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CN-121985947-A - 1,2, 4-Triazole-3-thione inhibitors of TREX2 for the treatment of psoriasis, atopic dermatitis or ichthyosis

CN121985947ACN 121985947 ACN121985947 ACN 121985947ACN-121985947-A

Abstract

The present invention provides a compound of formula (I) wherein A 1 is a group of formula (II) A 2 is a ring system consisting of one or two rings, wherein each ring is saturated, partially saturated or unsaturated and has 5 or 6 members selected from the group consisting of N, O, S, C. NR p 、CR z and C (R z ) 2 ;A 3 represents X 7 -(X 8 ) n ;X 1 represents CR 1 or N; X 2 represents CR 2 or N; X 3 represents CR 3 or N; X 4 represents CR 4 or N; X 5 represents CR 5 or N; X 6 represents CR 6 or N; X 7 represents CR 7 or N; and X 8 represents CR 8 or N, provided that one of X 1 to X 8 , two or three are N, and N is an integer selected from 0 or 1. the invention also provides compounds of formula (Ibis), pharmaceutical compositions comprising the same and methods of preparing the same.

Inventors

  • C. Soler Pratt
  • X. Barry Alonso
  • S. Pitichio
  • F. Xiluera Alfies
  • R. Lavila Griffords
  • O. Kashgaye
  • I. Philgira En Li
  • M. Lopez Kano
  • J. Nodario Rosa

Assignees

  • 巴塞罗那大学
  • 贝尔维特生物医学研究所
  • 加泰罗尼亚高级研究院

Dates

Publication Date
20260505
Application Date
20240426
Priority Date
20230426

Claims (16)

