# US 11,028,095 B2 · Spiro-lactam and bis-spiro-lactam NMDA receptor modulators and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,028,095 B2 - Document ID: US11028095B2 - Status: Granted - Kind: B2 - Application number: 16/321,906 - Filed: 2017-08-01 - Published: 2020-06-11 - Granted: 2021-06-08 - Earliest claimed: 2016-08-01 - Assignees: Aptinyx Inc. - Applicants: Aptinyx Inc. - Inventors: M. Amin Khan - Web page: https://patentgrep.com/patent/US11028095B2 ## CPC - C07D 487/20: Spiro-condensed systems - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/06: Antimigraine agents - A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia - A61P 25/22: Anxiolytics - A61P 25/24: Antidepressants - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - C07D 487/10: Spiro-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 1 A compound represented by Formula I or Formula II: or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein: R1 and R2 are independently selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—C1-C6alkyl, —C(O)—O—C1-C6alkyl, and —O—CH2-phenyl; R3 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—R31, and —C(O)—O—R32; 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, and phenyl; wherein any aforementioned C1-C6alkyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, hydroxyl, —SH, phenyl, —O—CH2-phenyl, and halogen; and any aforementioned phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, —C1-C3alkoxy, hydroxyl, and halogen; Ra and Rb are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH2-phenyl, and —C1-C3alkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring; R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C1-4alkyl, C2-4alkenyl, —NH—C(O)—C1-6 alkyl, —NH—C(O)—C1-6alkylene-phenyl, —NH—C(O)—O—C1-6alkyl, and —NH—C(O)—O—C1-6 alkylene-phenyl; wherein C1-4alkyl, C1-6alkylene, C2-4alkenyl, and phenyl are optionally substituted by one or more substituents selected from RP; or two R5s taken together form an oxo moiety; or wherein for the compound of Formula I, R6 and R7 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; and RP is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C1-6alkoxy, and C1-6alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and amino. ### Claim 2 (depends on 1) The compound of claim 1, wherein R1 and R2 are hydrogen. ### Claim 3 (depends on 1) The compound of claim 1, wherein R1 and R2 are —C1-C6alkyl each independently and optionally substituted by one, two or three substituents independently selected from the group consisting of —C(O)NRaRb, hydroxyl, —SH, and halogen. ### Claim 4 (depends on 1) The compound of claim 1, wherein R3 is hydrogen. ### Claim 5 (depends on 1) The compound of claim 1 wherein R3 is —C1-C6alkyl. ### Claim 6 (depends on 1) The compound of claim 1, wherein R3 is —C(O)—C1-C6alkyl. ### Claim 7 (depends on 1) The compound of claim 1, wherein R3 is —C(O)—O—C1-C6alkyl. ### Claim 8 (depends on 1) The compound of claim 1, wherein R4, R5, R6, and R7 are hydrogen. ### Claim 9 (depends on 1) The compound of claim 1 represented by Formula III or Formula IV: or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein: R1 and R2 are independently selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—C1-C6alkyl, —C(O)—O—C1-C6alkyl, and —O—H2-phenyl; R3 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—R31, and —C(O)—O—R32; 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, and phenyl; wherein any aforementioned C1-C6alkyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, hydroxyl, —SH, phenyl, —O—CH2-phenyl, and halogen; and any aforementioned phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, —C1-C3alkoxy, hydroxyl, and halogen; Ra and Rb are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH2-phenyl, and —C1-C3alkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring; R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C1-4alkyl, C2-4alkenyl, —NH—C(O)—C1-6alkyl, —NH—C(O)—C1-6alkylene-phenyl, —NH—C(O)—O—C1-6alkyl, and —NH—C(O)—O—C1-6 alkylene-phenyl; wherein C1-4 alkyl, C1-6alkylene, C2-4alkenyl, and phenyl are optionally substituted by one or more substituents selected from RP; or wherein for the compound of Formula III, R6 and R7 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; and RP is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C1-6alkoxy, and C1-6alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and amino. ### Claim 10 (depends on 1) The compound of claim 1 represented by Formula V or Formula VI: or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein: R3 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—R31, and —C(O)—O—R32; 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, and phenyl; wherein any aforementioned C1-C6alkyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, hydroxyl, —SH, phenyl, —O—CH2-phenyl, and halogen; and any aforementioned phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, —C1-C3alkoxy, hydroxyl, and halogen; and Ra and Rb are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH2-phenyl, and —C1-C3alkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring. ### Claim 11 A compound represented by Formula VI or Formula VII: or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein: R3 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—R31, and —C(O)—O—R32; 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, and phenyl; R10 and R11 for each occurrence are independently selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkyl, —C1-C6alkoxy, —CO2H, or —NR′R′, wherein R′ for each occurrence is independently selected from hydrogen and, —C1-C6 alkyl; and R12 and R13 for each occurrence are independently selected from the group consisting of hydrogen and —C1-C6 alkyl; or R13 and R12 together with the nitrogen to which they are bound form a 4-6 membered heterocycle; and wherein C1-C6 alkyl is optionally for each occurrence substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and amino. ### Claim 12 A compound represented by Formula IX or Formula X: or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein: R1 and R2 are independently selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—C1-C6alkyl, and —C(O)—O—C1-C6alkyl; or R1 and R2 taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring; R3 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—R31, and —C(O)—O—R32; 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, and phenyl; R4 is selected from the group consisting of hydrogen, —C1-C6alkyl, —C(O)—C1-C6alkyl, —C(O)—O—C1-C6alkyl, and —O—CH2-phenyl; wherein any aforementioned C1-C6alkyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, hydroxyl, —SH, phenyl, —O—CH2-phenyl, and halogen; and any aforementioned phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, —C1-C3alkoxy, hydroxyl, and halogen; Ra and Rb are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH2-phenyl, and —C1-C3alkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring; R5, R6, R7 and R8 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C1-4alkyl, C2-4alkenyl, —NH—C(O)—C1-6alkyl, —NH—C(O)—C1-6alkylene-phenyl, —NH—C(O)—O—C1-6alkyl, and —NH—C(O)—O—C1-6alkylene-phenyl; wherein C1-4alkyl and phenyl are optionally substituted by one or more substituents selected from RP; or R6 and R7 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; RP is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C1-6alkoxy, and C1-3alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and amino; R9 and R10 are each independently selected from the group consisting of hydrogen and —C1-C3alkyl, or R9 and R10 taken together form an oxo moiety; and m is 0 or 1. ### Claim 13 (depends on 12) The compound of claim 12, wherein R1 and R2 are hydrogen. ### Claim 14 (depends on 12) The compound of claim 12, wherein R1 is hydrogen and R2 is —C1-C6alkyl optionally substituted by one, two or three substituents independently selected from the group consisting of —C(O)NRaRb, hydroxyl, —SH, and halogen. ### Claim 15 (depends on 12) The compound of claim 12, wherein R3 is hydrogen. ### Claim 16 (depends on 12) The compound of claim 12, wherein R4, R5, R6, and R7 are hydrogen. ### Claim 17 A compound selected from the group consisting of and pharmaceutically acceptable salts, stereoisomers, and/or N-oxides thereof. ### Claim 18 (depends on 1) A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable excipient. ### Claim 19 (depends on 1) A method of lessening or reducing one or more symptoms of depression, Alzheimer's disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1. ### Claim 20 (depends on 1) A method of lessening or reducing one or more symptoms of a migraine, neuropathic pain, or traumatic brain injury in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1.