# US 10,946,018 B2 · Spirocyclic compounds as tryptophan hydroxylase inhibitors

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- Number: US 10,946,018 B2
- Document ID: US10946018B2
- Status: Granted
- Kind: B2
- Application number: 16/850,542
- Filed: 2020-04-16
- Published: 2020-07-30
- Granted: 2021-03-16
- Earliest claimed: 2013-09-06
- Assignees: Roivant Sciences GmbH
- Applicants: Roivant Sciences GmbH
- Inventors: Stéphane De Lombaert; Daniel R. Goldberg; Kenneth Brameld; Eric Brian Sjogren; Andrew Scribner
- Web page: https://patentgrep.com/patent/US10946018B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- 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 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/10: Spiro-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.

## Claims

### Claim 1

A method of treating idiopathic pulmonary arterial hypertension in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein administration is by inhalation.

### Claim 3 (depends on 2)

The method of claim 2, wherein inhalation is with a powder.

### Claim 4 (depends on 2)

The method of claim 2, wherein inhalation is with a spray or an aerosol.

### Claim 5 (depends on 4)

The method of claim 4, wherein the spray or aerosol is via a sonic nebulizer.

### Claim 6 (depends on 1)

The method of claim 1, wherein administration is by injection.

### Claim 7 (depends on 6)

The method of claim 6, wherein injection is subcutaneous, intravenous, or intramuscular.

### Claim 8 (depends on 1)

The method of claim 1, wherein administration is by infusion.

### Claim 9 (depends on 1)

The method of claim 1, wherein administration is oral.

### Claim 10

A method of lowering peripheral serotonin in a patient having idiopathic pulmonary arterial hypertension, comprising administering to the patient in need thereof a therapeutically effective amount of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein administration is by inhalation.

### Claim 12 (depends on 11)

The method of claim 11, wherein inhalation is with a powder.

### Claim 13 (depends on 11)

The method of claim 11, wherein inhalation is with a spray or an aerosol.

### Claim 14 (depends on 13)

The method of claim 13, wherein the spray or aerosol is via a sonic nebulizer.

### Claim 15 (depends on 10)

The method of claim 10, wherein administration is by injection.

### Claim 16 (depends on 15)

The method of claim 15, wherein injection is subcutaneous, intravenous, or intramuscular.

### Claim 17 (depends on 10)

The method of claim 10, wherein injection is subcutaneous, intravenous, or intramuscular.

### Claim 18 (depends on 10)

The method of claim 10, wherein administration is oral.