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Definitions

• This invention relates to compounds of formula (I)
• the compounds of the invention inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease.
• This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
• TNF Tumor necrosis factor
• IL-1 interleuki ⁇ -1
• proinflammatory cytokines which play a role in cytokine mediated diseases. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The fla matory response plays an important role in limiting and controlling pathogenic infections. Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al, 1984, Rev. Infect. Disease 6:51).
• rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A.E., et al, 1995, J. Invest. Med. 43: 28-38).
• cytokines may be involved in endothelial cell pathogenesis including restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al, 2001 Mar, Coron Artery Dis 12(2):107-13).
• TNF proinflammatory cytokines
• IL-l ⁇ proinflammatory cytokines
• a number of anti-cytokine therapies are currently in clinical trials. Efficacy has been demonstrated with a monoclonal antibody directed against TNF ⁇ in a number of autoimmune diseases (Heath, P., "CDP571: An
• a soluble TNF ⁇ receptor has been engineered that interacts with TNF ⁇ . The approach is similar to that described above for the monoclonal antibodies directed against TNF ⁇ ; both agents bind to soluble TNF ⁇ , thus reducing its concentration.
• Enbrel Immunex, Seattle, WA
• Another version of the TNF ⁇ receptor, Ro 45-2081 has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury.
• Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells (Renzetti, et al, 1997, Inflamm. Res. 46: S143). IL-1 has been implicated as an immunological effector molecule in a large number of disease processes. IL-1 receptor antagonist (IL-lra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In a phase III human clinical trial IL-lra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).
• Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage.
• IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.
• Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58).
• Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling.
• Cytokines such as IL-1 and TNF are potent stimulators of NO production.
• NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al, 1996, J Bone Miner Res. 11, 300).
• the promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated through other effectors such as prostaglandins and thromboxanes.
• IL- 1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al, 1996, Proc Soc Exp Biol Med. 211, 24).
• Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression.
• COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M.K. O'Banion et al, Proc. Natl. Acad. Sci.U.S.A, 1992, 89, 4888.)
• inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
• IBD active inflammatory bowel disease
• a mucosal imbalance of intestinal IL-1 and IL-lra is present in patients with IBD. Insufficient production of endogenous fX-lra may contribute to the pathogenesis of IBD (Cominelli, et al, 1996, Aliment Pharmacol Ther. 10, 49).
• Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al, 1995, Med Hypotheses, 45, 559).
• IL-1 A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.
• HIV human immunodeficiency virus
• IL-lra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al, 1997, Clin Exp Immunol. 109, 54).
• IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a disregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
• TNF ⁇ and IL-l ⁇ are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure.
• ARDS acute respiratory distress syndrome
• TNF ⁇ and IL-6 levels have also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al, 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease.
• TNF ⁇ expression Abnormalities in TNF ⁇ expression have been noted for each of the above conditions (Lommeda, et al, 1998, FASEB J. 12, 57). It has been proposed that elevated levels of TNF ⁇ are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al, 1996, Med Hypotheses 47, 423). An inhibitor of TNF ⁇ production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al, 1997, J Neuroimmunol 72, 169).
• Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease.
• cytokines such as IL-1 and TNF have been suggested to promote the disease.
• an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al, 1998, Circulation, 97, 242).
• TNF ⁇ levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M.A. Higham et al, 2000, Ewr. Respiratory J., 15, 281). Circulating TNF ⁇ may also contribute to weight loss associated with this disease (N. Takabatake et al, 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179).
• TNF ⁇ levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A.M. Feldman et al, 2000, J. Amer. College of Cardiology, 35, 537).
• TNF ⁇ has been implicated in reperfusion injury in lung (Borjesson et al, 2000, -4.?.er. J. Physiol, 278, L3-12), kidney (Lemay et al, 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al, 1999, Brain Res., 844, 192).
• TNF ⁇ is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al, 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al, 2000, Arthritis and Rheumatism, 41, 2165). TNF ⁇ has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al, 1998, Laboratory Investigation, 78, 1625).
• iNOS inducible nitric oxide synthetase
• IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1 blockers.
• Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65).
• IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis.
• Epicutaneous sensitization can be preve nted by the administration of an anti- IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al, 1996, Am J Contact Dermal 7, 177).
• IL-1 knock out mice Data obtained from IL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al, 1998, Clin Exp Pharmacol Physiol 25, 141).
• a variety of cytokines including TNF, IL-1, IL-6 and IL- 8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).
• the production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
• IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al, 1996, Molecular Medicine Today 2, 482).
• an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonepliritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
• neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonepliritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
• Rhinovirus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al, 1998, Am J Rhinol 12, 17).
• IL-8 diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
• IL-6 The proinflammatory cytokine IL-6 has been implicated with the acute phase response.
• IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al, 1998, Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al, 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in osteoporosis.
• cyto ine differences such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al, 1997, Calcif Tissue Int. 61, 16).
• a number of cytokines have been shown to be involved in cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al, 1995, Cytokins Mol Ther. 1, 107).
• IL-6 and IFN alpha are infectious diseases, such as influenza.
• Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al, 1997, Protein Sci. 6, 929).
• Compounds that interfered with the production of cytokines including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in mice (Scholz et al, 1998, J. Med. Chem., 41, 1050).
• GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including burn-wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al, 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998, JR Coll Physicians Lond 32, 56).
