EP4701635A1 - 1,2,4-triazole-3-thione inhibitors of trex2 for use in the treatment of psoriasis, atopic dermatitis or ichthyosis - Google Patents

1,2,4-triazole-3-thione inhibitors of trex2 for use in the treatment of psoriasis, atopic dermatitis or ichthyosis

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Publication number
EP4701635A1
EP4701635A1 EP24725409.7A EP24725409A EP4701635A1 EP 4701635 A1 EP4701635 A1 EP 4701635A1 EP 24725409 A EP24725409 A EP 24725409A EP 4701635 A1 EP4701635 A1 EP 4701635A1
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Prior art keywords
dihydro
optionally substituted
substituents
thione
triazole
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EP24725409.7A
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German (de)
French (fr)
Inventor
Concepció SOLER PRAT
Xavier BARRIL ALONSO
Serena PITICCHIO
Francisco Ciruela Alferez
Rodolfo Lavilla Grifols
Ouldouz GHASHGHAEI
Ingrid FILGAIRA ENRI
Marc LÓPEZ-CANO
Jaime NOTARIO ROSA
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Institut De Recerca Biomedica De Bellvitge
Universitat de Barcelona UB
Institucio Catalana de Recerca i Estudis Avancats ICREA
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Institut De Recerca Biomedica De Bellvitge
Universitat de Barcelona UB
Institucio Catalana de Recerca i Estudis Avancats ICREA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides compounds of formula (I) for use in the treatment or prevention of a pathological condition related to an increase in TREX2 expression and activity, wherein: A1 is a group of formula (II); A2 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, NRp, CRz, and C(Rz)2; A3 represents X7-(X8)n; X1 represents CR1 or N; X2 represents CR2 or N; X3 represents CR3 or N; X4 represents CR4 or N; X5 represents CR5 or N; X6 represents CR6 or N; X7 represents CR7 or N; and X8 represents CR8 or N; provided that one, two or three of X1 to X8 are N; n is an integer number selected from 0 or 1. The present invention also provides compounds of formula (Ibis), as well as pharmaceutical compositions comprising thereof and processes for their preparation.

Description

1,2,4-TRIAZOLE-3-THIONE INHIBITORS OF TREX2 FOR USE IN THE TREATMENT OF PSORIASIS, ATOPIC DERMATITIS OR ICHTHYOSIS
Field of the Invention
The present invention provides compounds suitable as TREX2 inhibitors, as well as processes for their preparation, pharmaceutical compositions, and uses thereof in therapy, particularly in the treatment of skin and mucosal inflammation.
Background of the invention
During the life of a cell, DNA replication, repair, and recombination, as well as DNA degradation, are essential tasks. Several proteins participate in these processes, and among them, 3’-5’-exonucleases play an important role.
Three-prime repair exonuclease 2 (TREX2) is a non-processive 3’-5’ exonuclease that is homologous to TREX1 , sharing similar biochemical characteristics. The preferred substrate for both proteins is DNA over RNA, and can be single-stranded DNA (ssDNA) or double stranded DNA (dsDNA) (Mazur & Perrino, 2001). However, TREX1 and TREX2 display different tissue expression profiles and biological functions. While TREX1 is ubiquitously expressed and plays an anti-inflammatory role (Morita et al., 2004; Gall et al., 2012), TREX2 shows restricted expression in squamous epithelial tissues such as skin, specifically in keratinocytes, where it plays a pro-inflammatory role (Parra et al., 2009; Manils et al., 2016). In particular, TREX2 shapes skin physiology by favouring DNA degradation and further cell death in damaged and stressed keratinocytes and thus promoting skin inflammation in psoriasis (Manils et al., 2016). Trex2 knockout mice are viable and do not show relevant differences in growth, survival, lymphocyte development, or spontaneous tumour incidence compared to their wild-type counterparts (Parra et al., 2009), supporting the critical role of TREX2 in keratinocytes under threats rather than under basal conditions.
The importance of the exonuclease TREX2 in skin homeostasis is apparent when its expression becomes aberrant. For example, TREX2 is overexpressed in psoriasis (Manils et al., 2016). Consistently, in murine models of psoriasis, with imiquimod or IL-23 induced inflammation, Trex2 knockout mice have been found to show a significant reduction of signs of psoriatic inflammation such as erythema or epidermal thickness (Manils et al., 2016). In addition, decreased transcription of inflammation-related genes, such as IL-23 and TNF-a, and inhibition of keratinocyte apoptosis was observed (Manils et al., 2016). In fact, dying keratinocyte cells release a variety of signals that contribute to trigger and amplify skin inflammation (Pasparakis et al., 2014). Overall, data indicate that TREX2 plays a critical role in promoting the inflammatory psoriatic phenotype, highlighting this keratinocyte-restricted exonuclease as a new therapeutic target for psoriasis.
Furthermore, analysis of available transcriptomic data has revealed that TREX2 expression is 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 between TREX2 expression and the severity score of atopic dermatitis has been shown (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 has been associated with reduced survival (Song et al., 2022). On the other hand, transcriptomic analysis revealed increased TREX2 expression in the K562 leukemia cell line after treatment with Nilotinib, a BCR-ABL tyrosine kinase inhibitor used for chronic myeloid leukemia therapy (GSE19567).
Up to now, TREX2 has been considered as a prognostic or diagnostic marker more than a therapeutic target for the management of the above diseases. In addition, TREX2 protein is being used as a tool to improve the efficiency of CRISPR/Cas9 editing (Yin et al., 2022).
In view of the above, there is the need of providing molecules which can efficiently inhibit TREX2 activity in a pathologic environment and can provide a therapeutic benefit.
SUMMARY OF THE INVENTION
The present inventors have found 1 ,2,4-triazole-3-thione compounds having a potent TREX2 inhibitory activity when they are substituted at positions 4 and 5 with ring systems.
As shown below, the potency of the compounds forming part of the invention to inhibit effectively and selectively TREX2 was determined on recombinant TREX2 and TREX1 proteins. The data are provided in Tables 1 and 2 below.
On the one hand, the compounds tested in the invention were found to be potent in inhibiting TREX2 exonuclease activity, providing IC50 values lower than 30 μM and close to 1 μM for the compounds with the highest potency, as shown in Table 1 below.
On the other hand, the inventors have proved that these compounds were selective in inhibiting TREX2 over TREX1 exonuclease. As shown in Table 2 below, the IC50 value for TREX1 of the most potent TREX2 inhibitors was greater than 100 μM, about 100-fold higher than the IC50 value for TREX2. This means that at the dose at which the compound of the invention inhibits TREX2, no significant effect on TREX1 would occur. Therefore, the compounds of the invention are not only potent, but also selective towards TREX2 over TREX1.
As explained above, TREX2 and TREX1 are homologous proteins that display similar biochemical and enzymatic properties, although these two exonucleases play distinct biological roles and show a differential pattern of tissue expression. In particular, TREX2, specifically expressed in keratinocytes, acts as a skin proinflammatory player, whereas TREX1 , ubiquitously expressed across cell types and tissues, has a broad anti-inflammatory function.
The above in vitro findings about the efficacy as TREX2 inhibitors was also confirmed in vivo in a well-established mouse model of psoriasis, wherein the compounds of the invention were tested when administered either orally, topically, or intraperitoneally. In all tested cases, a significant improvement in the condition (reduction of psoriasis-induced inflammation) was detected. In fact, all in vivo tested compounds of the invention reduced psoriasis inflammation related to TREX2 overexpression and subsequent increased activity. Specificity is supported by the absence of anti-inflammatory action of the compounds in the absence of TREX2 (Trex2 deficient mice).
The data provided below also indicate the suitability as pharmacological agents as they do not show broad cytotoxicity.
In view of the above, in a first aspect the present invention (1.1) provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: for use in the treatment of a pathological condition related to an increase in TREX2 expression, wherein:
Ai is a group of formula (II):
wherein:
A3 represents X7-(Xs)n;
Xi represents CR1 or N; X2 represents CR2 or N; X3 represents CR3 or N; X4 represents CR4 or N; X5 represents CR5 or N; Xe represents CR6 or N; X7 represents CR7 or N; Xs represents CRs or N; provided that one, two or three of Xi to Xs are N; n is an integer number selected from 0 or 1 ;
R1 to Rs are independently selected from the group consisting of: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; halogen; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively,
R3 and R4 form, together with X3 and X4 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
R4 and R5 form, together with X4 and X5 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rs and Re form, together with X5 and Xe to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rg and R10 are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; C(O)R11; or NR12R13;
R11 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRW;
Rx and Rw are independently selected from hydrogen; C(O)Ri4; C(O)ORis; NRwRw; ORw; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2- C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
Ry, R12, R13, RW, and R^are independently selected from hydrogen; C(0)Rw; C(0)OR2o; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
R14 and Rw are independently selected from hydrogen; NH2; NHR21; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1- C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRt
R15 and R20 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl;
Rw are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2- Cio)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; R21 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- C10)alkynyl, or -O-(C1-C10)alkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRS; being Rs selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Rt is selected from hydrogen; OH; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O- (C1-C10)alkyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRV; being Rv selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
L is selected from the group consisting of: -(CH2)P-, and -C(O)-; m is an entire number selected from 0 or 1 ; p is an entire number selected from 1 to 10, particularly from 1 to 5, particularly from 1 to 2;
A2 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, NRP, CRZ, and C(RZ)2; when the ring system consists of two rings, they are fused or isolated; and
Rp is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more Z substituents; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRd; being Rd selected from OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1- Cio)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl; Rz is selected from hydrogen; halogen; O(CH2)aR22; C(O)R23; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; SO2NR24R25; a cycloalkyl ring having from 3 to 7 members selected from C(Rb)2, NRC, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRe; being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl; a is an integer number representing 0 or 1 ;
R22, R23, and Rb are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; NR37R38; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; a cycloalkyl ring having from 3 to 7 members selected from C(R’b)2, NR’c, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRf; being Rf selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
R24, R25, Rb, Rc, R37, R38 and R’c are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more Z substituents; an aryl having five or six members selected from the group consisting of: N, O, S, and CRg; being Rg selected from hydrogen, OH, halogen, (C-i-Cio)alkyl, -O-(C1- C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Z is selected from the group consisting of: (C1-C10)alkyl; -O-(C1-C10)alkyl; (C1- Cio)haloalkyl; -O-(C1-C10)haloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; halogen; OR26; COOR27; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1- Cio)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, (C2- Cio)alkynyl, COOR28, NH2, or NHR29; an aryl optionally substituted with one or more OH, halogen, NH2, NHR30, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1- Cio)haloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, or COOR31; and a heteroaryl optionally substituted with one or more OH, halogen, NH2, NHR32, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, or COOR33; R26 to R28 and R31 to R33 are independently selected from hydrogen; (C1-C10)alkyl; (C1- Cio)haloalkyl; (C2-C10)alkenyl; and (C2-C10)alkynyl;
R29, R30, and R32 are independently selected from hydrogen, (C1-C10)alkyl; (C1- Cio)haloalkyl; (C2-C10)alkenyl; or (C2-C10)alkynyl; and
This aspect can be formulated as the use of a compound of formula (I) as defined above in the manufacture of a medicament for treating a pathological condition associated to an overexpression of TREX2. This aspect can also be formulated as a method for treating a pathological condition associated to an overexpression of TREX2, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I) as defined above to a subject in need thereof.
In a second aspect the present invention (1.2) provides a compound of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof: wherein:
Awis is a group of formula (IVbis): (IVbis) wherein: (i) R3, Rs to R? are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; and
R’4 is selected from hydrogen; F; Cl; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively
(ii) R3 and R’4 are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
(iii) X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached an aromatic ring system; R3 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; and R’4 is selected from hydrogen, F, Cl, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
A2, L and m are as defined in the first aspect of the invention.
In a third aspect the present invention (1.3) provides a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in the second aspect of the invention and one or more pharmaceutically acceptable excipient or carrier.
In a fourth aspect the present invention (1.4) provides a compound as defined in the second aspect of the invention for use in therapy or as a research tool in biotechnological applications.
For instance, TREX2 protein is being used as a tool to improve the efficiency of CRISPR/Cas9 editing. TREX2 exonuclease promotes DNA end resection avoiding precise ligation and perfect DNA repair. In this context, the inhibition of TREX2 could be used to tightly control TREX2 activity in this biotechnological assay.
In a fifth aspect the present invention (1.5) provides a kit comprising a compound as defined in the first or second aspect of the invention together with means for determining TREX2 activity.
In a final aspect the present invention (1.6) provides an in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, the method comprising the step of contacting the isolated sample with any of the compounds of formula (I), (Ibis) or pharmaceutically acceptable salt or solvate thereof, as defined in the first and second aspects of the invention.
Alternatively and separately to the above aspects, the present invention relates to the following further alternative aspects:
In an alternative first aspect (2.1), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: for use in the treatment or prevention of a disease caused by an increase in TREX2 expression, preferably selected from the list consisting of psoriasis, atopic dermatitis and ichthyosis, wherein:
Ai is of formula (III) or (IV) wherein X5 represents N or CR5, and R3 to R? are as defined below; or A1 is of formula: wherein K is as defined below; and wherein:
R3to R?are independently selected from the group consisting of: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; halogen; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively,
R3 and R4 form, together with X3 and X4 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
R4 and R5 form, together with X4 and X5 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rs and Re form, together with X5 and Xe to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rg and R10 are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; C(O)Rii; or NR12R13;
Rn is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRW;
Rx and Rw are independently selected from hydrogen; C(O)Ri4; C(O)ORis; NRwRw; ORw; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2- C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
Ry, R12, R13, RW, and R^are independently selected from hydrogen; C(0)Rw; C(0)OR2o; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
R14 and Rw are independently selected from hydrogen; NH2; NHR21; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1- C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRt
R15 and R20 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl;
Rw are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2- C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl;
R21 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- C10)alkynyl , or -O-(C1-C10)alkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRS; being Rs selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Rt is selected from hydrogen; OH; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O- (C1-C10)alkyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRV; being Rv selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
K is selected from one or more of hydrogen, halogen, (C1-C10)alkyl , (C2-C10)alkenyl, (C2- Cio)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl, an aryl having five or six members selected from the group consisting of: N, O, S, and CRV; being Rv selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl; or a cycloalkyl, optionally substituted with one or more Z substituents such as a (C1-C10)alkyl or a C(O)(Ci-C4)alkyl, having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; wherein Rx and Ry are as defined before; L is selected from the group consisting of: -(CH2)P-, and -C(O)-; m is an entire number selected from 0 or 1 ; p is an entire number selected from 1 to 10, particularly from 1 to 5, particularly from 1 to 2;
A2 is a ring having any of the following formulae:
or any one of the following rings: wherein: X9 represents NR34, O, S or CRzie;
X10 represents NR35, O, S or CRzi?;
Xu represents NR36, O, S or CRzis;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents, - 0-(C1-C10)haloalkyl, (C1-C10)haloalkyl, O(CH2)R22; C(O)R23; SO2NR24R25, OH, NR24R25; an aryl, including an o-aryl such as a phenoxy or a benzyloxy, having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2;
R22 to R25, and Rb are independently selected from hydrogen; halogen; OH; NR37R38; (C1- Cio)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; a cycloalkyl ring having from 3 to 7 members selected from C(R’b)2, NR’C, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRf; being Rf selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O- (C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
R37, R38, R’b and R’c are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more Z substituents; an aryl having five or six members selected from the group consisting of: N, O, S, and CRg; being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1- Cio)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl; and
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents.
In a preferred embodiment of the alternative first aspect of the invention, Ai is of formula (III) or (IV) wherein X5 represents N or CR5, and R3 to R? are as defined in claim 1.
In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, Ai is of formula (III) or (IV) wherein X5 represents CR5, and R3 to R? are as defined in claim 1.
In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, A1 is of formula (III), and
R3 to Re are selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; or -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; particularly R3 to Re are hydrogen.
In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, A1 is of formula (IV), and
R3 to R? are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively
R3 and R4 are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1- C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R3, R4 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents.
In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, Ai is of formula (III) or (IV) and A2 is an aryl ring of formula (V), (VI), (VII) or (VIII): wherein: X9 represents NR34, O, S or CRz16;
X10 represents NR35, O, S or CRz17;
Xu represents NR36, O, S or CRz18;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; O(CH2)aR22; C(O)R23; SO2NR24R25; an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2;
R22 to R25, and Rb are as defined in any of the preceding claims; and
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents. In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, Ai is of formula (III) or (IV) and
A2 is of formula (V), and Rzi to Rzs are selected from hydrogen; (C1-C10)alkyl optionally substituted by one or more Z substituents; O(CH2)aR22; a C6 aryl; halogen; COOH; or C(O)(C1- C10)alkyl; and R22 represents (C1-C10)alkyl optionally substituted by one or more Z substituents or a C6 aryl; or, alternatively,
A2 is of formula (VI) and Rze to Rzs are the same, particularly they are hydrogen; or, alternatively,
A2 is of formula (VII), and Rzg to RZ12 are independently selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; particularly Rzg9 to Rz11 are hydrogen, and RZ12 is selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; or, alternatively,
A2 is of formula (VIII) and X9, X10 and X10 are the same, particularly they are CH; or, alternatively, X9 and X11 are the same, particularly they are O.
In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention,
R3 to R7 are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; F; Cl; OR9; COOR10; or cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; particularly,
R3 to R? are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; F, or Cl; particularly,
R3 to R7 are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; or cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms. In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, is 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-thioxo-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-1/7-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-thioxo-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-3/7-
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-3/7-
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-3/7-
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-1/7-inden-5-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(4-methoxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol- 4-yl)benzenesulfonamide;
3-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)benzoic acid;
4-(4-((1/7-1 ,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-3/7- 1 ,2,4-triazole-3-thione;
[01-052] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione; [01-053] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(1 -methyl-1 /7-pyrazol-3-yl)-2,4-dihydro-3/7- 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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzamide;
[01-058] 5-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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-thioxo-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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenoxy)-/V-methylpicolinamide;
[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[cf][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[cf][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-thioxo-4,5-dihydro-1/7-1 ,2,4-triazol-3- y I) py ri d i n-2-y I) pi perazi n- 1 -yl)propan-1 -one;
[01-071] (3aR,4R,6aS)-4-(5-(4-(6-(4-(benzo[d][1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1 ,2,4- triazol-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)tetrahydro-1/7-thieno[3,4-c(]imidazol- 2(3/-/)-one;
[01-072] 1-(4-(6-(4-(Benzo[d][1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1/7-1 ,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1 -yl)-3-(5,5-difluoro-7-(1 /7-pyrrol-2-yl)-5/7-5l4,6l4-dipyrrolo[1 ,2-c:2', 1 '- f][1 ,3,2]diazaborinin-3-yl)propan-1-one;
[01-073] 4-(4-(6-(4-(Benzo[d][1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1/7-1 ,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1 -yl)-/V-(4-(5,5-difluoro-1 ,3,7,9-tetramethyl-5H -4l4,5l4-dipyrrolo[1 ,2- c:2',1'-/][1 ,3,2]diazaborinin-10-yl)phenyl)-4-oxobutanamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
In another preferred embodiment of the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, is 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-3/7- 1 ,2,4-triazole-3-thione;
[01-058] 5-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenoxy)picolinic acid;
/\/-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof. An specifc alternative embodiment of the invention (2.2) refers to a compound of formula I as defined in the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, for use in therapy, with the proviso that the compound is not selected from any one of the list of compounds 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;
[01-008] 1-(4-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenyl)ethan-1-one;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide;
A/-(5-ethyl- 1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide; and
/V- (4- meth oxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide.
On the other hand, the present invention further refers to an alternative second aspect of the invention (2.3), in particular to a compound of formula I as defined in the alternative first aspect of the invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the invention, with the proviso that such compound of formula I does not include any of the following 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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenyl)ethan-1-one;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide;
A/-(5-ethyl- 1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide;
/V- (4- meth oxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide;
[01-003] 4-(4-Chlorophenyl)-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;
[01-011] 4-(4-Methoxyphenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3-thione; [01-062] 4-(Benzo[c(][1 ,3]dioxol-5-yl)-5-(pyridin-3-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3- thione;
3-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)benzoic acid;
4-(4-((1/7-1 ,2,4-triazol-1-yl)methyl)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and
4-(Benzo[c(][1 ,3]dioxol-5-yl)-5-(2-hydroxyquinolin-4-yl)-2,4-dihydro-3H -1 ,2,4-triazole- 3-thione.
In a preferred embodiment of the alternative second aspect of the invention, the compound is of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof wherein:
Awis is a group of formula (IVbis): (IVbis) wherein:
(i) R3, Rs to R? are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; and R’4 is selected from hydrogen; F; Cl; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively
(ii) R3 and R’4 are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
(iii) X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached an aromatic ring system; R3 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; and R’4 is selected from hydrogen, F, Cl, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
A2 is of formula (V), (VI), (VII) or (VIII), as defined in any of the preceding claims 6-7; and
L and m are as defined in claim 1.
