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KR-20260062967-A - CYCLIC PHOSPHATE COMPOUNDS

KR20260062967AKR 20260062967 AKR20260062967 AKR 20260062967AKR-20260062967-A

Abstract

The present invention provides cyclic phosphate compounds, their preparation and their use, for treating, for example, liver disease or condition, or disease or condition in which a physiological or pathogenic pathway is associated with the liver.

Inventors

  • 지, 린

Assignees

  • 리간드 파마슈티칼스 인코포레이티드

Dates

Publication Date
20260507
Application Date
20200421
Priority Date
20190422

Claims (20)

  1. Compounds of the following chemical formulas Ib or Ic: (Ib) (Ic) In the above chemical formula, R 2a of the formula Ib or Ic is selected from the group consisting of H, OH, OR 8 , halo, CN, and optionally substituted C 1 -C 10 alkyls; R 2b of chemical formula Ib or Ic is selected from the group consisting of H, OR 8 , halo, CN, and optionally substituted C 1 -C 10 alkyls; R3 and R4 are each independently selected from the group consisting of H, OH, halo, CN, N3 , and optionally substituted C1 - C10 alkyls; R 5a is -C(O)OR 7 and; Each R6 is independently selected from the group consisting of halos and optionally substituted C2 - C10 alkyls; Each R7 is independently selected from the group consisting of H and optionally substituted C1 - C10 alkyls; Each R 8 is independently selected from the group of C(O)R 7 , C(O)OR 7 , and C(O)NHR 7 ; m is 1 or 2, and; n is 0 and; The base is , and Selected from a group composed of, R9 is H, halo, -CD3 , or optionally substituted C1 - C10 alkyl; R 10 is selected from the group consisting of H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkyl-OCH 2- , optionally substituted C 1 -C 10 alkyl-NHCH 2- , optionally substituted C 1 -C 10 acyl, optionally substituted C 1 -C 10 alkyl-OC(O)-, optionally substituted (C 6-10 aryl)-CH 2 OCH 2- , optionally substituted (C 6-10 aryl)-OCH 2- , optionally substituted (C 6-10 aryl)-C(O)-, and optionally substituted (C 6-10 aryl)-OC(O)-; R 11 is selected from the group consisting of OH, NH 2 , NHOR 8 , optionally substituted C 1 -C 10 alkyloxy, optionally substituted C 1 -C 10 alkylamino, optionally substituted C 1 -C 10 acyloxy, optionally substituted C 1 -C 10 acylamino, optionally substituted C 1 -C 10 alkyl-OC(O)NH-, optionally substituted (C 6-10 aryl)-C(O)O-, optionally substituted (C 6-10 aryl)-C(O)NH-, optionally substituted (C 6-10 aryl)-OC(O)NH-, optionally substituted C 1 -C 10 alkyl-OCH 2 NH-, and optionally substituted C 1 -C 10 alkyl-OCH 2 O-; R 12 is selected from the group consisting of H, NH 2 , optionally substituted C 1 -C 10 alkylamino, optionally substituted C 1 -C 10 acylamino, optionally substituted C 1 -C 10 alkyl-OC(O)NH-, optionally substituted (C 6-10 aryl)-C(O)NH-, optionally substituted (C 6-10 aryl)-OC(O)NH-, and optionally substituted C 1 -C 10 alkyl-OCH 2 NH-; The above base In this case, the above compound is not a compound of the chemical formula Ic; Herein, where a group is described as "optionally substituted," said group may be substituted with one or more substituents, said substituents being C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C7 carbocyclyl (optionally substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy), C3 - C7 -carbocyclyl- C1 - C6 -alkyl (optionally substituted with halo, C1 - C6 alkyl, C1-C6 alkoxy , C1 - C6 haloalkyl, and C1 - C6 haloalkoxy), 3-10-membered heterocycle (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1- C6 haloalkoxy 1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 3-10-membered heterocyclyl- C1 - C6 -alkyl (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1-C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), aryl (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), aryl ( C1 - C6 )alkyl (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 5-10-membered heteroaryl (halo, C 1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy (optionally substituted with 1-C6 alkyl, C1-C6 alkoxy, C1 - C6 haloalkyl, and C1- C6 haloalkoxy), 5-10-membered heteroaryl ( C1 -C6 )alkyl (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1-C6 haloalkyl, and C1 - C6 haloalkoxy (optionally substituted with 1-C6 alkyl, C1-C6 alkoxy, C1 - C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1 - C6 alkoxy, C1-C6 alkoxy ( C1 - C6 )alkyl (i.e., ether), aryloxy (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy (optionally substituted with 1-C6 haloalkoxy)), C3 - C7 Carbocyclyloxy (halo, C1 - C6 alkyl, C1 -C6 alkoxy, C1- C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 3-10-membered heterocyclyl-oxy (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 5-10 -membered heteroaryl-oxy (halo, C1 - C6 alkyl, C1- C6 alkoxy, C1 -C6 haloalkyl , and optionally substituted with C1 - C6 haloalkoxy), C3 - C7 -carbocyclyl- C1 - C6 -alkoxy (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C 1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 3-10-membered heterocyclyl- C1 - C6 -alkoxy (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1-C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), aryl ( C1 - C6 )alkoxy (halo, C1 - C6 alkyl , C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 5-10-membered heteroaryl ( C1 - C6 )alkoxy (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 (optionally substituted with haloalkoxy), sulfhydryl(mercapto), halo( C1 - C6 )alkyl (e.g., -CF3 ), halo( C1 - C6 )alkoxy (e.g., -OCF3 ), C1 - C6 alkylthio, aryltio (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1- C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), C3 - C7 carbocyclylthio (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 3-10 heterocyclyl-thio (halo, C1 - C6 alkyl, C1-C6 alkoxy, C1 - C6 haloalkyl) 1 - C6 haloalkyl and optionally substituted with C1 - C6 haloalkoxy), 5-10-membered heteroaryl-thio (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), C3 - C7 -carbocyclyl- C1 - C6 -alkylthio (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and optionally substituted with C1 - C6 haloalkoxy), 3-10-membered heterocyclyl- C1 - C6 -alkylthio (halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 Selectively substituted with haloalkoxy), aryl( C1 - C6 )alkylthio(halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and selectively substituted with C1 - C6 haloalkoxy), 5-10 heteroaryl( C1 - C6 )alkylthio(halo, C1 - C6 alkyl, C1- C6 alkoxy, C1 -C6 haloalkyl, and selectively substituted with C1 - C6 haloalkoxy), amino, amino( C1 - C6 ) alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N - amido, S-sulfonamido, N-sulfonamido, C-carboxy, Independently selected from O-carboxy, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O); or its stereoisomers or pharmaceutically acceptable salts.
  2. In Article 1, The above R 9 is a compound in which H.
  3. In Article 1, A compound in which R9 is an unsubstituted C1 - C10 alkyl.
  4. In Article 1, The above R 9 is a compound of -CD 3 .
  5. In Article 1, A compound in which at least one of the above R 2a and R 2b is H.
  6. In Article 1, A compound in which R 2a is an unsubstituted C 1 -C 10 alkyl.
  7. In Article 6, A compound in which R 2a is methyl and R 2b is fluoro.
  8. In Article 1, A compound in which R 2a is OH.
  9. In Article 1, R 2a and R 2b of the above chemical formula Ib or Ic are each a haloin, a compound.
  10. In Article 9, R2a and R2b of the above chemical formula Ib or Ic are each fluorophosphate compounds.
  11. In Article 1, The above base In the case where m is 1, the compound.
  12. In Article 1, The above compound is a compound of the following chemical formula Ib, or its stereoisomer or a pharmaceutically acceptable salt, [Chemical Formula Ib] compound.
  13. In Article 12, A compound in which R 5a is -COOR 13 , and R 13 is an unsubstituted C 1 -C 10 alkyl.
  14. In Article 13, The above R 13 is a compound that is i -propyl.
  15. In Article 13, The above R 13 is a compound that is n -propyl.
  16. In Article 1, The above compound is a compound of the following chemical formula Ic, or its stereoisomer or a pharmaceutically acceptable salt, [Chemical Formula Ic] compound.
  17. In Article 16, The above m is a compound of 1.
  18. In Article 1, The above compound is, , , , , , and A compound selected from the group consisting of
  19. As a pharmaceutical composition, A pharmaceutical composition comprising the compound of claim 1 and pharmaceutically acceptable excipients, intended for treating liver disease, or diseases or conditions in which a physiological or pathogenic pathway is related to the liver.
  20. A compound of claim 1 for use in treating liver disease, or diseases or conditions involving the liver through a physiological or pathogenic pathway.