• HIV human immunodeficiency virus
• Interferon ⁇ has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft- versus-host disease (Parkman, 1998, Curr Opin Hematol 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM- CSF and IFN ⁇ . These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al, 1995, Leuk Lymphoma. 19, 173).
• IFN ⁇ insulin- dependent diabetes
• MS multiple sclerosis
• AIDS dementia complex Alzheimer's disease complex
• cytokines such as TNF, IL-1 and IFN ⁇ . These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFN ⁇ following challenge with Vespula venom (Bonay, et al, 1997, Clin Exp Immunol. 109, 342).
• the nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as IFN ⁇ (Akaike, et al, 1998, Proc Soc Exp Biol Med. 217, 64).
• proinflammatory cytokines such as IFN ⁇
• Patients, chronically infected with hepatitis B virus ( ⁇ BV) can develop cirrhosis and hepatocellular carcinoma.
• Viral gene expression and replication in ⁇ BV transgenic mice can be suppressed by a post- transcriptional mechanism mediated by IFN ⁇ , TNF and IL-2 (Chisari, et al, 1995, Springer Semin Immunopathol 17, 261).
• IFN ⁇ can selectively inhibit cytokine induced bone resorption.
• NO nitric oxide
• rheumatoid arthritis a mediator of bone disease for such diseases as: rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis (Evans, et al, 1996, J Bone Miner Res. 11, 300).
• IL-12 dependent production of IFN ⁇ is critical in the control of early parasitic growth. Although this process is independent of nitric oxide the control of chronic infection does appear to be NO dependent (Alexander et al, 1997, Philos Trans R Soc LondB Biol Sci 352, 1355).
• NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilbourn, et al, 1997, Dis Mon. 43, 277).
• IFN ⁇ is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intemiediacy of CD4+ lymphocytes probably of the THl phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43).
• An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis.
• the level of IFN ⁇ was negatively correlated with serum IgE suggesting a role for IFN ⁇ in atopic patients (Teramoto et al, 1998, Clin Exp Allergy 28, 74).
• WO 01/01986 discloses particular compounds alleged to having the ability to inhibit TNF-alpha. Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke's encephaloph
• WO 02/32862 discloses that inhibitors of pro-inflammatory cytokines including TNF ⁇ are allegedly useful for treating acute and chronic inflammation in the lung caused by inhalation of smoke such as cigarette smoke.
• TNF ⁇ anatagonists are apparently also useful for the treatment of endometriosis, see EP 1022027 Al.
• Infliximab in clinical trials for RA, has also been indicated to be useful for treating various inflammatory diseases including Behcet's disease, uveitis and ankylosing spondylitis. Pancreatitis may also be regulated by inflammatory mediator production, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 Sep. 10(3):160-75.
• p38MAP kinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treating inflammation induced by the Lyme disease agent.
• WO 98/52558 discloses heteroaryl urea compounds which are indicated to be useful in treating cytokine mediated diseases.
• WO 99/23091 discloses another class of urea compounds which are useful as anti-inflammatory agents.
• WO 99/32463 relates to aryl ureas and their use in treating cytokine diseases and proteolytic enzyme mediated disease.
• WO 00/41698 discloses aryl ureas said to be useful in treating p38 MAP kinase diseases.
• Compounds active against p38 MAP kinase can also be useful for treating various types of cancers as described in WO 03/068223.
• U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N' -heterocyclic substituted urea compounds which are described as being useful for treating hypercholesterolemia and atheroclerosis.
• Di-substituted aryl and heteroaryl compounds are also disclosed in US Pat. Nos. 6,080,763; 6,319,921; 6,297,381 and 6,358,945. The compounds in the patents are alleged to possess anti-cytokine activity and are therefore useful in treating diseases associated with inflammation.
• Ari is carbocycle optionally substituted with one Ri, and wherein Ari is independently substituted with two R 2 groups;
• Ri is hydrogen, N0 2 , -N(R C ) 2 , J-C(O)- N(R C )- or J-S(0) m - N(R C )-
• n 0,1 or 2 and wherein R° is chosen from hydrogen or C 1-5 alkyl;
• J is chosen from Cl-10 alkyl and carbocycle each optionally substituted by R b ;
• R 2 is chosen from Cl-6 alkyl or C3-7 cycloalkyl which may optionally be partially or fully halogenated, Cl-4 acyl, aroyl, Cl-4 alkoxy, which may optionally be partially or fully halogenated, halogen, Cl-6 alkoxycarbonyl, carbocyclesulfonyl and -S0 2 -CF 3 ;
• R 3 , Ri, Rs, R 7 and R 8 are each independently chosen from hydrogen, halogen, Cl-5 alkyl, Cl-5 alkoxy, Cl-5 alkylCl-5 alkoxy, hydroxy, hydroxy Cl-5 alkyl or amino optionally mono- or di-substituted by Cl-5 alkyl, aryl or aryl Cl-5 alkyl;
• R 5 is: a bond, -0-, -S-, -N ⁇ , -NH-, C(O) , a linear chain chosen from -NH(CR 7 R 8 ) lake-, -(CR7R8 - -0(CR 7 Rs) n -, -C(0)-0(CR 7 Rs) n -, -S(CR 7 R 8 ) n -, C(0)(CR 7 R 8 ) n - and -C(0)NH(CR 7 R 8 ) n -, wherein n is 1-5 and each of the aforementioned R 5 is further substituted by R a ; or R 5 is a ring system chosen from aryl, heteroaryl or heterocyclyi each optionally substituted by R a ; R a and R b are each independently chosen from hydrogen, Cl-5 alkyl, hydroxyCl-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, carbocycle, heterocycle, heteroaryl, Cl
• each X is independently O or S or the pharmaceutically acceptable salts, acids, esters or isomers thereof.
