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US-20260125370-A1 - SULFOXIMINE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

US20260125370A1US 20260125370 A1US20260125370 A1US 20260125370A1US-20260125370-A1

Abstract

The present invention relates to a sulfoximine compound having a novel structure, stereoisomers thereof or pharmaceutically acceptable salts thereof, and a use thereof for preventing or treating histone deacetylase-mediated diseases The sulfoximine compound having a novel structure according to the present invention may be represented by Formula (I) below.

Inventors

  • Jung Taek Oh
  • Hyeseung SONG
  • Chang Sik Lee

Assignees

  • CHONG KUN DANG PHARMACEUTICAL CORP.

Dates

Publication Date
20260507
Application Date
20231012
Priority Date
20221014

Claims (15)

  1. 1 . A sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the sulfoximine compound is represented by formula I below: in above formula I, R 1 is CF 2 H or CF 3 ; L 1 is —(C 1-3 alkylene)-, —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(C 1-3 alkylene)-, —C(═O)N(R a )—, R a is H or C 1-6 alkyl; Q 1 and Q 2 are each independently CH or N; a, b, c, d and k are each independently 1 or 2; {circle around (A)} is C 3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, C 6 -C 12 aryl, —(C 1-3 alkylene)C 6 -C 12 aryl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or a 9- to 12-membered fused ring group including a structure in which an aromatic ring group and a non-aromatic ring group are fused; at least one H of above {circle around (A)} may be each independently substituted with C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-12 cycloalkenyl, C 1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S (in which at least one H of heterocycloalkyl may be substituted with —C(═O)(C 1-6 alkyl), 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, —CF 3 , —S(CF 3 ), halogen or —S(═NH)(═O)R c ; R c is H or C 1-6 alkyl; {circle around (B)} is C 6 -C 12 aryl or 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; at least one H of above {circle around (B)} may be each independently substituted with C 1-6 alkyl or halogen; {circle around (D)} is at least one H of above {circle around (D)} may be each independently substituted with C 1-6 alkyl or halogen; Z is CH or N; m and n are each independently 0, 1 or 2; p, q, r, s and t are each independently 1 or 2; L 2 is a single bond, —(C═O)—, —C(═O)O—, —C(═O)O—(C 1-3 alkylene)- or —S(═O) 2 —; R 2 is H, C 1-6 alkyl, C 6 -C 12 aryl, CF 3 or —(P═O)(OR b ) 2 ; R b is H or C 1-6 alkyl; and R 3 is C 1-6 alkyl.
  2. 2 . The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 , wherein: L 1 is —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(C 1-3 alkylene)-, —C(═O)N(R a )—, {circle around (A)} is C 6 -C 12 aryl, —(C 1-3 alkylene)C 6 -C 12 aryl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or Y 1 , Y 2 and Y 3 are each independently —CH 2 — or —O—; at least one H of above {circle around (A)} may be each independently substituted with C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S {in which at least one H of heterocycloalkyl may be substituted with —C(═O)(C 1-6 alkyl)}, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, —CF 3 , —S(CF 3 ), halogen or —S(═NH)(═O)R c ; {circle around (B)} is C 6 -C 12 aryl or 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; at least one H of above {circle around (B)} may be each independently substituted with halogen; {circle around (D)} is {in which, in at least one H of may be each independently substituted with C 1-6 alkyl or halogen}, and R 1 , R 2 , R 3 , R a , R b , R c , Q 1 , Q 2 , L 2 , Z, a, b, c, d, k, m, n, p, q, r, s and t are same as defined in claim 1 , respectively.
  3. 3 . The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 , wherein the sulfoximine compound is represented by formula Ia below: in above formula Ia, L 1 is —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(C 1-3 alkylene)-, —C(═O)N(R a )—, {circle around (A)} is C 6 -C 12 aryl, —(C 1-3 alkylene)C 6 -C 12 aryl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or a 9- to 12-membered fused ring group including a structure in which an aromatic ring group and a non-aromatic ring group are fused; at least one H of above {circle around (A)} may be each independently substituted with C 1-6 alkyl, C 1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S {in which at least one H of heterocycloalkyl may be substituted with —C(═O)(C 1-6 alkyl)}, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, —CF 3 , —S(CF 3 ), halogen or —S(═NH)(═O)R c ; and Z 1 , Z 2 , Z 3 and Z 4 are each independently CH, CX or N, in which at least one of Z 1 to Z 4 is CX or N; X is halogen; {circle around (E)} is in above at least one H of may be substituted with C 1-6 alkyl; and R 1 , R 2 , R 3 , R a , R c , Q 1 , Q 2 , L 2 , Z, k, m, n, p, q, r, s and t are same as defined in claim 1 , respectively.
  4. 4 . The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 3 , wherein in above formula Ia: Z 1 is CX or N; Z 2 is CH, CX or N; Z 3 and Z 4 are each independently CH or N; X is halogen; L 1 is —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(C 1-3 alkylene)-, —C(═O)NH—, {circle around (A)} is C 6 -C 12 aryl, benzyl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, or Y 1 , Y 2 and Y 3 are each independently —CH 2 — or —O—; At least one H of above {circle around (A)} may be each independently substituted with C 1-6 alkyl, C 1-6 alkoxy, 3- to 12-membered heterocycloalkyl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S {in which at least one H of heterocycloalkyl may be substituted with —C(═O)(C 1-6 alkyl)}, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, —CF 3 , —S(CF 3 ), halogen or —S(═NH)(═O)R c ; and R c is same as defined in claim 3 .
