Back to results
US 2019/0161442 A1Published application
Spiro-lactam nmda receptor modulators and uses thereof
AssigneeAptinyx Inc.
InventorM. Amin Khan
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
Claims48
A compound having the formula:
- or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:
- R1 is selected from the group consisting of H, —C1-C4alkyl, —C1-C4alkyl-phenyl, —C(O)—R31, —C(O)—O—R32, —O—C1-C4alkyl-phenyl, phenyl, and —CH(R8)—C(O)—R9;
- wherein phenyl is optionally substituted by one, two or three substituents each independently selected from —C1-C4alkyl, —C1-C4alkoxy, hydroxyl, and halogen;
- R2 is independently selected for each occurrence from the group consisting of H, —C1-C4alkyl, and —C1-C4haloalkyl;
- R3, R4, R6, and R7 are each independently selected for each occurrence from the group consisting of H, hydroxyl, halogen, cyano, —C1-C4alkyl, and —C1-C4haloalkyl;
- or R3 and R4 taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, —C1-C3alkyl, —C1-C3alkoxy, —C(O)NRaRb, and —NRaRb;
- R5a is selected from the group consisting of H, hydroxyl, halogen, cyano, —C1-C4alkoxy, —O—C1-C4 alkyl-phenyl, —C1-C4alkyl, —C(O)—C1-C4alkyl, —NRa—C(O)—C1-C4alkyl, —NRa—C(O)—O—C1-C4alkyl, —NRaRb, and —NRaCH(R10)—C(O)—R11;
- wherein C1-C4alkyl is optionally substituted by one, two or three substituents each independently selected from —COOH, —C(O)NH2, —NRaRb, —SH, —C(O)—C1-C4alkyl, —C(O)—O—C1-C4alkyl, —O—C(O)—C1-C4alkyl, —C1-C4alkoxy, phenyl, hydroxyl, and halogen;
- and phenyl, independently for each occurrence is optionally substituted by one, two or three substituents each independently selected from —C1-C4alkyl, —C1-C4haloalkyl, —C1-C4alkoxy, —NRaRb, hydroxyl, cyano, and halogen;
- R5b is selected from the group consisting of H, halogen, cyano, —C1-C4alkyl, and —C1-C4haloalkyl;
- or
- R5a and R5b taken together form an oxo group;
- R8 and R10 are independently selected from the group consisting of H and —C1-C4alkyl, wherein C1-C4alkyl is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRa—C(O)—C1-C4alkyl, —NRaRb, —SH, —C(O)—C1-C4alkyl, —C(O)—O—C1-C4alkyl, —O—C(O)—C1-C4alkyl, —C1-C4alkoxy, —COOH, hydroxyl, and halogen;
- R9 and R11 are independently selected from the group consisting of hydroxyl, —C1-C4alkoxy, and —NRaRb;
- R31 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C1-C6haloalkyl, —C3-C6cycloalkyl, and phenyl;
- R32 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C1-C6haloalkyl, —C3-C6cycloalkyl, benzyl, and phenyl;
- and
- Ra and Rb are each independently selected for each occurrence from the group consisting of H, —C1-C4alkyl, —C1-C4alkyl-phenyl, —C1-C4alkyl-C3-C7cycloalkyl, —C1-C4alkyl-heterocycloalkyl, and —C1-C4alkyl-heteroaryl, wherein heterocycloalkyl and heteroaryl include 1, 2, or 3 ring atoms independently selected from N, O and S, and phenyl is optionally substituted by one, two or three substituents selected from halogen, hydroxyl, —C(O)NH2, —C(O)NH(C1-C4alkyl), —C(O)N(C1-C4alkyl)2, —C1-C3alkyl and —C1-C3alkoxy;
- or
- Ra and Rb taken together with the nitrogen to which they are attached form a 4-6-membered heterocycloalkyl or a 5-8-membered heteroaryl.
