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WO2007014054A2 - Benzenesulfonamide inhibitor of ccr2 chemokine receptor - Google Patents

Benzenesulfonamide inhibitor of ccr2 chemokine receptor Download PDF

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Publication number
WO2007014054A2
WO2007014054A2 PCT/US2006/028419 US2006028419W WO2007014054A2 WO 2007014054 A2 WO2007014054 A2 WO 2007014054A2 US 2006028419 W US2006028419 W US 2006028419W WO 2007014054 A2 WO2007014054 A2 WO 2007014054A2
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WO
WIPO (PCT)
Prior art keywords
group
methyl
optionally substituted
phenyl
chloro
Prior art date
Application number
PCT/US2006/028419
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French (fr)
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WO2007014054A3 (en
Inventor
Carl Brooks
Pamela A. Cleary
Krista B. Goodman
Simon Peace
Joanne Philp
Clark A. Sehon
Christian Smethurst
Stephen Paul Watson
Original Assignee
Glaxo Group Limted
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Priority claimed from GB0515194A external-priority patent/GB0515194D0/en
Priority claimed from GB0519492A external-priority patent/GB0519492D0/en
Application filed by Glaxo Group Limted filed Critical Glaxo Group Limted
Publication of WO2007014054A2 publication Critical patent/WO2007014054A2/en
Publication of WO2007014054A3 publication Critical patent/WO2007014054A3/en

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Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, as modulators of chemokine receptors, particularly as CCR2 antagonists, as well as to processes for their preparation, and intermediates used in these processes.
  • Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928).
  • CXC chemotactic cytokines
  • CC chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928).
  • CXC single amino acid
  • CC adjacent
  • the CXC chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-Ia, MlP- ⁇ , the monocyte chemotactic proteins (MCP-1 , MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils.
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • lymphotactin-1 lymphotactin-1
  • lymphotactin-2 both C chemokines
  • fractalkine a CX 3 C chemokine
  • chemokines bind to specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which are termed "chemokine receptors.”
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration.
  • CCR-1 or "CKR-1 " or "CC-CKFM ”
  • MIP-1 ⁇ , MCP-3, MCP-4, RANTES Ben-Barruch, et al., ce// 1993, 72, 415-425, and Luster, New Eng. J. Med.
  • CCR2A and CCR2B (or "CKR-2AVCKR-2B” or "CC-CKR-2ATCC-CKR-2B") [MCP-1 , MCP-2, MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. ScL USA 1994, 91 , 2752-2756 Luster, New Eng. J Med. 1998, 338, 436-445); CCR-3 (or "CKR-3” or "CC-CKR-3”) [eotaxin-1 , eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem.
  • CCR-4 or "CKR-4" or "CC-CKR-4" [TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270, 19495- 19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or "CKR-5" or "CC- CKR-5") [MIP-1 ⁇ , RANTES, MIP-1 B] (Sanson, et al., Biochemistry 1996, 35, 3362-3367); CCR-6(or "CKR-6” [LARC] (Baba, et al., J. Biol.
  • CCR-7 or “CKR-7” or “CC-CKR-7" [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8 (or “CKR-8” or “CC-CKR-8”) [1 -309] (Napolitano et al., J. Immunol., 1996, 157, 2759-2763); CCR-10 (or “CKR-IO” or "CC-CKR-IO”) [MCP-1 , MCP-3] (Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256); and CCR-11 [MCP-1 , MCP-2, and MCP-4] (Schweickert, et al., J. bid. Chem. 2000, 275, 90550).
  • mammalian chemokine receptors In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpe's viruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin. Biotech. 1997, 8, 741-748).
  • Human CC chemokines such as RANTES and MCF-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection.
  • human chemokine receptors such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co- receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
  • HAV human immunodeficiency viruses
  • chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (reviewed in: F. H. Carter, Current Opinion in Chemical Biology 2002, 6, 510; Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191 ; Saunders and Tarby, Drug Disc. Today 1999, 4, 80; Fremack and Schall, Nature Medicine 1996, 2, 1174).
  • the chemokine monocyte chemoattractant-l (MCP-1) and its receptor CC Chemokine Receptor 2 (CCR2) play a pivotal role in attracting leukocytes to sites of inflammation and in subsequently activating these cells.
  • MCP-1 monocyte chemoattractant-l
  • CCR2 Chemokine Receptor 2
  • MCP-1 -/- mice had normal numbers of leukocytes and macrophages, but were unable to recruit monocytes into sites of inflammation after several different types of immune challenge (Bao Lu, et al., J. Exp. Med. 1998, 187, 601). Likewise, CCR2 -/- mice were unable to recruit monocytes or produce interferon- ⁇ when challenged with various exogenous agents; moreover, the leukocytes of CCR2 null mice did not migrate in response to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100, 2552), thereby demonstrating the specificity of the MCP-1/CCR2 interaction.
  • MCP-1 is upregulated in patients with rheumatoid arthritis (Alisa Koch, et al., J. CHn. Invest. 1992, 90, 772 - 779). Moreover, several studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating rheumatoid arthritis. A DNA vaccine encoding MCP-1 was shown recently to ameliorate chronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al., J. Clin. Invest. 2000, 106, 361).
  • MCP-1 collagen-induced arthritis
  • streptococcal cell wall-induced arthritis Roseptococcal cell wall-induced arthritis
  • MCP-1 a peptide antagonist of MCP-1 , MCP-1 (9-76)1 was shown both to prevent disease onset and to reduce disease symptoms (depending on the time of administration) in the MRL-1pr mouse model of arthritis (Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).
  • MCP-1 is upregulated in atherosclerotic lesions, and it has been shown that circulating levels of MCP-1 are reduced through treatment with therapeutic agents, plays a role in disease progression (Abdolreza Rezaie-Majd, et al, Arterioscler. Thromb. Vase. Biol. 2002, 22, 1194 - 1199).
  • Four key studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating atherosclerosis. For example, when MCP-1 -/- mice are mated with LDL receptor- deficient mice, an 83% reduction in aortic lipid deposition was observed (Long Gu, et al., MoI. Cell 1998, 2, 275).
  • mice which already overexpressed human apolipoprotein B were protected from atherosclerotic lesion formation relative to the MCP-1 +/+ apoB control mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773).
  • CCR2 -/- mice are crossed with apolipoprotein E -/- mice, a significant decrease in the incidence of atherosclerotic lesions was observed (Landin Boring, et al, Nature 1998, 394, 894).
  • MCP-1 is upregulated in human multiple sclerosis, and it has been shown that effective therapy with interferon b-lb reduces MCP-1 expression in peripheral blood mononuclear cells, suggesting that MCP-1 plays a role in disease progression (Carla larlori, et al., J. Neuroimmunol. 2002, 123, 170 - 179).
  • Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating multiple sclerosis; all of these studies have been demonstrated in experimental autoimmune encephalomyelitis (EAE), the conventional animal model for multiple sclerosis.
  • EAE experimental autoimmune encephalomyelitis
  • MCP-1 is upregulated in patients who develop bronchiolitis obliterans syndrome after lung transplantation (Martine Reynaud-Gaubert, et al., J. of Heart and Lung Transplant, 2002, 21, 721 - 730; John Belperio, et al., J. Clin. Invest. 2001, 108, 547 - 556).
  • bronchiolitis obliterans syndrome administration of an antibody to MCP-1 led to attenuation of airway obliteration; likewise, CCR2 -/- mice were resistant to airway obliteration in this same model (John Belperio, et al., J. Clin. Invest. 2001, 108, 547 - 556).
  • MCP-1 -/- mice with induced nephrotoxic serum nephritis showed significantly less tubular damage than their MCP-1 +/+ counterparts (Gregory H. Tesch, et al.7 J. Cur. Invest. 1999, 103, 73).
  • MCP-1 is overexpressed in various disease states not mentioned above. These reports provide correlative evidence that MCP-1 antagonists could be useful therapeutics for such diseases.
  • Two reports describe the overexpression of MCP-1 rats with induced brain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, and Joan W.
  • MCP-1 is overexpressed in the brains and cerebrospinal fluid of patients with HIV-associated dementia (Alfredo Garzino-Demo, WO 99/46991).
  • CCR2 has been implicated as a co-receptor for some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). It has also been determined that the use of CCR2 as an HIV co-receptor can be correlated with disease progression (Ruth I.
  • the present invention is a compound as represented in formula (I):
  • R 1 represents an aryl, a thienyl, a benzothienyl, an imidazolyl, a pyridyl, an isoquinolinyl, a piperonyl, a benzoxathiadiazolyl, or a benzoxadiazolyl group optionally substituted with one to three R 4 groups, wherein each R 4 group is independently selected from the group consisting of Ci_ 6 -alkyl, C ⁇ -haloalkyl, C ⁇ -alkoxy, C 1-6 -haloalkoxy, halo, -NH 2 , -OH, -CN, -NO 2 , CF 3 , phenyl, phenoxy, phenyl-C(O)-, isoxazolyl, and -C(O)NR 7 R 8 , wherein R 7 and R 8 each independently represent hydrogen or C 1-4 alkyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or
  • n 1 , 2, or 3; each R 2 is independently selected from the group consisting of halo, -CN, OCF 3 , and - CF 3 ,;
  • R 3 is a heteroaryl or a heterocycloalkyl group optionally substituted by up to three substituents independently selected from the group consisting of halo, hydroxy, hydroxy- d- 6 -alkyl-, C ⁇ alkoxy-d-ealkyl-, Ci -4 alkoxy-, C ⁇ thioalkoxy, amino, R 10 R 11 N-Ci. 4 alkyl-, heterocycloalkyl, heteroaryl, halogenated heteroaryl, phenyl, benzyl, halophenyl,
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and a pharmaceutically acceptable carrier, diluent, or excipient or combination thereof.
  • the present invention is a method for treating a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a combination thereof.
  • Compounds within the scope of the present invention have potential in the treatment of conditions wherein modulation, especially antagonism/inhibition, of the CCR2 receptor is thought to be beneficial.
  • the compounds may be effective in the treatment of diseases such as atherosclerosis, asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, food allergy, scombroid poisoning, pulmonary fibrosis, restenosis, including vascular restenosis, myocarditis, ulcerative colitis, psoriasis, urticaria, pruritis, eczema, atopic dermatitis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease, otis media, rheumatoid arthritis, nephritis (nephropathy), liver cirrhosis, multiple sclerosis and systemic sclerosis, lupus, erthematosis, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn's disease, endometriosis, cardiac disease, congestive heart failure, viral meningitis, cerebral infarction, neuropathy
  • CCR2 is also the receptor for the chemokines MCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338, 436-445). Since the new compounds of formula (I) described herein antagonize MCP-1 by binding to the CCR2 receptor, it may be that these compounds of formula (I) are also effective antagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that are mediated by CCR2.
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched alkyl containing at 1 to 6 carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl.
  • alkoxy refers to a straight or branched alkoxy group containing the specified number of carbon atoms.
  • Ci -6 alkoxy means a straight or branched alkoxy group containing 1 to 6 carbon atoms.
  • alkoxy include, but are not limited to methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.
  • alkylthio refers to a straight or branched alkylthio group containing the specified number of carbon atoms.
  • C 1-4 alkylthio means a straight or branched alkylthio group containing 1 to 6 carbon atoms.
  • alkylthio as used herein include, but are not limited to methylthio, ethylthio, propylthio, prop-2-thio, butylthio, but-2-thio, 2-methylprop-1 -thio, 2-methylprop-2-thio.
  • C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • halogen or halo refers to fluoro, chloro, bromo and iodo.
  • heterocycloalkyl groups include, but are not limited to pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, oxopiperidinyl, oxophenyltriazaspirodecyl, oxopyrazolidinyl, oxopyrazolyl, oxooxazolidinyl, oxoimidazolidinyl, dioxaazaspirodecyl groups.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzthiazolyl, indazolyl, indolazinyl, benzimidazolyl, benzotriazolyl, purinyl, coumarinyl, isocoumarinyl, chromonyl, quinolinyl, isoquinolinyl, cinnolinyl, quin
  • C 6-10 aryl ring systems include: phenyl and naphthyl.
  • ring systems covered by the definitions in this specification are those which are stable enough to be effective for the intended purpose. This stability is with reference to the preparation and storage of the compound containing said ring system and not with reference to in vivo metabolism.
  • pharmaceutically acceptable means suitable for pharmaceutical use.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include water, methanol, ethanol, and acetic acid.
  • the compounds of formula (I) as defined above contain a basic grouping and may also contain an acidic grouping and therefore may form salts with physiologically acceptable acids or bases.
  • Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation.
  • physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesul, in
  • Certain of the compounds of the invention may form acid addition salts with one or more equivalents of the acid. Certain of the compounds of the invention may form acid addition salts with less than one equivalent of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • the invention provides a method for treating a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a combination thereof.
  • a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and a pharmaceutically acceptable carrier, diluent, or excipient or a combination thereof.
  • the carrier, diluent and/or excipient must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, buccal, topical, inhalation or insufflation, implant, rectal or parenteral administration to mammals including humans.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcystalline cellulose, maize-starch, calcium phosphate, glycine or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, muci
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid; and, if desired, conventional flavouring or colouring agents.
  • the compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 1 to 10OOmg per day, dependent upon the route of administration.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • each unit will typically contain from 1 -1000 mg of the active ingredient.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis” by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups” by P.J. Kocienski (Georg Thieme Verlag 1994).
  • suitable amino protecting groups include acyl type protecting groups (e.g.
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl
  • alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl.
  • oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
  • alkyl silyl groups such as trimethylsilyl or tert-butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or tert-butyl
  • esters such as acetate.
  • the compounds of formula (I), wherein the R 3 group is attached to the methylene linker via a nitrogen atom, may in general be prepared by the reaction of a compound of formula (II):
  • R 3 is as defined above;
  • Suitable leaving groups L include chloro or bromo.
  • L may represents a sulfonyloxy group such C alkylsulfonyloxy (for example methanesulfonyloxy), C 1 4 alkylsulfonyloxy or haloC ⁇ alkylsulfonyloxy (for example trifluoromethanesulfonyloxy); or arylsulfonyloxy for example para-toluenesulfonyloxy.
  • such a reaction may be carried out by dissolving the compound of formula (III) in a suitable solvent, for example 1 ,4-dioxane, in the presence of an appropriate crown ether, for example 18-crown-6-ether, and then reacting it with a deprotonating agent such as potassium tert-butoxide, and then reacting the resulting solution with the compound of formula (II).
  • a suitable solvent for example 1 ,4-dioxane
  • an appropriate crown ether for example 18-crown-6-ether
  • a deprotonating agent such as potassium tert-butoxide
  • the compounds of formula (I) may be prepared by the reaction of a compound of formula (IV):
  • L' is a suitable leaving group, and R 1 is as defined above;
  • Suitable leaving groups L' include chloro, bromo or pentafluorophenoxy.
  • L' represents chloro
  • such a reaction may be carried out by dissolving the compound of formula (IV) in a suitable solvent, for example pyridine optionally mixed with a second solvent, such as chloroform or tetrahydrofuran, and reacting it with the compound of formula (V) also in a suitable solvent, for example pyridine.
  • a catalytic quantity of dimethylaminopyridine may also be used.
  • the reaction would generally be carried out at elevated temperature in the region of 80-250 s C, for example at about 200 9 C, for a period of 30 minutes to 1 hour or at 8O 0 C for a period of 5-24 hours.
  • this ring system may be formed de novo by methods well-known to the person skilled in the art.
  • n is a group capable of being converted by reaction with appropriate reagents into the group R 3 or a protected derivative thereof;
  • a suitable scheme to generate de novo a pyridazinone ring system would suitably involve reacting a compound of formula (II) wherein L represents chloro with tert- butyl carbazat ⁇ in a suitable solvent, for example DMF. Typically such a reaction would be carried out at ambient temperature for between 3 and 8 hours. The resulting product may then be dissolved in a suitable solvent containing 50% trifluoroacetic acid, for example dichloromethane, and stirred for a suitable time, typically 2 to 3 hours, at ambient temperature. Subsequent to the removal of the solvent the residue may be reacted with ethyl levulinate and glacial acetic acid, typically at elevated temperature in the region of 100 9 C for between 30 and 60 minutes. The final product will represent a compound of formula (I) wherein R 3 represents a 3-methyl-6-oxo-5,6-dihydro-1 (4H)- pyridazinyl group.
  • the compound of formula (IV), wherein the group R 3 is joined to the methylene linker by a nitrogen atom, may be prepared by reacting a compound of formula (VII):
  • such compounds may be prepared by de novo generation of a hetero-aryl ring, for example by the general process outlined in Scheme 6.
  • Generation of a di-acyl hydrazine of the type shown may be achieved by, for example, activation of a carboxylic acid to the acid chloride with oxalyl chloride in the presence of a catalytic quantity of dimethylformamide or dimethylacetamide and subsequent reaction with the appropriate acyl hydrazine.
  • Dehydration of the diacylhydrazine intermediate may be achieved with an appropriate reagent such as Burgess' reagent.
  • Reduction of the nitro-arene to the corresponding aniline (IV) may be achieved by hydrogenation with platinum or palladium catalysis in a suitable solvent, for example ethanol.
  • Substituted triazolyl examples may be constructed as outlined by the general method provided in Scheme 7.
  • Preparation of the intermediate azides may be achieved by treatment of relevant alcohol with an azidinating reagent such as diphenylphosphoryl azide in the presence of an appropriate base, such as 1 ,8-diazabicyclo[5.4.0]undec-7- ene.