  5. 5 . The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 3 , wherein in above formula Ia: Z 1 is CF or N; Z 2 is CH, CF or N; Z 3 and Z 4 are each independently CH or N; L 1 is —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(C 1-3 alkylene)-, —C(═O)NH—, R 2 is H, C 1-6 alkyl, C 6 -C 12 aryl, CF 3 or —(P═O)(OR b ) 2 ; R b is C 1-6 alkyl; {circle around (A)} is C 6 -C 12 aryl, benzyl, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, in above {circle around (A)}, at least one H of C 6 -C 12 aryl or 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S may be each independently substituted with C 1-6 alkyl, C 1-6 alkoxy, 5- to 12-membered heteroaryl including in a ring 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, —CF 3 , —S(CF 3 ), halogen or —S(═NH)(═O)R c ; and R c is C 1-6 alkyl.
  6. 6 . The sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 , wherein the sulfoximine compound is represented by formula Ib below: in above formula Ib {circle around (G)} is Z 5 , Z 6 , Z 7 and Z 8 are each independently CH, CX or N, in which at least one of Z 5 to Z 6 is CX or N; Z 9 is CH 2 , CHX, CX 2 , NR 7 , O or S; R 7 is H or C 1-6 alkyl; X is halogen; {circle around (A)}, R 1 , R 2 , L 2 , Z, m and n are same as defined in claim 1 , respectively.
  7. 7 . A sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the sulfoximine compound is any one selected from the group consisting of compounds shown in table below: Com- pound No. Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92
  8. 8 . A pharmaceutical composition comprising the sulfoximine compound according to claim 1 , stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.
  9. 9 . The pharmaceutical composition according to claim 8 , wherein the composition is for preventing or treating histone deacetylase-mediated diseases.
  10. 10 . The pharmaceutical composition according to claim 9 , 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; circulatory diseases; respiratory diseases; digestive troubles; renal failure; skin and subcutaneous tissue diseases; musculoskeletal system and connective tissue diseases; or teratosis, deformities and chromosomal aberration.
  11. 11 . The pharmaceutical composition according to claim 10 , wherein the endocrinopathy, nutritional and metabolic diseases comprise Wilson's disease, amyloidosis or diabetes; the mental and behavioral disorders comprise depression or Rett syndrome; the neurological diseases comprise central nervous system atrophy, neurodegenerative disease, motor disorder, neuropathy, motor neuron disease, central nervous system demyelinating disease, or Charcot-Marie-Tooth (CMT) disease; the eye and ocular adnexal diseases comprise uveitis; the skin and subcutaneous tissue diseases comprise psoriasis; the musculoskeletal system and connective tissue diseases comprise rheumatoid arthritis, osteoarthritis or systemic lupus erythematosis; the teratosis, deformities and chromosomal aberration comprise autosomal dominant polycystic kidney disease; the infectious disease comprises prion disease; the neoplasm comprises benign tumor or malignant tumor; the circulatory disease comprises atrial fibrillation, stroke, heart failure, or pulmonary hypertension; the respiratory disease comprises asthma or idiopathic pulmonary fibrosis; and the digestive troubles comprise alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease; and the renal failure comprises acute renal failure and chronic renal failure.
  12. 12 . A method for preventing or treating HDAC-mediated diseases including administering the sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 into an individual.
  13. 13 . Use of the sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 for inhibiting histone deacetylase.
  14. 14 . Use of the sulfoximine compound, stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 in preparing a medicament for preventing or treating HDAC-mediated diseases.
  15. 15 . The use according to claim 13 , wherein the histone deacetylase is a histone deacetylase 6 (HDAC6).

Description

TECHNICAL FIELD The present invention relates to a sulfoximine compound having a histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, and a use thereof. BACKGROUND ART 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, histone 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 histone 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). 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 (HDAC1, 2, 3, 8), Class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10) and Class IV (HDAC11). 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 HDACs. 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 II 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 IIb HDACs, is known to be mainly present in cytoplasma and contain a tubulin protein, thus being involved in the deacetylation of a number of non-histone 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 ubiquitinated protein. HDAC6 is known to have a number of non-histone 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: 2579-2589; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. 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: 5051-5055; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978). Most of said zinc binding group is comprised of hydroxamic acid or benzamide, out of which hydroxamic acid derivatives show a strong HDAC inhibitory effect, but have a problem with low bioavailability and serious off-target activity. Benzamide contains aniline, and thus has a problem in that it may produce toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication). Accordingly, unlike the non-selective inhibitors having side effects