# US 10,308,646 B2 · Pyrimidine compound as JAK kinase inhibitor

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- Number: US 10,308,646 B2
- Document ID: US10308646B2
- Status: Granted
- Kind: B2
- Application number: 16/171,693
- Filed: 2018-10-26
- Published: 2019-05-02
- Granted: 2019-06-04
- Earliest claimed: 2017-10-27
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Theravance Biopharma R&D IP, LLC
- Inventors: Jennifer Kozak; Ryan Hudson; Gary E. L. Brandt; Robert Murray McKinnell; Marta Dabros; Jerry Nzerem
- Web page: https://patentgrep.com/patent/US10308646B2

## CPC

- C07D 451/14: containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/14: for baldness or alopecia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 451/04: with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention provides a compound of formula (I): or a pharmaceutically-acceptable salt thereof, that is an inhibitor of JAK kinases. The invention also provides pharmaceutical compositions comprising such compound, a crystalline form, methods of using such compound to treat inflammatory skin diseases and other diseases, and processes and intermediates useful for preparing such compound.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically-acceptable salt thereof.

### Claim 2

A compound of formula (I):

### Claim 3

A crystalline form of the compound of formula (I):
wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 20 values of 11.4±0.2, 16.2±0.2, 16.6±0.2, 17.7±0.2, and 21.9±0.2.

### Claim 4 (depends on 3)

The crystalline form of claim 3, wherein the powder X-ray diffraction pattern is further characterized by having additional diffraction peaks at 20 values of 8.9±0.2, 9.5±0.2, and 10.2±0.2.

### Claim 5 (depends on 4)

The crystalline form of claim 4, wherein the powder X-ray diffraction pattern is further characterized by having two or more additional diffraction peaks at 2θ values selected from 14.4±0.2, 19.0±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, 20.4±0.2, 20.6±0.2, 20.8±0.2, 21.3±0.2, 25.9±0.2, 30.1±0.2, 30.5±0.2, 30.9±0.2, 32.6±0.2, and 33.8±0.2.

### Claim 6 (depends on 3)

The crystalline form of claim 3, wherein the crystalline form is characterized by a powder X-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 5.

### Claim 7 (depends on 3)

The crystalline form of claim 3, wherein the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10° C. per minute which shows a maximum in endothermic heat flow with a peak at 238.1° C.±2° C.

### Claim 8 (depends on 3)

The crystalline form of claim 3, wherein the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 6.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 3, 4, 5)

A pharmaceutical composition comprising a crystalline form of any one of claims 3 to 5, and a pharmaceutically-acceptable carrier.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9 further comprising one or more additional therapeutic agents.

### Claim 12 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is an ointment or a cream.

### Claim 13 (depends on 9)

The pharmaceutical composition of claim 9, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present at between 0.1 and 10% by weight.

### Claim 14 (depends on 9)

The pharmaceutical composition of claim 9, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present at between 0.25 and 5% by weight.

### Claim 15 (depends on 9)

The pharmaceutical composition of claim 9, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present at between 0.05 and 0.5% by weight.

### Claim 16 (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 to the mammal.

### Claim 17 (depends on 16)

The method of claim 16, wherein the compound is administered to the skin of the mammal in a pharmaceutical composition comprising the compound and a pharmaceutically-acceptable carrier.

### Claim 18 (depends on 16)

The method of claim 16, wherein the inflammatory or autoimmune skin disease is an inflammatory skin disease.

### Claim 19 (depends on 18)

The method of claim 18, wherein the inflammatory skin disease is atopic dermatitis.

### Claim 20 (depends on 19)

The method of claim 19, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

### Claim 21 (depends on 19)

The method of claim 19, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

### Claim 22 (depends on 16)

The method of claim 16, wherein the inflammatory or autoimmune skin disease is an autoimmune skin disease.

### Claim 23 (depends on 22)

The method of claim 22, wherein the autoimmune skin disease is alopecia areata.

### Claim 24 (depends on 16)

The method of claim 16, 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 foliculitis decalvans.

### Claim 25

A process for preparing a compound of formula (I):
or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula (II):
wherein R is a C1-12 alkyl group, with a reducing agent and
(b) optionally forming a pharmaceutically acceptable salt to provide a compound of formula (I), or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 25)

The process of claim 25, wherein the reducing agent is selected from the group consisting of LiAlH4, NaBH4, and LiBH4.

### Claim 27 (depends on 25)

The process of claim 25, wherein R is ethyl.

### Claim 28 (depends on 25)

The process of claim 25, wherein the compound of formula (II) is obtained by coupling a compound of formula (III)
wherein X is a halogen, with a compound of formula 1-9

### Claim 29

A compound of formula (II):
or a pharmaceutically acceptable salt thereof,
wherein R is a C1-12 alkyl group.

### Claim 30 (depends on 29)

The compound of claim 29, wherein R is ethyl.

### Claim 31

A compound of formula (III):
or a pharmaceutically acceptable salt thereof,
wherein R is a C1-12 alkyl group and X is halogen.

### Claim 32 (depends on 31)

The compound of claim 31, wherein R is ethyl and X is chloro.