  • the triazole products may be prepared by reaction of appropriately substituted acetylenes catalysed by, for example, copper sulfate in the presence of sodium ascorbate.
  • the compounds of formula (I), wherein the R 3 group is a dihydropyridazinone or a dihydropyrazolone may be prepared from a compound of formula (II) by a process analogous to that set out in Scheme 8. Direct displacement of the chloride with f-butyl carbazate followed by removal of the protecting group provides the hydrazine which can be cyclized upon treatment with a ketoester.
  • 1 ,2,4-Triazole examples may be constructed as by the general procedure illustrated in Scheme 10. Treatment with f-butyl carbazate, followed by a borane reduction and removal of the protecting group provides the hydrazine. Addition of 1 ,3,5-triazine yields the triazole.
  • 1 ,2,4-triazoles of formula (IV) may be constructed by the general methods shown in Scheme 11 and Scheme 12.
  • Carbon linked 1 ,2,4-triazoles of formula (IV) may be prepared by the method in Scheme 13.
  • Treatment of the nitrile with acetyl chloride provides the imine which is converted to the formyl hydrazone.
  • Addition of an amine allows for ring closure to the triazole.
  • Polymer supported isocyanate is added to capture any excess amine. Reduction of the nitrobenzene then provides the aniline.
  • Imidazoles of formula (I) may be constructed from the hydrazines in formed in Scheme 10 by the general procedure outlined in Scheme 14. Treatment of the hydrazine with a 3-substituted 3-oxoproanenitrile affords the imidazole.
  • Interconversion reactions between compounds of formula (I) may be performed using methods well known in the art. Included are conversions of the substituent(s) within the group R 3 and/or conversions within groups R 2 and R 1 for example: (i) converting an acid to an acid amide;
  • DMEM Dulbecco Minimal Essential Medium GDP: Guanosine Diphosphate
  • Mass spectra were obtained using either a Waters ZQ mass spectrometer or Micromass Platform 2 mass spectrometer and use electro-spray ionisoation to observe either MH+ or M-.
  • Proton Nuclear Magnetic Resonance ( 1 H-NMR) spectra were recorded at 400 MHz unless otherwise stated, chemical shifts are reported in ppm downfield from M ⁇ 4Si, used as internal standard, and are assigned as singlets (s), doublets (d), doublets of doublets (dd), triplets (t), doublet of triplets (dt), quartets (q) multiplets (m) or are otherwise described in full.
  • the prefix "br” refers to a broad peak; for example, a broad single may appear as br.s (or br s).
  • Methyl 2- ⁇ [(4-chlorophenyl)sulfonyl]amino ⁇ -4-(trifluoromethyl)benzoate (460 mg, 1.17 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 0 C.
  • Diisobutylaluminum hydride (1.5 M in toluene, 1.95 mL, 2.93 mmol) was added dropwise and then the reaction stirred at room temperature for 12 hours. A further portion of diisobutylaluminum hydride was added (1.17 mL, 1.76 mmol) and the solution allowed to stir for an additional 5 hours. The reaction was quenched with water and concentrated to dryness.
  • the resulting solid was dissolved in IMS (2.5 ml_) and water (30 mL) to which was added a 5M sodium hydroxide solution (1.5 mL). The mixture was then heated to reflux under argon overnight. The mixture was concentrated and the residue taken up in DCM (70 mL) and water (30 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was re-dissolved in IMS (2.5 mL) and water (30 mL) to which was added a 5M sodium hydroxide solution (1.5 mL) and the mixture heated to reflux under argon overnight. The mixture was concentrated and the residue taken up in DCM (70 mL) and water (30 mL).
  • Nitric acid was added slowly to a mixture of 1 ,2-dichloro-4-methylbenzene (10 g) in sulfuric acid at 0 °C, keeping the temperature below 10 0 C.
  • the mixture was allowed to warm to room temperature, stirred for 10 minutes, poured over ice (250 g) and stirred for 10 further minutes.
  • the solid was filtered, washed with water (50 mL) and dissolved in DCM (150 mL). The resulting solution was washed with water (120 ml_) and brine (100 mL), dried over magnesium sulfate and concentrated. To the resulting solid at 150 0 C was added bromine (3.4 mL).
  • tert-Butyl carbazate (0.08 g, 0.63 mmol) was added to a solution of 3,4-dichloro- ⁇ /-(5- chloro-2-formylphenyl)benzenesulfonamide (0.19 g, 0.52 mmol) in hexane (8 ml_) and the reaction mixture was heated under reflux for 1 hour. A solution of 1 M BF 3 THF (2 ml_) was added and the reaction was stirred at room temperature for 14 minutes. The reaction was then treated with HCI (1 N in dioxane, 2 ml_) for 18 hours and concentrated. The residue was taken up in THF and filtered. The filtrate was concentrated to afford the titled product (0.15 g, 76%)
  • Example 2 1 -(r2-(r(4-chlorophenyl)sulfonyllamino)-4-(trifluoromethyl)phenyl1methyl)-5- r(methylamino)carbonyll-1 H-pyrazole-3-carboxylic acid
  • Example 36 ⁇ /-l2-r(5-cylopropyl-1 H-tetrazole-1 -vDmethyli-4-f luorophenyll-2.11.3- benzoxadiazole-4-sulfonamide
  • Example 74 3.4-Dichloro- ⁇ /-(5-chloro-2-r(3-oxo ⁇ .2.41triazolor4.3-alPyridin-2(3HV yl)methvnphenyl ⁇ benzenesulfonamide
  • Example 78 3.4-Dichloro- ⁇ /-l5-chloro-2-lY1 -methyl-1 H-tetrazol-5- vDnnethyliphenyllbenzenesulfonamicle
  • Example 145 3.4-dichloro- ⁇ /-l5-fluoro-2-IT4-propyl-1 H- 1.2.3-triazol-1 - vDmethyliphenyDbenze ⁇ esulfonamide
  • the aqueous layer was removed using a hydrophobic frit and washed with DCM (2 x 1 mL) and the combined DCM layers concentrated.
  • the title compound was retained on an isolute SCX ion-exchange column and eluted in 2M ammonia in methanol to give 40 mg upon removal of solvent.
  • Example 159 ⁇ /-r2-r(5-cyclopropyl-1 H-tetrazol-1 -yl)methyll-5-(trifluoromethyl)phenyl]- 2,1.3-benzoxadiazole-4-sulfonamide
  • Example 160 ⁇ /-r4.5-dichloro-2-(1 HA ,2.3-triazol-1 -ylmethvnphenv ⁇ -3- (trifluoromethvObenzenesulfonamide
  • Example 184 4-chloro- ⁇ /-l5-chloro-2-r(3,3-difluoro-1- pyrrolidinyl)methvnphenyl>benzenesulfonannide
  • Example 323 3.4-Dichloro- ⁇ /-r5-chloro-2-(1 H-1.2.4-triazol-1 - ylmethvDphenyllbenzenesulfonamide trifluoroacetate
  • 3-Pyrrolidinol (0.02 g, 0.23 mmol) was added to a solution of 3,4-dichloro- ⁇ /-(5-chloro-2- formylphenyl)benzenesulfonamide (0.07 g, 0.19 mmol) in anhydrous THF (2 mL) at room temperature. After stirring for 10 minutes, sodium cyanoborohydride (0.24 g, 0.38 mmol) and acetic acid (0.1 mL) were added. The resulting reaction mixture was stirred at room temperature for additional 12 hours until the starting material was consumed completely. Saturated K 2 CO 3 aqueous solution (4 ml_) was added to quench the reaction.
  • Example 360 2.3-Dichloro- ⁇ /-r2-((5-r3-(methyloxybhenyll-2H-tetrazol-2-yl>methvn-5-
  • Acetonitrile (2.75 ml_) was added to 5-[3-(methyloxy)phenyl]-1 /-/-tetrazole (0.0145 g, 0.0825 mmol) and polymer supported BEMP (0.150 g, 0.33 mmol).
  • a solution of trif luoromethyl2,3-dichloro- ⁇ /-[2-(chloromethyl)-5-()phenyl]benzenesulfonamide (0.0314 g, 0.075 mmol) in N-methyl pyrrolidinone (0.5 ml_) was also added and the reaction was stirred at 120 0 C in a Biotage microwave.
  • Example 379 ⁇ /-r2-r(5-amino-3-phenyl-1 H-pyrazol-1 -yl)methvn-5- (trifluoromethyl)phenyll-4-chlorobenzenesulfonamide
  • Example 380 1 -(r2-(r(4-chlorophenyl)sulfonyllamino)-4-(trif luoromethvDphenylimethyl)- ⁇ /-methyl-3-(2-thienylH H-pyrazole-5-carboxamide

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Abstract

Disclosed are compounds of formula (I): or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof, as well as compositions of methods of use of the compound, wherein R1, R2, R3, and m are described herein.

Description

BENZENESULFONAMIDE INHIBITOR OF CCR2 CHEMOKINE RECEPTOR
Background of the Invention
The present invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, as modulators of chemokine receptors, particularly as CCR2 antagonists, as well as to processes for their preparation, and intermediates used in these processes.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-Ia, MlP-β, the monocyte chemotactic proteins (MCP-1 , MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1 , lymphotactin-2 (both C chemokines), and fractalkine (a CX3C chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with following characteristic patterns (reviewed in Zlotnik and Oshie Immunity 2000, 12, 121): CCR-1 (or "CKR-1 " or "CC-CKFM ") [MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., ce// 1993, 72, 415-425, and Luster, New Eng. J. Med. 1998, 338, 436-445; CCR2A and CCR2B (or "CKR-2AVCKR-2B" or "CC-CKR-2ATCC-CKR-2B") [MCP-1 , MCP-2, MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. ScL USA 1994, 91 , 2752-2756 Luster, New Eng. J Med. 1998, 338, 436-445); CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin-1 , eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270, 19495- 19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or "CKR-5" or "CC- CKR-5") [MIP-1 α, RANTES, MIP-1 B] (Sanson, et al., Biochemistry 1996, 35, 3362-3367); CCR-6(or "CKR-6" [LARC] (Baba, et al., J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or "CKR-7" or "CC-CKR-7") [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8 (or "CKR-8" or "CC-CKR-8") [1 -309] (Napolitano et al., J. Immunol., 1996, 157, 2759-2763); CCR-10 (or "CKR-IO" or "CC-CKR-IO") [MCP-1 , MCP-3] (Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256); and CCR-11 [MCP-1 , MCP-2, and MCP-4] (Schweickert, et al., J. bid. Chem. 2000, 275, 90550).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpe's viruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin. Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES and MCF-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co- receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
The chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (reviewed in: F. H. Carter, Current Opinion in Chemical Biology 2002, 6, 510; Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191 ; Saunders and Tarby, Drug Disc. Today 1999, 4, 80; Fremack and Schall, Nature Medicine 1996, 2, 1174). For example, the chemokine monocyte chemoattractant-l (MCP-1) and its receptor CC Chemokine Receptor 2 (CCR2) play a pivotal role in attracting leukocytes to sites of inflammation and in subsequently activating these cells. When the chemokine MCP-1 binds to CCR2, it induces a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of leukocyte migration. Demonstration of the importance of the MCP-1 /CCR2 interaction has been provided by experiments with genetically modified mice. MCP-1 -/- mice had normal numbers of leukocytes and macrophages, but were unable to recruit monocytes into sites of inflammation after several different types of immune challenge (Bao Lu, et al., J. Exp. Med. 1998, 187, 601). Likewise, CCR2 -/- mice were unable to recruit monocytes or produce interferon-γ when challenged with various exogenous agents; moreover, the leukocytes of CCR2 null mice did not migrate in response to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100, 2552), thereby demonstrating the specificity of the MCP-1/CCR2 interaction. Two other groups have independently reported equivalent results with different strains of CCR2 -/- mice (William A. Kuziel, et al., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, et al., J. Exp. Med. 1997, 186, 1757). The viability and generally normal health of the MCP-1 -/- and CCR2 -/- animals is noteworthy, in that disruption of the MCP-1 /CCR2 interaction does not induce physiological crisis. Taken together, these data lead one to the conclusion that molecules that block the actions of MCP-1 would be useful in treating a number of inflammatory and autoimmune disorders. This hypothesis has now been validated in a number of different animal disease models, as described below.
It is known that MCP-1 is upregulated in patients with rheumatoid arthritis (Alisa Koch, et al., J. CHn. Invest. 1992, 90, 772 - 779). Moreover, several studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating rheumatoid arthritis. A DNA vaccine encoding MCP-1 was shown recently to ameliorate chronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al., J. Clin. Invest. 2000, 106, 361). Likewise, 'inflammatory disease symptoms could be controlled via direct administration of antibodies for MCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J. Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis (Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps most significantly, a peptide antagonist of MCP-1 , MCP-1 (9-76)1 was shown both to prevent disease onset and to reduce disease symptoms (depending on the time of administration) in the MRL-1pr mouse model of arthritis (Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131). It is known that MCP-1 is upregulated in atherosclerotic lesions, and it has been shown that circulating levels of MCP-1 are reduced through treatment with therapeutic agents, plays a role in disease progression (Abdolreza Rezaie-Majd, et al, Arterioscler. Thromb. Vase. Biol. 2002, 22, 1194 - 1199). Four key studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating atherosclerosis. For example, when MCP-1 -/- mice are mated with LDL receptor- deficient mice, an 83% reduction in aortic lipid deposition was observed (Long Gu, et al., MoI. Cell 1998, 2, 275). Similarly, when MCP-1 was genetically ablated from mice which already overexpressed human apolipoprotein B, the resulting mice were protected from atherosclerotic lesion formation relative to the MCP-1 +/+ apoB control mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773). Likewise, when CCR2 -/- mice are crossed with apolipoprotein E -/- mice, a significant decrease in the incidence of atherosclerotic lesions was observed (Landin Boring, et al, Nature 1998, 394, 894). Finally, when apolipoprotein E -/- mice are administered a gene encoding a peptide antagonist of CCR2, then lesion size is decreased and plaque stability is increased (W Ni, et al. Circulation 2001, 103, 2096 -2101).
It is known that MCP-1 is upregulated in human multiple sclerosis, and it has been shown that effective therapy with interferon b-lb reduces MCP-1 expression in peripheral blood mononuclear cells, suggesting that MCP-1 plays a role in disease progression (Carla larlori, et al., J. Neuroimmunol. 2002, 123, 170 - 179). Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating multiple sclerosis; all of these studies have been demonstrated in experimental autoimmune encephalomyelitis (EAE), the conventional animal model for multiple sclerosis. Administration of antibodies for MCP-1 to animals with EAE significantly diminished disease relapse (K. J. Kennedy, et al., J. Neuroimmunol. 1998, 92, 98). Furthermore, two recent reports have now shown that CCR2 -/- mice are resistant to EAB (Brian T. Fife, et al., J. Exp. Med. 2000, 192, 899; Leonid Izikson, et al., J. Exp. Med. 2000, 192, 1075).
It is known that MCP-1 is upregulated in patients who develop bronchiolitis obliterans syndrome after lung transplantation (Martine Reynaud-Gaubert, et al., J. of Heart and Lung Transplant, 2002, 21, 721 - 730; John Belperio, et al., J. Clin. Invest. 2001, 108, 547 - 556). In a murine model of bronchiolitis obliterans syndrome, administration of an antibody to MCP-1 led to attenuation of airway obliteration; likewise, CCR2 -/- mice were resistant to airway obliteration in this same model (John Belperio, et al., J. Clin. Invest. 2001, 108, 547 - 556). These data suggest that antagonism of MCP-1/CCR2 may be beneficial in treating rejection of organs following transplantation.
Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating asthma. Sequestration of MCP-1 with a neutralizing antibody in ovalbumin-challenged mice resulted in marked decrease in bronchial hyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J. Exp. Med. 1998,
188, 157). It proved possible to reduce allergic airway inflammation in Schistosoma mansoni egg-challenged mice through the administration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J. Immunol. 1997, 158, 4398). Consistent with this, MCP-1 -
/- mice displayed a reduced response to challenge with Schistosoina mansoni egg (Bao
Lu, et al., J. Exp. Med. 1998, 187, 601).
Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating kidney disease. Administration of antibodies for
MCP-1 in a murine model of glomerularnephritis resulted in a marked decrease in glomerular crescent formation and deposition of type I collagen (Clare M. Lloyd, et al., J.
Exp. Med. 1997, 185, 1371). In addition, MCP-1 -/- mice with induced nephrotoxic serum nephritis showed significantly less tubular damage than their MCP-1 +/+ counterparts (Gregory H. Tesch, et al.7 J. Cur. Invest. 1999, 103, 73).
One study has demonstrated the potential therapeutic value of antagonism of the MCP- 1/CCR2 interaction in treating systemic lupus erythematosus. Crossing of MCP-1 -/- mice with MRL-FAS1 pr mice (the latter of which have a fatal autoimmune disease that is analogous to human systemic lupus erythematosus) results in mice that have less disease and longer survival than the wildtype MRLFASI pr mice (Gregory H. Tesch, et al., J. Exp. Med. 1999, 190, 1813). One study has demonstrated the potential therapeutic value of antagonism of the MCP-1 /CCR2 interaction in treating colitis. CCR2 -/- mice were protected from the effects of dextran sodium sulfate-induced colitis (Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).
