# US 11,998,553 B2 · Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating lupus nephritis

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,998,553 B2
- Document ID: US11998553B2
- Status: Granted
- Kind: B2
- Application number: 17/260,606
- Filed: 2019-07-16
- Published: 2021-10-21
- Granted: 2024-06-04
- Earliest claimed: 2018-07-17
- Assignees: Insmed Incorporated
- Applicants: Insmed Incorporated
- Inventors: Jimin Zhang
- Web page: https://patentgrep.com/patent/US11998553B2

## CPC

- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 31/52: Purines, e.g. adenine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 13/12: of the kidneys
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to methods for treating lupus nephritis with compositions comprising an effective amount of certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds of Formula (I), including pharmaceutically acceptable salts thereof, that inhibit dipeptidyl peptidase 1 (DPP1) activity. In one embodiment, the compound of Formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (INS1007).

## Claims

### Claim 1

A method for treating lupus nephritis (LN) in a patient in need of treatment, comprising, administering to the patient a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein,
R1 is
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl;
R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or
R6 is C1-3alkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran;
R7 is hydrogen, F, Cl or CH3;
X is O, S or CF2;
Y is O or S; and
Q is CH or N.

### Claim 2 (depends on 1)

The method of claim 1, wherein, R1 is

### Claim 3 (depends on 1)

The method of claim 1, wherein, X is O; R6 is C1-3alkyl; and R7 is hydrogen.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of
(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
4′-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate;
(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4′-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-2-(4′-Carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-1-Cyano-2-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-2-[4′-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;
(2S)—N-[(1S)-1-Cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;
(2S)—N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; and
(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;
and pharmaceutically acceptable salts thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide.

### Claim 7 (depends on 1)

The method of claim 1, wherein the composition comprises a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 8 (depends on 1)

The method of claim 1, wherein administering comprises oral administration.

### Claim 9 (depends on 1)

The method of claim 1, wherein the treating comprises decreasing the serum creatinine levels of the patient, as compared to a baseline serum creatinine level measurement taken prior to treatment.

### Claim 10 (depends on 1)

The method of claim 1, wherein the treating comprises decreasing the active urinary sediment and/or casts in the patient, as compared to an active urinary sediment measurement taken prior to treatment.

### Claim 11 (depends on 1)

The method of claim 1, wherein the treating comprises obtaining an inactive urinary sediment in the patient, defined as less than about 10 red blood cells (RBC) per high power field (HPF).

### Claim 12 (depends on 1)

The method of claim 1, wherein the treating comprises decreasing the urinary protein to creatinine ratio (UPCR) in the patient, as compared to an initial UPCR value measured prior to treatment.

### Claim 13 (depends on 1)

The method of claim 1, wherein the treating comprises decreasing proteinuria in the patient, as compared to an initial proteinuria measurement in the patient, measured prior to treatment.

### Claim 14 (depends on 13)

The method of claim 13, wherein the proteinuria is measured by a urine albumin to creatinine ratio (UACR) or by dipstick urinalysis.

### Claim 15 (depends on 1)

The method of claim 1, wherein the treating comprises achieving a complete renal response (CRR) in the patient or a partial renal response (PRR) in the patient.

### Claim 16 (depends on 1)

The method of claim 1, further comprising administering one or more additional active agents to the patient in need of treatment.

### Claim 17 (depends on 16)

The method of claim 16, wherein the one or more additional active agents comprises a corticosteroid or an immunosuppressant.

### Claim 18 (depends on 17)

The method of claim 17, wherein the corticosteroid is a glucocorticoid, and the immunosuppressant is mycophenolate mofetil (MFF) or azathioprine.

### Claim 19 (depends on 1)

The method of claim 1, wherein,
R1 is
X is O, S or CF2;
Y is O or S;
R6 is C1-3alkyl, optionally substituted by 1, 2 or 3 F and optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and
R7 is hydrogen, F, Cl or CH3.

### Claim 20 (depends on 19)

The method of claim 19, wherein, X is O; R6 is C1-3alkyl, optionally substituted by 1, 2 or 3 F; and R7 is hydrogen.