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US-20260124327-A1 - Compounds Targeting Carbonic Anhydrase IX and Uses Thereof

US20260124327A1US 20260124327 A1US20260124327 A1US 20260124327A1US-20260124327-A1

Abstract

Disclosed herein are compounds that target carbonic anhydrase 9 (CA IX) (such as compounds of structural formula (I) or (II) wherein values for variables are as described herein) and methods for the prevention and/or treatment of certain cancers, including solid tumors, using such compounds. Also disclosed herein are pharmaceutically acceptable salts of such compounds and pharmaceutical compositions comprising such compounds or salts for use in such methods of preventing or treating cancers.

Inventors

  • Andrew R. Hudson
  • Nicholas D. Smith
  • Joe A. TRAN
  • Yalda Bravo

Assignees

  • RAYZEBIO, INC.

Dates

Publication Date
20260507
Application Date
20251105

Claims (20)

  1. 1 - 110 . (canceled)
  2. 111 . A compound having the following structure: or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein X M is an alpha particle-emitting radionuclide or a beta particle-emitting radionuclide.
  3. 112 . The compound of claim 111 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein X M is an alpha particle-emitting radionuclide.
  4. 113 . The compound of claim 112 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225, Bi-212, Bi-213, Bi-209, Tb-149, Ra-223, Ra-224, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213.
  5. 114 . The compound of claim 113 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225.
  6. 115 . The compound of claim 111 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein X M is a beta particle-emitting radionuclide.
  7. 116 . The compound of claim 115 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or Tb-161.
  8. 117 . The compound of claim 116 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Lu-177, Tb-161, or Cu-67.
  9. 118 . The compound of claim 117 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Lu-177.
  10. 119 . The compound of claim 111 , having the following structure: or a pharmaceutically acceptable salt thereof, wherein X M is an alpha particle-emitting radionuclide or a beta particle-emitting radionuclide.
  11. 120 . The compound of claim 119 , or a pharmaceutically acceptable salt thereof, wherein X M is an alpha particle-emitting radionuclide.
  12. 121 . The compound of claim 120 , or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225, Bi-212, Bi-213, Bi-209, Tb-149, Ra-223, Ra-224, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213.
  13. 122 . The compound of claim 121 , or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225.
  14. 123 . The compound of claim 119 , or a pharmaceutically acceptable salt thereof, wherein X M is a beta particle-emitting radionuclide.
  15. 124 . The compound of claim 123 , or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or Tb-161.
  16. 125 . The compound of claim 124 , or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Lu-177, Tb-161, or Cu-67.
  17. 126 . The compound of claim 125 , or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Lu-177.
  18. 127 . A pharmaceutical composition comprising the compound of claim 111 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  19. 128 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 111 , or a stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  20. 129 . A pharmaceutical composition comprising the compound of claim 119 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Application No. 63/716,788, filed on Nov. 6, 2024, which is incorporated herein by reference in its entirety for any purpose. FIELD The present disclosure relates generally to compounds, compositions, and methods for their preparation, and use of the compounds and compositions for treating diseases and conditions associated with the expression of carbonic anhydrase 9. BACKGROUND The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition and activity of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins allow the use of noninvasive imaging techniques, such as molecular imaging or nuclear medicine, for detecting the presence and quantity of tumor associated proteins, thereby providing vital information related to the diagnosis and extent of disease, prognosis, and therapeutic management options. As radiopharmaceuticals can be prepared that are not only capable of imaging disease but also delivering a therapeutic radionuclide to the diseased tissue, therapy, in particular cancer therapy, can be realized. The selective expression of carbonic anhydrase 9 (CA-IX, or CA9) on tumors in response to hypoxia makes it an attractive target to exploit for noninvasive imaging as well as targeted radiotherapy. In order to grow beyond more than a few millimeters in diameter, tumor micrometastasis need to obtain a supply of oxygen to sustain the high metabolic rate characteristic of rapid growth, and do so by inducing the formation of new blood vessels. The distance that tumor cells reside from blood vessels is inversely proportional to the oxygen pressure of the tumor. Even when angiogenesis occurs and a blood supply is established, the less vascular interior region of the growing tumor mass remains hypoxic and eventually undergoes necrosis. Hypoxia is associated with a poor response to radiation therapy, and leads to tumor resistance. Since oxygen is necessary for the cytotoxic actions of free radicals generated by radiation, higher, often incompatible, levels of radiation are required to promote damage to the tumor. Therefore, there is a need for non-invasive techniques to stratify patients based on cancer hypoxia who are not expected to respond to radiation therapy because of low oxygen, and who may be candidates for alternative hypoxia-activated chemotherapies that are becoming available. As hypoxia constitutes a major difference between the tumor and normal tissues, it can be exploited for the development of tumor specific probes. Hypoxia is a potent stimulus for the expression of specific genes, several which function to trigger vasculogenesis and therefore supply oxygen to the tumor, increase metabolism to increase the oxygen extraction factor, and promote a favorable environment for tumor growth. The activation of hypoxia inducible genes is in part mediated by a transcription factor, HIF-1α. Under normoxic conditions, HIF-1α is hydroxylated on proline residues that reside in the oxygen induced degradation domain of the protein by proline hydroxylase. Hydroxyproline facilitates binding of Von-Hippel-Lindau Factor (VHL), a tumor suppressor that, when bound, promotes the ubiquitination and degradation of HIF-1α. During hypoxia, proline hydroxylase is inhibited, and VHL no longer binds HIF-1α; the now stabilized HIF-1α translocates to the nucleus and associates with HIF-1α. This heterodimeric transcription factor then binds to HIF-1 responsive DNA sequences in the promoter region of target genes including the carbonic anhydrase isoform CA-IX, as well as VEGF, erythropoietin, and glucose transporters. Carbonic anhydrases are a family of enzymes comprised of 16 isozymes that catalyze the reaction: CO2+H2OHCO3−+H+, and therefore play an important role in pH regulation. Specific isozymes are found either in the cytosol, anchored to the membrane, within the mitochondria, or secreted from the cell. The well-studied constitutively expressed isozyme, carbonic anhydrase II, is found in the cytosol of most cell types, and is the primary isoform responsible for the regulation of intracellular pH. CA-IX is a membrane-anchored isoform of the enzyme with its catalytic domain in the extracellular space. It has a limited tissue distribution and is found at low levels primarily in the gastrointestinal tract. The expression of CA-IX is under the control of HIF-1α, and this isozyme is highly expressed in tumor cells exposed to hypoxia both in vitro and in vivo. Increased CA-IX expression has been detected in carcinomas of the cervix, ovary, kidney, esophagus, lung, breast, and brain. CA-IX has been reported to promote extracellular acidification. The low extracellular pH as a result of the activity of CA-IX leads to tumorigenic transformation, chromosomal rearra