One study has demonstrated the potential therapeutic value of antagonism of the MCP- 1/CCR2 interaction in treating alveolitis. When rats with IgA immune complex lung injury were treated intravenously with antibodies raised against rat MCP-1 (JE), the symptoms of alveolitis were partially alleviated (Michael L. Jones, et al., J. Immunol. 1992, 149, 2147). One study has demonstrated the potential therapeutic value of antagonism of the MCP- 1/CCR2 interaction in treating cancer. When immunodeficient mice bearing human breast carcinoma cells were treated with an anti-MCP-1 antibody, inhibition of lung micrometastases and increases in survival were observed (Rosalba Salcedo, et al, Blood 2000, 96, 34 - 40).
One study has demonstrated the potential therapeutic value of antagonism of the MCP- 1/CCR2 interaction in treating restinosis. Mice deficient in CCR2 showed reductions in the intimal area and in the intima/media ratio (relative to wildtype littermates) after injury of the femoral artery (Merce Roque, et al. Arterioscier. Thromb. Vase. PIoI. 2002, 22, 554 - 559).
Other studies have provided evidence that MCP-1 is overexpressed in various disease states not mentioned above. These reports provide correlative evidence that MCP-1 antagonists could be useful therapeutics for such diseases. Two reports described the overexpression of MCP-1 in the intestinal epithelial cells and bowel mucosa of patients with inflammatory bowel disease (H. C. Reinecker, et al., Gastroenterology 1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc. Biol. 1996, 59, 804). Two reports describe the overexpression of MCP-1 rats with induced brain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, and Joan W. Berman, et al., J. lininunol. 1996, 156, 3017). Another study has demonstrated the overexpression of MCP-1 in rodent cardiac allografts, suggesting a role for MCP-1 in the pathogenesis of transplant arteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6086). The overexpression of MCP-1 has been noted in the lung endothelial cells of patients with idiopathic pulmonary fibrosis (Harry N. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371 ). Similarly, the overexpression of MCP-1 has been noted in the skin from patients with psoriasis (M. Deleuran, et al., J. Derinatol. Sci. 1996, 13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127). Finally, a recent report has shown that MCP-1 is overexpressed in the brains and cerebrospinal fluid of patients with HIV-associated dementia (Alfredo Garzino-Demo, WO 99/46991).
It should also be noted that CCR2 has been implicated as a co-receptor for some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). It has also been determined that the use of CCR2 as an HIV co-receptor can be correlated with disease progression (Ruth I.
Connor, et al., J. Exp. Med. 1997, 185, 621 ). This finding is consistent with the recent finding that the presence of a CCR2 mutant, CCR2-641 , is positively correlated with delayed onset of HIV in the human population (Michael W. Smith, et al., Science 1997, 277,959). Although MCP-1 has not been implicated in these processes, it may be that MCP-1 antagonists that act via binding to CCR2 may have beneficial therapeutic effects in delaying the disease progression to AIDS in HIV-infected patients.
There is a need in the art to discover compounds that antagonize MCP-1 by binding to the CCR2 receptor, more particularly the CCR2b receptor.
Summary of the Invention
In a first aspect, the present invention is a compound as represented in formula (I):
Figure imgf000008_0001
or a salt thereof, or a solvate thereof, or a combination thereof; wherein
R1 represents an aryl, a thienyl, a benzothienyl, an imidazolyl, a pyridyl, an isoquinolinyl, a piperonyl, a benzoxathiadiazolyl, or a benzoxadiazolyl group optionally substituted with one to three R4 groups, wherein each R4 group is independently selected from the group consisting of Ci_6-alkyl, C^-haloalkyl, C^-alkoxy, C1-6-haloalkoxy, halo, -NH2, -OH, -CN, -NO2, CF3, phenyl, phenoxy, phenyl-C(O)-, isoxazolyl, and -C(O)NR7R8, wherein R7 and R8 each independently represent hydrogen or C1-4 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocylic group optionally containing an additional heteroatom selected from nitrogen, oxygen and sulphur;
m is 1 , 2, or 3; each R2 is independently selected from the group consisting of halo, -CN, OCF3, and - CF3,;
R3 is a heteroaryl or a heterocycloalkyl group optionally substituted by up to three substituents independently selected from the group consisting of halo, hydroxy, hydroxy- d-6-alkyl-, C^alkoxy-d-ealkyl-, Ci-4alkoxy-, C^thioalkoxy, amino, R10R11N-Ci.4alkyl-, heterocycloalkyl, heteroaryl, halogenated heteroaryl, phenyl, benzyl, halophenyl,
C^-alkylphenyl, methoxyphenyl, trifluoromethylphenyl, cyanophenyl, C1-6-alkyl, C3.6- cycloalkyl, -CN, C1-4alkylthio-, -CF3, -CO2H, -CONR7R8, -NC(O)R12 N and -CO-C1-4 alkyl, wherein R10 and R11 each independently represent hydrogen or C1.6 alkyl and R12 is Ci-6 alkyl or C1.6 haloalkyl;
In a second aspect, the present invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and a pharmaceutically acceptable carrier, diluent, or excipient or combination thereof.
In a third aspect, the present invention is a method for treating a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a combination thereof.
Compounds within the scope of the present invention have potential in the treatment of conditions wherein modulation, especially antagonism/inhibition, of the CCR2 receptor is thought to be beneficial.
For example, the compounds may be effective in the treatment of diseases such as atherosclerosis, asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, food allergy, scombroid poisoning, pulmonary fibrosis, restenosis, including vascular restenosis, myocarditis, ulcerative colitis, psoriasis, urticaria, pruritis, eczema, atopic dermatitis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease, otis media, rheumatoid arthritis, nephritis (nephropathy), liver cirrhosis, multiple sclerosis and systemic sclerosis, lupus, erthematosis, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn's disease, endometriosis, cardiac disease, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, Alzheimer's disease, stroke, acute nerve injury, HIV infection, AIDS, autoimmune diseases, cancer, and sepsis.
Detailed Description of the Invention
It should be noted that CCR2 is also the receptor for the chemokines MCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338, 436-445). Since the new compounds of formula (I) described herein antagonize MCP-1 by binding to the CCR2 receptor, it may be that these compounds of formula (I) are also effective antagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that are mediated by CCR2.
For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-6 alkyl means a straight or branched alkyl containing at 1 to 6 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl.
As used herein, the term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci-6 alkoxy means a straight or branched alkoxy group containing 1 to 6 carbon atoms. Examples of "alkoxy" include, but are not limited to methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.
As used herein, the term "alkylthio" refers to a straight or branched alkylthio group containing the specified number of carbon atoms. For example, C1-4 alkylthio means a straight or branched alkylthio group containing 1 to 6 carbon atoms. Examples of "alkylthio" as used herein include, but are not limited to methylthio, ethylthio, propylthio, prop-2-thio, butylthio, but-2-thio, 2-methylprop-1 -thio, 2-methylprop-2-thio.
As used herein the term C3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. The term halogen or halo refers to fluoro, chloro, bromo and iodo.
Examples of heterocycloalkyl groups include, but are not limited to pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, oxopiperidinyl, oxophenyltriazaspirodecyl, oxopyrazolidinyl, oxopyrazolyl, oxooxazolidinyl, oxoimidazolidinyl, dioxaazaspirodecyl groups.
Heteroaryl groups include, but are not limited to, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzthiazolyl, indazolyl, indolazinyl, benzimidazolyl, benzotriazolyl, purinyl, coumarinyl, isocoumarinyl, chromonyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinly, quinoxalinyl, pteridinyl, 1 ,8- naphthyridinyl, oxo- or dioxo- benzoxazolyl, -benzotriazolyl, -pyridinyl, -pyrazolyl, - benzopiperidinyl and -benzopiperazinyl.
Suitable examples of C6-10 aryl ring systems include: phenyl and naphthyl.
It will be understood that ring systems covered by the definitions in this specification are those which are stable enough to be effective for the intended purpose. This stability is with reference to the preparation and storage of the compound containing said ring system and not with reference to in vivo metabolism.
As used herein, the term "pharmaceutically acceptable" means suitable for pharmaceutical use.
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol, and acetic acid.
The compounds of formula (I) as defined above contain a basic grouping and may also contain an acidic grouping and therefore may form salts with physiologically acceptable acids or bases. Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
Certain of the compounds of the invention may form acid addition salts with one or more equivalents of the acid. Certain of the compounds of the invention may form acid addition salts with less than one equivalent of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
When a specific enantiomer of a compound of general formula (I) is required, this may be obtained, for example, by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Thus the required enantiomer may be obtained from the racemic compound of formula (I) by use of chiral HPLC procedure.
According to a further aspect, the invention provides a method for treating a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a combination thereof.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
The invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and a pharmaceutically acceptable carrier, diluent, or excipient or a combination thereof. The carrier, diluent and/or excipient must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, buccal, topical, inhalation or insufflation, implant, rectal or parenteral administration to mammals including humans.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcystalline cellulose, maize-starch, calcium phosphate, glycine or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid; and, if desired, conventional flavouring or colouring agents. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 1 to 10OOmg per day, dependent upon the route of administration.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. Where the compositions comprise dosage units, each unit will typically contain from 1 -1000 mg of the active ingredient.
Compounds of the invention may be prepared, in known manner, in a variety of ways. In the following reaction schemes and hereafter, unless otherwise stated R1 to R3 etc. are as defined above. These processes form further aspects of the invention.
Those skilled in the art will appreciate that in the preparation of the compounds of the invention or a solvate thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
The compounds of formula (I), wherein the R3 group is attached to the methylene linker via a nitrogen atom, may in general be prepared by the reaction of a compound of formula (II):
Figure imgf000016_0001
(II)
wherein L is a leaving group, and R1, R2 and m are as defined above, with a compound of formula (111)
R3-H (III)
wherein R3 is as defined above;
and thereafter optionally
(i) removing any protecting group(s); and/or
(ii) forming a salt; and/or
(iii) converting a compound of formula (I) or a salt thereof to another compound of formula (I) or a salt thereof. Suitable leaving groups L include chloro or bromo. Alternatively L may represents a sulfonyloxy group such C alkylsulfonyloxy (for example methanesulfonyloxy), C1 4 alkylsulfonyloxy or haloC^ alkylsulfonyloxy (for example trifluoromethanesulfonyloxy); or arylsulfonyloxy for example para-toluenesulfonyloxy.
Typically, where L represents chloro, such a reaction may be carried out by dissolving the compound of formula (III) in a suitable solvent, for example 1 ,4-dioxane, in the presence of an appropriate crown ether, for example 18-crown-6-ether, and then reacting it with a deprotonating agent such as potassium tert-butoxide, and then reacting the resulting solution with the compound of formula (II). The reaction with the compound of formula (II) may generally be carried out at a temperature of between 50QC and 809C for period of between 12 and 24 hours.
Alternatively, the compounds of formula (I) may be prepared by the reaction of a compound of formula (IV):
Figure imgf000017_0001
(IV)
wherein R2 and R3 are as defined above, with a compound of formula (V)
U-SO2-R1 (V)
wherein L' is a suitable leaving group, and R1 is as defined above;
and thereafter optionally,
(i) removing any protecting group(s); and/or
(ii) forming a salt; and/or
(iii) converting a compound of formula (I) or a salt thereof to another compound of formula (I) or a salt thereof.
Suitable leaving groups L' include chloro, bromo or pentafluorophenoxy. Typically, where L' represents chloro, such a reaction may be carried out by dissolving the compound of formula (IV) in a suitable solvent, for example pyridine optionally mixed with a second solvent, such as chloroform or tetrahydrofuran, and reacting it with the compound of formula (V) also in a suitable solvent, for example pyridine. The addition of a catalytic quantity of dimethylaminopyridine may also be used. The reaction would generally be carried out at elevated temperature in the region of 80-250sC, for example at about 2009C, for a period of 30 minutes to 1 hour or at 8O0C for a period of 5-24 hours.
To prepare a compound of formula (I) wherein R3 represents a ring system carrying one or more oxo substituents, and wherein the group R3 is joined to the methylene linker by a nitrogen atom, this ring system may be formed de novo by methods well-known to the person skilled in the art.
Thus in a representative process a compound of formula (II), as defined above, may be reacted with an appropriate reagent to prepare a compound of formula (Vl):
Figure imgf000018_0001
(Vl)
wherein m, R1 and R2 are as defined above, and X is a group capable of being converted by reaction with appropriate reagents into the group R3 or a protected derivative thereof;
and thereafter, as necessary, (i) removing any protecting group(s); and/or (ii) forming a salt; and/or
(iii) converting a compound of formula (I) or a salt thereof to another compound of formula (I) or a salt thereof.
For example, a suitable scheme to generate de novo a pyridazinone ring system would suitably involve reacting a compound of formula (II) wherein L represents chloro with tert- butyl carbazatθ in a suitable solvent, for example DMF. Typically such a reaction would be carried out at ambient temperature for between 3 and 8 hours. The resulting product may then be dissolved in a suitable solvent containing 50% trifluoroacetic acid, for example dichloromethane, and stirred for a suitable time, typically 2 to 3 hours, at ambient temperature. Subsequent to the removal of the solvent the residue may be reacted with ethyl levulinate and glacial acetic acid, typically at elevated temperature in the region of 1009C for between 30 and 60 minutes. The final product will represent a compound of formula (I) wherein R3 represents a 3-methyl-6-oxo-5,6-dihydro-1 (4H)- pyridazinyl group.
The compound of formula (IV), wherein the group R3 is joined to the methylene linker by a nitrogen atom, may be prepared by reacting a compound of formula (VII):
Figure imgf000019_0001
(VII)
wherein L, R2 and m are as defined above, with a compound of formula (111) as defined above. Such a reaction will be analogous to the reaction of a compound of formula (II) with a compound of formula (III) described above.
Compounds of formula (II) may in general be prepared by a process analogous to that set out in Schemes 1 or 2 below:
Scheme 1
Figure imgf000020_0002
Figure imgf000020_0001
SOCI2ZCHCI3
DIBAL
Figure imgf000020_0004
Figure imgf000020_0003
(II)
Scheme 2
Figure imgf000020_0005
(II)
The compounds of formula (IV) may be prepared by a process analogous to that set out in Schemes 3 or 4 below:
Scheme 3
Figure imgf000021_0001
Figure imgf000021_0002
dioxane
(IV)
Scheme 4
Figure imgf000021_0003
Compounds of formula (IV) wherein the R3 group is joined to the methylene linker by a carbon atom may in general be prepared by a process analogous to that set out in Scheme 5 below. The ethyl ester starting materials may be prepared according to literature methods J.Mθd.Chem., 1990, 2982. and J.Am.Chem.Soc.^958, 3908. Treatment with an appropriate base, for example sodium hydride or sodium bis(trimethylsily) amide, and reaction with a nitro arene bearing a suitable leaving group L, such as chloro, gives intermediates of the type shown. Hydrolysis of the ester under hydrolytic conditions, for example aqueous hydrochloric acid in ethanol, concurrent decarboxylation and reduction of the nitro group using, for example, hydrogenation with platinum or palladium catalysis in a suitable solvent, for example ethanol, give compounds of the formula (IV). Scheme 5
Figure imgf000022_0001
Alternatively, such compounds may be prepared by de novo generation of a hetero-aryl ring, for example by the general process outlined in Scheme 6. Generation of a di-acyl hydrazine of the type shown may be achieved by, for example, activation of a carboxylic acid to the acid chloride with oxalyl chloride in the presence of a catalytic quantity of dimethylformamide or dimethylacetamide and subsequent reaction with the appropriate acyl hydrazine. Dehydration of the diacylhydrazine intermediate may be achieved with an appropriate reagent such as Burgess' reagent. Reduction of the nitro-arene to the corresponding aniline (IV) may be achieved by hydrogenation with platinum or palladium catalysis in a suitable solvent, for example ethanol.
Scheme 6
Figure imgf000022_0002
Substituted triazolyl examples may be constructed as outlined by the general method provided in Scheme 7. Preparation of the intermediate azides may be achieved by treatment of relevant alcohol with an azidinating reagent such as diphenylphosphoryl azide in the presence of an appropriate base, such as 1 ,8-diazabicyclo[5.4.0]undec-7- ene. The triazole products may be prepared by reaction of appropriately substituted acetylenes catalysed by, for example, copper sulfate in the presence of sodium ascorbate.
Figure imgf000022_0003
The compounds of formula (I), wherein the R3 group is a dihydropyridazinone or a dihydropyrazolone may be prepared from a compound of formula (II) by a process analogous to that set out in Scheme 8. Direct displacement of the chloride with f-butyl carbazate followed by removal of the protecting group provides the hydrazine which can be cyclized upon treatment with a ketoester.
Figure imgf000023_0001
(I)
An alternative method of preparing the compounds of formula (I) wherein the R3 group is attached to the methylene linker via a nitrogen atom is outlined in Scheme 9. Reductive amination of the aldehyde provides the amine of formula (I). Scheme 9
Figure imgf000023_0002
1 ,2,4-Triazole examples may be constructed as by the general procedure illustrated in Scheme 10. Treatment with f-butyl carbazate, followed by a borane reduction and removal of the protecting group provides the hydrazine. Addition of 1 ,3,5-triazine yields the triazole. Scheme 10
reflux
Figure imgf000023_0003
Figure imgf000023_0004
Alternatively, 1 ,2,4-triazoles of formula (IV) may be constructed by the general methods shown in Scheme 11 and Scheme 12. Scheme 11
Figure imgf000024_0001
Carbon linked 1 ,2,4-triazoles of formula (IV) may be prepared by the method in Scheme 13. Treatment of the nitrile with acetyl chloride provides the imine which is converted to the formyl hydrazone. Addition of an amine allows for ring closure to the triazole. Polymer supported isocyanate is added to capture any excess amine. Reduction of the nitrobenzene then provides the aniline. Scheme 13
Figure imgf000024_0002
Imidazoles of formula (I) may be constructed from the hydrazines in formed in Scheme 10 by the general procedure outlined in Scheme 14. Treatment of the hydrazine with a 3-substituted 3-oxoproanenitrile affords the imidazole. Scheme 14
Figure imgf000025_0001
Interconversion reactions between compounds of formula (I) may be performed using methods well known in the art. Included are conversions of the substituent(s) within the group R3 and/or conversions within groups R2 and R1 for example: (i) converting an acid to an acid amide;
(ii) converting an acid to an acid ester;
(iii) converting an acid amide to a cyano.