In another preferred embodiment of the alternative second aspect of the invention, the compound is selected from the group consisting of:
[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; [01-030] 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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4- triazol-4-yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol- 4-yl)(phenyl)methanone;
[01-037] 4-(Benzo[cf][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[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]quinolin-2-yl)-2,4-dihydro-3/7-
1 ,2,4-triazole-3-thione;
[01-039] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]pyrazin-2-yl)-2,4-dihydro-3/7-
1 ,2,4-triazole-3-thione;
[01-040] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-methylquinolin-4-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione;
[01-050] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-methylquinolin-4-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione;
[01-051] 4-(Benzo[cf][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-1/7-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-3/7-
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-thioxo-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-thioxo-1 ,5-di hydro-4H-1 ,2,4- triazol-4-yl)benzamide;
[01-058] 5-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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-thioxo-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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4- triazol-4-yl)phenoxy)-/V-methylpicolinamide;
[01-063] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-chloropyridin-4-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione;
[01-064] 4-(Benzo[cf][1,3]dioxol-5-yl)-5-(6-chloropyridin-3-yl)-2,4-dihydro-3H-1 ,2,4- triazole-3-thione;
[01-065] 4-(Benzo[cf][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[cf][1 ,3]dioxol-5-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione;
[01-067] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(6-morpholinopyridin-3-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione;
[01-068] 4-(Benzo[cf][1,3]dioxol-5-yl)-5-(6-chloropyridin-2-yl)-2,4-dihydro-3H-1 ,2,4- triazole-3-thione;
[01-069] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(6-(piperazin-1-yl)pyridin-2-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione;
[01-070] 1-(4-(6-(4-(Benzo[cf][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- y I) py ri d i n-2-y I) pi perazi n- 1 -yl)propan-1 -one;
[01-071] (3a/?,4/?,6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-
1/7-1 ,2,4-triazol-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)tetrahydro-1/7-thieno[3,4- cf]imidazol-2(3/7)-one;
[01-072] 1-(4-(6-(4-(Benzo[cf][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1-yl)-3-(5,5-difluoro-7-(1/7-pyrrol-2-yl)-5/7-5l4,6l4- dipyrrolo[1 ,2-c:2', 1'-/][1 ,3,2]diazaborinin-3-yl)propan-1 -one;
[01-073] 4-(4-(6-(4-(Benzo[cf][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1-yl)-/V-(4-(5,5-difluoro-1 ,3,7,9-tetramethyl-5/7-4l4,5l4- dipyrrolo[1 ,2-c:2', 1'-/][1 ,3,2]diazaborinin-10-yl)phenyl)-4-oxobutanamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof. In an alternative third aspect the present invention (2.4) provides a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in the alternative second aspect of the invention and one or more pharmaceutically acceptable excipient or carrier.
In an alternative fourth aspect the present invention (2.5) provides a compound as defined in the alternative second aspect of the invention for use in therapy or as a research tool in biotechnological applications.
In an alternative fifth aspect the present invention (2.6) provides a kit comprising a compound as defined in the alternative first or second aspect of the invention together with means for determining TREX2 activity.
In a final alternative aspect the present invention (2.7) provides an in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, the method comprising the step of contacting the isolated sample with any of the compounds of formula (I), (Ibis) or pharmaceutically acceptable salt or solvate thereof, as defined in the alternative first and second aspects of the invention.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 : represents the potency and selectivity of the 01-001 and 01-022 compounds in inhibiting TREX2 over TREX1 exonuclease activity. The IC50 of 01-001 (triangles) and 01-022 (rhombuses) compounds on TREX2 (A) and TREX1 (B) exonuclease activity was measured in vitro at the indicated compound concentrations or vehicle (V) using recombinant MBP- TREX2 and MBP-TREX1 protein isoforms and as substrate a dsDNA fragment of 3000 bp length. MBP was included as negative control for exonuclease activity. Representative concentration-response assays and calculated IC50 of each compound are depicted. The upper part shows DNA electrophoresis and lower part the concentration response curves showing DNA remaining at the indicated concentrations ([C]). Amount of DNA relative to the negative control is in arbitrary units (A.U.). The 01-001 and 01-022 compounds inhibited in a concentration-dependent manner TREX2 but not TREX1 exonuclease activity. The IC50 value of 01-001 and 01-022 compounds for TREX1 (> 100 μM) was about 100-fold higher than the IC50 value for TREX2 (0.9-1 .2 μM for 0-001 and 01-022, respectively).
FIG. 2: represents the activity of the 01-045 compound in decreasing IL-23-induced psoriasis inflammation in wild type (wt) (circles with continuous line) and Trex2 deficient (squares with dotted lines) mice. Intraperitoneal (i.p.) treatment with 01-045 triggers a significant reduction in IL-23-induced ear inflammation in wt mice, reaching values observed in the Trex2 knockout mice (Trex2-/-). Left and right ears of the mice were treated intradermally with IL-23 or PBS, respectively, once a day. Mice were treated with 01-045 (3mg/kg) (white circles and squares) or vehicle (V, black circles and squares) once a day, one day after starting the IL-23 treatment. Arrows indicate compound administration. The increase (A) in ear thickness caused by IL-23 is shown in relation to PBS (Y-axis), expressed in millimetres (mm) along the time (X-axis) expressed in days (d), is shown. Mean ± SEM of at least 5 mice per group. Analysis of significant differences among untreated and compound treated mice: two-way ANOVA with the Sidak's multiple comparison test, **** p<0.0001 , compound-treated vs untreated wt mice.
FIG. 3: represents the efficacy of the 01-001 compound in decreasing the IL-23-induced psoriasis inflammation. (A) Intraperitoneal (i.p.) and (B) intragastric (i.g.) treatment with 01- 001 trigger a significant reduction in IL-23-induced ear inflammation. Left and right ears of the mice were treated intradermally with IL-23 or PBS, respectively, once a day. Mice were treated with 01-001 (white triangles) at 3 mg/kg i.p. (A) and 20 mg/kg i.g. (B) or vehicle (V, black triangles) once a day, two days after starting IL-23 treatment. Arrows indicate compound administration. The increase in ear thickness caused by IL-23 is shown in relation to PBS (Y- axis), expressed in millimetres (mm) along time (X-axis), expressed in days (d). Mean ± SEM of at least 5 mice per group. Analysis of significant differences: two-way ANOVA with the Sidak's multiple comparison test, * p<0.05, ** p<0.01 , **** p<0.0001.
FIG.4: represents the efficacy of 01-022 in reducing IL-23-induced psoriasis inflammation. (A) Intragastric (i.g) and (B) topic 01-022 treatment trigger a significant reduction in IL-23-induced ear inflammation. Left and right ears of the mice were treated intradermally with IL-23 or PBS, respectively, once a day. Mice were treated with 01-022 (rhombuses) at 5 (a), 20 (b) and 50 (c) mg/kg or vehicle (V, black circles) twice daily, and 200 nmols (e) once a day, two days after starting IL-23 treatment. Arrows indicate compound administration. The increase in ear thickness caused by IL-23 is shown in relation to PBS (Y-axis), expressed in millimetres (mm) along time (X-axis), expressed in days (d). Mean ± SEM of at least 5 mice per group. Analysis of significant differences: two-way ANOVA with the Dunnett's (A) or the Sidak's (B) multiple comparison test, *** p<0.001 , **** p<0.0001.
FIG.5: represents the efficacy of 01-022 in reducing MC903-induced atopic dermatitis inflammation. (A, B) Topic 01-022 treatment trigger a significant reduction in MC903-induced ear inflammation. Left and right ears of the mice were treated topically with MC903 or Ethanol, respectively, once a day. Mice ears were treated with 01-022 (200 nmols) (rhombuses) once a day, eight days after starting MC903 treatment. Arrows indicate compound administration. (A) The increase in ear thickness caused by MC903 is shown in relation to Ethanol (Y-axis) along time (X-axis), and (B) at day twelve in relation to day eight, expressed in millimetres (mm). (C) The number of scratching bouts during ten minutes at day twelve in the MC903- treated left ear. Mean ± SEM of 10 mice per group. Analysis of significant differences: two- way ANOVA with the Sidak's multiple comparison test (A) and unpaired two-tailed Student’s t test (B, C), * p<0.05, *** p<0.001 , **** p<0.0001.
DETAILED DESCRIPTION
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated, and the following conventions are adhered to.
Throughout the present specification and the accompanying clauses, the words "comprise" and variations such as "comprises", "comprising" are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. The word “comprise” also includes the term “consists of”.
For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range.
It is noted that the following section below only relates to aspects first to fifth, including the final aspect, of the invention as clearly identified in the SUMMARY OF THE INVENTION and not to any of the alternative aspects, including the alternative final aspect, of the invention as clearly identified in the SUMMARY OF THE INVENTION.
- Section related to aspects first to fifth including the final aspect as identified in the summary of the invention (see aspects 1.1 to 1.6 of the summary of invention).
In a first aspect, the present invention provides the use of compounds of formula (I) in the treatment of a disease caused by an increase in TREX2 expression and activity.
In the context of the invention, the term “pathological condition caused by an increase in TREX2 expression” refers to any pathological condition in which there is an overexpression (i.e. , overactivity) of TREX2 compared to a reference value obtained from a control population. In one embodiment, the control population is a healthy population. In another embodiment, the determination of the level of TREX2 is performed in an isolated tissue or cells sample of the subject. In one embodiment, the level of RNA is determined. Analysis of TREX2 RNA expression can be performed using any routine protocol, using commercial and available reagents, such as those used by Manils and colleagues (Manils et al., 2016).
In the context of the invention, the term “subject” encompasses any animal, including domestic mammals and human beings. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human being.
Throughout the present description, the term "treatment" includes, but is not limited to, alleviating, diminishing, decreasing or eliminating one or more symptoms of the condition; reducing the degree of the condition, stabilizing (i.e., not worsening) the condition, delaying or slowing the progression, alleviating or improving its condition, and remitting (whether total or partial).
As used in the present invention, the term "prevention" refers to preventing the onset of the - pathological condition from occurring in a patient who is predisposed, but who does not yet have symptoms of the disease.
As used herein, the term “animal” shall refer to a vertebrate animal. Such animals include both domestic animals; for example, livestock, laboratory animals and household pets, and nondomestic animals such as wildlife. In one embodiment, the animal is a vertebrate. In a particular embodiment, the animal is a domestic mammal or a human.
In the context of the invention, the term "alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. Typical alkyl groups have from 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e. g., methyl, ethyl, n-propyl, /-propyl, n-butyl, f-butyl, n-pentyl, etc. If substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropyl methyl. When substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl, or phenethyl. When substituted by heterocyclyl, it corresponds to a "heterocyclylalkyl" radical.
In the context of the invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one C=C double bond, and which is attached to the rest of the molecule by a single bond. Typical alkenyl radicals have from 2 to about 10, 2 to about 8 or 2 to about 6 carbon atoms. In a particular embodiment, the alkenyl group is vinyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, or butenyl.
In the context of the invention, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical containing one or more C=C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. When the alkenyl or alkynyl is bound to a N atom (forming a substituted amine) the binding will occur via a C atom not forming part of the double or triple bond.
In the context of the invention, the term "halogen" refers to bromo, chloro, iodo or fluoro.
In the context of the invention, the term “haloalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogen atoms are replaced by halogen. Illustrative non-limitative examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like.
In the context of the invention, and unless otherwise specified, the term “cycloalkyl” refers to a saturated hydrocarbon ring. Illustrative non-limitative examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
In the context of the invention, the term “heteroaryl” refers to a monocyclic carbocyclic ring having 5 or 6 members, and wherein one, two or three of the members are heteroatoms, particularly selected from N, O, or S.
In the context of the present invention, the term "salt" must be understood as any form of a compound used in accordance with this invention in which said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly, complexes formed via ionic interactions. This definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts".
In the context of the present invention, the term "pharmaceutically acceptable salts" means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly, as a result of the counter-ion) when used in an appropriate manner for a treatment, applied or used, particularly, in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention -normally an acid (deprotonated)- such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used in humans and/or mammals. Salts with alkali and alkali earth metals are preferred particularly, as well as those formed with ammonium cations (NH4 +). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium, or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e. , salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals. Examples of this type of salts are those formed with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
In the context of the present invention, the term "solvate" should be understood as meaning any form of a compound in accordance with the invention in which the said compound is bonded by a noncovalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates, such as, for example, methanolate. A preferred solvate is the hydrate.
Any compound of formula (I) referred to herein is intended to represent such a specific compound, as well as certain variations or forms. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus, any compound of formula (I) referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, which could be the same as or different from, the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropoisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropoisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
Furthermore, any compound of formula (I) referred to herein may exist as tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another.
In one embodiment of the first aspect of the invention, one or two of Xi to Xs, represents N. In particular one of Xi to Xs represents N, particularly X? represents N. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, n is 1 and one of Xi to Xs represents N.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A1 is of formula (III): wherein R3 to Re are as defined in the first aspect of the invention.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A1 is of formula (III) and R3 to Re are selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; or -O-(C1-C10)alkyl optionally substituted with one or more Z substituents.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A1 is of formula (III), and R3 to Re are the same. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A1 is of formula (III), and R3 to Re are the hydrogen.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compound of formula (I) is one wherein n is 0, and two or three of Xi to X7 represents N.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, wherein A1 is of formula (IV): wherein: X5 represents N or CR5; and Rsto R? are as defined above. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A1 is of formula (IV), and Rs to R7: are independently selected from hydrogen, halogen, OH, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively
Rs and R4 are fused, forming with the carbon atoms to which they are attached, an aromatic ring system; and R5, Re and R7 are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
- X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached, an aromatic ring system; and R3, R4 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 consists of one ring, particularly consists of a 6-membered aromatic ring, wherein the members are as defined in the first aspect of the invention.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is an aryl ring of formula (V), (VI), (VII) or (VIII): wherein: X9 represents NR34, O, S or CRzie;
X10 represents NR35, O, S or CRzi?;
Xu represents NR36, O, S or CRzw;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; O(CH2)aR22; C(O)R23; SO2NR24R25; an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2;
R22 to R25, and Rb being as defined in any of the preceding embodiments; and
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (V), and Rzi to Rzis are independently selected from the group consisting of: hydrogen; halogen; (C1-C10)alkyl; (C1- Cio)haloalkyl; O(CH2)aR22; C(O)R23; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R22 and R23 are selected from H and (C1- C10)alkyl optionally substituted by one or more Z substituents.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R24 and R25 are independently selected from hydrogen; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRg, being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, one of R24 and R25 is H and the other is selected from H; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRg, being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (VI) and Rze to Rzs are the same, particularly they are hydrogen.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (VIII) and X9, X10 and X10 are the same, particularly they are CH; or, alternatively, X9 and Xu are the same, particularly they are O.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (VII), and Rzg to RZ12 are independently selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; particularly Rzg to Rzn are hydrogen, and RZ12 is selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (V), and Rzi to Rzs are selected from hydrogen; (C1-C10)alkyl optionally substituted by one or more Z substituents; O(CH2)aR22; a C6 aryl; halogen; COOH; and C(O)(C1-C10)alkyl; and R22 represents (C1-C10)alkyl optionally substituted by one or more Z substituents or a C6 aryl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 to Rs are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; F; Cl; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; particularly they are selected from hydrogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, (C2-C10)alkynyl optionally substituted with one or more Z substituents, F, and Cl. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, Ri to Rs are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2- Cio)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, Z is halogen.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compound is 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-thioxo-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-1/7-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-thioxo-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-3/7-
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-3/7-
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-3/7-
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-1/7-inden-5-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)(phenyl)methanone;
[01-037] 4-(Benzo[cf][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[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and
[01-039] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]pyrazin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(4-methoxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol- 4-yl)benzenesulfonamide;
3-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)benzoic acid;
4-(4-((1/7-1 ,2,4-triazol-1-yl)methyl)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3- thione;
4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-hydroxyquinolin-4-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3-thione; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compound is 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;
[01-003] 4-(4-Chlorophenyl)-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-3/7- 1 ,2,4-triazole-3-thione;
/\/-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the pathological condition related to an increase in TREX2 expression is a skin or mucosa inflammatory condition. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the condition is selected from psoriasis, atopic dermatitis or ichthyosis.
In a second aspect the present invention provides a compound of formula (Ibis), a pharmaceutically acceptable salt or solvate thereof.
All the embodiments provided above, under the first aspect of the invention, regarding A2, A3, Xi, X2. X3. X5, Xe, L, and m, are also embodiments of the compound of the second aspect of the invention.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, Awis is of formula (IVbis), and Rs to R? are independently selected from hydrogen, halogen, and (C1-C10)alkyl optionally substituted with one or more Z substituents.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 consists of one ring, particularly consists of a 6-membered aromatic ring, wherein the members are as defined in the first aspect of the invention. In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is an aryl ring of formula (V), (VI), (VII) or (VIII): wherein: X9 represents NR34, O, S or CRz16;
X10 represents NR35, O, S or CRz17;
Xu represents NR36, O, S or CRz18;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; O(CH2)aR22; C(O)R23; SO2NR24R25; an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2;
R22 to R25, and Rb being as defined in any of the preceding embodiments; and
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (V), and Rz1 to Rzis are independently selected from the group consisting of: hydrogen; halogen; (C1-C10)alkyl; (C1- Cio)haloalkyl; O(CH2)aR22; C(O)R23; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, R22 and R23 are selected from H and (C1- C10)alkyl optionally substituted by one or more Z substituents.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, R24 and R25 are independently selected from hydrogen; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRg, being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1- Cio)haloalkyl, or -O-(C1-C10)haloalkyl.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, one of R24 and R25 is H and the other is selected from H; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRg, being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1- Cio)haloalkyl, or -O-(C1-C10)haloalkyl.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (VI) and Rze to Rzs are the same, particularly they are hydrogen.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (VIII) and X9, X10 and X10 are the same, particularly they are CH; or, alternatively, X9 and Xu are the same, particularly they are O.
In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, A2 is of formula (VII), and Rzg to RZ12 are independently selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; particularly Rzg to Rzn are hydrogen, and RZ12 is selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2. In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, Ri to R3, R’4, and Rsto Rs are independently selected from the group consisting of: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms.
In another embodiment of the second aspect of the invention, the compound of formula (Ibis) is selected from the group consisting of:
[01-022] 4-(Benzo[d][1 ,3]dioxol-5-yl)-5-(7-chloroimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7-
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-3/7-
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-3/7-
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-1/7-inden-5-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)(phenyl)methanone;
[01-037] 4-(Benzo[cf][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[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and
[01-039] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]pyrazin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the invention (Ibis) or (I’) or a pharmaceutical salt thereof, as defined above.
By “therapeutically effective amount”, it is understood the amount of the compound(s) that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
The precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the invention, may depend on several variables. Some of these would be: route of administration, time of drug release (e.g., instant or extended), administration schedule, severity, condition of the patient, and the like.
The pharmaceutical compositions can be prepared as a liquid, semi-solid or solid dosage form, for example in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pills or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, or administered as such. These compositions can be prepared with the aid of conventional means, devices, methods or processes known in the art.
Pharmaceutically acceptable adjuvants, vehicles or excipients which may be used in such compositions are adjuvants, vehicles or excipients known to those skilled in the art or commonly used in the preparation of therapeutic compositions, which may be selected, for example, from the group consisting of excipients, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, flavoring agents or binders.
The term "pharmaceutically acceptable" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio in animals and, particularly, in humans.
The selection of physiologically compatible adjuvants or the number of adjuvants to be used depends on the form of administration of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, otic or intratympanic. Preparations in the form of tablets, dragees, capsules, granules, pills, drops, in particular otic drops, juices or syrups are preferably suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations or also sprays are preferably suitable for parenteral, topical or inhalation administration. The compounds in accordance with the invention used in the pharmaceutical composition in accordance with the invention in a depot, in a dissolved form or in a dressing, or if appropriate having added other agents favoring penetration into the skin, are preparations suitable for percutaneous administration. The preparation forms administrable orally or percutaneously can also release the respective compound according to the invention in a delayed form.
For instance, for oral administration in the form of a tablet or capsule, the active drug components can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.
The dosage administered of the pharmaceutical composition will, of course, vary depending on the use and known factors such as the age, health, and weight of the recipient; nature and extent of symptoms, concurrent treatments, if any, frequency of treatment, and the effect desired. The recipient may be any type of mammal, but it is preferably a human.
It is noted that the following section below only relates to the alternative aspects, including the alternative final aspect, of the invention as clearly identified in the SUMMARY OF THE INVENTION.
- Section related to alternative aspects first to fifth, including the final alternative aspect, as identified and defined in the summary of the invention (see aspects 2.1 to 2.7 of the summary of invention).
In a first alternative aspect, the present invention provides the use of compounds of formula (I), as defined the alternative first aspect of the invention, in the treatment of a disease caused by an increase in TREX2 expression and activity.
In the context of the invention, the term “pathological condition caused by an increase in TREX2 expression” refers to any pathological condition in which there is an overexpression (i.e. , overactivity) of TREX2 compared to a reference value obtained from a control population. In one embodiment, the control population is a healthy population. In another embodiment, the determination of the level of TREX2 is performed in an isolated tissue or cells sample of the subject. In one embodiment, the level of RNA is determined. Analysis of TREX2 RNA expression can be performed using any routine protocol, using commercial and available reagents, such as those used by Manils and colleagues (Manils et al., 2016).
In the context of the invention, the term “subject” encompasses any animal, including domestic mammals and human beings. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human being.
