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US 2026/0308159 A1Published application
Bicyclic heteroarylamides having gpr68 modulating activity
AssigneeRecursion Pharmaceuticals, Inc.
InventorsSimon Richards, Michael Prime, Konstantinos Papachristos, Manisha Naik, Reid Hans Johnson Olsen
Life of this patent
Estimating the term…
Abstract
Disclosed are novel GPR68 modulators according to Formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Also disclosed are methods of using such compounds and compositions to treat various diseases including cancer and proliferative diseases and disorders.
Claims27
A compound of formula (1):
- including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, wherein:
- Q is O or S;
- X1 is selected from C and N;
- X2 is selected from CR5 and N;
- X3 is selected from CR6 and N;
- X4 is selected from CR7 and N;
- X5 is selected from C and N;
- wherein X1, X2, X3, X4 and X5 are selected so that the ring labelled A is aromatic;
- X6 is selected from CR8R9, O and N;
- X7 is selected from CR10, CR11R12, O and N;
- q is 0 or 1;
- wherein when q is 0, X7 is O or N;
- and when X7 is O or N and q is 1, X6 is CR8R9;
- L1 is a bond, C1-C6 alkylene, C1-C6 haloalkylene, C3-C6 cycloalkylene, or a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;
- R1 is selected from C1-C4 alkyl, C3-C8 cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, phenyl, C9-C10 bicyclic aryl, 5- or 6-membered heteroaryl having one or more ring members selected from N, O, S and SO2, 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, phenoxy, and 5- or 6-membered heteroaryloxy having one or more heteroatoms selected from N, O and S, wherein said alkyl, cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, bicyclic aryl, heteroaryl, bicyclic heteroaryl, phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, NR1aR1b, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-NR1aR1b, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, benzyl, phenoxy, halophenoxy, 5- or 6-membered heteroaryloxy having one or more heteroatoms selected from N, O and S, and C1-C4 alkyl substituted by a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;
- R1a and R1b are each independently selected from H and C1-C4 alkyl;
- R2 is selected from H, C1-C4 alkyl and C3-C8 cycloakyl;
- or R1, R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, 8- to 11-membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N, O and S, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, or 8- to 10-membered bicyclic heteroaryl having one or more heteroatoms selected from N, O and S, wherein said heterocycloalkyl, bicyclic heterocycloalkyl, heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, NR1aR1b, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C1-C4 alkyl-NR1aR1b;
- R3 is selected from H, OH, CN, NR3aR3b, C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-C8 cycloalkyl-C1-C4 alkoxy, C1-C4 alkyl-S—C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, C1-C4 alkyl, and NR3cR3d;
- R3a is selected from H, C1-C4 alkyl, C1-C4 alkyl-OH, and C1-C4 alkyl-NR3eR3f;
- R3b, R3c, R3d, R3e and R3f are each independently selected from H and C1-C4 alkyl;
- R4 is selected from C(O)OH, C(O)NR4aR4b, C(S)NR4aR4b and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- R4a and R4b are each independently selected from H and C1-C4 alkyl;
- R5 and R6 are each independently selected from H, halogen, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- or
- R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;
- and
- R7, R8, R9, R10, R11, and R12 are each independently selected from H, halogen, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S.
25 more elements
The compound of any preceding claim, wherein
- L1 is a bond, C1-C6 alkylene, C1-C6 haloalkylene, or C3-C6 cycloalkylene;
- R1 is selected from C1-C4 alkyl, C3-C8 cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, phenyl, 5- or 6-membered heteroaryl having one or more ring members selected from N, O, S and SO2, 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, and phenoxy, wherein said alkyl, cycloalkyl, heterocycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, bicyclic heteroaryl, and phenoxy are each optionally substituted by one or more substituents independently selected from halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-NR1aR1b, C3-C8 cycloalkyl, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, benzyl, and C1-C4 alkyl substituted by a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;
- R1a and R1b are each independently selected from H and C1-C4 alkyl;
- R2 is H;
- R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-C8 cycloalkyl-C1-C4 alkoxy, C1-C4 alkyl-S—C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH and NR3cR3d;
- R3a is selected from H and C1-C4 alkyl;
- R3b is selected from C1-C4 alkyl;
- R3c is selected from H and C1-C4 alkyl;
- R3d is selected from C1-C4 alkyl;
- R4 is selected from C(O)OH, C(O)NR4aR4b, C(S)NR4aR4b and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- R4a is selected from H and C1-C4 alkyl;
- R4b is H;
- R5 is selected from H, C1-C4 alkyl, and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- R6 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl;
- and
- R7, R8, R9, R10, R11, and R12 are each H.
