Novel Substituted Tetrahydroquinoline Compounds as Indoleamine-2,3-dioxygenase (IDO) Inhibitors

Important Compound Classes

Title

Novel Substituted Tetrahydroquinoline Compounds as Indoleamine-2,3-dioxygenase (IDO) Inhibitors

Patent Publication Number

WO 2020/251871 A2

Publication Date

December 17, 2020

Priority Application

US 62/860,059

Priority Date

June 11, 2019

Inventors

Han, Y.; Deng, Y.; Zhou, H.; McGowan, M. A.; Zhang, H.; Yu, W.; Hopkins, B. A.; Fradera, X.; Sciammetta, N.

Assignee Company

Merck, Sharp & Dohme Corp., USA

Disease Area

Cancer, viral infection, depression, age-related cataracts, organ transplantation, and rheumatoid arthritis

Biological Target

Indoleamine-2,3-dioxygenase (IDO)

Summary

Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin, and the neurotransmitter 5-hydroxytryptamine (serotonin). The enzyme, indoleamine-2,3-dioxygenase (IDO), catalyzes the first and rate-limiting step in the degradation of l-tryptophan to N-formyl-kynurenine. IDO activity has an antiproliferative effect on many tumor cells.

It has been observed that HeLa cells cocultured with peripheral blood lymphocytes (PBLs) acquire an immune-inhibitory phenotype through up-regulation of IDO activity. Several lines of evidence suggest that IDO is involved in induction of immune tolerance. Studies of mammalian pregnancy, tumor resistance, chronic infections, and autoimmune diseases have shown that cells expressing IDO can suppress T-cell responses and promote tolerance. High levels of IDO were observed in cells isolated from the synovia of arthritic joints. IDO inhibition can enhance the levels of virus-specific T-cells and concomitantly reduce the number of virally infected macrophages in a mouse model of HIV.

Considering the potential role of IDO in immunosuppression, tumor resistance, chronic infections, HIV infection, AIDS, autoimmune diseases (rheumatoid arthritis), immunologic tolerance, and prevention of fetal rejection in utero, therapeutic agents aimed at suppression of tryptophan degradation by inhibiting IDO activity are desirable. Inhibition of IDO may also be important treatment strategy for patients with depression.

The present application describes a series of novel substituted tetrahydroquinoline compounds as indoleamine-2,3-dioxygenase (IDO) inhibitors for the treatment of cancer, viral infection, depression, age-related cataracts, organ transplantation, and rheumatoid arthritis. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

A = H, halogen, CN, C_1–6alkyl optionally substituted with 1–3 halogens;

Z₁, Z₂, and Z₃ = CR₈ or N;

R₈, if present, = H, halogen, C_1–6 alkyl, OC_1–6 alkyl or NH₂;

R₁ and R₂ = H, C_1–6alkyl, C_3–6cycloalkyl optionally substituted with C_3–6cycloalkyl, or R₁ and R₂ together with the carbon atom to which they are attached, optionally form C_3–6cycloalkyl optionally substituted with C_3–6cycloalkyl;

V is absent, a bond, or selected from H, C(O), CONH or C_3–6 heterocycle containing 1–4 nitrogen, wherein the C_3–6 heterocycle is optionally substituted CH₃ or CF₃;

R₃ = H, C_1–6alkyl, C_3–6cycloalkyl, OC_1–6alkyl, OC_3–6cycloalkyl, or C_3–10 heterocyclyl containing 1–4 nitrogen or oxygen, optionally substituted with halogen, C_1–6alkyl, or CF₃;

R₄ and R₅ = H, OH, halogen, or C_1–6alkyl;

R₆ = H, OH, halogen, or C_1–6alkyl; and

n = 0, 1, 2, 3, or 4.

Key Structures

Biological Assay

The IDO1 cellular assay in HeLa cells with IFNγ was performed. The compounds described in this application were tested for their ability to inhibit IDO1. The IDO1 IC₅₀ (nM) are shown in the following Table.

Biological Data

The Table below shows representative compounds were tested for IDO1 inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 26

Compound claims: 20

Composition claims: 1

Method of treating claims: 4

Use of compound claims: 1

Recent Review Articles

• 1Dolsak A.; Gobec S.; Sova M.. Pharmacol. Ther. 2021, 221, 107746.
• 2Singh R.; Salunke D. B.. Eur. J. Med. Chem. 2021, 211, 113071.
• 3Wells G.; Kennedy P. T.; Dahal L. N.. Front. Immunol. 2021, 12, 651687.
• 4Guo Y.; Liu Y.; Wu W.; Ling D.; Zhang Q.; Zhao P.; Hu X.. Biomaterials 2021, 276, 121018.
• 5Chen S.; Tan J.; Zhang A.. Bioorg. Chem. 2021, 110, 104815.
• 6Platten M.; Friedrich M.; Wainwright D. A.; Panitz V.; Opitz C. A.. Curr. Opin. Immunol. 2021, 70, 57.

The author declares no competing financial interest.