# US 11,896,595 B2 · JAK1 pathway inhibitors for the treatment of chronic lung allograft dysfunction

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- Number: US 11,896,595 B2
- Document ID: US11896595B2
- Status: Granted
- Kind: B2
- Application number: 17/854,443
- Filed: 2022-06-30
- Published: 2022-10-20
- Granted: 2024-02-13
- Earliest claimed: 2019-03-05
- Assignees: Incyte Corporation
- Applicants: Incyte Corporation
- Inventors: Richard L. Schaub; Kevin O'Hayer
- Web page: https://patentgrep.com/patent/US11896595B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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

This disclosure relates to JAK1 pathway inhibitors and the use thereof in treating chronic lung allograft dysfunction such as, e.g., bronchiolitis obliterans syndrome.

## Claims

### Claim 1

A method of treating chronic lung allograft dysfunction in a subject, said method comprising administering to the subject 4 [3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the chronic lung allograft dysfunction is bronchiolitis obliterans syndrome.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject is a lung transplant recipient.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject is a double lung transplant recipient.

### Claim 5 (depends on 2)

The method of claim 2, wherein the subject suffers from Grade Op, Grade 1, Grade 2, or Grade 3 bronchiolitis obliterans syndrome as determined by International Society for Heart and Lung Transplantation (ISHLT) criteria.

### Claim 6 (depends on 2)

The method of claim 2, wherein the treating of bronchiolitis obliterans syndrome comprises about a 10% or greater increase in FEVs at twelve weeks following the first administration of the 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro- 1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 7

A method of reducing the risk of bronchiolitis obliterans syndrome in a subject, said method comprising administering to the subject 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

The method of claim 7, wherein the subject is a lung transplant recipient.

### Claim 9 (depends on 7)

The method of claim 7, wherein the subject is a double lung transplant recipient.

### Claim 10

A method of reducing the risk of lung re-transplantation in a subject, said method comprising administering to the subject 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 11

A method of reducing the risk of hospitalization in a subject, said method comprising administering to said subject an effective amount of 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-R1S)-2,2,2-trifluoro-1-methylethyljbenzamide, or a pharmaceutically acceptable salt thereof, wherein said subject is (a) diagnosed with bronchiolitis obliterans syndrome; (b) has had a lung transplantation within 1 to 5 years prior to administering the, 4 [3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof, and (c) does not have a decrease in FEVs attributable to a cause other than bronchiolitis obliterans syndrome.

### Claim 12

A method of treating bronchiolitis obliterans syndrome in a subject, said method comprising administering to the subject a pharmaceutically acceptable salt of 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide.

### Claim 13 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt.

### Claim 14 (depends on 7)

The method of claim 7, wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt.

### Claim 15 (depends on 10)

The method of claim 10, wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt.

### Claim 16 (depends on 11)

The method of claim 11, wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt.

### Claim 17 (depends on 12)

The method of claim 12, wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt.