CA-3041058-C - CARBAMIMIDOYLPHENYLCARBAMOYL DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF USEFUL AS KALLIKREIN INHIBITHORS

Abstract

Disclosed are compounds of formula I, II, and III, and pharmaceutically acceptable salts thereof, which are inhibitors of kallikrein. Also provided are pharmaceutical compositions comprising such a compound, and methods involving use of the compounds and compositions in the treatment and prevention of acquired or hereditary angioedema, or other diseases and conditions characterized by aberrant kallikrein activity. (I) (II) (III)

Inventors

• Pravin L. Kotian
• Yarlagadda S. Babu
• V. Satish Kumar
• Venkat R. Chintareddy
• Weihe Zhang
• Lakshminarayana Vogeti

Assignees

• BIOCRYST PHARMACEUTICALS, INC.

Dates

Publication Date

20260505

Application Date

20171027

Priority Date

20161031

Claims (1)

1. CLAIMS What is claimed is: 1. A compound selected from the following compounds: ~I ~ H 0 A- N"(o.......,.... NH 0 H"? NY'll oyo 0 ~NH NH Date Re9ue/Date Received 2024-03-27 o I o ~OAO Date Re9ue/Date Received 2024-03-27 H~ NY) o,.,-o 0 ~NH NH ~~oyo~ 0 ~NH '-/ NH H ( N~oyo 0 ~NH NH Date Re9ue/Date Received 2024-03-27 H ( N'fn oyo o ~NH NH ~~ H O ~NyOvy NH O I 0 Date Re9ue/Date Received 2024-03-27 o I o ~ H fX N~O'YO 0 ~NH NH , and 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: Date Re9ue/Date Received 2024-03-27 H ( NY'n o,,-o 0 ~NH NH , and H ( NY'n OyO 0 ~NH NH 3. The compound according to claim l, or a pharmaceutically acceptable salt thereof, selected from the following compounds: Date Re9ue/Date Received 2024-03-27 o I o 'f--"--o.Ao H '? NY') oyo 0 ~NH NH ~½ I H 0 & N"l(OYOY NH O I 0 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: Date Re9ue/Date Received 2024-03-27 o I o '('aAa , and 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: Date Re9ue/Date Received 2024-03-27 , and 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof; selected from the following compounds: Date Re9ue/Date Received 2024-03-27 o I o YoAo H ;:>< N~ o.,..-o 0 ~NH NH , and ~Yi'l o ~~Yo~ NH 0 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof: selected from the following compounds: Date Re9ue/Date Received 2024-03-27 , and 8. A compound according to any one of claims l to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of acquired angioedema or hereditary angioedema. 9. The compound or pharmaceutically acceptable salt thereof for use according to claim 8, for use in the treatment of acquired angioedema. 10. The compound or pharmaceutically acceptable salt thereof for use according to claim 8, for use in the treatment of hereditary angioedema. Date Re9ue/Date Received 2024-03-27 11. The compound or pharmaceutically acceptable salt thereof for use according to claim 8, for use in the treatment of hereditary angioedema, wherein the hereditary angioedema is Type I hereditary angioedema. 12. The compound or pharmaceutically acceptable salt thereof for use according to claim 8, for use in the treatment of hereditary angioedema, wherein the hereditary angioedema is Type Il hereditary angioedema. 13. The compound or pharmaceutically acceptable salt thereof for use according to claim 8, for use in the treatment of hereditary angioedema, wherein the hereditary angioedema is Type Ill hereditary angioedem:a. 14. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with aberrant activity of kallikrein. 15. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in inhibiting blood coagulation. Date Re9ue/Date Received 2024-03-27