(iv) converting an aniline to a cyano
(v) converting an aniline to a chloro.
Abbreviations
HPLC - high-performance liquid chromatography DCM - dichloromethane DMF - dimethylformamide DMSO - dimethylsulfoxide
IMS - industrial methylated spirit HCI - hydrochloric acid EDTA: Ethylene Diamine Tetra-acetic Acid HBSS: Hanks Balanced Salt Solution PMSF: Phenyl Methyl Sulfonyl Fluoride
DMEM: Dulbecco Minimal Essential Medium GDP: Guanosine Diphosphate
Mass spectra were obtained using either a Waters ZQ mass spectrometer or Micromass Platform 2 mass spectrometer and use electro-spray ionisoation to observe either MH+ or M-. Proton Nuclear Magnetic Resonance (1 H-NMR) spectra were recorded at 400 MHz unless otherwise stated, chemical shifts are reported in ppm downfield from Mβ4Si, used as internal standard, and are assigned as singlets (s), doublets (d), doublets of doublets (dd), triplets (t), doublet of triplets (dt), quartets (q) multiplets (m) or are otherwise described in full. The prefix "br" refers to a broad peak; for example, a broad single may appear as br.s (or br s)..
The following non-limiting examples illustrate the present invention. Example Compounds and Intermediates
Intermediate 1 : 4-chloro-N-[2-(chloromethvD-5- (trifluoromethyl)phenvHbenzenesulfonamide
Figure imgf000026_0001
DIBAL
Figure imgf000026_0002
(a) Methyl-2-amino-4-(trifluoromethyl)benzoate
Figure imgf000026_0003
2-amino-4-(trifluoromethyl)benzoic acid (2.51 g, 12.24 mmol) was dissolved in methanol (100 mL) and concentrated hydrochloric acid was added (20 ml_). The resulting solution was heated to reflux for 12 hours and then the volatiles removed under reduced pressure. The residue was partitioned between diethyl ether (2x100 mL) and sodium hydroxide solution (50 mL). This provided the desired compound methyl-2-amino-4- (trifluoromethyl)benzoate as a colourless oil (1.86 g). HPLC Rt = 3.15 minutes; m/z [M+H]+ = 220. 1H NMR (CD3OD) δ 7.88 (d, 1H), 7.00 (s, 1H), 6.72 (d, 1 H), 3.85 (s, 3H).
(b) Methyl-2-{r(4-chlorophenyl)sulfonyl1amino}-4-(trifluoromethyl)benzoate
Figure imgf000026_0004
2-Amino-4-(trifluoromethyl)benzoate (1.86 g, 8.5 mmol) was dissolved in pyridine (12 mL) and 4-chlorobenzenesulfonyl chloride (1.79 g, 8.5 mmol) was added. The resulting solution was heated to 80 0C in a microwave reactor for 10 minutes and then concentrated to dryness. The crude product was purified by column chromatography on silica gel. The column was eluted with 0% to 30% ethyl acetate in cyclohexane to afford methyl 2-{[(4-chlorophenyl)sulfonyl]amino}-4-(trifluoromethyl)benzoate as a colourless oil (905 mg). HPLC Rt = 3.63 minutes; m/z [M+H]+ = 394. 1H NMR (CD3OD) δ 8.10 (d, 1 H), 7.91 (S, 1 H), 7.77 (d, 2H), 7.53 (d, 2H)1 7.44 (d, 1 H), 3.90 (s, 3H).
(c) 4-Chloro-N-f2-(hvdroxymethyl)-5-(trifluoromethyl)phenyllbenzenesulfonamide
Figure imgf000027_0001
Methyl 2-{[(4-chlorophenyl)sulfonyl]amino}-4-(trifluoromethyl)benzoate (460 mg, 1.17 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 0C. Diisobutylaluminum hydride (1.5 M in toluene, 1.95 mL, 2.93 mmol) was added dropwise and then the reaction stirred at room temperature for 12 hours. A further portion of diisobutylaluminum hydride was added (1.17 mL, 1.76 mmol) and the solution allowed to stir for an additional 5 hours. The reaction was quenched with water and concentrated to dryness. The residue was partitioned between dichloromethane (2 x 100 mL) and 5% citric acid (50 mL), the organic phases combined, dried over magnesium sulfate and evaporated to dryness. This provided the title compound (341 mg) which was used without further purification. HPLC Rt = 3.31 minutes; m/z [M-H]+ = 366. 1H NMR (CD3OD) δ 7.66 (d, 2H), 7.51 (m, 4H), 7.30 (s, 1 H), 4.55 (s, 2H).
(d) 4-Chloro-N-f2-(chloromethyl)-5-(trifluoromethvπphenvnbenzenesulfonamide
Figure imgf000027_0002
4-Chloro-Λ/-[2-(hydroxymethyl)-5-(trifluoromethyl)phenyl]benzenesulfonamide (341 mg, 0.93 mmol) dissolved in chloroform (25 mL) was added dropwise to a solution of thionyl chloride (332 mg, 2.79 mmol) in chloroform (25 mL). The resulting solution was stirred overnight at 40 0C and then poured into ice water. The organic phase was collected and dried over magnesium sulfate. This provided the title compound as a colourless oil (373 mg) which was used without further purification. HPLC Rt = 3.62 minutes; m/z [M+H]+ = 384. 1H NMR (CDCI3) δ 7.68 (d, 1 H), 7.65 (d, 2H), 7.53 (m, 4H), 4.72 (s, 2H).
Intermediate 2: 4-Chloro-N-r5-chloro-2-(chloromethyl)phenyl1benzenesulfonamide
Figure imgf000028_0001
(a) (2-Amino-4-chlorophenyl)methanol
Figure imgf000028_0002
(4-chloro-2-nitrophenyl)methanol (40.0 g, 0.21 mol) was dissolved in ethanol (700 ml_) and hydrogenated under hydrogen gas (20 psi) in the presence of 5% platinum on sulfided carbon (Pt-C/S) (5.0Og). After 2 hours the catalyst was removed by filtration through Celite®and the solvent removed under reduced pressure. This provided the desired compound (2-amino-4-chlorophenyl)methanol (32.9 g) which was used without further purification. HPLC Rt =1.70 minutes. 1H NMR (CDCI3) δ 6.96 (d, 1 H), 6.67 (m, 2H), 4.64 (s, 2H), 4.27 (bs, 2H)1 1.56 (bs, 1 H).
(b) 4-Chloro-N-r5-chloro-2-(hvdroxymethyl)phenyllbenzenesulfonamide
Figure imgf000028_0003
A solution of (2-amino-4-chlorophenyl)methanol (5.00 g, 31.85 mmol) and pyridine (3.1 mL) in anhydrous chloroform (150 mL) was treated dropwise with a solution of 4- chlorobenzenesulfonyl chloride (7.26g ,34.58 mmol) in chloroform (30 mL) over 20 minutes at room temperature. The reaction mixture was stirred for 5 hours and evaporated to dryness. The resulting residue was taken up in ethyl acetate (200 mL) and aqueous ammonium chloride (100 mL). After stirring for 30 minutes the organic phase was separated and further washed with dilute ammonium chloride (2 x 50 mL), dried over sodium sulfate, filtered and evaporated to give an oil. This was triturated in hot hexane (10OmL) and then stirred at ambient temperature for 2 hours. The solid was collected and washed with hexane to give the title compound (10.0 g). HPLC Rt = 3.04 minutes. 1H NMR (CDCI3) δ 7.75 (d, 2H), 7.53 (s, 1H), 7.45 (d, 2H), 7.09 (dd, 1 H), 7.01 (d, 1 H), 4.40 (s, 2H).
(c) 4-Chloro-Λ/-r5-chloro-2-(chloromethyl)phenyllbenzenesulfonamide
Figure imgf000029_0001
4-Chloro-N-[5-chloro-2-(hydroxymethyl)phenyl]benzenesulfonamide (4.00 g, 12.08 mmol) dissolved in chloroform (175 mL) was added dropwise to a solution of thionyl chloride (4.31 g, 36.24 mmol) in chloroform (175 mL). The resulting solution was stirred overnight at 40 0C and then poured into ice water. The organic phase was collected and dried over magnesium sulfate. This provided the title compound as a colourless oil (4.10 g) which was used without further purification. 1H NMR (CDCI3) δ 7.82 (d, 2H), 7.55 (d, 2H)1 7.50 (d, 1 H), 7.23 (dd, 1 H), 7.03 (s, 1 H), 4.38 (s, 2H).
Intermediate 3: 2-lY5-Cvclopropyl-1 H-tetrazol-1 -vOmethylM-f luoroaniline
Figure imgf000029_0002
Figure imgf000029_0003
tBuOK,18crown-6-ether, dioxane
Figure imgf000029_0004
(a) (5-Fluoro-2-nitrophenyl)methanol
Figure imgf000029_0005
5-Fluoro-2-nitrobenzoic acid (5.00 g, 27.0 mmol) was dissolved in anhydrous tetrahydrofuran (15 ml_). Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 62.1 mL, 62.1 mmol) was then added slowly under nitrogen. The mixture was stirred at 600C for 3 days and then quenched with water and evaporated to dryness. It was then loaded onto a 100 g flash silica chromatography column (pre-eluted with cyclohexane). The column was eluted with 20% ethylacetate/cyclohexane to afford (5-fluoro-2- nitrophenyl)methanol (2.54 g). HPLC Rt=2.10minutes; m/z [M+H]+=235. 1HNMR (CDCI3) δ 8.50 (m, 1 H), 7.60 (m, 1 H), 7.29 (m, 1 H), 5.07 (d, 2H).
(b) (2-Amino-5-fluorophenyl)methanol
Figure imgf000030_0001
(5-Fluoro-2-nitrophenyl)methanol (2.54 g 14.85 mmol) was dissolved in ethanol (200 ml) and added to 10% palladium on carbon catalyst (500 mg). This mixture was stirred under hydrogen at atmospheric pressure at room temperature for 3 hours. The catalyst was then removed by filtration through Celite®. The ethanol was removed in vacuo to give (2- amino-5-fluorophenyl)methanol (2.06 g). HPLC Rt=1.24 minutes; m/z [M=H]+=I 42. 1HNMR (CD3OD) δ 8.33 (s, 1 H), 8.00 (m, 1 H), 6.72 (m, 1 H), 3.93 (s, 2H).
(c) 2-(ChloromethvQ-4-fluoroaniline
Figure imgf000030_0002
A solution of (2-amino-5-fluorophenl)methanol (2.04 g, 14.46 mmol) in chloroform (50 ml) was added dropwise to a solution of thionyl chloride (5.74 g, 49 mmol) in dry chloroform (50 ml). The mixture was stirred at 40 0C under nitrogen for 2 hours, then the volatiles were removed in vacuo to give 2-(chloromethyl)-4-fluoroaniline (2.04 g , 12.8 mmol) which was used without further purification. HPLC Rt=1.75 minutes; m/z[M+H]+= 140. 1HNMR (CDCI3) δ 8.30 (d, 1 H), 7.50 (d, 1 H), 7.39 (dd, 1 H), 4.90 (s, 2H).
(d) 2-f(5-Cvclopropyl-1 H-tetrazol-1-yl)methvπ-4-fluoroaniline
Figure imgf000031_0001
A solution of 18-crown-6-ether (9.78 g, 37.0 mmol) dissolved in 1 ,4-dioxane (82 ml) was added to 5-cyclopropyl-4/-/-tetrazole (4.60 g, 41.5 mmol) under nitrogen. Potassium tert- butoxide solution (1 M in tetrahydrofuran, 37 ml, 37 mmol) was then added, and the mixture stirred under nitrogen for 15 minutes. A solution of 2-(chloromethyl)-4- fluoroaniline (2.04 g, 14.5 mmol) was added and the reaction stirred at 60 0C. After 18 hours the reaction mixture was quenched with water and evaporated under reduced pressure. Ammonium chloride (20 ml_) was added and the slurry extracted with ethyl acetate (2 x 100 ml_). The organic phases were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was loaded onto a 100 g flash silica chromatography column (pre-eluted with cyclohexane). The column was eluted with 50% ethyl acetate in cyclohexane to afford 2-[(5-cyclopropyl-1 H-tetrazol-1 - yl)methyl]-4-fluoroaniline (0.052 g). HPLC Rt=2.36 minutes; m/z[M+H]+=234. 1H NMR (CD3OD) δ 6.88(m, 1 H), 6.79 (dd, 1 H), 6.71 (dd, 1 H), 5.58 (s, 2H), 2.14 (m, 1 H), 1.17(m, 2H), 1.04 (m, 2H).
Intermediate 4: 1 ,1 -dimethylethyl 2-lY4-chloro-2-(r(4- chlorophenyl)sulfonyl1amino)phenyl)methvflhvdrazinecarboxylate
Figure imgf000031_0002
4-chloro-N-[5-chloro-2-(chloromethyl)phenyl]benzenesulfonamide (2.00 g, 5.20 mmol) and te/t-butyl carbazate (1.38 g, 10.4 mmol) were dissolved in Λ/,Λ/-dimethylformamide (10 ml_) at room temperature and stirred for 5 hours. The solvent was removed under reduced pressure and the residue loaded onto a silica column. The silica column was eluted with 0% to 50% ethyl acetate in cyclohexane to afford 1 ,1-dimethylethyl-2-[(4- chloro-2-{[(4-chlorophenyl)sulfonyl]amino}phenyl)methyl]hydrazinecarboxylate as a white solid (931 mg). HPLC Rt = 3.68 minutes; m/z [M+H]+ = 446. 1H NMR (CDCI3) δ 9.46 (br s, 1 H), 7.76 (d, 2H), 7.62 (d, 1 H), 7.42 (d, 2H), 7.01 (dd, 2H), 6.01 (br s, 1 H)1 4.00 (br d, 1 H), 3.64 (d, 2H), 1.48 (s, 9H).
Intermediates 5 and 6: (5-chloro-2-[(5-methyl-2/-/-tetrazol-2-vnmethvnphenyl)amine and (5-chloro-2-[(5-methyl-1 H-tetrazol-1-yl)methyl]phenyl}amine (1 :1 mixture)
(a) Λ/-r5-chloro-2-(chloromethvπphenvnacetamide
Figure imgf000032_0001
A suspension of (2-amino-4-chlorophenyl)methanol (5.9 g) in ethyl acetate (100 ml_) was heated until the former dissolved. Acetic anhydride (8 ml_) was added and the mixture removed from the heat. The precipitate was filtered to give a white solid and the filtrate was concentrated and slurried with hexane and filtered to give further white solid. The two batches were combined to give 5.3 g of the alcohol intermediate. The first phase of the experiment was repeated on 3x the scale described above. 21 g of the combined products was dissolved in DCM (65OmL) and added to a solution of thionyl chloride (23 ml_) in DCM (225 ml_) at room temperature under argon. The mixture was stirred for 30 minutes and concentrated to give a yellow/red solid. The solid was dissolved in DCM (500 ml_), washed with saturated sodium bicarbonate (200 ml_) and dried over magnesium sulfate. Removal of the solvent gave the 22 g of the title compound as a yellow/brown solid. 1H NMR (CDCI3) δ 8.01 (d, 1 H), 7.52 (br. s, 1 H), 7.23 (d, 1 H), 7.12 (dd, 1 H), 4.58 (s, 2H), 2.25 (s, 3H).
(b) {5-Chloro-2-r(5-methyl-2H-tetrazol-2-vDmethyliphenyl)amine and (5-chloro-2-IY5- methyl-1 H-tetrazol-1 -yl)methvπphenyl)amine (1:1 mixture)
Figure imgf000032_0002
A mixture of Λ/-[5-chloro-2-(chloromethyl)phenyl]acetamide (1.0 g), 5-methyl-1 H-tetrazole (424 mg) and potassium carbonate (1.27 g) in DMF (10 ml_) was heated to 70 0C under argon overnight. The DMF was removed in vacuo and water (10 mL) and ethyl acetate (70 mL) were added to the residue. The organic layer was separated and washed with water (2 x 10 mL) and brine (10 mL), dried over magnesium sulfate and reduced in vacuo. The resulting solid was dissolved in IMS (2.5 ml_) and water (30 mL) to which was added a 5M sodium hydroxide solution (1.5 mL). The mixture was then heated to reflux under argon overnight. The mixture was concentrated and the residue taken up in DCM (70 mL) and water (30 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was re-dissolved in IMS (2.5 mL) and water (30 mL) to which was added a 5M sodium hydroxide solution (1.5 mL) and the mixture heated to reflux under argon overnight. The mixture was concentrated and the residue taken up in DCM (70 mL) and water (30 mL). The organic phase was separated, dried over magnesium sulfate and concentrated to give a yellow oil containing a 1 :1 mixture of tetrazole isomers which were used without further purification. 1H NMR (d6- DMSO; letter indicates isomer referred to) δ 6.97 (d, 1 H, A), 6.79 (d, 1 H, B), 6.72 (d, 1 H, B), 6.70 (d, 1 H, A), 6.53 (dd, 1 H, B), 6.52 (dd, 1 H, A), 5.68 (s, 2H, A), 5.52 (br. s, 2H, A), 5.50 (br. s, 2H, B), 5.40 (s, 2H, B), 2.45 (s, 3H, B), 2.40 (s, 3H, A).
