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WO2025048759A1 - Benzimidazole derivatives as mpges-1 inhibitors - Google Patents

Benzimidazole derivatives as mpges-1 inhibitors Download PDF

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WO2025048759A1
WO2025048759A1 PCT/TR2024/051005 TR2024051005W WO2025048759A1 WO 2025048759 A1 WO2025048759 A1 WO 2025048759A1 TR 2024051005 W TR2024051005 W TR 2024051005W WO 2025048759 A1 WO2025048759 A1 WO 2025048759A1
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methyl
benzo
chloro
imidazol
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Erden BANOGLU
Burcu CALISKAN
Azize Gizem ERGUL
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Icosyn Therapeutics Saglik Teknolojileri AS
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Icosyn Therapeutics Saglik Teknolojileri AS
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Definitions

  • This invention pertains to new chemical compounds, their use in pharmaceutical compositions, methods for synthesizing these compounds, and their application as inhibitors of microsomal prostaglandin E2 synthase- 1 (mPGES-1) in therapeutic settings.
  • mPGES-1 microsomal prostaglandin E2 synthase- 1
  • Prostaglandin E2 is the primary prostaglandin (PG) responsible for mediating pain, fever, and inflammatory processes. Its biosynthesis involves a series of enzymatic steps that begin after arachidonic acid (AA) is released from membrane phospholipids through the action of cytosolic phospholipase A2 [1]. Next, cyclooxygenases (COX-1/2) transform AA into the common precursor PGH2, which is then converted into PGE2, PGI2, PGD2, PGF2, and thromboxane A2 through the action of different synthases [2].
  • AA arachidonic acid
  • COX-1/2 cyclooxygenases
  • cytosolic prostaglandin E2 synthase cPGES
  • microsomal prostaglandin E2 synthase- 1 mPGES-1
  • microsomal prostaglandin E2 synthase-2 mPGES-2
  • the inducible isoform mPGES-1 which is functionally linked to upstream COX-2, catalyzes the conversion of PGH2 to pro- inflammatory PGE2 and is upregulated by inflammatory stimuli [3].
  • Various stimulants including IL- 10, TNFa, lipopolysaccharide (LPS), and epidermal growth factor, trigger the expression of mPGES-1 across different tissues [4],
  • Non-steroidal anti-inflammatory drugs reduce PGE2 production by non- selectively inhibiting COX-1 and COX-2, thereby impacting the synthesis of all prostanoids derived from PGH2 [1].
  • Inhibition of COX enzymes in a non-selective manner leads to gastrointestinal, renal, and cardiovascular side effects due to the suppression of the biosynthesis of physiologically important prostaglandins, such as PGI2 and TXA2, along with the inflammatory PGE2 [5].
  • selective COX-2 inhibitors were developed as a next-generation solution.
  • these COX-2 inhibitors have proven problematic, as their use has been linked to an increased risk of cardiovascular events, including myocardial infarction .
  • Merck Frosst identified the mPGES-1 inhibitor MF-63 through high-throughput screening (HTS), which features a phenanthrene imidazole structure. This compound demonstrated strong activity in humans and guinea pigs (IC50: 1.3 and 0.9 nM, respectively), but its effectiveness was significantly reduced in human whole blood tests (IC50: 1300 nM). Despite this, MF-63 was recognized as a potent, selective, and orally active mPGES-1 inhibitor, lacking the side effects commonly associated with traditional NSAIDs [1].
  • HTS high-throughput screening
  • Pfizer researchers have identified a potent mPGES-1 inhibitor, PF-4693627, derived from benzoxazole piperidine carboxamide compounds through a high-throughput screening process, achieving an IC50 value of 3 nM.
  • This compound demonstrated significant in vitro potency with selective inhibition of mPGES-1, coupled with promising in vivo efficacy and a favorable pharmacokinetic profile [8].
  • its low water solubility posed dose limitations in clinical studies, and the presence of an acidic group led to reduced metabolic stability.
  • researchers conducted several structural optimizations, resulting in potent derivatives with enhanced whole blood activity (IC50 ⁇ 250 nM). Due to its safety profile observed in preliminary clinical studies, PF-4693627 has progressed to clinical trials in patients with osteoarthritis and rheumatoid arthritis. However, no results from these trials have been reported as of yet [9].
  • Dainippon Sumitomo Pharma identified a novel structural class while developing candidate compounds with good oral bioavailability, derived from imidazoquinoline derivatives featuring phenyl groups at positions 2 and 7. These compounds exhibit 1,000-fold higher selectivity for mPGES-1 over COX-1/2, combined with a strong ADME profile and potent inhibitory activity (IC50: 4.1 nM) [14, 15].
  • mPGES-1 expression and PGE2 production have been notably associated with diseases such as atherosclerosis, rheumatoid arthritis, osteoarthritis, periodontitis, inflammatory kidney damage, Alzheimer's disease, and cancer. Due to its role in these conditions, mPGES-1 has been recognized as a promising target for developing drugs aimed at treating these and other inflammatory diseases [4],
  • MAPEG membrane-associated proteins in eicosanoid and glutathione metabolism
  • FLAP 5-lipoxygenase- activating protein
  • MGST1, MGST2, and MGST3 microsomal glutathione S-transferases
  • novel benzimidazole compounds were designed and synthesized as mPGES-1 inhibitors to address the limitations of previous inhibitors.
  • This invention pertains to compounds represented by the structure shown in Formula I:
  • R is selected from the group consisting of 5-trifluoromethyl, 5-trifluoromethoxy, 5-cyano, 5,6- dichloro, 5-fluorine, 5-chlorine, 5-tert-butyl or 5-sulfonylmethyl; n is 0 or 1 ;
  • A is selected from the group consisting of B is selected from the group consisting of relates to a compound, and/or its pharmaceutically acceptable salts and/or solvates.
  • the purpose of this invention is to create novel compounds that inhibit inducible mPGES-1, an enzyme responsible for catalyzing the final step in the biosynthesis of PGE2 from AA.
  • These compounds are intended for the treatment of various inflammatory conditions, including but not limited to Parkinson's disease, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, ulcers, osteoarthritis, rheumatoid arthritis, systemic sclerosis, periodontitis, colon cancer, inflammatory bowel disease, cutaneous sclerosis, neuropathic pain, inflammation, pain, fever, migraine, chronic pain, acute pain, headache, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, rheumatic fever, multiple sclerosis, Hodgkin's disease, conjunctivitis, ankylosing spondylitis, eczema, psoriasis, systemic lupus erythematosus,
  • Formula I R is selected from the substituent group whose structure is drawn below, 5-trifluoromethyl, 5-trifluoromethoxy, 5-cyano, 5,6-dichloro, 5-fluorine, 5-chlorine, 5-tert- buthyl or 5-sulphonylmethyl; n is 0 or 1;
  • A is selected from the substituent group whose structure is drawn below,
  • B is selected from the substituent group whose structure is drawn below, pertains to a compound derived from these substitution groups, including any pharmaceutically acceptable salts and/or solvates thereof.
  • the compounds of the present invention may be any of the following compounds:
  • Step A Methyl 5-(aminomethyl)-2-chlorobenzoate was taken into a solution of NaHCO 3 and DCM, ditert-butyl dicarbonate was added, and Compound 1 was obtained by stirring at room temperature (Method A).
  • Step B Ester hydrolysis, Compound 1 was dissolved in a 1 : 1 mixture of THF and water, followed by the addition of LiOH H 2 O, and stirred at room temperature (Method B).
