# US 11,299,495 B2 · Spiro-lactam NMDA receptor modulators and uses thereof

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- Number: US 11,299,495 B2
- Document ID: US11299495B2
- Status: Granted
- Kind: B2
- Application number: 16/321,905
- Filed: 2017-08-01
- Published: 2019-06-13
- Granted: 2022-04-12
- Earliest claimed: 2016-08-01
- Assignees: Aptinyx Inc.
- Applicants: Aptinyx Inc.
- Inventors: M. Amin Khan
- Web page: https://patentgrep.com/patent/US11299495B2

## CPC

- C07D 487/10: Spiro-condensed systems
- A61P 25/02: for peripheral neuropathies
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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 471/10: 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:
or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:
R1 is selected from the group consisting of C1-C6alkyl, phenyl,
wherein C1-C6 alkyl substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, hydroxyl, S(O)w—C1-C3alkyl, SH, phenyl and halogen, and wherein phenyl is substituted by one, two or three substituents independently selected for each occurrence from —C(O)—C1-C3alkyl, hydroxyl, —C(O)— C1-C3alkyl, methyl, CF3 and halogen;
R7 is independently selected from the group consisting of H, —C1-C6alkyl, —S(O)w—C1-C3alkyl, and halogen;
R9 is independently selected from the group consisting of H, —C1-C6alkyl, —S(O)w—C1-C3alkyl, and halogen, or one R7 and one R9 taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which can be 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;
R2 is independently selected for each occurrence from the group consisting of H, C1-C6alkyl, —S(O)w—C1-C3alkyl, —NRaRb and halogen;
R6 represents one or two optional substitutions each on one or more available ring carbons, and is independently selected for each occurrence from the group consisting of C1-C6alkyl, —S(O)w—C1-C3alkyl, —NRaRb and halogen;
w is 0, 1, or 2;
R3 is selected from the group consisting of H, C1-C6 alkyl, —C(O)R31 and —C(O)OR32;
R31 and R32 are each independently selected from the group consisting of H, C1-C6alkyl, —C3-C6cycloalkyl, and phenyl; and
Ra and Rb are each independently for each occurrence selected from the group consisting of H, 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;
wherein any aforementioned C1-C6 alkyl of R2, R3, R5, R6, R7, R9, R31 and R32, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NRaRb, —NRaRb, hydroxyl, S(O)w—C1-C3alkyl, SH, 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)—C1-C3alkyl, hydroxyl, methyl, CF3 and halogen.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is

### Claim 3 (depends on 1)

The compound of claim 1, wherein R3 is H.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R3 is selected from the group consisting of:
wherein Ra and Rb are each independently selected for each occurrence from the group consisting of hydrogen and —C1-C3.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 is H at each occurrence.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R7 is H at each occurrence.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt and/or a stereoisomer thereof.

### Claim 8 (depends on 1)

The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt and/or a stereoisomer thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 is —C(O)—C1-C6alkyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is

### Claim 12 (depends on 1)

The compound of claim 1, wherein R9 is H at each occurrence.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R6 is absent.

### Claim 14 (depends on 1)

The compound of claim 1, wherein each R2, R7 and R9 is H.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R6 is absent.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable excipient.

### Claim 17 (depends on 7)

A pharmaceutical composition comprising a compound of claim 7, and a pharmaceutically acceptable excipient.

### Claim 18 (depends on 8)

A pharmaceutical composition comprising a compound of claim 8, and a pharmaceutically acceptable excipient.