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CA-3191319-C - NOVEL COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

CA3191319CCA 3191319 CCA3191319 CCA 3191319CCA-3191319-C

Abstract

The present invention relates to a novel compound having a selective HDAC6 inhibitory activity, stereoisomers thereof, pharmaceutically acceptable salts thereof, a use thereof in preparation of a therapeutic medicament, a pharmaceutical composition containing the same, a therapeutic method using the composition, and a method for preparing the same, wherein the novel compound having the selective HDAC6 inhibitory activity is represented by chemical formula (I) below.

Inventors

  • Chang Sik Lee
  • Jung Taek Oh
  • Hokeun Yun
  • Hyeseung SONG
  • Hyunjin Michael Kim

Assignees

  • CHONG KUN DANG PHARMACEUTICAL CORP.

Dates

Publication Date
20260505
Application Date
20210901
Priority Date
20200902

Claims (9)

  1. 93 Claims 1. A compound represented by a following chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof: [Chemical Formula I] wherein, Z1 to Z4 are each independently N or CR0, R0 is H or halogen; R1 is CX3 or CX2H, X is halogen; N N O A is , or N N O O Z5 n m , when N N O A is , R4 and R5 are each independently H or C1-C4 alkyl, when N N O A is , R4 and R5 are each independently C1-C4 alkyl, 94 Z5 is N-R6 or CH2, R6 is C1-C4 alkyl, -C(=O)-(C1-C4 alkyl), -C(=O)-O-(C1-C4 alkyl) or 4- to 6- membered heterocycloalkyl having one O; L1 is -(C1-C2 alkylene)-; is C6-C12 aryl, 5- to 9-membered heteroaryl having at least one N or HN ; R2 and R3 are each independently H, halogen, C6-C12 aryl, 5- or 6-membered heteroaryl having N or O, 5- or 6-membered heterocycloalkyl having N, 5- or 6-membered heterocycloalkenyl having N, -C(=O)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -NH-C(=O)- (C1-C4 alkyl), -NO2 or -NH2, at least one H of above R2 and R3 may be each independently substituted with halogen or C1-C4 alkyl; and n and m are each independently 1 or 2.
  2. 2. The compound represented by the chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to claim 1, wherein Z1 and Z2 are each independently N, CH or CF, and Z3 and Z4 are each CH; R1 is CF3 or CF2H; N N O A is , or N N O O Z5 n m , 95 when N N O A is , R4 and R5 are each independently H or C1- C4 alkyl, when N N O A is , R4 and R5 are each independently C1-C4 alkyl, Z5 is N-R6 or CH2, R6 is C1-C4 alkyl, -C(=O)-(C1-C4 alkyl), -C(=O)-O-(C1-C4 alkyl) or oxetane; L1 is -(C1-C2 alkylene)-; R2 and R3 are each independently H, halogen, halogen substituted or unsubstituted phenyl, furanyl, pyridinyl, C1-C4 alkyl substituted or unsubstituted piperidinyl, C1-C4 alkyl substituted or unsubstituted tetrahydropyridinyl, -C(=O)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -NH-C(=O)-(C1-C4 alkyl), -NO2 or -NH2, B is phenyl, indole or HN , if B is indole or HN , H of NH thereof may be substituted with -C(=O)- O-(C1-C4 alkyl) or -C(=O)-(C1-C4 alkyl), if B is phenyl, at least one H of phenyl may be each independently substituted with halogen, and n and m are each independently 1 or 2. 96
  3. 3. The compound represented by the chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound represented by chemical formula I is one selected from the group consisting of following compounds 1 to 37: Compound Structure Compound Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 97 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 98 35 36 37 .
  4. 4. A pharmaceutical composition comprising the compound represented by the chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 3 as an effective ingredient for use in preventing or treating histone deacetylase (HDAC)-mediated diseases, wherein the histone deacetylase-mediated diseases comprise infectious diseases, neoplasm, endocrinopathy, nutritional and metabolic diseases, mental and behavioral disorders, neurological diseases, eye and ocular adnexal diseases, respiratory diseases, digestive diseases, skin and subcutaneous tissue diseases, musculoskeletal system and connective tissue diseases, or teratosis, deformities and chromosomal aberration.
