TREA

Substituted pyridine compounds and methods of use

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  • Patent Grant
  • 6022884
  • Patent Number
    6,022,884
  • Date Filed
    Tuesday, November 3, 1998
    25 years ago
  • Date Issued
    Tuesday, February 8, 2000
    24 years ago
Information
Abstract
Selected novel substituted pyridine compounds are effective for prophylaxis and treatment of diseases, such as TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases, and other maladies, such as pain and diabetes. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving inflammation, pain, diabetes, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Description

BACKGROUND OF THE INVENTION
The present invention comprises a new class of compounds useful in treating diseases, such as TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases and other maladies, such as pain, cancer, and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Interleukin-1 (IL-1) and Tumor Necrosis Factor .alpha. (TNF-.alpha.) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharide--LPS) or external cellular stress (e.g., osmotic shock and peroxide).
Elevated levels of TNF-.alpha. and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic .beta. cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-.alpha..
It has been reported that TNF-.alpha. plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-.alpha. levels increased in the contused hemisphere (Shohami et al., J. Cereb. Blood Flow Metab. 14, 615 (1994)). In a rat model of ischemia wherein the middle cerebral artery was occluded, the levels of TNF-.alpha. MRNA of TNF-.alpha. increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)). Administration of TNF-.alpha. into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels. TNF-.alpha. promotes the infiltration of other cytokines (IL-1.beta., IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein, Stroke 25, 1481 (1994)). TNF-.alpha. has also been implicated to play a role in type II diabetes (Endocrinol. 130, 43-52, 1992; and Endocrinol. 136, 1474-1481, 1995).
TNF-.alpha. appears to play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-.alpha. secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al., J. Immunol. 142, 431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role of TNF-.alpha. in the HIV associated states of cachexia and muscle degradation.
TNF-.alpha. is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-.alpha. may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6, and IL-8.
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. Viruses sensitive to TNF-.alpha. inhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.
TNF-.alpha. and IL-1 appear to play a role in pancreatic .beta. cell destruction and diabetes. Pancreatic .beta. cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic .beta. cells often accompanies type I diabetes. Pancreatic .beta. cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue. Thus glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing the glucagon receptors, it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than is TNF-.alpha. (Firestein, Am. J. Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531 (1994)).
IL-1 also appears to play a role in promoting certain viral life cycles. For example, cytokine-induced increase of HIV expression in a chronically infected macrophage line has been associated with a concomitant and selective increase in IL-1 production (Folks et al., J. Immunol. 136, 4049 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 553 (1983)) discussed the role of IL-1 in muscle degeneration.
In rheumatoid arthritis, both IL-1 and TNF-.alpha. induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen-induced arthritis (CIA) in rats and mice), intra-articular administration of TNF-.alpha. either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
Several approaches have been taken to block the effect of TNF-.alpha.. One approach involves using soluble receptors for TNF-.alpha. (e.g., TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-.alpha.-mediated disease states. A second approach to neutralizing TNF-.alpha. using a monoclonal antibody specific to TNF-.alpha., cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Maini et al., Immunological Reviews, pp. 195-223 (1995)). These approaches block the effects of TNF-.alpha. and IL-1 by either protein sequestration or receptor antagonism.
The present invention also relates to a method of treating cancer which is mediated by Raf and Raf-inducable proteins. Raf proteins are kinases activated in response to extracellular mitogenic stimuli such as PDGF, EGF, acidic FGF, thrombin, insulin or endothelin, and also in response to oncoproteins such as v-src, v-sis, and v-fms. Raf functions downstream of ras in signal transduction from the cellular membrane to the nucleus. Compounds in the present invention may be oncolytics through the antagonism of Raf kinase. Antisense constructs which reduce cellular levels of c-Raf and hence Raf activity inhibit the growth of rodent fibroblasts in soft agar, while exhibiting little or no general cytotoxicity. This inhibition of growth in soft agar is highly predictive of tumor responsiveness in whole animals. Moreover Raf antisense constructs have shown efficacy in reducing tumor burden in animals. Examples of cancers where Raf kinase is implicated by overexpression include cancers of the brain, larynx, lung, lymphatic system, urinary tract and stomach, including hystocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Other examples include cancers involving overexpression of upstream activators of Raf or Raf-activating oncogenes, including pancreatic and breast carcinoma.
Substituted imidazole and pyrrole compounds have been described for use in the treatment of cytokine mediated diseases by inhibition of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF. Substituted imidazoles for use in the treatment of cytokine mediated diseases have been described in U.S. Pat. No. 5,593,992; WO 93/14081; WO 97/18626; WO 96/21452; WO 96/21654; WO 96/40143; WO 97/05878; WO 97/05878; (each of which is incorporated herein by reference in its entirety). Substituted imidazoles for use in the treatment of inflammation has been described in U.S. Pat. No. 3,929,807 (which is incorporated herein by reference in its entirety). Substituted pyrrole compounds for use in the treatment of cytokine mediated diseases have been described in WO 97/05877; WO 97/05878; WO 97/16426; WO 97/16441; and WO 97/16442 (each of which is incorporated herein by reference in its entirety).
Substituted 2-aminopyridine compounds have been described as nitric oxide synthase inhibitors for use in the treatment of inflammation, neurodegenerative disorders and disorders of gastrointestinal motility in WO 96/18616 and WO 96/18617.
Diaryl substituted pyridine compounds have been described for use in the treatment of inflammation and inflammation related disorders in WO 96/24584 and U.S. Pat. No. 5,596,008.
U.S. Pat. No. 3,980,652, U.S. Pat. No. 3,991,057 and U.S. Pat. No. 4,002,629 describe piperazinyl substituted pyridine compounds for use as anti-inflammatory and cardiovascular agents.
JP 6135934 describes substituted pyridine compounds as phospholipase A2 inhibitors for use as antiphlogistic and anti-pancreatitis agents. GB 1,189,188 describes pyrimidin-2-ylamino substituted pyridine compounds as therapeutically valuable compounds for use as antiphlogistic agents.
BRIEF DESCRIPTION OF THE INVENTION
The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases and other maladies, such as pain, cancer, and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases, such as inflammatory, pain and diabetes diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure: ##STR1## wherein R.sup.1, R.sup.5, R.sup.6, R.sup.7, X and Y are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided compounds of the formula: ##STR2## or a pharmaceutically acceptable salt thereof, wherein X is O, S, S(O) , S(O).sub.2 or NR.sup.2 ; preferably, X is O, S or NR.sup.2 ; more preferably, X is O or NR.sup.2 ; most preferably, X is NR.sup.2 ;
Y is --C(O)--NR.sup.3 R.sup.4 or --NR.sup.4 --C(O)--R.sup.3 ;
R.sup.1 is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 -alkyl;
preferably, R.sup.1 is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.6 alkyl;
more preferably, R.sup.1 is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.4 alkyl;
provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R.sup.1 is 1-3, preferably, 1-2, and provided when Y is --NR.sup.4 --C(O)--R.sup.3 and X is O or S, R.sup.1 is other than a 2-pyrimidinyl radical;
more preferably, R.sup.1 is a radical of the formula ##STR3## wherein R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are each independently a radical of hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.4 alkyl; provided at least one of R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 is hydrogen; and provided that the combined total number of aryl and heteroaryl radicals in R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 is 0-1;
R.sup.2 is a hydrogen or alkyl radical; preferably, R.sup.2 is a hydrogen or C.sub.1 -C.sub.4 alkyl radical; more preferably, R.sup.2 is a hydrogen or C.sub.1 -C.sub.2 alkyl radical; more preferably, R.sup.2 is a hydrogen or methyl radical; and most preferably, R.sup.2 is a hydrogen radical;
R.sup.3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 -alkyl; preferably, R.sup.3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 --C.sub.1 -C.sub.6 alkyl;
more preferably, R.sup.3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 --C.sub.1 -C.sub.4 alkyl;
provided that the total number of aryl and heteroaryl radicals in R.sup.3 is 1-3, preferably, 1-2; and provided when Y is --C(O)--NR.sup.3 R.sup.4, R.sup.3 is other than a phenyl or naphthyl having an amino, nitro, cyano, carboxy or alkoxycarbonyl substituent bonded to the ring carbon atom adjacent to the ring carbon atom bonded to --NR.sup.4 --;
more preferably, R.sup.3 is a radical of the formula ##STR4## wherein U is C--R.sup.13 or N;
V and W are each independently C--R.sup.12 or N;
R.sup.11 and R.sup.13 are each independently a radical of hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R.sup.19 --Z.sup.19 --; preferably, R.sup.11 and R.sup.13 are each independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, azido, nitro, amidino, R.sup.19 --O--, R.sup.19 --S(O).sub.2 --, R.sup.19 --O--C(O)--, R.sup.19 --C(O)--, R.sup.19 --NR.sup.21 --C(O)-- or R.sup.19 --NR.sup.21 --S(O).sub.2 --;
each R.sup.12 is independently a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, R.sup.31 --Z.sup.31 -- or R.sup.31 --Z.sup.31 --C.sub.1 -C.sub.4 alkyl; preferably, each R.sup.12 is independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl, (methylamino)methyl or (dimethylamino)methyl;
provided that the combined total number of aryl and heteroaryl radicals in R.sup.11, R.sup.12 and R.sup.13 is 0-1;
wherein each R.sup.31 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl or heteroaryl-C.sub.1 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
each Z.sup.31 is independently --O--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
R.sup.4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R.sup.20 --Z.sup.20 -alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 haloalkyl of 1-3 halo radicals, C.sub.2 -C.sub.6 haloalkenyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl, heteroaryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.1 -C.sub.6 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 --C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, (C.sub.1 -C.sub.4 alkoxy)carbonylamino, (C.sub.1 -C.sub.4 alkoxy)carbonyl, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals or C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals;
more preferably, R.sup.4 is a radical of hydrogen, C.sub.l -C.sub.6 alkyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl, heteroaryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.2 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy;
more preferably, R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl, heteroaryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.2 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
more preferably, R.sup.4 is a radical of hydrogen, methyl or ethyl radical;
wherein each R.sup.18 is independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R.sup.18 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl or heteroaryl-C.sub.1 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, (C.sub.1 -C.sub.4 alkoxy)carbonylamino, (C.sub.1 -C.sub.4 alkoxy)carbonyl, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals or C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals;
more preferably, each R.sup.18 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.2 alkyl or heteroaryl-C.sub.1 -C.sub.2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy;
each Z.sup.18 is independently --O--, --S--, --S(O)--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --; preferably, each Z.sup.18 is independently --O--, --S--, --S(O).sub.2 --, --CO.sub.2 --, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
wherein each R.sup.19 is independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl or heteroaryl-C.sub.1 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, (C.sub.1 -C.sub.4 alkoxy)carbonylamino, (C.sub.1 -C.sub.4 alkoxy)carbonyl, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals or C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals;
more preferably, each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl or heteroaryl-C.sub.1 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, cyano, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy;
more preferably, each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl or heteroaryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
more preferably, each R.sup.19 is independently a hydrogen, methyl, ethyl, trifluoromethyl, phenyl, heteroaryl, phenylmethyl or heteroaryl-methyl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
each Z.sup.19 is independently --O--, --S--, --S(O)--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --; preferably, each Z.sup.19 is independently --O--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --; more preferably, each Z.sup.19 is independently --O--, --S(O).sub.2 --, --O--C(O)--, --C(O)--, --NR.sup.21 --C(O)-- or --NR.sup.21 --S(O).sub.2 --;
wherein each R.sup.20 is independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R.sup.20 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C.sub.1 -C.sub.4 alkyl or heteroaryl-C.sub.1 -C.sub.4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, (C.sub.1 -C.sub.4 alkoxy)carbonylamino, (C.sub.1 -C.sub.4 alkoxy)carbonyl, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals or C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals;
more preferably, each R.sup.20 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.2 alkyl or heteroaryl-C.sub.1 -C.sub.2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy;
more preferably, each R.sup.20 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, aryl, heteroaryl, aryl-C.sub.1 -C.sub.2 alkyl or heteroaryl-C.sub.1 -C.sub.2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
each Z.sup.20 is independently --O--, --S--, --S(O)--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --; preferably, each Z.sup.20 is independently --O-- or --NR.sup.21 --;
wherein each R.sup.21 is independently a hydrogen or alkyl radical; preferably, each R.sup.21 is independently a hydrogen or C.sub.1 -C.sub.4 alkyl radical; more preferably, each R.sup.21 is independently a hydrogen or methyl radical;
R.sup.5 and R.sup.6 are each independently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
preferably, R.sup.5 and R.sup.6 are each independently a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals, C.sub.1 -C.sub.4 aminoalkyl, (C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, di(C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, aminosulfonyl, C.sub.1 -C.sub.4 alkylaminosulfonyl, di(C.sub.1 --C.sub.4 alkyl)aminosulfonyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkylthiol, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkoxy)C.sub.1 -C.sub.4 alkyl, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical;
more preferably, R.sup.5 and R.sup.6 are each independently a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical;
more preferably, R.sup.5 and R.sup.6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C.sub.1 -C.sub.2 alkylamino, di(C.sub.1 -C.sub.2 alkyl)amino, hydroxy, methoxy or ethoxy radical; most preferably, R.sup.5 and R.sup.6 are each a hydrogen radical;
R.sup.7 is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
preferably, R.sup.7 is a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals, C.sub.1 -C.sub.4 aminoalkyl, (C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, di(C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, aminosulfonyl, C.sub.1 -C.sub.4 alkylaminosulfonyl, di(C.sub.1 -C.sub.4 alkyl)aminosulfonyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkylthiol, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkoxy)C.sub.1 -C.sub.4 alkyl, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical;
more preferably, R.sup.7 is a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical;
more preferably, R.sup.7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; most preferably, R.sup.7 is a hydrogen radical.
The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
Compounds of interest include the following:
2-cyclohexyloxy-5-(2-chlorophenylcarbonylamino)pyridine;
2-cyclohexyloxy-5-(2-methylphenylcarbonylamino)pyridine;
2-cyclohexyloxy-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-cyclohexyloxy-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2,4-dimethylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;
2-(2,4-dimethylphenoxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenoxy)-5-(2-methylphenylcarbonylamino) pyridine;
2-(2,6-dimethyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino) pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2-chlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;
2-(2-methylphenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methylphenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(2-methylphenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2-fluorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenoxy)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(1-naphthyloxy)-5-(2-methylphenylcarbonylamino) pyridine;
2-(1-naphthyloxy)-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-(1-naphthyloxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-((3,5-dimethyl-4-isoxazolyl)carbonylamino)pyridine;
2-(2-methyl-4-chlorophenylthiol)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenylthiol)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-cyclohexylamino-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-cyclohexylamino-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methylcyclohexylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methylcyclohexylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2-fluorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2-chlorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl carbonylamino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2,6-dimethylphenyl carbonylamino)pyridine; and
2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl aminocarbonyl)pyridine.
As utilized herein, the following terms shall have the following meanings:
"Alkyl", alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1-15 carbon atoms (C.sub.1 -C.sub.15), more preferably 1-8 carbon atoms (C.sub.1 -C.sub.8), even more preferably 1-6 carbon atoms (C.sub.1 -C.sub.6), yet more preferably 1-4 carbon atoms (C.sub.1 -C.sub.4), still more preferably 1-3 carbon atoms (C.sub.1 -C.sub.3), and most preferably 1-2 carbon atoms (C.sub.1 -C.sub.2). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
"Hydroxyalkyl", alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and most preferably one hydrogen radical is replaced by a hydroxyl radical. Examples of such radicals include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.
"Alkenyl", alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C.sub.2 -C.sub.15), more preferably 2-8 carbon atoms (C.sub.2 -C.sub.8), even more preferably 2-6 carbon atoms (C.sub.2 -C.sub.6), yet more preferably 2-4 carbon atoms (C.sub.2 -C.sub.4), and still more preferably 2-3 carbon atoms (C.sub.2 -C.sub.3). Examples of such alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
"Alkoxy", alone or in combination, means a radical of the type "R--O--" wherein "R" is an alkyl radical as defined above and "O" is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
"Alkoxycarbonyl", alone or in combination, means a radical of the type "R--O--C(O)--" wherein "R--O--" is an alkoxy radical as defined above and "C(O)" is a carbonyl radical.
"Alkoxycarbonylamino", alone or in combination, means a radical of the type "R--O--C(O)--NH--" wherein "R--O--C(O)" is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
"Alkylthio", alone or in combination, means a radical of the type "R--S--" wherein "R" is an alkyl radical as defined above and "S" is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
"Alkylsulfinyl", alone or in combination, means a radical of the type "R--S(O)--" wherein "R" is an alkyl radical as defined above and "S(O)" is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
"Alkylsulfonyl", alone or in combination, means a radical of the type "R--S(O).sub.2 --" wherein "R" is an alkyl radical as defined above and "S(O).sub.2 " is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
"Aryl", alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo fused or heterocyclo fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, oxo and the like. Examples of aryl radicals are phenyl, o-tolyl, 4-methoxyphenyl, 2-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 2-CF.sub.3 -phenyl, 2-fluorophenyl, 2-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 2-amino-3-(aminomethyl)phenyl, 6-methyl-3-acetamidophenyl, 6-methyl-2-aminophenyl, 6-methyl-2,3-diaminophenyl, 2-amino-3-methylphenyl, 4,6-dimethyl-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4-(2-methoxyphenyl)phenyl, 2-amino-1-naphthyl, 2-naphthyl, 3-amino-2-naphthyl, 1-methyl-3-amino-2-naphthyl, 2,3-diamino-1-naphthyl, 4,8-dimethoxy-2-naphthyl and the like.
"Aralkyl" and "arylalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.
"Aralkoxy", alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy and the like.
"Aralkoxycarbonyl", alone or in combination, means a radical of the type "R--O--C(O)--" wherein "R--O--" is an aralkoxy radical as defined above and "--C(O)--" is a carbonyl radical.
"Alkanoyl", alone or in combination, means a radical of the type "R--C(O)--" wherein "R" is an alkyl radical as defined above and "--C(O)--" is a carbonyl radical. Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
"Alkanoylamino", alone or in combination, means a radical of the type "R--C(O)--NH--" wherein "R--C(O)--" is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
"Aminocarbonyl", alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
"Aminosulfonyl", alone or in combination, means an amino substituted sulfonyl radical.
"Benzo", alone or in combination, means the divalent radical C.sub.6 H.sub.4 =derived from benzene. "Benzo fused" forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like.
"Bicyclic" as used herein is intended to include both fused ring systems, such as naphthyl and .beta.-carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl.
"Cycloalkyl", alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic carbocyclic alkyl radical, preferably monocyclic, containing preferably 5-12 carbon atoms (C.sub.5 -C.sub.12), more preferably 5-10 carbon atoms (C.sub.5 -C.sub.10), even more preferably 5-7 carbon atoms (C.sub.5 -C.sub.7), which is optionally benzo fused or heterocyclo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl, azabicyclo[3.2.1]octyl and the like.
"Heteroatoms" means nitrogen, oxygen and sulfur heteroatoms.
"Heterocyclo fused" forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.
"Heterocyclyl" means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. "Heterocyclyl" is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems. "Heterocyclyl" radicals may optionally be substituted on at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. More preferably, "heterocyclyl", alone or in combination, is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
"Heteroaryl" means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally saturated carbocyclic fused, preferably 3-4 carbon atoms (C.sub.3 -C.sub.4) to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 3-(2-methyl)pyridyl, 3-(4-trifluoromethyl)pyridyl, pyrimidinyl, 5-(4-trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.