  1. 1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of psoriasis, atopic dermatitis and ichthyosis, Wherein: A 1 is of the formula (III) or (IV) Wherein X 5 represents N or CR 5 and R 3 to R 7 are defined as follows; Or A 1 is of the formula: Wherein K is defined as follows; R 3 to R 7 are independently selected from the group consisting of hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one OR more Z substituents, halogen, OR 9 ;COOR 10 , and cycloalkyl having 3 to 7 members selected from C (R x ) 2 、NR y , O, OR S, provided that at least one OR two members are heteroatoms; or alternatively, the number of the cells to be processed, R 3 and R 4 together with the X 3 and X 4 to which they are attached form a partially saturated or aromatic ring having 5 or 6 members, said ring optionally being substituted with one or more Z substituents, or alternatively, R 4 and R 5 together with the X 4 and X 5 to which they are attached form a partially saturated or aromatic ring having 5 or 6 members, said ring optionally being substituted with one or more Z substituents, or alternatively, R 5 and R 6 together with the X 5 and X 6 to which they are attached form a partially saturated or aromatic ring having 5 or 6 members, said ring optionally being substituted with one or more Z substituents, or alternatively, R 9 and R 10 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C x ) 2 、NR y , O or S, C (O) R 11 , or NR 12 R 13 ; R 11 is selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C x ) 2 、NR y , O or S with 3 to 7 members selected from C, or aryl with five or six members selected from N, O, S and CR w ; R x and R w are independently selected from hydrogen, C (O) R 14 ;C(O)OR 15 ;NR 16 R 17 ;OR 18 , (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents; R y 、R 12 、R 13 、R 16 and R 17 are independently selected from hydrogen, C (O) R 19 ;C(O)OR 20 , (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents; R 14 and R 19 are independently selected from hydrogen, NH 2 ;NHR 21 , (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl, (C 3 -C 7 ) cycloalkyl, or aryl having five or six members selected from N, O, S and CR t ; R 15 and R 20 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C 3 -C 7 ) cycloalkyl optionally substituted with one or more OH, halogen, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl; R 18 is independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C 3 -C 7 ) cycloalkyl optionally substituted with one or more OH, halogen, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl; R 21 is selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl or-O- (C 1 -C 10 ) alkyl substituted (C 3 -C 7 ) cycloalkyl, or aryl having five or six members selected from N, O, S and CR s ;R s is selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl, -O- (C 1 -C 10 ) haloalkyl, (C 2 -C 10 ) alkenyl or (C 2 -C 10 ) alkynyl; R t is selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, -O- (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, and, Halogen, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl substituted (C 3 -C 7 ) cycloalkyl, or aryl having five or six members selected from N, O, S and CR v ;R v selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl, -O- (C 1 -C 10 ) haloalkyl, (C 2 -C 10 ) alkenyl or (C 2 -C 10 ) alkynyl; K is selected from one or more of hydrogen, halogen, (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl, aryl having five or six members selected from N, O, S and CR v ,R v selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl, -O- (C 1 -C 10 ) haloalkyl, (C 2 -C 10 ) alkenyl or (C 2 -C 10 ) alkynyl, or cycloalkyl, optionally substituted with one or more Z substituents, e.g. (C 1 -C 10 ) alkyl or C (O) (C 1 -C 4 ) alkyl, having 3 to 7 members selected from C (R x ) 2 、NR y ), o or S, provided that at least one or both members are heteroatoms, wherein R x and R y are as previously defined, L is selected from- (CH 2 ) p -and-C (O) -; m is an integer selected from 0 or 1; p is an integer selected from 1 to 10, in particular 1 to 5, in particular 1 to 2; A 2 is a ring having any one of the following formulas: Or a ring selected from any of the following: Wherein: X 9 represents NR 34 , O, S or CR z16 ; x 10 represents NR 35 , O, S or CR z17 ; X 11 represents NR 36 , O, S or CR z18 ; R z1 to R z18 are independently selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, -O- (C 1 -C 10 ) haloalkyl, (C 1 -C 10 ) haloalkyl, O (CH 2 )R 22 ;C(O)R 23 ;SO 2 NR 24 R 25 ,OH,NR 24 R 25 ; aryl including ortho-aryl such as phenoxy or benzyloxy, having five or six members selected from N, O, S and CR e ,R e selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl, or cycloalkyl having 5 or 6 members selected from NH, O, S and C (R b ) 2 ; R 22 to R 25 and R b are independently selected from hydrogen, halogen, OH, NR 37 R 38 , (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, -O- (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, -cycloalkyl ring having 3 to 7 members selected from C (R' b )2、NR' c , O or S), or aryl having five or six members selected from N, O, S and CR f ;R f selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl, -O- (C 1 -C 10 ) haloalkyl, (C 2 -C 10 ) alkenyl or (C 2 -C 10 ) alkynyl; R 37 、R 38 、R' b and R' c are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (C 3 -C 7 ) cycloalkyl optionally substituted with one or more Z substituents, (C 1 -C 10 ) aryl having five or six members selected from N, O, S and CR g ;R g is selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl, -O- (C 1 -C 10 ) haloalkyl, (C 2 -C 10 ) alkenyl or (C 2 -C 10 ) alkynyl, and R 34 、R 35 and R 36 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, and (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents.
  2. 2. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to claim 1, wherein a 1 is formula (III) or (IV) Wherein X 5 represents N or CR 5 and R 3 to R 7 are as defined in claim 1.
  3. 3. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to claim 1 or 2, wherein a 1 is of formula (III) or (IV) Wherein X 5 represents CR 5 and R 3 to R 7 are as defined in claim 1.
  4. 4. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to claim 1 or 2, wherein A 1 is of formula (III), and R 3 to R 6 are selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted by one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted by one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted by one or more Z substituents, or-O- (C 1 -C 10 ) alkyl optionally substituted by one or more Z substituents, in particular R 3 to R 6 are hydrogen.