Intermediate 7: r5-Chloro-2-(1 H- 1 ,2,3-triazol-1 -ylmethvOphenvHamine
Figure imgf000033_0001
Prepared by a similar procedure to that described for Intermediate 6 from Λ/-[5-chloro-2- (chloromethyl)phenyl]acetamide and 1HA ,2,3-triazole. 1H NMR (CDCI3) δ 7.68 (d, 1 H), 7.51 (d, 1 H), 7.10 (d, 1 H), 6.65-6.70 (m, 2H), 5.42 (s, 2H), 4.30 (br. s, 2H).
Intermediates 8 and 9: r5-Fluoro-2-(2/-/-tetrazol-2-ylmethyl)phenyl1amine and r5-Fluoro- 2-(1 /-/-tetrazol-1-ylmethyl)phenyllamine (1:1 mixture)
(a) N-r2-(chloromethyl)-5-fluorophenyl1acetamide
Figure imgf000033_0002
(2-Amino-4-fluorophenyl)-methanol (20 g) was dissolved in ethyl acetate (200 mL), heated to reflux, and treated with acetic anhydride (30 mL). The mixture was heated at reflux for 4 hours and cooled to room temperature overnight. The mixture was diluted with additional ethyl acetate (200 mL) and added to a saturated aqueous sodium bicarbonate solution (400 mL) The organic layer was separated and washed with further sodium bicarbonate solution (450 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo. The residue was dissolved in methanol (120 ml_), a solution of 0.5 M sodium hydroxide (250 mL) was added and the mixture was stirred at room temperature for 2 hours. The methanol was removed and the mixture extracted with DCM (2 x 250 mL), the combined organics dried over magnesium sulfate and concentrated. 7.1 g of the residue was dissolved in DCM (355 mL) and the mixture was added to a solution of thionyl chloride (8.5 mL) in DCM (120 mL) at room temperature under argon. The mixture was stirred at room temperature for 1 V≥ hours then concentrated. The solid was dissolved in DCM (600 mL) and washed with saturated sodium bicarbonate (200 mL) and dried over magnesium sulfate. Removal of the solvent gave the 7.1 g of the title compound as a yellow/brown solid. 1H NMR (CDCI3) δ 7.82 (dd, 1 H), 7.60 (br. s, 1 H), 7.28 (dd, 1 H), 6.83 (dt, 1 H), 4.60 (s, 2H), 2.25 (s, 3H)
(b) r5-Fluoro-2-(2H-tetrazol-2-ylmethvDphenvHamine and r5-Fluoro-2-(1 H-tetrazol-1 ■ ylmethvDphenyllamine
Figure imgf000034_0001
Prepared by a similar procedure to that described for Intermediate 6 from /V-[2- (chloromethyl)-5-fluorophenyl]acetamide and 1 /-/-tetrazole. 1H NMR (d3-MeOD) δ 9.04 (s, 1 H1 B), 8.67 (s, 1 H, A), 6.32-6.50 (m, 3H, A+B), 5.76 (s, 2H, A), 5.55 (s, 2H, B).
Intermediate 10: r4,5-Dichloro-2-(1 H- 1 ,2,3-triazol-1 -ylmethvhphenyllamine
Figure imgf000034_0002
(a) 1 -(Bromomethyl)-4,5-dichloro-2-nitrobenzene
Figure imgf000034_0003
Nitric acid was added slowly to a mixture of 1 ,2-dichloro-4-methylbenzene (10 g) in sulfuric acid at 0 °C, keeping the temperature below 100C. The mixture was allowed to warm to room temperature, stirred for 10 minutes, poured over ice (250 g) and stirred for 10 further minutes. The solid was filtered, washed with water (50 mL) and dissolved in DCM (150 mL). The resulting solution was washed with water (120 ml_) and brine (100 mL), dried over magnesium sulfate and concentrated. To the resulting solid at 150 0C was added bromine (3.4 mL). The mixture stirred for 30 minutes, poured into hexane (50 mL) and stirred for a further 10 minutes. The solution was filtered and the filter-pad washed with hexanes. The filtrates were combined and washed with water (2 x 100 mL), dried over magnesium sulfate and concentrated to give the crude title compound (8.2 g). 1H NMR (CDCI3) δ 8.20 (s, 1 H), 7.69 (s, 1 H), 4.77 (s, 2H)
(b) r4.5-Dichloro-2-(1 H-1.2,3-triazol-1-ylmethvnphenyllamine
Figure imgf000035_0001
A mixture of 1-(bromomethyl)-4,5-dichloro-2-nitrobenzene (2.0 g), 1 H-1 ,2,3-triazole (544 mg) and potassium carbonate (1.98 g) in DMF (20 mL) was heated to 70 0C under argon overnight. The mixture was diluted with water (200 mL) and extracted with diethyl ether (2 x 400 mL). The combined organics were washed with water (200 mL) and brine (100 mL), dried over magnesium sulfate and concentrated. The resulting brown oil was warmed in hexane and 650 mg of a light-brown solid collected by hot-filtration. The solid was dissolved in 2:1 ethyl acetate/IMS (9 mL) to which was added 1 % platinum on carbon (650 mg) and the mixture warmed to 40 0C under a balloon of hydrogen. The mixture was left overnight and filtered through celite to give 527 mg of the title compound as a brown gum. 1H NMR (d6-DMSO) δ 8.11 (s, 1 H), 7.71 (s, 1 H), 7.08 (s, 1 H), 6.85 (s, 1 H), 5.68 (br. s, 2H), 5.44 (s, 2H).
Intermediates 11 and 12: {5-chloro-2-r(2-methyl-2H-tetrazol-5-vDmethvHphenyl}amine and (5-chloro-2-r(1 -methyl-1 H-tetrazol-5-v0methvnphenyl)amine
Figure imgf000035_0002
Figure imgf000035_0003
(+lsomer)
Figure imgf000035_0004
Sodium hydride (461 mg) was washed with hexane (5 ml_) and a solution of ethyl (2- methyl-2H-tetrazol-5-yl)acetate (see Chem. Pharm. Bull., 1991, 1099. - contains other tetrazole isomer also, 1.5 g) in DMF was added. 2,5-Dichloronitrobenzene (1.38 g) was added, the mixture was stirred for 2 hours and neutralised with 2M HCI. The mixture was concentrated and partitioned between ethyl acetate (70 mL) and 2M HCI (50 ml_). The layers were separated and the organic layer was washed with water (50 mL) and brine (50 mL). The resulting oil was dissolved in IMS (19 mL), concentrated HCI (6.25 mL) was added, and the mixture was heated to reflux for 18 hours. Upon cooling, the reaction mixture was poured on to ice (30 g) and extracted with DCM (2 x 50 mL). The combined organics were washed with brine (20 mL) and concentrated. The resulting yellow oil was dissolved in IMS (15 mL), 1% platinum on carbon (0.7 g) was added and the mixture stirred under a hydrogen balloon for 6 hours at 50 0C. The mixture was cooled, filtered through Celite® and reduced in vacuo. Separation of the isomers was achieved by silica column chromatography, eluting the products with 30% ethyl acetate/hexane in the order given below.
{5-Chloro-2-[(2-methyl-2H-tetrazol-5-yl)methyl]phenyl}amine; 229 mg. 1H NMR (d6- DMSO) δ 6.80 (m, 1 H), 6.65 (m, 1 H), 6.47 (m, 1 H), 5.28 (br.s, 2H), 4.27 (s, 3H), 3.97 (s, 2H). {5-Chloro-2-[(1-methyl-1 H-tetrazol-5-yl)methyl]phenyl}amine; 409 mg. 1H NMR (d6-
DMSO) δ 6.81 (d, 1 H), 6.67 (d, 1 H), 6.5 (dd, 1 H), 5.34 (br.s, 2H), 4.05 (s, 2H), 3.93 (s, 3H).
Intermediate 13: r2-r(5-methyl-1 ,3,4-oxadiazol-2-yl)methvπ-5- (trifluoromethyl)phenyllamine
Figure imgf000036_0001
(a) 2-Methyl-5-lf2-nitro-4-(trifluoromethvπphenvnmethyl)-1 ,3,4-oxadiazole
Figure imgf000036_0002
A solution of [2-nitro-4-(trifluoromethyl)phenyl]acetic acid (2 g) in dichloromethane (20 mL) was treated with oxalyl chloride (1 mL) and dimethyl acetamide (2 drops). The mixture was stirred for 1 hour and then overnight. The reaction was evaporated to give 2.1 g of a brownish oil. In the second step, a solution of 400 mg of this product was dissolved in 10 mL of DCM and treated portionwise with 270 mg of acetyl hydrazine. After 30 minutes 10 mL of saturated sodium bicarbonate was added. The mixture was filtered, the filtered solid washed with water and ether, and then dried to give 448 mg of a white solid. In a third step, 400 mg of this solid and 670 mg of Burgess' reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide) in a microwave vial was treated with anhydrous THF, sealed and heated at 120 0C for 10 minutes. The mixture was cooled, evaporated and purified by flash column chromatography, eluting with cyclohexane and ethyl acetate to give the title compound as an off-white solid (230 mg). 1H NMR (CDCI3) δ 8.39 (s, 2H), 7.89 (d, 1 H), 7.64 (d, 1 H), 7.27 (s, 1 H - partially obscured by chloroform) 4.61 (s, 3H).
(b) r2-r(5-Methyl-1 ,3Λ-oxadiazol-2-yl)methyl1-5-(trifluoromethv0phenvπamine
Figure imgf000037_0001
230 mg of 2-methyl-5-{[2-nitro-4-(trifluoromethyl)phenyl]methyl}-1 ,3,4-oxadiazole in ethanol (10 mL) was added to 50 mg of wet palladium on carbon (10% wt, Degussa type) and the mixture stirred in a hydrogen atmosphere for four hours. The mixture was filtered and evaporated to give the title compound as a colourless gum (215 mg) 1H NMR (CDCI3) δ 7.26 (d, 1 H - partially obscured by chloroform), 7.00 (d, 1 H), 6.93 (s, 1 H), 4.28 (br.s, 2H)1 4.10 (s, 2H), 2.40 (s, 3H).
Intermediate 14: Λ/-r2-(azidomethvO-5-f luorophenyll-3.4-dichlorobenzenesulf onamide
Figure imgf000037_0002
To a suspension of 3,4-dichloro-Λ/-[5-fluoro-2-
(hydroxymethyl)phenyl]benzenesulfonamide (906 mg, similarly prepared to 4-chloro-Λ/- [5-chloro-2-(hydroxymethyl)phenyl]benzenesulfonamide) in toluene (13 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.93 mL) and diphenylphosphoryl azide (DPPA, 0.78 mL). The mixture was stirred for 2 hours and water (20 mL), ethyl acetate (20 mL) and 2M HCI (3.2 mL) were added. The organic layer was washed with water, saturated sodium chloride, dried and reduced in vacuo. Column chromatography (ethyl acetate/cyclohexane) gave the title compound as a clear oil (460 mg). 1H NMR (CDCI3) δ 7.92 (d, 1 H), 7.63 (dd, 1 H), 7.57 (d, 1 H), 7.16-7.27 (m, 3H), 6.89 (dt, 1 H), 4.13 (s, 2H).
Intermediate 15: Λ/-r2-(azidomethvD-5-chlorophenyll-3,4-dichlorobenzenesulfonamide
Figure imgf000038_0001
Prepared by a similar procedure to that described for Intermediate 14 from 3,4-dichloro- Λ/-[5-chloro-2-(hydroxymethyl)phenyl]benzenesulfonamide;
1H NMR (CDCI3) δ 7.91 (s, 1 H), 7.61 (dd, 1 H), 7.57 (d, 1 H), 7.44 (d, 1 H), 7.15-7.26 (m, 3H), 4.15 (2H).
Intermediates 16 and 17 below were prepared employing methods analogous to those employed for Intermediates 12.
Intermediate 16: 2-1Ϊ1 -methyl-1 H-tetrazol-5-vDmethvH-5-Ktrifluoromethyl)oxylaniline
Figure imgf000038_0002
Similarly prepared from 4-chloro-3-nitrophenyl trifluoromethyl ether (J. Org. Chem., 1964, 5.). 1H NMR (DMSOd6) δ 6.91 (d, 1 H), 6.60 (s, 1), 6.41 (d, 1 H), 5.45 (br.s, 2H), 4.10 (s, 2H), 3.98 (s, 3H).
Intermediate 17: 5-chloro-2-(2-pyrazinylmethyl)aniline
Figure imgf000038_0003
Similarly prepared from methyl 2-pyrazinylacetate. 1H NMR (CDCI3) δ 8.54 (s, 1 H), 8.43 (s, 2H), 7.06 (d, 1 H), 6.66-6.71 (m, 2H), 4.46 (br.s, 2H), 4.00 (s, 2H). Intermediate 18: 5-chloro-2-(1 H-pyrazol-1-ylmethvQaniline
Figure imgf000039_0001
Potassium carbonate (3mmol) was added to a 0.5 M solution of pyrazole (3 mmol) in DMF, followed by a 1 M solution of 1-(bromomethyl)-4-chloro-2-nitrobenzene (3 mmol, see J.Med.Chem., 1975, 752) in DMF. Tetra-n-butylammonium iodide (20 mol %) was added, the mixture was stirred for 2.5 hours and reduced in volume by 50%. The resulting solution was diluted with ethyl acetate and water and the organic phase collected, dried (sodium sulfate) and reduced in vacuo. The resulting residue was purified by silica-gel column chromatography eluting with cyclohexane/DCM (0-50% DCM) to provide 83 mg of a clear oil. In a second synthetic step this compound was reduced to the aniline by transfer hydrogenation with ammonium formate (10 eq) in ethanol (0.25 M) in the presence of 5% platinum on carbon (1 mol %, 50% water, Degussa-type) at reflux for 18 hours. The mixture was filtered through celite onto a 5 g sulphonic acid ion-exchange column which was washed with ethanol (20 mL) and the product eluted in 2M ammonia in methanol. Reduction of the latter in vacuo gave 66 mg of the title compound as a brown oil. HPLC Rt = 2.9 minutes; m/z MH+ = 210/208.
Intermediates 19 to 26 were prepared employing methods analogous to those employed for Intermediates 18.
Intermediate 19: 5-chloro-2-(1 H-imidazol-1-ylmethyl)aniline
Figure imgf000039_0002
Similarly prepared. HPLC Rt = 1.8 minutes; m/z MH+ = 210/208.
Intermediate 20: 5-chloro-2-r(2-methyl-1 H-imidazol-1-yl)methvπaniline
Figure imgf000039_0003
Similarly prepared. HPLC Rt = 1.9 minutes; m/z MH+ = 224/222.
Intermediate 21: 5-chloro-2-r(2-ethyl-1 H-imidazol-1-yl)rnethvπaniline
Figure imgf000040_0001
Similarly prepared; required heating at 800C during the first step. HPLC Rt = 2.0 minutes; m/z MH+ = 238/236.
Intermediate 22: 5-chloro-2-ir2-(1-methylethvO-1 H-imidazol-1-yllmethyllaniline
Figure imgf000040_0002
Similarly prepared; required heating at 80 0C during the first step. HPLC Rt = 2.3 minutes; m/z MH+ = 251/250.
Intermediate 23: 5-chloro-2-f(2,4-dimethyl-1 /-/-imidazol-i-vDmethylianiline
Figure imgf000040_0003
Similarly prepared; required heating at 80 0C during the first step. HPLC Rt = 2.2 minutes; m/z MH+ = 238/226.
Intermediate 24: 5-fluoro-2-r(2-methyl-1 /-/-imidazol-1-yl)methvπaniline
Figure imgf000040_0004
Similarly prepared from 1 -(bromomethyl)-4-fluoro-2-nitrobenzene (J.Hθt.Chem., 1982, 401). HPLC Rt = 2.1 minutes.
Intermediate 25: 5-fluoro-2-(1 /-/-pyrazol-1 -ylmethyl)aniline
Figure imgf000041_0001
Similarly prepared from 1-(bromomethyl)-4-fluoro-2-nitrobenzene (J.Het.Chem., 1982, 401 ); during the first step the reaction was heated in a microwave at 1000C for 1 minute (50W). HPLC Rt = 2.7 minutes.
Intermediate 26: 3-amino-4-lY2-nπethyl-1 /-/-imidazol-1 -vhrnethylibenzonitrile
Figure imgf000041_0002
Similarly prepared from 4-(bromomethyl)-3-nitrobenzonitrile (Chem. Ber., 1894, 2165). HPLC Rt = 1.03 minutes; m/z MH+ = 213.
Intermediate 27: |"2-r(3,5-dimethyl-1 H-pyrazol-1 -yl)methyll-5- (trifluoromethvQphenvnamine
Figure imgf000041_0003
Prepared by a similar procedure to that described for Intermediate 3 (steps b-d) from [2- nitro-4-(trifluoromethyl)phenyl]methanol (in step b) and 3,5-dimethyl-1 H-pyrazole (in step d). HPLC Rt = 3.23 minutes; m/z MH+ = 270.