"Heteroaralkyl" and "heteroarylalkyl," alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
"Halogen" and "halo", alone or in combination, means fluoro, chloro, bromo or iodo radicals.
"Haloalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
"Pharmacologically acceptable salt" means a salt prepared by conventional means, and are well known by those skilled in the art. The "pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of "pharmacologically acceptable salts," see infra and Berge et al, J. Pharm. Sci. 66, 1 (1977).
"Cytokine" means a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response. Examples of cytokines include but are not limited to interleukin 1 (IL-1), preferably IL-1.beta., interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-.alpha. (tumor necrosis factor-.alpha.).
"TNF, IL-1, IL-6, and/or IL-8 mediated disease or disease state" means all disease states wherein TNF, IL-1, IL-6, and/or IL-8 plays a role, either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1, IL-6, and/or IL-8 inducing another cytokine to be released. For example, a disease state in which IL-1 plays a major role, but in which the production of or action of IL-1 is a result of TNF, would be considered mediated by TNF.
"Leaving group" generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
"Protecting group" generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
The symbols used above have the following meanings: ##STR5##
Procedures for preparing the compounds of this invention are set forth below. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
Preparation of Compounds of Formula I
The compounds of the present invention represented by Formula I above can be prepared utilizing the following general procedures. Hetero-aromatic Nitrogen Compounds; Pyrroles and Pyridines: Schofield, Kenneth; Plenum Press, New York, N.Y.; (1967) and Advances in Nitrogen Heterocycles: JAI Press, Greenwich, Conn.; (1995) describe procedures and references that may be useful in preparing compounds of the present invention.
2-Halo-5-nitro-pyridine analogs (2) can be treated with the appropriate amine, alcohol, phenol, or thiol (R.sup.1 --X--H) in the presence of base or Cu(I) in an appropriate solvent, such as THF, DMF, DME, DMSO and the like, at a temperature from -20.degree. C. to 120.degree. C. to form 2-substituted-5-nitropyridines (3) (Scheme I). Reduction of the nitro group can be perfomed by treatment of (3) with hydrogen gas in the presence of palladium on carbon or Raney nickel, or alternatively, by treatment with SnCl.sub.2 in an alcoholic solvent and in the presence or absence of HCl to obtain 2-substituted-5-aminopyridines (4). The aminopyridines (4) may be alkylated using alkylhalides and an appropriate base or by reductive alkylation employing the appropriate aldehyde or ketone in the presence of a reducing agent, such as sodium triacetoxy borohydride, borane THF and the like, to form the substituted aminopyridines (5). Either (4) or (5) may be acylated with an appropriate acid halide (e.g., R.sup.3 C(O)Cl or R.sup.3 C(O)Br) in the presence of a base, such as pyridine, DMAP and the like, or alternatively may be acylated with an anhydride, either mixed or symmetrical, or alternatively may be acylated by treatment with the appropriate acid (R.sup.3 CO.sub.2 H) in the presence of a coupling agent such as a carbodiimide reagent to form the final product (1). Alternatively, substituted 2-bromo-5-nitropyridine analogs may be reduced to, substituted 2-bromo-5-aminopyridine analogs by the action of SnBr.sub.2 in methanolic solvent. Subsequent acylation with an appropriate activated ester (i.e.: R.sup.3 CO.sub.2 H in the presence of diisopropylcarbodiimide in methylene chloride as solvent) produces 2-bromopyridine-5-carboxamide compounds of structure (5a). Coupling of (5a) with an appropriate phenol in the presence of Cu(Ac).sub.2 and K.sub.2 CO.sub.3 in DMF at 140.degree. C. provides compounds of formula (1) where X=O. ##STR6##
6-Substituted-2-halo-5-nitro-pyridine analogs (6) may be prepared from 2,6-dichloro-5-nitropyridine according to the methods outlined in Scheme II. Treatment with one equivalent of an appropriate nucleophile of R.sup.7 or a precursor thereof (such as, HO.sup.--, RO.sup.--, AcS.sup.--, NC.sup.--, RS.sup.-- and the like) provides (6). Subsequent reaction to form (7) (treatment with R.sup.1 --X--H in the presence of base or Cu(I) in an appropriate solvent, such as THF, DMF, DME, DMSO and the like, at a temperature from -20.degree. C. to 120.degree. C.) and (8) (reduction of the nitro group and substitution with R.sup.4) is as described in Scheme I (cf. Colbry, N. L. et al.; J. Heterocyclic Chem., 21: 1521-1525 (1984); Matsumoto, Jun-ichi, et al.; J. Heterocyclic Chem., 21: 673-679 (1984)). (8) may be reacted with an acid halide or an activated ##STR7## ester as shown in Scheme I to provide compounds of formula (1). Where R.sup.7 =CN, compounds of formula (8) may be hydrolyzed to acids (R.sup.7 =CO.sub.2 H) of formula (9) using acidic media such as HBr and the like. Utilizing the appropriate N-protecting groups, acids of formula (9) may be transformed into esters, amides and alcohols. Compounds of formula (9) and derivatives described above may be be reacted with an acid halide or an activated ester as shown in Scheme I to provide compounds of formula (1). Compounds of formula (8), where R.sup.7 =--CN, may be reduced to the primary amine (R.sup.7 =--CH.sub.2 NH.sub.2) using reagents such as BH.sub.3 or hydrogen gas in the presence of palladium on carbon or Raney nickel. Subsequent manipulation and reaction of the primary amine may be performed in the presence of the pyridine-5-amine substituent due to it's greater reactivity. Specifically, compounds of formula (8) where R.sup.7 =--CH.sub.2 NH.sub.2 may be alkylated by treatment with an appropriate aldehyde or ketone in the presence of a reducing agent, such as sodium triacetoxy borohydride, or may be acylated by treatment with an appropriate activated ester, chloroformate, isocyanate and the like, or may be sulfonylated by treatment with an appropriate sulfonyl halide. Alternatively, substituted 3-aminopyridine intermediates may be prepared from the corresponding nicotinamide compound using Hofmann's reaction.
When R.sup.6 and/or R.sup.7 is an alkyl group, such as methyl, in compound (7), containing the appropriate protecting groups of or avoiding the presence of base sensitive groups, can be treated with strong base such as NaNH.sub.2, PhLi, NaH or the like at temperatures from -78.degree. C. to 22.degree. C. then treated with electrophiles, such as alkyl halides, aldehydes, ketones and the like (cf. Fuerst, Feustel; CHEMTECH; 10: 693-699 (1958); Nishigaki, S. et al.; Chem. Pharm. Bull.; 17: 1827-1831 (1969); Kaiser, Edwin M.; Tetrahedron; 39: 2055-2064 (1983)). Alternatively, the alkyl group may be halogenated and the haloalkyl group may be reacted with a nucleophile, such as an amino group, alkoxy, alkylthiol and the like.
6-Chloronicotinoyl chloride analogs (10) are treated with the appropriate amine (R.sup.3 R.sup.4 NH) in the presence of base in an appropriate solvent, such as dichloromethane, acetonitrile, DMF, THF and the like, at a temperature from -20.degree. C. to 120.degree. C. to form nicotinamides (11) as shown in Scheme III. Alternatively, 6-chloronicotinic acid analogs (12) may be coupled with the appropriate amine via an anhydride, either mixed or symmetrical, or alternatively by treatment with the appropriate amine in the presence of a coupling agent such as a carbodiimide reagent to form the amide (11). 6-Chloronicotinamide analogs (11) are treated with the appropriate R.sup.1 --X--H in the presence of absence of base, or Cu(I) in an appropriate solvent, such as pyridine, ethylene glycol, DMF, DME, DMSO and the like, at a temperature from -20.degree. C. to 180.degree. C. to form the final product (13). ##STR8##
Substituted halopyridines may be readily prepared from the corresponding pyridones using phosphorus oxychloride or pentachloride.
Amines of formula NHR.sup.1 R.sup.2 and NHR.sup.3 R.sup.4 are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials. For example, an amide, nitro or cyano group can be reduced under reducing conditions, such as in the prescence of a reducing agent like lithium aluminum hydride and the like, to form the corresponding amine. Alkylation and acylation of amino groups are well known in the art. Chiral and achiral substituted amines can be prepared from chiral amino acids and amino acid amides (for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like) using methods well known in the art, such as H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M. Freifelder and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 985, 1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W. Wheeler and D. O'Bannon, Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, O. Ichihara and I. Walters, J. Chem. Soc., Chem. Commun. 1153, 1993.
Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids, heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans, heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides, heterocyclylhalides, heteroarylhalides, and the like are commercially available or can be readily prepared from starting materials commercially available using standard methods well known in the art.
Thioether derivatives can be converted into the corresponding sulfone or sulfoxide by oxidizing the thioether derivative with a suitable oxidation agent in a suitable solvent. Suitable oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, oxone (potassium peroxy monosulfate), meta-chloroperoxybenzoic acid, periodic acid and the like, including mixtures thereof. Suitable solvents include acetic acid (for sodium meta-perborate) and, for other peracids, ethers such as THF and dioxane, and acetonitrile, DMF and the like, including mixtures thereof.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily prepared from known starting materials.
Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following adminstration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. The following Examples illustrate the preparation of compounds of the present invention and intermediates useful in preparing the compounds of the present invention.





EXAMPLE 1 ##STR9## Preparation of 2-(4-Chloro-2-methyl-phenoxy)-5-amino-pyridine
Step A: 2-(4-Chloro-2-methyl-phenoxy)-5-nitropyridine
4-Chloro-2-methylphenol (101 mg, 0.71 mmol) was dissolved in tetrahydrofuran (2.1 mL) and the solution was treated with sodium hydride (60% dispersed in mineral oil, 31 mg, 0.78 mmol). After stirring for 30 minutes at 22.degree. C., 2-chloro-5-nitropyridine (101 mg, 0.64 mmol) was added and the reaction mixture was heated to reflux for 1 hour. The solution was cooled to ambient temperature, quenched with saturated aqueous NH.sub.4 Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2.times. with saturated NaHCO.sub.3, saturated NaCl, dried over anhydrous Na.sub.2 SO.sub.4 and concentrated in vacuo.
Step B: 2-(4-Chloro-2-methyl-phenoxy)-5-amino-pyridine
2-(4-chloro-2-methyl-phenoxy)-5-nitropyridine (203 mg, 0.77 mmol) was dissolved in 95% ethanol (3 mL) and treated with 20% palladium hydroxide on carbon (50 mg). The reaction mixture was shaken in a hydrogen atmosphere (40 psi) for 1 hour. The solution was filtered through celite and concentrated in vacuo. MS (m/z): 234/236 (M+H).sup.+ ; C.sub.12 H.sub.11 N.sub.2 OCl requires 234.7.
EXAMPLE 2
The compounds listed in Table 1 were prepared from 2-chloro-5-nitropyridine and the appropriate alcohol, amine or thiol in the same manner as 2-(4-Chloro-2-methyl-phenoxy)-5-amino-pyridine was prepared.
TABLE 1______________________________________ MS (m/z)______________________________________2-(4-Chloro-2-methylphenoxy)-5-amino-pyridine 2352-(4-Chloro-2,6-dimethylphenoxy)-5-amino- 249pyridine2-(2-Methyl-pyridin-3-yloxy)-5-amino-pyridine 2012-(4-Fluoro-2-methylphenoxy)-5-amino-pyridine 2182-(2-Isopropylphenoxy)-5-amino-pyridine 2282-(1-Naphthyloxy)-5-amino-pyridine 2362-(Cyclohexyloxy)-5-amino-pyridine 1922-(2-Methylphenoxy)-5-amino-pyridine 2002-(2,4-Dimethylphenoxy)-5-amino-pyridine 2142-(4-Chlorophenoxy)-5-amino-pyridine 2222-(Phenoxy)-5-amino-pyridine 1862-(2-Methylcyclohexylamino)-5-amino-pyridine 2052-(Cyclohexylamino)-5-amino-pyridine 1912-(2-Methylanilino)-5-amino-pyridine 1992-(4-Chloro-2-methylanilino)-5-amino-pyridine 2332-(2,4-Dimethylanilino)-5-amino-pyridine 2122-(4-Chloro-2-methylthiophenoxy)-5-amino- 251pyridine______________________________________
EXAMPLE 3 ##STR10## Preparation of 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-amino-pyridine
Step A: 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-nitropyridine
Sodium hydride (60% in mineral oil, 1.08 g, 27 mmol) was washed 3.times. with hexanes then a solution of 4-chloro-2-methylphenol (3.50 g, 24.5 mmol) dissolved in tetrahydrofuran (40 mL) was added. The solution was stirred for 20 minutes then 2-chloro-3-methyl-5-nitropyridine (4.02 g, 23.3 mmol) was added and the reaction mixture was heated to reflux for 3 hours. After cooling, the mixture was concentrated in vacuo then dissolved in ethyl acetate and washed with water, 3.times. with saturated NaHCO.sub.3 and saturated NaCl then dried over Na.sub.2 SO.sub.4 and concentrated in vacuo.
Step B: 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-amino-pyridine
2- (4-chloro-2-methyl-phenoxy) -3-methyl-5-nitropyridine (5.8 g, 20.8 mmol) was dissolved in 95% ethanol (50 mL) and treated with 20% palladium hydroxide on carbon (350 mg). The reaction mixture was shaken in a hydrogen atmosphere (40 psi) for 1 hour. The solution was filtered through celite and concentrated in vacuo followed by chromatography on SiO.sub.2 using 1:1 ethyl acetate/hexanes as eluant. MS (m/z): 248/250 (M+H).sup.+ ; C.sub.13 H.sub.13 N.sub.2 OCl requires 248.7.
EXAMPLE 4
The compounds listed in Table 2 were prepared from substituted 2-chloro-5-nitropyridine and 4-chloro-2-methylphenol in the same manner as 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-amino-pyridine was prepared.
TABLE 2______________________________________ MS (m/z)______________________________________2-(4-Chloro-2-methyl-phenoxy)-4-methyl-5-amino- 249pyridine6-(4-Chloro-2-methyl-phenoxy)-2-methyl-3-amino- 249pyridine6-(4-Chloro-2-methyl-phenoxy)-2,3-diamino- 250pyridine______________________________________
EXAMPLE 5 ##STR11## Preparation of N-(2-(4-Chloro-2-methyl-phenoxy)-pyridin-5-yl)-benzamide
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (211 mg, 0.90 mmol) was dissolved in methylene chloride (2.7 mL) then treated with triethylamine (0.19 mL, 1.35 mmol) followed by benzoyl chloride (0.13 mL, 1.12 mmol). The reaction mixture was stirred for 3 hours at 22.degree. C. then saturated aqueous NaHCO.sub.3 was added and the mixture was stirred for another hour. The organic layer was separated and washed 2.times. with 6% aqueous NaHCO.sub.3, dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The product was recovered as a white solid. MS (m/z): 338/340 (M+H).sup.+ ; C.sub.19 H.sub.15 N.sub.2 O.sub.2 Cl requires 338.8.
EXAMPLE 6
The compounds listed in Table 3 were prepared from substituted 5-aminopyridine compounds and the appropriate acid chloride in the same manner as N-(2-(4-Chloro-2-methyl-phenoxy)-pyridin-5-yl)-benzamide was prepared.
TABLE 3______________________________________ MS (m/z)______________________________________2-(4-Chloro-2-methyl-phenoxy)-5-(3- 340pyridylcarbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 408dichlorophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-(4- 340pyridylcarbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((4- 369methoxyphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((4- 409pentylphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-(2- 389naphthylcarbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-(2- 345thienylcarbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((3,5-dimethyl- 3584-isoxazolyl) carbonylamino) pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((5- 383benzo[1,3]dioxol-yl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((5-tert-butyl- 3992-methyl-2H-pyrazol-3-yl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 395benzo[b]thiophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 369methoxyphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((3,5- 408dichlorophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 367dimethylphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 353methylphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 384nitrophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 397acetoxyphenyl)carbonylamino)pyridine2-(4-chloro-2,6-dimethylphenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)pyridine2-(4-chloro-2,6-dimethylphenoxy)-5-((2,6- 381dimethylphenyl)carbonylamino)pyridine2-(2-methyl-pyridin-3-yloxy)-5-((2,6- 374dichlorophenyl)carbonylamino)pyridine2-(2-methyl-pyridin-3-yloxy)-5-((2,6- 333dimethylphenyl)carbonylamino)pyridine2-(2-methyl-pyridin-3-yloxy)-5-((2- 319methylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2,6- 391dichlorophenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2,6- 350dimethylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2- 336methylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2- 390trifluoromethylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2- 340fluorophenyl)carbonylamino)pyridine2-(2-isopropylphenoxy)-5-((2,6- 401dichlorophenyl)carbonylamino)pyridine2-(2-isopropylphenoxy)-5-((2,6- 360dimethylphenyl)carbonylamino)pyridine2-(2-isopropylphenoxy)-5-((2- 346methylphenyl)carbonylamino)pyridine2-(1-naphthyloxy)-5-((2,6- 409dichlorophenyl)carbonylamino)pyridine2-(1-naphthyloxy)-5-((2,6- 368dimethylphenyl)carbonylamino)pyridine2-(1-naphthyloxy)-5-((2- 354methylphenyl)carbonylamino)pyridine2-(cyclohexyloxy)-5-((2,6- 365dichlorophenyl)carbonylamino)pyridine2-(cyclohexyloxy)-5-((2,6- 324dimethylphenyl)carbonylamino)pyridine2-(cyclohexyloxy)-5-((2- 331chlorophenyl)carbonylamino)pyridine2-(cyclohexyloxy)-5-((2- 310methylphenyl)carbonylamino)pyridine2-(2-methylphenoxy)-5-((2,6- 373dichlorophenyl)carbonylamino)pyridine2-(2-methylphenoxy)-5-((2,6- 332dimethylphenyl)carbonylamino)pyridine2-(2-methylphehoxy)-5-((2- 339chlorophenyl)carbonylamino)pyridine2-(2-methylphenoxy)-5-((2- 318methylphenyl)carbonylamino)pyridine2-(2,4-dimethylphenoxy)-5-((2,6- 387dichlorophenyl)carbonylamino)pyridine2-(2,4-dimethylphenoxy)-5-((2,6- 346dimethylphenyl)carbonylamino)pyridine2-(2,4-dimethylphenoxy)-5-((2- 353chlorophenyl)carbonylamino)pyridine2-(2,4-dimethylphenoxy)-5-((2- 332methylphenyl)carbonylamino)pyridine2-(4-chlorophenoxy)-5-((2,6- 394dichlorophenyl)carbonylamino)pyridine2-(4-chlorophenoxy)-5-((2,6- 353dimethylphenyl)carbonylamino)pyridine2-(2-methylcyclohexylamino)-5-((2,6- 378dichlorophenyl)carbonylamino)pyridine2-(2-methylcyclohexylamino)-5-((2- 323methylphenyl)carbonylamino)pyridine2-(cyclohexylamino)-5-((2,6- 364dichlorophenyl)carbonylamino)pyridine2-(cyclohexylamino)-5-((2,6- 323dimethylphenyl)carbonylamino)pyridine2-(cyclohexylamino)-5-((2- 309methylphenyl)carbonylamino)pyridine2-(2-methylamino)-5-((2,6- 372dichlorophenyl)carbonylamino)pyridine2-(2-methylamino)-5-((2,6- 331dimethylphenyl) carbonylamino) pyridine2-(2-methylanilino)-5-((2- 317methylphenyl)carbonylamino)pyridine2-(4-chloro-2-methylanilino)-5-((2,6- 407dichlorophenyl)carbonylamino)pyridine2-(4-chloro-2-methylanilino)-5-((2,6- 366dimethylphenyl)carbonylamino)pyridine2-(4-chloro-2-methylanilino)-5-((2- 352methylphenyl)carbonylamino)pyridine2-(2,4-dimethylanilino)-5-((2,6- 386dichlorophenyl)carbonylamino)pyridine2-(2,4-dimethylanilino)-5-((2,6- 345dimethylphenyl)carbonylamino)pyridine2-(2,4-dimethylamino)-5-((2- 331methylphenyl)carbonylamino)pyridine2-(2,4-dimethylamino)-5-((2- 352chlorophenyl)carbonylamino)pyridine2-(2,4-dimethylanilino)-5-((2- 335fluorophenyl)carbonylamino)pyridine2-(4-chloro-2-methyl-thiophenyl)-5-((2,6- 424dichlorophenyl)carbonylamino)pyridine2-(4-chloro-2-methyl-thiophenyl)-5-((2,6- 383dimethylphenyl)carbonylamino)pyridine2-(4-chloro-2-methyl-thiophenyl)-5-((2- 369methylphenyl)carbonylamino)pyridine______________________________________
EXAMPLE 7
The compounds listed in Table 4 were prepared from substituted 5-aminopyridine compounds and the appropriate acid chloride in the same manner as N-(2-(4-Chloro-2-methyl-phenoxy)-pyridin-5-yl)-benzamide was prepared.