  5. 5. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 3, wherein, A 1 is of formula (IV), and R 3 to R 7 are independently selected from hydrogen, halogen, OH, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, or alternatively, R 3 and R 4 are fused together to form an aromatic ring system together with the carbon atom to which they are attached, and R 5 、R 6 and R 7 are independently selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, or alternatively, X 5 is CR 5 ;R 5 and R 6 are fused together to form an aromatic ring system together with the carbon atom to which they are attached, and R 3 、R 4 and R 7 are independently selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents.
  6. 6. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use according to any one of the preceding claims, wherein a 1 is as defined in claims 2 to 5, and a 2 is an aryl ring of formula (V), (VI), (VII) or (VIII): Wherein: X 9 represents NR 34 , O, S or CR z16 ; x 10 represents NR 35 , O, S or CR z17 ; X 11 represents NR 36 , O, S or CR z18 ; R z1 to R z18 are independently selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, (O (CH 2 ) a R 22 ;C(O)R 23 ;SO 2 NR 24 R 25 ), aryl having five or six members selected from N, O, S and CR e ,R e is selected from hydrogen, OH, halogen, (C 1 -C 10 ) alkyl, -O- (C 1 -C 10 ) alkyl, (C 1 -C 10 ) haloalkyl or-O- (C 1 -C 10 ) haloalkyl, or cycloalkyl having 5 or 6 members selected from NH, O, S and C (R b ) 2 ; R 22 to R 25 and R b are as defined in any one of the preceding claims, and R 34 、R 35 and R 36 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, and (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents.
  7. 7. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any one of the preceding claims 1to 6, wherein A 1 is as defined in claims 2 to 5 and a 2 is of formula (V) and R z1 to R z5 are selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (CH 2 )aR 22 ;C 6 aryl; halogen; COOH; or C (O) (C 1 -C 10 ) alkyl and R 22 represents (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents or C 6 aryl, or alternatively, A 1 is as defined in claims 2 to 5, and a 2 is of formula (VI) and R z6 to R z8 are identical, in particular they are hydrogen, or alternatively, A 1 is as defined in claims 2 to 5, and a 2 is formula (VII), a 2 is formula (VII), and R z9 to R z12 are independently selected from hydrogen, halogen, SO 2 NH 2 , or cycloalkyl having 5 or 6 members selected from NH, O, S, and C (R b ) 2 ; particularly R z9 to R z11 are hydrogen, and R z12 is selected from hydrogen, halogen, SO 2 NH 2 , or cycloalkyl having 5 or 6 members selected from NH, O, S, and C (R b ) 2 ; or alternatively, A 1 is as defined in claims 2 to 5, and a 2 is of formula (VIII) and X 9 、X 10 and X 10 are identical, in particular they are CH, or alternatively X 9 and X 11 are identical, in particular they are O.
  8. 8. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any one of the preceding claims 1to 7, wherein R 3 to R 7 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one OR more Z substituents, F, cl, OR 9 ;COOR 10 , OR cycloalkyl having 3 to 7 members selected from C (R x ) 2 、NR y , O OR S, provided that at least one OR two members are heteroatoms, in particular, R 3 to R 7 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, F, or Cl, in particular, R 3 to R 7 are independently selected from hydrogen, (C 1 -C 10 ) alkyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one OR more Z substituents, OR 9 ;COOR 10 , OR cycloalkyl having 3 to 7 members selected from C (R x ) 2 、NR y , O OR S, provided that at least one OR two members are heteroatoms.
  9. 9. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any one of the preceding claims, selected from the group consisting of: [01-001] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-002] 5- (quinolin-2-yl) -4- (4- (trifluoromethyl) phenyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-003] 4- (4-chlorophenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-004] 5- (quinolin-2-yl) -4- (p-tolyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-005] 4- (3-bromophenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-006] 4-benzyl-5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-007] 4-phenyl-5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-008] 1- (4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenyl) ethan-1-one; [01-009] 4- (4-phenoxybenzyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-010] 4- (4-methoxy-2-methylphenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-011] 4- (4-methoxyphenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-012] 4- ([ 1,1' -biphenyl ] -3-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-013] 4- (4- (benzyloxy) phenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-014] 5- (quinolin-2-yl) -4- (thiophen-2-ylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-015] 4- (4-phenoxyphenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-016] 4- (3- (benzyloxy) phenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-017] 4- (2, 3-dihydro-1H-inden-5-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-018] 4- (6-chloropyridin-3-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-019] 4- (6- (piperazin-1-yl) pyridin-3-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-020] phenyl (3- (quinolin-2-yl) -5-thioxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methanone; [01-021] (4-chlorophenyl) (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methanone; [01-022] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-023] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-024] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (5-methylimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-025] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-methylimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-026] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (4- (trifluoromethoxy) benzyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-027] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (2, 3-dihydro-1H-inden-5-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-028] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (4-phenoxyphenyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-029] 4- (4- (benzyloxy) phenyl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-030] 4- (3- (benzyloxy) phenyl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-031] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (4-methoxy-2-methylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-032] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (6-chloropyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-033] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (6- (pyrrolidin-1-yl) pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-034] 4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid; [01-035] 4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; [01-036] (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) (phenyl) methanone; [01-037] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [2,1-a ] isoquinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-038] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [1,2-a ] quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-039] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [1,2-a ] pyrazin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; n- (4, 6-dimethylpyrimidin-2-yl) -4- (3- (quinolin-2-yl) -5-thioxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; N- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; N- (4-methoxy-1, 2, 5-thiadiazol-3-yl) -4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; 3- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid; 4- (4- ((1H-1, 2, 4-triazol-1-yl) methyl) phenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (2-hydroxyquinolin-4-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [1-050] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (2-methylquinolin-4-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-051] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-bromoimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-052] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (thiophen-2-ylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-053] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (1-methyl-1H-pyrazol-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-054] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (2, 2-diphenylethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-055] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (3-morpholinopropyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-056] 3- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid; [01-057] 3- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzamide; [01-058] 5- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) -2-methoxybenzoic acid; [01-059] 5- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) -2-methoxybenzamide; [01-060] 4- (4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenoxy) picolinic acid; [01-061] 4- (4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenoxy) -N-methylpyridine carboxamide; [01-062] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-063] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (2-chloropyridin-4-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-064] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6-chloropyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-065] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-066] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-067] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6-morpholinopyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-068] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6-chloropyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-069] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6- (piperazin-1-yl) pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-070] 1- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperazin-1-one; [01-071] (3 ar,4r,6 as) -4- (5- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperazin-1-yl) -5-oxopentyl) tetrahydro-1H-thieno [3,4-d ] imidazol-2 (3H) -one; [01-072] 1- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -piperazin-1-yl) -3- (5, 5-difluoro-7- (1H-pyrrol-2-yl) -5H-5l 4 ,6l 4 -bipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaborolan-3-yl) propan-1-one; [01-073] 4- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperazin-1-yl) -N- (4- (5, 5-difluoro-1, 3,7, 9-tetramethyl-5H-4 l 4 ,5l 4 -dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaborolan-10-yl) phenyl) -4-oxobutanamide; And any pharmaceutically acceptable salt or solvate thereof, in particular the sodium salt thereof.
  10. 10. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any one of the preceding claims, selected from the group consisting of: [01-001] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-022] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-058] 5- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) -2-methoxybenzoic acid; [01-060] 4- (4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenoxy) picolinic acid; N- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; And any pharmaceutically acceptable salt or solvate thereof, in particular the sodium salt thereof.
  11. 11. A compound of formula (I) as defined in any one of claims 1 to 10 for use in therapy, provided that the compound is not selected from any one of the following list of compounds: [01-001] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-008] 1- (4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenyl) ethan-1-one; n- (4, 6-dimethylpyrimidin-2-yl) -4- (3- (quinolin-2-yl) -5-thioxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; N- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide, and N- (4-methoxy-1, 2, 5-thiadiazol-3-yl) -4- (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide.
  12. 12. Formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof (Ibis) Wherein: a 1bis is a group of formula (IVbis): Wherein: (i) R 3 、R 5 to R 7 are independently selected from hydrogen, halogen, OH, (C 1 -C 10 ) alkyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one OR more Z substituents, (OR 9 ;COOR 10 ), and cycloalkyl ring having 3 to 7 members selected from C (R x ) 2 、NR y , O OR S, provided that at least one OR two members are heteroatoms, and R' 4 is selected from hydrogen, F, cl, OH, (C 1 -C 10 ) alkyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one OR more Z substituents, (C 2 -C 10 ) alkynyl optionally substituted with one OR more Z substituents, OR 9 ;COOR 10 , and cycloalkyl rings having 3 to 7 members selected from C (R x ) 2 、NR y , O, OR S, provided that at least one OR two members are heteroatoms; or alternatively, the number of the cells to be processed, (Ii) R 3 and R' 4 are fused together to form an aromatic ring system with the carbon atom to which they are attached, and R 5 、R 6 and R 7 are independently selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, or alternatively, (Iii) X 5 is CR 5 ;R 5 and R 6 are fused together to form an aromatic ring system with the carbon atom to which they are attached, R 3 and R 7 are independently selected from hydrogen, halogen, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents, and R' 4 is selected from hydrogen, F, cl, (C 1 -C 10 ) alkyl optionally substituted with one or more Z substituents, (C 2 -C 10 ) alkenyl optionally substituted with one or more Z substituents, or (C 2 -C 10 ) alkynyl optionally substituted with one or more Z substituents; a 2 is of formula (V), (VI), (VII) or (VIII), as defined in any of the preceding claims 6 to 7, and L and m are as defined in claim 1.