• J is chosen from Cl-10 alkyl, aryl or C3-7 cycloalkyl each optionally substituted by R b ;
• R 2 is independently chosen from Cl-6 alkyl which may optionally be partially or fully halogenated, acetyl, aroyl, Cl-4 alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl, phenylsulfonyl and-S0 2 -CF 3 ;
• n 1-4;
• R a and R b are each independently chosen from hydrogen, Cl-5 alkyl, C2-5 alkenyl, C2- 5 alkynyl, C3-8 cycloalkylCO-2 alkyl, aryl, Cl-5 alkoxy, Cl-5 alkylthio, amino, Cl-5 alkylamino, Cl-5 dialkylamino, Cl-5 acyl, Cl-5 alkoxycarbonyl, Cl-5 acyloxy, Cl-5 acylamino, Cl-5 sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile or R and R b are chosen from; heterocycle chosen from pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyr
• R 7 is hydrogen; and each X is O.
• R 5 is: -0-, -S-, -NH-, C(O), a linear chain chosen from -NH(CR 7 R 8 ) prom-, -(CR 7 R 8 ) lake-, -0(CR 7 R 8 ) n -, -C(0)-0(CR 7 R 8 ) n -, -S(CR 7 R 8 ) n -, C(0)(CR 7 R 8 ) n - and -C(0)NH(CR 7 R 8 ) n - wherein n is 1-3 and each of the aforementioned R 5 is further substituted by R a .
• Ar 1 is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl, each Ar 1 is substituted with one R 1 , and independently substituted with two R 2 groups;
• R 1 is N0 2 , NH 2 , Cl-3acylNH- or the formula: J-S(0) m -N(R c )-;
• J is Cl-10 alkyl
• R 2 is independently chosen from Cl-6 alkyl which may optionally be partially or fully halogenated and Cl-3 alkoxy, which may optionally be partially or fully halogenated;
• R 3 and R-j are each independently chosen from hydrogen, Cl-3 alkyl and chloro;
• R 6 is chosen from hydrogen and amino
• R 5 is: -NH-, C(O), a linear chain chosen from -NH(CR 7 R 8 ) n -, -(CR 7 R 8 ) n -, -0(CR 7 R 8 ) n -, -C(0)-0(CR 7 R 8 ) n -, C(0)(CR 7 R 8 ) n - and -C(0)NH(CR 7 R 8 ) n - wherein n is 1-2 and each of the aforementioned R 5 is further substituted by R a ,
• R a and R b are each independently chosen from hydrogen, Cl-5 alkyl, C3-7 cycloalkylCO-2 alkyl, aryl, Cl-5 alkoxy, amino, Cl-5 alkylamino, Cl-3 dialkylamino, Cl-3 acyl, Cl-5 alkoxycarbonyl, Cl-3 acyloxy, Cl-3 acylamino, Cl-3 sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile; or R is chosen from pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl, piperazinyl, piperidinonyl, tetrahydropyrimidonyl, aziridinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazol
• R 1 is the formula: J-S(0) 2 -NH-; J is Cl-5 alkyl;
• R 2 is independently chosen from Cl-5 alkyl which may optionally be partially or fully halogenated and Cl-2 alkoxy, which may optionally be partially or fully halogenated;
• R 3 is hydrogen
• R 4 is chosen from hydrogen and methyl
• R 8 is hydrogen, methyl, ethyl, CH 2 OH and CH 2 OCH 3 .
• R-i is methyl
• R a is chosen from hydrogen, Cl-5 alkyl, C3-6 cycloalkylCO-2 alkyl, phenyl, Cl-5 alkoxy, amino, Cl-5 alkylamino, Cl-3 dialkylamino, Cl-3 acyl, Cl-5 alkoxycarbonyl, Cl-3 acyloxy, Cl-3 acylamino, hydroxy, halogen; or R is chosen from morpholinyl, tl iomo ⁇ holinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl, piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.
• R a is chosen from hydrogen, Cl-5 alkyl, C3-6 cycloalkyl, phenyl, Cl-5 alkoxy, Cl-5 alkoxycarbonyl, Cl-3 acyloxy, Cl-3 acylamino, hydroxy, halogen; or R a is chosen morpholinyl, piperidinyl and pyridinyl.
• R 5 is -NH(CR 7 R 8 ) n -R a , wherein R a is chosen from phenyl, mo ⁇ holinyl, piperidinyl, pyridinyl, cyclopropyl, cyclohexyl, Cl-5 alkyl and Cl-3 alkoxy.
• the invention also relates to the use of a compound of formula (I), wherein Ari, X, R 3 , R-j, R 5 and Re have the meaning indicated, for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine mediated disease or condition..
• the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of formula (I), wherein Ari, ? 3? Rjj R 5 and Re have the meanings indicated, or the pharmaceutically acceptable derivatives thereof, optionally combined with conventional excipients and/or carriers.