TABLE 4______________________________________ MS (m/z)______________________________________2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 422dichlprophenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 387chlorophenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 367methylphenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 332dimethylphenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)-4-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2-fluoro-6- 439trifluoromethylphenyl)carbonylamino)-4-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,4,6- 479triisopropylphenyl)carbonylamino)-4-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 367methylphenyl)carbonylamino)-6-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 387chlorophenyl)carbonylamino)-6-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)-6-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 423dichlorophenyl)carbonylamino)-6-amino-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 388chlorophenyl)carbonylamino)-6-amino-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 382dimethylphenyl)carbonylamino)-6-amino-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 368methylphenyl)carbonylamino)-6-amino-pyridine______________________________________
EXAMPLE 8 ##STR12## Preparation of 2-Amino-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-benzamide
N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-2-nitro-benzamide (301 mg, 0.7 mmol) was dissolved in 95% ethanol (4 mL) and treated with 20% palladium hydroxide on carbon (Pearlman's catalyst, 50 mg) and subjected to a hydrogen atmosphere (40 psi) for 2 hours. The catalyst was removed by filtration and the solvents were removed in vacuo. The product was purified by chromatography on SiO2 using 1:1 ethyl acetate/hexanes as eluent. MS (m/z) 353/355 (M+H).sup.+ ; C.sub.19 H.sub.16 N.sub.3 O.sub.2 Cl requires 353.8.
EXAMPLE 9 ##STR13## Preparation of N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-2-hydroxy-benzamide
Acetic acid 2-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-ylcarbamoyl)-phenyl ester (304 mg, 0.77 mmol) dissolved in tetrahydrofuran (3.8 mL) was treated with an aqueous lithium hydroxide solution (1.0 M, 3.8 mL, 3.8 mmol). The solution was stirred for 30 minutes at 22.degree. C. then quenched with aqueous saturated NH.sub.4 Cl. The mixture was diluted with ethyl acetate then the organics were washed with water, 2.times. saturated NaHCO.sub.3, saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. MS (m/z): 354/356 (M+H).sup.+ ; C.sub.19 H.sub.15 N.sub.2 O.sub.3 Cl requires 354.8.
EXAMPLE 10 ##STR14## Preparation of 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine
Step A: 2-(Cyclohexylamino)-5-nitro-pyridine
Sodium hydride (60% dispersion in mineral oil, 1.99 g, 49.8 mmol) was washed 3.times. with hexanes then a solution of cyclohexylamine (3.8 mL, 33.2 mmol) dissolved in tetrahydrofuran (50 mL) was added. After stirring for 30 minutes at 22.degree. C., 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol) was added and the reaction mixture was heated to reflux for 3 hours. The solution was cooled to ambient temperature, quenched with saturated aqueous NH.sub.4 Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2.times. with saturated NaHCO.sub.3, saturated NaCl, dried over anhydrous Na.sub.2 SO.sub.4 and concentrated in vacuo. The product was recovered as a brown oil.
Step B: 2-(N-Cyclohexyl-N-methylamino)-5-nitro-pyridine
Sodium hydride (60% dispersion in mineral oil, 0.38 g, 9.48 mmol) was washed 3.times. with hexanes then a solution of 2-cyclohexylamino-5-nitropyridine (1.88 g, 8.5 mmol) dissolved in dimethylformamide (20 mL) was added. After stirring for 30 minutes at 22.degree. C., the reaction mixture was cooled to 0.degree. C. and methyl iodide (0.55 mL, 8.9 mmol) was added. The solution was stirred for 1.5 hours at 0.degree. C. followed by quenching with saturated aqueous NH.sub.4 Cl. The reaction mixture was diluted with ethyl acetate and extracted 5.times. with water (200 mL), saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated in vacuo oil was chromatographed on SiO.sub.2 using 2:1 hexanes/ethyl acetate as eluent.
Step C: 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine
Cyclohexyl-methyl-(5-nitro-pyridin-2-yl)-amine (1.72 g, 7.3 mmol) was dissolved in ethanol (80 mL) and treated with 20% palladium hydroxide on carbon (Pearlman's catalyst, 0.5 g) and the mixture was shaken under a hydrogen atmosphere (50 psi) for 6 hours. The catalyst was removed by filtration through celite then the filtrate was concentrated in vacuo and the resultant oil was chromatographed on SiO.sub.2 using 1:1 ethyl acetate/hexanes as eluent. MS (m/z): 206 (M+H).sup.+ ; C.sub.12 H.sub.19 N.sub.3 requires 205.3.
EXAMPLE 11 ##STR15## Preparation of 2-(N-(2,4-dimethylphenyl)-N-methylamino)-5-amino-pyridine
2-(N-(2,4-dimethylphenyl)-N-methylamino)-5-amino-pyridine was prepared from 1-amino-2,4-dimethylbenzene and 2-chloro-5-nitropyridine in the same manner as 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine was prepared.
EXAMPLE 12 ##STR16## Preparation of 2,6-Dichloro-N-(2-(N'-cyclohexyl-N'-methylamino)-pyridin-5-yl)-benzamide
2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine (26 mg, 0.13 mmol) dissolved in methylene chloride (0.25 mL) was treated with triethylamine (0.026 mL, 0.18 mmol) followed by a solution of 2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol) dissolved in methylene chloride (0.15 mL). The reaction mixture was shaken at 22.degree. C. for 18 hours followed by quenching with saturated aqueous NH.sub.4 Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na.sub.2 SO.sub.4 then concentrated in vacuo. The crude product was purified by chromatography on SiO.sub.2 using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 378/380 (M+H).sup.+ ; C.sub.19 H.sub.21 N.sub.3 OCl requires 377.
EXAMPLE 13
The compounds listed in Table 5 were prepared from substituted 5-aminopyridine compounds and the appropriate acid chloride in the same manner as 2,6-Dichloro-N-(2-(N'-cyclohexyl-N'-methylamino)-pyridin-5-yl)-benzamide was prepared.
TABLE 5______________________________________ MS (m/z)______________________________________2-(N-cyclohexyl-N-methylamino)-5-((2,6- 378dichlorophenyl)carbonylamino)pyridine2-(N-cyclohexyl-N-methylamino)-5-((2- 344chlorophenyl)carbonylamino)pyridine2-(N-cyclohexyl-N-methylamino)-5-((2- 323methylphenyl)carbonylamino)pyridine2-(N-cyclohexyl-N-methylamino)-5-((2,6- 337dimethylphenyl)carbonylamino)pyridine2-(2,4-dimethylphenyl)-5-((2,6- 359dimethylphenyl)carbonylamino)pyridine2-(2,4-dimethylphenyl)-5-((2- 345methylphenyl)carbonylamino)pyridine2-(2,4-dimethylphenyl)-5-((2- 366chlorophenyl)carbonylamino)pyridine2-(2,4-dimethylphenyl)-5-((2- 349fluorophenyl)carbonylamino)pyridine2-(2,4-dimethylphenyl)-5-((2,6- 400dichlorophenyl)carbonylamino)pyridine______________________________________
EXAMPLE 14 ##STR17## Preparation of 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (2.15 g, 9.16 mmol) was combined with powdered sodium hydroxide (1.46 g, 36.6 mmol), potassium carbonate (1.27 g, 9.16 mmol), tetrabutyl ammonium bromide (60 mg, 0.18 mmol) and toluene (10 mL) was stirred for 1 hour at 35.degree. C. A solution of dimethyl sulfate (0.91 mL, 9.6 mmol) dissolved in toluene (5 mL) was added slowly. The mixture was heated at 35.degree. C. for 20 hours. After cooling, the solids were removed by filtration and the solvent was concentrated in vacuo. The desired material was purified by chromatography on SiO.sub.2 using 30% ethyl acetate/hexanes as eluent. MS (m/z): 248/250 (M+H).sup.+ ; C.sub.13 H.sub.13 N.sub.2 OCl requires 249.
EXAMPLE 15 ##STR18## Preparation of 2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide
2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine (32 mg, 0.13 mmol) dissolved in methylene chloride (0.25 mL) was treated with triethylamine (0.026 mL, 0.18 mmol) followed by a solution of 2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol) dissolved in methylene chloride (0.15 mL). The reaction mixture was shaken at 22.degree. C. for 18 hours followed by quenching with saturated aqueous NH.sub.4 Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na.sub.2 SO.sub.4 then concentrated in vacuo. The crude product was purified by chromatography on SiO.sub.2 using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 422/424 (M+H).sup.+ ; C.sub.20 H.sub.15 N.sub.2 O.sub.2 Cl.sub.3 requires 422.
EXAMPLE 16 ##STR19## Preparation of 2-Chloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide
2-Chloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared from 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine and 2-chlorobenzoyl chloride in the same manner as 2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared.
EXAMPLE 17 ##STR20## Preparation of 2-Methyl-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide
2-Methyl-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared from 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine and 2-methylbenzoyl chloride in the same manner as 2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared.
EXAMPLE 18 ##STR21## General procedure for the synthesis of 2-substituted-5-acylamino-pyridines
A solution of the 2-substituted-5-aminopyridine (10 mmol), triethylamine (20 mmol) and an acid chloride (20 mmol) in ethanol free chloroform (250 mL) was shaken for 16 hours. The mixture was then diluted with saturated aqueous sodium hydrogencarbonate (50 mL) and dichloromethane (500 mL), and shaken for 30 min. The mixture was then filtered through anhydrous magnesium sulfate, washing with dichloromethane (250 mL). Concentration of the filtrate under reduced pressure afforded the desired 2-substituted-5-acylamino-pyridines.
The compounds listed in Table 6 were prepared from substituted 5-aminopyridine compounds and the appropriate acid chloride according to the general procedure above.
TABLE 6______________________________________ MSR.sup.1 X R.sup.3 (m/z)______________________________________4-chloro-2- 4-biphenyl 415methylphenoxy4-chloro-2- 3,4-dimethoxyphenyl 319methylphenoxy4-chloro-2- 2-(trifluoromethyl)phenyl 407methylphenoxy4-chloro-2- 2,4-difluorophenyl 375methylphenoxy4-chloro-2- 4-cyanophenyl 364methylphenoxy4-chloro-2- 3-(trifluoromethyl)phenyl 407methylphenoxy4-chloro-2- 3-cyanophenyl 364methylphenoxy4-chloro-2- 2-naphthyl 389methylphenoxy4-chloro-2- 2-methoxyphenyl 369methylphenoxy4-chloro-2- 3,4,5-trimethylphenyl 429methylphenoxy4-chloro-2- 4-nitrophenyl 384methylphenoxy4-chloro-2- 3,4-dichlorophenyl 408methylphenoxy4-chloro-2- 5-nitrofuran-2-yl 374methylphenoxy4-chloro-2- 3-bromophenyl 418methylphenoxy4-chloro-2- 3-pyridyl 340methylphenoxy4-chloro-2- 2-ethoxynaphth-1-yl 433methylphenoxy4-chloro-2- 2,3-dichlorophenyl 408methylphenoxy4-chloro-2- 3-nitrophenyl 384methylphenoxy4-chloro-2- 6-chloropyrid-3-yl 374methylphenoxy4-chloro-2- 4-(trifluoromethoxy)phenyl 423methylphenoxy4-chloro-2- 2-fluoro-4- 425methylphenoxy (trifluoromethyl)phenyl4-chloro-2- 2-acetoxyphenyl 397methylphenoxy4-chloro-2- 5-methylisoxazol-3-yl 344methylphenoxy4-chloro-2- 2-(phenylthio)pyrid-3-yl 448methylphenoxy4-chloro-2- 2-(trifluoromethoxy)phenyl 423methylphenoxy4-chloro-2- 1-phenyl-5-propyl-pyrazin- 447methylphenoxy 4-yl4-chloro-2- 2-ethoxyphenyl 383methylphenoxy4-chloro-2- 3-chlorothien-2-yl 379methylphenoxy4-chloro-2- 3-bromothien-2-yl 424methylphenoxy4-chloro-2- 1-(2-(2-methyl)propyl)-3- 399methylphenoxy methylpyrazol-5-yl4-chloro-2- 3,5-dichlorophenyl 408methylphenoxy4-chloro-2- 2-(propylthio)pyridin-3-yl 414methylphenoxy4-chloro-2- 2-(ethylthio)pyridin-3-yl 400methylphenoxy4-chloro-2- 3-bromopyridin-5-yl 419methylphenoxy4-chloro-2- 4-methyl-1,2,3-thiadiazol- 361methylphenoxy 5-yl4-chloro-2- 1-methyl-3-(2-(2- 399methylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-2- 3-chlorobenzo[b]thiophen- 429methylphenoxy 2-yl4-chloro-2- 4-chlorophenyl 373methylphenoxy4-chloro-2- 4-methyl-2-phenyl-1,2,3- 420methylphenoxy triazol-5-yl4-chloro-2- benzo[b]thiophen-2-yl 395methylphenoxy4-chloro-2- 3,4-dimethylphenyl 367methylphenoxy4-chloro-2- 2-(phenoxy)pyridin-3-yl 432methylphenoxy4-chloro-2- 2-(methylthio)pyridin-3-yl 386methylphenoxy4-chloro-2- 5-methyl-3-phenylisoxazol- 420methylphenoxy 4-yl4-chloro-2- 4-chloro-1,3-dimethyl 442methylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 388methylphenoxy 4-yl4-chloro-2- 