EP-4735436-A1 - 6-(6-(((1 R,2R,3S,5S)-2-FLUORO-9-AZABICYCLO[3.3.1]NONAN-3-YL)(METHYL)AMINO)PYRIDA ZIN-3- YL)-2- METHYLBENZO[D]OXAZOL-5-OL AS A SPLICING MODULATOR FOR THE TREATMENT OF NEUROLOGICAL DISEASES

Abstract

Described herein is 6-(6-(((lR,2R,3S,5S)-2-fluoro-9- aza bicyclo[ 3.3.1 ]nonan-3-y l)(methyl)a mino) pyridazin-3-y l)-2- methylbenzo[d]oxazol-5-ol (structure B) as a small molecule splicing modulator (SMSM) of mRNA, such as pre-mRNA, encoded by genes, for the treatment of neurological and neurodegenerative diseases, such as e.g. Huntigton's disease, and brain cancer.

Inventors

• LUZZIO, MICHAEL
• LUCAS, BRIAN

Assignees

• Skyhawk Therapeutics, Inc.

Dates

Publication Date

20260506

Application Date

20240628

Claims (1)

1. WSGR Docket No.51503-767.601 CLAIMS What is claimed is: 1. A compound of structure B, or a pharmaceutically acceptable salt or a stereoisomer thereof: 2. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 3. A method of modulating splicing comprising administering to cells the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or a functional RNA. 4. A method of treating a disease or condition comprising administering the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof. 5. Use of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a condition or disease.

Description

WSGR Docket No.51503-767.601 COMPOSITIONS FOR MODULATING SPLICING CROSS REFERENCE [0001] This application claims the benefit of priority to U.S. Provisional Application No.63/511,248, filed June 30, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted in electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 17, 2024, is named 51503-767_601_SL.xml and is 1,885 bytes in size. BACKGROUND [0003] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing. [0004] Small molecule splicing modulators (SMSMs) overcome many of the problems associated with therapies such as oligonucleotide technologies (antisense, RNA interference, etc.), including lack of oral bioavailability, and lack of blood-brain-barrier penetration, with the latter precluding delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancers, etc.). [0005] SMSMs disclosed in WO2020/163541, such as, 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, are useful in treating and preventing a wide range of diseases and conditions through modulating splicing of pre- mRNAs, including, but not limited to, neurodegenerative diseases, such as Huntington’s Disease. SMSMs, however, can also have challenges, such as metabolic profiles in patients, clearance rates, the amount of compound available to exert an effect (e.g., fraction unbound in plasma, half-life of the compound in circulation, etc.). SUMMARY [0006] Provided herein are small molecule splicing modulators and uses thereof that fulfill this need. [0007] As mentioned above, WO2020/163541 discloses 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, which is useful in treating and preventing a wide range of diseases and conditions through modulating splicing of pre-mRNAs, including, but not limited to, neurodegenerative diseases, such as Huntington’s Disease. Certain parameters for SMSMs such as metabolic profiles in patients, clearance rates, the WSGR Docket No.51503-767.601 amount of compound available to exert an effect (e.g., fraction unbound in plasma, half-life of the compound in circulation, etc.) can be affected by small changes between two similar compounds. Thus, compounds similar to 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, but with improved metabolic profiles are useful in developing therapies for neurodegenerative diseases, such as Huntington’s Disease. [0008] In one aspect, described herein is a compound of structure B, or a pharmaceutically acceptable salt or stereoisomer thereof: Structure B. [0009] In some aspects, the compound of structure B is 6-(6-(((1R,2R,3S,5S)-2-Fluoro-9- azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5-ol. [0010] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. [0011] Also provided herein are methods of modulating splicing comprising contacting a compound disclosed herein to cells, wherein the compound modulates splicing at a splice site sequence of a pre- mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or a functional RNA. [0012] Also provided herein are methods of treating a disease or condition comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof. [0013] Also provided herein are uses of a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a condition or disease. INCORPORATION BY REFERENCE [0014] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION [0015] Certain specific details of this description are