17 more elements
A compound having the formula:
- or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:
- R1 is selected from the group consisting of H, —C1-C4alkyl, —C1-C4alkyl-phenyl, and —CH(R8)—C(O)—R9;
- wherein phenyl is optionally substituted by one, two or three substituents each independently selected from —C1-C4alkyl, C1-C4alkoxy, hydroxyl, and halogen;
- and
- R5a is selected from the group consisting of H, hydroxyl, halogen, cyano, —C1-C4alkoxy, —O—C1-C4 alkyl-phenyl, —C1-C4alkyl, —C(O)—C1-C4alkyl, —NRa—C(O)—C1-C4alkyl, —NRa—C(O)—O—C1-C4alkyl, —NRaRb, and —NRaCH(R10)—C(O)—R11;
- wherein C1-C4alkyl is optionally substituted by one, two or three substituents each independently selected from —COOH, —C(O)NH2, —NRaRb, —SH, —C(O)—C1-C4alkyl, —C(O)—O—C1-C4alkyl, —O—C(O)—C1-C4alkyl, —C1-C4alkoxy, hydroxyl, and halogen;
- and phenyl is optionally substituted by one, two or three substituents each independently selected from —C1-C4alkyl, —C1-C4haloalkyl, —C1-C4alkoxy, —NRaRb, hydroxyl, and halogen;
- R5b is selected from the group consisting of H, halogen, —C1-C4alkyl, and —C1-C4haloalkyl;
- or
- R5a and R5b taken together form an oxo group;
- R8 and R10 are selected independently from the group consisting of H and —C1-C4alkyl, wherein C1-C4alkyl is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRa—C(O)—C1-C4alkyl, —NRaRb, —SH, —C(O)—C1-C4alkyl, —C(O)—O—C1-C4alkyl, —O—C(O)—C1-C4alkyl, C1-C4alkoxy, —COOH, hydroxyl, and halogen;
- R9 and R11 are selected independently from the group consisting of hydroxyl, C1-C4alkoxy, and —NRaRb;
- and
- Ra and Rb are each independently selected for each occurrence from the group consisting of H, —C1-C4alkyl, —C1-C4alkyl-phenyl, —C1-C4alkyl-C3-C7cycloalkyl, —C1-C4alkyl-heterocycloalkyl, and —C1-C4alkyl-heteroaryl, wherein heterocycloalkyl and heteroaryl include 1, 2, or 3 ring atoms independently selected from N, O and S, and phenyl is optionally substituted by one, two or three substituents selected from halogen, hydroxyl, —C(O)NH2, —C(O)NH(C1-C4alkyl), —C(O)N(C1-C4alkyl)2, —C_C3alkyl and —C1-C3alkoxy;
- or
- Ra and Rb taken together with the nitrogen to which they are attached form a 4-6-membered heterocycloalkyl or a 5-8-membered heteroaryl.
13 more elements
A compound having the formula:
- or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:
- R5a is selected from the group consisting of H, hydroxyl, halogen, —CH3, —C(O)—C1-C4alkyl, —O—CH2-Ph, —NH2, —NH—C1-C4alkyl, —NH—C(O)—C1-C4alkyl, —NH—C(O)—O—C1-C4alkyl, and —NRaCH(R10)—C(O)—R11;
- wherein C1-C4alkyl is optionally substituted by one or two substituents each independently selected from —C(O)NH2, —NH2, —SH, —OC(O)CH3, hydroxyl, and halogen;
- R5b is H or halogen;
- R8 and R10 are selected independently from the group consisting of H and C1-C4alkyl, wherein the C1-C4alkyl may be optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRa—C(O)—C1-C4alkyl, —NRaRb, —SH, —C(O)—C1-C4alkyl, —C(O)—O—C1-C4alkyl, —O—C(O)—C1-C4alkyl, C1-C4alkoxy, —COOH, hydroxyl, and halogen;
- and
- R9 and R11 are selected independently from the group consisting of hydroxyl, C1-C4alkoxy, and —NRaRb;
- and
- Ra and Rb are each independently selected for each occurrence from the group consisting of H, —C1-C4alkyl, —C1-C4alkyl-phenyl, —C1-C4alkyl-C3-C7cycloalkyl, —C1-C4alkyl-heterocycloalkyl, and —C1-C4alkyl-heteroaryl, wherein heterocycloalkyl and heteroaryl include 1, 2, or 3 ring atoms independently selected from N, O and S, and phenyl is optionally substituted by one, two or three substituents selected from halogen, hydroxyl, —C(O)NH2, —C(O)NH(C1-C4alkyl), —C(O)N(C1-C4alkyl)2, —C1-C3alkyl and —C1-C3alkoxy;
- or
- Ra and Rb taken together with the nitrogen to which they are attached form a 4-6-membered heterocycloalkyl or a 5-8-membered heteroaryl.
8 more elements
A compound is selected from the group consisting of:
- or a pharmaceutically acceptable salt and/or a stereoisomer thereof.
Dependencies are inferred from the claim text.