• the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
• Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
• Some of the compounds of formula (I) can exist in more than one tautomeric form. The invention includes methods using all such tautomers.
• C ⁇ - alkoxy is a C ⁇ . 4 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy.
• All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
• Carbocycles include hydrocarbon rings containing from three to twelve carbon atoms. These carbocycles may be either aromatic either aromatic or non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used interchangeably.
• heterocycle refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated.
• Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
• the heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure.
• heterocycles include but are not limited to, for example pyrrolidinyl, pyrrolinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, thiomo ⁇ holinyl sulfoxide, thiomo ⁇ holinyl sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahyc-jofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone.
• heteroaryl shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N,0 and S. Unless otherwise stated, such heteroaryls include aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidin
• heteroatom as used herein shall be understood to mean atoms other than carbon such as O, N, S and P.
• one or more carbon atoms can be optionally replaced by heteroatoms: O, S or N, it shall be understood that if N is not substituted then it is NH, it shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain.
• Such groups can be substituted as herein above described by groups such as oxo to result in defintions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
• aryl as used herein shall be understood to mean aromatic carbocycle or heteroaryl as defined herein.
• Each aryl or heteroaryl unless otherwise specified includes it's partially or fully hydrogenated derivative.
• quinolinyl may include decahydroquinolinyl and tetrahydroquinolinyl
• naphthyl may include it's hydrogenated derivatives such as tetrahydranaphthyl.
• Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art.
• nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quatemized form of any basic nitrogen.
• -S-C ⁇ - 6 alkyl radical unless otherwise specified, this shall be understood to include -S(0)-C ⁇ - 6 alkyl and -S(0) 2 -C ⁇ - 6 alkyl.
• halogen as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine, preferably fluorine.
• alkyl a nonlimiting example would be -CH 2 CHF 2 , -CF 3 etc.
• the compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art.
• a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the inventive methods disclosed herein.
• the invention includes pharmaceutically acceptable derivatives of compounds of formula (I).
• a "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof.
• a pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formula (I).
• Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
• suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.
• Other acids such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts.
• Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C ⁇ -C4 alkyl)4 salts.
• prodrugs of compounds of the formula (I) include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
• the invention additionally provides for methods of making the compounds of formula (I).
• the compounds of the invention may be prepared by the general methods and examples presented below, and methods known to those of ordinary skill in the art. In the schemes below, unless otherwise specified, Ari, Ri -Rg and X in the formulas shown below shall have the meanings defined for these groups in the definition of the formula (I) of the invention, described hereinabove. Intermediates used in the syntheses below are either commercially available or easily prepared by methods known to those skilled in the art. Further reference in this regard may be made to US patent no. 6,358,945, US application nos. 09/714,539, 09/834,797, 10/120,028, 10/143,322 and 10/147,675. Each of the aforementioned are inco ⁇ orated in their entirety.
• Reaction progress may be monitored by conventional methods such as thin layer chromatography (TLC).
• TLC thin layer chromatography
• Intermediates and products may be purified by methods known in the art, including column chromatography, HPLC or recrystallization.
• an optionally substituted 3-aminobenzoic acid (II) is reacted with NaN0 2 in an aqueous acid such as 2N HCl, at about 0 °C.
• the diazonium salt that forms is reacted in situ with a cold aqueous solution of NaN 3 at about 0 °C to provide the azide III.
• Reaction of the azide with alkyne ester IVa in a suitable solvent such as dimethylacetamide (DMA), ethanol, or toluene while heating at about 80 °C to 120 °C in a sealed tube provides the triazole V and its regioisomer.
• DMA dimethylacetamide
• an appropriate copper salt such as Cul (Perez-Balderas, F. et al., Org. Lett. 2003, 1951- 1954) or CuS0 and sodium ascorbate (Rostovtsev, V. V. et alAngew. Chem. Int. Ed. Engl. 2002, 41, 2596-2599), can catalyze the reaction of azide III and alkyne IVa to provide triazole V.
• Coupling methods may include conversion of the benzoic acid V to the acid chloride, for example by treatment with oxalyl chloride and DMF in a suitable solvent such as dichloromethane or THF, followed by reaction with the desired aniline compound Ar ⁇ NH 2 in the presence of a suitable base such as 2,6-lutidine, in a suitable solvent such as dichloromethane.
• a suitable solvent such as dichloromethane or THF
• EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
• HOBt 1- hydroxybenzotriazole
• the initially formed (I) may be further modified by methods known in the art to provide additional compounds of the invention. Some of these methods are illustrated in the Synthetic Examples section below.
• Compounds of formula (I) in which R 5 is an aryl, cycloalkyl, heteroaryl or heterocyclyi group may be prepared from III as illustrated in Scheme II.
• the nitro group is then reduced by methods known in the art, for example by stirring under a hydrogen atmosphere in a suitable solvent such as MeOH with 1% HO Ac, in the presence of a suitable catalyst such as palladium on carbon to provide aniline VTII.
• a suitable solvent such as MeOH with 1% HO Ac
• a suitable catalyst such as palladium on carbon
• one couples the 3-azidobenzoic acid III with the desired Ar ⁇ NH 2 as described for the coupling steps above to form amide VTII.
• Reaction of VTII with the desired alkyn intermediate as described above provides the desired compound of formula (I).