Throughout the present description, the term "treatment" includes, but is not limited to, alleviating, diminishing, decreasing or eliminating one or more symptoms of the condition; reducing the degree of the condition, stabilizing (i.e., not worsening) the condition, delaying or slowing the progression, alleviating or improving its condition, and remitting (whether total or partial).
As used in the present invention, the term "prevention" refers to preventing the onset of the - pathological condition from occurring in a patient who is predisposed, but who does not yet have symptoms of the disease.
As used herein, the term “animal” shall refer to a vertebrate animal. Such animals include both domestic animals; for example, livestock, laboratory animals and household pets, and nondomestic animals such as wildlife. In one embodiment, the animal is a vertebrate. In a particular embodiment, the animal is a domestic mammal or a human.
In the context of the invention, the term "alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. Typical alkyl groups have from 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e. g., methyl, ethyl, n-propyl, /-propyl, n-butyl, f-butyl, n-pentyl, etc. If substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropyl methyl. When substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl, or phenethyl. When substituted by heterocyclyl, it corresponds to a "heterocyclylalkyl" radical.
In the context of the invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one C=C double bond, and which is attached to the rest of the molecule by a single bond. Typical alkenyl radicals have from 2 to about 10, 2 to about 8 or 2 to about 6 carbon atoms. In a particular embodiment, the alkenyl group is vinyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, or butenyl.
In the context of the invention, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical containing one or more C=C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. When the alkenyl or alkynyl is bound to a N atom (forming a substituted amine) the binding will occur via a C atom not forming part of the double or triple bond.
In the context of the invention, the term "halogen" refers to bromo, chloro, iodo or fluoro.
In the context of the invention, the term “haloalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogen atoms are replaced by halogen. Illustrative non-limitative examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like.
In the context of the invention, and unless otherwise specified, the term “cycloalkyl” refers to a saturated hydrocarbon ring. Illustrative non-limitative examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
In the context of the invention, the term “heteroaryl” refers to a monocyclic carbocyclic ring having 5 or 6 members, and wherein one, two or three of the members are heteroatoms, particularly selected from N, O, or S.
In the context of the present invention, the term "salt" must be understood as any form of a compound used in accordance with this invention in which said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly, complexes formed via ionic interactions. This definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts".
In the context of the present invention, the term "pharmaceutically acceptable salts" means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly, as a result of the counter-ion) when used in an appropriate manner for a treatment, applied or used, particularly, in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention -normally an acid (deprotonated)- such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used in humans and/or mammals. Salts with alkali and alkali earth metals are preferred particularly, as well as those formed with ammonium cations (NH4 +). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium, or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e. , salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals. Examples of this type of salts are those formed with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
In the context of the present invention, the term "solvate" should be understood as meaning any form of a compound in accordance with the invention in which the said compound is bonded by a noncovalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates, such as, for example, methanolate. A preferred solvate is the hydrate.
Any compound of formula (I), as defined in the alternative first or second aspect of the invention, referred to herein is intended to represent such a specific compound, as well as certain variations or forms. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus, any compound of formula (I), as defined in the alternative first or second aspect of the invention, referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, which could be the same as or different from, the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropoisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropoisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
Furthermore, any compound of formula (I), as defined in the alternative first or second aspect of the invention, referred to herein may exist as tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another.
In an embodiment of the alternative first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the pathological condition related to an increase in TREX2 expression is a skin or mucosa inflammatory condition. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the condition is selected from psoriasis, atopic dermatitis or ichthyosis.
On the other hand, and in relation to the alternative third aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds as defined in the alternative second aspect of the invention or a pharmaceutical salt thereof, as defined above.
By “therapeutically effective amount”, it is understood the amount of the compound(s) that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
The precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the invention, may depend on several variables. Some of these would be: route of administration, time of drug release (e.g., instant or extended), administration schedule, severity, condition of the patient, and the like.
The pharmaceutical compositions can be prepared as a liquid, semi-solid or solid dosage form, for example in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pills or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, or administered as such.
These compositions can be prepared with the aid of conventional means, devices, methods or processes known in the art.
Pharmaceutically acceptable adjuvants, vehicles or excipients which may be used in such compositions are adjuvants, vehicles or excipients known to those skilled in the art or commonly used in the preparation of therapeutic compositions, which may be selected, for example, from the group consisting of excipients, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, flavoring agents or binders. The term "pharmaceutically acceptable" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio in animals and, particularly, in humans.
The selection of physiologically compatible adjuvants or the number of adjuvants to be used depends on the form of administration of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, otic or intratympanic. Preparations in the form of tablets, dragees, capsules, granules, pills, drops, in particular otic drops, juices or syrups are preferably suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations or also sprays are preferably suitable for parenteral, topical or inhalation administration. The compounds in accordance with the invention used in the pharmaceutical composition in accordance with the invention in a depot, in a dissolved form or in a dressing, or if appropriate having added other agents favoring penetration into the skin, are preparations suitable for percutaneous administration. The preparation forms administrable orally or percutaneously can also release the respective compound according to the invention in a delayed form.
For instance, for oral administration in the form of a tablet or capsule, the active drug components can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.
The dosage administered of the pharmaceutical composition will, of course, vary depending on the use and known factors such as the age, health, and weight of the recipient; nature and extent of symptoms, concurrent treatments, if any, frequency of treatment, and the effect desired. The recipient may be any type of mammal, but it is preferably a human.
********************************
Finally, according to another aspect of the present invention, the compounds of the invention, including those defined in the first to second aspects of the invention as well as those defined in the alternative first to second aspects of the invention, may be prepared by cycling a N- carbonylaminothiourea of formula (IX) wherein L, m, A1 and A2 are as defined above.
There are well-known methods for cycling the N-carbonylaminothiourea of formula (IX), for example, by adding a base.
The N-carbonylaminothiourea can also be obtained using well-known synthetic routes. Illustrative non-limitative examples are provided below.
To those skilled in the art, other objects, advantages or features of the invention will be apparent in part from the description or in part from the practice of the invention. The following examples are provided by way of illustration or are not intended to be limiting of the present invention.
EXAMPLES
Chemicals and Chemical Synthesis
1. General information All chemicals were purchased from commercial sources and used as received unless otherwise stated. Microwave- irradiated reactions were carried out using a Biotage Initiator Classic. Column chromatographies were carried out on commercial silica gel. Flash column chromatographies were carried out using an Isolera Prime Biotage equipped with dual UV detection over pre-packed normal or reverse phase (4, 12 and 24 g). Thin layer chromatographies were performed using pre-coated Merck silica gel 60 F254 plates and visualized under UV light at 254 nm and 365 nm.
The 1H NMR spectra were recorded on 400 MHz or 600 MHz NMR spectrometers. Chemical shifts were reported in ppm(b) as s (singlet), d (doublet), t (triplet), dd (doublet of doublet), m (multiplet), etc. The residual solvent signals were used as references. HPLC-MS spectra were carried out as follows:
1) Agilent 1260 Infinity II: A Poroshell 120 EC-C15 (4.6 mm x 50 mm, 2.7 pm) at 40 °C with mobile phase A (H2O + 0.05% formic acid) and B (ACN + 0.05% formic acid) using a gradient elution and flow rate 0.6 mL/min. The DAD detector was set at 254 or 220 nm, the injection volume was 5 pL, and oven temperature was 40 °C.
2) Waters 2795 Alliance A ZORBOX Extended-C181 (2.1 mm x 50 mm, 3.5 pm) at 35 °C with mobile phase A (H2O + 0.05% formic acid) and B (ACN + 0.05% formic acid) using a gradient elution and flow rate 0.7 mL/min. The DAD detector was set in the range of 210-600 nm and the injection volume was 5 pL.
2. General Procedures and Characterization Data
The following synthetic route was used to access the final triazoles 1 and their corresponding sodium salts 1-Na. 2.1. Synthesis of Esters and Prepared Compounds 6
P01A: In a 2-neck flask fitted with a condenser, a 0.2 M solution of carboxylic acids 7 in dry methanol was prepared. Thionyl chloride (3 eq) was added dropwise, and the mixture was stirred at 60 °C for 6 hours. The solvent was then evaporated and the remaining solid was dissolved in water. The mixture was carefully neutralized with sodium bicarbonate aqueous solution and was extracted 3 times with dichloromethane. The combined organic phases were dried over magnesium sulphate and condensed to afford the title compounds 6.
P01 B: In a Schlenk tube a suspension of a-aminoazines 8 in DCM was heated to 60 °C for 5- 24 hours. The reaction mixture was cooled, and the intermediate was filtered in the form of a solid. In a second Schlenk tube, the obtained intermediate was resuspended in ethanol, the tube was sealed, and the mixture was refluxed for 4-24 hours. The mixture was then condensed, and the residue was carefully basified to pH of 8 with sodium bicarbonate aqueous solution and was extracted 3 times with dichloromethane. The combined organic phases were dried over magnesium sulphate and condensed. The solid obtained was either purified on silica or recrystallized from ethanol to provide the title compounds 6.
[06-001] Methyl quinoline-2-carboxylate (Following P01A upon 2-quinaldic acid, 3.21 g, 95%),
[06-002] Ethyl imidazo[1,2-a]isoquinoline-2-carboxylate (Following P01B upon 1- aminoisoquinoline, 320 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1 H), 8.66 - 8.61 (m, 1 H), 8.44 (d, J= 7.3 Hz, 1H), 8.03 - 7.96 (m, 1H), 7.84 - 7.75 (m, 2H), 7.54 (d, J= 7.2 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H).
[06-003] Ethyl imidazo[1,2-a]quinoline-2-carboxylate (Following P01B upon 2- aminoquinoline, 228 mg, 27%). LC-MS (ES) m/z = 406 [M+H]+. [06-004] Ethyl imidazo[1,2-a]pyrazine-2-carboxylate (Following P01B upon 2- aminopyrazine, 370 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 9.18 (dd, J = 1.5, 0.6 Hz, 1 H), 8.69 (d, J = 0.7 Hz, 1 H), 8.59 (dd, J = 4.7, 1.6 Hz, 1 H), 7.98 (d, J = 4.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). LC-MS (ES) m/z = 192 [M+H]+.
[06-005] [06-005] Methyl 2-methylquinoline-4-carboxylate (Following P01A upon 2- methylquinoline-4-carboxylic acid, 403 mg, 80%). 1H NMR (400 MHz, CDCfe) 6 8.68 (d, J = 8.6 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.81 (s, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.59 (t, J = 7.7 Hz, 1 H), 4.04 (s, 3H), 2.80 (s, 3H).
2.2. Synthesis of Hydrazides 4
A3 = Alkyl
P02A: To a 0.8 M solution of the esters 6 in ethanol was added hydrazine monohydrate (40 eq, 80% solution). The reaction mixture was refluxed for 5-12 hours. Once the completion of the reaction was confirmed by TLC, ethanol was removed in vacuum. The remaining solution was poured into ice water and the resulting precipitate was filtered and freeze-dried to obtain the title compounds 4.
P02B: To a 0.8 M solution of the esters 6 in ethanol was added hydrazine monohydrate (4 eq, 80% solution) in a pressure tube. The tube was sealed, and the reaction mixture was heated at 120 °C for 12-24 hours. Once the completion of the reaction was confirmed by TLC, ethanol was partially removed in vacuum, the resulting precipitate was filtered and washed with cold ethanol or ether to obtain the title compounds 4.
[04-001] Quinoline-2-carbohydrazide (2.02 g, 67%, applying P02A upon 06-001). LC-MS (ES) m/z = 188.28 [M+H]+.
[04-002]
[04-002] lmidazo[2,1-a]isoquinoline-2-carbohydrazide (63 mg, 67%, applying P02B upon 06-002).
[04-003]
[04-003] lmidazo[1,2-a]quinoline-2-carbohydrazide (98 mg, 52%, applying P02B upon 06- 003). LC-MS (ES) m/z = 227 [M+H]+.
[04-004] [04-004] lmidazo[1,2-a]pyrazine-2-carbohydrazide (46 mg, 50%, applying P02B upon 06- 004). LC-MS (ES) m/z = 178 [M+H]+.
[04-005]
[04-005] 2-Methylquinoline-4-carbohydrazide (Applying a modified version of P02A upon
06-005, the reaction mixture was irradiated in a microwave reactor for 45 minutes at 80°C to afford 0.184 g, 45%): LC-MS (ES) m/z = 202.23 [M+H]+.
[04-006] 6-Bromoimidazo[1,2-a]pyridine-2-carbohydrazide (Applying a modified version of P02B upon ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate, the reaction mixture was refluxed overnight, the formed solid was filtered and washed with ethanol to afford 0.164 g, 69%).
[04-007] 7-Bromoimidazo[1,2-a]pyridine-2-carbohydrazide (Applying a modified version of P02B upon ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate, the reaction mixture was refluxed for 4h, the formed solid was filtered and washed with ethanol to afford 0.398 g, 93%).
2.3. Synthesis of Isothiocyanates 3
SCCI2
NaHCO3 (aq)
A2-NH2 Chloroform
P03: A solution of sodium bicarbonate (3 eq) in water (12 mL) was added to amines 5 (1 eq) in a mixture of chloroform (12 mL) and water (12 mL). Thiophosgene (1.05 eq) was added dropwise at 0 °C. The biphasic solution was stirred at room temperature for 1 h or until the completion of the reaction was confirmed by TLC. The two phases were separated. The combined organic layer was washed with brine, dried over Na2SO4, and was condensed in reduced pressure to obtain the title compounds 3.
[03-001]
[03-001] 3-lsothiocyanatobenzamide (318 mg, 61 %, applying P03 upon 3- aminobenzamide). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (bs, 1 H), 7.88 (t, J = 1 .6 Hz, 1 H), 7.85 (dt, J = 7.4, 1.5 Hz, 1 H), 7.60 - 7.51 (m, 3H).
[03-002] [03-002] 5-lsothiocyanato-2-methoxybenzamide (260 mg, 52%, applying P03 upon 5- amino-2-methoxybenzamide). 1H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.64 (m, 2H), 7.56 (dd, J = 8.8, 2.8 Hz, 1 H), 7.20 (d, J = 8.9 Hz, 1 H), 3.91 (s, 3H).
[03-003] 4-(4-lsothiocyanatophenoxy)-A/-methylpicolinamide (561 mg, 86%, applying P03 upon 4-(4-aminophenoxy)-/V-methylpicolinamide). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (q, J = 4.7 Hz, 1 H), 8.54 (d, J = 5.6 Hz, 1 H), 7.59 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 2.5 Hz, 1 H), 7.32 (d, J = 8.9 Hz, 2H), 7.20 (dd, J = 5.6, 2.6 Hz, 1 H), 2.79 (d, J = 4.9 Hz, 3H).
2.4. Synthesis of Intermediate Carbothioamides 2
EtOH
A2-NCS Reflux
3
P04: In a Carousel® tube, equimolar amounts of isothiocyanates 3 and hydrazides 4 were suspended in ethanol (typically 0.1 M), the tube was sealed, and the mixture was refluxed for 2-16 hours. Once the consumption of starting material was confirmed, the tube was cooled to rt or 0°C, and the formed precipitate was filtered, washed with small amounts of cold ethanol and dried to afford the intermediates 2. In cases where no precipitate was formed, the solvent was evaporated, and the crude was directly used after trituration with cold ether or pentane.
Representative examples were characterized with HPLC-MS and/or 1H NMR.
[02-001]
[02-001] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(quinoline-2-carbonyl)hydrazine-1- carbothioamide (from 04-001 and isothiocyanatobenzo[d][1,3]dioxole, 120 mg, 65%).
[02-002]
[02-002] 2-(Quinoline-2-carbonyl)-A/-(4-(trifluoromethyl)phenyl)hydrazine-1- carbothioamide (from 04-001 and 1-isothiocyanato-4-(trifluoromethyl)benzene, 116 mg, 59%). LC-MS (ES) m/z = 391 [M+H]+.
[02-003]
[02-003] A/-(4-chlorophenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and 1-chloro-4-isothiocyanatobenzene, 101 mg, 57%).
[02-004] 2-(Quinoline-2-carbonyl)-/V-(p-tolyl)hydrazine-1 -carbothioamide (from 04-001 and 1-isothiocyanato-4-methylbenzene, 78 mg, 46%).
[02-005] A/-(3-bromophenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and 1-bromo-3-isothiocyanatobenzene,134 mg, 67%). LC-MS (ES) m/z = 385 [M+H]+. [02-006] A/-benzyl-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and (isothiocyanatomethyl)benzene, 148 mg, 88%).
[02-007] A/-phenyl-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and isothiocyanatobenzene, 107 mg, 66%).
[02-008] A/-(4-acetylphenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and 1-(4-isothiocyanatophenyl)ethan-1-one, 118 mg, 65%). LC-MS (ES) m/z = 365 [M+H]+. [02-009] A/-(4-phenoxybenzyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide
(from 04-001 and 1-(isothiocyanatomethyl)-4-phenoxybenzene, 166 mg, 77%).
[02-010] A/-(4-methoxy-2-methylphenyl)-2-(quinoline-2-carbonyl)hydrazine-1- carbothioamide (from 04-001 and 1-isothiocyanato-4-methoxy-2-methylbenzene, 159 mg, 88%). LC-MS (ES) m/z = 367 [M+H]+
[02-011] A/-(4-methoxyphenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide
(from 04-001 and 1-isothiocyanato-4-methoxybenzene, 109 mg, 61%). [02-012] A/-([1,T-biphenyl]-3-yl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and 3-isothiocyanato-1,1 ’-biphenyl, 273 mg, 98%). LC-MS (ES) m/z = 399 [M+H]+.
[02-013] A/-(4-(benzyloxy)phenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and 1-(benzyloxy)-4-isothiocyanatobenzene, 201 mg, 93%). LC-MS (ES) m/z = 339 [M+H]+
[02-014] 2-(Quinoline-2-carbonyl)-/V-(thiophen-2-ylmethyl)hydrazine-1 -carbothioamide (from 04-001 and 2-(4-isothiocyanatobenzyl)thiophene, 161 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1 H), 9.58 (s, 1H), 8.68 (s, J = 30.0 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H),
8.13 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1 H), 7.36 (d, J = 5.0 Hz, 1H), 7.01 (s, 1 H), 6.96 - 6.90 (m, 1 H), 4.86 (d, J = 5.8 Hz, 2H).
[02-015] A/-(4-phenoxyphenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide
(from 04-001 and 1-isothiocyanato-4-phenoxybenzene , 290 mg, 64%). LC-MS (ES) m/z = 415 [M+H]+. [02-016] A/-(3-(benzyloxy)phenyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide (from 04-001 and 1-(benzyloxy)-3-isothiocyanatobenzene, 360 mg, 84%). LC-MS (ES) m/z = 429 [M+H]+ .
[02-017] A/-(2,3-dihydro-1H-inden-5-yl)-2-(quinoline-2-carbonyl)hydrazine-1- carbothioamide (from 04-001 and 5-isothiocyanato-2,3-dihydro-1H-indene, 292 mg, 81%). LC-MS (ES) m/z = 363 [M+H]+.
[02-018] A/-(6-chloropyridin-3-yl)-2-(quinoline-2-carbonyl)hydrazine-1 -carbothioamide
(from 04-001 and 2-chloro-5-isothiocyanatopyridine, 176 mg, 70%). LC-MS (ES) m/z = 358 [M+H]+.
[02-020] A/-(2-(quinoline-2-carbonyl)hydrazine-1-carbonothioyl)benzamide (from 04-001 and benzoyl isothiocyanate, 248 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1 H), 11.98 (s, 1 H), 11.48 (s, 1 H), 8.67 (d, J = 8.5 Hz, 1 H), 8.25 - 8.11 (m, 3H), 8.02 (d, J = 7.8 Hz, 2H), 7.93 (t, J = 7.6 Hz, 1 H), 7.79 (t, J = 7.5 Hz, 1 H), 7.69 (t, J = 7.4 Hz, 1 H), 7.60 - 7.52 (m, 2H). LC-MS (ES) m/z = 351 [M+H]+.
[02-021] 4-Chloro-/V-(2-(quinoline-2-carbonyl)hydrazine-1-carbonothioyl)benzamide
(from 04-001 and 4-chlorobenzoyl isothiocyanate, 275 mg, 72%). LC-MS (ES) m/z = 385 [M+H]+.
[02-022] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl) hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 345 mg, 89%). LC-MS (ES) m/z = 390 [M+H]+.
[02-023] [02-023] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(imidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1- carbothioamide (from imidazo[1,2-a]pyridine-2-carbohydrazide and isothiocyanatobenzo[cf][1,3]dioxole, 230 mg, 77%). LC-MS (ES) m/z = 356 [M+H]+. [02-024] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(5-methylimidazo[1,2-a]pyridine-2- carbonyl)hydrazine-1 -carbothioamide (from 5-methylimidazo[1,2-a]pyridine-2- carbohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 249 mg, 81%). LC-MS (ES) m/z = 370 [M+H]+. [02-025] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(7-methylimidazo[1,2-a]pyridine-2- carbonyl)hydrazine-1 -carbothioamide (from 7-methylimidazo[1,2-a]pyridine-2- carbohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 143 mg, 61%).
[02-026] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(4- (trifluoromethoxy)benzyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2- a]pyridine-2-carbohydrazide and 1-(isothiocyanatomethyl)-4-
(trifluoromethoxy)benzene, 210 mg, 65%).