  • Step C Amide formation on the amino group: 4-(trifluoromethyl)benzene-l,2-diamine was dissolved in DCM.
  • Step D The resulting amide derivative intermediate was refluxed in AcOH, and Compound 3 was synthesized (Method D).
  • Step E Nitro reduction: The nitro derivative Compound 3 was taken into EtOH, and SnClz ZHzO was added and refluxed (Method E).
  • Step F Amide formation on the amino group: Compound 5 was synthesized from Compound 4 and Compound 2 under the same condition that was used in Method C.
  • Step G Deprotection: Compound 5 was dissolved in DCM, then trifluoroacetic acid (TFA) was added, and stirred (Method F).
  • Step H Compounds 7-19 were synthesized from Compound 6 and appropriate acid derivatives according to Method C.
  • Step A Pivalic acid was taken in DCM and SOCI2 and catalytic amount of DMF were added. The mixture was stirred at 50 °C under N2 atmosphere for 2 h. In a separate flask, methyl-5-(aminomethyl)-2-chlorobenzoate hydrochloride was taken in DCM, EtsN was added, and the mixture was stirred for 30 min at 30 °C under N2. The first reaction mixture was slowly added to the second flask at 0 °C and the resulting mixture was allowed to warm to RT and left to stir for 4 h under N2. At the end of the time, the reaction mixture was extracted with DCM.
  • Step B Compound 21a was synthesized from Compound 20a according to Method B.
  • Step C and D Compound 22a-g were prepared from appropriate o-phenylenediamine derivatives and 4-nitrophenylacetic acid using Methods C and D.
  • Step E Compounds 23a-g were synthesized from Compound 22a-g according to Method B.
  • Step F Compound 24-30 were synthesized from Compound 23a-g and Compound 21a according to Method C.
  • Step A Compound 20a-d were prepared from appropriate acid and methyl 5-(amino methyl)-2-chlorobenzoate hydrochloride according to Method G.
  • Step B Compound 21a-d was synthesized from Compound 20a-d according to Method B.
  • Step C and D Compound 31 were prepared from 5-(trifhioromethyl)benzene-l,2- diamine and 2-(3-((tert-butoxycarbonyl)amino)phenyl)acetic acid using Methods C and D.
  • Step E Compound 32 was prepared from Compound 31 according to Method F.
  • Step F Compound 33-36 were prepared from Compound 32 and Compound 21a-d using Method C.
  • Step A Compound 20e-f were synthesized from methyl 5-(aminomethyl)-2-chloro benzoate hydrochloride and appropriate acid derivatives according to Method G.
  • Step B Compound 21e-f were synthesized from Compound 20e-f according to Method B.
  • Step C Compound 45 was obtained by stirring 5-(trifluoromethyl)benzene-l,2-diamine, 4-nitrobenzaldehyde and Na 2 S 2 O 5 in DMF at 60°C (Method H).
  • Step D Compound 46 was synthesized from Compound 45 according to Method E.
  • Step E Compound 47-48 were synthesized from Compound 46 and Compounds 21e-f according to Method C.
  • Step A Compounds 53a, b, e or f are synthesized by stirring appropriate piperidine derivatives and 2-(chloromethyl)-5-(trifluoromethyl)-1H-benzimidazole in acetonitrile in the presence of Na2COs at rt.
  • Compounds 53c, or d are synthesized by stirring appropriate piperidine derivatives and 2-chloro-5-(trifluoromethyl)-1H-benzimidazole in AcCN at refluks.
  • Step B Compounds 54a-f were synthesized from Compound 53a-f according to Method F.
  • Step C Compound 55-60 were synthesized from Compound 54a-f and Compound 21a according to Method C.
  • Scheme 7. Reagent and conditions: A) for 53a, b, e and f: 2-(chloromethyl)-5- ( trifluoromethyl)- 1 //-benzimidazole, tert-butyl piperidin-4-ylcarbamate (for 53a); tert- butylpiperidin-3-ylcarbamate (for 53b); tert-butyl pyrrolidin-3-ylcarbamate (for 53e) or tertbutyl azetidin-3-ylcarbamate (for 53f), Na2CCh, AcCN, Rt; for 53c and d: 2-chloro-5- ( trifluoromethyl)- 1 //-benzimidazole, tert-butyl piperidin-4-ylcarbamate (for 53c); tert-butyl piperidin-3-ylcarbamate
  • Step C and D An amide derivative was synthesized from 5-(trifluoromethyl)benzene- 1,2-diamine and Compound 61 according to Method C. Compound 62 was then synthesized from this amide derivative by closing the benzimidazole ring according to Method D.
  • Step A and B Amit derivatives were synthesized from methyl 4-amino-2- oxabicyclo[2.2.2]octane-l-carboxylate hydrochloride and Compound 2 or Compound 21a according to Method C.
  • Compound 64a-b were synthesized according to Method B from an amide derivative containing an ester group.
  • Step C and D An amide derivative was synthesized from 4-(trifluoromethyl)benzene- 1,2-diamine and Compound 64a-b according to Method C.
  • Compound 65-66 were then synthesized from this amide derivative by closing the benzimidazole ring according to Method D.
  • Step E Compound 67 was synthesized from Compound 65 according to Method F.
  • Step F Compound 68 was synthesized from Compound 67 and 2-methyloxetane-2- carboxylic acid according to Method C.
  • A549 cells were prepared as described in the literature [18]. In brief, A549 cells were incubated for 72 hours at 37°C in an atmosphere of 5% CO2 using DMEM (Dulbecco's Modified Eagle Medium) supplemented with 2% fetal calf serum (FCS) and 2 ng/mL IL- 10. After incubation, the cells were collected and stored in a solution containing 0.1 M potassium phosphate buffer (pH 7.4), 1 pM phenylmethanesulfonyl fluoride (PMSF), 60 pg/mL soy trypsin inhibitor (STI), 1 pg/mL leupeptin, and 2.5 pM glutathione.
  • DMEM Dynamic fetal calf serum
  • the cells were then suspended in 1 mL of homogenization solution containing 250 pM sucrose and further diluted with 0.1 M potassium phosphate buffer containing 2.5 pM glutathione.
  • the cells were flash-frozen in liquid nitrogen, followed by three cycles of sonication, each lasting 20 seconds. Differential centrifugation was then carried out, first at 4°C for 10 minutes, and subsequently for 1 hour at the same temperature. The resulting pellets were resuspended in the homogenization buffer.
  • Microsomes were diluted with 2 mM glutathione in 0.1 M potassium phosphate buffer (pH 7.4) and pre-incubated for 15 minutes with either the test compound or a control (0.1% DMSO).
  • mPGES-1 activity values of the compounds of the present invention (IC50 values are represented as A ⁇ 10 nM, B ⁇ 50 nM, and C ⁇ 400 nM.).

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Abstract

The present invention pertains to benzimidazole derivatives of formula (I) and their inhibitory activity against mPGES-1. It also encompasses pharmaceutical compositions that include these benzimidazole derivatives and their application in treating mPGES-1-mediated diseases. The purpose of this invention is to create novel compounds that inhibit inducible mPGES-1, an enzyme responsible for catalyzing the final step in the biosynthesis of PGE2 from AA. These compounds are intended for the treatment of various inflammatory conditions, including but not limited to Parkinson's disease, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, ulcers, osteoarthritis, rheumatoid arthritis, systemic sclerosis, periodontitis, colon cancer, inflammatory bowel disease, cutaneous sclerosis, neuropathic pain, inflammation, pain, fever, migraine, chronic pain, acute pain, headache, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, rheumatic fever, multiple sclerosis, Hodgkin's disease.