• Aniline compounds Ar ⁇ NH 2 are readily prepared from commercially available intermediates by methods known in the art. Further reference in this regard may be made to references cited in the first paragraph of this section. Synthetic Examples
• Methyl(triphenylphosphonium) bromide (17.1 g, 48.0 mmol) was suspended in THF (96 L) and cooled to 0 °C.
• n-Butyllithium 2.5 M in hexane, 19.2 mL, 48.0 mmol
• the red solution was stirred at rt for 0.5 h.
• l-[4-(tert- Butyl-dimethyl-silanyloxy)-phenyl]-ethanone (10.0 g, 40.0 mmol) was added.
• the solution turned bright yellow and a white precipitate formed.
• the mixture was stirred for 1 h at rt and then the solution was quenched with saturated NaHC0 3 .
• aqueous phase was extracted with diethyl ether and the combined organic layers were washed with saturated NaHC0 3 .
• the organic layers were dried over sodium sulfate, filtered and concentrated.
• the resultant mixture was eluted through a plug of silica gel (hexanes) and the filtrate was concentrated to provide tert-butyl-(4-isopropenyl-phenoxy)- dimethyl-silane (8.36 g, 84%) as a colorless oil.
• ESI MS m/z 249, M+H).
• the aqueous phase was extracted with CH C1 2 and the combined organic layers were washed with saturated aqueous NaHC0 3 . The organic layers were dried over sodium sulfate, filtered through celite, and concentrated.
• the crude TBS ether was dissolved in THF (50 mL) and TBAF (1.0 M in THF, 28 mL, 28 mmol) was added at rt. The solution was stirred for 2 h and then quenched with aqueous 1.0 M HCl.
• the aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHC0 3 . The organic layers were dried over sodium sulfate, filtered and concentrated.
• Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution of 2-methoxy-5- (l-methyl-cyclopropyl)-l,3-dinitro-benzene (2.21 g, 8.76 mmol) in ethyl acetate (30 mL). The mixture was heated to reflux for 0.25 h upon which the solution became red in color. The solution was cooled to rt and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHC0 3 .
• Triethylamine (521 ⁇ L, 3.74 mmol) was added to a solution of 2-methoxy-5-(l-methyl- cyclopropyl)-benzene-l,3-diamine (718 mg, 3.74 mmol) in methylene chloride at -10 °C.
• Methanesulfonyl chloride (290 ⁇ L, 3.74 mmol) was then added dropwise over a 10 min period and the resultant solution was allowed to slowly warm to rt over 2 h. The mixture was quenched with saturated aqueous NaHC0 3 and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated.
• Example 1 Synthesis of l-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazoIe-4-carboxyIic acid methyl ester
• Example 7 l-[5-(5-tert-ButyI-3-methanesuIfonylamino-2-methoxyphenyl- carbamoyl)-3-fluoro-2-methyl-phenyl]-l ⁇ -[l,2,3]triazole-4-carboxyIic acid ethyl ester
• Example 8 l-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxyphenyl- carbamoyI)-2-chloro-phenyl]-lH-l,2,3-triazole-4-carboxylic acid methyl ester
• Example 6 (115 mg, 209 mmol) 4 mL of MeOH and 0.4 mL of 4M HCl in dioxane in a sealed mbe at 60 °C for 6 h. The vessel was carefully vented at about 55 °C and 1 mL of water was added. The solution was slowly cooled, and the resulting precipitate was filtered and washed with water to provide 68.3 mg (127mmol, 61%) of Example 8, mp 251-252 °C (dec). ESI MS (m/z 534, 100, M-H).
• Example 9 (1.14 g, 61%) as a white solid: mp 204-205 °C. ESI MS (m/z 531, 100, M+H).
• Example 10 As an off-white solid, mp: 212-124 °C.
• ESI MS m/z 560, 100, M-H).
• Example 15 Synthesis of l-[5-(3-methanesu!fonyIamino-2-methoxy-5- trifluoromethyl-phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4- carboxylic acid methyl ester
• Example 16 Synthesis of l-[5-(5-tert-butyI-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2,3-dimethyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid methyl ester
• N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3,4-dimethyl-5-nitro- benzamide (0.198, 0.440 mmol) was dissolved in warm MeOH with 1% HOAc, and 20 mg of Pd/C was added. The mixture was cooled to room temperature and stirred under an atmosphere of H 2 for 6 h. The mixture was filtered through diatomaceous earth and concentrated. The resulting residue was taken up in EtOAc, and washed with ⁇ aHC0 3 and brine. The organic portion was then dried with Na 2 S0 4 , filtered, and concentrated.
• the residue was chromatographed with 0-7.5% MeOH in dichloromethane to provide 184 mg (0.439, 99.7%) of the aniline product.
• the resulting aniline (0.186 g, 0.443 mmol) was suspended in 1 M H 2 S0 4 (about 5 mL), and a solution of 37 mg (0.53 mmol) NaN0 2 was slowly added. After 10 min, the aniline had not dissolved, and MeOH was slowly added until a homogeneous solution was obtained.
• the mixture was then diluted with 20 mL of water, and a solution of NaN 3 (32 mg, 0.49 mmol) in 2 mL of water was slowly added. Gas was evolved and a precipitate formed.