[02-027] [02-027] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-A/-(2,3-dihydro-1H-inden-5- yl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 5-isothiocyanato-2,3-dihydro-1H-indene, 162 mg, 88%). [02-028] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(4-phenoxyphenyl)hydrazine- 1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1- isothiocyanato-4-phenoxynenzene, 167 mg, 80%).
[02-029] A/-(4-(benzyloxy)phenyl)-2-(7-chloroimidazo[1,2-a]pyridine-2- carbonyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and 1-(benzyloxy)-4-isothiocyanatobenzene, 199 mg, 92%).
[02-030] A/-(3-(benzyloxy)phenyl)-2-(7-chloroimidazo[1,2-a]pyridine-2- carbonyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and 1-(benzyloxy)-3-isothiocyanatobenzene, 187 mg, 88%).
[02-031] [02-031] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-A/-(4-methoxy-2-methylphenyl) hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1-isothiocyanato-4-methoxy-2-methylbenzene, 159 mg, 86%).
[02-032] [02-032] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-A/-(6-chloropyridin-3- yl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 2-chloro-5-isothiocyanatopyridine, 172 mg, 63%).
[02-034] 4-(2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1 -carbothioamido) benzoic acid (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 4- isothiocyanatobenzoic acid, 332 mg, 89%). LC-MS (ES) m/z = 390 [M+H]+.
[02-035] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(4- sulfamoylphenyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and 4-isothiocyanatobenzenesulfonamide, 343 mg, 85%). LC-MS (ES) m/z = 425 [M+H]+.
[02-036] A/-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1- carbonothioyl)benzamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and benzoylisothiocyanate, 174 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 11.91 (s, 1H), 10.90 (s, 1 H), 8.65 (dd, J = 7.3, 0.7 Hz, 1 H), 8.60 (d, J = 0.6 Hz, 1 H), 8.01 - 7.97 (m, 2H), 7.91 - 7.88 (m, 1H), 7.71 - 7.64 (m, 1 H), 7.54 (dd, J = 10.6, 4.8 Hz, 2H), 7.14 (dd, J = 7.3, 2.1 Hz, 1 H). LC-MS (ES) m/z = 374 [M+H]+.
[02-037]
[02-037] A/-(benzo[cf][1,3]dioxol-5-yl)-2-(imidazo[2,1-a]isoquinoline-2- carbonyl)hydrazine-1 -carbothioamide (from 04-002 and isothiocyanatobenzo[cf][1,3]dioxole, 53 mg, 69%).
[02-038]
[02-038] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(imidazo[1,2-a]quinoline-2-carbonyl)hydrazine- 1 -carbothioamide (from 04-003 and isothiocyanatobenzo[cf][1,3]dioxole, 72 mg, 63%).
[02-039] [02-039] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(imidazo[1,2-a]pyrazine-2-carbonyl)hydrazine-1- carbothioamide (from 04-004 and isothiocyanatobenzo[d][1,3]dioxole, 46 mg, 65%).
[02-040] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(2-methylquinoline-4-carbonyl)hydrazine-1- carbothioamide (from 04-005 and isothiocyanatobenzo[d][1,3]dioxole, 82 mg, 64%). LC- MS (ES) m/z = 381 [M+H]+.
[02-041] A/-(3,4-dimethoxybenzyl)-2-(quinoline-2-carbonyl)hydrazine-1 -carboxamide
(183 mg, 69%, applying P04 to condense 04-001 and 4-(isocyanatomethyl)-1,2- dimethoxybenzene). LC-MS (ES) m/z = 382 [M+H]+.
[02-042]
[02-042] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(6-bromoimidazo[1,2-a]pyridine-2- carbonyl)hydrazine-1 -carbothioamide (from 04-006 and isothiocyanatobenzo[d][1,3]dioxole, 65 mg, 54%). LC-MS (ES) m/z = 435 [M+H]+.
[02-043] [02-043] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(7-bromoimidazo[1,2-a]pyridine-2- carbonyl)hydrazine-1 -carbothioamide (from 04-007 and isothiocyanatobenzo[d][1,3]dioxole, 152 mg, 89%).
[02-044]
[02-044] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(thiophen-2- ylmethyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and 2-(isothiocyanatomethyl)thiophene, 152 mg, 87%).
[02-045]
[02-045] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(1-methyl-1H-pyrazol-3- yl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 3-isothiocyanato-1-methyl-1H-pyrazole, 198 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 5 11.87 (s, 1H), 10.90 (s, 1H), 10.64 (s, 1H), 8.65 (dd, J = 7.3, 0.8 Hz, 1H), 8.53 (d, J = 0.7 Hz, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 7.12 (dd, J = 7.3, 2.1 Hz, 1H), 5.96 (s, 1H), 3.80 (s, 4H).
[02-046] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(2,2- diphenylethyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and (2-isothiocyanatoethane-1,1-diyl)dibenzene, 177 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.42 (bs, 1H), 8.64 (dd, J = 7.3, 0.9 Hz, 1H), 8.46 (d, J = 0.8 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.32 - 7.08 (m, 11 H), 4.49 (d, J = 8.1 Hz, 1H), 4.07 (t, J = 6.5 Hz, 2H).
[02-047]
[02-047] 2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)-/V-(3- morpholinopropyl)hydrazine-1 -carbothioamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and 4-(3-isothiocyanatopropyl)morpholine, 155 mg, 82%).1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.30 (s, 1H), 8.65 (dd, J= 7.3, 0.9 Hz, 1H), 8.50 (d, J = 0.8 Hz, 1H), 7.92 (s, 1H), 7.78 (dd, J= 1.9, 1.0 Hz, 1H), 7.10 (dd, J= 7.3, 2.1 Hz, 1H), 3.51-3.40 (m, 6H), 2.32-2.22 (m, 6H), 1.64 (p, J= 7.0 Hz, 2H).
[02-048]
[02-048] 3-(2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1- carbothioamido)benzamide (from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 03-001, 188 mg, quant.). 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.81 (s, 2H), 8.66 (dd, J= 7.3, 0.9 Hz, 1H), 8.52 (s, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.63 (dt, J= 7.8, 1.3 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.33 (s, 1H), 7.11 (dd, J= 7.3, 2.1 Hz, 1H).
[02-049]
[02-049] 5-(2-(7-Chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1- carbothioamido)-2-methoxybenzamide (from 7-chloroimidazo[1,2-a]pyridine-2- carbohydrazide and 03-002, 108 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.70 (s, 2H), 8.66 (dd, J= 7.3, 0.9 Hz, 1H), 8.52 (d, J= 0.8 Hz, 1H), 7.80 (d, J= 2.4 Hz, 2H), 7.67 - 7.60 (m, 2H), 7.52 (s, 1H), 7.14 - 7.05 (m, 2H), 3.89 (s, 3H).
[02-050]
[02-050] 4-(4-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1- carbothioamido)phenoxy)-A/-methylpicolinamide (from 7-chloroimidazo[1,2-a]pyridine- 2-carbohydrazide and 03-003, 182 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.81 (bs, 2H), 8.76 (q, J = 4.7 Hz, 1H), 8.66 (dd, J = 7.3, 0.9 Hz, 1H), 8.55 - 8.49 (m, 2H), 7.81 (d, J= 2.1 Hz, 1H), 7.60 (d, J= 8.3 Hz, 2H), 7.40 (d, J= 2.6 Hz, 1H), 7.22 - 7.09 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H).
[02-051]
[02-051] A/-(benzo[oQ[1,3]dioxol-5-y/)-2-nicotinoylhydrazine-1 -carbothioamide (from nicotinohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 68 mg, 43%).
[02-052]
[02-052] A/-(benzo[oQ[1,3]dioxol-5-y/)-2-(2-chloroisonicotinoyl)hydrazine-1- carbothioamide (from 2-chloroisonicotinohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 342 mg, 98%). LC-MS (ES) m/z = 351 [M+H]+.
[02-053]
[02-053] A/-(benzo[oQ[1,3]dioxol-5-yl)-2-(6-chloronicotinoyl)hydrazine-1- carbothioamide (from 6-chloronicotinohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 316 mg, 90%). LC-MS (ES) m/z = 352 [M+H]+.
[02-054]
[02-054] A/-(benzo[oQ[1 ,3]dioxol-5-yl)-2-(6-chloropicolinoyl)hydrazine-1 -carbothioamide (from 6-chloropicolinohydrazide and isothiocyanatobenzo[d][1,3]dioxole, 795 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1 H), 9.72 (s, 1 H), 9.64 (s, 1 H), 8.15 - 7.96 (m, 2H), 7.77 (dd, J = 7.6, 1.3 Hz, 1 H), 7.04 (s, 1 H), 6.85 (d, J = 8.3 Hz, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 6.01 (s, 2H). LC-MS (ES) m/z = 351 [M+H]+.
2.5. Synthesis of Triazoles 1 and Related Compounds
P05: In a Carousel® tube, compound 2 (1 eq) was suspended in aqueous NaOH solution (typically 1 M, 20-40 eq). After three cycles of vacuum-argon, the tube was sealed, and the mixture was refluxed for 6-24 hours. Once the consumption of the starting material was confirmed by HPLC-MS or TLC, the tube was cooled to rt and the pH was adjusted to 3 using an aqueous HCI solution (typically 1 M). The precipitate formed was filtered, washed with very small amount of cold water, and was freeze-dried to obtain the title compound 1. In case of having highly lipophilic intermediates, up to 5% (v/v) of ethanol was added to the reaction mixture.
P06: In a Carousel® tube, compound 2 (1 eq) was suspended in 10% aqueous Na2COs solution (typically 20-40 eq). After three cycles of vacuum-argon, the tube was sealed, and the mixture was refluxed for 6-24 hours. Once the consumption of the starting material was confirmed by HPLC-MS or TLC, the tube was cooled to rt and the pH was adjusted to 3 using an aqueous HCI solution (typically 2 M, while stirring). The precipitate formed was filtered, washed with very small amount of cold water and freeze-dried to obtain the title compound 1 .
P07: In a pressure tube, compound 2 was suspended in glacial acetic acid (typically 70-100 eq). The tube was sealed, and the mixture was stirred at 160 °C for 6-24 hours. Once the consumption of the starting material was confirmed by HPLC-MS, the tube was cooled to rt. The precipitate formed was filtered, washed with cold water and freeze-dried to obtain the title compound 1. P08: To improve the solubility of compounds 1 , they were converted to corresponding sodium salts 1-Na as follows. In a falcon tube 5-10 mgs of the compound 1 was dissolved in the smallest amount of acetonitrile (typically 2-3 mL) and 1eq of NaOH (in the form of aqueous solution) was added. The solution was then diluted with water to reach a 1 :9 solution of acetonitrile: water. The solution was then freeze-dried to obtain the sodium salts 1-Na in quantitative yields. Representative examples were characterized by LC-MS or 1HNMR.
[01-001] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione. (197 mg, 78%, applying P05 upon intermediate 02-001): 1H NMR (400 MHz, DMSO- d6) 5 14.29 (s, 1 H), 8.47 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 5.3 Hz, 2H), 7.73 (d, J = 7.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.10 - 6.91 (m, 2H), 6.82 (d, J= 8.1 Hz, 1H), 6.13 (s, 2H). LC-MS (ES) m/z = 349 [M+H]+.
[01 -001 -Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro- 1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 8.1 Hz, 1H), 7.61 (ddd, J = 8.4, 7.0, 1.4 Hz, 1 H), 7.48 (ddd, J = 8.1, 7.0, 1.2 Hz, 1 H), 7.34 (d, J = 8.5 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.75 (d, J = 2.0 Hz, 1H), 6.53 (dd, J = 8.2, 2.0 Hz, 1H), 6.08 (s, 2H). LC-MS (ES) m/z = 349 [M-Na+H]+.
[01-002] 5-(Quinolin-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (33 g, 86%, applying P06 upon intermediate 02-002): 1H NMR (400 MHz, DMSO-d6) δ 14.46 (s, 1 H), 8.49 (d, J = 8.7 Hz, 1 H), 8.10 (d, J = 8.6 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.69 (dd, J= 13.8, 7.1 Hz, 3H), 7.61 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H). LC-MS (ES) m/z = 342 [M+H]+.
[01 -002-Na] Sodium 3-(quinolin-2-yl)-5-thioxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro- 1,2,4-triazol-1-ide.1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J= 8.7 Hz, 1H), 8.14 (d, J= 8.7 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.74 (d, J= 8.3 Hz, 2H), 7.57 (t, J= 7.6 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H). LC-MS (ES) m/z = 342 [M- Na+H]+.
[01 -003] 4-(4-Chlorophenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1 ,2,4-triazole-3-thione (53 mg, 70%, applying P05 upon intermediate 02-003): 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 8.45 (d, J= 8.6 Hz, 1H), 8.08 (t, J= 10.8 Hz, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.60 (t, J= 7.3 Hz, 1H), 7.55 (d, J= 8.6 Hz, 2H), 7.41 (d, J= 8.6 Hz, 2H), 7.31 (d, J= 8.4 Hz, 1H). LC-MS (ES) m/z = 339 [M+H]+.
[01 -003-Na] Sodium 4-(4-chlorophenyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J= 8.7 Hz, 1H), 8.11 (d, J= 8.7 Hz, 1H), 7.86 (d, J= 7.6 Hz, 1H), 7.60 (t, J= 7.0 Hz, 1H), 7.47 (t, J= 7.0 Hz, 1H), 7.42 (d, J= 8.6 Hz, 2H), 7.23 - 7.16 (m, 3H). LC-MS (ES) m/z = 339 [M-Na+H]+.
[01-004] 5-(Quinolin-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (56 mg, 69%, applying P05 upon intermediate 02-004): 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J= 8.6 Hz, 1H), 8.00 (d, J= 8.6 Hz, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.63 (t, J= 7.5 Hz, 1H), 7.51 (t, J= 7.4 Hz, 1H), 7.31 (d, J= 8.3 Hz, 1H), 7.20 (d, J= 8.1 Hz, 2H), 7.10 (d, J= 8.1 Hz, 2H), 2.38 (s, 3H), The mobile proton is missing. LC-MS (ES) m/z = 319 [M+H]+. [01 -004-Na] Sodium 3-(quinolin-2-yl)-5-thioxo-4-(p-tolyl)-4,5-dihydro-1 ,2,4-triazol-1 -ide.
LC-MS (ES) m/z = 319 [M-Na+H]+
[01 -005] 4-(3-Bromophenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1 ,2,4-triazole-3-thione (48 mg, 46%, applying P05 upon intermediate 02-005): 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1 H), 7.77 - 7.69 (m, 3H), 7.62 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.42 (dt, J = 8.0, 1.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H). LC-MS (ES) m/z = 385 [M+H]+.
[01 -005-Na] Sodium 4-(3-bromophenyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide. LC-MS (ES) m/z = 385 [M-Na+H]+.
[01-006] 4-Benzyl-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (62 mg, 66%, applying P05 upon intermediate 02-006): 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1 H), 8.48 (d, J = 8.6 Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 8.03 (d, J = 4.3 Hz, 1 H), 8.01 (d, J = 3.3 Hz, 1 H), 7.83 (t, J = 8.3 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.28 (d, J = 7.3 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 6.04 (s, 2H). LC-MS (ES) m/z = 319 [M+H]+.
[01 -006-Na] Sodium 4-benzyl-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4-triazol-1 -ide. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (dt, J = 13.1 , 6.7 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1 H), 7.72 (t, J = 7.7 Hz, 1 H), 7.53 (t, J = 8.9 Hz, 1 H), 7.32 - 7.26 (m, 2H), 7.18 - 7.11 (m, 2H), 7.06 (t, J = 6.9 Hz, 1 H), 6.02 (s, 2H). LC-MS (ES) m/z = 319 [M-Na+H]+.
[01-007] 4-Phenyl-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (51 mg, 72%, applying P05 upon intermediate 02-007): 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1 H), 8.46 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1 H), 7.61 (t, J = 7.3 Hz, 1H), 7.53 - 7.40 (m, 3H), 7.39 - 7.34 (m, 2H), 7.29 (d, J= 8.3 Hz, 1 H). LC- MS (ES) m/z = 305 [M+H]+.
[01-007-Na] Sodium 4-phenyl-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.7 Hz, 1 H), 8.06 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 6.9 Hz, 1 H), 7.40 - 7.29 (m, 3H), 7.20 - 7.10 (m, 3H). LC-MS (ES) m/z = 305 [M-Na+H]+.
[01 -008] 1 -(4-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)phenyl)ethan- 1-one (37 mg, 43%, applying P06 upon intermediate 02-008): 1H NMR (400 MHz, DMSO-d6) δ
5 14.43 (s, 1H), 8.47 (d, J = 8.7 Hz, 1H), 8.11 - 8.00 (m, 3H), 7.97 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.0 Hz, 1H), 7.59 (dd, J = 15.3, 8.3 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H), 2.65 (s, J = 37.2 Hz, 3H). LC-MS (ES) m/z = 347 [M+H]+.
[01-009] [01 -009] 4-(4-Phenoxybenzyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1 ,2,4-triazole-3-thione (44 mg, 57%, applying P05 upon intermediate 02-009): 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1 H), 8.51 (d, J = 8.6 Hz, 1 H), 8.11 (d, J = 8.6 Hz, 1H), 8.06 (t, J = 7.6 Hz, 2H), 7.85 (t, J = 7.8 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.37 - 7.29 (m, 4H), 7.09 (t, J = 7.3 Hz, 1 H), 6.92 - 6.81 (m, 4H), 6.02 (s, 2H). LC-MS (ES) m/z = 411 [M+H]+.
[01 -009-Na] Sodium 4-(4-phenoxybenzyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.7 Hz, 1 H), 8.19 (d, J = 8.7 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1 H), 7.71 (t, J = 7.0 Hz, 1 H), 7.53 (t, J = 7.3 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 2H), 7.33 - 7.25 (m, 2H), 7.05 (t, J = 7.4 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.00 (s, 2H). LC-MS (ES) m/z = 411 [M-Na+H]+.
[01-010] 4-(4-Methoxy-2-methylphenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (51 mg, 67%, applying P05 upon intermediate 02-010). 1H NMR (400 MHz, DMSO-d6) 5 14.33 (s, 1H), 8.47 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 8.6 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1 H), 6.98 (d, J = 2.7 Hz, 1 H), 6.81 (dd, J = 8.6, 2.8 Hz, 1H), 3.81 (s, J = 5.4 Hz, 3H), 2.06 (s, 3H). LC-MS (ES) m/z = 349 [M+H]+.
[01 -010-Na] Sodium 4-(4-methoxy-2-methylphenyl)-3-(quinolin-2-yl)-5-thioxo-4,5- dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J= 8.6 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.57 (t, J= 7.7 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 6.86 - 6.79 (m, 2H), 6.72 (dd, J = 8.5, 2.8 Hz, 1 H), 3.79 (s, 3H), 1.91 (s, 3H). LC-MS (ES) m/z = 349 [M-Na+H]+. [01-011] 4-(4-Methoxyphenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (50 mg, 88%, applying P05 upon intermediate 02-011). 1H NMR (400 MHz, DMSO-d6) δ 14.30 (s, 1 H), 8.46 (d, J = 8.6 Hz, 1 H), 8.01 - 7.93 (m, 2H), 7.73 (t, J = 7.3 Hz, 1 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). LC-MS (ES) m/z = 335 [M+H]+.
[01 -011 -Na] Sodium 4-(4-methoxyphenyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide. LC-MS (ES) m/z = 335 [M-Na+H]+.
[01-012] 4-([1,1'-Biphenyl]-3-yl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (70 mg, 92%, applying P05 upon intermediate 02-012). 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1 H), 8.47 (d, J = 8.5 Hz, 1 H), 8.05 (d, J = 8.6 Hz, 1 H), 8.01 - 7.93 (m, 1 H), 7.86 - 7.80 (m, 1H), 7.75 (t, J= 1.8 Hz, 1H), 7.70 - 7.54 (m, 5H), 7.44 (t, J= 7.5 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H). LC-MS (ES) m/z = 381 [M+H]+.
[01 -012-Na] Sodium 4-([1 ,1 '-biphenyl]-3-yl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide. LC-MS (ES) m/z = 381 [M-Na+H]+.
[01-013] 4-(4-(Benzyloxy)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (44 mg, 55%, applying P05 upon intermediate 02-013). 1H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 8.45 (d, J = 8.6 Hz, 1 H), 7.98 (d, J= 8.2 Hz, 2H), 7.72 (t, J= 7.6 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1 H), 7.49 (d, J = 7.1 Hz, 2H), 7.42 (t, J = 7.1 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 5.20 (s, 2H). LC-MS (ES) m/z = 411 [M+H]+. [01 -013-Na] Sodium 4-(4-(benzyloxy)phenyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro- 1,2,4-triazol-1-ide. LC-MS (ES) m/z = 411 [M-Na+H]+.
[01-014] 5-(Quinolin-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (55 mg, 73%, applying P05 upon intermediate 02-014). 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1 H), 8.56 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1 H), 7.91 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 5.0 Hz, 1H), 7.24 (d, J = 3.1 Hz, 1H), 6.93 - 6.83 (m, 1H), 6.25 (s, 2H). LC-MS (ES) m/z = 325 [M+H]+.
