Novel Thienopyrimidines as Acetyl-CoA Carboxylase Inhibitors for Treating Liver Diseases

Important Compound Classes

Title

Thienopyrimidine Derivatives as ACC Inhibitors and Uses Thereof

Patent Publication Number

WO 2021/030142 A1

Publication Date

February 18, 2021

Priority Application

US 62/885,038

Priority Date

August 9, 2019

Inventors

Bates, J. G.; Gonzalez Buenrostro, A. Z.; Guo, H.; Han, X.; Kirby, B. J.; Lai, Y.; Mitchell, M. L.; Schwarzwalder, G. M.; Taylor, J. G.; Wang, T.

Assignee Company

Gilead Sciences Inc., USA

Disease Area

Liver diseases

Biological Target

Acetyl-CoA Carboxylase (ACC)

Summary

The ACC enzyme catalyzes the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is considered both a building block for fatty acid (FA) biosynthesis and a regulator of mitochondrial FA oxidation. Due to its role in malonyl-CoA formation, ACC is positioned at the metabolic intersection between lipid synthesis and oxidation pathways. ACC is believed to help control the switch between carbohydrate and fat utilization in lipogenic tissues (liver, adipose) and oxidative tissues (liver, heart, skeletal muscle). ACC has been a target of interest for the development of therapies for a variety of disorders. ACC inhibitors have been explored for the treatment of diabetes and obesity.

The present application describes a series of novel thienopyrimidines as ACC inhibitors for the treatment of liver diseases, particularly nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = CN, halogen, -R, -OR, -SR, -N(R)₂, -N(R)C(O)R, -C(O)N(R)₂, -N(R)C(O)N(R)₂, N(R)C(O)OR, -OC(O)N(R)₂, -N(R)SO₂R, -SO₂N(R)₂, -C(O)R, -C(O)OR, -OC(O)R, -S(O)R, -SO₂R, or a cyclic group;

R₂ = H, or C_1–4 alkyl, optionally substituted with one or more halogen, -OR, -SR, -N(R)₂, -N(R)C(O)R, -C(O)N(R)₂, -N(R)C(O)N(R)₂, N(R)C(O)OR, -OC(O)N(R)₂, -N(R)SO₂R, -SO₂N(R)₂, -C(O)R, -C(O)OR, -OC(O)R, -S(O)R, or -SO₂R;

R_3a and R_3b = H or C_1–3 alkyl, each optionally substituted with 1–3 substituents selected from halogen, CN, C_1–3 alkyl, or C_1–3 alkoxy; or

R_3a and R_3b = together with the carbon to which they are attached form cyclopropylenyl, cyclobutylenyl, oxetanyl, or tetrahydrofuanyl, each optionally substituted with 1–3 substituents selected from halogen, CN, C_1–3 alkyl, or C_1–3 alkoxy;

R_4a = C_1–6 alkyl, C_1–6 alkoxy, C_3–6 cycloalkyl, C_3–6 cycloalkoxy, phenyl, phenoxy, each optionally substituted with 1–3 substituents selected from halogen, cyano, C_1–3 alkyl, C_1–6 alkoxy, C_3–6 cycloalkyl, or C_3–6 cycloalkoxy, wherein C_1–3 alkyl, C_1–6 alkoxy, C_3–6 cycloalkyl, or C_3–6 cycloalkoxy, is substituted with C_1–3 alkoxy, or 1–3 halogens, -OR₄₁, or -N(R₄₂)₂;

R_4b = oxo or = NR₄₃;

R₅ = 6–12 membered bridged, fused or spiro heterocycle having 1 or 2 heteroatoms independently selected from O, S, or N;

R₆ = H, halogen, C_1–3 alkyl, C_1–6 alkoxy, C_3–6 cycloalkyl, or C_3–6 cycloalkoxy, wherein C_1–3 alkyl, C_1–6 alkoxy, C_3–6 cycloalkyl, or C_3–6 cycloalkoxy is optionally substituted with 1–3 substituents selected from halogen, CN, C_1–3 alkyl, or C_1–3 alkoxy; and

n = 1, 2, or 3.

Key Structures

Biological Assay

The in vitro De Novo Lipogenesis (DNL) enzymatic assay was performed. The compounds described in this application were tested for their ability to inhibit ACC. The DNL EC₅₀ (nM) are shown in the following Table.

Biological Data

The Table below shows representative compounds tested for ACC inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 78

Compound claims: 46

Pharmaceutical composition claims: 16

Method of treatment claims: 15

Use of compound claims: 1

Recent Review Articles

• 1.White P. J.; Abdelmalek M. F.. Clin. Liver Dis. 2021, 17, 29.
• 2.Botello-Manilla A. E.; Lopez-Sanchez G. N.; Chavez-Tapia N. C.; Uribe M.; Nuno-Lambarri N.. Ann. Hepatol. 2021, 24, 100320.
• 3.Attia S. L.; Softic S.; Mouzaki M.. Clin. Transl. Sci. 2021, 14, 11.
• 4.Bence K. K.; Birnbaum M. J.. Mol. Metab. 2021, in press.
• 5.Chen H.Liver Res. 2020, 4, 15.
• 6.Alannan M.; Fayyad-Kazan H.; Trezeguet V.; Merched A.. Biochemistry 2020, 59, 3951.

The author declares no competing financial interest.