Description

Cyclic Phosphate Compounds The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to cyclic nucleotide compounds, methods of preparation thereof, and uses thereof. In some embodiments, these compounds are useful for selectively delivering certain pharmaceutical preparations to the liver. The following description of the background technology is provided to aid in understanding the present invention, but is not recognized or described as prior art. Natural nucleosides, once phosphorylated into nucleotides, are the building blocks of DNA and RNA. Human nucleosides are primarily obtained from the digestion of nucleic acids in the diet and can be biosynthesized, particularly in the liver, when needed. Nucleosides can be phosphorylated into nucleotides in cells by specific nucleoside kinases to maintain normal cell function and growth. These kinases can be impaired in one or more tissues due to genetic defects or non-genetic factors, which can lead to certain diseases or disorders, including but not limited to certain mitochondrial DNA depletion syndromes. For example, see the literature “El-Hattab, A. and F. Scaglia (2013) Neurotherapeutics. 2013 Apr; 10(2): 186-198 (published online 2013 Feb 6. doi: 10.1007/s13311-013-0177-6)”. Theoretically, nucleotide supplementation can address deficiencies in the body; however, since nucleotides possess molecular properties, such as hydrophilicity, that prevent them from easily passing through cell membranes, treatment using nucleotide supplements may be inefficient or require large amounts of supplements. Synthetic nucleotides are widely used as antiviral or anticancer agents. Prodrug technology has been used to improve the molecular properties of nucleotides to make them more bioavailable, including by improving oral bioavailability. Therefore, novel compounds with liver-targeting profiles, in addition to improved oral bioavailability, can significantly enhance the benefits of nucleotide-based therapeutic regimens. The present embodiment relates to a novel cyclic phosphate compound, a method of preparing the same, and compositions and methods related to the use thereof. In some embodiments, the novel cyclic phosphate compound promotes the delivery into cells of nucleotide-derived preparations, e.g., ribonucleotides and deoxyribonucleotides, containing adenine, cytosine, guanine, inosine, thymine, uracil, and derivatives thereof and prodrugs. The above cyclic phosphate compounds and their stereoisomers and pharmaceutically acceptable salts are represented by compounds of the following formulas I, Ia, Ib, Ic and Id, or their stereoisomers or pharmaceutically acceptable salts. [Chemical Formula I] [Chemical Formula Ia] [Chemical Formula Ib] [Chemical Formula Ic] [Chemical Formula Id] In the above chemical formula, R 2 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6 , n, m, q, r, and bases have any values described herein. In some embodiments, R 2a and R 2b is independently selected from the group consisting of H, OR 8 , halo, CN, and optionally substituted C 1 -C 10 alkyls. In some embodiments, the alkyl is methyl. In some embodiments, the halo is F or Cl. In some embodiments, R3 and R4 are independently selected from the group consisting of H, OH, CN, N3 , and optionally substituted C1 - C10 alkyls. In some embodiments, the alkyl is methyl. In some embodiments, the halo is F. In some embodiments, R 5a is H, -CH(OR 7 ) 2 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -CH 2 OR 8 , -CH 2 N(R 8 ) 2 , -CH 2 OCH 2 OR 8 , and am. In some embodiments, R 5b is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 1 -C 10 alkyloxy, optionally substituted (C 6-10 aryl), optionally substituted (C 6-10 aryl)-CH 2- , optionally substituted (C 6-10 aryl)-CH 2 CH 2- , -CH(OR 7 ) 2 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -CH 2 OR 8 , -CH 2 N(R 8 ) 2 , -CH 2 O CH 2 OR 8 , and It is selected from the army. In some embodiments, each R6 is independently selected from the group consisting of a halo and optionally substituted C1 - C10 alkyls. In some embodiments, the halo is F or Cl. In some embodiments, the optionally substituted alkyl is methyl. In some embodiments, each R7 is independently selected from the group of H and optionally substituted C1 - C10 alkyls. In some embodiments, each R 8 is independently selected from the group of H, C(O)R 7 , C(O)OR 7 , and C(O)NHR 7 . In some implementations, n is 0, 1, 2, or 3. In some embodiments, m, q, and r are independently 0, 1, or 2. In some embodiments, the base is a derivative or analog of a natural nucleoside optimized for pharmaceutical use, wherein the base It does not include. In some embodiments, the base In the case where q is 1, and R 5a is H or It is not. In some embodiments, the base In the case where m is 1, q is 1, n is 0, r is 0, and R 5a is H or It is not, and R 5b is not methyl. In some embodiments, the base is , and It is selected fr