Intermediate 28: 2-F2-amino-4-(trifluoromethyl)phenyl1acetohvdrazide
Figure imgf000041_0004
a) 2-r2-nitro-4-(trifluoromethyl)phenvnacetohvdrazide
Figure imgf000042_0001
N.N'-Carbonyldiimidazole (1.42 g, 8.76 tnmol) was added to a solution of [2-nitro-4- (trifluoromethyl)phenyl]acetic acid (2.0 g, 7.96 mmol) in THF (50 mL). After stirring at room temperature for 15 minutes, hydrazine hydrate was added and the reaction was stirred for an additional 20 minutes. The reaction was extracted with EtOAc (3x) and the organic layer was washed with NaHCO3 (3x), dried over MgSO4, and concentrated to give the titled product (1.4 g, 67%) as a light yellow solid, m/z MH+ = 264.
b) 2-f2-Amino-4-(trifluoromethyl)phenyl1acetohydrazide
Figure imgf000042_0002
To 5% Pt/C catalyst (0.1 g) in a flask was added 2-[2-nitro-4-
(trifluoromethyl)phenyl]acetohydrazide (0.2 g, 0.7 mmol) as a solution in ethanol (10 mL). The flask was then flushed with nitrogen and ammonium formate (0.22 g, 3.5 mmol) was added to the stirred solution. The reaction was heated at reflux under nitrogen overnight.
On cooling to room temperature the catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was partitioned between water and EtOAc, the aqueous extract was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the titled compound.
Intermediate 29: 3,4-Dichloro-ΛH5-chloro-2- (hvdrazinomethvQphenyllbenzenesulfonamide
Figure imgf000043_0001
tert-Butyl carbazate (0.08 g, 0.63 mmol) was added to a solution of 3,4-dichloro-Λ/-(5- chloro-2-formylphenyl)benzenesulfonamide (0.19 g, 0.52 mmol) in hexane (8 ml_) and the reaction mixture was heated under reflux for 1 hour. A solution of 1 M BF3THF (2 ml_) was added and the reaction was stirred at room temperature for 14 minutes. The reaction was then treated with HCI (1 N in dioxane, 2 ml_) for 18 hours and concentrated. The residue was taken up in THF and filtered. The filtrate was concentrated to afford the titled product (0.15 g, 76%)
Intermediate 30: 3,4-Dichloro-N-(5-chloro-2-formylphenyl)benzenesulfonamide
Figure imgf000043_0002
Activated Ms-Tso-TEMPO resin (21 g, 10.91 mmol) was added to a solution of 3,4- dichloro-Λ/-[5-chloro-2-(hydroxymethyl)phenyl]benzenesulfonamide (2.0 g, 5.45 mmol) in DCM (100 ml_) and a slow stream of air was bubbled through the reaction for 10 minutes. The resulting mixture was shaken for 24 hours. The resin was filtered off and washed with DCM (3 x 50 ml_). The filtrate was evaporated to give the desired intermediate as an off-white solid (1.98 g, 100%). HPLC Rt = 3.37 minutes m/z [MH]+= 364 1H NMR (MeOD) δ 9.90 (s, 1 H), 7.99 (s, 1 H), 7.81 (d, 1 H), 7.73 (m, 2H), 7.54 (d, 1 H), 7.33 (dd, 1 H).
Intermediate 31: l"4,5-Dichloro-2-(4/-/-1 ,2,4-triazol-4-ylmethyl)phenvπamine
Figure imgf000044_0001
a) 4-r(3,4-Dichlorophenv0methvπ-4H-1 ,2.4-triazole
Figure imgf000044_0002
A mixture of formylhydrazine (5 g) and triethylorthoformate (10.2 mL) was stirred at 105 0C for 2 hours. The reaction solution was cooled to 50 0C and a suspension of 1 -(3,4- dichlorophenyl)methanamine (9.7 g) in 0.1 N aqueous HCI (160 mL) was added dropwise over 5 minutes. The resultant mixture was heated at 55 0C for 72 hours. The mixture was cooled and extracted with DCM (3 x 75 mL), the combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude oil isolated was purified by silica gel chromatography eluting from 10-100% ethyl acetate in cyclohexane to afford the title compound (2.83 g). HPLC Rt= 2.48 minutes, m/z [MH]+= 228 b) r4,5-Dichloro-2-(4H-1 ,2,4-triazol-4-ylmethyltohenyllamine
Figure imgf000044_0003
4,5-dichloro-2-(4H-1 ,2,4-triazol-4-ylmethyl)aniline was prepared in a similar manner to intermediate 10 from 4-[(3,4-dichlorophenyl)methyl]-4H-1 ,2,4-triazole to afford the title compound. HPLC Rt = 2.30 minutes, m/z [MH]+= 243.
Intermediate 32: 4,5-dichloro-2-(1 H-Λ ,2,4-triazol-1-ylmethyl)aniline
Figure imgf000045_0001
a) 1-r(3.4-Dichlorophenyl)methvn-1 H-1 ,2,4-triazole
Figure imgf000045_0002
To a solution of 4-(bromomethyl)-1 ,2-dichlorobenzene (5 g) in DMF (50 mL) was added 1 ,2,4 triazole (1.58 g) and potassium carbonate (5.75 g). The mixture was heated to 60 0C for 1 hour, cooled, and concentrated in vacuo. The resulting residue was partitioned between DCM (150ml) and water (50ml). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to afford the title compound (4.8 g). HPLC Rt =2.73 minutes, m/z [MH]+=228. Product contains approx 15% of 1 ,3,4 N linked triazole isomer.
b) 1 -lϊ4.5-Dichloro-2-nitrophenvnmethyll-1 H-1 ,2.4-triazole
Figure imgf000045_0003
To a suspension of 1 -[(3,4-dichlorophenyl)methyl]-1 H-1 ,2,4-triazole (1 g) in concentrated sulphuric acid (10 mL) at room temperature was added fuming nitric acid (210 uL) in 1 portion. The mixture was stirred for 30 minutes and then poured into ice. The acidic aqueous was adjusted to pH 12 using 2N sodium hydroxide solution and then extracted with DCM (4 x 20 mL). The organic extracts were washed with water and brine, dried over Na2SO4, and concentrated to afford the title compound (0.36 g). HPLC Rt = 2.73 minutes, m/z [MH]+=273. Product still contains approx 15% of triazole regioisomer.
c) 4,5-Dichloro-2-(1 /-7-1 ,2,4-triazol-1-ylmethyl)aniline
Figure imgf000046_0001
To a solution of 1-[(4,5-dichloro-2-nitrophenyl)methyl]-1 H- 1 ,2,4-triazole (0.36 g) in ethanol (10 ml_) was added ammonium formate (1.7 g) and 5% platinum on carbon (0.2 g). The mixture was heated to 6O0C for 3 hours, filtered through Celite, concentrated in vacuo and resubmitted back using the condition described previously for an additional 16 hours. The mixture was filtered through Celite, concentrated and the residue was partitioned between water and DCM (15 ml_ each). The organic layer was concentrated in vacuo to afford the title compound (245mg). HPLC Rt = 2.71 minutes, m/z [MH]+= 243. The product contains less than 10% of triazole regioisomer.
Intermediate 33: 4.5-difluoro-2-(1 H- 1.2.3-triazol-1 -ylmethvDaniline
Figure imgf000046_0002
Prepared by a similar procedure to that described for Intermediate 32 from 4- (bromomethyl)-i ,2-difluorobenzene and 1 H- 1 ,2,3-triazole. HPLC Rt = 2.32 minutes, m/z [MH]+= 211.
Intermediate 34: 3-chloro-5-fluoro-2-(1 H- 1 ,2,3-triazol-1 -ylmethvDaniline
Figure imgf000046_0003
Prepared by a similar procedure to that described for Intermediate 32 from 1- (bromomethyl)-2-chloro-4-fluorobenzene and 1 H- 1 ,2,3-triazole. HPLC Rt = 2.70 minutes, m/z [MH]+= 227
Intermediate 35: 4-chloro-5-fluoro-2-r(2-methyl-1 /-/-imidazol-1 -vDmethyllaniline
Figure imgf000047_0001
Prepared by a similar procedure to that described for Intermediate 32 from 4- (bromomethyl)-2-chloro-1 -f luorobenzene and 2-methyl-1 /-/-imidazole.
Intermediates 36 and 37: 4,5-dichloro-2-r(1 -methyl-1 H-tetrazol-5-yl)methvnaniline and 4,5-dichloro-2-r(2-methyl-2H-tetrazol-5-vDmethvπaniline
Figure imgf000047_0002
These intermediates were prepared by a similar procedure to that described for
Intermediates 11 and 12 from 1 ,2-dichloro-4-fluoro-5-nitrobenzene. Separation of the regio isomers was performed after the hydrolysis and decarboxylation step.
4,5-dichloro-2-[(1 -methyl-1 /-/-tetrazol-5-yl)methylJaniline. HPLC Rt = 2.81 minutes, m/z
[MH]+= 258
4,5-dichloro-2-[(2-methyl-2H-tetrazol-5-yl)methyl]aniline. HPLC Rt = 2.99, m/z [MH]+ =
258
Intermediate 38: r2-{r4-(Phenylmethvn-4H-1 ,2,4-triazol-3-yllmethyl)-5- (trifluoromethyl)phenvπamine
Figure imgf000048_0001
a) Methyl 2-[2-nitro-4-(trifluoromethyl)phenyllethanimidoate hydrochloride
Figure imgf000048_0002
To a sealable tube containing methanol (10 ml_) at 0 0C was added acetyl chloride (12 ml_) dropwise. [2-Nitro-4-(trifluoromethyl)phenyl]acetonitrile was then added. The tube was sealed and allowed to stand at 0 0C overnight. The resulting precipitate was filtered, washed with ether, and dried to provide the title product (5.3 g). HPLC Rt = 2.8 minutes
b) Methyl (1 Z)-Λ/-formyl-2-r2-nitro-4-(trifluoromethvπphenyllethanehydrazonoate
Figure imgf000048_0003
To a solution of methyl 2-[2-nitro-4-(trifluoromethyl)phenyl]ethanimidoate hydrochloride (0.153 g) in methanol (2 ml_) was added formic hydrazide (0.031 g). After 2 hours, the solution was diluted with saturated sodium bicarbonate and ether. The layers were separated, and the ether layer was washed with brine. After drying over Na2SO4, the solution was filtered and concentrated to provide the title product (0.11 g). HPLC Rt = 2.4 minutes; m/z [MH]+= 306 c) 3-(r2-Nitro-4-(trifluoromethvnphenvnmethyl)-4-(phenylnnethvn-4/-/-1 ,2.4-triazole
Figure imgf000049_0001
To a solution of methyl (1Z)-Λ/-formyl-2-[2-nitro-4-
(trifluoromethyl)phenyl]ethanehydrazonoate (0.1 g) in methanol (1.6 mL) was added benzylamine (0.36 mL). The reaction mixture was stirred for three days whereupon polymer supported isocyanate was added (3 g). Stirring was continued for 12 hours at room temperature. The mixture was filtered and the filtrate was concentrated.
Purification by flash column chromatography (10% MeOH in CH2CI2) provided the title product (0.028 g). HPLC Rt = 2.6 minutes; m/z [MH]+= 363
d) F2-{r4-(PhenylmethylV4H-1 ,2,4-triazol-3-vnmethyl}-5-(trifluoromethvπphenyllamine
Figure imgf000049_0002
To a solution of 3-{[2-nitro-4-(trifluoromethyl)phenyl]methyl}-4-(phenylmethyl)-4/-/-1 ,2,4- triazole (0.028 g) in ethanol (3 mL) was added saturated ammonium chloride (1 mL) and indium powder (0.062 g). The reaction mixture was heated to reflux for 12 hours. After cooling to room temperature, the heterogeneous mixture was filtered. The aqueous mixture was then extracted with diethyl ether. The ether layer was concentrated and taken up in methanol (5 mL). Filtration through an acidic SPE column (H2SO4) followed by elution with 5% NH3ZMeOH and concentration provided the title product (0.017 g). HPLC Rt = 2.5 minutes; m/z [MH]+ = 333
Intermediate 39: r2-{r4-(3-phenylpropyl)-4H-1 ,2.4-triazol-3-yllmethyl)-5- (trifluoromethyl)phenvπamine
Figure imgf000050_0001
Prepared by a similar procedure to that described for Intermediate 38 except substituting 3-phenylpropylamine for benzyl amine in step c. HPLC Rt = 2.5 minutes; m/z [MH]+ = 361.
Intermediate 40: [2-(1 H-tetrazol-5-ylmethvD-5-(trifluoromethyl)phenyl1amine
Figure imgf000050_0002
a) 5-(r2-Nitro-4-(trifluoromethyl)phenvπmethyl)-1 H-tetrazole
Figure imgf000050_0003
A solution containing [2-nitro-4-(trifluoromethyl)phenyl]acetonitrile (0.206 g), sodium azide (0.064 g), zinc bromide (0.203 g), water (1.8 ml_), and isopropanol (0.18 mL) was brought to reflux for 48 hours. After cooling to room temperature, the mixture was diluted with ether (3 mL), and the layers were separated. The aqueous layer was diluted with 2N HCI and reextracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated to provide the title product (0.17 g). HPLC Rt = 2.4 minutes; m/z [MH]+ = 274
b) [2-(1 H-tetrazol-5-ylmethvD-5-(trifluoromethv0phenyl1amine
Figure imgf000051_0001
Prepared by a similar procedure to that described for Intermediate 38 step d except substituting 5-{[2-nitro-4-(trifluoromethyl)phenyl]methyl}-1 H-tetrazole for 3-{[2-nitro-4- (trifluoromethyl)phenyl]methyl}-4-(phenylmethyl)-4H-1 ,2,4-triazole. HPLC Rt = 2.3 minutes; m/z [MH]+= 244.
Intermediate 41 : 2,3-dichloro-Λ/-r2-(chloromethvD-5- (trifluoromethvhphenvHbenzenesulfonamide
Figure imgf000051_0002
Prepared by a similar procedure to that described for Intermediate 1 except substituting 2,3-dichlorobenzenesulfonyl chloride for 4-chlorobenzenesulfonyl chloride in step b. HPLC Rt = 3.65 minutes; m/z [M+H]+ = no M+1. 1H NMR (CDCI3) δ 8.03 (d, 1 H)1 7.75 (d, 1 H)1 7.45 (m, 2H), 7.35 (m 2H),4.6 (s, 2H).
EXAMPLE COMPOUNDS
Example 1: 3-r(4-Chloro-2-(r(4-chlorophenyl)sulfonvnamino)phenyl)methyll-4-fluoro-1 H- pyrazole-3-carboxylic acid
Figure imgf000051_0003
tBuOK/18-crown-6-ether/
Figure imgf000051_0004
dioxane
Figure imgf000051_0005
To ethyl 4-fluoro-1 H-pyrazole-3-carboxy!ate (0.034 g, 0.26 mmol) a solution of 18-crown- 6-ether (144 mg, 0.55 mmol) dissolved in 1 ,4-dioxane (2 mL) was added under nitrogen. Potassium fe/t-butoxide solution (1 M in tetrahydrofuran, 0.2 mL, 0.2 mmol) was then added and the mixture stirred under nitrogen for 15 minutes. A solution of 4-chloro-N-[5- chloro-2-(chloromethyl)phenylJbenzenesulfonamide (0.05 g, 0.13 mmol) in 1 ,4-dioxane (2 mL) was added and the reaction stirred at 60 0C. After 18 hours the reaction mixture was quenched with water and evaporated in vacuo. Ammonium chloride (10 mL) was added and the slurry extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by mass directed autoprep to give the desired product isomer 3-[(4-chloro-2-{[(4-chlorophenyl)sulfonyl]amino}phenyl)methyl]-4-fluoro-1 H-pyrazole-3- carboxylic acid (9.6 mg). HPLC Rt=3.58minutes; m/z[M+H]+=494. 1H NMR (CD3OD) δ 7.68 (m, 3H), 7.57 (d, 2H), 7.55 (s, 1 H), 7.27 (d, 1 H), 7.00 (s, 1 H), 5.47 (s, 2H).
Example 2: 1 -(r2-(r(4-chlorophenyl)sulfonyllamino)-4-(trifluoromethyl)phenyl1methyl)-5- r(methylamino)carbonyll-1 H-pyrazole-3-carboxylic acid
Figure imgf000052_0001
Example 2 was prepared similarly to Example 1 using the appropriate starting materials. HPLC Rt = 3.6 minutes; m/z M+ = 517.
Example 3: 4-Chloro-Λ/-r2-K2-ethyl-1 H-benzimidazol-1 -yl)methvn-5- (trifluoromethyl)phenyllbenzenesulfonamide
Figure imgf000052_0002
2-Ethyl-1 /-/-benzimidazole (0.03 g, 0.26 mmol) was added under nitrogen to a solution of 18-crown-6-ether (0.07 g, 0.27 mmol) dissolved in 1 ,4-dioxane (2 mL). Potassium tert- butoxide solution (1 M in tetrahydrofuran, 0.2 mL, 0.2 mmol) was then added, and the mixture stirred under nitrogen for 15 minutes. A solution of 4-chloro-Λ/-[2-(chloromethyl- 5-(trifluoromethyl)phenyl]benzenesulfonamide (0.05 g, 0.13 mmol) in 1 ,4-dioxane (2 ml_) was added and the reaction was stirred at 60 0C. After 18 hours the reaction mixture was quenched with water and evaporated under reduced pressure. Aqueous saturated ammonium chloride (10 ml_) was added and the slurry extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over magnesium sulfate and then concentrated in vacuo. The mixture was purified by mass directed autoprep to give the desired product isomer (18 mg). HPLC Rt=3.99 minutes; m/z[M+H]=493. 1H NMR (CDCI3) 5 7.70 (d, 2H), 7.64 (d, 1 H), 7.55 (d, 2H), 7.33 (d, 1 H), 7.23 (t, 1 H), 7.17 (t, 1 H), 7.05 (d, 1 H), 7,01 (s, 1 H), 6,54 (d, 1 H), 5.56 (s, 2H), 2.77 (q, 2H), 1.29 (t, 3H).