3,5-dimethylisoxazol-4-yl 358methylphenoxy4-chloro-2- 1-naphthyl 389methylphenoxy4-chloro-2- 2-fluorophenyl 357methylphenoxy4-chloro-2- 4-propylphenyl 381methylphenoxy4-chloro-2- 4-(trifluoromethyl)phenyl 407methylphenoxy4-chloro-2- 3-fluorophenyl 357methylphenoxy4-chloro-2- 2,6-difluorophenyl 375methylphenoxy4-chloro-2- 2-chlorophenyl 373methylphenoxy4-chloro-2- 3-(chloromethyl)phenyl 387methylphenoxy4-chloro-2- 4-(2-(2-methyl) 395methylphenoxy propyl)phenyl4-chloro-2- 3-chlorophenyl 373methylphenoxy4-chloro-2- 2-nitrophenyl 384methylphenoxy4-chloro-2- 3,5-dimethoxyphenyl 399methylphenoxy4-chloro-2- 2,6-dichlorophenyl 408methylphenoxy4-chloro-2- 2,4-dichlorophenyl 408methylphenoxy4-chloro-2- 4-fluorophenyl 357methylphenoxy4-chloro-2- 4-butylphenyl 395methylphenoxy4-chloro-2- 2-methylphenyl 353methylphenoxy4-chloro-2- phenyl 339methylphenoxy4-chloro-2- 4-ethylphenyl 367methylphenoxy4-chloro-2- 2,3-difluorophenyl 375methylphenoxy4-chloro-2- 2,6-dimethoxyphenyl 399methylphenoxy4-chloro-2- 2,5-difluorophenyl 375methylphenoxy4-chloro-2- 4-ethoxyphenyl 383methylphenoxy4-chloro-2- 2,4,6-trichlorophenyl 442methylphenoxy4-chloro-2- 3-methylphenyl 353methylphenoxy4-chloro-2- 2-fluoro-5- 425methylphenoxy (trifluoromethyl)phenyl4-chloro-2- 3-methoxyphenyl 369methylphenoxy4-chloro-2- thien-2-yl 345methylphenoxy4-chloro-2- 2-bromophenyl 418methylphenoxy4-chloro-2- 4-bromophenyl 418methylphenoxy4-chloro-2- 4-fluoro-3- 425methylphenoxy (trifluoromethyl)phenyl4-chloro-2- 3-(trifluoromethoxy)phenyl 423methylphenoxy4-chloro-2- 9-fluorenon-4-yl 441methylphenoxy4-chloro-2- isoxazol-5-yl 330methylphenoxy4-chloro-2- benzofuroxan-5-yl 397methylphenoxy4-chloro-2- 2-chloropyrid-3-yl 374methylphenoxy4-chloro-2- 3,5-difluorophenyl 375methylphenoxy4-chloro-2- 2-(4- 446methylphenoxy methylphenoxy)pyridin-3-yl4-chloro-2- pyridin-4-yl 340methylphenoxy4-chloro-2- anthraquinon-2-yl 469methylphenoxy4-chloro-2- 2-iodophenyl 465methylphenoxy1-naphthoxy 4-biphenyl 4161-naphthoxy 3,4-dimethoxyphenyl 4001-naphthoxy 2-(trifluoromethyl)phenyl 4081-naphthoxy 2,4-difluorophenyl 3761-naphthoxy 4-cyanophenyl 3651-naphthoxy 3-(trifluoromethyl)phenyl 4081-naphthoxy 3-cyanophenyl 3651-naphthoxy 2-naphthyl 3901-naphthoxy 2-methoxyphenyl 3701-naphthoxy 3,4,5-trimethylphenyl 4301-naphthoxy 4-nitrophenyl 3851-naphthoxy 3,4-dichlorophenyl 4091-naphthoxy 5-nitrofuran-2-yl 3751-naphthoxy 3-bromophenyl 4191-naphthoxy 3-pyridyl 3411-naphthoxy 2-ethoxynaphth-1-yl 3341-naphthoxy 2,3-dichlorophenyl 4091-naphthoxy 3-nitrophenyl 3851-naphthoxy 6-chloropyrid-3-yl 3761-naphthoxy 4-(trifluoromethoxy)phenyl 4241-naphthoxy 2-fluoro-4- 426 (trifluoromethyl)phenyl1-naphthoxy 3-bromothiophenyl 4251-naphthoxy 2-acetoxyphenyl 3981-naphthoxy 5-methylisoxazol-3-yl 3451-naphthoxy 2-(phenylthio)pyrid-3-yl 4491-naphthoxy 2-(trifluoromethoxy)phenyl 4241-naphthoxy 1-phenyl-5-propylpyrazin- 448 4-yl1-naphthoxy 2-ethoxyphenyl 3841-naphthoxy 3-chlorothien-2-yl 3811-naphthoxy 1-(2-(2-methyl)propyl)-3- 400 methylpyrazol-5-yl1-naphthoxy 3,5-dichlorophenyl 4091-naphthoxy 2-(propylthio)pyridin-3-yl 4151-naphthoxy 2-(ethylthio)pyridin-3-yl 4011-naphthoxy 3-bromopyridin-5-yl 4201-naphthoxy 4-methyl-1,2,3-thiadiazol- 362 5-yl1-naphthoxy 1-methyl-3-(2-(2- 400 methyl)propyl)pyrazol-5-yl1-naphthoxy 3-chlorobenzo[b]thiophen- 431 2-yl1-naphthoxy 4-chlorophenyl 3751-naphthoxy 4-methyl-2-phenyl-1,2,3- 421 triazol-5-yl1-naphthoxy benzo[b]thiophen-2-yl 3961-naphthoxy 3,4-dimethylphenyl 3681-naphthoxy 2-(phenoxy)pyridin-3-yl 4331-naphthoxy 2-(methylthio)pyridin-3-yl 3871-naphthoxy 5-methyl-3-phenylisoxazol- 421 4-yl1-naphthoxy 4-chloro-1,3-dimethyl 444 pyrazolo[3,4-b]pyridin-3- yl1-naphthoxy 2-chloro-6-methylpyridin- 390 4-yl1-naphthoxy 3,5-dimethylisoxazol-4-yl 3591-naphthoxy 1-naphthyl 3901-naphthoxy 2-fluorophenyl 3581-naphthoxy 4-propylphenyl 3821-naphthoxy 4-(trifluoromethyl)phenyl 4081-naphthoxy 3-fluorophenyl 3581-naphthoxy 2,6-difluorophenyl 3761-naphthoxy 2-chlorophenyl 3751-naphthoxy 3-(chloromethyl)phenyl 3891-naphthoxy 4-(2-(2- 396 methyl)propyl)phenyl1-naphthoxy 3-chlorophenyl 3751-naphthoxy 2-nitrophenyl 3851-naphthoxy 3,5-dimethoxyphenyl 4001-naphthoxy 2,6-dichlorophenyl 4091-naphthoxy 2,4-dichlorophenyl 4091-naphthoxy 4-fluorophenyl 3581-naphthoxy 4-butylphenyl 3961-naphthoxy 2-methylphenyl 3541-naphthoxy phenyl 3401-naphthoxy 4-ethylphenyl 3681-naphthoxy 2,3-difluorophenyl 3761-naphthoxy 2,6-dimethoxyphenyl 4001-naphthoxy 3,4-difluorophenyl 3761-naphthoxy 2,5-difluorophenyl 3761-naphthoxy 4-ethoxyphenyl 3841-naphthoxy 2,4,6-trichlorophenyl 4441-naphthoxy 3-methylphenyl 3541-naphthoxy 2-fluoro-5- 426 (trifluoromethyl)phenyl1-naphthoxy 3-methoxyphenyl 3701-naphthoxy thien-2-yl 3461-naphthoxy 2-bromophenyl 4191-naphthoxy 4-bromophenyl 4191-naphthoxy 4-fluoro-3- 426 (trifluoromethyl)phenyl1-naphthoxy 3-(trifluoromethoxy)phenyl 4241-naphthoxy 9-fluorenon-4-yl 4421-naphthoxy isoxazol-5-yl 3311-naphthoxy benzofuroxan-5-yl 3981-naphthoxy 2-chloropyrid-3-yl 3761-naphthoxy 3,5-difluorophenyl 3761-naphthoxy 2-(4- 447 methylphenoxy)pyridin-3-yl1-naphthoxy pyridin-4-yl 3411-naphthoxy anthraquinon-2-yl 4701-naphthoxy 2-iodophenyl 4662-(2-propyl)phenoxy 4-biphenyl 4082-(2-propyl)phenoxy 3,4-dimethoxyphenyl 3922-(2-propyl)phenoxy 2-(trifluoromethyl)phenyl 4002-(2-propyl)phenoxy 2,4-difluorophenyl 3682-(2-propyl)phenoxy 4-cyanophenyl 3572-(2-propyl)phenoxy 3-(trifluoromethyl)phenyl 4002-(2-propyl)phenoxy 3-cyanophenyl 3572-(2-propyl)phenoxy 2-naphthyl 3822-(2-propyl)phenoxy 2-methoxyphenyl 3622-(2-propyl)phenoxy 3,4,5,-trimethylphenyl 4222-(2-propyl)phenoxy 4-nitrophenyl 3772-(2-propyl)phenoxy 3,4-dichlorophenyl 4012-(2-propyl)phenoxy 5-nitrofuran-2-yl 3672-(2-propyl)phenoxy 3-bromophenyl 4112-(2-propyl)phenoxy 3-pyridyl 3332-(2-propyl)phenoxy 2-ethoxynaphth-1-yl 4262-(2-propyl)phenoxy 2,3-dichlorophenyl 4012-(2-propyl)phenoxy 3-nitrophenyl 3772-(2-propyl)phenoxy 6-chloropyrid-3-yl 3682-(2-propyl)phenoxy 4-(trifluoromethoxy)phenyl 4162-(2-propyl)phenoxy 2-fluoro-4- 418 (trifluoromethyl)phenyl2-(2-propyl)phenoxy 3-bromothiophenyl 4172-(2-propyl)phenoxy 2-acetoxyphenyl 3902-(2-propyl)phenoxy 5-methylisoxazol-3-yl 3372-(2-propyl)phenoxy 2-(phenylthio)pyrid-3-yl 4422-(2-propyl)phenoxy 2-(trifluoromethoxy)phenyl 4162-(2-propyl)phenoxy 1-phenyl-5-propylpyrazin- 441 4-yl2-(2-propyl)phenoxy 2-ethoxyphenyl 3762-(2-propyl)phenoxy 3-chlorothien-2-yl 3732-(2-propyl)phenoxy 1-(2-(2-methyl)propyl)-3- 392 methylpyrazol-5-yl2-(2-propyl)phenoxy 3,5-dichlorophenyl 4012-(2-propyl)phenoxy 2-(propylthio)pyridin-3-yl 4072-(2-propyl)phenoxy 2-(ethylthio)pyridin-3-yl 3932-(2-propyl)phenoxy 3-bromopyridin-5-yl 4122-(2-propyl)phenoxy 4-methyl-1,2,3-thiadiazol- 354 5-yl2-(2-propyl)phenoxy 1-methyl-3-(2-(2- 392 methyl)propyl)pyrazol-5-yl2-(2-propyl)phenoxy 3-chlorobenzo[b]thiophen- 423 2-yl2-(2-propyl)phenoxy 4-chlorophenyl 3672-(2-propyl)phenoxy 4-methyl-2-phenyl-1,2,3- 413 triazol-5-yl2-(2-propyl)phenoxy benzo[b]thiophen-2-yl 3882-(2-propyl)phenoxy 3,4-dimethylphenyl 3602-(2-propyl)phenoxy 2-(phenoxy)pyridin-3-yl 4252-(2-propyl)phenoxy 2-(methylthio)pyridin-3-yl 3792-(2-propyl)phenoxy 5-methyl-3-phenylisoxazol- 413 4-yl2-(2-propyl)phenoxy 4-chloro-1,3- 436 dimethylpyrazolo[3,4- b]pyridin-3-yl2-(2-propyl)phenoxy 2-chloro-6-methylpyridin- 382 4-yl2-(2-propyl)phenoxy 3,5-dimethylisoxazol-4-yl 3512-(2-propyl)phenoxy 1-naphthyl 3822-(2-propyl)phenoxy 2-fluorophenyl 3502-(2-propyl)phenoxy 4-propylphenyl 3742-(2-propyl)phenoxy 4-(trifluoromethyl)phenyl 4002-(2-propyl)phenoxy 3-fluorophenyl 3502-(2-propyl)phenoxy 2,6-difluorophenyl 3682-(2-propyl)phenoxy 2-chlorophenyl 3672-(2-propyl)phenoxy 3-(chloromethyl)phenyl 3812-(2-propyl)phenoxy 4-(2-(2- 388 methyl)propyl)phenyl2-(2-propyl)phenoxy 3-chlorophenyl 3672-(2-propyl)phenoxy 2-nitrophenyl 3772-(2-propyl)phenoxy 3,5-dimethoxyphenyl 3922-(2-propyl)phenoxy 2,6-dichlorophenyl 4012-(2-propyl)phenoxy 2,4-dichlorophenyl 4012-(2-propyl)phenoxy 4-fluorophenyl 3502-(2-propyl)phenoxy 4-butylphenyl 3882-(2-propyl)phenoxy 2-methylphenyl 3462-(2-propyl)phenoxy phenyl 3322-(2-propyl)phenoxy 4-ethylphenyl 3602-(2-propyl)phenoxy 2,3-difluorophenyl 3682-(2-propyl)phenoxy 2,6-dimethoxyphenyl 3922-(2-propyl)phenoxy 3,4-difluorophenyl 3682-(2-propyl)phenoxy 2,5-difluorophenyl 3682-(2-propyl)phenoxy 4-ethoxyphenyl 3762-(2-propyl)phenoxy 2,4,6-trichlorophenyl 4362-(2-propyl)phenoxy 3-methylphenyl 3462-(2-propyl)phenoxy 2-fluoro-5- 418 (trifluoromethyl)phenyl2-(2-propyl)phenoxy 3-methoxyphenyl 3622-(2-propyl)phenoxy thien-2-yl 3382-(2-propyl)phenoxy 2-bromophenyl 4112-(2-propyl)phenoxy 4-bromophenyl 4112-(2-propyl)phenoxy 4-fluoro-3- 418 (trifluoromethyl)phenyl2-(2-propyl)phenoxy 3-(trifluoromethoxy)phenyl 4162-(2-propyl)phenoxy 9-fluorenon-4-yl 4342-(2-propyl)phenoxy isoxazol-5-yl 3232-(2-propyl)phenoxy benzofuroxan-5-yl 3902-(2-propyl)phenoxy 2-chloropyrid-3-yl 3682-(2-propyl)phenoxy 3,5-difluorophenyl 3682-(2-propyl)phenoxy 2-(4- 439 methylphenoxy)pyridin-3-yl2-(2-propyl)phenoxy pyridin-4-yl 3332-(2-propyl)phenoxy anthraquinon-2-yl 4622-(2-propyl)phenoxy 2-iodophenyl 4583-fluoro-5- 4-biphenyl 398methylphenoxy3-fluoro-5- 3,4-dimethoxyphenyl 382methylphenoxy3-fluoro-5- 2-(trifluoromethyl)phenyl 390methylphenoxy3-fluoro-5- 2,4-difluorophenyl 358methylphenoxy3-fluoro-5- 4-cyanophenyl 347methylphenoxy3-fluoro-5- 3-(trifluoromethyl)phenyl 390methylphenoxy3-fluoro-5- 3-cyanophenyl 347methylphenoxy3-fluoro-5- 2-naphthyl 372methylphenoxy3-fluoro-5- 2-methoxyphenyl 352methylphenoxy3-fluoro-5- 3,4,5,-trimethylphenyl 412methylphenoxy3-fluoro-5- 4-nitrophenyl 367methylphenoxy3-fluoro-5- 3,4-dichlorophenyl 391methylphenoxy3-fluoro-5- 5-nitrofuran-2-yl 357methylphenoxy3-fluoro-5- 3-bromophenyl 401methylphenoxy3-fluoro-5- 3-pyridyl 323methylphenoxy3-fluoro-5- 2-ethoxynaphth-1-yl 416methylphenoxy3-fluoro-5- 2,3-dichlorophenyl 391methylphenoxy3-fluoro-5- 3-nitrophenyl 367methylphenoxy3-fluoro-5- 6-chloropyrid-3-yl 358methylphenoxy3-fluoro-5- 4-(trifluoromethoxy)phenyl 406methylphenoxy3-fluoro-5- 2-fluoro-4- 408methylphenoxy (trifluoromethyl)phenyl3-fluoro-5- 3-bromothienyl 407methylphenoxy3-fluoro-5- 2-acetoxyphenyl 380methylphenoxy3-fluoro-5- 5-methylisoxazol-3-yl 327methylphenoxy3-fluoro-5- 2-(phenylthio)pyrid-3-yl 431methylphenoxy3-fluoro-5- 2-(trifluoromethoxy)phenyl 406methylphenoxy3-fluoro-5- 1-phenyl-5-propylpyrazin- 430methylphenoxy 4-yl3-fluoro-5- 2-ethoxyphenyl 366methylphenoxy3-fluoro-5- 3-chlorothien-2-yl 363methylphenoxy3-fluoro-5- 1-(2-(2-methyl)propyl)-3- 382methylphenoxy methylpyrazol-5-yl3-fluoro-5- 3,5-dichlorophenyl 391methylphenoxy3-fluoro-5- 2-(propylthio)pyridin-3-yl 397methylphenoxy3-fluoro-5- 2-(ethylthio)pyridin-3-yl 383methylphenoxy3-fluoro-5- 3-bromopyridin-5-yl 402methylphenoxy3-fluoro-5- 4-methyl-1,2,3-thiadiazol- 344methylphenoxy 5-yl3-fluoro-5- 1-methyl-3-(2-(2- 382methylphenoxy methyl)propyl)pyrazol-5-yl3-fluoro-5- 3-chlorobenzo[b]thiophen- 413methylphenoxy 2-yl3-fluoro-5- 4-chlorophenyl 357methylphenoxy3-fluoro-5- 4-methyl-2-phenyl-1,2,3- 403methylphenoxy triazol-5-yl3-fluoro-5- benzo[b]thiophen-2-yl 378methylphenoxy3-fluoro-5- 3,4-dimethylphenyl 350methylphenoxy3-fluoro-5- 2-(phenoxy)pyridin-3-yl 415methylphenoxy3-fluoro-5- 2-(methylthio)pyridin-3-yl 369methylphenoxy3-fluoro-5- 5-methyl-3-phenylisoxazol- 403methylphenoxy 4-yl3-fluoro-5- 4-chloro-1,3-dimethyl 426methylphenoxy pyrazolo[3,4-b]pyridin-3- yl3-fluoro-5- 2-chloro-6-methylpyridin- 372methylphenoxy 4-yl3-fluoro-5- 3,5-dimethylisoxazol-4-yl 341methylphenoxy3-fluoro-5- 1-naphthyl 372methylphenoxy3-fluoro-5- 2-fluorophenyl 340methylphenoxy3-fluoro-5- 4-propylphenyl 364methylphenoxy3-fluoro-5- 4-(trifluoromethyl)phenyl 390methylphenoxy3-fluoro-5- 3-fluorophenyl 340methylphenoxy3-fluoro-5- 2,6-difluorophenyl 358methylphenoxy3-fluoro-5- 2-chlorophenyl 357methylphenoxy3-fluoro-5- 3-(chloromethyl)phenyl 371methylphenoxy3-fluoro-5- 4-(2-(2- 378methylphenoxy methyl)propyl)phenyl3-fluoro-5- 3-chlorophenyl 357methylphenoxy3-fluoro-5- 2-nitrophenyl 367methylphenoxy3-fluoro-5- 3,5-dimethoxyphenyl 382methylphenoxy3-fluoro-5- 2,6-dichlorophenyl 391methylphenoxy3-fluoro-5- 2,4-dichlorophenyl 391methylphenoxy3-fluoro-5- 4-fluorophenyl 340methylphenoxy3-fluoro-5- 4-butylphenyl 378methylphenoxy3-fluoro-5- 2-methylphenyl 336methylphenoxy3-fluoro-5- phenyl 322methylphenoxy3-fluoro-5- 4-ethylphenyl 350methylphenoxy3-fluoro-5- 2,3-difluorophenyl 358methylphenoxy3-fluoro-5- 2,6-dimethoxyphenyl 382methylphenoxy3-fluoro-5- 3,4-difluorophenyl 358methylphenoxy3-fluoro-5- 2,5-difluorophenyl 