Description

BENZIMIDAZOLE DERIVATIVES AS mPGES-1 INHIBITORS
Field of Invention
This invention pertains to new chemical compounds, their use in pharmaceutical compositions, methods for synthesizing these compounds, and their application as inhibitors of microsomal prostaglandin E2 synthase- 1 (mPGES-1) in therapeutic settings.
Background of the Invention
Prostaglandin E2 (PGE2) is the primary prostaglandin (PG) responsible for mediating pain, fever, and inflammatory processes. Its biosynthesis involves a series of enzymatic steps that begin after arachidonic acid (AA) is released from membrane phospholipids through the action of cytosolic phospholipase A2 [1]. Next, cyclooxygenases (COX-1/2) transform AA into the common precursor PGH2, which is then converted into PGE2, PGI2, PGD2, PGF2, and thromboxane A2 through the action of different synthases [2]. Three enzymes such as cytosolic prostaglandin E2 synthase (cPGES), microsomal prostaglandin E2 synthase- 1 (mPGES-1), and microsomal prostaglandin E2 synthase-2 (mPGES-2) play crucial roles in the final step of the AA cascade during PGE2 biosynthesis. Among them, the inducible isoform mPGES-1, which is functionally linked to upstream COX-2, catalyzes the conversion of PGH2 to pro- inflammatory PGE2 and is upregulated by inflammatory stimuli [3]. Various stimulants, including IL- 10, TNFa, lipopolysaccharide (LPS), and epidermal growth factor, trigger the expression of mPGES-1 across different tissues [4],
Non-steroidal anti-inflammatory drugs (NSAIDs) reduce PGE2 production by non- selectively inhibiting COX-1 and COX-2, thereby impacting the synthesis of all prostanoids derived from PGH2 [1]. Inhibition of COX enzymes in a non-selective manner leads to gastrointestinal, renal, and cardiovascular side effects due to the suppression of the biosynthesis of physiologically important prostaglandins, such as PGI2 and TXA2, along with the inflammatory PGE2 [5]. To mitigate the common gastrointestinal side effects associated with NSAIDs, selective COX-2 inhibitors were developed as a next-generation solution. However, these COX-2 inhibitors have proven problematic, as their use has been linked to an increased risk of cardiovascular events, including myocardial infarction .
In 1999, the membrane-associated, GSH-dependent mPGES-1 protein was identified in A549 cells, sparking a rapid increase in research within this field. It was found that mPGES-1 expression is upregulated in response to IL- 10 stimulation [6]. As part of the search for a new biological target with a favorable safety profile — one that avoids the side effects associated with traditional NSAIDs and COX-2 selective inhibitors — researchers aimed to regulate inflammatory PGE2 biosynthesis by inhibiting mPGES-1. Consequently, mPGES-1 has emerged as a promising target for the development of next-generation NSAIDs [5].
Over the past 22 years, numerous pharmaceutical companies have pursued research in this area, but the clinical development of mPGES-1 inhibitors has faced several challenges. These challenges include the high lipophilicity of active compounds, significant plasma protein binding, inadequate physicochemical properties, and variations in activity due to species differences observed in in-vivo and in-vitro studies [4],
Merck Frosst identified the mPGES-1 inhibitor MF-63 through high-throughput screening (HTS), which features a phenanthrene imidazole structure. This compound demonstrated strong activity in humans and guinea pigs (IC50: 1.3 and 0.9 nM, respectively), but its effectiveness was significantly reduced in human whole blood tests (IC50: 1300 nM). Despite this, MF-63 was recognized as a potent, selective, and orally active mPGES-1 inhibitor, lacking the side effects commonly associated with traditional NSAIDs [1].
Merck Frosst further advanced their research by developing new compounds with enhanced activity by optimizing 2,4-biarylimidazole derivatives (IC50: 1 nM). The addition of a phenyl alkyne group to the most promising compound in this series improved its lipophilicity. However, this modification led to reduced activity in whole blood due to increased plasma protein binding (IC50: 1600 nM) [7].
Pfizer researchers have identified a potent mPGES-1 inhibitor, PF-4693627, derived from benzoxazole piperidine carboxamide compounds through a high-throughput screening process, achieving an IC50 value of 3 nM. This compound demonstrated significant in vitro potency with selective inhibition of mPGES-1, coupled with promising in vivo efficacy and a favorable pharmacokinetic profile [8]. However, its low water solubility posed dose limitations in clinical studies, and the presence of an acidic group led to reduced metabolic stability. To address these challenges, researchers conducted several structural optimizations, resulting in potent derivatives with enhanced whole blood activity (IC50 < 250 nM). Due to its safety profile observed in preliminary clinical studies, PF-4693627 has progressed to clinical trials in patients with osteoarthritis and rheumatoid arthritis. However, no results from these trials have been reported as of yet [9].
Despite the high potency of Boehringer Ingelheim's 2-amino benzimidazole derivatives (IC50: 3-220 nM) (WO2012/022793A1), the company advanced to a new structural framework, which then entered clinical trials. This compound is now owned by Gesynta Pharma and is referred to as Vipoglanstat (GS-248/OX-MPI/BI-1029539). Aclinical trial (NCT04036227) for endometriosis is currently ongoing [10].
Glenmark Pharma researchers explored the mPGES-1 inhibitory properties of quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one, and pyrido[2,3-d]pyrimidin-4(3H)- one derivatives, demonstrating strong mPGES-1 inhibition in cell-free assays (IC50: 4-16 nM). These derivatives also exhibited effective inhibitoiy activity in whole blood assays (IC50: 234- 328 nM). Among them, a pyrido[4,3-d]pyrimidin-4(3H)-one derivative was identified as a selective mPGES-1 inhibitor, significantly reducing PGE2 production in in vivo animal studies (IC50: 5 nM) [5]. Glenmark Pharma also investigated the mPGES-1 inhibitory potential of 2- aminobenzimidazole derivatives, which showed potent inhibitory effects [11].
Lilly’s LY3031207 and LY3023703, both 2-acylamino imidazole derivatives, were the first compounds to enter clinical trials, highlighting the potential of mPGES-1 as a therapeutic target for treating pain and inflammation. However, the clinical studies were halted during Phase II due to drug-induced hepatotoxicity [12, 13].
Dainippon Sumitomo Pharma identified a novel structural class while developing candidate compounds with good oral bioavailability, derived from imidazoquinoline derivatives featuring phenyl groups at positions 2 and 7. These compounds exhibit 1,000-fold higher selectivity for mPGES-1 over COX-1/2, combined with a strong ADME profile and potent inhibitory activity (IC50: 4.1 nM) [14, 15].
Eli Lilly, utilizing molecular modeling studies, discovered two potent derivatives containing 2-aminoimidazole, 2-chlorobenzamide, and pivaloyl amide or isosteric structures (IC50: 26-27 nM). While these compounds demonstrated strong inhibition of mPGES-1, they also inhibited FLAP, making them dual inhibitors [16].