Example 4: 3,4-dichloro-/V-r5-chloro-2-(1 H- 1 ,2,3-triazol-1 - ylmethvDphenyllbenzenesulfonamide
Figure imgf000053_0001
To a solution of intermediate 7 (1.03 g) in pyridine (12 mL) was added 4- (dimethylamino)-pyridine (6 mg) and 3,4-dichlorobenzenesulfonyl chloride (0.84 mL). These reagents were heated to 90 0C for 4 hours cooled and allowed to stand for 68 hours. The mixture was reduced in vacuo and purified by silica-gel column chromatography eluting with 0-100% ethyl acetate in cyclohexane. The resulting solid was triturated with DCM to provide the product upon drying in vacuo. HPLC Rt = 3.5 minutes; m/z MH+ = 419. 1H NMR (MeOD) δ 7.94 (s, 1 H), 7.79 (d, 1 H), 7.73 (dd, 1 H), 7.56 (dd, 1 H), 7.24 (dd, 1 H), 7.04 (d, 1 H), 6.71 (d, 1 H), 5.74 (s, 2H).
The following compounds of formula (I) set out in Table 1 were prepared by a similar procedure to that described for Example 3 and 4 using the appropriate starting materials.
Table 1
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000060_0002
Example 36: Λ/-l2-r(5-cylopropyl-1 H-tetrazole-1 -vDmethyli-4-f luorophenyll-2.11.3- benzoxadiazole-4-sulfonamide
Figure imgf000060_0001
To a solution of 2-[(5-cyclopropyl-1 H-tetrazol-1 -yl)methyl]-4-f luoroaniline (40 mg, 0.18 mmol) in pyridine (1 ml) , was added a solution of 2,1 ,3-benzoxadiazole-4-sulfonyl chloride (0.075 g, 0.34 mmol) in pyridine (1 ml) and N,N-dirnethyl-4-pyridinamine (5 mg) and the mixture was heated to 200 0C for 30 minutes in a microwave reactor. The pyridine was removed in vacuo and the mixture was dissolved in dimethylsulfoxide/methanol 1 :1 (1 mL). The resulting solution was purified by mass directed autoprep to give Λ/-{2-[(5-cylopropyl-1 H-tetrazole-1 ~yl)methyl]-4-fluorophenyl}- 2,11 ,3-benzoxadiazole-4-sulfonamide (0.061 g). HPLC Rt=2.92 minutes; m/z [M+H]+= 416. 1H NMR (CD3OD) δ 8.23 (d, 1 H), 7.92 (d, 1 H), 7.61 (t, 1 H)1 6.93 (m, 1 H), 6.83 (m, 1 H), 6.61 (m, 1 H), 5.93 (s, 2H), 2.10 (m,1 H), 1.20 (m, 2H), 1.07(m, 2H).
The following compounds of formula (I) set out in Table 2 were prepared by a similar procedure to that described for Example 36 using the appropriate starting materials.
Table 2
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Example 57: 4-Chloro-N-(5-chloro-2-r(3-methyl-6-oxo-5.6-dihvdro-1 (4H)- PyridazinvDmethyllphenvDbenzenesulfonamide
Figure imgf000064_0002
1 ,1 -Dimethylethyl 2-[(4-chloro-2-{[(4-chlorophenyl)sulfonyl]amino}phenyl)methyl]- hydrazinecarboxylate (25 mg, 0.06 mmol) in 50 % trifluoroacetic acid / dichloromethane (2 mL) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and then ethyl levulinate (9 mg, 0.06 mmol) and glacial acetic acid (1 mL) added. The mixture was heated at 100 0C for 30 mins in a microwave reactor. The solvent was removed under reduced pressure and the residue dissolved in dimethyl sulphoxide (0.5 mL) and then purified by mass directed autoprep to give 4-chloro-N-{5- chloro-2-[(3-methyl-6-oxo-5,6-dihydro-1 (4H)- pyridazinyl)methyl]phenyl}benzenesulfonamide as a colourless gum (10.3 mg). HPLC Rt = 3.43 minutes; m/z [M+Hf = 426 / 428. 1H NMR (CD3OD) δ 7.72 (d, 2H), 7.54 (d, 2H), 7.32 (d, 1 H), 7.24(d, 1 H), 7.12 (dd, 1 H), 4.47 (s, 2H), 2.47 (m, 4H), 2.04 (s, 3H).
The following compounds of formula (I) set out in Table 3 were prepared by a similar procedure to that described for Example 57 using the appropriate starting materials. Table 3
Figure imgf000065_0001
-
-
Figure imgf000066_0001
-
Figure imgf000067_0001
Example 74: 3.4-Dichloro-Λ/-(5-chloro-2-r(3-oxoπ .2.41triazolor4.3-alPyridin-2(3HV yl)methvnphenyl}benzenesulfonamide
Figure imgf000068_0001
To the commercially available [112,4]triazolo[4,3-a]pyridin-3(2H)-one (27 mg, 0.20 mmol) and 18-crown-6 ether (55 mg, 0.21 mmol) in anhydrous 1 ,4-dioxan (1 ml.) was added a 1 M solution of potassium te/t-butoxide in tetrahydrofuran (210 μl_, 0.21 mmol) . The mixture was stirred at room temperature for 15 minutes and then 1 ml_ of a solution of 3,4-dichloro-N-[5-chloro-2-(chloromethyl)phenyl]benzenesulfonamide (655 mg, 1.7 mmol) in anhydrous 1 ,4-dioxane (17 mL) was added. The mixture was heated at 60 0C for 15 hours and then left to cool to room temperature. The solvent was removed under reduced pressure and the residue dissolved in dimethyl sulphoxide (0.5 mL) and then purified by mass directed autoprep to give 3,4-dichloro-N-{5-chloro-2-[(3- oxo[1 ,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl]phenyl}benzenesulfonamide as a white solid (6.6mg). HPLC Rt = 3.23 minutes; m/z [M+H]+ = 483. 1H NMR (d6-DMSO) δ 7.85 (m, 3H), 7.63 (d, 1 H), 7.28 (d, 1 H), 7.24 (t, 1 H), 7.17 (d, 1 H), 7.09 (d, 1 H), 6.99 (s, 1 H), 6.63 (t, 1 H)1 5.00 (S1 2H).
The following compounds of formula (I) set out in Table 4 were prepared by a similar procedure to that described for Example 74 using the appropriate starting materials. Table 4
Figure imgf000068_0002
Example 78: 3.4-Dichloro-Λ/-l5-chloro-2-lY1 -methyl-1 H-tetrazol-5- vDnnethyliphenyllbenzenesulfonamicle
Figure imgf000069_0001
A mixture of {5-chloro-2-[(1 -methyl-1 /-/-tetrazol-5~yl)methyl]phenyl}amine (163 mg), 3,4- dichlorobenzenesulfonyl chloride (197 mg) and 4-(dimethylamino)~pyridine (10 mg) in pyridine (3 mL) was stirred overnight at 80 0C under an atmosphere of argon. The mixture was cooled and concentrated. The resulting residue was partitioned between ethyl acetate (20 mL) and 2M HCI (3 mL), the organic layer was washed with brine (3 mL) and concentrated. The resulting residue was purified by column chromatography (10-30% ethyl acetate in hexane) and the product slurried in methanol, cooled and filtered to give the title compound, 130 mg. HPLC Rt = 3.4 minutes; m/z [M]" = 432. 1H NMR (d6-DMSO) δ 10.2 (s, 1 H), 7.88 (d, 1 H), 7.81 (d, 1 H), 7.59 (dd, 1 H), 7.32 (br.d, 1 H1), 7.25 (d, 1 H), 6.91 (d, 1 H), 7.21 (s, 2H), 3.95 (s, 3H). The following compounds of formula (I) set out in Table 5 were prepared by a similar procedure to that described for Example 78 using the appropriate starting materials. Table 5
Figure imgf000069_0002
-
Figure imgf000070_0001
Figure imgf000071_0001
-
Figure imgf000072_0001
■
•
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0002
Example 145: 3.4-dichloro-Λ/-l5-fluoro-2-IT4-propyl-1 H- 1.2.3-triazol-1 - vDmethyliphenyDbenzeπesulfonamide
Figure imgf000075_0001
Λ/-[2-(azidomethyl)-5-fluorophenyl]-3,4-dichlorobenzenesulfonamide (450 mg) was dissolved in 2-methyl propanol (5 ml_). To one-fifth of this solution was added a 0.025M aqueous solution of sodium ascorbate (1 ml_) and a 0.1 M aqueous solution of copper sulfate (0.024 ml_). 1-Pentyne (0.24 ml.) was added and the mixture stirred for 72 hours at room temperate. DCM (5 ml_) and water (1 mL) was added and the mixture vigorously stirred for 5 minutes. The aqueous layer was removed using a hydrophobic frit and washed with DCM (2 x 1 mL) and the combined DCM layers concentrated. The title compound was retained on an isolute SCX ion-exchange column and eluted in 2M ammonia in methanol to give 40 mg upon removal of solvent. HPLC Rt = 3.7 minutes; m/z [MH]+= 443 1H NMR (CDCI3) δ 7.97 (d, 1 H), 7.70 (dd, 1 H), 7.57 (d, 1 H), 7.27 (d, 1 H), 7.25 (dd, 1 H), 7.14 (dd, 1 H), 6.89 (dt, 1 H), 5./19 (s, 2H), 2.66 (t, 2H), 1.67 (sextet, 2H), 0.96 (t, 3H).
The following compounds of formula (I) set out in Table 6 were prepared by a similar procedure to that described for Example 145 using the appropriate starting materials. In some cases the product was isolated via additional silica chromatography or mass- directed autopreparative HPLC.
Table 6
Figure imgf000075_0003
Figure imgf000076_0001
The following compounds of formula (I) set out in Table 7 were prepared by a similar procedure to that described for Example 3 using the appropriate starting materials.
Table 7
Figure imgf000076_0002
Figure imgf000077_0001
The following compounds of formula (I) set out in Table 8 were prepared by a similar procedure to that described for Example 74 using the appropriate starting materials. Table 8
Figure imgf000077_0002
Example 159: Λ/-r2-r(5-cyclopropyl-1 H-tetrazol-1 -yl)methyll-5-(trifluoromethyl)phenyl]- 2,1.3-benzoxadiazole-4-sulfonamide
Figure imgf000077_0003
Example 159 was prepared by a similar procedure to that described for Example 36 using the appropriate starting materials. HPLC Rt = 3.2 minutes; m/z [MH]+= 466
Example 160: Λ/-r4.5-dichloro-2-(1 HA ,2.3-triazol-1 -ylmethvnphenvπ-3- (trifluoromethvObenzenesulfonamide
Figure imgf000078_0001
To a solution of intermediate 10 (100 mg) in pyridine was added 4-(dimethylamino)- pyridine (2.5 mg) and 3-(trifluoromethyl)-benzenesulfonyl chloride (79 uL). The mixture was stirred at 20 0C overnight and passed through a 5 g amino-propyl ion-exchange column. The sulfonamide was eluted in 2 M ammonia in methanol and the solvent removed. The residue was partitioned between DCM and water and the organic layer separated and the solvent removed to provide 53 mg of the title compound as a cream solid. HPLC Rt = 3.4 minutes; m/z MH+ = 451. 1H NMR (CDCI3) δ 8.12 (s, 1 H), 8.05 (d, 1 H), 7.88 (d, 1 H), 7.75-7.62 (m, 3H), 7.33 (s, 1 H), 7.18 (s, 1 H), 5.35 (s, 1 H).
The following compound of formula (I) set out in Table 9 was prepared by a similar procedure to that described for Example 160 using the appropriate starting materials. Table 9
Figure imgf000078_0002
Figure imgf000079_0001
P..P ?' 2-chloro-N-[5-chloro-2-(1 H-1 ,2,3-
178 •σ 382 3.04 383 381 triazol-1 - ylmethyl)phenyl]benzenesu!fonamide
N-[5-chloro-2-(1 H-1 ,2,3-triazoM ■
179 393 2.99 394 392 ylmethyl)phenyl]-2-
Figure imgf000080_0001
nitrobenzenesulfonamide
X N-[5-chloro-2-(1 H-1 ,2,3-triazoM ■
180 366 2.94 367 365 ylmethyl)phenyl]-2- fluorobenzenesulfonamide
2-bromo-N-[5-chloro-2-(1 H-1 ,2,3-
181 427 3.09 429 427 triazol-1- ylmethyl)phenyl]benzenesulfonamide
N-[5-chloro-2-(1 H-1 ,2,3-triazoM -
182 416 3.11 417 415 ylmethyl)phenyl]-2-
Figure imgf000080_0002
(trifluoromethyl)benzenesulfonamide
A. N-[5-chloro-2-(1 H-1 ,2,3-triazol-1 - ylmethyl)phenyl]-2-
183 432 3.18 433 431 [(trifluoromethyl)oxy]benzenesulfonam ide
Example 184: 4-chloro-Λ/-l5-chloro-2-r(3,3-difluoro-1- pyrrolidinyl)methvnphenyl>benzenesulfonannide
Figure imgf000080_0003
A 0.5 M solution of the aldehyde in 2:1 THF:NMP (200 ul,0.1 mmol) was added to the Reaction Vessel (RV). Then a 0.5 M solution of the amine in 2:1 THF:NMP (240 ul, 0.12 mmol) was added to the RV. A 0.65M solution of acetic acid in THF (200 ul, 0.13 mmol) was added to the RV. MP-tricetoxyborohydride (140 mg, loading 1.8 mmol/g)was added to the RV. The mixture was then vortexed for 24 hrs at room temperature. A further quantity of MP-triacetoxyborohydride (140 mg) was added. The mixture was then vortexed for 24 hrs at room temperature. Scavenger resins were added (70 mg MP- TsNHNH2; 70 mg MP-Benzaldehyde for primary amines or 70 mg PS-lsocyanate for secondary amines). A 1 :1 mixture of DCM:THF (1 ml) was added to the RV and vortexed for 2 days. The resin was removed by filtration using a filter probe and washed with a further 4 washes of DMF (500 ul). The combined washes were evaporated to dryness and appropriate compounds were treated with 90% aq. trifluoroacetic acid to remove BOC protecting groups. The resulting material was analysed by LCMS and purified by Mass Directed Auto Prep if its purity was <80%. HPLC Rt = 3.6 minutes; m/z MH+ = 421.
The following compounds of formula (I) set out in Table 10 were prepared similarly to example 184 described above using the appropriate aldehyde and amine starting materials. Table 10
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
The following compound of formula (I) set out in Table 11 was prepared by a similar procedure to that described for Example 3 using the appropriate starting materials. Table 11
Figure imgf000085_0002
Figure imgf000086_0001
H-
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
- -
Figure imgf000090_0001
The following compound of formula (|) set out in Table 12 was prepared by a similar procedure to that described for Example 160 using the appropriate starting materials except that no N,N-dimethyl-4-pyridinamine was used and that the product was purified by mass directed autoprep instead of amino-propyl ion-exchange column.
Table 12
-
-
-
-
Figure imgf000091_0001
Example 297: 4-chloro-Λ/-r2-r(3,5-dimethyl-1 H-Pyrazol-1 -yl)methyll-5- (trifluoromethvQphenyllbenzenesulfonamide
Figure imgf000092_0001
Example 297 was prepared by a similar procedure to that described for example 36 using the appropriate starting materials with the exception that no N,N-dimethyl-4- pyridinamine was used. HPLC Rt=3.65 minutes; m/z [M+H]+= 444.
Example 298: Λ/-(2-{r5-Amino-1-methyl-3-(2-thienyl)-1 H-pyrazol^-ylimethyll-S- chlorophenyl)-4-chlorobenzenesulfonamide
Figure imgf000092_0002
To a solution of 5-chloro-2-(chloromethyl)-Λ/-(4-chlorophenyl)benzenesulfonamide (0.05 g, 0.14 mmol) in a microwave tube was added a solution of 1 -methyl-3-(2-thienyl)-1 H- pyrazol-5-amine (0.051 g, 0.28 mmol) in dioxane (1.5 mL) and NEt3 (0.029 g, 0.28 mmol). The reaction mixture was heated to 100 °C for 30 minutes in a microwave reactor. Dioxane was then removed and half of the crude mixture was dissolved in dimethylsulfoxide/methanol 1 :1 (1 mL). The resulting solution was purified by mass directed autoprep to give Λ/-(2-{[5-amino-1 -methyl-3-(2-thienyl)-1 H-pyrazol-4-yl]methyl}- 5-chlorophenyl)-4-chlorobenzenesulfonamide (0.0092 g, 13%). HPLC Rt=3.41 minutes; m/z [M+H]+= 494.