• Example 17 Synthesis of l-[5 ⁇ (5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl] -1H-1 ,2,3-triazole-4-car boxylic acid
• Example 1 (0.271 g, 0.525 mmol) was suspended in 2 mL of MeOH and 10 mL of 10% ⁇ aOH solution was slowly added. The solid dissolved quickly, and the solution was stirred rapidly for about 1 h. Concentrated HCl was added dropwise until a pH ⁇ 2 was achieved, and the resulting white slurry was stirred until it cooled to room temperature. The precipitate was filtered and washed with water and dried under a stream of air to provide 0.250 g (0.498 mmol) of Examplel7 as a white solid, mp: 222-224 °C. ESI MS (m/z 500, 100, M-H).
• Example 9 5-A-mino-l-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2- methyl-phenyl]-lH-l,2,3-triazoIe-4-carboxylic acid methyl ester (Example 9) (500 mg) was dissolved in MeO ⁇ (4 mL). A solution of 10% sodium hydroxide (20 mL) was added. The reaction was stirred for 5 h and then acidified to p ⁇ 4 with concentrated hydrochloric acid. The suspension was cooled in ice and the solid was collected by vacuum filtration, washed with water and dried under vacuum overnight. The solid was chromatographed over silica gel (6:3:1 chlorofo ⁇ n/MeO ⁇ /ammonium hydroxide) to provide Example 22 (375 mg, 77%) as a white solid.
• Example 23 (Intermediate): l-[5-(5-tert-Butyl-3-methanesuIfonyIamino-2- methoxy-phenylcarbamoyl)-2-fluoro-phenyl]-l ⁇ -[l,2,3]triazole-4-carboxylic acid ethyl ester.
• Example 17 was suspended in CH 2 C1 2 at 0 °C. Oxalyl chloride was added, followed by 1 drop of 10% DMF in THF. The mixture was stirred for 30 min, and the resulting yellow solution was concentrated to provide l-[5-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3- triazole-4-carbonyl chloride.
• Example 24 The following examples were prepared from the appropriate acid and amine coupling partners in a manner analogous to Example 24.
• Example 25 N-(5-tert-Butyl-3-methanesulfonylamino-2 -methoxy-phenyl)-4- methyl-3-[4-(m ⁇ holine-4-carbonyl)-l,2,3-triazol-l-yl]-benzamide, mp: 244-245 °C.
• Example 28 Synthesis of l-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2,3-dimethyl-phenyl]-lH-l,2,3-triazoIe-4-carboxyIic acid (2- morpholin-4-yl-ethyl)-amide
• Example 18 To a solution of 0.075 g (0.145 mmol) of Example 18 in 1 mL DMF was added 33 mg (0.174 mmol) of HOBt and 33 mg (0.217 mmol) of EDC. Twenty minutes later, 0.044 mL (0.290) of aminoethylmo ⁇ holine was added. The mixture was stirred for 12 h, and then poured into water, and the resulting mixture was extracted with EtOAc. The organic portion was collected, dried with Na 2 S0 , filtered, and concentrated. The resulting residue was chromatographed (0-10% MeOH in CH 2 C1 2 ) to provide Example 28, mp: >200 °C (dec). ESI MS (m/z 628, 100, M+H).
• Example 29 1 -[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid (2- mo ⁇ holin-4-yl-ethyl)-amide, mp: 210 (dec).
• Example 37 l-[5-(5-tert-Butyl-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]- lH-l,2,3-triazole-4-carboxylic acid (2-mo ⁇ holin-4-yl-ethyl)-amide, mp: 198-200 °C.
• ESI MS m/z 521, 100, M+ ⁇ );
• Example 38 1 -[5-(5-tert-Butyl-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]- lH-l,2,3-triazole-4-carboxylic acid ((R)-l-phenyl-ethyl)-amide, mp: 128-131 °C.
• ESI MS m/z 512, 100, M+ ⁇ );
• Example 40 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid ((R)-l- cyclohexyl-ethyl)-amide, mp: 266-268 °C.
• Example 44 1 -[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2,3-dimethyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid benzylamide, mp: 191 (dec).
• Example 47 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl] ⁇ 1H-1 ,2,3-triazole-4-carboxylic acid ((S)-l - phenyl-ethyl)-amide, mp: 227-230 °C.
• Example 52 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid tert- butylamide, mp: 219-222 °C.
• Example 55 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-chloro-phenyl]-lH-l,2,3-triazole-4-carboxylic acid ((R)-l- phenyl-propyl)-amide, ESI MS (m/z 637, 100, M+ ⁇ )
• Example 56 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]- IH- 1 ,2,3-triazole-4-carboxylic acid ((R)- 1 - phenyl-propyl)-amide, ESI MS (m/z 619, 100, M+ ⁇ )
• Example 57 1 -[5-(5-(5-tert-Butyl-3-methane
• Example 63 l-[5-(5-tert-Butyl-3-dibenzylamino-2-methoxy-phenylcarbamoyl)-2- methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid (2,2-dimethyl-propyl)-amide.