  13. 13. A compound as defined in any one of claims 1 to 10 selected from: [01-002] 5- (quinolin-2-yl) -4- (4- (trifluoromethyl) phenyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-004] 5- (quinolin-2-yl) -4- (p-tolyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-005] 4- (3-bromophenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-007] 4-phenyl-5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-009] 4- (4-phenoxybenzyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-010] 4- (4-methoxy-2-methylphenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-012] 4- ([ 1,1' -biphenyl ] -3-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-013] 4- (4- (benzyloxy) phenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-014] 5- (quinolin-2-yl) -4- (thiophen-2-ylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-015] 4- (4-phenoxyphenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-016] 4- (3- (benzyloxy) phenyl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-017] 4- (2, 3-dihydro-1H-inden-5-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-018] 4- (6-chloropyridin-3-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-019] 4- (6- (piperazin-1-yl) pyridin-3-yl) -5- (quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-020] phenyl (3- (quinolin-2-yl) -5-thioxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methanone; [01-021] (4-chlorophenyl) (3- (quinolin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) methanone; [01-022] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-023] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-024] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (5-methylimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-025] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-methylimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-026] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (4- (trifluoromethoxy) benzyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-027] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (2, 3-dihydro-1H-inden-5-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-028] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (4-phenoxyphenyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-029] 4- (4- (benzyloxy) phenyl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-030] 4- (3- (benzyloxy) phenyl) -5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-031] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (4-methoxy-2-methylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-032] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (6-chloropyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-033] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (6- (pyrrolidin-1-yl) pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-034] 4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid; [01-035] 4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzenesulfonamide; [01-036] (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) (phenyl) methanone; [01-037] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [2,1-a ] isoquinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-038] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [1,2-a ] quinolin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-039] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (imidazo [1,2-a ] pyrazin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-040] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (2-methylquinolin-4-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-050] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (2-methylquinolin-4-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-051] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (7-bromoimidazo [1,2-a ] pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-052] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (thiophen-2-ylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-053] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (1-methyl-1H-pyrazol-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-054] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (2, 2-diphenylethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-055] 5- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -4- (3-morpholinopropyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-056] 3- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid; [01-057] 3- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzamide; [01-058] 5- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) -2-methoxybenzoic acid; [01-059] 5- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) -2-methoxybenzamide; [01-060] 4- (4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenoxy) picolinic acid; [01-061] 4- (4- (3- (7-chloroimidazo [1,2-a ] pyridin-2-yl) -5-thio-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) phenoxy) -N-methylpyridine carboxamide; [01-063] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (2-chloropyridin-4-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-064] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6-chloropyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-065] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-066] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-067] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6-morpholinopyridin-3-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-068] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6-chloropyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-069] 4- (benzo [ d ] [1,3] dioxol-5-yl) -5- (6- (piperazin-1-yl) pyridin-2-yl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione; [01-070] 1- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperazin-1-one; [01-071] (3 ar,4r,6 as) -4- (5- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperazin-1-yl) -5-oxopentyl) tetrahydro-1H-thieno [3,4-d ] imidazol-2 (3H) -one; [01-072] 1- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -piperazin-1-yl) -3- (5, 5-difluoro-7- (1H-pyrrol-2-yl) -5H-5l 4 ,6l 4 -bipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaborolan-3-yl) propan-1-one; [01-073] 4- (4- (6- (4- (benzo [ d ] [1,3] dioxol-5-yl) -5-thio-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperazin-1-yl) -N- (4- (5, 5-difluoro-1, 3,7, 9-tetramethyl-5H-4 l 4 ,5l 4 -dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaborolan-10-yl) phenyl) -4-oxobutanamide; And any pharmaceutically acceptable salt or solvate thereof, in particular the sodium salt thereof.
  14. 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 12 to 13, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  15. 15. A compound as defined in any one of claims 12 to 13 for use in diagnosis or as a research tool.
  16. 16. A method of inhibiting TREX2 activity in an isolated sample of a subject in vitro, the method comprising the step of contacting the isolated sample with any of the compounds as defined in any one of claims 12 to 13, or a pharmaceutically acceptable salt or solvate thereof.

