# US 11,999,750 B2 · Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

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- Number: US 11,999,750 B2
- Document ID: US11999750B2
- Status: Granted
- Kind: B2
- Application number: 18/095,621
- Filed: 2023-01-11
- Published: 2023-08-31
- Granted: 2024-06-04
- Earliest claimed: 2022-01-12
- Assignees: Denali Therapeutics Inc.
- Applicants: Denali Therapeutics Inc.
- Inventors: Anantha Sudhakar
- Web page: https://patentgrep.com/patent/US11999750B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 37/00: Drugs for immunological or allergic disorders
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Described herein are crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, the process of preparing the forms, and pharmaceutical compositions methods of use thereof.

## Claims

### Claim 1

A crystalline form selected from the group consisting of:
Form A of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;
Form B of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;
Form C of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;
Form D of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;
Form E of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide; and
Form F of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

### Claim 2

A crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, characterized as Form A.

### Claim 3 (depends on 2)

The crystalline form of claim 2, having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising three, four, five, six, seven or more peaks, in terms of 2-theta degrees, selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0±0.2 degrees.

### Claim 4 (depends on 2)

The crystalline form of claim 2, having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG. 1.

### Claim 5 (depends on 2)

The crystalline form of claim 2, characterized by a differential scanning calorimetry (DSC) curve with an onset at about 186.7° C. and an endothermic peak at 188.9° C.

### Claim 6 (depends on 2)

The crystalline form of claim 2, characterized as having one or more of:
a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1;
b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation with peaks, in terms of 2-theta degrees, at about 6.9, 13.0, 16.6, and 23.4±0.2 degrees;
c) a Differential Scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 2;
d) a Differential Scanning calorimetry (DSC) thermogram with three endothermic events having an onset at about 186.7° C. and a peak at about 188.9° C.
e) a Thermogravimetric Analysis (TGA) pattern substantially the same as shown in FIG. 2;
f) a Thermogravimetric Analysis (TGA) pattern with an about 1.0% w/w loss from about 27.8° C. to about 150° C.; or
g) combinations thereof.

### Claim 7

A crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, characterized as Form B.

### Claim 8 (depends on 7)

The crystalline form of claim 7, having an X-ray powder diffraction pattern comprising a peak, in term of 2-theta degree, at about 9.6 and 16.4±0.2 degrees.

### Claim 9 (depends on 7)

The crystalline form of claim 7, having an X-ray powder diffraction pattern derived using Cu(Kα) radiation comprising three, four, five, six or more peaks, in terms of degrees, selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8±0.2 degrees.

### Claim 10 (depends on 7)

The crystalline form of claim 7, having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG. 3.

### Claim 11 (depends on 7)

The crystalline form of claim 7, characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 189.2° C. and an endothermic peak at 191.9° C.

### Claim 12 (depends on 7)

The crystalline form of claim 7, characterized as having one or more of:
a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3;
b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation with peaks, in terms of 2-theta degrees, at about 9.6, 11.5, 16.4, 19.2, and 23.8±0.2 degrees;
c) a Differential Scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 4;
d) a Differential Scanning calorimetry (DSC) thermogram with three endothermic events having an onset at about 189.2° C. and a peak at about 191.9° C.
e) a Thermogravimetric Analysis (TGA) pattern substantially the same as shown in FIG. 4;
f) a Thermogravimetric Analysis (TGA) pattern with a about 1.0% w/w loss from about 23.8° C. to about 150° C.; or
g) combinations thereof.

### Claim 13

A crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, characterized as Form C.

### Claim 14 (depends on 13)

The crystalline form of claim 13, having an X-ray powder diffraction pattern derived using Cu(Kα) radiation comprising three, four, five, six or more peaks, in terms of 2-theta_degrees, selected from the group consisting of: 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3±0.2 degrees.

### Claim 15 (depends on 13)

The crystalline form of claim 13, having the X-ray powder diffraction pattern substantially in accordance with that shown in FIG. 5.

### Claim 16 (depends on 13)

The crystalline form of claim 13, characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 124.9° C. and an endothermic peak at 131.3° C.

### Claim 17 (depends on 13)

The crystalline form of claim 13, characterized as having one or more of:
a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5;
b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation with peaks, in terms of 2-theta degrees, at about 9.8, 10.2, 14.8, 15.2, and 20.4±0.2 degrees;
c) a Differential Scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 7;
d) a Differential Scanning calorimetry (DSC) thermogram with three endothermic events having an onset at about 124.9° C. and a peak at about 131.3° C.
e) a Thermogravimetric Analysis (TGA) pattern substantially the same as shown in FIG. 7;
f) a Thermogravimetric Analysis (TGA) pattern with a about 5.7% w/w loss from about 22.4° C. to about 100° C.; or
g) combinations thereof.

### Claim 18 (depends on 1)

A method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of the crystalline form of claim 1, wherein the disease or disorder is chosen from inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, cutaneous lupus erythematosus, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cytokine release syndrome, covid-19 infection, cerebrovascular accident, myocardial infarction, Huntington's disease, Parkinson's disease, allergic diseases, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, peridontitis, trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Gaucher's disease, Krabbe disease, Niemann-Pick disease, sepsis, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), HIV-associated dementia, retinal degenerative disease, glaucoma, age related macular degeneration, psoriatic arthritis, Friedreich's ataxia, Lewy body disease, spinal muscular atrophy, brain injury, spinal cord injury, dementia, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, and a prion disorder.