In 2020, the novel mPGES-1 inhibitor Zaloglanstat (ISC-27864/GRC-27864) successfully completed a Phase II study for the treatment of moderate osteoarthritis pain. Although the results of these studies have yet to be published, no adverse reports have emerged during the trials [10],
In addition, a drug candidate from Nippon Shinyaku, Firuluglanstat (NS-580), has entered clinical trials and a late Phase H double-blind randomized controlled trial (RCT) of 380 women is being conducted to examine its effect on symptoms in endometriosis patients GRCT20312110685) [17]. mPGES-1 expression and PGE2 production have been notably associated with diseases such as atherosclerosis, rheumatoid arthritis, osteoarthritis, periodontitis, inflammatory kidney damage, Alzheimer's disease, and cancer. Due to its role in these conditions, mPGES-1 has been recognized as a promising target for developing drugs aimed at treating these and other inflammatory diseases [4],
One notable study in this technical area is detailed in patent publication WO 2011/099832 A2. This patent introduces a novel compound featuring a benzimidazole structure, emphasizing its potential as an inhibitor of the microsomal prostaglandin E synthase- 1 (mPGES-1) enzyme.
Another relevant patent is WO 2008/084218 Al, which discusses innovative benzimidazole derivatives designed for inflammation treatment. The patent highlights that these derivatives may inhibit enzymes associated with the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) family, including mPGES-1, 5-lipoxygenase- activating protein (FLAP), leukotriene C4 synthase, and microsomal glutathione S-transferases (MGST1, MGST2, and MGST3).
In this invention, novel benzimidazole compounds were designed and synthesized as mPGES-1 inhibitors to address the limitations of previous inhibitors.
Summary of the Invention
This invention pertains to compounds represented by the structure shown in Formula I:
Figure imgf000005_0001
R is selected from the group consisting of 5-trifluoromethyl, 5-trifluoromethoxy, 5-cyano, 5,6- dichloro, 5-fluorine, 5-chlorine, 5-tert-butyl or 5-sulfonylmethyl; n is 0 or 1 ;
A is selected from the group consisting of
Figure imgf000005_0002
B is selected from the group consisting of
Figure imgf000006_0003
Figure imgf000006_0001
relates to a compound, and/or its pharmaceutically acceptable salts and/or solvates.
Purpose of the Invention
The purpose of this invention is to create novel compounds that inhibit inducible mPGES-1, an enzyme responsible for catalyzing the final step in the biosynthesis of PGE2 from AA. These compounds are intended for the treatment of various inflammatory conditions, including but not limited to Parkinson's disease, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, ulcers, osteoarthritis, rheumatoid arthritis, systemic sclerosis, periodontitis, colon cancer, inflammatory bowel disease, cutaneous sclerosis, neuropathic pain, inflammation, pain, fever, migraine, chronic pain, acute pain, headache, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, rheumatic fever, multiple sclerosis, Hodgkin's disease, conjunctivitis, ankylosing spondylitis, eczema, psoriasis, systemic lupus erythematosus, pancreatitis, diabetes, cancer, vasculitis, and neurodegenerative disorders such as Alzheimer's disease.
Given that epidemiological studies conducted between 1990 and 2017 indicate that nearly 50% of the global population suffers from a chronic inflammatory disease, the selective inhibition of mPGES-1 with a lower side -effect profile compared to traditional NSAIDs and COX-2 inhibitors offers promising new treatment options for a wide range of inflammation- related disorders.
Detailed Description of the Invention
Figure imgf000006_0002
Formula I R is selected from the substituent group whose structure is drawn below, 5-trifluoromethyl, 5-trifluoromethoxy, 5-cyano, 5,6-dichloro, 5-fluorine, 5-chlorine, 5-tert- buthyl or 5-sulphonylmethyl; n is 0 or 1;
A is selected from the substituent group whose structure is drawn below,
Figure imgf000007_0001
B is selected from the substituent group whose structure is drawn below,
Figure imgf000007_0002
pertains to a compound derived from these substitution groups, including any pharmaceutically acceptable salts and/or solvates thereof.
The compounds of the present invention may be any of the following compounds:
2-Chloro-5-((3,3-dimethylbutanamido)methyl)-7V-(4-((5-(trifluoromethyl)-1H- benzo[</]imidazol-2-yl)methyl)phenyl)benzamide (Compound 7)
2-Chloro-5-(isobutyramidomethyl)-7V-(4-((5-(trifluoromethyl)-1H-benzo[</]imidazol-
2-yl)methyl)phenyl)benzamide (Compound 8)
2-Chloro-5-((2,2-difluoroacetamido)methyl)-7V-(4-((5-(trifluoromethyl)-1H- benzo[</]imidazol-2-yl)methyl)phenyl)benzamide (Compound 9)
2-Chloro-5-((l-isopropylcyclopropane-l-carboxamido)methyl)-7V-(4-((5-
( trifluorometh yl)-1H-benzo[</Jimidazol-2-yl)methyl)phenyl)benzamide (Compound 10)
2-Chloro-5-((l -cyanocyclopropane- 1 -carboxamido)methyl)-7V-(4-((5-
( trifluorometh yl)-1H-benzo[</Jimidazol-2-yl)methyl)phenyl)benzamide (Compound 11)
7V-(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[</]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 12)
7V-(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[</]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-3-methyloxetane-3-carboxamide (Compound 13) 2-Chloro-5-((3,3-difluoro-l-methylcyclobutane-l-carboxamido)methyl)-Ai-(4-((5-
Orifluoromethyl)- 1 //-benzo, t/|imidazol-2-yl (methyl (phenyl (benzamide (Compound 14) 2-chloro-5-((3,3-dimethylcyclobutane-l-carboxamido)methyl)-7V-(4-((5-
( trifluorometh yl)- I //-benzo, t/|i midazol-2-yl (methyl (phenyl (benzamide (Compound 15) 7V-(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)spiro[3.3]heptane-2-carboxamide (Compound 16)
2-chlororiV-(4-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-((l-
( trifluorometh yl)cyclopentane- 1 -carboxamido)methyl)benzamide (Compound 17)
2-chlororiV-(4-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-((l-
( trifluorometh yl)cyclohexane- 1 -carboxamido)methyl)benzamide (Compound 18)
N -(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-3-(trifluoromethyl)bicyclo[ 1.1. l]pentane-l - carboxamide (Compound 19)
2-chloro-5-(pival amidometh yl)riV-(4-((5-(trifluoromethoxy)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)benzamide (Compound 24)
2-chlororiV-(4-((5-cyano-17/-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 25)
2-chlororiV-(4-((5,6-dichloro-17/-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 26)
2-chlororiV-(4-((5-fluoro-17/-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 27)
2-chlororiV-(4-((5-chloro-17/-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 28) lV-(4-((5-(tert-butyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-2-chloro-5-
(pivalamidomethyl)benzamide (Compound 29)
2-chlororiV-(4-((5-(methylsulfonyl)-17/-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 30)