[01-014-Na] Sodium 3-(quinolin-2-yl)-4-(thiophen-2-ylmethyl)-5-thioxo-4,5-dihydro- 1,2,4-triazol-1-ide. LC-MS (ES) m/z = 325 [M-Na+H]+.
[01-015] 4-(4-Phenoxyphenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (34 mg, 44%, applying P05 upon intermediate 02-015): 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.0 Hz, 1 H), 7.52 (t, J = 7.0 Hz, 1 H), 7.46 - 7.39 (m, 2H), 7.35 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1 H), 7.07 (dd, J = 8.6, 0.9 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H). The mobile proton signal is missing. LC-MS (ES) m/z = 397 [M+H]+.
[01 -015-Na] Sodium 4-(4-phenoxyphenyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide. LC-MS (ES) m/z = 397 [M-Na+H]+.
[01-016] 4-(3-(Benzyloxy)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (27 mg, 37%, applying P05 upon intermediate 02-016).1H NMR (400 MHz, DMSO-d6) δ
6 14.29 (s, 1H), 8.43 (d, J =8.6 Hz, 1H), 8.02-7.93 (m, 2H), 7.69 (t, J = 6.9 Hz, 1H), 7.61 (t, J= 7.5 Hz, 1H), 7.40-7.34 (m, 3H), 7.33-7.24 (m, 4H), 7.13 (dd, J= 8.2, 2.2 Hz, 1H), 7.06 (s, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 5.07 (d, J = 12.9 Hz, 2H). LC-MS (ES) m/z = 411 [M+H]+.
[01 -016-Na] Sodium 4-(3-(benzyloxy)phenyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro- 1,2,4-triazol-1-ide . LC-MS (ES) m/z = 411 [M-Na+H]+. [01-017] 4-(2,3-Dihydro-1H-inden-5-yl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (46 mg, 60%, applying P05 upon intermediate 02-017).1H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 8.45 (d, J= 8.6 Hz, 1H), 7.98 (d, J= 8.2 Hz, 1H), 7.95 (d, J= 8.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.08 (d, J= 7.6 Hz, 1H), 2.90 (dt, J= 23.2, 7.2 Hz, 4H), 2.16-2.01 (m, 2H). LC-MS (ES) m/z = 345 [M+H]+.
[01 -017-Na] Sodium 4-(2,3-dihydro-1 H-inden-5-yl)-3-(quinolin-2-yl)-5-thioxo-4,5- dihydro-1,2,4-triazol-1-ide. LC-MS (ES) m/z = 345 [M-Na+H]+. [01-018] 4-(6-Chloropyridin-3-yl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (43 mg, 35%, applying P06 upon intermediate 02-018). 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1 H), 8.58 - 8.46 (m, 2H), 8.13 (d, J = 8.5 Hz, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 7.83 - 7.70 (m, 2H), 7.64 (t, J = 7.4 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H). LC-MS (ES) m/z = 340 [M+H]+.
[01 -018-Na] Sodium 4-(6-chloropyridin-3-yl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-
1,2,4-triazol-1-ide. LC-MS (ES) m/z = 340 [M-Na+H]+.
[01-019] 4-(6-(Piperazin-1-yl)pyridin-3-yl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazole- 3-thione: In a pressure tube, a solution of compound 01-018 (30 mg, 1 eq) and piperazine (38 mg, 5 eq) in dioxane (8.8 mL, 0.1 M) was stirred at 100 °C for 60 hours. The solvent was evaporated and the crude was purified by reverse-phase chromatography (wateracetonitrile gradient, both containing 0.07% TFA) to obtain the title compound. ( 8 mg, 23%). LC-MS (ES) m/z = 390 [M+H]+.
[01 -020] Phenyl(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)methanone (46 mg, 68%, applying P07 upon intermediate 02-020, isolated as the acetic acid salt). 1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1 H), 11.98 (s, 1 H), 8.58 (d, J = 8.6 Hz, 1 H), 8.38 (d, J = 8.6 Hz, 1 H), 8.18 (d, J = 7.6 Hz, 2H), 8.13 (d, J = 8.4 Hz, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), 7.87 (t, J = 7.6 Hz, 1 H), 7.70 (t, J = 8.6 Hz, 2H), 7.60 (t, J = 7.6 Hz, 2H), 1.91 (s, 3H). LC-MS (ES) m/z = 333 [M+H]+.
[01-021] (4-Chlorophenyl)(3-(quinolin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl) methanone (25 mg, 33%, applying P07 upon intermediate 02-021). 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1 H), 8.59 (d, J = 8.6 Hz, 1 H), 8.38 (d, J = 8.6 Hz, 1 H), 8.19 (d, J = 8.6 Hz, 2H), 8.13 (d, J = 8.5 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.87 (t, J = 7.7 Hz, 1H), 7.76 - 7.60 (m, 3H). LC-MS (ES) m/z = 367 [M+H]+.
[01 -021 -Na] Sodium 4-(4-chlorobenzoyl)-3-(quinolin-2-yl)-5-thioxo-4,5-dihydro-1 ,2,4- triazol-1-ide. LC-MS (ES) m/z = 367 [M-Na+H]+. [01-022] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridin-2-yl)-2,4-dihydro- 3H-1,2,4-triazole-3-thione (811 mg, 87%, applying P05 upon intermediate 02-022). 1H NMR (400 MHz, DMSO-d6) δ 14.07 (s, 1 H), 8.58 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 2.1 Hz, 1 H), 7.64 (s, 1 H), 7.08 - 6.96 (m, 3H), 6.84 (dd, J = 8.2, 2.1 Hz, 1 H), 6.16 (s, 2H). LC-MS (ES) m/z = 372[M+H]+. [01-022-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(7-chloroimidazo[1,2-a]pyridin-2-yl)- 5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 7.2 Hz, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 6.92 (dd, J= 7.3, 2.1 Hz, 1 H), 6.88 (d, J= 8.2 Hz, 1 H), 6.76 (d, J = 1.9 Hz, 1 H), 6.54 (dd, J = 8.2, 2.0 Hz, 1 H), 6.08 (s, 2H). LC-MS (ES) m/z = 372 [M-Na+H]+.
[01-023] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridin-2-yl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione (51 mg, 45%, applying P05 upon intermediate 02-023). 1H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1 H), 8.67 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.62 (s, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.15 - 7.04 (m, 3H), 6.91 (dd, J = 8.0, 1.9 Hz, 1 H), 6.18 (s, 2H). LC-MS (ES) m/z = 338 [M+H]+.
[01-023-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(imidazo[1,2-a]pyridin-2-yl)-5-thioxo- 4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (dt, J = 6.8, 1.2 Hz, 1H), 7.53 (s, 1H), 7.48 - 7.39 (m, 1H), 7.17 (ddd, J= 9.1, 6.7, 1.3 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.82 (td, J= 6.8, 1.2 Hz, 1H), 6.76 (d, J= 2.0 Hz, 1H), 6.54 (dd, J= 8.2, 2.0 Hz, 1H), 6.07 (s, 2H). LC-MS (ES) m/z = 338 [M-Na+H]+.
[01-024] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridin-2-yl)-2,4-dihydro- 3H-1,2,4-triazole-3-thione (66 mg, 57%, applying P05 upon intermediate 02-024). 1H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 7.57 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 9.2, 6.8 Hz, 1 H), 7.06 (d, J = 2.1 Hz, 1 H), 7.04 (d, J = 8.3 Hz, 1 H), 6.93 (d, J = 7.1 Hz, 1H), 6.88 (dd, J = 8.2, 2.1 Hz, 1 H), 6.15 (s, 2H), 2.49 (s, overlapped with solvent peak). LC-MS (ES) m/z = 352 [M+H]+.
[01-024-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(5-methylimidazo[1,2-a]pyridin-2-yl)- 5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 0.7 Hz, 1 H), 7.34 (d, J = 8.9 Hz, 1 H), 7.15 (dd, J = 9.1 , 6.8 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1 H), 6.73 (d, J = 6.8 Hz, 1 H), 6.56 (dd, J = 8.2, 2.0 Hz, 1 H), 6.06 (s, 2H). The methyl signal is overlapped by solvent peak. LC-MS (ES) m/z = 352 [M-Na+H]+.
[01-025] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridin-2-yl)-2,4-dihydro- 3H-1,2,4-triazole-3-thione (49 mg, 64%, applying P05 upon intermediate 02-025). 1H NMR (400 MHz, DMSO-d6) δ 14.24 (s, 1 H), 8.54 (d, J = 7.1 Hz, 1 H), 7.51 (s, 1 H), 7.43 (s, 1 H), 7.09 (d, J = 3.3 Hz, 1 H), 7.07 (d, J = 3.1 Hz, 1 H), 6.99 (d, J = 7.2 Hz, 1 H), 6.90 (dd, J = 8.3, 2.0 Hz, 1 H), 6.18 (s, 2H), 2.40 (s, J = 27.6 Hz, 3H). LC-MS (ES) m/z = 352 [M-Na+H]+.
[01-025-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)- 5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.0 Hz, 1 H), 7.42 (s, 1 H), 7.23 (s, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.78 (s, 1 H), 6.68 (dd, J = 6.9, 1.6 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 6.08 (s, 2H), 2.30 (s, 3H). LC-MS (ES) m/z = 352 [M-Na+H]+.
[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 (210 mg, 66%, applying P05 upon intermediate 02-026). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 7.2 Hz, 1 H), 8.23 (s, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.00 (dd, J = 7.2, 2.1 Hz, 1 H), 5.79 (s,
J = 14.9 Hz, 2H). LC-MS (ES) m/z = 426 [M+H]+.
[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 (55 mg, 72%, applying P05 upon intermediate 02-027). 1H NMR (400 MHz, DMSO-d6) δ 14.10 (s, 1H), 8.56 (d, J=7.3Hz, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.36 (d, J= 8.1 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J = 6.5 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 2.98 - 2.84 (m, 4H), 2.14 - 2.03 (m, 2H).
[01-027-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(2,3-dihydro-1H-inden-5- yl)-5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 7.3, 0.8 Hz, 1 H), 7.60 (dd, J= 1.4, 0.8 Hz, 1H), 7.48 (d, J= 0.7 Hz, 1H), 7.18 (d, J= 7.9 Hz, 1H), 7.05 (s, 1H), 6.90 (dd, J= 7.3, 2.1 Hz, 1H), 6.85 (dd, J= 7.8, 1.9 Hz, 1H), 2.87 (dt, J = 11.1, 7.4 Hz, 4H), 2.13-1.97 (m, 2H).
[01-028] 5-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione (43 mg, 56%, applying P05 upon intermediate 02-028).1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.44 (dd, J = 14.6, 7.6 Hz, 2H), 7.22 - 7.13 (m, 3H), 7.09 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 6.8 Hz, 1H). The mobile proton signal is missing, likely swapped with the adventitious H2O in the solvent.
[01-028-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(4-phenoxyphenyl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide.1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J= 7.2, 0.8 Hz, 1H), 7.64 (d, J = 0.7 Hz, 1H), 7.59 (d, J= 2.1 Hz, 1H), 7.46-7.38 (m, 2H), 7.20-7.13 (m, 3H), 7.08 (dd, J= 8.7, 1.1 Hz, 2H), 7.00-6.95 (m, 2H), 6.93 (dd, J= 7.2, 2.1 Hz, 1H).
[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 (29 mg, 38%, applying P05 upon intermediate 02-029).1H NMR (400 MHz, DMSO-d6) δ 14.09 (s, 1H), 8.56 (d, J= 7.2 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.46-7.39 (m, 2H), 7.37 (d, J= 7.3 Hz, 1H), 7.31 (d, J= 8.8 Hz, 2H), 7.15 (d, J= 8.9 Hz, 2H), 7.02 (dd, J= 7.2, 1.9 Hz, 1H), 5.17 (s, 2H).
[01-029-Na] Sodium 4-(4-(benzyloxy)phenyl)-3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 7.3, 0.8 Hz, 1 H), 7.58 (dd, J = 1.4, 0.8 Hz, 1 H), 7.52 (d, J = 0.7 Hz, 1 H), 7.50 - 7.46 (m, 2H), 7.45 -7.30 (m, 3H), 7.11 -7.04 (m, 2H), 7.02-6.95 (m, 2H), 6.91 (dd, J= 7.3, 2.1 Hz, 1H), 5.12 (s, 2H).
[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 (47 g, 61%, applying P05 upon intermediate 02-030). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J= 7.2 Hz, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.44 - 7.20 (m, 6H), 7.10 (d, J = 8.5 Hz, 1H), 7.04-6.93 (m, 2H), 6.87 (d, J= 7.7 Hz, 1H), 5.07 (s, 2H). The mobile proton signal is missing, likely swapped with the adventitious H2O in the solvent.
[01-030-Na] Sodium 4-(3-(benzyloxy)phenyl)-3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide.1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J= 7.2 Hz, 1H), 7.58 (d, J= 2.1 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J= 6.9 Hz, 2H), 7.37-7.31 (m, 2H), 7.30 -7.22 (m, 2H), 6.98 (dd, J= 8.0, 2.1 Hz, 1H), 6.91 (dd, J= 7.3, 2.1 Hz, 1H), 6.88 - 6.84 (m, 1H), 6.73 (d, J= 8.8 Hz, 1H), 5.05 (s, 2H).
[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 (49 mg, 64%, applying P05 upon intermediate 02-031). 1H NMR (400 MHz, DMSO-d6) δ 14.13 (s, 1H), 8.56 (d, J =7.4 Hz, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.20 (d, J = 8.8 Hz, 1 H), 7.03 - 6.97 (m, 2H), 6.91 (dd, J = 8.6, 2.4 Hz, 1 H), 3.83 (s, 3H), 2.00 (s, 3H).
[01 -031 -Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(4-methoxy-2- methylphenyl)-5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 6 8.46 (dd, J = 7.3, 0.7 Hz, 1 H), 7.58 (dd, J = 1.4, 0.8 Hz, 1H), 7.20 (d, J = 0.6 Hz, 1 H), 6.90 - 6.84 (m, 3H), 6.78 (dd, J = 8.6, 2.7 Hz, 1H), 3.79 (s, 3H), 1.91 (s, 3H).
[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 (36 mg, 38%, applying P05 upon intermediate 02-032). 1H NMR (400 MHz, DMSO-d6) δ 14.30 (s, 1 H), 8.59 (d, J = 7.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.20 (s, 1H), 8.01 (dd, J = 8.4, 2.7 Hz, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.67 (s, 1 H), 7.06 (dd, J = 7.3, 2.1 Hz, 1 H).
[01-032-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(6-chloropyridin-3-yl)-5- thioxo-4,5-dihydro-1 ,2,4-triazol-1 -ide.
[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. In a Schleck tube under argon, a solution of compound 01-032 (35 mg, 1 eq) in pyrrolidine (1.2 mL, 0.8 M) was stirred at reflux for 24h. The solvent was evaporated and the title compound ( 8 mg, 23%) was isolated through recrystalization from MeOH. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (dd, J = 7.3, 0.8 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1 H), 7.87 (d, J = 0.6 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1 H), 7.48 (dd, J = 8.9, 2.7 Hz, 1 H), 7.02 (dd, J = 7.3, 2.1 Hz, 1H), 6.53 (d, J= 9.1 Hz, 1H), 3.44 (t, J = 6.1 Hz, 4H), 2.03 - 1.88 (m, 6H). The mobile proton signal is missing, likely swapped with the adventitious H2O in the solvent. LC-MS (ES) m/z = 398 [M+H]+.
[01-034] 4-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol- 4-yl)benzoic acid ( 48 mg, 63%, applying P05 upon intermediate 02-034). 1H NMR (400 MHz, DMSO-d6) δ 14.22 (s, 1H), 13.24 (s, 1H), 8.56 (dd, J = 7.3, 0.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 0.6 Hz, 1 H), 7.67 (d, J = 2.1 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 2H), 7.02 (dd, J = 7.3, 2.1 Hz, 1 H). LC-MS (ES) m/z = 372 [M+H]+.
[01-034-Na] Disodium 4-(4-carboxylatophenyl)-3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide (applying a modified P08 upon compound 01-034 using 2 eq of NaOH). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 7.3, 0.8 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.60 (dd, J = 1.4, 0.8 Hz, 1H), 7.42 (d, J= 0.7 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.88 (dd, J = 7.3, 2.1 Hz, 1 H). LC-MS (ES) m/z = 372 [M-2Na+H]+.
[01-035] 4-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol- 4-yl)benzenesulfonamide (84 mg, 88%, applying P05 upon intermediate 02-035). 1H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1H), 8.59 (d, J= 7.2 Hz, 1H), 8.07 (s, 1H), 7.90 (dd, J = 24.5, 5.3 Hz, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.52 (s, 2H), 7.05 (dd, J = 7.3, 2.1 Hz, 1 H). LC-MS (ES) m/z = 407 [M+H]+.
[01-035-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(4-sulfamoylphenyl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J= 7.3, 0.7 Hz, 1 H), 7.76 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 2.1 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 2H), 6.92 (dd, J = 7.2, 2.1 Hz, 1 H). LC-MS (ES) m/z = 407 [M-Na+H]+.
[01-036] (3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4- yl)(phenyl)methanone (21 mg, 37%, applying P07 upon intermediate 02-036, isolated with traces of acetic acid). 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.66 (dd, J= 7.3, 0.6 Hz, 1H), 8.64 (d, J = 0.5 Hz, 1 H), 8.18 - 8.12 (m, 2H), 7.89 (d, J = 2.1 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1 H), 7.62 - 7.53 (m, 2H), 7.12 (dd, J = 7.3, 2.1 Hz, 1 H). LC-MS (ES) m/z = 356 [M+H]+.
[01-036-Na] Sodium 4-benzoyl-3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-4,5- dihydro-1,2,4-triazol-1-ide. LC-MS (ES) m/z = 356 [M-Na+H]+. [01-037] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinolin-2-yl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione (13 mg, 34%, applying P05 upon intermediate 02-037). 1H NMR (400 MHz, DMSO-d6) δ 14.05 (s, 1 H), 8.36 - 8.30 (m, 2H), 7.89 - 7.85 (m, 1 H), 7.72 - 7.63 (m, 2H), 7.62 (s, 1 H), 7.28 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.1 Hz, 1 H), 6.17 (s, J = 9.7 Hz, 2H). LC-MS (ES) m/z = 388 [M+H]+. [01-038] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinolin-2-yl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione (22 mg, 46%, applying P05 upon intermediate 02-038). 1H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1 H), 8.66 (s, 1 H), 8.25 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 7.9, 1.2 Hz, 1 H), 7.78 - 7.68 (m, 2H), 7.60 - 7.53 (m, 1H), 7.47 (d, J = 9.6 Hz, 1 H), 7.04 (d, J = 2.1 Hz, 1 H), 7.01 (d, J= 8.2 Hz, 1H), 6.85 (dd, J = 8.2, 2.1 Hz, 1H), 6.14 (s, 2H). LC-MS (ES) m/z = 388 [M+H]+.
[01-039] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazin-2-yl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione (11 mg, 34%, applying P05 upon intermediate 02-039). 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1 H), 9.06 (d, J = 0.9 Hz, 1 H), 8.59 (dd, J = 4.6, 1.6 Hz, 1H), 7.90 (t, J = 5.1 Hz, 1 H), 7.85 (d, J = 0.7 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1 H), 6.86 (dd, J = 8.2, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m/z = 339 [M+H]+. [01-040] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(2-methylquinolin-4-yl)-2,4-dihydro-3H-1,2,4- triazole-3-thione (28 mg, 37%, applying P05 upon intermediate 02-040). 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1 H), 7.94 (d, J = 8.3 Hz, 2H), 7.74 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 7.66 - 7.42 (m, 2H), 7.05 (d, J = 2.0 Hz, 1 H), 6.81 (d, J = 8.3 Hz, 1 H), 6.75 (dd, J = 8.3, 2.0 Hz, 1 H), 6.01 (s, 2H), 2.60 (s, 3H). LC-MS (ES) m/z = 363 [M+H]+. [01-050] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(2-methylquinolin-4-yl)-2,4-dihydro-3H-1,2,4- triazole-3-thione (17 mg, 59%, applying P05 upon intermediate 02-042). 1H NMR (400 MHz, DMSO-d6) δ 14.08 (s, 1 H), 8.92 (dd, J = 1.9, 0.9 Hz, 1 H), 7.57 - 7.51 (m, 2H), 7.41 (dd, J = 9.7, 1.9 Hz, 1H), 7.07 - 7.03 (m, 2H), 6.85 (dd, J = 8.2, 2.1 Hz, 1 H), 6.16 (s, 2H). LC-MS (ES) m/z = 417 [M+H]+.
[01-050-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(6-bromoimidazo[1,2-a]pyridin-2-yl)- 5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, J = 2.0, 0.9 Hz, 1 H), 7.50 (d, J = 0.7 Hz, 1 H), 7.43 (dt, J = 9.7, 0.8 Hz, 1 H), 7.27 (dd, J = 9.6, 2.0 Hz, 1 H), 6.87 (d, J = 8.2 Hz, 1 H), 6.75 (d, J = 2.0 Hz, 1 H), 6.53 (dd, J = 8.2, 2.0 Hz, 1 H), 6.08 (s, 2H). LC-MS (ES) m/z = 417 [M-Na+H]+.
