Novel Cyclic Tetramer Compounds as PCSK9 Inhibitors for Treating Metabolic Disorders

Important Compound Classes

Title

Cyclic Tetramer Compounds as Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors for the Treatment of Metabolic Disorders

Patent Publication Number

WO 2020/110009 A1

Publication Date

June 4, 2020

Priority Application

US 62/772,030 and US 62/924,828

Priority Date

November 27, 2018, and October 23, 2019

Inventors

Briner, K.; Dechristopher, B. A.; Flyer, A. N.; Golosov, A. A.; Grosche, P.; Liu, E. Y.; Mao, J. Y. C.; Monovich, L. G.; Patel, T. J.; Sanchez, C. C.; Su, L.; Yang, L.; Zheng, R.

Assignee Company

Novartis AG, Switzerland

Disease Area

Metabolic disorders including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, sepsis, and xanthoma.

Biological Target

Proprotein convertase subtilisin/kexin type 9 (PCSK9)

Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the secretory subtilase, subtilisin serine protein family, and is expressed in many tissue and cell types. The PCSK9 protein contains a signal sequence, a prodomain, a catalytic domain containing a conserved triad of residues, and a C-terminal domain and is synthesized as a soluble 74-kDa precursor that undergoes autocatalytic cleavage in the endoplasmic reticulum. The autocatalytic activity has been shown to be required for secretion.

PCSK9 has pronounced effects on plasma low density lipoprotein cholesterol (LDL-C) levels via its modulation of hepatic low-density lipoprotein receptors (LDLR), the main route by which cholesterol is removed from circulation. PCSK9 binds the LDLR and directs it to lysosomal degradation, thereby increasing plasma LDL-C levels and, in turn, coronary heart disease (CHD) risk. Moreover, mutations in PCSK9 that cause loss of PCSK9 function in mouse models have been shown to lower total and LDL-C levels, indicating that modulation of PCSK9 results in a reduction of LDLR protein levels.

PCSK9 plays a role in Lipoprotein (a) (Lp(a)) metabolism. Lp(a) is a proatherogenic lipoprotein comprised of an LDL particle covalently linked to apoLp(a). Human genetic studies indicate that Lp(a) is causally associated with CHD risk. PCSK9 therapeutic antibodies have significantly reduced Lp(a) levels in patients with hypercholesterolemia.

In addition to having cardiovascular effects, PCSK9 plays an important role in sepsis, a life-threatening condition caused by a body’s response to infection. Overexpression of PCSK9 in septic mice has been shown to aggravate sepsis by increasing inflammation, while inhibition of PCSK9 has been shown to reduce mortality. Thus, inhibition of PCSK9 has the potential to treat sepsis by reducing the body’s immune response to an infection.

Currently, there are no small molecule inhibitors of PCSK9. The only known marketed inhibitors of PCSK9 are anti-PCSK9 antibodies. The present application describes a series of novel cyclic tetramer compounds as PCSK9 inhibitors for treating metabolic disorders including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, sepsis, and xanthoma. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X₁ and X₂ = each independently H or (C₁–C₆)alkyl, or X₁ and X₂ together with the carbon atom to which they are attached form =(O);

X₃ is -CH₂- when X₁ and X₂ are each independently H or (C₁–C₆)alkyl, or X₁ and X₂ together with the carbon atom to which they are attached form =(O), or X₃ is -O-, -NH-, or -N(C₁–C₆)alkyl-, when X₁ and X₂ are each independently H or (C₁–C₆)alkyl, or X₁ and X₂ together with the carbon atom to which they are attached form =(O);

R₁ = (C₆–C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1–3 heteroatoms selected from N, O, and S, wherein aryl and heteroaryl are substituted with -OR₁₀ or NR₂₁R₁₀ and optionally substituted with one or more R₁₁;

R₂ = H, (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₁–C₆)haloalkyl, -NR₁₂R₁₃, (C₃–C₇)carbocyclyl, (C₃–C₇)cycloalkenyl, 5–7 membered heterocyclyl comprising 1–3 heteroatoms selected from N, O, and S, (C₆–C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1–3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more R₁₈ and the carbocyclyl, (C₃–C₇)cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R₁₉;

R₃ = H, D, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, or (C₁–C₆)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more R₁₄;