2-chloro-5-(pival amidometh yl)-Ai-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)benzamide (Compound 33)
2-chloro-Ai-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-((l-
( trifluorometh yl)cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 34)
2-chloro-Ai-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-((l-
(trifluoromethyl)cyclobutane-l-carboxamido)methyl)benzamide (Compound 35) Ai-(4-chloro-3-((3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 36)
2-chloro-lV-(3-((5-fluoro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 40)
2-chloro-lV-(3-((5-cyano-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 41)
2-chloro-lV-(3-((5-chloro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 42)
2-chloro-lV-(3-((5,6-dichloro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-
(pivalamidomethyl)benzamide (Compound 43)
2-chloro-5-(pival amidometh yl)-lV-(3-((5-(trifluoromethoxy)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)benzamide (Compound 44)
2-chloro-Ai-(4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)phenyl)-5-((l-
( trifluorometh yl)cyclopentane- 1 -carboxamido)methyl)benzamide (Compound 47)
2-chloro-5-((3,3-difluoro-l-methylcyclobutane-l-carboxamido)methyl)-7V-(4-(5-
(trifluoromethyl)- lH-benzo[riJimidazol-2-yl)phenyl)benzamide (Compound 48)
Ai-(4-chloro-3-((4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)phenyl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 51)
Ai-(4-chloro-3-((4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)phenyl)carbamoyl)benzyl)-3-methyloxetane-3-carboxamide (Compound 52)
2-chloro-5-(pival amidometh yl)-Ai-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)piperidin-4-yl)benzamide (Compound 55)
2-chloro-5-(pival amidometh yl)-Ai-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)piperidin-3-yl)benzamide (Compound 56)
2-chloro-5-(pival amidometh yl)-lV-(l-(5-(trifluoromethyl)-1H-benzo[ri]imidazol -2- yl)piperidin-4-yl)benzamide (Compound 57)
2-chloro-5-(pival amidometh yl)-lV-(l-(5-(trifluoromethyl)-1H-benzo[ri]imidazol -2- yl)piperidin-3-yl)benzamide (Compound 58)
2-chloro-5-(pival amidometh yl)-Ai-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)pyrrolidin-3-yl)benzamide (Compound 59)
2-chloro-5-(pival amidometh yl)-Ai-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)azetidin-3-yl)benzamide (Compound 60)
2-chloro-lV-(4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)bicyclo[2.2.2]octan-l- yl)-5 -(( 1 -(trifluorometh yl)cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 62) 2-chloro-5-(pival amidometh yl)-7V-(4-((5-(trifluoromethyl)-1H-benzo[</]imidazol-2- yl)methyl)bicyclo[2.2.2]octan-l-yl)benzamide (Compound 63)
2-chloro-5-(pival amidometh yl)-A-( 1- (5 -(trifluorometh yl)-1H-benzo[tZ] imidazol-2-yl)- 2-oxabicyclo[2.2.2]octan-4-yl)benzamide (Compound 66)
N -(4-chloro-3-((l -(5-(tri fluoromethyl)- lH-benzo[tZ] imidazol-2-yl)-2- oxabicyclo[2.2.2]octan-4-yl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 68)
2-chloro-A-(3-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)bicyclo[l.l.l]pentan-l- yl)-5 -(( 1 -(trifluorometh yl)cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 71)
2-chloro-5-(pival amidometh yl)-7V-(3-((5-(trifluoromethyl)-1H-benzo[</]imidazol-2- yl)methyl)bicyclo[l.l.l]pentan-l-yl)benzamide (Compound 72)
2-chloro-5-(pivalamidomethyl)-7V-(4-((5-(trifluoromethyl)-1H-benzo[</]imidazol-2- yl)methyl)thiazol-2-yl)benzamide (Compound 77)
Synthetic Methodology for Compounds of the Invention
Figure imgf000010_0001
Derivatives with B modifications when n is 1, A is p-disubstituted phenyl and R is 5-CFs:
Synthesis methods including the following steps for Compounds 7-19 are shown in Scheme 1: i) Step A: Methyl 5-(aminomethyl)-2-chlorobenzoate was taken into a solution of NaHCO3 and DCM, ditert-butyl dicarbonate was added, and Compound 1 was obtained by stirring at room temperature (Method A). ii) Step B: Ester hydrolysis, Compound 1 was dissolved in a 1 : 1 mixture of THF and water, followed by the addition of LiOH H2O, and stirred at room temperature (Method B). iii) Step C: Amide formation on the amino group: 4-(trifluoromethyl)benzene-l,2-diamine was dissolved in DCM. Then, 4-nitrophenylacetic acid, EDC.HC1 and DMAP were added and stirred at rt under nitrogen gas (Method C). iv) Step D: The resulting amide derivative intermediate was refluxed in AcOH, and Compound 3 was synthesized (Method D). v) Step E: Nitro reduction: The nitro derivative Compound 3 was taken into EtOH, and SnClz ZHzO was added and refluxed (Method E). vi) Step F: Amide formation on the amino group: Compound 5 was synthesized from Compound 4 and Compound 2 under the same condition that was used in Method C. vii) Step G: Deprotection: Compound 5 was dissolved in DCM, then trifluoroacetic acid (TFA) was added, and stirred (Method F). viii) Step H: Compounds 7-19 were synthesized from Compound 6 and appropriate acid derivatives according to Method C.
Figure imgf000011_0001
Scheme 1. Reagent and conditions: A) Di-tert-buthyldicarbonate, NaHCCh solution, DCM, Rt; B) LiOH’FhO, THF:H2O (1:1), A; C) 4-(trifluoromethyl)benzene-l,2-diamine, 4- nitrophenylacetic acid, EDC.HC1, DMAP, DCM, Rt; D) AcOH, A; E) SnC12.2H2O, EtOH, A;
F) Compound 2, EDC.HC1, DMAP, DCM, Rt; G) TFA, DCM, Rt; H) Appropriate acid derivatives, EDC.HC1, DMAP, DCM, Rt. Derivatives with R modifications when n is 1, A is p-disubstituted phenyl and B is tertbutyl:
Synthesis methods including the following steps for Compounds 24-30 are shown in Scheme 2: i) Step A: Pivalic acid was taken in DCM and SOCI2 and catalytic amount of DMF were added. The mixture was stirred at 50 °C under N2 atmosphere for 2 h. In a separate flask, methyl-5-(aminomethyl)-2-chlorobenzoate hydrochloride was taken in DCM, EtsN was added, and the mixture was stirred for 30 min at 30 °C under N2. The first reaction mixture was slowly added to the second flask at 0 °C and the resulting mixture was allowed to warm to RT and left to stir for 4 h under N2. At the end of the time, the reaction mixture was extracted with DCM. The obtained crudes were purified by flash chromatography to give pure ester derivatives (Method G). ii) Step B: Compound 21a was synthesized from Compound 20a according to Method B. iii) Step C and D: Compound 22a-g were prepared from appropriate o-phenylenediamine derivatives and 4-nitrophenylacetic acid using Methods C and D. iv) Step E: Compounds 23a-g were synthesized from Compound 22a-g according to Method B. v) Step F: Compound 24-30 were synthesized from Compound 23a-g and Compound 21a according to Method C.
Figure imgf000012_0001
Scheme 2. Reagent and conditions: A) i. Pivalic acid, SOCI2, DMF, CHCh, 50°C; ii. Methyl 5-(aminomethyl)-2-chlorobenzoate HC1, EtaN, CHCh, rt; B) LiOELJhO, THF: Water (1:1), A; C) Appropriate o-phenylendiamine derivatives, 4-nitrophenylacetic acid, EDC.HC1, DMAP, DCM, Rt; D) AcOH, A; E) SnC12.2H2O, EtOH, A; F)Compound 21a, EDC.HC1, DMAP, DCM, Rt.
