, or three halogen;
- R9 and R10 are each independently hydrogen, halogen, or C1-C6 alkyl optionally substituted with one, two, or three halogen;
- X is —O— or —CR11R12—;
- R11 and R12 are each independently hydrogen, halogen, or C1-C6 alkyl optionally substituted with one, two, or three halogen;
- Y1, Y2, and Y3 are independently —O—, —S—, or —CR13R14—;
- R13 and R14 are each independently hydrogen, halogen, —OH, —OR15, —NR16R17, C1-C6 alkyl optionally substituted with one, two, or three halogen;
- R15 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20e;
- R16 and R17 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20f;
- or R16 and R17 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl;
- R18 is C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20g;
- n, m, and p, are each independently 0 or 1;
- each R20a, R20b, R20c, R20d, R20e, R20f, and R20g are independently halogen, —CN, —OH, —ORa, —SH, —SRa, —S(═O)Ra, —NO2, —NRbRc, —S(═O)2Ra, —NHS(═O)2Ra, —S(═O)2NRbRc, —C(═O)Ra, —OC(═O)Ra, —C(═ORb, —OC(═O)ORb, —C(═O)NRbRc, —OC(═O)NRbRc, —NRbC(═O)NRbRc, —NRbC(═O)Ra, —NRbC(═O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R21;
- each R21 is independently halogen, —CN, —OH, —ORa, —SH, —SRa, —S(═O)Ra, —NO2, —NRbRc, —S(═O)2Ra, —NHS(═O)2Ra, —S(═O)2NRbRc, —C(═O)Ra, —OC(═O)Ra, —C(═O)ORb, —OC(═O)ORb, —C(O)NRbRc, —OC(═O)NRbRc, —NRbC(═O)NRbRc, —NRbC(═O)Ra, —NRbC(O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or cycloalkyl;
- each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- and
- Rb and Rc are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or Rb and Rc are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
29 more elements
A compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
- A is —O— or —CH2—;
- R1 and R2 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), —S(═O)2R15, —S(═O)2NR16R17, or —C(═O)2R15;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20a;
- or R1 and R2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20a;
- R3 is halogen, —CN, OR15, SR18, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20b;
- R4 and R7 are each independently hydrogen, halogen, —OH, —OR15, —NR16S(═O)2R15, —NR16C(═O)R15, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20c;
- R5 and R6 are each independently hydrogen, halogen, —OH, —OR15, —NR16S(═O)2R15, —NR16C(═O)R15, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20d;
- R8 is hydrogen, halogen, or C1-C6 alkyl optionally substituted with one, two, or three halogen;
- R9 and R10 are each independently hydrogen, halogen, or C1-C6 alkyl optionally substituted with one, two, or three halogen;
- Y3 is —O—, —S—, or —CR13R14—;
- R13 and R14 are each independently hydrogen, halogen, —OH, —OR15, —NR16R17, C1-C6 alkyl optionally substituted with one, two, or three halogen;
- R15 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20e;
- R16 and R17 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl;
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20f;
- or R16 and R17 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl;
- R18 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R20g;
- each R20a, R20b, R20c, R20d, R20e, R20f, and R20g are independently halogen, —CN, —OH, —ORa, —SH, —SRa, —S(═O)Ra, —NO2, —NRbRc, —S(═O)2Ra, —NHS(═O)2Ra, —S(═C)2NRbRc, —C(═O)Ra, —OC(═O)Ra, —C(═ORb, —OC(═O)ORb, —C(═O)NRbRc, —OC(═O)NRbRc, —NRbC(═O)NRbRc, —NRbC(═O)Ra, —NRbC(═ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R21;
- each R21 is independently halogen, —CN, —OH, —ORa, —SH, —SRa, —S(═O)Ra, —NO2, —NRbRc, —S(═O)2Ra, —NHS(═O)2Ra, —S(═O)2NRbRc, —C(═O)Ra, —OC(═O)Ra, —C(═O)ORb, —OC(═O)ORb, —C(═O)NRbRc, —OC(═O)NRbRc, —NRbC(═O)NRbRc, —NRbC(═O)Ra, —NRbC(═O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- Rb and Rc are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- or Rb and Rc are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl;
- and
- R30, R33, and R34 are each independently hydrogen, C1-C20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), —(CR50R51)vC(═O)OR40, —(CR50R51)vOC(═O)R40, —(CR50R51)vSC(═O)R40, —(CR50R51)vOC(═O)OR40, —(CR50R51)vOC(═O)(CR52R53)vC(═O)R41, or —(C1-C6 alkylene)[OC(═O)R40]2;
- provided that at least one of R30, R33, or R34 is not hydrogen;
- or R34 and R33 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R22;
- R40 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R24;
- R41 is a glycerol ester derivative, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R24;
- R50 and R51 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- R52 and R53 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl);
- each R22 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl);
- wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R23;
- each R23 is independently halogen, —CN, —OH, —ORa, —SH, —SRa, —S(═O)Ra, —NO2, —NRbRc, —S(═O)2Ra, —NHS(═O)2Ra, —S(═O)2NRbRc, —C(═O)Ra, —OC(═O)Ra, —C(═O)ORb, —OC(═O)ORb, —C(═O)NRbRc, —OC(═O)NRbRc, —NRbC(═O)NRbRc, —NRbC(═O)Ra, —NRbC(═O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- each R24 are independently halogen, —CN, —OH, —ORa, —SH, —SRa, —S(═O)Ra, —NO2, —NRbRc, —S(═O)2Ra, —NHS(═O)2Ra, —S(═O)2NRbRc, —C(═O)Ra, —OC(═O)Ra, —C(═O)ORb, —OC(═O)ORb, —C(═O)NRbRc, —OC(═O)NRbRc, —NRbC(═O)NRbRc, —NRbC(═O)Ra, —NRbC(═O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- and
- v is 1, 2, 3, or 4.
40 more elements
Dependencies are inferred from the claim text.