13 more elements
The compound of any preceding claim, wherein
- L1 is a bond, C1-C6 alkylene, C1-C6 haloalkylene, or C3-C6 cycloalkylene;
- R1 is selected from C3-C8 cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, phenyl, 5- or 6-membered heteroaryl having one or more ring members selected from N, O, S and SO2, and 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, wherein said cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-NR1aR1b, and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- R1a and R1b are each independently selected from H and C1-C4 alkyl;
- R2 is H;
- R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-C8 cycloalkyl-C1-C4 alkoxy, C1-C4 alkyl-S—C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH and NR3cR3d;
- R3a is selected from H and C1-C4 alkyl;
- R3b is selected from C1-C4 alkyl;
- R3c is selected from H and C1-C4 alkyl;
- R3d is selected from C1-C4 alkyl;
- R4 is selected from the following groups:
- wherein indicates the point of attachment to the rest of the compound;
- R5 is selected from H and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- R6 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkoxy-C1-C4 alkyl;
- and
- R7, R8, R9, R10, R11, and R12 are each H.
12 more elements
The compound of any preceding claim, wherein
- L1 is a bond, C1-C6 alkylene, or C3-C6 cycloalkylene;
- R1 is selected from C3-C8 cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, phenyl, 5- or 6-membered heteroaryl having one or more ring members selected from N, O, S and SO2, and 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, wherein said cycloalkyl, heterocycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;
- R2 is H;
- R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl optionally substituted by OH, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-C4 alkoxy-C1-C4 alkyl, C3-C8 cycloalkyl-C1-C4 alkoxy, C1-C4 haloalkoxy-C1-C4 alkyl, C1-C4 alkyl-S—C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl;
- R3a is H;
- R3b is selected from C1-C4 alkyl;
- R4 is selected from the following groups:
- wherein indicates the point of attachment to the rest of the compound;
- R5 is H;
- R6 is selected from H and C1-C4 alkyl;
- and
- R7, R8, R9, R10, R11, and R12 are each H.
9 more elements
The compound of any preceding claim, wherein
- L1 is either a bond or C1-C6 alkylene;
- R1 is selected from C3-C8 cycloalkyl, C8-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, phenyl, 5- or 6-membered heteroaryl having one or more ring members selected from N, O, S and SO2, and 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, wherein said cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;
- R2 is H;
- R3 is selected from NR3aR3b, C1-C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S, C3-C8 cycloalkoxy-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkyl-C1-C4 alkoxy, and alkyl-S—C1-C4 alkyl;
- R3a is H;
- R3b is selected from C1-C4 alkyl;
- R4 is selected from the following groups:
- wherein indicates the point of attachment to the rest of the compound R5, R7, R8, R9, R10, R11, and R12 are each H;
- and
- R6 is selected from H and C1-C4 alkyl.
7 more elements
The compound of any preceding claim, wherein Q is O.
The compound of any preceding claim, wherein L1 is either a bond or methylene.
The compound of any preceding claim, wherein
- R1 is selected from:
- C3-C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and C1-C4 haloalkoxy;
- C8-C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl and C1-C4 alkoxy;
- 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2;
- 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, optionally substituted by one or more substituents independently selected from halogen;
- phenyl optionally substituted by one or more substituents independently selected from halogen and C1-C4 alkyl;
- 5- or 6-membered heteroaryl having one or more ring members selected from N, O, S and SO2, optionally substituted by one or more substituents independently selected from C1-C4 alkyl and C1-C4 haloalkyl;
- and
- 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, optionally substituted substituted by one or more substituents independently selected from halogen and C1-C4 alkyl.
6 more elements
The compound of any preceding claim, wherein
- R2 is H.
The compound of any preceding claim, wherein
- R3 is selected from:
- NR3aR3b;
- C1-C4 alkyl optionally substituted by OH;
- C3-C8 cycloalkyl;
- 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;
- 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;
- C1-C4 alkoxy-C1-C4 alkyl;
- C3-C8 cycloalkyl-C1-C4 alkoxy;
- C3-C8 cycloalkoxy-C1-C4 alkyl;
- C1-C4 haloalkoxy-C1-C4 alkyl;
- and
- C1-C4 alkyl-S—C1-C4 alkyl;
- wherein
- R3a is H;
- and
- R3b is selected from C1-C4 alkyl.
13 more elements
The compound of any preceding claim, wherein R3 is selected from C1-C4 alkoxy-C1-C4 alkyl.
A compound of any preceding claim, wherein
- R5 is H.
The compound of any preceding claim, wherein
- R6 is H or methyl.
A compound according to any preceding claim, wherein
- R7, R8, R9, R10, R11, and R12 are each H.
Dependencies are inferred from the claim text.