Derivatives with B modifications when R is 5-CFs, n is 1, and A is m-disubstituted phenyl:
Synthesis methods including the following steps for Compounds 33-36 are shown in Scheme 3: i) Step A: Compound 20a-d were prepared from appropriate acid and methyl 5-(amino methyl)-2-chlorobenzoate hydrochloride according to Method G. ii) Step B: Compound 21a-d was synthesized from Compound 20a-d according to Method B. vi) Step C and D: Compound 31 were prepared from 5-(trifhioromethyl)benzene-l,2- diamine and 2-(3-((tert-butoxycarbonyl)amino)phenyl)acetic acid using Methods C and D. iii) Step E: Compound 32 was prepared from Compound 31 according to Method F. iv)Step F: Compound 33-36 were prepared from Compound 32 and Compound 21a-d using Method C.
Figure imgf000013_0001
Scheme 3. Reagent and conditions: A) i. SOCI2, DMF, CHCI2, 50 °C, pivalic acid (for 20a); l-(trifluoromethyl)cyclopropane-l -carboxylic acid (for 20b), l-(trifluoromethyl)cyclobutane- 1 -carboxylic acid (for 20c) or 2-methyloxetane-2-carboxylic acid (for 20d); ii. Methyl 5-(amino methyl)-2-chlorobenzoate hydrochloride, EtsN, CHCh, rt; B) LiOH’thO, THFzthO (1:1), A; C) 2-(3-((ieri-butoxycarbonyl)amino)phenyl)acetic acid, EDC.HC1, DMAP, DCM, Rt; D) AcOH, A; E) TFA, DCM, Rt; F) Compound 21a, b, c or d, EDC.HC1, DMAP, DCM, Rt.
Derivatives with R modifications when n is 1, A is m-disubstituted pheyl, and B is tertbutyl:
Synthesis methods including the following steps for Compounds 40-44 are shown in Scheme 4: i) Step A and B: Amide derivatives based on appropriate o-phenylendiamine and 3- nitrophenylacetic acid were synthesized according to Method C. Then, Compound 38a-e was then synthesized from these amide derivatives according to Method D. ii) Step C: Compound 39a-e were synthesized from Compound 38a-e according to Method E. iii) Step D: Compound 40-44 were synthesized from Compound 39a-e and Compound 21a according to Method C.
Figure imgf000014_0001
Scheme 4. Reagent and conditions: A) 4- fluorobenzene- 1, 2-di amine (for 38a); 3,4- diaminobenzonitrile (for 38b); 4-chlorobenzene-l,2-diamine (for 38c); 4,5-dichlorobenzene- 1,2-diamine (for 38d) or 4-(trifhioromethoxy)benzene-l,2-diamine (for 38e), 3- nitrophenylacetic acid, EDC.HC1, DMAP, DCM, Rt; B) AcOH, A; C) SnCh.2H2O, EtOH, A;
D) Compound 21a, EDC.HC1, DMAP, DCM, Rt.
Derivatives with B modifications when R is 5-CFs, n is 0 and A is p-disubstituted phenyl:
Synthesis methods including the following steps for Compounds 47-48 are shown in Scheme 5: i) Step A: Compound 20e-f were synthesized from methyl 5-(aminomethyl)-2-chloro benzoate hydrochloride and appropriate acid derivatives according to Method G. ii) Step B: Compound 21e-f were synthesized from Compound 20e-f according to Method B. iii) Step C: Compound 45 was obtained by stirring 5-(trifluoromethyl)benzene-l,2-diamine, 4-nitrobenzaldehyde and Na2S2O5 in DMF at 60°C (Method H). iv) Step D: Compound 46 was synthesized from Compound 45 according to Method E. v) Step E: Compound 47-48 were synthesized from Compound 46 and Compounds 21e-f according to Method C.
Figure imgf000015_0001
Figure imgf000015_0002
Scheme 5. Reagent and conditions: A) i. SOC12, DMF, CHCh, 50 °C, 1- (trifluoromethyl)cyclopentane carboxylic acid (for 20e); 3,3-difluoro-l- (trifluoromethyl)cyclobutane- 1 -carboxylic acid (for 20f); ii. Methyl 5-(aminomethyl)-2- chlorobenzoate HC1, EtsN, CHCh, rt; B) LiOH*H2O, THF:H2O (1:1), A; C) 4- nitrobenzaldehyde, Na2S20s, DMF, 60 °C; D) SnCl2.2H2O, EtOH, A; E) Compound 21e or 21f, EDC.HC1, DMAP, DCM, Rt.
Svnthesis methods including the following steps for Compounds 51-52 are shown in Scheme 6: i) Step A: Compound 49 were synthesized from Compound 46 and Compound 2 according to Method C. ii) Step B: Compound 50 was synthesized from Compound 49 according to Method F. iii) Step C: Compound 51-52 were synthesized from Compound 50 and appropriate acid derivatives according to Method C.
Figure imgf000016_0002
Figure imgf000016_0003
Scheme 6. Reagent and conditions: A) Compound 2, EDC.HC1, DMAP, DCM, rt; B) TFA, DCM, rt; C) 2-methyloxetane-2-carboxylic acid (for 51) or 3 -methyloxetane-3 -carboxylic acid (for 52), EDC.HC1, DMAP, DCM, Rt.
Derivatives with A modifications when R is 5-CFs and B is tert-butyl:
Synthesis methods including the following steps for Compounds 55-60 are shown in Scheme 7: i) Step A: Compounds 53a, b, e or f are synthesized by stirring appropriate piperidine derivatives and 2-(chloromethyl)-5-(trifluoromethyl)-1H-benzimidazole in acetonitrile in the presence of Na2COs at rt. Compounds 53c, or d are synthesized by stirring appropriate piperidine derivatives and 2-chloro-5-(trifluoromethyl)-1H-benzimidazole in AcCN at refluks. ii) Step B: Compounds 54a-f were synthesized from Compound 53a-f according to Method F. iii) Step C: Compound 55-60 were synthesized from Compound 54a-f and Compound 21a according to Method C.
Figure imgf000016_0001
Scheme 7. Reagent and conditions: A) for 53a, b, e and f: 2-(chloromethyl)-5- ( trifluoromethyl)- 1 //-benzimidazole, tert-butyl piperidin-4-ylcarbamate (for 53a); tert- butylpiperidin-3-ylcarbamate (for 53b); tert-butyl pyrrolidin-3-ylcarbamate (for 53e) or tertbutyl azetidin-3-ylcarbamate (for 53f), Na2CCh, AcCN, Rt; for 53c and d: 2-chloro-5- ( trifluoromethyl)- 1 //-benzimidazole, tert-butyl piperidin-4-ylcarbamate (for 53c); tert-butyl piperidin-3-ylcarbamate (for 53d), n-butanol, A; B) TFA, DCM, Rt; C) Compound 21a, EDC.HC1, DMAP, DCM, Rt.
Derivatives with A modification when R is 5-CFs, n is 0 and B is 1- (trifluoromethyl)cyclopropane: nthesis methods including the following steps for Compound 62 are shown in Scheme 8: i) Step A and B: Amide formation: Methyl 4-aminobicyclo[2.2.2]octane-l-carboxylate was dissolved in DCM. Then, Compound 21b, HOBt, EDC.HC1 and EtsN were added and stirred at rt under nitrogen gas (Method I). Compound 61 was synthesized according to Method B from an amide derivative containing an ester group. ii) Step C and D: An amide derivative was synthesized from 5-(trifluoromethyl)benzene- 1,2-diamine and Compound 61 according to Method C. Compound 62 was then synthesized from this amide derivative by closing the benzimidazole ring according to Method D.
