FMS-LIKE TYROSINE KINASE INHIBITORS

• US 20200131194A1
• Filed: 04/03/2018
• Published: 04/30/2020
• Est. Priority Date: 04/03/2018
• Status: Active Grant

• Current Assignee: Sagabio Co., Ltd.
• Original Assignee: 3Sm Biotron Inc.
• Inventors: Chen, Jung-Hsiang, Chen, Tsung-Chih, Ly, Tai Wei, Chen, I-Chun, Hsu, Jiunn-Yuan
• Granted Patent: US 11,332,476 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention relates to Fms-like tyrosine kinase (FLT3) inhibitors. The present invention provides novel 4-quinolinone derivatives used as FLT3 inhibitors and for treatment and/or prevention of tumors.

Claims

1. A compound having the following Formula (I-1), (I-2), (I-3) or (I-4),

2. The compound of claim 1, Q is —

S— and

n is 1.

3. The compound of claim 1, P is —

C—

or —

N— and

n is 1.

4. The compound of claim 1, R₁ is CN, F, Cl, —

OC_1-4alkyl, C_1-4alkyl or haloC_1-4alkyl. In a further embodiment, Cl bonds to C₁₁, C₁₀, C₉ or 8 when P is —

C—

; and

—

OC_1-4alkyl, F, CN, —

OC_1-4alkyl, C_1-4alkyl or haloC_1-4alkyl bonds to C₁₀ when P is —

C—

.

5. The compound of claim 1, R₂ is —

NH—

C_1-3alkylene-NHR_a, —

NH—

C_1-3alkylene-NH₂, —

NH—

C_1-3alkylene-OH, —

NH—

C_1-3alkylene-NHC_1-4alkylOH, —

C_1-3alkylene-5- or 6-membered aryl, —

C_1-3alkylene-5- or 6-membered heteroaryl. In a further embodiment, R_a is H;

R_c is hydroxyC_1-4alkyl.

6. The compound of claim 1, R₃ is H.

7. The compound of claim 1, which is selected from the group consisting of:

8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.

9. A method of inhibiting FLT3, comprising contacting a cell with a compound of claim 1.

10. A method of treating or preventing the disease associated with FLT3 inhibition in a subject, which comprises administrating an effective amount of a compound of claim 1.

11. The method of claim 10, wherein the disease associated with FLT3 inhibition is a cancer.

12. The method of claim 11, wherein the cancer is invasive breast carcinoma, adenocarcinoma, lung cancer (non-small cell, squamous cell carcinoma, adenocarcinoma, and large cell lung cancer), liver cancer, colorectal cancer, brain, head and neck cancer (e.g., neuro/glioblastoma), breast cancer, ovarian cancer, transitional cell carcinoma of the bladder, prostate cancer, oral squamous cell carcinoma, bone sarcoma, adrenocortical cancer, gastrointestinal tumors including colorectal cancer, biliary tract cancer such as gallbladder carcinoma (GBC), bladder cancer, esophageal cancer, gastric cancer, cervical cancer, salivary gland cancer, diarrhea benign neoplasm, ductal carcinoma in situ, paronychia, cholangiocarcinoma, kidney cancer, pancreatic cancer, medulloblastoma, glioblastoma, luminal, HER2-positive and triple negative mammary tumors, hematologic malignancies or leukemia (acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemia (ALL), a fraction of T-cell ALL, and chronic myelogenous leukemia (CML).

13. The method of claim 11, wherein the cancer is leukemia.