Novel Tricyclic Heteroaryl Compounds as IRAK4 Inhibitors for Treating Cancer, Autoimmune and Inflammatory Diseases

Important Compound Classes

Title

Tricyclic Heteroaryl Compounds Useful as IRAK4 Inhibitors

Patent Publication Number

WO 2021/158498 A1

URL: https://patents.google.com/patent/WO2021158498A1/en

Publication Date

August 12, 2021

Priority Application

US 62/969,406

Priority Date

February 3, 2020

Inventors

Ahmad, S.; Negash, L. A.

Assignee Company

Bristol-Myers Squibb Company, USA

Disease Area

Cancer, inflammatory and autoimmune diseases

Biological Target

IRAK4

Summary

Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The toll-like receptor (TLR) family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD88. Members of the interleukin-1 receptor-associated kinase (IRAK) family of serine/threonine kinases are recruited to the receptor via interactions with MyD88. The family consists of four members. Several lines of evidence indicate that IRAK4 plays a critical and nonredundant role in initiating signaling via MyD88 dependent TLRs and IL-1R family members. IRAK4 directly interacts with MyD88 and subsequently recruits either IRAK1 or IRAK2 to the receptor complex to facilitate downstream signaling.

IRAK4 is the only member of the IRAK family whose kinase activity has been shown to be required for initiation of signaling. IRAK4 inhibitors will block all MyD88 dependent signaling. MyD88 dependent TLRs have been shown to contribute to the pathogenesis of multiple sclerosis, rheumatoid arthritis, cardiovascular disease, metabolic syndrome, sepsis, systemic lupus erythematosus, inflammatory bowel diseases including Crohn’s disease and ulcerative colitis, autoimmune uveitis, asthma, allergy, type I diabetes, and allograft rejection.

Oncogenically active MyD88 mutations in diffuse large B cell lymphomas have been identified that are sensitive to IRAK4 inhibition. Whole genome sequencing also identified mutations in MyD88 associated with chronic lymphatic leukemia suggesting that IRAK4 inhibitors have utility in treating leukemias.

The present application describes a series of novel tricyclic heteroaryl compounds as IRAK4 inhibitors for the treatment of inflammatory diseases, autoimmune diseases, and cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = CR_3a or N;

R₁ = −C(O)NR_XR_1a or pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, each substituted with 0 to 2 R_1b;

R₂ = H, C_1–6 alkyl substituted with 0 to 4 substituents selected from F, Cl, OH, CN, C_3–6 cycloalkyl and dimethoxyphenyl, or a cyclic group selected from C_3–6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrazolyl, and thiazolyl, wherein the cyclic group is substituted with 0–3 substituents selected from F, Cl, OH, CN, C_1–2 alkyl, C_1–2 fluoroalkyl, C_1–2 hydroxyalkyl, and −S(O)₂(C_1–2 alkyl);

R₃ = CN, −C(O)NR_xR_x, or a cyclic group selected from phenyl, or pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridinonyl, and pyrimidinyl, each cyclic group is substituted with 0–3 substituents selected from F, Cl, OH, CN, C_1–2 alkyl, −CF₃, and −CH₂OH; and n = 0, 1 or 2.

Key Structures

Biological Assay

The IRAK4 inhibition assay was performed. The compounds described in this application were tested for their ability to inhibit IRAK4. The IRAK4 IC₅₀ (μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for IRAK4 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 12

Compound claims: 11

Pharmaceutical composition claims: 1

Recent Review Articles

• 1.Li X.; Sun X.; Guo X.; Li X.; Peng S.; Mu X.. Biomed. Pharmacother. 2022, 147, 112622.
• 2.Bennett J.; Starczynowski D. T.. Curr. Opin. Hematol 2022, 29, 8.
• 3.Munier C. C.; Ottmann C.; Perry M. W. D.. Pharmacol. Res. 2021, 163, 105236.
• 4.Takada H.Front. Immunol. 2021, 12, 803459.
• 5.Zheng J.; Wu J.; Ding X.; Shen H. C.; Zou G.. Bioorg. Med. Chem. Lett. 2021, 38, 127862.
• 6.Su L.; Xu W.; Huang A.. Autoimmun. Rev. 2020, 19, 102461.

The author declares no competing financial interest.