Search

US-12617810-B2 - Prodrugs of STAT3 inhibitors

US12617810B2US 12617810 B2US12617810 B2US 12617810B2US-12617810-B2

Abstract

Provided herein, in certain embodiments, are compounds of Formula I: or a pharmaceutically acceptable salt or a solvate thereof, compositions comprising a compounds of Formula I, or a pharmaceutically acceptable salt or a solvate thereof, and uses thereof such as in treating certain diseases or disorders (e.g., cancer, fibrosis, chronic inflammation).

Inventors

  • Imran Alibhai
  • Sofia De Achaval
  • Jeffrey Larson
  • Brad Henke

Assignees

  • TVARDI OPERATING COMPANY, INC.

Dates

Publication Date
20260505
Application Date
20240612

Claims (14)

  1. 1 . A compound of Formula I-B: or a pharmaceutically acceptable salt or a solvate thereof, wherein A is halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; R C is hydroxy; and n is 0 or 1.
  2. 2 . The compound of claim 1 , wherein A is C 1-4 alkoxy.
  3. 3 . A pharmaceutical composition comprising: a) a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof, and b) a pharmaceutically acceptable carrier.
  4. 4 . A method of treating cancer by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof.
  5. 5 . The method of claim 4 , wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, or lymphoma.
  6. 6 . A method of treating fibrosis by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof.
  7. 7 . The method of claim 6 , wherein the fibrosis is pulmonary fibrosis, bone marrow fibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneum fibrosis, renal fibrosis, myelofibrosis, dermal fibrosis, or systemic sclerosis.
  8. 8 . A method of treating an inflammatory disease or disorder by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof.
  9. 9 . The method of claim 8 , wherein the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleritis, multiple sclerosis, pancreatitis, or asthma.
  10. 10 . A method of treating a neurodegenerative disease or disorder by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof.
  11. 11 . The method of claim 10 , wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy.
  12. 12 . A method of treating non-alcoholic fatty liver disease or steatohepatitis by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 .
  13. 13 . A method of treating cachexia by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof.
  14. 14 . A method of treating anaphylaxis by inhibiting signal transducer and activator of transcription 3 (STAT3) in an individual in need thereof, comprising administering to the individual and effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or a solvate thereof.

Description

CROSS REFERENCE This application is a continuation of U.S. application Ser. No. 18/446,987, filed on Aug. 9, 2023, now issued as U.S. Pat. No. 12,043,640 on Jul. 23, 2024, which is a continuation of International Application No. PCT/US2023/068240, filed Jun. 9, 2023, which claims the benefit of and priority to U.S. Provisional Patent Application No. 63/366,437, filed Jun. 15, 2022, each of which are incorporated herein by reference in their entireties. SUMMARY Disclosed herein, in certain embodiments, are compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof, and compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the compounds and compositions disclosed herein are effective at inhibiting signal transducer and activator of transcription 3 (STAT3) and thus are useful in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders such as cancer, fibrosis, and inflammatory diseases or disorders. In certain embodiments, provided herein is a compound of Formula I: or a pharmaceutically acceptable salt or a solvate thereof, wherein A is halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, or C1-4haloalkoxy;R1, R2, and R3 are each independently H, C(═O)NRARB, P(═O)(OH)(RC), or C1-4alkylene-O—P(═O)(OH)(RC); orR1 and R2 together form: provided that R1, R2 and R3 are not simultaneously H;RA is H or C1-4alkyl;RB is C1-6alkylene-N(H)(C1-6alkyl), C1-6alkylene-(5-8 membered heterocyclyl), C1-6alkylene-C(═O) OH optionally substituted with amine, C1-4alkyl, or benzyl;RC is C1-4alkyl or hydroxy; andn is an integer 0, 1, 2, or 3. In certain embodiments, provided herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable carrier. In certain embodiments, provided herein are methods that involve the use of (e.g., comprise the administration of) a compound of formula (I), a STAT3 inhibitor, wherein the compound of formula (I) is formulated in a manner described herein (e.g., is present in a composition as described herein). In specific embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of cancer. In other specific embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of fibrosis. In still other specific embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of an inflammatory disease/disorder. Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims. BRIEF DESCRIPTION OF THE DRAWINGS The FIGURE shows the comparison of exposures of TTI-101 SEDD and Compound 9 (in PBS) in H22 syngeneic mice. DETAILED DESCRIPTION The present disclosure provides, in certain embodiments, compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof, and compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the compounds and compositions disclosed herein are effective at inhibiting signal transducer and activator of transcription 3 (STAT3). Thus, also provided herein, in certain embodiments, are uses of the compounds and compositions in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders (e.g., cancer, fibrosis, and inflammatory diseases or disorders). Definitions The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. As used herein the specification, “a” or “an” may mean one or more. As used herein, when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one. As used herein “another” may mean at least a second or more. Still further, the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and/or methods of the invention. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein. “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precis