Description

Carbamimidoylphenylcarbamoyl .Derivatives and .Pharmaceutical Compositions Thereof Useful as Kallikrein lnhibitor,'i RELATED APPLICATIONS This application claims the benefit of priority to United States Provisional Patent Application serial number 62/415 ,202, filed October 31, 2016. BACKGROUND OF THE INVENTION Hereditary angioedema (HAE) is a serious and potentially life-threatening rare genetic illness, caused by mutations in the Cl-esterase inhibitor (CllNH) gene, located on chromosome 11 q. HAE is inherited as an autosomal dominant condition, although one quarter of diagnosed cases arise from a new mutation. HAE has been classed as an orphan disease in Europe, with an estimated prevalence of I in 50,000. Individuals with HAE experience recurrent acute attacks of painful subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs or genitalia which, if untreated, may last up to 5 days. Attacks vary in frequency, severity and location and can be life-threatening. Laryngeal attacks, with the potential for asphyxiation, pose the greatest risk. Abdominal attacks are especially painful, and often result in exploratory procedures or unnecessary surgery .. Facial and peripheral attacks are disfiguring and debilitating. HAE has a number of subtypes. HAE type I is defined by C IINH gene mutations which produce low levels of C 1-inhibitor, whereas HAE type II is defined by mutations which produce normal levels of ineffective CI protein. HAE type III has separate pathogenesis, being caused by mutations in the FI2 gene which codes for the serine protease known as Factor XII. Diagnostic criteria for distinguishing the subtypes of HAE, and distinguishing HAE from other angioedemas, can be found in Ann Allergy Asthma lmmunol 2008; 100(Suppl2): S30-S40 andJAllergy Clin lmmuno/2004; 114: 629-37. Current treatments for HAE fall into two main types. Older non-specific treatments including androgens and antifibrinolytics are associated with significant side effects, particularly in females. Newer treatments are based on an understanding of the molecular pathology of the disease, namely that CIINH is the most important inhibitor ofkallikrein in human plasma a:nd that C lINH deficiency leads to unopposed activation of the kallikrein- - l - Date Re9ue/Date Received 2024-03-27 WO 2018/081513 PCT/0S2017/058685 bradykinin cascade, with bradykinin the most important mediator of the locally increased vascular permeability that is the hallmark of an attack. Approved therapies include purified plasma-derived C lINH (Cinryze®, Berinert), the recombinant peptide kallikrein inhibitor ecallantide (Kalbitor®), and the bradykinin receptor B2 inhibitor icatibant (Firazyr®). All of the currently available targeted therapies are administered by intravenous or subcutaneous injection. There is currently no specific targeted oral chronic therapy for HAE. There are many delivery routes for active pharmaceutical ingredients (APis). Generally, the oral route of administration is favored due to advantages, such as, but not limited to, patient convenience, flexibility of timing of administration, location of administration and non-invasiveness. Oral administration also provides more prolonged drug exposure compared with intermittent intravenous infusion, which may be important for drugs with schedule-dependent efficacy. For example, a drug with a short half-life can achieve a greater exposure time by either continuous infusion or by continuous oral dosing. The use of oral therapy further has the potential to reduce the cost of healthcare resources for inpatient and ambulatory patient care services. • In the pharmaceutical arts, it is known that a number of APis cannot be administered effectively by the oral route. The main reasons why these compounds cannot be administered by the oral route are: a) rapid enzymatic and metabolic degradation; b) chemical and/or . biological instability; c) low solubility in aqueous medium; and/or d) limited permeability in the gastrointestinal tract. For such compounds, non-oral routes of delivery, such as parenteral administration, mainly via intramuscular or subcutaneous injections, may be developed. However, non-oral administration poses a disadvantage for the patient as well as healthcare providers, and for this reason, it is important to develop alternative routes of administration for such compounds, such as oral routes of administration. While the oral route of administration is the most convenient for the patient and the most economical, designing formulations for administration by the oral route involves many complications. Several methods are available to predict the ease by which an API may be formulated into a formulation suitable for administration by the oral route. Such methods include, but are not limited to, the Lipinski rule (also referred to as the Rule of Five) and the Biopharmaceutical Drug Disposition Classification System (BDDCS). WO 2018/081513 PCT/US2017 /058685 The BDDC