Figure imgf000017_0001
Scheme 8. Reajanlar ve ko§ullar: A) Compound 21b, HOBt, EDC.HC1, EtgN, DCM, oda stcakhgi, azot gazi altinda; B) LiOH.H2O, THF:su (1:1), A; C) 4-(triflorometil)benzen-l,2- diamin, EDC.HC1, DMAP, DCM, oda stcakhgi, azot gazi altinda; D) AcOH, A.
Derivatives with A and B modifications when R is 5-CFa and n is 0:
Synthesis methods including the following steps for Compounds 66 and 68 are shown in
Scheme 9: i) Step A and B: Amit derivatives were synthesized from methyl 4-amino-2- oxabicyclo[2.2.2]octane-l-carboxylate hydrochloride and Compound 2 or Compound 21a according to Method C. Compound 64a-b were synthesized according to Method B from an amide derivative containing an ester group. ii) Step C and D: An amide derivative was synthesized from 4-(trifluoromethyl)benzene- 1,2-diamine and Compound 64a-b according to Method C. Compound 65-66 were then synthesized from this amide derivative by closing the benzimidazole ring according to Method D. iii) Step E: Compound 67 was synthesized from Compound 65 according to Method F. iv) Step F: Compound 68 was synthesized from Compound 67 and 2-methyloxetane-2- carboxylic acid according to Method C.
Figure imgf000018_0001
Scheme 9. Reagent and conditions: A) Compound 2 (for 64a) or Compound 21a (for 64b), EDC.HC1, DMAP, DCM, Rt; B) LiOH●H2O, THF:H2O (1:1), A; C) 4-(trifluoromethyl) benzene- 1,2-diamine, EDC.HC1, DMAP, DCM, Rt; D) AcOH, A; E) TFA, DCM, Rt; F) 2- methyloxetane-2-carboxylic acid, EDC.HC1, DMAP, DCM, Rt.
Derivatives with A and B modifications when R is 5-CF3 and n is 1:
Synthesis methods including the following steps for Compounds 71-72 are shown in Scheme 10: i) Step A and B : An amide derivative was synthesized from 4-(trifhioromethyl)benzene- 1 ,2- diamine and appropriate acid derivatives according to Method C. Compound 69a-b were then synthesized from this amide derivative by closing the benzimidazole ring according to Method D. ii) Step C: Compound 70a-b were synthesized from Compound 69a-b according to Method F. iii) Step D: Compound 71-72 were synthesized from Compound 70a or b and Compound 21a or b according to Method C.
Figure imgf000019_0001
Scheme 10. Reagent and conditions: A) 3-((tert-butoxycarbonyl)amino)bicyclo[l.l.l]pentan- 1-carboxylic acid (for 69a) or 2-(3 -((/ert-butoxycarbonyl)amino)bicyclo [1.1.1 ] pentan- 1- yl)acetic acid (for 69b), EDC.HC1, DMAP, DCM, rt, under nitrogen gas; B) AcOH, A; C) for 70a: dioxane, 4N HC1, rt; for 70b: TFA, DCM, rt; D) for 71: Compound 21b, HOBt, EDC.HC1, Et3N, THF, rt; for 72: Compound 21a, EDC.HC1, DMAP, DCM, rt.
Derivatives with A modifications when R is 5-CFj, n is 1 and B is tert-butyl:
Synthesis methods including the following steps for Compound 77 are shown in Scheme 11 : i) Step A: Compound 73 was synthesized from methyl 2-(2-aminothiazol-4-yl)acetate according to Method A. ii) Step B: Compound 74 was synthesized from Compound 73 according to Method B. iii) Step C and D: An amide derivative was synthesized from 4-(trifluoromethyl)benzene- 1,2-diamine and Compound 74 according to Method C. Compound 75 was synthesized from this amide derivative by closing the benzimidazole ring according to Method D. iv) Step E: Compound 76 was synthesized from Compound 75 according to Method F. v) Step F: Compound 77 was synthesized from Compound 76 and Compound 21a according to Method C.
Figure imgf000020_0001
Scheme 11. Reagent and conditions: A) Di-tert-buthyldicarbonate, NaHCCh, dioxane:water (1:1), O^Rt; B) LiOH«H2O, THF:H2O (1:1), A; C) Compound 74, EDC.HC1, DMAP, DCM, Rt; D) AcOH, A; E) TFA, DCM, Rt; F) Compound 21a, EDC.HC1, DMAP, DCM, Rt.
Table 1. Chemical structures of the compounds of the present invention
Figure imgf000020_0002
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Biological Activity
Determination of microsomal Prostaglandin E2 synthase activity
For the mPGES-1 activity assay, A549 cells were prepared as described in the literature [18]. In brief, A549 cells were incubated for 72 hours at 37°C in an atmosphere of 5% CO2 using DMEM (Dulbecco's Modified Eagle Medium) supplemented with 2% fetal calf serum (FCS) and 2 ng/mL IL- 10. After incubation, the cells were collected and stored in a solution containing 0.1 M potassium phosphate buffer (pH 7.4), 1 pM phenylmethanesulfonyl fluoride (PMSF), 60 pg/mL soy trypsin inhibitor (STI), 1 pg/mL leupeptin, and 2.5 pM glutathione. The cells were then suspended in 1 mL of homogenization solution containing 250 pM sucrose and further diluted with 0.1 M potassium phosphate buffer containing 2.5 pM glutathione. The cells were flash-frozen in liquid nitrogen, followed by three cycles of sonication, each lasting 20 seconds. Differential centrifugation was then carried out, first at 4°C for 10 minutes, and subsequently for 1 hour at the same temperature. The resulting pellets were resuspended in the homogenization buffer. Microsomes were diluted with 2 mM glutathione in 0.1 M potassium phosphate buffer (pH 7.4) and pre-incubated for 15 minutes with either the test compound or a control (0.1% DMSO). Following the pre-incubation, 20 pM PGH2 substrate was added. After 1 minute at 4°C, the reaction was stopped by adding 100 pL of a stop solution containing 40 pM FeCl2, 80 pM citric acid, and 10 pM 110-PGE2. The production of PGE2 was subsequently analyzed using HPLC. The activity results for the compounds tested for mPGES-1 inhibition using this method are presented in Table 2.
Table 2. mPGES-1 activity values of the compounds of the present invention. (IC50 values are represented as A < 10 nM, B < 50 nM, and C < 400 nM.).