[01-051] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(7-bromoimidazo[1,2-a]pyridin-2-yl)-2,4-dihydro- 3H-1,2,4-triazole-3-thione (32 mg, 71%, applying P05 upon intermediate 02-043). 1H NMR (400 MHz, DMSO-d6) δ 14.07 (s, 1 H), 8.52 (dd, J= 7.3, 0.9 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1 H), 7.64 (d, J = 0.8 Hz, 1H), 7.10 (dd, J = 7.2, 2.0 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.84 (dd, J = 8.2, 2.1 Hz, 1 H), 6.16 (s, 2H). LC-MS (ES) m/z = 417 [M+H]+.
[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 (29 mg, 61%, applying P05 upon intermediate 02-044). LC-MS (ES) m/z = 407 [M+H]+.
[01-052-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(thiophen-2-ylmethyl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 7.2, 0.8 Hz, 1H), 8.24 (s, 1 H), 7.83 (dt, J = 2.1, 0.8 Hz, 1H), 7.19 (dd, J = 5.1, 1.3 Hz, 1 H), 7.07 (dd, J = 3.5, 1.3 Hz, 1 H), 7.03 (dd, J = 7.2, 2.1 Hz, 1 H), 6.78 (dd, J = 5.1 , 3.4 Hz, 1H), 5.94 (s, 2H). LC-MS (ES) m/z = 407 [M-Na+H]+.
[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 (43 mg, 78%, applying P05 upon intermediate 02-045). 1H NMR (400 MHz, DMSO-d6) δ 14.17 (s, 1H), 8.61 (dd, J = 7.3, 0.9 Hz, 1 H), 7.94 (d, J = 2.3 Hz, 1 H), 7.77 (d, J = 2.3 Hz, 1H), 7.56 (s, 1 H), 7.08 (dd, J = 7.3, 2.2 Hz, 1 H), 6.45 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H). LC-MS (ES) m/z = 363 [M+H]+.
[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 (66 mg, 86%, applying P05 upon intermediate 02-046). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 7.2, 0.9 Hz, 1 H), 7.93 (d, J = 2.0 Hz, 1H), 7.88 (s, 1 H), 7.11 - 6.99 (m, 11 H), 5.22 (d, J = 8.0 Hz, 2H), 4.79 (t, J = 8.0 Hz, 1 H). The mobile proton signal is missing, likely swapped with the adventitious H2O in the solvent. LC-MS (ES) m/z = 432 [M+H]+.
[01-055] 5-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione (36 mg, 47%, P05 upon intermediate 02-047, the title compound was isolated as HCI salt). 1H NMR (400 MHz, DMSO-d6) δ 14.07 (s, 1 H), 10.59 (s, 1H), 8.68 (dd, J = 7.3, 0.8 Hz, 1 H), 8.60 (d, J = 0.8 Hz, 1 H), 7.93 (dt, J = 2.2, 0.8 Hz, 1 H), 7.16 (dd, J = 7.3, 2.1 Hz, 1 H), 4.52 (t, J= 7.2 Hz, 2H), 3.99 - 3.91 (m, 3H), 3.73 (t, J= 12.1 Hz, 2H), 3.28 - 3.18 (m, 3H), 3.14 - 3.01 (m, 3H), 2.26 (p, J = 7.3 Hz, 3H). One methylene signal is overlapped by the solvents water residue peak. LC-MS (ES) m/z = 380 [M+H]+.
[01-056] 3-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol- 4-yl)benzoic acid (22 mg, 29%, applying P05 upon intermediate 02-048). 1H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1 H), 13.26 (s, 1H), 8.55 (dd, J = 7.3, 0.8 Hz, 1 H), 8.14 - 8.04 (m, 1 H), 7.96 - 7.90 (m, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.70 - 7.60 (m, 3H), 7.02 (dd, J = 7.3, 2.1 Hz, 1 H). 13C NMR (101 MHz, DMSO-d6) δ 168.6, 166.4, 145.9, 144.1, 134.9, 133.2, 132.0, 131.8, 131.4, 130.3, 129.7, 129.5, 128.4, 115.7, 114.4, 114.1. LC-MS (ES) m/z = 372 [M+H]+.
[01-057] 3-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol- 4-yl)benzamide (39 mg, 58%, applying P06 upon intermediate 02-048). 1H NMR (400 MHz, DMSO-d6) δ 14.21 (s, 1 H), 8.55 (dd, J = 7.3, 0.9 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.97 - 7.75 (m, 2H), 7.71 - 7.41 (m, 4H), 7.02 (dt, J = 7.3, 1.7 Hz, 1 H). LC-MS (ES) m/z = 371 [M+H]+.
[01-058] 5-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol- 4-yl)-2-methoxybenzoic acid (21 mg, 44%, applying P05 upon intermediate 02-049). 1H NMR (400 MHz, DMSO-d6) δ 14.15 (s, 1 H), 8.59 (dd, J= 7.3, 0.8 Hz, 1 H), 7.77 (d, J = 0.7 Hz, 1 H), 7.70 (dd, J = 2.0, 1.0 Hz, 1 H), 7.66 (d, J = 2.7 Hz, 1 H), 7.54 (dd, J = 8.8, 2.7 Hz, 1 H), 7.26 (d, J = 9.0 Hz, 1 H), 7.03 (dd, J = 7.3, 2.1 Hz, 1H), 3.90 (s, 3H). The mobile proton signal of carboxilic acid is missing, likely swapped with the adventitious H2O in the solvent. LC-MS (ES) m/z = 402 [M+H]+.
[01-059] 5-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol- 4-yl)-2-methoxybenzamide (31 mg, 65%, applying P06 upon intermediate 02-049). 1H NMR (400 MHz, DMSO-d6) δ 14.13 (s, 1 H), 8.56 (dd, J= 7.3, 0.8 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1 H), 7.74 - 7.62 (m, 4H), 7.51 (dd, J = 8.8, 2.8 Hz, 1 H), 7.28 (d, J = 8.9 Hz, 1 H), 7.01 (dd, J = 7.3, 2.1 Hz, 1 H), 3.98 (s, 3H). LC-MS (ES) m/z = 401 [M+H]+.
[01-060] 4-(4-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4- triazol-4-yl)phenoxy)picolinic acid (61 mg, 65%, applying P05 upon intermediate 02-050). 1H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1 H), 8.68 (d, J = 5.7 Hz, 1 H), 8.59 (dd, J = 7.3, 0.8 Hz, 1 H), 7.87 (d, J = 0.7 Hz, 1H), 7.72 (dd, J = 2.0, 1.0 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.35 (dd, J = 5.7, 2.6 Hz, 1H), 7.05 (dd, J = 7.3, 2.1 Hz, 1 H). The mobile proton signal of carboxilic acid is missing, likely swapped with the adventitious H2O in the solvent. LC-MS (ES) m/z = 465 [M+H]+. [01-061] 4-(4-(3-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4- triazol-4-yl)phenoxy)-/V-methylpicolinamide (46 mg, 68%, applying P06 upon intermediate 02-050). 1H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 8.83 (q, J = 4.8 Hz, 1 H), 8.63 (dd, J = 7.3, 0.8 Hz, 1 H), 8.59 (d, J= 5.6 Hz, 1H), 7.95 (d, J = 0.8 Hz, 1 H), 7.87 (dd, J = 2.1 , 1.0 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 2.6 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 5.6, 2.6 Hz, 1 H), 7.05 (dd, J = 7.3, 2.1 Hz, 1 H), 2.84 (d, J = 4.8 Hz, 3H). LC-MS (ES) m/z = 479 [M+H]+.
[01-062] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (36 mg, 76%, applying P05 upon intermediate 02-051). 1H NMR (400 MHz, DMSO-d6) δ 5 14.19 (s, 1 H), 8.61 (dd, J = 4.8, 1.7 Hz, 1 H), 8.57 (d, J = 2.2 Hz, 1 H), 7.73 (dt, J = 8.0, 2.0 Hz, 1 H), 7.43 (dd, J = 7.9, 4.9 Hz, 1 H), 7.08 (d, J= 2.1 Hz, 1H), 6.99 (d, J= 8.2 Hz, 1 H), 6.84 (dd, J = 8.3, 2.1 Hz, 1 H), 6.13 (s, 2H). LC-MS (ES) m/z = 299 [M+H]+.
[01-062-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(pyridin-3-yl)-5-thioxo-4,5-dihydro- 1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J = 2.3, 0.9 Hz, 1 H), 8.41 (dd, J = 4.8, 1.7 Hz, 1 H), 7.56 (dt, J = 8.0, 2.0 Hz, 1H), 7.29 (ddd, J = 8.0, 4.7, 0.9 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.84 (d, J = 2.0 Hz, 1 H), 6.51 (dd, J = 8.1, 2.1 Hz, 1 H), 6.09 (s, 2H). LC-MS (ES) m/z = 299 [M-Na+H]+.
[01-063] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(2-chloropyridin-4-yl)-2,4-dihydro-3H-1,2,4- triazole-3-thione (91 mg, 32%, applying P06 upon intermediate 02-052). 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.28 (dd, J = 5.1 , 1.5 Hz, 1 H), 7.10 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1 H), 6.88 (dd, J = 8.3, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m/z = 333 [M+H]+.
[01-063-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(2-chloropyridin-4-yl)-5-thioxo-4,5- dihydro-1,2,4-triazol-1-ide. LC-MS (ES) m/z = 333 [M-Na+H]+.
[01-064] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(6-chloropyridin-3-yl)-2,4-dihydro-3H-1,2,4- triazole-3-thione (82 mg, 66%, applying P06 upon intermediate 02-053). 1H NMR (400 MHz, DMSO-d6) δ 14.24 (s, 1H), 8.39 (d, J = 2.2 Hz, 1 H), 7.76 (dd, J = 8.4, 2.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.2, 1.9 Hz, 1 H), 6.14 (s, 2H). LC-MS (ES) m/z = 333 [M+H]+.
[01-064-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(6-chloropyridin-3-yl)-5-thioxo-4,5- dihydro-1,2,4-triazol-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 2.4 Hz, 1 H), 7.60 (dd, J= 8.4, 2.5 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.84 (d, J= 2.0 Hz, 1 H), 6.52 (dd, J = 8.1 , 2.1 Hz, 1 H), 6.10 (s, 2H). LC-MS (ES) m/z = 333 [M-Na+H]+.
[01-065] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2,4- dihydro-3H-1,2,4-triazole-3-thione. In a pressure tube under argon, a solution of compound 01-064 (45 mg, 1 eq) and 1 -methylpiperazine (0.3 mL, 20 eq) in dioxane (1.0 mL) was stirred at 130 °C overnight. The solvent was evaporated and the title compound (16 mg, 30%) was isolated through reverse-phase column chromatography (H2O:ACN). 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 8.03 (d, J = 2.5 Hz, 1 H), 7.39 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.82 - 6.77 (m, 2H), 6.14 (s, 2H), 3.51 (s, 4H), 2.35 (s, 4H), 2.19 (s, 3H). LC-MS (ES) m/z = 397 [M+H]+.
[01 -065-Na] Sodium 4-(benzo[oQ[1 ,3]dioxol-5-yl)-3-(6-(4-methylpiperazin-1 -yl)pyridin-3- yl)-5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide.
[01-066] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione. In a pressure tube under argon, a solution of compound 01-064 (30 mg, 1 eq) and piperazine (23 mg, 3 eq) in ethanol (1.3 mL) was stirred at reflux overnight. The solvent was evaporated and the title compound (15 mg, 44%) was isolated through reversephase column chromatography (H2O:ACN). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 2.4 Hz, 1 H), 7.40 (dd, J = 9.0, 2.5 Hz, 1 H), 7.04 (d, J = 2.1 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.84 - 6.75 (m, 2H), 6.14 (s, 2H), 3.55 - 3.48 (m, 4H), 2.82 (t, J = 5.2 Hz, 4H). The mobile protons signal is missing, likely swapped with the adventitious H2O in the solvent and/or overlapped by the residual solvent peaks. LC-MS (ES) m/z = 383 [M+H]+.
[01 -066-Na] Sodium 4-(benzo[oQ[1 ,3]dioxol-5-yl)-3-(6-(piperazin-1 -yl)pyridin-3-yl)-5- thioxo-4,5-dihydro-1,2,4-triazol-1-ide. LC-MS (ES) m/z = 383 [M-Na+H]+.
[01-067] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(6-morpholinopyridin-3-yl)-2,4-dihydro-3H-1,2,4- triazole-3-thione. In a pressure tube under argon, a solution of compound 01-064 (30 mg, 1 eq) and morpholine (0.8 mL, 15 eq) in dioxane (9 mL) was stirred at reflux for 48 h. The solvent was evaporated and the title compound (16 mg, 46%) was isolated through flash column chromatography over silica (DCM:MeOH). 1H NMR (400 MHz, DMSO-d6) δ 13.95 (s, 1 H), 8.09 - 8.03 (m, 1 H), 7.42 (dd, J = 9.0, 2.5 Hz, 1 H), 7.04 (d, J = 2.0 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.84 - 6.76 (m, 2H), 6.14 (s, 2H), 3.64 (dd, J = 5.8, 4.0 Hz, 4H), 3.48 (dd, J = 5.8, 4.1 Hz, 4H). LC-MS (ES) m/z = 384 [M+H]+.
[01-067-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(6-morpholinopyridin-3-yl)-5-thioxo- 4,5-dihydro-1,2,4-triazol-1-ide. LC-MS (ES) m/z = 384 [M-Na+H]+.
[01-068] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(6-chloropyridin-2-yl)-2,4-dihydro-3H-1,2,4- triazole-3-thione (175 mg, 74%, applying P06 upon intermediate 02-054). 1H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1 H), 7.96 (t, J = 7.8 Hz, 1 H), 7.76 (d, J = 7.7 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.01 - 6.94 (m, 2H), 6.76 (dd, J = 8.2, 2.1 Hz, 1H), 6.11 (s, 2H). LC-MS (ES) m/z = 333 [M+H]+.
[01-068-Na] Sodium 4-(benzo[oQ[1,3]dioxol-5-yl)-3-(6-chloropyridin-2-yl)-5-thioxo-4,5- dihydro-1,2,4-triazol-1-ide. LC-MS (ES) m/z = 333 [M-Na+H]+. [01-069] 4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(6-(piperazin-1-yl)pyridin-2-yl)-2,4-dihydro-3H- 1,2,4-triazole-3-thione. In a pressure tube under argon, a solution of compound 01-068 (100 mg, 1 eq) and piperazine (130 mg, 5 eq) in dioxane (1.2 mL) was stirred at reflux for 48h. The solvent was evaporated and the title compound (15 mg, 44%) was isolated through trituration in DCM and Et2O. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 8.6, 7.4 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 6.92 (d, J = 2.1 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 8.2, 2.1 Hz, 1H), 6.10 (s, 2H), 2.98 (dd, J= 6.4, 3.7 Hz, 4H), 2.59 (dd, J = 6.2, 3.7 Hz, 4H). The mobile protons signal is missing, likely swapped with the adventitious H2O in the solvent and/or overlapped by the residual solvent peaks. LC-MS (ES) m/z = 383 [M+H]+.
[01 -070] 1 -(4-(6-(4-(Benzo[oQ[1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1 H-1 ,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1-yl)propan-1-one. A solution of compound 01-069 (50 mg, 1 eq) and propionic acid (12 mg, 1 ,2 eq) in DMF:AcOEt:DMSO (10:10:11 , 4,2 mL) under argon was added DIPEA ( 91 μL, 4 eq). After stirring at rt for 20 min, HATLI (60 mg, 1 .2 eq) was added. The mixture was stirred at rt overnight. The solution was then concentrated in reduced pressure and the title compound (19 mg, 33%) was isolated through reverse phase flash chromatography (H2O: ACN). 1H NMR (400 MHz, DMSO-d6) δ 14.05 (s, 1 H), 7.64 (dd, J = 8.6, 7.4 Hz, 1 H), 7.23 (d, J = 7.3 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 2.1 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.73 (dd, J = 8.3, 2.1 Hz, 1 H), 6.12 (s, 2H), 3.09 (d, J = 39.0 Hz, 4H), 2.32 (q, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). Two methylene signals of the piperazine are missing, overlapped by the residual solvent peaks. LC-MS (ES) m/z = 439 [M+H]+.
[01-071] (3a/?,4/?,6aS)-4-(5-(4-(6-(4-(benzo[dl[1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)piperazin-1 -yl)-5-oxopentyl)tetrahydro-1 H-thieno[3,4- d]imidazol-2(3/7)-one. A solution of compound 01-069 (35 mg, 1 eq) and biotin (26 mg, 1 ,2 eq) in DMF:AcOEt:DMSO (10:10:11 , 5.4 mL) under argon was added DIPEA ( 64 μL, 4 eq). After stirring at rt for 20 min, HATLI (42 mg, 1 .2 eq) was added. The mixture was stirred at rt overnight. The solution was then concentrated in reduced pressure and the title compound (19 mg, 33%) was isolated through reverse phase flash chromatography (H2O: ACN). 1H NMR (400 MHz, DMSO-d6) δ 14.03 (s, 1 H), 7.68 - 7.60 (m, 1 H), 7.23 (d, J = 7.4 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.94 (s, 1 H), 6.83 (d, J = 8.7 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 6.43 (s, 1 H), 6.36 (s, 1 H), 6.12 (s, 2H), 4.31 (dd, J = 7.6, 5.1 Hz, 1 H), 4.18 - 4.10 (m, 1 H), 3.16 - 3.07 (m, 3H), 3.03 (s, 2H), 2.83 (dd, J = 12.4, 5.1 Hz, 1 H), 2.62 - 2.52 (m, 3H), 2.37 - 2.27 (m, 3H), 1.72 - 0.68 (m, 9H). LC-MS (ES) m/z = 609 [M+H]+. [01 -072] 1 -(4-(6-(4-(Benzo[oQ[1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1 H-1,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1-yl)-3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-5A,4,6A,4-dipyrrolo[1,2- c:2',1'-fl[1,3,2]diazaborinin-3-yl)propan-1-one. In an amber vial in the dark and under argon, a solution of compound 01-069 (4.5 mg, 1 eq) in DM F: DM SO (20:1 4, 2 mL) was prepared. DIPEA ( 91 μL, 4 eq) was added and after 20 min, the commercial NanoBRET-590- SE (5.0 mg, 1 eq) was added. The mixture was stirred at rt for 1h. The solution was then diluted with 30 mLs of water and was freezedried. The powder was washed with cold ether and diried to obtain the title compound title compound (6.0 mg, 73%). LC-MS (ES) m/z = 695 [M+H]+. BODIPY-NH2 was prepared following a reported procedure: Nonperturbative Fluorogenic Labeling of Immunophilins Enables the Wash-free Detection of Immunosuppressants. M. Bertolini, L. Mendive-Tapia, O. Ghashghaei, A. Reese, C. Lochenie, A. M. Schoepf, M. Sintes, K. Tokarczyk, Z. Nare, A. D. Scott, S. R. Knight, A. R. Aithal, A. Sachdeva, R. Lavilla, M. Vendrell. ACS Central Sci. 2024. https://doi.org/10.1021/acscentsci.3c01590.
BODIPY-COOH: Succinic anhydride (15 mg, 1.1 eq) was dissolved in DCM (4 mL) and the solution of BODIPY-NH2 (50 mg, 1.000 eq) in DCM (4 mL) was added dropwise. The mixture was stirred overnight ar rt. The solution was washed with brine and sat. NH4CI solution. The organic phase was dried and evaporated to yield the title adduct (58 mg, 89.6%). 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1 H), 10.20 (s, 1 H), 7.78 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.17 (s, 2H), 2.65 - 2.57 (m, 2H), 2.58 - 2.49 (m, 3H), 2.44 (s, 6H), 1.40 (s, 6H).
[01-073] 4-(4-(6-(4-(Benzo[oQ[1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1-yl)-/V-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4A,4,5A,4- dipyrrolo[1,2-c:2',1 '-f][1,3,2]diazaborinin-10-yl)phenyl)-4-oxobutanamide. A solution of compound 01-069 (32 mg, 1 eq) and BODIPY-COOH (44 mg, 1 ,2 eq) in DMF DMSO (10:1 , 9.0 mL) under argon was added DI PEA ( 58 μL, 4 eq). After stirring at rt for 20 min, HATU (38 mg, 1.2 eq) was added. The mixture was stirred at rt for 2 h. The solution was then concentrated in reduced pressure. Water was added to the crude and was extracted with DCM three times. The combined organic layers were dried and evaporated, and purified by flash chromatography over silica (DCM:MeOH) to afford the title compound (26 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 14.08 (s, 1 H), 10.21 (s, 1 H), 7.80 (dd, J = 8.8, 2.3 Hz, 2H), 7.65 (dd, J = 8.6, 7.4 Hz, 1 H), 7.30 - 7.21 (m, 3H), 7.01 (d, J = 8.2 Hz, 1 H), 6.96 (d, J = 2.1 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 6.74 (dd, J = 8.2, 2.1 Hz, 1 H), 6.18 (s, 2H), 6.13 (s, 2H), 3.37 (m, 6H), 3.19 (s, 2H), 3.05 (s, 2H), 2.73 - 2.60 (m, 2H), 2.44 (s, 6H), 1.40 (s, 6H). LC-MS (ES) m/z = 805 [M+H]+.