R₄ = H or (C₁–C₆)alkyl; or

R₃ and R₄ together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring comprising 1–3 heteroatoms selected from N, O, and S;

R₅ and R₇ = H, D, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, or (C₁–C₆)hydroxyalkyl, wherein the (C₁–C₆)alkyl is optionally substituted with one or more D;

R₆ = (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, or (C₁–C₆)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C₁–C₆)alkoxy, (C₁–C₆)haloalkoxy, −C(O)(C₁–C₆)alkyl, −C(O)OH, and −C(O)O(C₁–C₆)alkyl;

R₈ = H, (C₁–C₆)alkyl, or (C₁–C₆)haloalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C₃–C₇)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1–3 heteroatoms selected from N, O, and S, -NR₁₆R₁₇, and −C(O)NR₁₆R₁₇;

R₉ = halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, -OH or CN;

R₁₀ = (C₆–C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1–3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R₂₂;

R₁₁ = halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, -OH or CN;

R₁₂ and R₁₃ = each independently H or (C₁–C₆)alkyl;

R₁₄ = D, NR₁₅R_15′, (C₃–C₇)carbocyclyl, or 3- to 7-membered heterocyclyl comprising 1–3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more substituents each independently selected from halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy;

R₁₅ and R_15′ = H or (C₁–C₆)alkyl;

R₁₆ and R₁₇ = H or (C₁–C₆)alkyl, or

R₁₆ and R₁₇ = together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl ring optionally comprising 1–2 additional heteroatoms selected from N, O, and S;

R₁₈ = (C₃–C₇)carbocyclyl, or 5- to 7-membered heterocyclyl comprising 1–3 heteroatoms selected from N, O, and S, (C₆–C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1–3 heteroatoms selected from N, O, and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R₂₀;

R₁₉ = halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, −OH or CN; or two R₁₉ together, when on adjacent atoms, form a (C₆–C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1–3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, −OH or CN;

R₂₀ = halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, −OH or CN; or when R₁₈ is a carbocyclyl or a heterocyclyl, two R₂₀, when attached to the same carbon atom, together form = (O);

R₂₁ = H, (C₁–C₆)alkyl;

R₂₂ = halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, −OH or CN; (C₆–C₁₀)aryl or 5- or 6-membered heteroaryl comprising 1–3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R₂₃;

R₂₃ = halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, −CH₂(OCH₂CH₂)_1–3OCH₂CH₃, −OH or CN, or 4- to 7-membered heterocyclyl comprising 1–3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents each independently selected from halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy; -OH, -C(O)R₂₄R₂₅, -NR₂₄C(O)R₂₅, -NH₂, -NH(C₁–C₆)alkyl, and -N((C₁–C₆)alkyl)₂, and the alkyl is optionally substituted with -NR₂₄R₂₅ or 4- to 7-membered heterocyclyl comprising 1–3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents each independently selected from halogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, (C₁–C₆)haloalkyl, (C₁–C₆)haloalkoxy, -OH, -NH₂, -NH(C₁–C₆)alkyl, and -N((C₁–C₆)alkyl)₂; and

R₂₄ and R₂₅ = each independently H or (C₁–C₆)alkyl, or (C₃–C₇)carbocyclyl optionally substituted with one to two (C₁–C₆)alkyl.

Key Structures

Biological Assay

The human PCSK9 ligand binding assay was performed. The compounds described in this application were tested using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to test the ability of the compounds to inhibit PCSK9. The PCSK9 FRET Assay IC₅₀ (μM) and Max % Inhibition are shown in the following table.

Biological Data

The table below shows representative compounds were tested for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 36

Compound claims: 24

Use of compound claims: 2

Pharmaceutical composition claims: 3

Method claims: 7

Recent Review Articles

• 1.Gallego-Colon E.; Daum A.; Yosefy C.. Eur. J. Pharmacol. 2020, 878, 173114.
• 2.Warden B. A.; Fazio S.; Shapiro M. D.. Trends Cardiovasc. Med. 2020, 30, 179.
• 3.Preiss D.; Tobert J. A.; Hovingh G. K.; Reith C.. J. Am. Coll. Cardiol. 2020, 75, 1945.
• 4.Alkhalil M.Curr. Drug Metab. 2019, 20, 72.

The author declares no competing financial interest.