The following compounds of formula (I) set out in Table 13 were prepared by a similar procedure to that described for Example 160 using the appropriate starting materials. Table 13
Figure imgf000093_0001
Figure imgf000094_0002
Example 308 : 3-Amino-N-r5-chloro-2-(1H-1,2.3-triazol-1- ylmethvDphenyllbenzenesulfonannide
Figure imgf000094_0001
To 5% Pt/C catalyst (50 mg) (Degussa type F101 RA/W) in a flask was added N-[5- chloro-2-(1 H-1 ,2,3-triazol-1 -ylmethyl)phenyl]-3-nitrobenzenesulfonamide (0.44 g) as a solution in ethanol (20 ml_). The flask was then flushed with nitrogen and ammonium formate (0.705 g) was added with stirring. The reaction was heated at reflux under nitrogen overnight. On cooling to room temperature the catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was partitioned between water (10 mL) and EtOAc (25 ml_), and the aqueous phase was further extracted with EtOAc (25 mL). The combined organic phases were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo to afford the titled compound (0.38g). HPLC Rt=2.8 minutes m/z[M+H]=364, [M-H] 362
The following compounds of formula (I) set out in Table 14 were prepared by a similar procedure to that described for Example 57 using the appropriate starting materials.
Table 14
Figure imgf000094_0003
Figure imgf000095_0001
Figure imgf000096_0001
The following compounds of formula (I) set out in Table 15 were prepared by a similar procedure to that described for Example 74 using the appropriate starting materials. Table 15
Figure imgf000096_0002
The following compounds of formula (I) set out in Table 16 were prepared by a similar procedure to that described for Example 145 using the appropriate starting materials. As is appreciated by those skilled in the art, these analogous examples may involve routine variations in synthetic procedure.
Table 16
Figure imgf000096_0003
Figure imgf000097_0004
Example 323: 3.4-Dichloro-Λ/-r5-chloro-2-(1 H-1.2.4-triazol-1 - ylmethvDphenyllbenzenesulfonamide trifluoroacetate
Figure imgf000097_0001
EtOH, reflux
Figure imgf000097_0003
Figure imgf000097_0002
1 ,3,5-Triazine (0.096 g, 1.18 mmol) was added to a solution of 3,4-dichloro-Λ/-[5-chloro- 2-(hydrazinomethyl)phenyl]benzenesulfonamide (0.15 g, 0.39 mmol) in EtOH (10 ml_) and the reaction was heated at reflux for 18 hours. After cooled down, the reaction was filtered and purified by preparative HPLC (Sunfire prep C18, 30 x 150 mm, 50 mL/min; CH3CN/H2O, 0.1% TFA; UV detection at 214 nm) to yield the titled product (0.054 g) as a white solid. HPLC Rt=1.04 minutes m/z[M+H]=419
The following compounds of formula (I) set out in Table 17 were prepared by a similar procedure to that described for Example 78 using the appropriate starting materials. As is appreciated by those skilled in the art, these analogous examples may involve routine variations in synthetic procedure. Table 17
Parent Rt
Ex Structure Mwt min +ve -ve Name
4-chloro-Λ/-{5-chloro-2-[(2-methyl-1 H-
324 396 2.56 397 imidazol-1- yl)methyl]phenyl}benzenesulfonamide
4-chloro-N-{5-chloro-2-[(2,4-dimethyl-
325 410 2.61 411 1 H-imidazol-1 - yl)methyl]phenyl}benzenesulfonamide
N-{5-chloro-2-[(5-methyl-1 H-tetrazol-
326 423 2.86 424 1 -yl)methyl]phenyl}-3,4- bis(methyloxy)benzenesulfonamide
Figure imgf000098_0001
Example 327: 3,4-Dichloro-Λ/-{5-chloro-2-r(3-hydroxy-1 -pyrrolidinvDmethyllphenyl) benzenesulfonamide
Figure imgf000098_0002
3-Pyrrolidinol (0.02 g, 0.23 mmol) was added to a solution of 3,4-dichloro-Λ/-(5-chloro-2- formylphenyl)benzenesulfonamide (0.07 g, 0.19 mmol) in anhydrous THF (2 mL) at room temperature. After stirring for 10 minutes, sodium cyanoborohydride (0.24 g, 0.38 mmol) and acetic acid (0.1 mL) were added. The resulting reaction mixture was stirred at room temperature for additional 12 hours until the starting material was consumed completely. Saturated K2CO3 aqueous solution (4 ml_) was added to quench the reaction. After stirring for 5 min, the solution was extracted with ethyl acetate (2 X 3ml_). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by Gilson HPLC (Phenomenex 75x30 mm column, 40 mL/min, A: 0.1% TFA in acetonitrile B: 0.1 % TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give the desired product. HPLC Rt = 2.24 minutes m/z [MH]+= 437. 1H NMR (MeOD) δ 7.79 (m, 2H), 7.68 (d, 1 H), 7.59(dd, 1 H), 7.48 (dd, 1 H), 6.61 (d, 1 H), 4.70(m, 2H), 4.59 (m, 1 H), 3.64(m, 1 H), 3.50(m, 2H), 2.33(m, 1 H), 2.10(m, 2H).
The following compounds in Table 18 were prepared by a similar procedure to that described above for Example 327 using the appropriate starting materials. In some cases the product was isolated via additional silica chromatography or mass-directed autopreparative HPLC.
Table 18
Figure imgf000099_0001
pyrrolidinyl}acetamide
3,4-dichloro-N-[5-chloro-2- (1 ,5,6,7-tetrahydro-4H-
334 473 3.29 474 [1 ,2,3]triazolo[4,5-b]pyridin-4- ylmethyl)phenyl]benzenesulfona mide
The following compounds in Table 19 were prepared by a similar procedure to that described for Example 78 using the appropriate starting materials. Table 19
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
The following compounds in Table 20 were prepared by a similar procedure to that described for Example 78 using the appropriate starting materials.
Table 20
Figure imgf000105_0001
Example 360: 2.3-Dichloro-Λ/-r2-((5-r3-(methyloxybhenyll-2H-tetrazol-2-yl>methvn-5-
(trifluoromethvnphenvnbenzenesulfonamide and 2,3-dichloro-A/-r2-({5-r3-(methyloxy)phenvn-1 H- tetrazol-1-yl)methyl)-5-(trifluoronnethvnDhenyllbenzenesulfonamide
Figure imgf000106_0001
Acetonitrile (2.75 ml_) was added to 5-[3-(methyloxy)phenyl]-1 /-/-tetrazole (0.0145 g, 0.0825 mmol) and polymer supported BEMP (0.150 g, 0.33 mmol). A solution of trif luoromethyl2,3-dichloro-Λ/-[2-(chloromethyl)-5-()phenyl]benzenesulfonamide (0.0314 g, 0.075 mmol) in N-methyl pyrrolidinone (0.5 ml_) was also added and the reaction was stirred at 120 0C in a Biotage microwave. After 30 minutes the reaction mixture was filtered and the resin was washed with methanol (2 x 20 ml_). The resin was then washed with a mixture of ethanokacetic acid (90:10) ( 2 x 20 mL) and the acidic fractions were evaporated in vacuo . The residue was purified by mass directed autoprep to give the desired product isomer 2,3-dichloro-N-[2-({5-[3-(methyloxy)phenyl]-2H-tetrazol-2- yl}methyl)-5-(trifluoromethyl)phenyl]benzenesulfonamide (5.5 mg) as determined by NMR (NOE). HPLC Rt=3.83 minutes; m/z[M+H]+=558/560 (2Cl). 1H NMR (CDCL3) δ 8.1 (dd, 1 H), 7.73 (m, 4H), 7.5 (m, 5H), 7.07 (dd, 1 H), 5.92 (s, 2H), 3.92 (s, 3H) and product isomer 2,3-dichloro-Λ/-[2-({5-[3-(methyloxy)phenyl]-1 H-tetrazol-1 -yl}methyl)- 5-(trifluoromethyl)phenyl]benzenesulfonamide (5.5 mg) as determined by NMR (NOE). HPLC RT =3.6 minutes; m/z[M+H]+=558/560 (2Cl).1H NMR (CDCL3) δ 7.9 (dd, 1 H), 7.76 (dd, 2H), 7.42 (m, 5H), 7.17 (m, 3H), 5.83 (s, 2H), 3.88 (s, 3H) The following compounds in Table 24 were prepared by a similar procedure to that described for Example 360 using the appropriate starting materials. Table 21
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0003
Figure imgf000109_0001
methylbenzenesulfonamide
Figure imgf000109_0002
5-Chloro-2-(1 H-1,2,3-triazol-1-ylmethyl)aniline (62.4 mg, 0.3 mmol, 1 equiv) was dissolved in chloroform (1.5 mL). Pyridine (0.049 ml_, 0.6 mmol, 2 equiv) was added. A solution of 3-chloro-4-methylbenzenesulfonyl chloride (67.5 mg, 0.3 mmol, 1 equiv) in chloroform (1.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 16 hours. The mixture was concentrated and redissolved in DMSO. Purification by reverse phase HPLC (35-70% CH3CN/H20 + 0.1% TFA, 50 mL/min over 10 min, 30 x 50 Sunfire Prep C18) afforded the title compound as a white powder (94.4 mg, 79% yield). LC-MS m/z [MH]+= 397. The following compounds of formula (I) set out in Table 22 were prepared by a similar procedure to that described for Example 373 using the appropriate starting materials.
Table 22
Figure imgf000110_0001
Example 379: Λ/-r2-r(5-amino-3-phenyl-1 H-pyrazol-1 -yl)methvn-5- (trifluoromethyl)phenyll-4-chlorobenzenesulfonamide
Figure imgf000110_0002
4-chloro-Λ/-[2-(hydrazinomethyl)-5-(trifluoromethyl)phenyl]benzenesulfonamide (50 mg, 0.10 mmol) and 3-oxo-3-phenylpropanenitrile (16 mg, 0.11 mmol) were refluxed in toluene overnight. The solvent was then removed and the desired compound isolated by mass directed autoprep. LC-MS Rt = 3.82 min; m/z[+ve]=507. 1H NMR (CD3OD) δ 7.75-7.70 (m, 4H), 7.50 (d, 2H), 7.45-7.25 (m, 6H), 5.85 (s, 1 H), 5.10 (s, 2H).
Example 380: 1 -(r2-(r(4-chlorophenyl)sulfonyllamino)-4-(trif luoromethvDphenylimethyl)- Λ/-methyl-3-(2-thienylH H-pyrazole-5-carboxamide
Figure imgf000111_0001
1-{[2-{[(4-chlorophenyl)sulfonyl]amino}-4-(trifluoromethyl)phenyl]methyl}-3-(2-thienyl)-1 H- pyrazole-5-carboxylic acid (45 mg, 0.098 mmol), O-(benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/- tetramethyluronium hexafluorophosphate (44 mg, 0.116mmol) and dimethylamine (0.1 mL, 2M in THF, 0.2 mmol) was stirred in acetonitrile (5 mL) overnight at room temperature. Additional HBTU (20 mg) and amine (0.15 mL) was added and stirring was continued for 10 hours at 60 0C. The solvent was removed in vacuo and the desired product isolated by mass directed autoprep. LC-MS Rt = 3.79 min; m/z[+ve]=555. 1H NMR (CD3OD) δ 7.65 (m, 2H), 7.47 (m, 2H), 7.41 (m, 4H), 7.29 (d, 1 H), 7.07 (m, 1 H), 6.99 (s, 1 H), 5.63 (s, 2H), 3.61 (s, 3H).
Example 381 : 3,4-dichloro-Λ/-r5-fluoro-2-(1 -pyrrolidinylmethyPphenvπ benzenesulfonamide
The title compound was prepared according to the method described for Example 184 using appropriate starting materials. LC-MS Rt = min; m/z[+ve]=403.

Claims

Claims
1. A compound as represented in formula (I):
Figure imgf000112_0001
or a salt thereof, or a solvate thereof, or a combination thereof; wherein R1 represents an aryl, a thienyl, a benzothienyl, an imidazolyl, a pyridyl, an isoquinolinyl, a piperonyl, a benzoxathiadiazolyl, or a benzoxadiazolyl group optionally substituted with one to three R4 groups, wherein each R4 group is independently selected from the group consisting of Ci.6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, halo, -NH2, -OH, -CN, -NO2, CF3, phenyl, phenoxy, phenyl-C(O)-, isoxazolyl, and -C(O)NR7R8, wherein R7 and R8 each independently represent hydrogen or C1-4 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocylic group optionally containing an additional heteroatom selected from nitrogen, oxygen and sulphur;
m is 1,
2, or 3;
each R2 is independently selected from the group consisting of halo, -CN, -OCF3, and CF3;
R3 is a heteroaryl or a heterocycloalkyl group optionally substituted by up to three substituents independently selected from the group consisting of halo, hydroxy, hydroxy- C1-6-alkyl-, C1-4alkoxy-C1-6alkyl-, C1-4alkoxy-, C1-4thioalkoxy, amino, R10R11N-C1-4alkyl-, heterocycloalkyl, heteroaryl, halogenated heteroaryl, phenyl, benzyl, halophenyl, C1-4-alkylphenyl, methoxyphenyl, trifluoromethylphenyl, cyanophenyl, C1-6-alkyl, C3-6- cycloalkyl, -CN, C1-4alkylthio-, -CF3, -CO2H, -CONR7R8, -NC(O)R12 N and -CO-C1-4 alkyl, wherein R10 and R11 each independently represent hydrogen or C1-6 alkyl and R12 is C1-6 alkyl or C1-6 haloalkyl; -i. I ne compound of Claim 1 wherein R1 is substituted with up to three substituents selected from the group consisting of -F, -Cl, -Br, -CF3, -CH3, -OCH3, -OCF3, -NO2, phenyl, phenoxy, -NH2, -OH, phenyl-C(O)-, isoxazolyl, and -CN;
R2 is selected from the group consisting of F, Cl, -CF3, -OCF3 and -CN;
m is 1 or 2; and
R3 is a) triazolyl or benzotriazolyl optionally substituted with up to two substituents selected from the group consisting of methyl, propyl, benzyl, pyridyl, CH3S- , -CN, dimethylaminomethyl, methoxymethyl, C(O)NHCH3, and phenpropyl; b) tetrazolyl optionally substituted with a substituent selected from the group consisting of methyl, benzyl, tolyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, thienyl, chlorothienyl, methoxyphenyl, cyclopropyl, and N-morpholino; c) imidazolyl or benzimidazolyl optionally substituted with up to 3 substituents selected from the group consisting of methyl, ethyl, isopropyl, phenyl, -COOH, -Cl, and pyridinyl; d) pyrazolyl optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, propyl, butyl, hydroxymethyl, phenyl, -COOH, amino, thienyl, pyridinyl, - C(O)NHCH3, chlorophenyl, fluorophenyl, chlorothienyl, trifluoromethyl, and fluoro; e) oxopyrazolidinyl or oxopyrazolyl optionally substituted with a substituent selected from the group consisting of methyl, cyanophenyl, fluorophenyl, trifluoromethylphenyl, furyl, phenyl, pyridinyl, methoxyphenyl, benzyl, isopropyl, trifluoromethyl, n-propyl, f-butyl, n- butyl, n-hexyl, n-pentyl, fluoro; f) dimethylaminopurinyl; g) indazolyl; h) methyl dihydropyradazinonyl; i) oxooxazolidinyl; j) oxobenzoxazolyl; k) oxopiperidinyl; I) methyloxadiazolyl; m) oxobenzotriazolyl; n) pyrazinyl; o) methyldioxoimidazolidinyl; p) methyloxoimidazolidinyl; q) methyloxopyridinyl; r) pyrroϋdinyl optionally substituted with up to 3 substituents selected from the group consisting of hydroxymethyl, methyl, - COOH, hydroxy, fluoro, -NHC(O)CF3, and -NHC(O)CH3; s) piperidinyl optionally substituted with up to 3 substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, hydroxy, -C(O)NH2; t) morpholino; u) thiomorpholino; v) tetrahydrotriazolylpyridinyl; w) isoindolyl; x) dioxaazaspirodecyl; or y) oxophenyltriazaspirodecyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof.
3. The compound of Claim 1 wherein R1 is substituted with one or two substituents selected from the group consisting of -F, -Cl, -CF3, -CH3, -OCH3, -OCF3, and -CN;
R2 is selected from the group consisting of F, Cl, -CF3, -OCF3, -CN; m is 1 or 2; and the substituent or one of the substituents is para to the -CH2R3 group; and
R3 is a) triazolyl optionally substituted with up to two substituents selected from the group consisting of methyl and propyl b) tetrazolyl optionally substituted with methyl, c) imidazolyl or benzimidazolyl optionally substituted with up to 3 substituents selected from the group consisting of methyl, ethyl, isopropyl, and -COOH; d) pyrazolyl optionally substituted with up to 3 substituents selected from the group consisting of methyl, - COOH, and trifluoromethyl; e) oxopyrazolidinyl or oxodihydropyrazolidinyl optionally substituted with a substituent selected from the group consisting of methyl, trifluoromethyl, n-propyl, f-butyl, n-butyl, n-hexyl, or n-pentyl; f) pyrrolidinyl optionally substituted with up to 3 substituents selected from the group consisting of hydroxymethyl, methyl, -COOH, hydroxy, and fluoro; g) piperidinyl optionally substituted with up to 3 substituents selected from the group consisting of fluoro and methyl; h) morpholino; i) thiomorpholino; j) tetrahydrotriazolylpyridinyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof.
4. A method for treating or preventing a disease or condition mediated by CCR2 comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of Claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate thereof, of a combination thereof.
5. A pharmaceutical composition comprising a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof and b) a pharmaceutically acceptable carrier, diluent, or excipient or combination thereof.
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