  5. 5. The compound represented by the chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, for use in preventing or treating histone deacetylase (HDAC)-mediated diseases, wherein the histone deacetylase-mediated diseases comprise infectious diseases, neoplasm, endocrinopathy, nutritional and metabolic diseases, mental and behavioral disorders, neurological diseases, eye and ocular adnexal diseases, respiratory diseases, digestive diseases, skin and subcutaneous tissue diseases, musculoskeletal system and connective tissue diseases, or teratosis, deformities and chromosomal aberration.
  6. 6. The pharmaceutical composition for use according to claim 4 or the compound 99 represented by the chemical formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof for use according to claim 5, wherein the endocrinopathy, nutritional and metabolic diseases are Wilson's disease, amyloidosis or diabetes; the mental and behavioral disorders are depression or Rett syndrome; the neurological diseases are central nervous system atrophy, neurodegenerative disease, motor disorder, neuropathy, motor neuron disease or central nervous system demyelinating disease; the eye and ocular adnexal diseases are uveitis; the skin and subcutaneous tissue diseases are psoriasis; the musculoskeletal system and connective tissue diseases are rheumatoid arthritis, osteoarthritis or systemic lupus erythematosis; the teratosis, deformities and chromosomal aberration are autosomal dominant polycystic kidney disease; the infectious diseases are prion disease; the neoplasm is benign tumor or malignant tumor; the respiratory diseases are asthma; and the digestive diseases are alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease.
  7. 7. Use of the compound represented by chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 3; or a pharmaceutical composition comprising the same as an effective ingredient for preventing or treating histone deacetylase (HDAC)-mediated diseases, wherein the histone deacetylasemediated diseases comprise infectious diseases, neoplasm, endocrinopathy, nutritional and 100 metabolic diseases, mental and behavioral disorders, neurological diseases, eye and ocular adnexal diseases, respiratory diseases, digestive diseases, skin and subcutaneous tissue diseases, musculoskeletal system and connective tissue diseases, or teratosis, deformities and chromosomal aberration.
  8. 8. Use of the compound represented by chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 3; or a pharmaceutical composition comprising the same as an effective ingredient in preparation of a medicament for preventing or treating histone deacetylase (HDAC)-mediated diseases, wherein the histone deacetylase-mediated diseases comprise infectious diseases, neoplasm, endocrinopathy, nutritional and metabolic diseases, mental and behavioral disorders, neurological diseases, eye and ocular adnexal diseases, respiratory diseases, digestive diseases, skin and subcutaneous tissue diseases, musculoskeletal system and connective tissue diseases or teratosis, deformities and chromosomal aberration.
  9. 9. The use according to claim 7 or 8, wherein the endocrinopathy, nutritional and metabolic diseases are Wilson's disease, amyloidosis or diabetes; the mental and behavioral disorders are depression or Rett syndrome; the neurological diseases are central nervous system atrophy, neurodegenerative disease, motor disorder, neuropathy, motor neuron disease or central nervous system demyelinating disease; the eye and ocular adnexal diseases are uveitis; the skin and subcutaneous tissue diseases are psoriasis; the musculoskeletal system and connective tissue diseases are rheumatoid arthritis, 101 osteoarthritis or systemic lupus erythematosis; the teratosis, deformities and chromosomal aberration are autosomal dominant polycystic kidney disease; the infectious diseases are prion disease; the neoplasm is benign tumor or malignant tumor; the respiratory diseases are asthma; and the digestive diseases are alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease.