358methylphenoxy3-fluoro-5- 4-ethoxyphenyl 366methylphenoxy3-fluoro-5- 2,4,6-trichlorophenyl 426methylphenoxy3-fluoro-5- 3-methylphenyl 336methylphenoxy3-fluoro-5- 2-fluoro-5- 408methylphenoxy (trifluoromethyl)phenyl3-fluoro-5- 3-methoxyphenyl 352methylphenoxy3-fluoro-5- thien-2-yl 328methylphenoxy3-fluoro-5- 2-bromophenyl 401methylphenoxy3-fluoro-5- 4-bromophenyl 401methylphenoxy3-fluoro-5- 4-fluoro-3- 408methylphenoxy (trifluoromethyl)phenyl3-fluoro-5- 3-(trifluoromethoxy)phenyl 406methylphenoxy3-fluoro-5- 9-fluorenon-4-yl 424methylphenoxy3-fluoro-5- isoxazol-5-yl 313methylphenoxy3-fluoro-5- benzofuroxan-5-yl 380methylphenoxy3-fluoro-5- 2-chloropyrid-3-yl 358methylphenoxy3-fluoro-5- 3,5-difluorophenyl 358methylphenoxy3-fluoro-5- 2-(4- 429methylphenoxy methylphenoxy)pyridin-3-yl3-fluoro-5- pyridin-4-yl 323methylphenoxy3-fluoro-5- anthraquinon-2-yl 452methylphenoxy3-fluoro-5- 2-iodophenyl 448methylphenoxy2-methylpyrid-3-yloxy 4-biphenyl 3812-methylpyrid-3-yloxy 3,4-dimethoxyphenyl 3652-methylpyrid-3-yloxy 2-(trifluoromethyl)phenyl 3732-methylpyrid-3-yloxy 2,4-difluorophenyl 3412-methylpyrid-3-yloxy 4-cyanophenyl 3302-methylpyrid-3-yloxy 3-(trifluoromethyl)phenyl 3732-methylpyrid-3-yloxy 3-cyanophenyl 3302-methylpyrid-3-yloxy 2-naphthyl 3 552-methylpyrid-3-yloxy 2-methoxyphenyl 3352-methylpyrid-3-yloxy 3,4,5-trimethylphenyl 3952-methylpyrid-3-yloxy 4-nitrophenyl 3502-methylpyrid-3-yloxy 3,4-dichlorophenyl 3742-methylpyrid-3-yloxy 5-nitrofuran-2-yl 3402-methylpyrid-3-yloxy 3-bromophenyl 3842-methylpyrid-3-yloxy 3-pyridyl 3062-methylpyrid-3-yloxy 2-ethoxynaphth-1-yl 3992-methylpyrid-3-yloxy 2,3-dichlorophenyl 3742-methylpyrid-3-yloxy 3-nitrophenyl 3502-methylpyrid-3-yloxy 6-chloropyrid-3-yl 3412-methylpyrid-3-yloxy 4-(trifluoromethoxy)phenyl 3892-methylpyrid-3-yloxy 2-fluoro-4- 391 (trifluoromethyl)phenyl2-methylpyrid-3-yloxy 3-bromothienyl 3902-methylpyrid-3-yloxy 2-acetoxyphenyl 3632-methylpyrid-3-yloxy 5-methylisoxazol-3-yl 3102-methylpyrid-3-yloxy 2-(phenylthio)pyrid-3-yl 4142-methylpyrid-3-yloxy 2-(trifluoromethoxy)phenyl 3892-methylpyrid-3-yloxy 1-phenyl-5-propylpyrazin- 413 4-yl2-methylpyrid-3-yloxy 2-ethoxyphenyl 3492-methylpyrid-3-yloxy 3-chlorothien-2-yl 3462-methylpyrid-3-yloxy 1-(2-(2-methyl)propyl)-3- 365 methylpyrazol-5-yl2-methylpyrid-3-yloxy 3,5-dichlorophenyl 3742-methylpyrid-3-yloxy 2-(propylthio)pyridin-3-yl 3802-methylpyrid-3-yloxy 2-(ethylthio)pyridin-3-yl 3662-methylpyrid-3-yloxy 3-bromopyridin-5-yl 3852-methylpyrid-3-yloxy 4-methyl-1,2,3-thiadiazol- 327 5-yl2-methylpyrid-3-yloxy 1-methyl-3-(2-(2- 365 methyl)propyl)pyrazol-5-yl2-methylpyrid-3-yloxy 3-chlorobenzo[b]thiophen- 396 2-yl2-methylpyrid-3-yloxy 4-chlorophenyl 3402-methylpyrid-3-yloxy 4-methyl-2-phenyl-1,2,3- 386 triazol-5-yl2-methylpyrid-3-yloxy benzo[b]thiophen-2-yl 3612-methylpyrid-3-yloxy 3,4-dimethylphenyl 3332-methylpyrid-3-yloxy 2-(phenoxy)pyridin-3-yl 3982-methylpyrid-3-yloxy 2-(methylthio)pyridin-3-yl 3522-methylpyrid-3-yloxy 5-methyl-3-phenylisoxazol- 386 4-yl2-methylpyrid-3-yloxy 4-chloro-1,3-dimethyl 409 pyrazolo[3,4-b]pyridin-3- yl2-methylpyrid-3-yloxy 2-chloro-6-methylpyridin- 355 4-yl2-methylpyrid-3-yloxy 3,5-dimethylisoxazol-4-yl 3242-methylpyrid-3-yloxy 1-naphthyl 3552-methylpyrid-3-yloxy 2-fluorophenyl 3232-methylpyrid-3-yloxy 4-propylphenyl 3472-methylpyrid-3-yloxy 4-(trifluoromethyl)phenyl 3732-methylpyrid-3-yloxy 3-fluorophenyl 3232-methylpyrid-3-yloxy 2,6-difluorophenyl 3412-methylpyrid-3-yloxy 2-chlorophenyl 3402-methylpyrid-3-yloxy 3-(chloromethyl)phenyl 3542-methylpyrid-3-yloxy 4-(2-(2- 361 methyl)propyl)phenyl2-methylpyrid-3-yloxy 3-chlorophenyl 3402-methylpyrid-3-yloxy 2-nitrophenyl 3502-methylpyrid-3-yloxy 3,5-dimethoxyphenyl 3652-methylpyrid-3-yloxy 2,6-dichlorophenyl 3742-methylpyrid-3-yloxy 2,4-dichlorophenyl 3742-methylpyrid-3-yloxy 4-fluorophenyl 3232-methylpyrid-3-yloxy 4-butylphenyl 3612-methylpyrid-3-yloxy 2-methylphenyl 3192-methylpyrid-3-yloxy phenyl 3052-methylpyrid-3-yloxy 4-ethylphenyl 3332-methylpyrid-3-yloxy 2,3-difluorophenyl 3412-methylpyrid-3-yloxy 2,6-dimethoxyphenyl 3652-methylpyrid-3-yloxy 3,4-difluorophenyl 3412-methylpyrid-3-yloxy 2,5-difluorophenyl 3412-methylpyrid-3-yloxy 4-ethoxyphenyl 3492-methylpyrid-3-yloxy 2,4,6-trichlorophenyl 4092-methylpyrid-3-yloxy 3-methylphenyl 3192-methylpyrid-3-yloxy 2-fluoro-5- 391 (trifluoromethyl)phenyl2-methylpyrid-3-yloxy 3-methoxyphenyl 3352-methylpyrid-3-yloxy thien-2-yl 3112-methylpyrid-3-yloxy 2-bromophenyl 3842-methylpyrid-3-yloxy 4-bromophenyl 3842-methylpyrid-3-yloxy 4-fluoro-3- 391 (trifluoromethyl)phenyl2-methylpyrid-3-yloxy 3-(trifluoromethoxy)phenyl 3892-methylpyrid-3-yloxy 9-fluorenon-4-yl 4072-methylpyrid-3-yloxy isoxazol-5-yl 2962-methylpyrid-3-yloxy benzofuroxan-5-yl 3632-methylpyrid-3-yloxy 2-chloropyrid-3-yl 3412-methylpyrid-3-yloxy 3,5-difluorophenyl 3412-methylpyrid-3-yloxy 2-(4- 412 methylphenoxy)pyridin-3-yl2-methylpyrid-3-yloxy pyridin-4-yl 3062-methylpyrid-3-yloxy anthraquinon-2-yl 4352-methylpyrid-3-yloxy 2-iodophenyl 4314-chloro-2,5- 3,4-dimethoxyphenyl 413dimethylphenoxy4-chloro-2,5- 2-(trifluoromethyl)phenyl 421dimethylphenoxy4-chloro-2,5- 2,4-difluorophenyl 389dimethylphenoxy4-chloro-2,5- 3-(trifluoromethyl)phenyl 421dimethylphenoxy4-chloro-2,5- 2-naphthyl 403dimethylphenoxy4-chloro-2,5- 2-methoxyphenyl 484dimethylphenoxy4-chloro-2,5- 3,4,5-trimethylphenyl 443dimethylphenoxy4-chloro-2,5- 3,4-dichlorophenyl 422dimethylphenoxy4-chloro-2,5- 3-bromophenyl 432dimethylphenoxy4-chloro-2,5- 3-pyridyl 354dimethylphenoxy4-chloro-2,5- 2-ethoxynaphth-1-yl 447dimethylphenoxy4-chloro-2,5- 2,3-dichlorophenyl 422dimethylphenoxy4-chloro-2,5- 6-chloropyrid-3-yl 388dimethylphenoxy4-chloro-2,5- 4-(trifluoromethoxy)phenyl 437dimethylphenoxy4-chloro-2,5- 2-fluoro-4- 439dimethylphenoxy (trifluoromethyl)phenyl4-chloro-2,5- 3-bromothienyl 438dimethylphenoxy4-chloro-2,5- 2-acetoxyphenyl 411dimethylphenoxy4-chloro-2,5- 5-methylisoxazol-3-yl 358dimethylphenoxy4-chloro-2,5- 2-(phenylthio)pyrid-3-yl 462dimethylphenoxy4-chloro-2,5- 2-(trifluoromethoxy)phenyl 437dimethylphenoxy4-chloro-2,5- 1-phenyl-5-propylpyrazin- 461dimethylphenoxy 4-yl4-chloro-2,5- 2-ethoxyphenyl 397dimethylphenoxy4-chloro-2,5- 3-chlorothien-2-yl 393dimethylphenoxy4-chloro-2,5- 1-(2-(2-methyl)propyl)-3- 413dimethylphenoxy methylpyrazol-5-yl4-chloro-2,5- 3,5-dichlorophenyl 422dimethylphenoxy4-chloro-2,5- 2-(propylthio)pyridin-3-yl 428dimethylphenoxy4-chloro-2,5- 2-(ethylthio)pyridin-3-yl 414dimethylphenoxy4-chloro-2,5- 3-bromopyridin-5-yl 433dimethylphenoxy4-chloro-2,5- 4-methyl-1,2,3-thiadiazol- 375dimethylphenoxy 5-yl4-chloro-2,5- 1-methyl-3-(2-(2- 413dimethylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-2,5- 3-chlorobenzo[b]thiophen- 443dimethylphenoxy 2-yl4-chloro-2,5- 4-chlorophenyl 387dimethylphenoxy4-chloro-2,5- 4-methyl-2-phenyl-1,2,3- 434dimethylphenoxy triazol-5-yl4-chloro-2,5- benzo[b]thiophen-2-yl 409dimethylphenoxy4-chloro-2,5- 3,4-dimethylphenyl 381dimethylphenoxy4-chloro-2,5- 2-(phenoxy)pyridin-3-yl 446dimethylphenoxy4-chloro-2,5- 2-(methylthio)pyridin-3-yl 400dimethylphenoxy4-chloro-2,5- 5-methyl-3-phenylisoxazol- 434dimethylphenoxy 4-yl4-chloro-2,5- 4-chloro-1,3-dimethyl 456dimethylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-2,5- 2-chloro-6-methylpyridin- 402dimethylphenoxy 4-yl4-chloro-2,5- 3,5-dimethylisoxazol-4-yl 372dimethylphenoxy4-chloro-2,5- 1-naphthyl 403dimethylphenoxy4-chloro-2,5- 2-fluorophenyl 371dimethylphenoxy4-chloro-2,5- 4-propylphenyl 395dimethylphenoxy4-chloro-2,5- 3-fluorophenyl 371dimethylphenoxy4-chloro-2,5- 2,6-difluorophenyl 389dimethylphenoxy4-chloro-2,5- 2-chlorophenyl 387dimethylphenoxy4-chloro-2,5- 3-(chloromethyl)phenyl 401dimethylphenoxy4-chloro-2,5- 4-(2-(2- 409dimethylphenoxy methyl)propyl)phenyl4-chloro-2,5- 3-chlorophenyl 387dimethylphenoxy4-chloro-2,5- 3,5-dimethoxyphenyl 413dimethylphenoxy4-chloro-2,5- 2,6-dichlorophenyl 422dimethylphenoxy4-chloro-2,5- 2,4-dichlorophenyl 422dimethylphenoxy4-chloro-2,5- 4-fluorophenyl 371dimethylphenoxy4-chloro-2,5- 4-butylphenyl 409dimethylphenoxy4-chloro-2,5- 2-methylphenyl 367dimethylphenoxy4-chloro-2,5- phenyl 353dimethylphenoxy4-chloro-2,5- 4-ethylphenyl 381dimethylphenoxy4-chloro-2,5- 2,3-difluorophenyl 389dimethylphenoxy4-chloro-2,5- 2,6-dimethoxyphenyl 413dimethylphenoxy4-chloro-2,5- 3,4-difluorophenyl 389dimethylphenoxy4-chloro-2,5- 2,5-difluorophenyl 389dimethylphenoxy4-chloro-2,5- 4-ethoxyphenyl 397dimethylphenoxy4-chloro-2,5- 2,4,6-trichlorophenyl 456dimethylphenoxy4-chloro-2,5- 3-methylphenyl 367dimethylphenoxy4-chloro-2,5- 2-fluoro-5- 439dimethylphenoxy (trifluoromethyl)phenyl4-chloro-2,5- 3-methoxyphenyl 383dimethylphenoxy4-chloro-2,5- 2-bromophenyl 432dimethylphenoxy4-chloro-2,5- 4-bromophenyl 432dimethylphenoxy4-chloro-2,5- 4-fluoro-3- 439dimethylphenoxy (trifluoromethyl)phenyl4-chloro-2,5- 3-(trifluoromethoxy)phenyl 437dimethylphenoxy4-chloro-2,5- 9-fluorenon-4-yl 455dimethylphenoxy4-chloro-2,5- isoxazol-5-yl 344dimethylphenoxy4-chloro-2,5- benzofuroxan-5-yl 411dimethylphenoxy4-chloro-2,5- 2-chloropyrid-3-yl 388dimethylphenoxy4-chloro-2,5- 2-(4- 460dimethylphenoxy methylphenoxy)pyridin-3-yl4-chloro-2,5- pyridin-4-yl 354dimethylphenoxy4-chloro-2,5- anthraquinon-2-yl 483dimethylphenoxy4-chloro-2,5- 2-iodophenyl 479dimethylphenoxy4-chloro-2,5- 4-pentylphenyl 423dimethylphenoxy4-chloro-2,5- 2-(4-chlorophenylthio) 496dimethylphenoxy pyridin-3-yl4-chloro-2,5- 2,6-dimethylphenyl 381dimethylphenoxy4-chloro-2,5- 2,5-dimethoxyphenyl 413dimethylphenoxy4-chloro-2,5- 2,5-dichloropyridin-3-yl 423dimethylphenoxy4-chloro-2,5- 2-chloro-6-methoxypyridin- 418dimethylphenoxy 4-yl4-chloro-2,5 2,3-dichloropyridin-5-yl 423dimethylphenoxy4-chloro-2,5 1-naphthyl 417dimethylphenoxy4-chloro-2,5- 2,4-dimethoxyphenyl 413dimethylphenoxy4-chloro-2,5- 3,5-bis(trifluoromethyl) 489dimethylphenoxy phenyl4-chloro-2,5- 2-(4- 480dimethylphenoxy chlorophenoxy)pyridin-3-yl4-chloro-2,5- pentafluorophenyl 443dimethylphenoxy4-methoxyphenoxy 3,4-dimethoxyphenyl 3804-methoxyphenoxy 2-(trifluoromethyl)phenyl 3884-methoxyphenoxy 2,4-difluorophenyl 3564-methoxyphenoxy 3-(trifluoromethyl)phenyl 3884-methoxyphenoxy 2-naphthyl 3704-methoxyphenoxy 2-methoxyphenyl 3504-methoxyphenoxy 3,5-trimethylphenyl 4104-methoxyphenoxy 3,4-dichlorophenyl 3894-methoxyphenoxy 3-bromophenyl 3994-methoxyphenoxy 3-pyridyl 3214-methoxyphenoxy 2-ethoxynaphth-1-yl 4144-methoxyphenoxy 2,3-dichlorophenyl 3894-methoxyphenoxy 6-chloropyrid-3-yl 3564-methoxyphenoxy 4-(trifluoromethoxy)phenyl 4044-methoxyphenoxy 2-fluoro-4- 406 (trifluoromethyl)phenyl4-methoxyphenoxy 3-bromothienyl 4054-methoxyphenoxy 2-acetoxyphenyl 3784-methoxyphenoxy 5-methylisoxazol-3-yl 3254-methoxyphenoxy 2-(phenylthio)pyrid-3-yl 4294-methoxyphenoxy 2-(trifluoromethoxy)phenyl 4044-methoxyphenoxy 1-phenyl-5-propylpyrazin- 428 4-yl4-methoxyphenoxy 2-ethoxyphenyl 3644-methoxyphenoxy 3-chlorothien-2-yl 3614-methoxyphenoxy 1-(2-(2-methyl)propyl)-3- 380 methylpyrazol-5-yl4-methoxyphenoxy 3,5-dichlorophenyl 3894-methoxyphenoxy 2-(propylthio)pyridin-3-yl 3954-methoxyphenoxy 2-(ethylthio)pyridin-3-yl 3814-methoxyphenoxy 3-bromopyridin-5-yl 4004-methoxyphenoxy 4-methyl-1,2,3-thiadiazol- 342 5-yl4-methoxyphenoxy 1-methyl-3-(2-(2- 380 methyl)propyl)pyrazol-5-yl4-methoxyphenoxy 3-chlorobenzo[b]thiophen- 411 2-yl4-methoxyphenoxy 4-chlorophenyl 3554-methoxyphenoxy 4-methyl-2-phenyl-1,2,3- 401 triazol-5-yl4-methoxyphenoxy benzo[b]thiophen-2-yl 3764-methoxyphenoxy 3,4-dimethylphenyl 3484-methoxyphenoxy 2-(phenoxy)pyridin-3-yl 4134-methoxyphenoxy 2-(methylthio)pyridin-3-yl 3674-methoxyphenoxy 5-methyl-3-phenylisoxazol- 401 4-yl4-methoxyphenoxy 4-chloro-1,3-dimethyl 424 pyrazolo[3,4-b]pyridin-3- yl4-methoxyphenoxy 2-chloro-6-methylpyridin- 370 4-yl4-methoxyphenoxy 3,5-dimethylisoxazol-4-yl 3394-methoxyphenoxy 1-naphthyl 3704-methoxyphenoxy 2-fluorophenyl 3384-methoxyphenoxy 4-propylphenyl 3624-methoxyphenoxy 3-fluorophenyl 3384-methoxyphenoxy 2,6-difluorophenyl 3564-methoxyphenoxy 2-chlorophenyl 3554-methoxyphenoxy 3-(chloromethyl)phenyl 3694-methoxyphenoxy 4-(2-(2- 376 methyl)propyl)phenyl4-methoxyphenoxy 3-chlorophenyl 3554-methoxyphenoxy 3,5-dimethoxyphenyl 3804-methoxyphenoxy 2,6-dichlorophenyl 3894-methoxyphenoxy 2,4-dichlorophenyl 3894-methoxyphenoxy 4-fluorophenyl 3384-methoxyphenoxy 4-butylphenyl 3764-methoxyphenoxy 2-methylphenyl 3344-methoxyphenoxy phenyl 3204-methoxyphenoxy 4-ethylphenyl 3484-methoxyphenoxy 2,3-difluorophenyl 3564-methoxyphenoxy 2,6-dimethoxyphenyl 3804-methoxyphenoxy 