• Example 64 l- ⁇ 5-[3-Methanesulfonylamino-2-methoxy-5-(2,2,2-trifluoro-l- trifluoromethyl-ethyl)-phenylcarbamoyl]-2-methyl-phenyl ⁇ -lH-[l,2,3]triazole-4- carboxylic acid ((E)-l-phenyl-ethyl)-amide, mp: 126 - 129 °C. ESI MS (m/z 699,
• Example 65 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-3-fluoro-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid
• Example 66 l-[5-(5-tert-butyI-3-methanesulfonylamino-2-methoxyphenyI- carbamoyl)-2-methyl-phenyl]-l-fiT-l,2,3-triazole-4-carboxyIic acid amide
• Example 1 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl- phenyl]-lH-l,2,3-triazole-4-carboxylic acid metliyl ester (Example 1) (108 mg, 0.209 mmol) was suspended in 4 mL of 0.5 M N ⁇ 3 in MeOH in a sealed tube. The tube was then heated to 65 °C for 36 h. After cooling to room temperature, the suspension was filtered and the filter cake was washed with MeOH. The filter cake was then suspended in 20 mL of hot EtOH and DMF was added slowly until a homogeneous solution resulted.
• Example 67 1- [5-(5-tert-butyl-3-methanesuIfonylamino-2-methoxyphenyI- carbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid (piperidin-4- ylmethyl)-amide
• Example 68 5-amino-l- [5-(5-tert-butyl-3-methanesulfonyIamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid (2,2- dimethyl-propyl)-amide
• HATU 0-(7-Azabenzotriazol-l-yl)-N, N, N', N',-tetramethyluronium hexafluorophosphate
• Example 22 75 mg, 0.15 mmol
• Neopentylamine (18 microL, 0.23 mmol) and N,N- diisopropylethylamine (78 microL, 0.45 mmol) were added and the reaction stirred 20 min.
• Water (5 mL) was added and the cloudy solution was extracted with CH 2 C1 2 (4 x 15 mL). The combined organic extracts were washed with 5% lithium chloride (2x) solution and brine.
• Example 68 (75 mg, 88%) as a white solid, mp 189-193 °C.
• ESI MS (m/z 586, 100, M+H).
• Example 70 5-Amino-l-[5-(5-tert- butyl-3 -methanesulfonylamino-2- methoxy-phenylcarbamoyl)-2-methyl- phenyl]-lH-[l,2,3]triazole-4-carboxylic acid (3 -dimethylamino-2,2-dimethyl- propyl)-amide, mp 194-197 °C. ESI MS (m/z 629, M+ ⁇ ).
• Example 71 5-Amino-l-[5-(5-tert- butyl-3 -methanesulfonylamino-2- methoxy-phenylcarbamoyl)-2-methyl- phenyl]-lH-[l,2,3]triazole-4-carboxylic acid ((S)-l ,2,2-trimethyl-propyl)- amide:m mp 208-210 °C. ESI MS (m/z 600, M+ ⁇ ).
• Example 72 3 -[( ⁇ 1 -[5 -(5 -tert-Butyl-3 -methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]- lH-[ 1 ,2,3]triazole-4-carbonyl ⁇ -amino)- methyl] -piperidine-1 -carboxylic acid tert-butyl ester, mp: 200-202 °C.
• ESI MS m/z 696, M- ⁇
• Example 73 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid (3- dimethylamino-2,2-dimethyI-propyl)-amide, ESI MS (m/z 614, 62, M+ ⁇ )
• Example 74 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-l ⁇ -[l,2,3]triazole-4-carboxylic acid (2- dimethylamino-2-methyl-propyl)-amide, mp: 190 - 293 °C. ESI MS (m/z 600, M+H)
• Example 75 l-[5-(5-tert-Butyl-3-metl ⁇ anesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]- lH-[ 1 ,2,3]triazole-4-carboxylic acid ((R)- 1 - ethyl-pyrrolidin-2-ylmethyl)-amide, mp: 209 - 211 °C.
• ESI MS m/z 612, 100, M+H
• Example 76 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]- lH-[ 1 ,2,3]triazole-4-carboxylic acid ((S)- 1 - ethyl-pyrrolidin-2-ylmethyl)-amide, mp: 205 - 207 °C.
• ESI MS m/z 612, 100, M+H
• Example 77 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2 ⁇ methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-l,2,3-triazole-4-carboxylic acid benzyl- methyl-amide, ESI MS (m/z 603, 100, M-H)
• Example 78 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxyphenyl- carbamoyl)-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid ((R)-3- dimethylamino-l-phenyl-propyl)-amide, mp: 110 -199 °C.
• ESI MS (m z 662, 100, M+H)
• Example 79 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid phenylamide, mp: 263 - 264 °C.
• Example 82 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid o- tolylamide, mp: 220 - 222 °C.
• ESI MS (m/z 591, 100, M+H)
• Example 83 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid p- tolylamide, mp: 268 - 270 °C.
• ESI MS (m/z 591, 100, M+H)
• Example 84 l- ⁇ 5-[3-Methanesulfonylamino-2-methoxy-5-(l-methyl- cyclopropyl)-phenylcarbamoyl]-2-methyl-phenyl ⁇ -lH-[l,2,3]triazole-4-carboxylic acid (2,2-dimethyl-propyl)-amide, mp: 226 - 228 °C (dec).
• ESI MS m/z 569, 100,
• Example 85 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-fluoro-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid benzylamide, mp: 209 - 210 °C.