2.6. Synthesis of Compounds with Modifications on the Sulphur Atom (COMPARATIVE PURPOSE)
[01-041] 4-(3,4-Bimethoxybenzyl)-5-(quinolin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (19 mg, 20%, applying P05 upon intermediate 02-041). 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1 H), 8.46 (d, J = 8.6 Hz, 1 H), 8.17 (d, J = 8.3 Hz, 1 H), 8.08 - 7.99 (m, 2H), 7.85 (t, J = 7.0 Hz, 1 H), 7.68 (t, J = 7.0 Hz, 1 H), 7.03 (s, 1 H), 6.79 (s, 2H), 5.54 (s, 2H), 3.63 (s, 3H), 3.53 (s, 3H). LC-MS (ES) m/z = 363 [M+H]+.
[01 -041 -Na] Sodium 4-(3,4-dimethoxybenzyl)-5-oxo-3-(quinolin-2-yl)-4,5-dihydro-1 ,2,4- triazol-1-ide. LC-MS (ES) m/z = 363 [M-Na+H]+.
[01-042] 2-(4-(Benzo[oQ[1,3]dioxol-5-yl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)quinoline. In a Pyrex tube, compound 01-001 (80 mg, 1 eq) and K2CO3 (39 mg, 2 eq) were suspended in dry DMF (1.3 mL, 0.175 M). lodomethane (0.03mL, 2 eq) was added dropwise. The mixture was stirred at rt for 2 hours. Once the consumption of the starting material was confirmed, the mixture was quenched with 10 mL of water. It was then extracted with ethyl acetate (3x30 mL), the combined organic layers were dried over magnesium sulphate, concentrated and purified over silica (hexane- ethyl acetate (50% )) to obtain the title compound (46 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.5 Hz, 1 H), 8.18 (d, J = 8.6 Hz, 1 H), 7.98 (d, J = 7.3 Hz, 1 H), 7.72 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.61 (ddd, J = 8.1 , 7.0, 1.2 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 1 H), 7.13 (d, J = 2.0 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 6.93 (dd, J = 8.2, 2.1 Hz, 1 H), 6.16 (s, 2H), 2.67 (s, 3H). LC-MS (ES) m/z = 363 [M+H]+.
[01-043] 2-(4-(Benzo[oQ[1,3]dioxol-5-yl)-4H-1,2,4-triazol-3-yl)quinoline. In a small Pyrex tube, compound 01-001 (80 mg, 1 eq) and CuBr2 (8 mg, 15%) were suspended in DMSO (0.9 mL, 0.25 M) and the mixture was stirred at 80 °C for 1 hour. Once the consumption of the starting material was confirmed, the tube was cooled to rt and the mixture was quenched with 20 mL of water. It was then extracted with ethyl acetate (3x40 mL), the combined organic layers were dried over magnesium sulphate, concentrated and purified over silica (hexaneethyl acetate (50% to 70%) to obtain the title compound (36 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1 H), 8.50 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1H), 7.17 (s, 1H), 7.01 (d, J = 8.2 Hz, 1 H), 6.94 (dd, J = 8.2, 1.8 Hz, 1 H), 6.14 (s, 2H). LC-MS (ES) m/z = 317 [M+H]+. 3. Purchased Compounds
[01 -044] A/-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H- 1 ,2,4-triazol-4-yl)benzenesulfonamide. [01-045] A/-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1,5-dihydro-4H- 1 ,2,4-triazol-4-yl)benzenesulfonamide [01-046] A/-(4-methoxy-1,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1,5-dihydro- 4H-1,2,4-triazol-4-yl)benzenesulfonamide.
[01 -047] 3-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)benzoic acid. [01 -048] 4-(4-((1 H-1 ,2,4-triazol-1 -yl)methyl)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H- 1 ,2,4-triazole-3-thione.
[01 -049] 4-(Benzo[oQ[1 ,3]dioxol-5-yl)-5-(2-hydroxyquinolin-4-yl)-2,4-dihydro-3H-1 ,2,4- triazole-3-thione. Biochemical and Biological Tests
1. Generation of recombinant TREX2 and TREX1 proteins
Human and murine- TREX2 and TREX1 proteins were expressed as a fusion with maltose binding protein (MBP) in the pMAL-c2 plasmid (New England Biolabs). MBP and recombinant MBP-TREX2 and MBP-TREX1 proteins were produced in Escherichia coli BL21 after induction with isopropyl-1-thio-b-D-galactopyranoside (0.3 mM) and affinity-purified using an amylose resin according to manufacturer procedures (New England Biolabs). The expression and purification of recombinant MBP-TREX2 and MBP-TREX1 for characterizing TREX2 and TREX1 exonuclease activities have previously been reported (Manils et al., 2015; Hemphill & Perrino, 2019).
2 TREX2 and TREX1 exonuclease activity assay. Evaluation of the potency and selectivity of TREX2 inhibitors
A TREX2 and TREX1 exonuclease activity assay was performed assessing double stranded DNA (dsDNA) degradation by purified MBP-TREX2 and MBP-TREX1 recombinant proteins obtained as disclosed in the previous section, in the absence and presence of TREX2 inhibitors.
In brief, the compounds were preincubated at the designated concentrations with recombinant proteins in exonuclease reaction buffer (20 mM Tris-HCI pH 7.4, 5 mM MgCh and 100 pg/ml bovine serum albumin) for 15 min at room temperature. Compounds were dissolved in dimethylsulfoxide (DMSO), included as a vehicle (5% final concentration) in the analysis. The reaction was then initiated by adding dsDNA (3000 bp length EcoRI digested dsDNA GFPpcDNA3 plasmid, 200 ng). Reactions were carried out for 15 min at 37°C and ended with the addition of 3x stop sample loading buffer (9 mM EDTA, 60 mM T ris-HCI pH 8, 25% glycerol, 0.125% orange G). Subsequently, the reaction products were subjected to electrophoresis on agarose gels with SYBR Safe dye (Thermo Fisher Scientific™) to separate and visualize DNA bands. Remaining DNA was quantified using the Quantity One 1-D Analysis (Bio-Rad) software.
The recombinant proteins MBP-TREX2 and MBP-TREX1 were titrated, and assays were performed with the concentration (100 - 200 nM) of each isoform exhibiting similar degradation kinetics of dsDNA. MBP was used as a negative control. Compounds were tested at concentrations ranging from 1 to 100 μM to determine the IC50 range for inhibition of DNA degradation. The selected highest potent compounds were further tested in a wide concentration range (from 0.03 to 100 μM) to accurately calculate the IC50 value.
3. Animal Models. Evaluation of in vivo efficacy and specificity of TREX2 inhibitors
Trex2 knockout mice (Trex2'/_) have previously been described (Parra et al., 2009) and were used to test the specificity of TREX2 inhibitors in vivo. Trex?^ and wild-type (wt) mice in a C57BL/6N background were bred and housed at the Animal Facility of the University of Barcelona at the Bellvitge Campus according to the requirements of the Ethics Committee on Animal Use and Care of the Universitat de Barcelona. All experiments were carried out with the authorization of the Catalan Government.
To determine the in vivo efficacy of the representative and most active series of TREX2 inhibitors for the treatment of psoriasis, we used the well-characterised mouse model of IL- 23-induced psoriasis as previously reported (Manils et al., 2015). Briefly, the left and right ear of mice were injected intradermally (i.d.) with murine interleukin-23 (IL-23) (Miltenyi; 0.5 pg in 10 pl PBS) or PBS (10 pl), respectively, once a day. The compounds were administered intraperitoneally (i.p.), intragastrically (i.g.) or topically, once or twice daily, one or two days after starting treatment with IL-23 once a day, as indicated, in male and female mice aged 12 to 16 weeks. The formulation vehicle used for i.p. was 10% DMSO, 90% v/v normal saline, for i.g. administration 10% DMSO, 0.5% carboxymethylcellulose, 90% normal saline, and for topical administration 10% DMSO, 90% acetone. The thickness of the ears was measured using a digital calliper and the increase in the thickness of the ears caused by IL-23 was calculated in relation to PBS.
To determine the in vivo efficacy of a representative of TREX2 inhibitor for the treatment of atopic dermatitis, we used the well-described mouse model of MC903-induced atopic dermatitis (Moosbrugger-Martinz et al., 2017). Briefly, the left and right ear of mice were treated topically with MC903 (1 nmol per ear; 10 pl on dorsal and 10 pl on ventral ear sides) or Ethanol 99%, respectively, every day, following a sequence of 5 days treatment, 2 days interruption and 4 days treatment, for a 11 day-treatment period. The TREX2 inhibitor compound was administered topically, once daily, eight days after starting the treatment with MC903, as indicated, in female aged 16 to 20 weeks. The formulation vehicle used for topical administration was 10% DMSO, 90% ethanol (indicated amount per ear; 10 pl on dorsal and 10 pl on ventral ear sides).
4. Proliferation assays. Assessment of the TREX2 inhibitors cytotoxicity.
Cytotoxicity studies of TREX2 inhibitors were carried out on different cell lines, including Hep- G2 cell line (human hepatocellular carcinoma cells), SH-SY5Y cell line (human neuroblastoma cells), HEK293 cell line (human embryonic kidney cells) and HaCaT cell line (immortalized human keratinocyte cells). Proliferation assays were performed using the Crystal Violet (Sigma-Aldrich) technique for Hep-G2 and SH-SY5Y, and the alamarBlue™ HS Cell Viability Reagent (ThermoFisher) for HEK293 and HaCaT cell lines. In brief, the cells were seeded in a sterile 96-well plate and the compound dissolved in DMSO was added to the cells. For crystal violet staining, cells were stained with a 0.1 % crystal violet solution and incubated for 15 minutes at RT with shaking. Absorbance of the cell plate was measured at a wavelength of 595nm (Tecan M1000 infinite Pro). For the alamarBlue-based assay, alamarBlue™ HS Cell Viability Reagent was directly added to cells in culture medium and incubated for 1-4 hours at 37°C in a cell culture incubator, protected from direct light. The absorbance of the reagent was measured at 570 nm using 600 nm as a reference wavelength (POLARstar Omega) and normalized to the 600-nm value. Controls with DMSO at the same proportion in which the compound was dissolved were included in all experiments. The % growth inhibition was calculated based on the formula: % inhibition = 100-((AO*100)/AT) where AO is the absorbance observed in the wells with the compound under study and AT is the absorbance observed in the wells with DMSO controls.
The effects of TREX2 inhibitors were evaluated at 100 μM and compared with those of Cisplatin, an inhibitor of DNA synthesis that was included as a positive control of cytotoxicity.
5. Statistical Analysis
Statistical analyses were performed using GraphPad PrismTM 10. The unpaired t test and the two-way analysis of variance test with the Dunnett's or the Sidak's multiple comparison test were used for multiple comparisons post-hoc tests as indicated. P values < 0.05 were considered statistically significant.
Results and Discussion
We developed small molecule compounds that inhibit effectively and selectively TREX2 over TREX1.
Table 1 below provides the IC50 values of the compounds of the invention for TREX2 exonuclease inhibition. The most active compounds showed IC50 values close to 1 μM.
TABLE 1 : TREX2 inhibitors potency. The IC50 values of TREX2 inhibitors for the inhibition of TREX2 exonuclease activity are shown.
Some of the compounds of the invention were tested by their ability to inhibit TREX1. Table 2 below provides the IC50 values for TREX1 exonuclease of the most potent TREX2 inhibitors. All tested compounds showed a lower potency (>100 μM) to inhibit TREX1 exonuclease activity, indicating high selectivity of these compounds inhibiting TREX2 over TREX1 exonuclease activity. TABLE 2: TREX2 inhibitors selectivity. The IC50 values for TREX1 of selected potent TREX2 inhibitors are shown.
From the above data, it can be concluded that the compounds of the invention efficiently and selectively inhibit TREX2. Among them, 01-001 and 01-022 compounds were found to display the highest potency inhibiting TREX2 exonuclease (IC50 ~ 1.2 and 0.9 μM, respectively) (FIG. 1). Additionally, data demonstrate that these compounds are highly selective for inhibition of TREX2 exonuclease over the closely related TREX1 exonuclease, as the IC50 for TREX1 (> 100 μM) is about 100-fold higher than the IC50 value for TREX2 (FIG. 1 , TABLES 1 and 2).
In addition, analogues of TREX2 inhibitor compounds were tested to gain an initial understanding of the structure-activity relationship (SAR) of these compounds. This allowed the determination of the structural characteristics and essential scaffold for the inhibition of TREX2. Specifically, loss of TREX2 inhibitory capacity of compounds 01-041 , 01-042 and 01- 043, where the sulfur is changed to oxygen, methylated or removed, respectively, indicate that the central ring is essential and changes in the sulfur atom were not allowed.
Furthermore, an initial proof-of-concept assay using the IL-23-induced mouse model of psoriasis in wild-type (wt) and Trex2 knockout (Trex2'/_) mice, demonstrated efficacy and specificity in vivo in reducing inflammation induced by IL-23. As shown in FIG. 2, the 01-045 compound administered intraperitoneally (i.p.) once-daily at relatively low doses (3mg/kg) significantly reduced IL-23-induced increase in ear thickness in wt mice closely to the levels of the IL-23 treated TrexZ7' mice, whereas no effect was observed in the Trex?^ mice, supporting a TREX2-dependent action of TREX2 inhibitors.
Consistently, the TREX2 inhibitors 01-001 and 01-022, which showed the highest in vitro potency to inhibit TREX2 exonuclease activity (IC50 ~ 1.2 μM and 0.9 μM, respectively) and selectivity over TREXI (IC50 > 100 μM) (TABLES 1 and 2, FIG. 1), showed efficacy in vivo by reducing IL-23-induced psoriasis inflammation in mouse when administered intraperitoneally (i.p.), intragastrically (i.g.) or topically (FIG. 3 and FIG. 4). Of note, dose response assays (FIG. 4) demonstrated the efficacy of 01-022 in decreasing IL-23-induced psoriatic inflammation when administered i.g. at doses as low as 5 mg/kg after three days of treatment (FIG. 4A) and topically (FIG. 4B) as well. In summary, TREX2 inhibitory compounds showed efficacy in reducing IL-23-induced inflammation by systemic, oral, and topical administration.
Moreover, the TREX2 inhibitor 01-001 showed efficacy in vivo by reducing MC903-induced atopic dermatitis inflammation (FIG. 5A and FIG. 5B) and itching (FIG. 5C) in mouse when administered topically.
On the other hand, to evaluate the suitability as therapeutics of some of the compounds of the invention, particularly of 01-001 and 01-022, cytotoxicity was evaluated (TABLE 3). In particular, the effects of 01-001 and 01-022 on cell proliferation were assessed on several cell types, including hepatic HEP-G2, neuronal SH-SY5Y, kidney HEK293 and keratinocyte HaCaT cell line. As shown below in TABLE 3, 01-001-Na and 01-022-Na compounds did not show significant cytotoxicity in any cell line tested. Therefore, these data support absence of cytotoxicity of TREX2 inhibitors and its suitability as therapeutics.
TABLE 3. Lack of cytotoxicity of TREX2 inhibitors
In summary, the TREX2 inhibitors of the invention block in a potent, specific and selective manner TREX2 exonuclease activity, show efficacy reducing IL-23 induced psoriasis inflammation, and do not display cytotoxicity.
Further Results
We developed further small molecule compounds that inhibit effectively and selectively TREX2 over TREX1 .
The compounds are reproduced herein below:
Moreover, we developed still further small molecule compounds that inhibit effectively and selectively TREX2 over TREX1. The compounds are also reproduced herein below: Table 4 below provides the IC50 values of the further compounds of the invention for TREX2 exonuclease inhibition. The most active compounds showed IC50 values close to 1 μM.
TABLE 4: TREX2 inhibitors potency. The IC50 values of TREX2 inhibitors for the inhibition of TREX2 exonuclease activity are shown.
From the above data, it can be concluded that the further compounds of the invention efficiently inhibit TREX2.
Some of the further compounds of the invention were tested by their ability to inhibit TREX1 . Table 5 below provides the IC50 values for TREX1 exonuclease of the most potent TREX2 inhibitors. All tested compounds showed a lower potency (>100 μM) to inhibit TREX1 exonuclease activity, indicating high selectivity of these compounds inhibiting TREX2 over TREX1 exonuclease activity.
TABLE 5: TREX2 inhibitors selectivity. The IC50 values for TREX1 of selected potent TREX2 inhibitors are shown.
From the above data, it can be concluded that the still further compounds of the invention efficiently and selectively inhibit TREX2 and are thus useful for the present invention.
CLAUSES
For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:
Clause 1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: for use in the treatment or prevention of a pathological condition related to an increase in TREX2 expression, wherein:
Ai is a group of formula (II): wherein:
A3 represents X7-(Xs)n;
Xi represents CR1 or N;
X2 represents CR2 or N;
X3 represents CR3 or N;
X4 represents CR4 or N;
X5 represents CR5 or N;
Xe represents CRe or N;
X7 represents CR7 or N;
Xs represents CRs or N; provided that one, two or three of Xi to Xs are N; n is an integer number selected from 0 or 1 ;
R1 to Rs are independently selected from the group consisting of: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; halogen; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively,
R3 and R4 form, together with X3 and X4 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively, R4 and Rs form, together with X4 and X5 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rs and Re form, together with X5 and Xe to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rg and Rw are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; C(O)Rii; or NR12R13;
R11 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRW;
Rx and Rw are independently selected from hydrogen; C(O)Ri4; C(0)0Rw; NRwRi?; ORw; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2- C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
Ry, R12, R13, RW, and Ri?are independently selected from hydrogen; C(0)Rw; C(0)OR2o; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
R14 and R19 are independently selected from hydrogen; NH2; NHR21; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1- C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRt
R15 and R20 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl;
Ris are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2- Cio)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl;
R21 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- Cio)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- Cio)alkynyl, or -O-(C1-C10)alkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRS; being Rs selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Rt is selected from hydrogen; OH; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O- (C1-C10)alkyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRV; being Rv selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
L is selected from the group consisting of: -(CH2)P-, and -C(O)-; m is an entire number selected from 0 or 1 ; p is an entire number selected from 1 to 10, particularly from 1 to 5, particularly from 1 to 2;
A2 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, NRP, CRZ, and C(RZ)2; when the ring system consists of two rings, they are fused or isolated; and
Rp is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more Z substituents; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRd; being Rd selected from OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1- Cio)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Rz is selected from hydrogen; halogen; O(CH2)aR22; C(O)R23;; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; SO2NR24R25; a cycloalkyl ring having from 3 to 7 members selected from C(Rb)2, NRC, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRe; being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl; a is an integer number representing 0 or 1 ;
R22, R23, and Rb are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; NR37R38; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; a cycloalkyl ring having from 3 to 7 members selected from C(R’b)2, NR’c, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRf; being Rf selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
R24, R25, Rb, Rc, R37, R38 and R’c are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more Z substituents; an aryl having five or six members selected from the group consisting of: N, O, S, and CRg; being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1- C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Z is selected from the group consisting of: (C1-C10)alkyl; -O-(C1-C10)alkyl; (C1- Cio)haloalkyl; -O-(C1-C10)haloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; halogen; OR26; COOR27; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1- Cio)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, (C2- Cio)alkynyl, COOR28, NH2, or NHR29; an aryl optionally substituted with one or more OH, halogen, NH2, NHR30, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1- Cio)haloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, or COOR31; and a heteroaryl optionally substituted with one or more OH, halogen, NH2, NHR32, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, or COOR33;
R26 to R28 and R31 to R33 are independently selected from hydrogen; (C1-C10)alkyl; (C1- Cio)haloalkyl; (C2-C10)alkenyl; and (C2-C10)alkynyl; and
R29, R30, and R32 are independently selected from hydrogen, (C1-C10)alkyl; (C1- Cio)haloalkyl; (C2-C10)alkenyl; or (C2-C10)alkynyl.
Clause 2. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 1 , wherein one or two of Xi to Xs represents N.
Clause 3. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the preceding clauses, wherein n is 1 and one of Xi to Xs represents N.
Clause 4. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the preceding clauses, wherein X7 represents N.
Clause 5. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the preceding clauses, wherein A1 is of formula (III): wherein R3 to Re are as defined in clause 1 .
Clause 6. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 5, wherein R3 to Rs are the same. Clause 7. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any one of the clauses 5-6, wherein R3 to Re are selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; or -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; particularly R3 to Re are hydrogen.
Clause 8. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 1 , wherein n is 0, and two or three of Xi to X7 represents N.
Clause 9. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the clauses 1 and 8, wherein A1 is of formula (IV):
X5 represents N or CR5; and R3to R7 are as defined above.
Clause 10. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 9, wherein Rs to R? are independently selected from hydrogen, halogen, OH, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively
R3 and R4 are fused, forming with the carbon atoms to which they are attached, an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1- C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached, an aromatic ring system; and R3, R4 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents. Clause 11. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any one of the preceding clauses, wherein A2 consists of one ring, particularly consists of a 6-membered aromatic ring, wherein the members are as defined in clause 1.
Clause 12. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 11 , wherein A2 is an aryl ring of formula (V), (VI), (VII) or (VIII): wherein: X9 represents NR34, O, S or CRzie;
X10 represents NR35, O, S or CRzi?;
Xu represents NR36, O, S or CRzw;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; O(CH2)aR22; C(O)R23; SO2NR24R25; an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2;
R22 to R25, and Rb being as defined in any of the preceding clauses; and
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents.