3,4-difluorophenyl 3564-methoxyphenoxy 2,5-difluorophenyl 3564-methoxyphenoxy 4-ethoxyphenyl 3644-methoxyphenoxy 2,4,6-trichlorophenyl 4244-methoxyphenoxy 3-methylphenyl 3344-methoxyphenoxy 2-fluoro-5- 406 (trifluoromethyl)phenyl4-methoxyphenoxy 3-methoxyphenyl 3504-methoxyphenoxy 2-bromophenyl 3994-methoxyphenoxy 4-bromophenyl 3994-methoxyphenoxy 4-fluoro-3- 406 (trifluoromethyl)phenyl4-methoxyphenoxy 3-(trifluoromethoxy)phenyl 4044-methoxyphenoxy 9-fluorenon-4-yl 4224-methoxyphenoxy isoxazol-5-yl 3114-methoxyphenoxy benzofuroxan-5-yl 3784-methoxyphenoxy 2-chloropyrid-3-yl 3564-methoxyphenoxy 2-(4- 427 methylphenoxy)pyridin-3-yl4-methoxyphenoxy pyridin-4-yl 3214-methoxyphenoxy anthraquinon-2-yl 4504-methoxyphenoxy 2-iodophenyl 4464-methoxyphenoxy 4-pentylphenyl 3904-methoxyphenoxy 2-(4-chlorophenylthio) 464 pyridin-3-yl4-methoxyphenoxy 2,6-dimethylphenyl 3484-methoxyphenoxy 2,5-dimethoxyphenyl 3804-methoxyphenoxy 2,5-dichloropyridin-3-yl 3904-methoxyphenoxy 2-chloro-6-methoxypyridin- 386 4-yl4-methoxyphenoxy 2,3-dichloropyridin-5-yl 3904-methoxyphenoxy 1-naphthyl 3844-methoxyphenoxy 2,4-dimethoxyphenyl 3804-methoxyphenoxy 3,5-bis(trifluoromethyl) 456 phenyl4-methoxyphenoxy 2-(4- 448 chlorophenoxy)pyridin-3-yl4-methoxyphenoxy pentafluorophenyl 4102-(2-propoxy)phenoxy 3,4-dimethoxyphenyl 4082-(2-propoxy)phenoxy 2-(trifluoromethyl)phenyl 4162-(2-propoxy)phenoxy 2,4-difluorophenyl 3842-(2-propoxy)phenoxy 3-(trifluoromethyl)phenyl 4162-(2-propoxy)phenoxy 2-naphthyl 3982-(2-propoxy)phenoxy 2-methoxyphenyl 3782-(2-propoxy)phenoxy 3,4,5-trimethylphenyl 4382-(2-propoxy)phenoxy 3,4-dichlorophenyl 4172-(2-propoxy)phenoxy 3-bromophenyl 4272-(2-propoxy)phenoxy 3-pyridyl 3492-(2-propoxy)phenoxy 2-ethoxynaphth-1-yl 4422-(2-propoxy)phenoxy 2,3-dichlorophenyl 4172-(2-propoxy)phenoxy 6-chloropyrid-3-yl 3842-(2-propoxy)phenoxy 4-(trifluoromethoxy)phenyl 4322-(2-propoxy)phenoxy 2-fluoro-4- 434 (trifluoromethyl)phenyl2-(2-propoxy)phenoxy 3-bromothienyl 4332-(2-propoxy)phenoxy 2-acetoxyphenyl 4062-(2-propoxy)phenoxy 5-methylisoxazol-3-yl 3532-(2-propoxy)phenoxy 2-(phenylthio)pyrid-3-yl 4582-(2-propoxy)phenoxy 2-(trifluoromethoxy)phenyl 4322-(2-propoxy)phenoxy 1-phenyl-5-propylpyrazin- 457 4-yl2-(2-propoxy)phenoxy 2-ethoxyphenyl 3922-(2-propoxy)phenoxy 3-chlorothien-2-yl 3892-(2-propoxy)phenoxy 1-(2-(2-methyl)propyl)-3- 408 methylpyrazol-5-yl2-(2-propoxy)phenoxy 3,5-dichlorophenyl 4172-(2-propoxy)phenoxy 2-(propylthio)pyridin-3-yl 4232-(2-propoxy)phenoxy 2-(ethylthio)pyridin-3-yl 4092-(2-propoxy)phenoxy 3-bromopyridin-5-yl 4282-(2-propoxy)phenoxy 4-methyl-1,2,3-thiadiazol- 370 5-yl2-(2-propoxy)phenoxy 1-methyl-3-(2-(2- 408 methyl)propyl)pyrazol-5-yl2-(2-propoxy)phenoxy 3-chlorobenzo[b]thiophen- 439 2-yl2-(2-propoxy)phenoxy 4-chlorophenyl 3832-(2-propoxy)phenoxy 4-methyl-2-phenyl-1,2,3- 429 triazol-5-yl2-(2-propoxy)phenoxy benzo[b]thiophen-2-yl 4042-(2-propoxy)phenoxy 3,4-dimethylphenyl 3762-(2-propoxy)phenoxy 2-(phenoxy)pyridin-3-yl 4412-(2-propoxy)phenoxy 2-(methylthio)pyridin-3-yl 3952-(2-propoxy)phenoxy 5-methyl-3-phenylisoxazol- 429 4-yl2-(2-propoxy)phenoxy 4-chloro-1,3-dimethyl 452 pyrazolo[3,4-b]pyridin-3- yl2-(2-propoxy)phenoxy 2-chloro-6-methylpyridin- 398 4-yl2-(2-propoxy)phenoxy 3,5-dimethylisoxazol-4-yl 3672-(2-propoxy)phenoxy 1-naphthyl 3982-(2-propoxy)phenoxy 2-fluorophenyl 3662-(2-propoxy)phenoxy 4-propylphenyl 3902-(2-propoxy)phenoxy 3-fluorophenyl 3662-(2-propoxy)phenoxy 2,6-difluorophenyl 3842-(2-propoxy)phenoxy 2-chlorophenyl 3832-(2-propoxy)phenoxy 3-(chloromethyl)phenyl 3972-(2-propoxy)phenoxy 4-(2-(2- 404 methyl)propyl)phenyl2-(2-propoxy)phenoxy 3-chlorophenyl 3832-(2-propoxy)phenoxy 3,5-dimethoxyphenyl 4082-(2-propoxy)phenoxy 2,6-dichlorophenyl 4172-(2-propoxy)phenoxy 2,4-dichlorophenyl 4172-(2-propoxy)phenoxy 4-fluorophenyl 3662-(2-propoxy)phenoxy 4-butylphenyl 4042-(2-propoxy)phenoxy 2-methylphenyl 3622-(2-propoxy)phenoxy phenyl 3482-(2-propoxy)phenoxy 4-ethylphenyl 3762-(2-propoxy)phenoxy 2,3-difluorophenyl 3842-(2-propoxy)phenoxy 2,6-dimethoxyphenyl 4082-(2-propoxy)phenoxy 3,4-difluorophenyl 3842-(2-propoxy)phenoxy 2,5-difluorophenyl 3842-(2-propoxy)phenoxy 4-ethoxyphenyl 3922-(2-propoxy)phenoxy 2,4,6-trichlorophenyl 4522-(2-propoxy)phenoxy 3-methylphenyl 3622-(2-propoxy)phenoxy 2-fluoro-5- 434 (trifluoromethyl)phenyl2-(2-propoxy)phenoxy 3-methoxyphenyl 3782-(2-propoxy)phenoxy 2-bromophenyl 4272-(2-propoxy)phenoxy 4-bromophenyl 4272-(2-propoxy)phenoxy 4-fluoro-3- 434 (trifluoromethyl)phenyl2-(2-propoxy)phenoxy 3-(trifluoromethoxy)phenyl 4322-(2-propoxy)phenoxy 9-fluorenon-4-yl 4502-(2-propoxy)phenoxy isoxazol-5-yl 3392-(2-propoxy)phenoxy benzofuroxan-5-yl 4062-(2-propoxy)phenoxy 2-chloropyrid-3-yl 3842-(2-propoxy)phenoxy 2-(4- 455 methylphenoxy)pyridin-3-yl2-(2-propoxy)phenoxy pyridin-4-yl 3492-(2-propoxy)phenoxy anthraquinon-2-yl 4782-(2-propoxy)phenoxy 2-iodophenyl 4742-(2-propoxy)phenoxy 4-pentylphenyl 4192-(2-propoxy)phenoxy 2-(4-chlorophenylthio) 492 pyridin-3-yl2-(2-propoxy)phenoxy 2,6-dimethylphenyl 3762-(2-propoxy)phenoxy 2,5-dimethoxyphenyl 4082-(2-propoxy)phenoxy 2,5-dichloropyridin-3-yl 4182-(2-propoxy)phenoxy 2-chloro-6-methoxypyridin- 414 4-yl2-(2-propoxy)phenoxy 2,3-dichloropyridin-5-yl 4182-(2-propoxy)phenoxy 1-naphthyl 4122-(2-propoxy)phenoxy 2,4-dimethoxyphenyl 4082-(2-propoxy)phenoxy 3,5-bis(trifluoromethyl) 484 phenyl2-(2-propoxy)phenoxy 2-(4- 476 chlorophenoxy)pyridin-3-yl2-(2-propoxy)phenoxy pentafluorophenyl 4384-fluorophenoxy 3,4-dimethoxyphenyl 3684-fluorophenoxy 2-(trifluoromethyl)phenyl 3764-fluorophenoxy 2,4-difluorophenyl 3444-fluorophenoxy 3-(trifluoromethyl)phenyl 3764-fluorophenoxy 2-naphthyl 3584-fluorophenoxy 2-methoxyphenyl 3384-fluorophenoxy 3,4,5-trimethylphenyl 3984-fluorophenoxy 3,4-dichlorophenyl 3774-fluorophenoxy 3-bromophenyl 3874-fluorophenoxy 3-pyridyl 3094-fluorophenoxy 2-ethoxynaphth-1-yl 4024-fluorophenoxy 2,3-dichlorophenyl 3774-fluorophenoxy 6-chloropyrid-3-yl 3444-fluorophenoxy 4-(trifluoromethoxy)phenyl 3924-fluorophenoxy 2-fluoro-4- 394 (trifluoromethyl)phenyl4-fluorophenoxy 3-bromothienyl 3934-fluorophenoxy 2-acetoxyphenyl 3664-fluorophenoxy 5-methylisoxazol-3-yl 3134-fluorophenoxy 2-(phenylthio)pyrid-3-yl 4174-fluorophenoxy 2-(trifluoromethoxy)phenyl 3924-fluorophenoxy 1-phenyl-5-propylpyrazin- 416 4-yl4-fluorophenoxy 2-ethoxyphenyl 3524-fluorophenoxy 3-chlorothien-2-yl 3494-fluorophenoxy 1-(2-(2-methyl)propyl)-3- 368 methylpyrazol-5-yl4-fluorophenoxy 3,5-dichlorophenyl 3774-fluorophenoxy 2-(propylthio)pyridin-3-yl 3834-fluorophenoxy 2-(ethylthio)pyridin-3-yl 3694-fluorophenoxy 3-bromopyridin-5-yl 3884-fluorophenoxy 4-methyl-1,2,3-thiadiazol- 330 5-yl4-fluorophenoxy 1-methyl-3-(2-(2- 368 methyl)propyl)pyrazol-5-yl4-fluorophenoxy 3-chlorobenzo[b]thiophen- 399 2-yl4-fluorophenoxy 4-chlorophenyl 3434-fluorophenoxy 4-methyl-2-phenyl-1,2,3- 389 triazol-5-yl4-fluorophenoxy benzo[b]thiophen-2-yl 3644-fluorophenoxy 3,4-dimethylphenyl 3364-fluorophenoxy 2-(phenoxy)pyridin-3-yl 4014-fluorophenoxy 2-(methylthio)pyridin-3-yl 3554-fluorophenoxy 5-methyl-3-phenylisoxazol- 389 4-yl4-fluorophenoxy 4-chloro-1,3-dimethyl 412 pyrazolo[3,4-b]pyridin-3- yl4-fluorophenoxy 2-chloro-6-methylpyridin- 358 4-yl4-fluorophenoxy 3,5-dimethylisoxazol-4-yl 3274-fluorophenoxy 1-naphthyl 3584-fluorophenoxy 2-fluorophenyl 3264-fluorophenoxy 4-propylphenyl 3504-fluorophenoxy 3-fluorophenyl 3264-fluorophenoxy 2,6-difluorophenyl 3444-fluorophenoxy 2-chlorophenyl 3434-fluorophenoxy 3-(chloromethyl)phenyl 3574-fluorophenoxy 4-(2-(2- 364 methyl)propyl)phenyl4-fluorophenoxy 3-chlorophenyl 3434-fluorophenoxy 3,5-dimethoxyphenyl 3684-fluorophenoxy 2,6-dichlorophenyl 3774-fluorophenoxy 2,4-dichlorophenyl 3774-fluorophenoxy 4-fluorophenyl 3264-fluorophenoxy 4-butylphenyl 3644-fluorophenoxy 2-methylphenyl 3224-fluorophenoxy phenyl 3084-fluorophenoxy 4-ethylphenyl 3364-fluorophenoxy 2,3-difluorophenyl 3444-fluorophenoxy 2,6-dimethoxyphenyl 3684-fluorophenoxy 3,4-difluorophenyl 3444-fluorophenoxy 2,5-difluorophenyl 3444-fluorophenoxy 4-ethoxyphenyl 3524-fluorophenoxy 2,4,6-trichlorophenyl 4124-fluorophenoxy 3-methylphenyl 3224-fluorophenoxy 2-fluoro-5- 394 (trifluoromethyl)phenyl4-fluorophenoxy 3-methoxyphenyl 3384-fluorophenoxy 2-bromophenyl 3874-fluorophenoxy 4-bromophenyl 3874-fluorophenoxy 4-fluoro-3- 394 (trifluoromethyl)phenyl4-fluorophenoxy 3-(trifluoromethoxy)phenyl 3924-fluorophenoxy 9-fluorenon-4-yl 4104-fluorophenoxy isoxazol-5-yl 2994-fluorophenoxy benzofuroxan-5-yl 3664-fluorophenoxy 2-chloropyrid-3-yl 3444-fluorophenoxy 2-(4- 415 methylphenoxy)pyridin-3-yl4-fluorophenoxy pyridin-4-yl 3094-fluorophenoxy anthraquinon-2-yl 4384-fluorophenoxy 2-iodophenyl 4344-fluorophenoxy 4-pentylphenyl 3784-fluorophenoxy 2-(4-chlorophenylthio) 452 pyridin-3-yl4-fluorophenoxy 2,6-dimethylphenyl 3364-fluorophenoxy 2,5-dimethoxyphenyl 3684-fluorophenoxy 2,5-dichloropyridin-3-yl 3784-fluorophenoxy 2-chloro-6-methoxypyridin- 374 4-yl4-fluorophenoxy 2,3-dichloropyridin-5-yl 3784-fluorophenoxy 1-naphthyl 3724-fluorophenoxy 2,4-dimethoxyphenyl 3684-fluorophenoxy 3,5- 444 bis(trifluoromethyl)phenyl4-fluorophenoxy 2-(4- 436 chlorophenoxy)pyridin-3-yl4-fluorophenoxy pentafluorophenyl 3984-chlorophenoxy 3,4-dimethoxyphenyl 3854-chlorophenoxy 2-(trifluoromethyl)phenyl 3934-chlorophenoxy 2,4-difluorophenyl 3614-chlorophenoxy 3-(trifluoromethyl)phenyl 3934-chlorophenoxy 2-naphthyl 3754-chlorophenoxy 2-methoxyphenyl 3554-chlorophenoxy 3,4,5-trimethylphenyl 4154-chlorophenoxy 3,4-dichlorophenyl 3944-chlorophenoxy 3-bromophenyl 4044-chlorophenoxy 3-pyridyl 3264-chlorophenoxy 2-ethoxynaphth-1-yl 4194-chlorophenoxy 2,3-dichlorophenyl 3944-chlorophenoxy 6-chloropyrid-3-yl 3604-chlorophenoxy 4-(trifluoromethoxy)phenyl 4094-chlorophenoxy 2-fluoro-4- 411 (trifluoromethyl)phenyl4-chlorophenoxy 3-bromothienyl 4104-chlorophenoxy 2-acetoxyphenyl 3834-chlorophenoxy 5-methylisoxazol-3-yl 3304-chlorophenoxy 2-(phenylthio)pyrid-3-yl 4344-chlorophenoxy 2-(trifluoromethoxy)phenyl 4094-chlorophenoxy 1-phenyl-5-propylpyrazin- 433 4-yl4-chlorophenoxy 2-ethoxyphenyl 3694-chlorophenoxy 3-chlorothien-2-yl 3654-chlorophenoxy 1-(2-(2-methyl)propyl)-3- 385 methylpyrazol-5-yl4-chlorophenoxy 3,5-dichlorophenyl 3944-chlorophenoxy 2-(propylthio)pyridin-3-yl 4004-chlorophenoxy 2-(ethylthio)pyridin-3-yl 3864-chlorophenoxy 3-bromopyridin-5-yl 4054-chlorophenoxy 4-methyl-1,2,3-thiadiazol- 347 5-yl4-chlorophenoxy 1-methyl-3-(2-(2- 385 methyl)propyl)pyrazol-5-yl4-chlorophenoxy 3-chlorobenzo[b]thiophen- 415 2-yl4-chlorophenoxy 4-chlorophenyl 3594-chlorophenoxy 4-methyl-2-phenyl-1,2,3- 406 triazol-5-yl4-chlorophenoxy benzo[b]thiophen-2-yl 3814-chlorophenoxy 3,4-dimethylphenyl 3534-chlorophenoxy 2-(phenoxy)pyridin-3-yl 4184-chlorophenoxy 2-(methylthio)pyridin-3-yl 3724-chlorophenoxy 5-methyl-3-phenylisoxazol- 406 4-yl4-chlorophenoxy 4-chloro-1,3-dimethyl 428 pyrazolo[3,4-b]pyridin-3- yl4-chlorophenoxy 2-chloro-6-methylpyridin- 374 4-yl4-chlorophenoxy 3,5-dimethylisoxazol-4-yl 3444-chlorophenoxy 1-naphthyl 3754-chlorophenoxy 2-fluorophenyl 3434-chlorophenoxy 4-propylphenyl 3674-chlorophenoxy 3-fluorophenyl 3434-chlorophenoxy 2,6-difluorophenyl 3614-chlorophenoxy 2-chlorophenyl 3594-chlorophenoxy 3-(chloromethyl)phenyl 3734-chlorophenoxy 4-(2-(2- 381 methyl)propyl)phenyl4-chlorophenoxy 3-chlorophenyl 3594-chlorophenoxy 3,5-dimethoxyphenyl 3854-chlorophenoxy 2,6-dichlorophenyl 3944-chlorophenoxy 2,4-dichlorophenyl 3944-chlorophenoxy 4-fluorophenyl 3434-chlorophenoxy 4-butylphenyl 3814-chlorophenoxy 2-methylphenyl 3394-chlorophenoxy phenyl 3254-chlorophenoxy 4-ethylphenyl 3534-chlorophenoxy 2,3-difluorophenyl 3614-chlorophenoxy 2,6-dimethoxyphenyl 3854-chlorophenoxy 3,4-difluorophenyl 3614-chlorophenoxy 2,5-difluorophenyl 3614-chlorophenoxy 4-ethoxyphenyl 3694-chlorophenoxy 2,4,6-trichlorophenyl 4284-chlorophenoxy 3-methylphenyl 3394-chlorophenoxy 2-fluoro-5- 411 (trifluoromethyl)phenyl4-chlorophenoxy 3-methoxyphenyl 3554-chlorophenoxy 2-bromophenyl 4044-chlorophenoxy 4-bromophenyl 4044-chlorophenoxy 4-fluoro-3- 411 (trifluoromethyl)phenyl4-chlorophenoxy 3-(trifluoromethoxy)phenyl 4094-chlorophenoxy 9-fluorenon-4-yl 4274-chlorophenoxy isoxazol-5-yl 3164-chlorophenoxy benzofuroxan-5-yl 3834-chlorophenoxy 2-chloropyrid-3-yl 3604-chlorophenoxy 2-(4- 432 methylphenoxy)pyridin-3-yl4-chlorophenoxy pyridin-4-yl 3264-chlorophenoxy anthraquinon-2-yl 4554-chlorophenoxy 2-iodophenyl 4514-chlorophenoxy 4-pentylphenyl 3954-chlorophenoxy 2-(4-chlorophenylthio) 468 pyridin-3-yl4-chlorophenoxy 2,6-dimethylphenyl 