Description

1,2, 4-Triazole-3-thione inhibitors of TREX2 for the treatment of psoriasis, atopic dermatitis or ichthyosis Technical Field The present invention provides compounds suitable as TREX2 inhibitors, as well as methods for their preparation, pharmaceutical compositions, and their use in therapy, particularly in the treatment of skin and mucosal inflammation. Background DNA replication, repair and recombination and DNA degradation are essential tasks during the life of the cell. A variety of proteins are involved in these processes, with 3'-5' exonucleases playing an important role. 3' Exonuclease 2 (Three-PRIME REPAIR exonuclease, TREX 2) is a non-progressive 3' -5' exonuclease, homologous to TREX1, with similar biochemical features. The preferred substrates for both proteins are DNA rather than RNA, and may be single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA) (Mazur & Perrino, 2001). However, TREX1 and TREX2 exhibit different tissue expression profiles and biological functions. TREX1 is ubiquitously expressed and exerts anti-inflammatory effects (Morita et al, 2004; gal et al, 2012), whereas TREX2 is restricted in expression in squamous epithelial tissue (such as skin, particularly keratinocytes) and exerts pro-inflammatory effects (Parra et al, 2009; manils et al, 2016). In particular, TREX2 shapes skin physiology by promoting DNA degradation and further cell death in damaged and stressed keratinocytes, thereby promoting skin inflammation in psoriasis (Manils et al, 2016). Trex2 knockout mice were able to survive and showed no relevant differences compared to wild-type counterparts in terms of growth, survival, lymphocyte development, or spontaneous tumor incidence (Parra et al, 2009), supporting the critical role of Trex2 in compromised keratinocytes rather than under basal conditions. When TREX2 expression becomes abnormal, its importance in skin homeostasis emerges. TREX2 is, for example, overexpressed in psoriasis (Manils et al, 2016). Consistently, in a mouse model of psoriasis, inflammation was induced using imiquimod or IL-23, and it has been found that Trex2 knockout mice have significantly reduced signs of psoriatic inflammation (e.g. erythema or epidermal thickness) (Manils et al, 2016). In addition, reduced transcription of inflammation-associated genes such as IL-23 and TNF- α, and inhibition of keratinocyte apoptosis have been observed (Manils et al, 2016). In fact, dying keratinocytes release a variety of signals that help trigger and amplify skin inflammation (PASPARAKIS et al, 2014). Overall, the data indicate that TREX2 plays a key role in promoting the inflammatory psoriasis phenotype, highlighting this keratinocyte-limiting exonuclease as a novel therapeutic target for psoriasis. Furthermore, analysis of existing transcriptome data showed that TREX2 expression was increased in at least two other chronic skin inflammatory diseases, such as ichthyosis (Krieg et al, 2020, kim et al, 2022) and atopic dermatitis (Esaki et al, 2015). Importantly, a significant Spearman correlation has been shown to exist between TREX2 expression and severity score for atopic dermatitis (Tsoi et al, 2019). These expression data also highlight TREX2 as a potential target for ichthyosis and atopic dermatitis. Regarding the role of TREX2 in cancer, upregulation of TREX2 in colorectal cancer is associated with reduced survival (Song et al 2022). On the other hand, transcriptome analysis showed increased TREX2 expression (GSE 19567) in K562 leukemia cell line following treatment with nilotinib, a BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia treatment. TREX2 has been more of a prognostic or diagnostic marker of the above disease management than a therapeutic target to date. In addition, TREX2 protein is being used as a tool to increase CRISPR/Cas9 editing efficiency (Yin et al 2022). In view of the above, there is a need to provide molecules that are capable of effectively inhibiting TREX2 activity and providing therapeutic benefits in a pathological environment. Disclosure of Invention The inventors found that 1,2, 4-triazole-3-thione compounds have potent TREX2 inhibitory activity when the 4-and 5-positions are substituted with a ring system. As shown below, compounds forming part of the present invention were tested for their efficacy in effectively and selectively inhibiting TREX2 on recombinant TREX2 and TREX1 proteins. The data are shown in tables 1 and 2 below. In one aspect, the test compounds of the invention were found to be effective in inhibiting TREX2 exonuclease activity, providing IC 50 values below 30 μm, with IC 50 values approaching 1 μm for the most potent compounds, as shown in table 1 below. On the other hand, the inventors have demonstrated that these compounds are selective in inhibiting TREX2 over TREX1 exonuclease. As shown in table 2 below, the most potent TREX2 inhibitors have an IC 50 value for TREX1 greater than 100 μm, about 100 times the IC 50 value for TREX 2. T