Clause 13. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 12, wherein Rz1 to Rz18 are independently selected from the group consisting of: hydrogen; halogen; (C1-C10)alkyl; (C1-C10)haloalkyl; O(CH2)aR22; C(O)R23; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1- Cio)haloalkyl.
Clause 14. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the clauses 12-13, wherein R22 and R23 are selected from H and (C1-C10)alkyl optionally substituted by one or more Z substituents.
Clause 15. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 12, wherein R24 and R25 are independently selected from hydrogen; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRg, being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl.
Clause 16. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 15, wherein one of R24 and R25 is H and the other is selected from H; a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; and an aryl having five or six members selected from the group consisting of N, O, S and CRg, being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1- Cio)haloalkyl.
Clause 17. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the clauses 1-16, wherein A2 is of formula (VI) and Rze to Rzs are the same, particularly they are hydrogen.
Clause 18. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the clauses 1-16, wherein A2 is of formula (VIII) and X9, X10 and X10 are the same, particularly they are CH; or, alternatively, X9 and Xu are the same, particularly they are O.
Clause 19. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the clauses 1-16, wherein A2 is of formula (VII), and Rz9 to RZ12 are independently selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; particularly Rz9 to Rzn are hydrogen, and RZ12 is selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2.
Clause 20. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of the clauses 1-16, wherein A2 is of formula (V), and Rzi to Rzs are selected from hydrogen; (C1-C10)alkyl optionally substituted by one or more Z substituents; O(CH2)aR22; a C6 aryl; halogen; COOH; and C(0)(C1-C10)alkyl; and R22 represents (C1- C10)alkyl optionally substituted by one or more Z substituents or a C6 aryl.
Clause 21. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the preceding clauses, wherein R1 to Rs are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; F; Cl; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; particularly they are selected from hydrogen, (C1- C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, (C2-C10)alkynyl optionally substituted with one or more Z substituents, F, and Cl.
Clause 22. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to clause 21 , wherein R1 to Rs are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms.
Clause 23. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any of the preceding clauses, wherein Z is halogen.
Clause 24. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding clauses, which is 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-thioxo-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-1/7-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-thioxo-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-3/7- 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-3/7-
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-3/7-
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-1/7-inden-5-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)(phenyl)methanone;
[01-037] 4-(Benzo[cf][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; and
[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;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/\/-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(4-methoxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol- 4-yl)benzenesulfonamide;
3-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4-yl)benzoic acid;
4-(4-((1/7-1 ,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; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
Clause 25. The compound of formula (I) for use according to clause 24, which is 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;
[01-003] 4-(4-Chlorophenyl)-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-3/7- 1 ,2,4-triazole-3-thione;
/\/-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
Clause 26. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding clauses 1-25, wherein the condition is a skin or mucosa inflammatory condition. Clause 27. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding clauses 1-26, wherein the condition is selected from psoriasis, atopic dermatitis or ichthyosis.
Clause 28. A compound of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof wherein:
Awis is a group of formula (IVbis): wherein:
(i) R3, Rs to R? are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; and
R’4 is selected from hydrogen; F; Cl; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively
(ii) R3 and R’4 are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
(iii) X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached an aromatic ring system; R3 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; and R’4 is selected from hydrogen, F, Cl, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
A2, L, m, Rg, R10, Rx and Ry are as defined in any of the preceding clauses.
Clause 29. The compound of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof according to clause 28, wherein R1 to R3, R’4, and Rsto Rs are independently selected from the group consisting of: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- Cio)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms.
Clause 30. The compound of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof according to clause 29, wherein R1 to R3, R’4, and Rsto Rs are independently selected from the group consisting of: hydrogen; and (C1-C10)alkyl optionally substituted with one or more Z substituents.
Clause 31. The compound of formula (Ibis) of any of the clauses 28-30, which is selected from the group consisting of:
[01-022] 4-(Benzo[c(][1 ,3]dioxol-5-yl)-5-(7-chloroimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione;
[01-023] 4-(Benzo[c(][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[c/][1 ,3]dioxol-5-yl)-5-(5-methylimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7-
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-3/7-
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-1/7-inden-5-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)(phenyl)methanone;
[01-037] 4-(Benzo[cf][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[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and [01-039] 4-(Benzo[c/][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]pyrazin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
Clause 32. A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in any one of the preceding clauses 28-32, and one or more pharmaceutically acceptable carriers or excipients.
Clause 33. The compound of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof, as defined in any of the clauses 28-31 , for use in therapy or diagnostics or research tool.
Clause 34. A kit comprising the compound of formula (I), (Ibis) or a pharmaceutically acceptable salt or solvate thereof, as defined in any of the preceding clauses, together with means for determining the level of expression of TREX2 protein.
Clause 35. An in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, the method comprising the step of contacting the isolated sample with any of the compounds of formula (I), (Ibis) or pharmaceutically acceptable salt or solvate thereof.
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Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: for use in the treatment or prevention of psoriasis, atopic dermatitis or ichthyosis, wherein:
A1 is of formula (111) or (IV) wherein X5 represents N or CR5, and R3 to R? are as defined below; or Ai is of formula: wherein K is as defined below;
R3 to R7are independently selected from the group consisting of: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; halogen; OR9; COOR10; and cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively,
Rs and R4 form, together with X3 and X4 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
R4 and R5 form, together with X4 and X5 to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rs and Re form, together with X5 and Xe to which they are attached, a partially saturated or aromatic ring having 5 or 6 members, which is optionally substituted with one or more Z substituents; or, alternatively,
Rg and Rw are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; C(O)Rii; or NR12R13;
R11 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- C10)alkynyl optionally substituted with one or more Z substituents; a cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRW;
Rx and Rw are independently selected from hydrogen; C(O)Ri4; C(0)0Rw; NRwRi?; ORw; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2- C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
Ry, R12, R13, RW, and Ri?are independently selected from hydrogen; C(0)Rw; C(0)OR2o; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
R14 and R19 are independently selected from hydrogen; NH2; NHR21; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1- C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRt
Ris and R20 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O- (C1-C10)haloalkyl;
Ris are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2- Cio)alkenyl, (C2-C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl;
R21 is selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2- Cio)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- Cio)alkynyl, or -O-(C1-C10)alkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRS; being Rs selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
Rt is selected from hydrogen; OH; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O- (C1-C10)alkyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more OH, halogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2- C10)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRV; being Rv selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
K is selected from one or more of hydrogen, halogen, (C1-C10)alkyl , (C2-C10)alkenyl, (C2- Cio)alkynyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl, an aryl having five or six members selected from the group consisting of: N, O, S, and CRV; being Rv selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl; or a cycloalkyl, optionally substituted with one or more Z substituents such as a (C1-C10)alkyl or a C(O)(Ci-C4)alkyl, having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; wherein Rx and Ry are as defined before; L is selected from the group consisting of: -(CH2)P-, and -C(O)-; m is an entire number selected from 0 or 1 ; p is an entire number selected from 1 to 10, particularly from 1 to 5, particularly from 1 to 2;
A2 is a ring having any of the following formulae: or a ring selected from any one of the following: wherein: X9 represents NR34, O, S or CRz16;
X10 represents NR35, O, S or CRz17;
Xu represents NR36, O, S or CRz18;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents, - 0-(C1-C10)haloalkyl, (C1-C10)haloalkyl, O(CH2)R22; C(O)R23; SO2NR24R25, OH, NR24R25; an aryl, including an o-aryl such as a phenoxy or a benzyloxy, having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2;
R22 to R25, and Rb are independently selected from hydrogen; halogen; OH; NR37R38; (C1- Cio)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; a cycloalkyl ring having from 3 to 7 members selected from C(R’b)2, NR’C, O, or S; or an aryl having five or six members selected from the group consisting of: N, O, S, and CRf; being Rf selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O- (C1-C10)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
R37, R38, R’b and R’c are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; a (C3-C7)cycloalkyl optionally substituted with one or more Z substituents; an aryl having five or six members selected from the group consisting of: N, O, S, and CRg; being Rg selected from hydrogen, OH, halogen, (C1-C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, -O-(C1- Cio)haloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl;
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents.
2. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to claim 1 , wherein A1 is of formula (III) or (IV) wherein X5 represents N or CR5, and R3 to R7 are as defined in claim 1.
3. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding claims 1-2, wherein Ai is of formula (III) or (IV) wherein X5 represents CR5, and R3 to R? are as defined in claim 1.
4. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to claim 3, wherein
Ai is of formula (III), and
R3 to Re are selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; or -O-(C1-C10)alkyl optionally substituted with one or more Z substituents; particularly R3 to Re are hydrogen.
5. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to claim 3, wherein
A1 is of formula (IV), and
R3 to R? are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively
R3 and R4 are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1- Cio)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R3, R4 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2-C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents.
6. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding claims, wherein Ai is as defined in any of claims 2 to 5 and A2 is an aryl ring of formula (V), (VI), (VII) or (VIII): wherein: X9 represents NR34, O, S or CRz16;
X10 represents NR35, O, S or CRz17;
Xu represents NR36, O, S or CRz18;
Rzi to RZ18 are independently selected from hydrogen; halogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; O(CH2)aR22; C(O)R23; SO2NR24R25; an aryl having five or six members selected from the group consisting of N, O, S and CRe, being Re selected from hydrogen, OH, halogen, (C1- C10)alkyl, -O-(C1-C10)alkyl, (C1-C10)haloalkyl, or -O-(C1-C10)haloalkyl; or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; R22 to R25, and Rb are as defined in any of the preceding claims; and
R34, R35, and R36 are independently selected from hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; and (C2-C10)alkynyl optionally substituted with one or more Z substituents.
7. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding claims 1-6, wherein:
A1 is as defined in any of claims 2 to 5 and A2 is of formula (V), and Rzi to Rzs are selected from hydrogen; (C1-C10)alkyl optionally substituted by one or more Z substituents; O(CH2)aR22; a C6 aryl; halogen; COOH; or C(O)(C1-C10)alkyl; and R22 represents (C1-C10)alkyl optionally substituted by one or more Z substituents or a C6 aryl; or, alternatively,
A1 is as defined in any of claims 2 to 5 and A2 is of formula (VI) and Rze to Rzs are the same, particularly they are hydrogen; or, alternatively,
A1 is as defined in any of claims 2 to 5 and A2 is of formula (VII), and Rzg to RZ12 are independently selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; particularly Rzg to Rzn are hydrogen, and RZ12 is selected from hydrogen, halogen, SO2NH2, or a cycloalkyl having 5 or 6 members selected from NH, O, S and C(Rb)2; or, alternatively,
A1 is as defined in any of claims 2 to 5 and A2 is of formula (VIII) and X9, X10 and Xu are the same, particularly they are CH; or, alternatively, X9 and Xu are the same, particularly they are O.
8. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding claims 1-7, wherein
R3 to R? are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; F; Cl; OR9; COOR10; or cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; particularly,
R3 to R? are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; F, or Cl; particularly, Rs to R? are independently selected from: hydrogen; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; or cycloalkyl having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms.
9. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding claims, which is 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-thioxo-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-1/7-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-thioxo-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-3/7-
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-3/7-
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-3/7-
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-1/7-inden-5-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
[01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)(phenyl)methanone;
[01-037] 4-(Benzo[cf][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[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione; and
[01-039] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(imidazo[1 ,2-a]pyrazin-2-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/V-(4-methoxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol- 4-yl)benzenesulfonamide;
3-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4-triazol-4-yl)benzoic acid;
4-(4-((1/7-1 ,2,4-triazol-1-yl)methyl)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3- thione;
4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-hydroxyquinolin-4-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3-thione;
[1-050] 4-(Benzo[c(][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-3/7-
1 ,2,4-triazole-3-thione;
[01-052] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3/7-
1 ,2,4-triazole-3-thione;
[01-053] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(1-methyl-1/7-pyrazol-3-yl)-2,4-dihydro-3/7-
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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzamide;
[01-058] 5-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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-thioxo-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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenoxy)-/V-methylpicolinamide;
[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-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- y I) py ri d i n-2-y I) pi perazi n- 1 -yl)propan-1 -one;
[01-071] (3a/?,4/?,6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4- triazol-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)tetrahydro-1/7-thieno[3,4-c(]imidazol- 2(3/-/)-one;
[01-072] 1-(4-(6-(4-(Benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1 -yl)-3-(5,5-difluoro-7-(1 /7-pyrrol-2-yl)-5/7-5l4,6l4-dipyrrolo[1 ,2-c:2', 1 '- f][1 ,3,2]diazaborinin-3-yl)propan-1-one;
[01-073] 4-(4-(6-(4-(Benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1 -yl)-A/-(4-(5,5-difluoro-1 ,3,7,9-tetramethyl-5/7-4l4,5l4-dipyrrolo[1 ,2- c:2',1'-/][1 ,3,2]diazaborinin-10-yl)phenyl)-4-oxobutanamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
10. The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use according to any of the preceding claims, which is 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-3/7- 1 ,2,4-triazole-3-thione;
[01-058] 5-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenoxy)picolinic acid; /V-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide; and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
11. A compound of formula I as defined in any one of claims 1 to 10, for use in therapy, with the proviso that the compound is not selected from any one of the list 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;
[01-008] 1-(4-(3-(Quinolin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4-triazol-4-yl)phenyl)ethan-1- one;
/V-(4,6-dimethylpyrimidin-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide;
/\/-(5-ethyl-1 ,3,4-thiadiazol-2-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzenesulfonamide; and
/V-(4-methoxy-1 ,2,5-thiadiazol-3-yl)-4-(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol- 4-yl)benzenesulfonamide.
12. A compound of formula (Ibis) or a pharmaceutically acceptable salt or solvate thereof wherein:
Awis is a group of formula (IVbis): (IVbis) wherein: (i) R3, Rs to R? are independently selected from hydrogen; halogen; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; and
R’4 is selected from hydrogen; F; Cl; OH; (C1-C10)alkyl optionally substituted with one or more Z substituents; (C2-C10)alkenyl optionally substituted with one or more Z substituents; (C2-C10)alkynyl optionally substituted with one or more Z substituents; OR9; COOR10; and cycloalkyl ring having from 3 to 7 members selected from C(RX)2, NRy, O, or S, provided that at least one or two of the members are heteroatoms; or, alternatively
(ii) R3 and R’4 are fused, forming with the carbon atoms to which they are attached an aromatic ring system; and R5, Re and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; or, alternatively,
(iii) X5 is CR5; Rs and Re are fused, forming with the carbon atoms to which they are attached an aromatic ring system; R3 and R? are independently selected from hydrogen, halogen, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents; and R’4 is selected from hydrogen, F, Cl, (C1-C10)alkyl optionally substituted with one or more Z substituents, (C2- C10)alkenyl optionally substituted with one or more Z substituents, or (C2-C10)alkynyl optionally substituted with one or more Z substituents;
A2 is of formula (V), (VI), (VII) or (VIII), as defined in any of the preceding claims 6-7; and
L and m are as defined in claim 1.
13. A compound as defined in any one of claims 1 to 10, which is selected from the group consisting of:
[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-3/7-1 ,2,4-triazole-3-thione;
[01-007] 4-Phenyl-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione;
[01-009] 4-(4-Phenoxybenzyl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione
[01-010] 4-(4-Methoxy-2-methylphenyl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3- thione
[01-012] 4-([1 ,1'-Biphenyl]-3-yl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione
[01-013] 4-(4-(Benzyloxy)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione
[01-014] 5-(Quinolin-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione
[01-015] 4-(4-Phenoxyphenyl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione [01-016] 4-(3-(Benzyloxy)phenyl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione
[01-017] 4-(2,3-Dihydro-1/7-inden-5-yl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3- thione
[01-018] 4-(6-Chloropyridin-3-yl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3-thione
[01-019] 4-(6-(Piperazin-1-yl)pyridin-3-yl)-5-(quinolin-2-yl)-2,4-dihydro-3/7-1 ,2,4-triazole-3- thione
[01-020] Phenyl(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4 H-1 ,2,4-triazol-4-yl)methanone
[01-021] (4-Chlorophenyl)(3-(quinolin-2-yl)-5-thioxo-1 ,5-dihydro-4 H-1 ,2,4-triazol-4-yl) methanone
[01-022] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(7-chloroimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7- 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[cf][1 ,3]dioxol-5-yl)-5-(5-methylimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7- 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-3/7- 1 ,2,4-triazole-3-thione
[01-026] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-
3/7-1 ,2,4-triazole-3-thione
[01-027] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(2,3-dihydro-1/7-inden-5-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione
[01-028] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3/7-1 ,2,4- triazole-3-thione [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7-1 ,2,4- triazole-3-thione
[01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7-1 ,2,4- triazole-3-thione [01-031] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-
3/7-1 ,2,4-triazole-3-thione
[01-032] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(6-chloropyridin-3-yl)-2,4-dihydro-3/7-1 ,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- 3/7-1 ,2,4-triazole-3-thione
[01-034] 4-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4 H-1 ,2,4-triazol-4- yl)benzoic acid
[01-035] 4-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4 H-1 ,2,4-triazol-4- yl)benzenesulfonamide [01-036] (3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4 H-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[cfl[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-3/7-1 ,2,4-triazole-
3-thione [01-050] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-methylquinolin-4-yl)-2,4-dihydro-3/7-1 ,2,4-triazole- 3-thione
[01-051] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(7-bromoimidazo[1 ,2-a]pyridin-2-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione
[01-052] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3/7-1 ,2,4- triazole-3-thione
[01-053] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(1-methyl-1/7-pyrazol-3-yl)-2,4-dihydro-3/7- 1 ,2,4-triazole-3-thione
[01-054] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(2,2-diphenylethyl)-2,4-dihydro-3/7-1 ,2,4- triazole-3-thione [01-055] 5-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3/7-1 ,2,4- triazole-3-thione [01-056] 3-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-di hydro-4H-1 ,2,4-triazol-4- yl)benzoic acid
[01-057] 3-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)benzamide
[01-058] 5-(3-(7-Chloroimidazo[1 ,2-a]pyridin-2-yl)-5-thioxo-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-thioxo-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-thioxo-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-thioxo-1 ,5-dihydro-4H-1 ,2,4-triazol-4- yl)phenoxy)-/V-methylpicolinamide
[01-063] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(2-chloropyridin-4-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3- thione
[01-064] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(6-chloropyridin-3-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3- thione
[01-065] 4-(Benzo[cf][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[cf][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[cf][1 ,3]dioxol-5-yl)-5-(6-morpholinopyridin-3-yl)-2,4-dihydro-3H -1 ,2,4- triazole-3-thione.
[01-068] 4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-(6-chloropyridin-2-yl)-2,4-dihydro-3H -1 ,2,4-triazole-3- thione
[01-069] 4-(Benzo[cf][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-thioxo-4,5-dihydro-1H-1 ,2,4-triazol-3- y I) py ri d i n-2-y I) pi perazi n- 1 -yl)propan-1 -one.
[01-071] (3a/?,4/?,6aS)-4-(5-(4-(6-(4-(benzo[d][1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1 ,2,4- triazol-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)tetrahydro-1/7-thieno[3,4-c(]imidazol- 2(3/7)-one.
[01-072] 1-(4-(6-(4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1/7-1 ,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1 -yl)-3-(5,5-difluoro-7-(1 /7-pyrrol-2-yl)-5/7-5l4,6l4-dipyrrolo[1 ,2-c:2', 1 '- /][1 ,3,2]diazaborinin-3-yl)propan-1-one.
[01-073] 4-(4-(6-(4-(Benzo[cf][1 ,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1/7-1 ,2,4-triazol-3- yl)pyridin-2-yl)piperazin-1 -yl)-/V-(4-(5,5-difluoro-1 ,3,7,9-tetramethyl-5/7-4l4,5l4-dipyrrolo[1 ,2- c:2',1'-/][1 ,3,2]diazaborinin-10-yl)phenyl)-4-oxobutanamide. and any pharmaceutically acceptable salt or solvate thereof, particularly a sodium salt thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of the preceding claims 12 to 13, and one or more pharmaceutically acceptable carriers or excipients.
15. The compound as defined in any one of the claims 12 to 13 for use in diagnostics or as a research tool.
16. An in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, the method comprising the step of contacting the isolated sample with any of the compounds as defined in any of claims 12 to 13 or pharmaceutically acceptable salt or solvate thereof.
EP24725409.7A 2023-04-26 2024-04-26 1,2,4-triazole-3-thione inhibitors of trex2 for use in the treatment of psoriasis, atopic dermatitis or ichthyosis Pending EP4701635A1 (en)

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EP23382389 2023-04-26
PCT/EP2024/061679 WO2024223907A1 (en) 2023-04-26 2024-04-26 1,2,4-triazole-3-thione inhibitors of trex2 for use in the treatment of psoriasis, atopic dermatitis or ichthyosis

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GB2361003A (en) * 2000-04-07 2001-10-10 Astrazeneca Ab Novel compounds
SI2035396T1 (en) * 2006-05-25 2014-08-29 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
JP6026284B2 (en) * 2010-03-03 2016-11-16 プロビオドルグ エージー Inhibitors of glutaminyl cyclase
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