3534-chlorophenoxy 2,5-dimethoxyphenyl 3854-chlorophenoxy 2,5-dichloropyridin-3-yl 3954-chlorophenoxy 2-chloro-6-methoxypyridin- 390 4-yl4-chlorophenoxy 2,3-dichloropyridin-5-yl 3954-chlorophenoxy 1-naphthyl 3894-chlorophenoxy 2,4-dimethoxyphenyl 3854-chlorophenoxy 3,5- 461 bis(trifluoromethyl)phenyl4-chlorophenoxy 2-(4- 452 chlorophenoxy)pyridin-3-yl4-chlorophenoxy pentafluorophenyl 4152,4-difluorophenoxy 3,4-dimethoxyphenyl 3862,4-difluorophenoxy 2-(trifluoromethyl)phenyl 3942,4-difluorophenoxy 2,4-difluorophenyl 3622,4-difluorophenoxy 3-(trifluoromethyl)phenyl 3942,4-difluorophenoxy 2-naphthyl 3762,4-difluorophenoxy 2-methoxyphenyl 3562,4-difluorophenoxy 3,4,5-trimethylphenyl 4162,4-difluorophenoxy 3,4-dichlorophenyl 3952,4-difluorophenoxy 3-bromophenyl 4052,4-difluorophenoxy 3-pyridyl 3272,4-difluorophenoxy 2-ethoxynaphth-1-yl 4202,4-difluorophenoxy 2,3-dichlorophenyl 3952,4-difluorophenoxy 6-chloropyrid-3-yl 3622,4-difluorophenoxy 4-(trifluoromethoxy)phenyl 4102,4-difluorophenoxy 2-fluoro-4- 412 (trifluoromethyl)phenyl2,4-difluorophenoxy 3-bromothienyl 4112,4-difluorophenoxy 2-acetoxyphenyl 3842,4-difluorophenoxy 5-methylisoxazol-3-yl 3312,4-difluorophenoxy 2-(phenylthio)pyrid-3-yl 4352,4-difluorophenoxy 2-(trifluoromethoxy)phenyl 4102,4-difluorophenoxy 1-phenyl-5-propylpyrazin- 434 4-yl2,4-difluorophenoxy 2-ethoxyphenyl 3702,4-difluorophenoxy 3-chlorothien-2-yl 3672,4-difluorophenoxy 1-(2-(2-methyl)propyl)-3- 386 methylpyrazol-5-yl2,4-difluorophenoxy 3,5-dichlorophenyl 3952,4-difluorophenoxy 2-(propylthio)pyridin-3-yl 4012,4-difluorophenoxy 2-(ethylthio)pyridin-3-yl 3872,4-difluorophenoxy 3-bromopyridin-5-yl 4062,4-difluorophenoxy 4-methyl-1,2,3-thiadiazol- 348 5-yl2,4-difluorophenoxy 1-methyl-3-(2-(2- 386 methyl)propyl)pyrazol-5-yl2,4-difluorophenoxy 3-chlorobenzo[b]thiophen- 417 2-yl2,4-difluorophenoxy 4-chlorophenyl 3612,4-difluorophenoxy 4-methyl-2-phenyl-1,2,3- 407 triazol-5-yl2,4-difluorophenoxy benzo[b]thiophen-2-yl 3822,4-difluorophenoxy 3,4-dimethylphenyl 3542,4-difluorophenoxy 2-(phenoxy)pyridin-3-yl 4092,4-difluorophenoxy 2-(methylthio)pyridin-3-yl 3732,4-difluorophenoxy 5-methyl-3-phenylisoxazol- 407 4-yl2,4-difluorophenoxy 4-chloro-1,3-dimethyl 430 pyrazolo[3,4-b]pyridin-3- yl2,4-difluorophenoxy 2-chloro-6-methylpyridin- 376 4-yl2,4-difluorophenoxy 3,5-dimethylisoxazol-4-yl 3452,4-difluorophenoxy 1-naphthyl 3762,4-difluorophenoxy 2-fluorophenyl 3442,4-difluorophenoxy 4-propylphenyl 3682,4-difluorophenoxy 3-fluorophenyl 3442,4-difluorophenoxy 2,6-difluorophenyl 3622,4-difluorophenoxy 2-chlorophenyl 3612,4-difluorophenoxy 3-(chloromethyl)phenyl 3752,4-difluorophenoxy 4-(2-(2- 382 methyl)propyl)phenyl2,4-difluorophenoxy 3-chlorophenyl 3612,4-difluorophenoxy 3,5-dimethoxyphenyl 3862,4-difluorophenoxy 2,6-dichlorophenyl 3952,4-difluorophenoxy 2,4-dichlorophenyl 3922,4-difluorophenoxy 4-fluorophenyl 3442,4-difluorophenoxy 4-butylphenyl 3822,4-difluorophenoxy 2-methylphenyl 3402,4-difluorophenoxy phenyl 3262,4-difluorophenoxy 4-ethylphenyl 3542,4-difluorophenoxy 2,3-difluorophenyl 3622,4-difluorophenoxy 2,6-dimethoxyphenyl 3862,4-difluorophenoxy 3,4-difluorophenyl 3622,4-difluorophenoxy 2,5-difluorophenyl 3622,4-difluorophenoxy 4-ethoxyphenyl 3702,4-difluorophenoxy 2,4,6-trichlorophenyl 4302,4-difluorophenoxy 3-methylphenyl 3402,4-difluorophenoxy 2-fluoro-5- 412 (trifluoromethyl)phenyl2,4-difluorophenoxy 3-methoxyphenyl 3562,4-difluorophenoxy 2-bromophenyl 4052,4-difluorophenoxy 4-bromophenyl 4052,4-difluorophenoxy 4-fluoro-3- 412 (trifluoromethyl)phenyl2,4-difluorophenoxy 3-(trifluoromethoxy)phenyl 4102,4-difluorophenoxy 9-fluorenon-4-yl 4282,4-difluorophenoxy isoxazol-5-yl 3172,4-difluorophenoxy benzofuroxan-5-yl 3842,4-difluorophenoxy 2-chloropyrid-3-yl 3622,4-difluorophenoxy 2-(4- 433 methylphenoxy)pyridin-3-yl2,4-difluorophenoxy pyridin-4-yl 3272,4-difluorophenoxy anthraquinon-2-yl 4562,4-difluorophenoxy 2-iodophenyl 4522,4-difluorophenoxy 4-pentylphenyl 3962,4-difluorophenoxy 2-(4-chlorophenylthio) 470 pyridin-3-yl2,4-difluorophenoxy 2,6-dimethylphenyl 3542,4-difluorophenoxy 2,5-dimethoxyphenyl 3862,4-difluorophenoxy 2,5-dichloropyridin-3-yl 3962,4-difluorophenoxy 2-chloro-6-methoxypyridin- 392 4-yl2,4-difluorophenoxy 2,3-dichloropyridin-5-yl 3962,4-difluorophenoxy 1-naphthyl 3902 ,4-difluorophenoxy 2,4-dimethoxyphenyl 3862,4-difluorophenoxy 3,5- 462 bis(trifluoromethyl)phenyl2,4-difluorophenoxy 2-(4- 454 chlorophenoxy)pyridin-3-yl2,4-difluorophenoxy pentafluorophenyl 4164-thiomethylphenoxy 3,4-dimethoxyphenyl 3964-thiomethylphenoxy 2-(trifluoromethyl)phenyl 4044-thiomethylphenoxy 2,4-difluorophenyl 3724-thiomethylphenoxy 3-(trifluoromethyl)phenyl 4044-thiomethylphenoxy 2-naphthyl 3864-thiomethylphenoxy 2-methoxyphenyl 3664-thiomethylphenoxy 3,4,5,-trimethylphenyl 4264-thiomethylphenoxy 3,4-dichlorophenyl 4054-thiomethylphenoxy 3-bromophenyl 4154-thiomethylphenoxy 3-pyridyl 3374-thiomethylphenoxy 2-ethoxynaphth-1-yl 4304-thiomethylphenoxy 2,3-dichlorophenyl 4054-thiomethylphenoxy 6-chloropyrid-3-yl 3724-thiomethylphenoxy 4-(trifluoromethoxy)phenyl 4204-thiomethylphenoxy 2-fluoro-4- 422 (trifluoromethyl)phenyl4-thiomethylphenoxy 3-bromothienyl 4214-thiomethylphenoxy 2-acetoxyphenyl 3944-thiomethylphenoxy 5-methylisoxazol-3-yl 3414-thiomethylphenoxy 2-(phenylthio)pyrid-3-yl 4464-thiomethylphenoxy 2-(trifluoromethoxy)phenyl 4204-thiomethylphenoxy 1-phenyl-5-propylpyrazin- 445 4-yl4-thiomethylphenoxy 2-ethoxyphenyl 3804-thiomethylphenoxy 3-chlorothien-2-yl 3774-thiomethylphenoxy 1-(2-(2-methyl)propyl)-3- 396 methylpyrazol-5-yl4-thiomethylphenoxy 3,5-dichlorophenyl 4054-thiomethylphenoxy 2-(propylthio)pyridin-3-yl 4124-thiomethylphenoxy 2-(ethylthio)pyridin-3-yl 3974-thiomethylphenoxy 3-bromopyridin-5-yl 4164-thiomethylphenoxy 4-methyl-1,2,3-thiadiazol- 358 5-yl4-thiomethylphenoxy 1-methyl-3-(2-(2- 396 methyl)propyl)pyrazol-5-yl4-thiomethylphenoxy 3-chlorobenzo[b]thiophen- 427 2-yl4-thiomethylphenoxy 4-chlorophenyl 3714-thiomethylphenoxy 4-methyl-2-phenyl-1,2,3- 417 triazol-5-yl4-thiomethylphenoxy benzo[b]thiophen-2-yl 3924-thiomethylphenoxy 3,4-dimethylphenyl 3644-thiomethylphenoxy 2-(phenoxy)pyridin-3-yl 4294-thiomethylphenoxy 2-(methylthio)pyridin-3-yl 3834-thiomethylphenoxy 5-methyl-3-phenylisoxazol- 417 4-yl4-thiomethylphenoxy 4-chloro-1,3-dimethyl 440 pyrazolo[3,4-b]pyridin-3- yl4-thiomethylphenoxy 2-chloro-6-methylpyridin- 386 4-yl4-thiomethylphenoxy 3,5-dimethylisoxazol-4-yl 3554-thiomethylphenoxy 1-naphthyl 3864-thiomethylphenoxy 2-fluorophenyl 3544-thiomethylphenoxy 4-propylphenyl 3784-thiomethylphenoxy 3-fluorophenyl 3544-thiomethylphenoxy 2,6-difluorophenyl 3724-thiomethylphenoxy 2-chlorophenyl 3714-thiomethylphenoxy 3-(chloromethyl)phenyl 3854-thiomethylphenoxy 4-(2-(2- 392 methyl)propyl)phenyl4-thiomethylphenoxy 3-chlorophenyl 3714-thiomethylphenoxy 3,5-dimethoxyphenyl 3964-thiomethylphenoxy 2,6-dichlorophenyl 4054-thiomethylphenoxy 2,4-dichlorophenyl 4054-thiomethylphenoxy 4-fluorophenyl 3544-thiomethylphenoxy 4-butylphenyl 3924-thiomethylphenoxy 2-methylphenyl 3504-thiomethylphenoxy phenyl 3364-thiomethylphenoxy 4-ethylphenyl 3644-thiomethylphenoxy 2,3-difluorophenyl 3724-thiomethylphenoxy 2,6-dimethoxyphenyl 3964-thiomethylphenoxy 3,4-difluorophenyl 3724-thiomethylphenoxy 2,5-difluorophenyl 3724-thiomethylphenoxy 4-ethoxyphenyl 3804-thiomethylphenoxy 2,4,6-trichlorophenyl 4404-thiomethylphenoxy 3-methylphenyl 3504-thiomethylphenoxy 2-fluoro-5- 422 (trifluoromethyl)phenyl4-thiomethylphenoxy 3-methoxyphenyl 3664-thiomethylphenoxy 2-bromophenyl 4154-thiomethylphenoxy 4-bromophenyl 4154-thiomethylphenoxy 4-fluoro-3- 422 (trifluoromethyl)phenyl4-thiomethylphenoxy 3-(trifluoromethoxy)phenyl 4204-thiomethylphenoxy 9-fluorenon-4-yl 4384-thiomethylphenoxy isoxazol-5-yl 3274-thiomethylphenoxy benzofuroxan-5-yl 3944-thiomethylphenoxy 2-chloropyrid-3-yl 3724-thiomethylphenoxy 2-(4- 443 methylphenoxy)pyridin-3-yl4-thiomethylphenoxy pyridin-4-yl 3374-thiomethylphenoxy anthraquinon-2-yl 4664-thiomethylphenoxy 2-iodophenyl 4624-thiomethylphenoxy 4-pentylphenyl 4074-thiomethylphenoxy 2-(4-chlorophenylthio) 480 pyridin-3-yl4-thiomethylphenoxy 2,6-dimethylphenyl 3644-thiomethylphenoxy 2,5-dimethoxyphenyl 3964-thiomethylphenoxy 2,5-dichloropyridin-3-yl 4064-thiomethylphenoxy 2-chloro-6-methoxypyridin- 402 4-yl4-thiomethylphenoxy 2,3-dichloropyridin-5-yl 4064-thiomethylphenoxy 1-naphthyl 4004-thiomethylphenoxy 2,4-dimethoxyphenyl 3964-thiomethylphenoxy 3,5- 372 bis(trifluoromethyl)phenyl4-thiomethylphenoxy 2-(4- 464 chlorophenoxy)pyridin-3-yl4-thiomethylphenoxy pentafluorophenyl 4264-(2-(2- 3,4-dimethoxyphenyl 406methyl)propyl)phenoxy4-(2-(2- 2-(trifluoromethyl)phenyl 414methyl)propyl)phenoxy4-(2-(2- 2,4-difluorophenyl 382methyl)propyl)phenoxy4-(2-(2- 3-(trifluoromethyl)phenyl 414methyl)propyl)phenoxy4-(2-(2- 2-naphthyl 396methyl)propyl)phenoxy4-(2-(2- 2-methoxyphenyl 376methyl)propyl)phenoxy4-(2-(2- 3,4,5-trimethylphenyl 436methyl)propyl)phenoxy4-(2-(2- 3,4-dichlorophenyl 415methyl)propyl)phenoxy4-(2-(2- 3-bromophenyl 425methyl)propyl)phenoxy4-(2-(2- 3-pyridyl 347methyl)propyl)phenoxy4-(2-(2- 2-ethoxynaphth-1-yl 441methyl)propyl)phenoxy4-(2-(2- 2,3-dichlorophenyl 415methyl)propyl)phenoxy4-(2-(2- 6-chloropyrid-3-yl 382methyl)propyl)phenoxy4-(2-(2- 4-(trifluoromethoxy)phenyl 430methyl)propyl)phenoxy4-(2-(2- 2-fluoro-4- 432methyl)propyl)phenoxy (trifluoromethyl)phenyl4-(2-(2- 3-bromothienyl 431methyl)propyl)phenoxy4-(2-(2- 2-acetoxyphenyl 404methyl)propyl)phenoxy4-(2-(2- 5-methylisoxazol-3-yl 351methyl)propyl)phenoxy4-(2-(2- 2-(phenylthio)pyrid-3-yl 456methyl)propyl)phenoxy4-(2-(2- 2-(trifluoromethoxy)phenyl 430methyl)propyl)phenoxy4-(2-(2- 1-phenyl-5-propylpyrazin- 455methyl)propyl)phenoxy 4-yl4-(2-(2- 2-ethoxyphenyl 390methyl)propyl)phenoxy4-(2-(2- 3-chlorothien-2-yl 387methyl)propyl)phenoxy4-(2-(2- 1-(2-(2-methyl)propyl)-3- 406methyl)propyl)phenoxy methylpyrazol-5-yl4-(2-(2- 3,5-dichlorophenyl 415methyl)propyl)phenoxy4-(2-(2- 2-(propylthio)pyridin-3-yl 422methyl)propyl)phenoxy4-(2-(2- 2-(ethylthio)pyridin-3-yl 407methyl)propyl)phenoxy4-(2-(2- 3-bromopyridin-5-yl 426methyl)propyl)phenoxy4-(2-(2- 4-methyl-1,2,3-thiadiazol- 368methyl)propyl)phenoxy 5-yl4-(2-(2- 1-methyl-3-(2-(2- 406methyl)propyl)phenoxy methyl)propyl)pyrazol-5-yl4-(2-(2- 3-chlorobenzo[b]thiophen- 437methyl)propyl)phenoxy 2-yl4-(2-(2- 4-chlorophenyl 381methyl)propyl)phenoxy4-(2-(2- 4-methyl-2-phenyl-1,2,3- 427methyl)propyl)phenoxy triazol-5-yl4-(2-(2- benzo[b]thiophen-2-yl 402methyl)propyl)phenoxy4-(2-(2- 3,4-dimethylphenyl 374methyl)propyl)phenoxy4-(2-(2- 2-(phenoxy)pyridin-3-yl 439methyl)propyl)phenoxy4-(2-(2- 2-(methylthio)pyridin-3-yl 393methyl)propyl)phenoxy4-(2-(2- 5-methyl-3-phenylisoxazol- 427methyl)propyl)phenoxy 4-yl4-(2-(2- 4-chloro-1,3-dimethyl 450methyl)propyl)phenoxy pyrazolo[3,4-b]pyridin-3- yl4-(2-(2- 2-chloro-6-methylpyridin- 396methyl)propyl)phenoxy 4-yl4-(2-(2- 3,5-dimethylisoxazol-4-yl 365methyl)propyl)phenoxy4-(2-(2- 1-naphthyl 396methyl)propyl)phenoxy4-(2-(2- 2-fluorophenyl 364methyl)propyl)phenoxy4-(2-(2- 4-propylphenyl 388methyl)propyl)phenoxy4-(2-(2- 3-fluorophenyl 364methyl)propyl)phenoxy4-(2-(2- 2,6-difluorophenyl 382methyl)propyl)phenoxy4-(2-(2- 2-chlorophenyl 381methyl)propyl)phenoxy4-(2-(2- 3-(chloromethyl)phenyl 395methyl)propyl)phenoxy4-(2-(2- 4-(2-(2- 402methyl)propyl)phenoxy methyl)propyl)phenyl4-(2-(2- 3-chlorophenyl 381methyl)propyl)phenoxy4-(2-(2- 3,5-dimethoxyphenyl 406methyl)propyl)phenoxy4-(2-(2- 2,6-dichlorophenyl 415methyl)propyl)phenoxy4-(2-(2- 2,4-dichlorophenyl 415methyl)propyl)phenoxy4-(2-(2- 4-fluorophenyl 364methyl)propyl)phenoxy4-(2-(2- 4-butylphenyl 402methyl)propyl)phenoxy4-(2-(2- 2-methylphenyl 360methyl)propyl)phenoxy4-(2-(2- phenyl 346methyl)propyl)phenoxy4-(2-(2- 4-ethylphenyl 374methyl)propyl)phenoxy4-(2-(2- 2,3-difluorophenyl 382methyl)propyl)phenoxy4-(2-(2- 2,6-dimethoxyphenyl 406methyl)propyl)phenoxy4-(2-(2- 3,4-difluorophenyl 382methyl)propyl)phenoxy4-(2-(2- 2,5-difluorophenyl 382methyl)propyl)phenoxy4-(2-(2- 4-ethoxyphenyl 390methyl)propyl)phenoxy4-(2-(2- 2,4,6-trichlorophenyl 450methyl)propyl)phenoxy4-(2-(2- 3-methylphenyl 360methyl)propyl)phenoxy4-(2-(2- 2-fluoro-5- 432methyl)propyl)phenoxy (trifluoromethyl)phenyl4-(2-(2- 3-methoxyphenyl 376methyl)propyl)phenoxy4-(2-(2- 2-bromophenyl 425methyl)propyl)phenoxy4-(2-(2- 4-bromophenyl 425methyl)propyl)phenoxy4-(2-(2- 4-fluoro-3- 432methyl)propyl)phenoxy (trifluoromethyl)phenyl4-(2-(2- 3-(trifluoromethoxy)phenyl 430methyl)propyl)phenoxy4-(2-(2- 