Figure imgf000024_0001
Table 3. ’H-NMR, 13C-NMR and LC-MS values of the compounds of the present invention
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
REFERENCES
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Claims

1. At least one of the compounds shown in Formula (I) and/or its pharmaceutically acceptable salt and/or solvate thereof:
Figure imgf000038_0001
wherein,
- R is selected from the group consisting of 5-trifluoromethyl, 5-trifluoromethoxy, 5- cyano, 5,6-dichloro, 5-fluorine, 5-chlorine, 5-tert-butyl or 5-sulfonylmethyl;
- n is O or l; - A is selected from the substituent group whose structure is drawn below,
Figure imgf000038_0002
B is selected from the group consisting
Figure imgf000038_0004
Figure imgf000038_0005
2. The compound according to claim 1 is a compound and/or its pharmaceutically acceptable salts and/or solvates from the compounds whose chemical structure is drawn below:
Figure imgf000038_0003
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
3. The compounds or pharmaceutically acceptable salts and/or solvates thereof according to claim 1 and 2 selected from the group consisting of the following compounds: 2-Chloro-5-((3,3-dimethylbutanamido)methyl)--N-(4-((5-(trifluoromethyl)-177- benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound 7) 2-Chloro-5-(isobutyramidomethyl)-2V-(4-((5-(trifluoromethyl)-177-benzo[</]imidazol-2- yl)methyl)phenyl)benzamide (Compound 8) 2-Chloro-5-((2,2-difluoroacetamido)methyl)-lV-(4-((5-(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound 9) 2-Chloro-5-(( 1 -isopropylcyclopropane- l-carboxamido)methyl)-2V-(4-((5- (trifluoromethyl)-lfl-benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound 10) 2-Chloro-5-((l-cyanocyclopropane-l-caiboxamido)methyl)-lV-(4-((5-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound 11) N -(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 12) N -(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-3-methyloxetane-3-carboxamide (Compound 13) 2-Chloro-5-((3,3-difluoro-l -methylcyclobutane- 1 -carboxamido)methyl)--N-(4-((5- (trifluoromethyl)-lfl-benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound 14) 2-chloro-5-((3,3-dimethylcyclobutane-l-carboxamido)methyl)-lV-(4-((5-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound 15) N -(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)spiro[3.3]heptane-2-carboxamide (Compound 16) 2-chloro-N -(4-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluoromethyl)cyclopentane-l-carboxamido)methyl)benzamide (Compound 17) 2-chloro-N -(4-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluoromethyl)cyclohexane-l-carboxamido)methyl)benzamide (Compound 18) N -(4-chloro-3-((4-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-3-(trifluoromethyl)bicyclo[ 1.1. IJpentane- 1- carboxamide (Compound 19) 2-chloro-5-(pivalamidomethyl)-lV-(4-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-2- yl)methyl)phenyl)benzamide (Compound 24) 2-chloro-2V-(4-((5-cyano-1H-benzo[d]imidazol-2-yl)mrthyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 25) 2-chloro-lV-(4-((5,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 26) 2-chloro-7V-(4-((5-fluoro- 1 H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 27)
2-chloro-7V-(4-((5-chloro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 28)
7V-(4-((5-(tert-butyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-2-chloro-5- (pivalamidomethyl)benzamide (Compound 29) 2-chloro-7V-(4-((5-(methylsulfonyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 30) 2-chloro-5-(pivalamidomethyl)riV-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)benzamide (Compound 33)
2-chlororiV-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluorometh yl)cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 34) 2-chlororiV-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluoromethyl)cyclobutane-l-carboxamido)methyl)benzamide (Compound 35) A^-(4-chloro-3-((3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 36) 2-chloro-7V-(3-((5-fluoro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 40)
2-chloro-7V-(3-((5-cyano-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 41)
2-chloro-7V-(3-((5-chloro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 42)
2-chloro-7V-(3-((5,6-dichloro-1H-benzo[ri]imidazol-2-yl)methyl)phenyl)-5- (pivalamidomethyl)benzamide (Compound 43)
2-chloro-5-(pivalamidomethyl)riV-(3-((5-(trifluoromethoxy)-1H-benzo[ri]imidazol-2- yl)methyl)phenyl)benzamide (Compound 44)
2-chloro-7V-(4-(5-(trifluoromethyl)- lH-benzo[ri]imidazol-2-yl)phenyl)-5-(( 1 - (trifluorometh yl)cyclopentane- 1 -carboxamido)methyl)benzamide (Compound 47) 2-chloro-5-((3,3-difluoro-l-methylcyclobutane-l-carboxamido)methyl)-7V-(4-(5- (trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)phenyl)benzamide (Compound 48) 7V-(4-chloro-3-((4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)phenyl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 51) 7V-(4-chloro-3-((4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)phenyl)carbamoyl)benzyl)-3-methyloxetane-3-carboxamide (Compound 52) 2-chloro-5-(pivalamidomethyl)-jV-(l-((5-(trifluoromethyl)-l H-benzo[ri]imidazol-2- yl)methyl)piperidin-4-yl)benzamide (Compound 55) 2-chloro-5-(pivalamidomethyl)-jV-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)piperidin-3-yl)benzamide (Compound 56) 2-chloro-5-(pivalamidomethyl)-jV-(l-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)piperidin-4-yl)benzamide (Compound 57)
2-chloro-5-(pivalamidomethyl)-jV-(l-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)piperidin-3-yl)benzamide (Compound 58)
2-chloro-5-(pivalamidomethyl)-jV-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)pyrrolidin-3-yl)benzamide (Compound 59)
2-chloro-5-(pivalamidomethyl)-jV-(l-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)azetidin-3-yl)benzamide (Compound 60)
2-chloro-A-(4-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)bicyclo[2.2.2]octan-l-yl)-5- ((1 -(trifluoromethyl )cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 62) 2-chloro-5-(pivalamidomethyl)riV-(4-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)bicyclo[2.2.2]octan-l-yl)benzamide (Compound 63) 2-chloro-5-(pivalamidomethyl)-7V-(l-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)-2- oxabicyclo[2.2.2]octan-4-yl)benzamide (Compound 66)
A-(4-chloro-3-((l-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)-2- oxabicyclo[2.2.2]octan-4-yl)carbamoyl)benzyl)-2-methyloxetane-2-carboxamide (Compound 68) 2-chloro-A-(3-(5-(trifluoromethyl)-1H-benzo[ri]imidazol-2-yl)bicyclo[l.l.l]pentan-l-yl)- 5-(( 1 -(trifluorometh yl)cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 71) 2-chloro-5-(pivalamidomethyl)-jV-(3-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)bicyclo[l.l.l]pentan-l-yl)benzamide (Compound 72)
2-chloro-5-(pivalamidomethyl)-jV-(4-((5-(trifluoromethyl)-1H-benzo[ri]imidazol-2- yl)methyl)thiazol-2-yl)benzamide (Compound 77)
4. Compound according to claims 1, 2 and 3 are inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1).
5. A method for treating a disease, disorder, or syndrome mediated by mPGES-1, which involves administering an effective amount of a compound as specified in any of claims 1, 2, or 3.
6. The method of claim 5, wherein the disease, disorder, syndrome or condition is chronic or acute pain.
7. The method of claim 5, wherein the disease, disorder, syndrome or condition is rheumatoid arthritic pain or osteoarthritic pain.
8. The method of claim 5, wherein the disease, disorder, syndrome or condition is inflammation or inflammatory disease.
9. Use of the compounds described in claims 1, 2, and 3, or their pharmaceutically acceptable salts, for the treatment or prevention of conditions including inflammation, pain, fever, migraine, chronic pain, acute pain, headache, neuropathic pain, inflammatory bowel disease, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, osteoarthritis, rheumatoid arthritis, rheumatic fever, multiple sclerosis, ankylosing spondylitis, periodontitis, endometriosis, eczema, psoriasis, systemic lupus erythematosus, pancreatitis, Hodgkin's disease, conjunctivitis, diabetes, cancer, vasculitis, neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, systemic sclerosis, and ulcers.
10. A pharmaceutical composition comprising a compound according to any one of claims 1, 2 or 3.
11. A pharmaceutical composition for oral and/or intravenous administration according to claim 10.
12. Use of a compound of the formula according to claim 1, 2 or 3 or a pharmaceutically acceptable salt and/or solvates of a medicament for the treatment of inflammatory diseases or conditions.
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ZHANG, Y.-Y., PHARMACOLOGICAL RESEARCH, 2022

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