# US 11,439,641 B2 · Pyrimidine JAK inhibitors for the treatment of skin diseases

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- Number: US 11,439,641 B2
- Document ID: US11439641B2
- Status: Granted
- Kind: B2
- Application number: 16/856,283
- Filed: 2020-04-23
- Published: 2020-10-29
- Granted: 2022-09-13
- Earliest claimed: 2019-04-24
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Theravance Biopharma R&D IP, LLC
- Inventors: Philip A. Gerken; Jianhua Chao
- Web page: https://patentgrep.com/patent/US11439641B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61P 17/00: Drugs for dermatological disorders
- C07D 471/08: Bridged systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides compounds of formula (I): or pharmaceutically-acceptable salts thereof, that are inhibitors of Janus kinases. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat inflammatory and autoimmune skin diseases.

## Claims

### Claim 1

A compound of formula (I):
wherein R1 is F or H;
L is selected from the group consisting of a bond, —CH2O—, —O—, and —OCH2—;
R2 is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, and oxepane; each of which is optionally substituted with 1 to 3 Ra;
each Ra is independently selected from the group consisting of F, CN, OH, C1-4 alkyl-OH, C1-4 alkoxy, and C1-4 alkyl wherein the C1-4 alkyl is optionally substituted with 1 to 3 fluoro groups;
R3 is selected from the group consisting of:
(a) —S(O)2-C1-4alkyl, wherein C1-4alkyl is optionally substituted with CN or 1 to 3 fluoro groups;
(b) —C1-4 alkyl-CONRxRy, wherein each of Rx and Ry is independently selected from H and C1-4 alkyl, wherein optionally Rx and Ry may be joined to form a 4 to 6 membered heterocyclic group;
(c) —C(O)Rb, wherein Rb is C1-4alkyl optionally substituted with C3-6cycloalkyl, C1-4 alkoxy, or 1 to 3 fluoro groups; and
(d) —CO2Rc wherein Rc is selected from
(i) C1-4 alkyl optionally substituted with C1-4 alkoxy, and
(ii) 4 to 7 membered heterocyclic group;
or a pharmaceutically-acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R3 is selected from the group consisting of:
(a) —S(O)2-C1-4 alkyl;
(b) —C1-4 alkyl-CONRxRy, wherein each of Rx and Ry is independently selected from H and C1-4 alkyl, wherein optionally Rx and Ry may be joined to form a 4 to 6 membered heterocyclic group;
(c) —C(O)Rb, wherein Rb is C1-4alkyl optionally substituted with C3-6 cycloalkyl or C1-4 alkoxy; and
(d) —CO2Rc wherein Rc is selected from
(i) C1-4 alkyl optionally substituted with C1-4 alkoxy, and
(ii) 4 to 7 membered heterocyclic group.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R3 is selected from the group consisting of:
(a) —S(O)2-C1-2 alkyl;
(b) —C1-2 alkyl-CONRxRy, wherein each of Rx and Ry is independently selected from H and C1-3 alkyl, wherein optionally Rx and Ry may be joined to form a 4 or 5 membered heterocyclic group;
(c) —C(O)Rb, wherein Rb is C1-2alkyl optionally substituted with C3-5 cycloalkyl or C1-2 alkoxy; and
(d) —CO2Rc wherein Rc is selected from
(i) C1-2alkyl optionally substituted with C1-2alkoxy, and
(ii) 5 to 6 membered heterocyclic group.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R3 is selected from the group consisting of:

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R3 is selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R3 is

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R1 is F.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R1 is H.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R1 is selected from the group consisting of oxetane, tetrahydrofuran, and tetrahydropyran, each of which is optionally substituted with 1 to 3 Ra.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R2 is selected from the group consisting of:
each of which is optionally substituted with 1 to 3 Ra.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein L is a bond.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein L is —CH2O—.

### Claim 13 (depends on 10)

The compound of claim 10, or a pharmaceutically-acceptable salt thereof, wherein L is —O—.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein L is —OCH2—.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein
is selected from the group consisting of:
wherein R2 is optionally substituted with 1 to 2 Ra, wherein each Ra is independently selected from the group consisting of F, OH, C1-3 alkyl-OH, C1-3 alkoxy and C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with 1 to 3 fluoro groups.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein
is selected from the group consisting of:

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein
is selected from the group consisting of:

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R1 is F or H, R3 is selected from the group consisting of:
is selected from the group consisting of:

### Claim 19 (depends on 1)

The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein the compound is selected from the group consisting of:

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, further comprising one or more additional therapeutic agents.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is an ointment or a cream.

### Claim 23 (depends on 1)

A method of treating an inflammatory or autoimmune skin disease in a mammal, the method comprising administering the compound of claim 1, or a pharmaceutically acceptable salt thereof, to the mammal.

### Claim 24 (depends on 23)

The method of claim 23, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the skin of the mammal in a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier.

### Claim 25 (depends on 24)

The method of claim 24, wherein the inflammatory or autoimmune skin disease is an inflammatory skin disease.

### Claim 26 (depends on 25)

The method of claim 25, wherein the inflammatory skin disease is atopic dermatitis.

### Claim 27 (depends on 26)

The method of claim 26, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

### Claim 28 (depends on 26)

The method of claim 26, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

### Claim 29 (depends on 24)

The method of claim 24, wherein the inflammatory or autoimmune skin disease is an autoimmune skin disease.

### Claim 30 (depends on 29)

The method of claim 29, wherein the autoimmune skin disease is alopecia areata.

### Claim 31 (depends on 24)

The method of claim 24, wherein the inflammatory or autoimmune skin disease is selected from the group consisting of: vitiligo, prurigo nodularis, lichen planus, contact dermatitis, skin manifestations of graft versus host disease, pemphigoid, discoid lupus, lichen sclerosus, lichen planopilaris, psoriasis, and folliculitis decalvans.