• ESI MS (m/z 595, 100, M+H)
• Example 86 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid (1- pyridin-3-yl-ethyl)-amide trifluroacetic acid salt, mp: 220 - 223 °C (dec). ESI MS
• Example 88 1- [3 -(5 -tert-Butyl-3 -methanesulfonylamino-2-methoxy- phenylcarbamoyl)-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid benzylamide, mp:
• Example 90 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyl-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid ((S)-2- dimethylamino-l-phenyl-ethyl)-methyl-amide, mp: 101 - 111 °C.
• ESI MS m/z
• Example 22 50 mg, 0.1 mmol), EDC (21 mg, 0.11 mmol), and HOBt (16 mg, 0.12 mmol) were dissolved in dry DMF (0.75 mL).
• (R)-(+)-l-methylbenzylamine 39 ⁇ L, 0.3 mmol was added and the reaction stirred overnight. Water was added and a precipitate formed. The precipitate was collected by vacuum filtration and washed with water. The solid was dissolved in CH 2 Cl 2 and dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel (5% MeOH in CH 2 C1 2 ) to provide Example 91.
• ESI MS m/z 620, 100, M+H).
• Example 92 1- [5-(3-Amino-5-tert-butyl-2-methoxy-phenyIcarbamoyl)-2-methyl- phenyl]-l-H-[l,2,3]triazole-4-carboxylic acid (2,2-dimethyl-propyl)-amide
• Example 93 l-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy- phenylcarbamoyl)-2-methyI-phenyl]-lH-[l,2,3]triazoIe-4-carboxyIic acid (1- methyl-piperidin-3-ylmethyl)-amide
• Example 94 l-[5-(5-ter/-Butyl-3-methanesulfonylamino-2-methoxy- phenykarbamoyl)-2-methyI-phenyl]-lH-[l,2,3]triazole-4-carboxylic acid (1- methyl-piperidin-4-ylmethyl)-amide was prepared from 4-[( ⁇ l-[5-(5-tert-Butyl-3- methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-lH- [1 ,2,3]triazole-4-carbonyl ⁇ -amino)-methyl] -piperidine- 1 -carboxylic acid tert-butyl ester in a manner analogous to Example 93. mp: 202 - 203 °C. ESI MS (m/z 612, M+ ⁇ ).
• the compounds disclosed therein effectively block inflammatory cytokine production from cells.
• the inhibition of cytokine production is an attractive means for preventing and treating a variety of cytokine mediated diseases or conditions associated with excess cytokine production, e.g., diseases and pathological conditions involving inflammation.
• the compounds are useful for the treatment of diseases and conditions as described in the Background section, including the following conditions and diseases: osteoarthritis, atherosclerosis, contact dermatitis, bone reso ⁇ tion diseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus and insulin- dependent diabetes mellitus, rheumatoid arthritis, toxic shock syndrome, Alzheimer's disease, diabetes, inflammatory bowel diseases, acute and chronic pain as well as symptoms of inflammation and cardiovascular disease, stroke, myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonepliritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, syndromes associated with hemodialysis, leukopherisis, granulocyte trans
• the compounds of the invention are also p38 MAP kinase inhibitors. As disclosed in the Background of the Invention, the compounds of the invention will therefore be useful for treating oncological diseases. These diseases include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
• breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
• cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma and mesothelioma .
• brain cancers include, but are not limited to brain stem, optic and hypophtalmic glioma, cerebella and cerebral astrocytoma, medulloblastoma, ependymoma, as well as pituitary,neuroectodermal and pineal tumor.
• peripheral nervous system tumors include, but are not limited to neuroblastoma, ganglioneuroblastoma, and peripheral nerve sheath tumors.
• tumors of the endocrine and exocrine system include, but are not limited to thyroid carcinoma, adrenocortical carcinoma, pheochromocytoma, and carcinoid tumors.
• Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
• Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
• Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
• Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
• Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
• liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), hepatoblastoma, cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
• Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
• Head-and-neck cancers include, but are not limited to laryngeal/ hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lip and oral cavity cancer.
• Lymphomas include, but are not limited to AIDS-related lymphoma, non- Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous T-cell lymphoma, and lymphoma of the central nervous system.
• Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma,
• Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
• Plasma cell dyscrasias include, but are not limited to multiple myeloma, and Waldenstrom's macroglobulinemia. These disorders have been well characterized in man, but also exist with a similar etiology in other mammals, and can be treated by pharmaceutical compositions of the present invention.
• the compounds may be administered in any conventional dosage form in any conventional manner.
• Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation.
• the preferred modes of administration are oral and intravenous.
• the compounds may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
• combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
• the above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is tins regard may be made to Cappola et al.: US patent application no.
• the compounds may then be administered together in a single dosage form.
• the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof.
• the optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art.
• the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
• dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
• carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances.
• Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G.
• Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. Reference in this regard may also be made to US provisional application no. 60/339,249. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician.
• the inhibition of cytokine production can be observed by measuring inhibition of TNF ⁇ in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et al, 1995, J. Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all cone final). Assay was performed under sterile conditions; only test compound preparation was nonsterile.
• LPS lipopolysaccharide
• Assay was terminated by centrifuging plates 5 min, room temperature, 1600 rpm (400 x g); supernatants were transferred to clean 96 well plates and stored -80°C until analyzed for human TNF ⁇ by a commercially available ELISA kit (Biosource #KHC3015,
• IC 50 value is the concentration of the test compound that caused a 50% decrease in the maximal TNF ⁇ production.
• Preferred compounds have an IC 50 ⁇ 1 uM in this assay.

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