Description

CA 03191319 2023-3-1 1 NOVEL COMPOUNDS AS HTSTONE DEACETYLASE 6 INHIBITOR, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME Technical Field The present invention relates to a novel compound having a histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof, pharmaceutically acceptable salts thereof, a use thereof in preparation of a therapeutic medicament, a pharmaceutical composition containing the same, a therapeutic method using the composition, and a method for preparing the same. Background In cells, a post-translational modification such as acetylation serves as a very important regulatory module at the hub of biological processes, and is also strictly controlled by a number of enzymes. As a core protein constituting chromatin, hi stone functions as an axis, around which DNA winds, and thus helps a DNA condensation. Also, a balance between acetylation and deacetylation of histone plays a very important role in gene expression. As an enzyme for removing an acetyl group from lysine residue of hi stone protein, which constitutes chromatin, histone deacetylase (HDAC) is known to be associated with gene silencing and induce a cell cycle arrest, angiogenic inhibition, immunoregulation, apoptosis, etc. (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). Also, it is reported that the inhibition of HDAC enzyme functions induces cancer cells into committing apoptosis for themselves by lowering an activity of cancer cell survival-related factors and activating cancer cell death-related factors in the body (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625). CA 03191319 2023-3-1 WO 2022/049496 PCT /IB2021/05 7975 2 For humans, 18 HDACs are known and classified into four classes according to homology with yeast HDAC. In this case, eleven HDACs using zinc as a cofactor may be divided into three groups: Class I (HDACl, 2, 3, 8), Class II (Ila: HDAC4, 5, 7, 9; lib: HDAC6, 10) and Class IV (HDACll). Further, seven HDACs of Class III (SIRT 1-7) use NAD+ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784). Various HDAC inhibitors are now in a preclinical or clinical development stage, but only non-selective HDAC inhibitors have been known as an anti-cancer agent so far. Vorinostat (SAHA) and romidepsin (FK228) have obtained an approval as a therapeutic agent for cutaneous T-cell lymphoma, while panobinostat (LBH-589) has won an approval as a therapeutic agent for multiple myeloma. However, it is known that the non-selective HDAC inhibitors generally bring about side effects such as fatigue, nausea and the like at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). It is reported that the side effects are caused by the inhibition of class I HD A Cs. Due to the side effects, etc., the non-selective HDAC inhibitors have been subject to restriction on drug development in other fields than an anticancer agent (Witt et al., Cancer Letters 277 (2009) 8 .21 ). Meanwhile, it is reported that the selective inhibition of class 11 HDACs would not show toxicity, which have occurred in the inhibition of class I HDACs. In case of developing the selective HDAC inhibitors, it would be likely to solve side effects such as toxicity, etc., caused by the non-selective inhibition of HDACs. Accordingly, there is a chance that the selective HDAC inhibitors may be developed as an effective therapeutic agent for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701). HDAC6, one of the class Ilb HDACs, is known to be mainly present in cytoplasma and contain a tubulin protein, thus being involved in the deacetylation of a number of nonhistone substrates (HSP90, cortactin, etc) (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, in which a zinc finger domain of C-terminal may bind to an CA 03191319 2023-3-1 WO 2022/049496 PCT /IB2021/05 7975 3 ubiquitinated protein. HDAC6 is known to have a number of non-hi stone proteins as a substrate, and thus play an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders and the like (Santo et al., Blood 2012 119: 2579-258; Vishwakarrna et al., International Irnrnunopharmacology 2013, 16, 72-78; Hu et al., J. Neural. Sci. 2011, 304, 1-8). A structural feature that various HDAC inhibitors have in common is comprised of a cap group, a linker group and a zinc binding group (ZBG) as shown in a following structure of vorinostat. Many researchers have conducted a study on the inhibitory activity and selectivity with regard to enzymes through a structural modification of the cap group and the linker group. Out of the groups, it is known that the zinc binding group plays a more important role in the enzyme inhibitory activity and selectivity (Wiest et al., J. Org. Chem. 2013 78: 5051-5065; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978). Cap Group Linker 2 inc Binding Group (ZBD) ~ ,--------, H ?