9-fluorenon-4-yl 448methyl)propyl)phenoxy4-(2-(2- isoxazol-5-yl 338methyl)propyl)phenoxy4-(2-(2- benzofuroxan-5-yl 404methyl)propyl)phenoxy4-(2-(2- 2-chloropyrid-3-yl 382methyl)propyl)phenoxy4-(2-(2- 2-(4- 454methyl)propyl)phenoxy methylphenoxy)pyridin-3-yl4-(2-(2- pyridin-4-yl 347methyl)propyl)phenoxy4-(2-(2- anthraquinon-2-yl 476methyl)propyl)phenoxy4-(2-(2- 2-iodophenyl 472methyl)propyl)phenoxy4-(2-(2- 4-pentylphenyl 417methyl)propyl)phenoxy4-(2-(2- 2-(4-chlorophenylthio) 490methyl)propyl)phenoxy pyridin-3-yl4-(2-(2- 2,6-dimethylphenyl 374methyl)propyl)phenoxy4-(2-(2- 2,5-dimethoxyphenyl 406methyl)propyl)phenoxy4-(2-(2- 2,5-dichloropyridin-3-yl 416methyl)propyl)phenoxy4-(2-(2- 2-chloro-6-methoxypyridin- 412methyl)propyl)phenoxy 4-yl4-(2-(2- 2,3-dichloropyridin-5-yl 416methyl)propyl)phenoxy4-(2-(2- 1-naphthyl 410methyl)propyl)phenoxy4-(2-(2- 2,4-dimethoxyphenyl 406methyl)propyl)phenoxy4-(2-(2- 3,5-bis(trifluoromethyl) 482methyl)propyl)phenoxy phenyl4-(2-(2- 2-(4- 474methyl)propyl)phenoxy chlorophenoxy)pyridin-3-yl4-(2-(2- pentafluorophenyl 436methyl)propyl)phenoxy2,3-dimethylphenoxy 3,4-dimethoxyphenyl 3782,3-dimethylphenoxy 2-(trifluoromethyl)phenyl 3862,3-dimethylphenoxy 2,4-difluorophenyl 3542,3-dimethylphenoxy 3-(trifluoromethyl)phenyl 3862,3-dimethylphenoxy 2-naphthyl 3682,3-dimethylphenoxy 2-methoxyphenyl 3482,3-dimethylphenoxy 3,4,5-trimethylphenyl 4082,3-dimethylphenoxy 3,4-dichlorophenyl 3872,3-dimethylphenoxy 3-bromophenyl 3972,3-dimethylphenoxy 3-pyridyl 3192,3-dimethylphenoxy 2-ethoxynaphth-1-yl 4122,3-dimethylphenoxy 2,3-dichlorophenyl 3872,3-dimethylphenoxy 6-chloropyrid-3-yl 3542,3-dimethylphenoxy 4-(trifluoromethoxy)phenyl 4022,3-dimethylphenoxy 2-fluoro-4- 404 (trifluoromethyl)phenyl2,3-dimethylphenoxy 3-bromothienyl 4032,3-dimethylphenoxy 2-acetoxyphenyl 3762,3-dimethylphenoxy 5-methylisoxazol-3-yl 3232,3-dimethylphenoxy 2-(phenylthio)pyrid-3-yl 4272,3-dimethylphenoxy 2-(trifluoromethoxy)phenyl 4022,3-dimethylphenoxy 1-phenyl-5-propylpyrazin- 426 4-yl2,3-dimethylphenoxy 2-ethoxyphenyl 3622,3-dimethylphenoxy 3-chlorothien-2-yl 3592,3-dimethylphenoxy 1-(2-(2-methyl)propyl)-3- 378 methylpyrazol-5-yl2,3-dimethylphenoxy 3,5-dichlorophenyl 3872,3-dimethylphenoxy 2-(propylthio)pyridin-3-yl 3932,3-dimethylphenoxy 2-(ethylthio)pyridin-3-yl 3792,3-dimethylphenoxy 3-bromopyridin-5-yl 3982,3-dimethylphenoxy 4-methyl-1,2,3-thiadiazol- 340 5-yl2,3-dimethylphenoxy 1-methyl-3-(2-(2- 378 methyl)propyl)pyrazol-5-yl2,3-dimethylphenoxy 3-chlorobenzo[b]thiophen- 409 2-yl2,3-dimethylphenoxy 4-chlorophenyl 3532,3-dimethylphenoxy 4-methyl-2-phenyl-1,2,3- 399 triazol-5-yl2,3-dimethylphenoxy benzo[b]thiophen-2-yl 3742,3-dimethylphenoxy 3,4-dimethylphenyl 3462,3-dimethylphenoxy 2-(phenoxy)pyridin-3-yl 4112,3-dimethylphenoxy 2-(methylthio)pyridin-3-yl 3652,3-dimethylphenoxy 5-methyl-3-phenylisoxazol- 399 4-yl2,3-dimethylphenoxy 4-chloro-1,3-dimethyl 422 pyrazolo[3,4-b]pyridin-3- yl2,3-dimethylphenoxy 2-chloro-6-methylpyridin- 368 4-yl2,3-dimethylphenoxy 3,5-dimethylisoxazol-4-yl 3372,3-dimethylphenoxy 1-naphthyl 3682,3-dimethylphenoxy 2-fluorophenyl 3362,3-dimethylphenoxy 4-propylphenyl 3602,3-dimethylphenoxy 3-fluorophenyl 3362,3-dimethylphenoxy 2,6-difluorophenyl 3542,3-dimethylphenoxy 2-chlorophenyl 3532,3-dimethylphenoxy 3-(chloromethyl)phenyl 3682,3-dimethylphenoxy 4-(2-(2-methyl)propyl) 374 phenyl2,3-dimethylphenoxy 3-chlorophenyl 3532,3-dimethylphenoxy 3,5-dimethoxyphenyl 3782,3-dimethylphenoxy 2,6-dichlorophenyl 3872,3-dimethylphenoxy 2,4-dichlorophenyl 3872,3-dimethylphenoxy 4-fluorophenyl 3362,3-dimethylphenoxy 4-butylphenyl 3742,3-dimethylphenoxy 2-methylphenyl 3322,3-dimethylphenoxy phenyl 3182,3-dimethylphenoxy 4-ethylphenyl 3462,3-dimethylphenoxy 2,3-difluorophenyl 3542,3-dimethylphenoxy 2,6-dimethoxyphenyl 3782,3-dimethylphenoxy 3,4-difluorophenyl 3542,3-dimethylphenoxy 2,5-difluorophenyl 3542,3-dimethylphenoxy 4-ethoxyphenyl 3622,3-dimethylphenoxy 2,4,6-trichlorophenyl 4222,3-dimethylphenoxy 3-methylphenyl 3322,3-dimethylphenoxy 2-fluoro-5- 404 (trifluoromethyl)phenyl2,3-dimethylphenoxy 3-methoxyphenyl 3482,3-dimethylphenoxy 2-bromophenyl 3972,3-dimethylphenoxy 4-bromophenyl 3972,3-dimethylphenoxy 4-fluoro-3- 404 (trifluoromethyl)phenyl2,3-dimethylphenoxy 3-(trifluoromethoxy)phenyl 4022,3-dimethylphenoxy 9-fluorenon-4-yl 4202,3-dimethylphenoxy isoxazol-5-yl 6092,3-dimethylphenoxy benzofuroxan-5-yl 3762,3-dimethylphenoxy 2-chloropyrid-3-yl 3542,3-dimethylphenoxy 2-(4- 425 methylphenoxy)pyridin-3-yl2,3-dimethylphenoxy pyridin-4-yl 3192,3-dimethylphenoxy anthraquinon-2-yl 4482,3-dimethylphenoxy 2-iodophenyl 4442,3-dimethylphenoxy 4-pentylphenyl 3882,3-dimethylphenoxy 2-(4-chlorophenylthio) 462 pyridin-3-yl2,3-dimethylphenoxy 2,6-dimethylphenyl 3462,3-dimethylphenoxy 2,5-dimethoxyphenyl 3782,3-dimethylphenoxy 2,5-dichloropyridin-3-yl 3882,3-dimethylphenoxy 2-chloro-6-methoxypyridin- 384 4-yl2,3-dimethylphenoxy 2,3-dichloropyridin-5-yl 3882,3-dimethylphenoxy 1-naphthyl 3822,3-dimethylphenoxy 2,4-dimethoxyphenyl 3782,3-dimethylphenoxy 3,5-bis(trifluoromethyl) 454 phenyl2,3-dimethylphenoxy 2-(4- 446 chlorophenoxy)pyridin-3-yl2,3-dimethylphenoxy pentafluorophenyl 4083,5-(bis-2- 3,4-dimethoxyphenyl 434propyl)phenoxy3,5-(bis-2- 2-(trifluoromethyl)phenyl 442propyl)phenoxy3,5-(bis-2- 2,4-difluorophenyl 410propyl)phenoxy3,5-(bis-2- 3-(trifluoromethyl)phenyl 442propyl)phenoxy3,5-(bis-2- 2-naphthyl 425propyl)phenoxy3,5-(bis-2- 2-methoxyphenyl 404propyl)phenoxy3,5-(bis-2- 3,4,5-trimethylphenyl 465propyl)phenoxy3,5-(bis-2- 3,4-dichlorophenyl 443propyl)phenoxy3,5-(bis-2- 3-bromophenyl 453propyl)phenoxy3,5-(bis-2- 3-pyridyl 375propyl)phenoxy3,5-(bis-2- 2-ethoxynaphth-1-yl 469propyl)phenoxy3,5-(bis-2- 2,3-dichlorophenyl 443propyl)phenoxy3,5-(bis-2- 6-chloropyrid-3-yl 410propyl)phenoxy3,5-(bis-2- 4-(trifluoromethoxy)phenyl 458propyl)phenoxy3,5-(bis-2- 2-fluoro-4- 460propyl)phenoxy (trifluoromethyl)phenyl3,5-(bis-2- 3-bromothienyl 459propyl)phenoxy3,5-(bis-2- 2-acetoxyphenyl 432propyl)phenoxy3,5-(bis-2- 5-methylisoxazol-3-yl 379propyl)phenoxy3,5-(bis-2- 2-(phenylthio)pyrid-3-yl 484propyl)phenoxy3,5-(bis-2- 2-(trifluoromethoxy)phenyl 458propyl)phenoxy3,5-(bis-2- 1-phenyl-5-propylpyrazin- 483propyl)phenoxy 4-yl3,5-(bis-2- 2-ethoxyphenyl 418propyl)phenoxy3,5-(bis-2- 3-chlorothiophen-2-yl 415propyl)phenoxy3,5-(bis-2- 1-(2-(2-methyl)propyl)-3- 435propyl)phenoxy methylpyrazol-5-yl3,5-(bis-2- 3,5-dichlorophenyl 443propyl)phenoxy3,5-(bis-2- 2-(propylthio)pyridin-3-yl 450propyl)phenoxy3,5-(bis-2- 2-(ethylthio)pyridin-3-yl 436propyl)phenoxy3,5-(bis-2- 3-bromopyridin-5-yl 454propyl)phenoxy3,5-(bis-2- 4-methyl-1,2,3-thiadiazol- 396propyl)phenoxy 5-yl3,5-(bis-2- 1-methyl-3-(2-(2- 435propyl)phenoxy methyl)propyl)pyrazol-5-yl3,5-(bis-2- 3-chlorobenzo[b]thiophen- 465propyl)phenoxy 2-yl3,5-(bis-2- 4-chlorophenyl 409propyl)phenoxy3,5-(bis-2- 4-methyl-2-phenyl-1,2,3- 456propyl)phenoxy triazol-5-yl3,5-(bis-2- benzo[b]thiophen-2-yl 431propyl)phenoxy3,5-(bis-2- 3,4-dimethylphenyl 402propyl)phenoxy3,5-(bis-2- 2-(phenoxy)pyridin-3-yl 468propyl)phenoxy3,5-(bis-2- 2-(methylthio)pyridin-3-yl 422propyl)phenoxy3,5-(bis-2- 5-methyl-3-phenylisoxazol- 456propyl)phenoxy 4-yl3,5-(bis-2- 4-chloro-1,3-dimethyl 478propyl)phenoxy pyrazolo[3,4-b]pyridin-3- yl3,5-(bis-2- 2-chloro-6-methylpyridin- 424propyl)phenoxy 4-yl3,5-(bis-2- 3,5-dimethylisoxazol-4-yl 393propyl)phenoxy3,5-(bis-2- 1-naphthyl 425propyl)phenoxy3,5-(bis-2- 2-fluorophenyl 392propyl)phenoxy3,5-(bis-2- 4-propylphenyl 417propyl)phenoxy3,5-(bis-2- 3-fluorophenyl 392propyl)phenoxy3,5-(bis-2- 2,6-difluorophenyl 410propyl)phenoxy3,5-(bis-2- 2-chlorophenyl 409propyl)phenoxy3,5-(bis-2- 3-(chloromethyl)phenyl 423propyl)phenoxy3,5-(bis-2- 4-(2-(2-methyl)propyl) 431propyl)phenoxy phenyl3,5-(bis-2- 3-chlorophenyl 409propyl)phenoxy3,5-(bis-2- 3,5-dimethoxyphenyl 434propyl)phenoxy3,5-(bis-2- 2,6-dichlorophenyl 443propyl)phenoxy3,5-(bis-2- 2,4-dichlorophenyl 443propyl)phenoxy3,5-(bis-2- 4-fluorophenyl 392propyl)phenoxy3,5-(bis-2- 4-butylphenyl 431propyl)phenoxy3,5-(bis-2- 2-methylphenyl 388propyl)phenoxy3,5-(bis-2- phenyl 374propyl)phenoxy3,5-(bis-2- 4-ethylphenyl 402propyl)phenoxy3,5-(bis-2- 2,3-difluorophenyl 410propyl)phenoxy3,5-(bis-2- 2,6-dimethoxyphenyl 434propyl)phenoxy3,5-(bis-2- 3,4-difluorophenyl 410propyl)phenoxy3,5-(bis-2- 2,5-difluorophenyl 410propyl)phenoxy3,5-(bis-2- 4-ethoxyphenyl 418propyl)phenoxy3,5-(bis-2- 2,4,6-trichlorophenyl 478propyl)phenoxy3,5-(bis-2- 3-methylphenyl 388propyl)phenoxy3,5-(bis-2- 2-fluoro-5- 460propyl)phenoxy (trifluoromethyl)phenyl3,5-(bis-2- 3-methoxyphenyl 404propyl)phenoxy3,5-(bis-2- 2-bromophenyl 453propyl)phenoxy3,5-(bis-2- 4-bromophenyl 453propyl)phenoxy3,5-(bis-2- 4-fluoro-3- 460propyl)phenoxy (trifluoromethyl)phenyl3,5-(bis-2- 3-(trifluoromethoxy)phenyl 458propyl)phenoxy3,5-(bis-2- 9-fluorenon-4-yl 477propyl)phenoxy3,5-(bis-2- isoxazol-5-yl 365propyl)phenoxy3,5-(bis-2- benzofuroxan-5-yl 432propyl)phenoxy3,5-(bis-2- 2-chloropyrid-3-yl 410propyl)phenoxy3,5-(bis-2- 2-(4- 482propyl)phenoxy methylphenoxy)pyridin-3-yl3,5-(bis-2- pyridin-4-yl 375propyl)phenoxy3,5-(bis-2- anthraquinon-2-yl 505propyl)phenoxy3,5-(bis-2- 2-iodophenyl 500propyl)phenoxy3,5-(bis-2- 4-pentylphenyl 445propyl)phenoxy3,5-(bis-2- 2-(4-chlorophenylthio) 518propyl)phenoxy pyridin-3-yl3,5-(bis-2- 2,6-dimethylphenyl 402propyl)phenoxy3,5-(bis-2- 2,5-dimethoxyphenyl 434propyl)phenoxy3,5-(bis-2- 2,5-dichloropyridin-3-yl 444propyl)phenoxy3,5-(bis-2- 2-chloro-6-methoxypyridin- 440propyl)phenoxy 4-yl3,5-(bis-2- 2,3-dichloropyridin-5-yl 444propyl)phenoxy3,5-(bis-2- 1-naphthyl 439propyl)phenoxy3,5-(bis-2- 2,4-dimethoxyphenyl 434propyl)phenoxy3,5-(bis-2- 3,5-bis(trifluoromethyl) 510propyl)phenoxy phenyl3,5-(bis-2- 2-(4- 502propyl)phenoxy chlorophenoxy)pyridin-3-yl3,5-(bis-2- pentafluorophenyl 464propyl)phenoxy3-trifluoromethyl 3,4-dimethoxyphenyl 418phenoxy3-trifluoromethyl 2-(trifluoromethyl)phenyl 426phenoxy3-trifluoromethyl 2,4-difluorophenyl 394phenoxy3-trifluoromethyl 3-(trifluoromethyl)phenyl 426phenoxy3-trifluoromethyl 2-naphthyl 408phenoxy3-trifluoromethyl 2-methoxyphenyl 388phenoxy3-trifluoromethyl 3,4,5-trimethylphenyl 448phenoxy3-trifluoromethyl 3,4-dichlorophenyl 427phenoxy3-trifluoromethyl 3-bromophenyl 437phenoxy3-trifluoromethyl 3-pyridyl 359phenoxy3-trifluoromethyl 2-ethoxynaphth-1-yl 452phenoxy3-trifluoromethyl 2,3-dichlorophenyl 427phenoxy3-trifluoromethyl 6-chloropyrid-3-yl 394phenoxy3-trifluoromethyl 4-(trifluoromethoxy)phenyl 442phenoxy3-trifluoromethyl 2-fluoro-4- 444phenoxy (trifluoromethyl)phenyl3-trifluoromethyl 3-bromothienyl 443phenoxy3-trifluoromethyl 2-acetoxyphenyl 416phenoxy3-trifluoromethyl 5-methylisoxazol-3-yl 363phenoxy3-trifluoromethyl 2-(phenylthio)pyrid-3-yl 467phenoxy3-trifluoromethyl 2-(trifluoromethoxy)phenyl 442phenoxy3-trifluoromethyl 1-phenyl-5-propylpyrazin- 466phenoxy 4-yl3-trifluoromethyl 2-ethoxyphenyl 402phenoxy3-trifluoromethyl 3-chlorothien-2-yl 399phenoxy3-trifluoromethyl 1-(2-(2-methyl)propyl)-3- 418phenoxy methylpyrazol-5-yl3-trifluoromethyl 3,5-dichlorophenyl 427phenoxy3-trifluoromethyl 2-(propylthio)pyridin-3-yl 433phenoxy3-trifluoromethyl 2-(ethylthio)pyridin-3-yl 419phenoxy3-trifluoromethyl 3-bromopyridin-5-yl 438phenoxy3-trifluoromethyl 4-methyl-1,2,3-thiadiazol- 380phenoxy 5-yl3-trifluoromethyl 1-methyl-3-(2-(2- 418phenoxy methyl)propyl)pyrazol-5-yl3-trifluoromethyl 3-chlorobenzo[b]thiophen- 449phenoxy 2-yl3-trifluoromethyl 4-chlorophenyl 393phenoxy3-trifluoromethyl 4-methyl-2-phenyl-1,2,3- 439phenoxy triazol-5-yl3-trifluoromethyl benzo[b]thiophen-2-yl 414phenoxy3-trifluoromethyl 3,4-dimethylphenyl 386phenoxy3-trifluoromethyl 2-(phenoxy)pyridin-3-yl 451phenoxy3-trifluoromethyl 2-(methylthio)pyridin-3-yl 405phenoxy3-trifluoromethyl 5-methyl-3-phenylisoxazol- 439phenoxy 4-yl3-trifluoromethyl 4-chloro-1,3-dimethyl 462phenoxy pyrazolo[3,4-b]pyridin-3- yl3-trifluoromethyl 2-chloro-6-methylpyridin- 408phenoxy 4-yl3-trifluoromethyl 3,5-dimethylisoxazol-4-yl 377phenoxy3-trifluoromethyl 1-naphthyl 408phenoxy3-trifluoromethyl 2-fluorophenyl 476phenoxy3-trifluoromethyl 4-propylphenyl 400phenoxy3-trifluoromethyl 3-fluorophenyl 376phenoxy3-trifluoromethyl 2,6-difluorophenyl 394phenoxy3-trifluoromethyl 2-chlorophenyl 393phenoxy3-trifluoromethyl 3-(chloromethyl)phenyl 407phenoxy3-trifluoromethyl 4-(2-(2-methyl)propyl) 414phenoxy phenyl3-trifluoromethyl 3-chlorophenyl 393phenoxy3-trifluoromethyl 3,5-dimethoxyphenyl 418phenoxy3-trifluoromethyl 2,6-dichlorophenyl 427phenoxy3-trifluoromethyl 2,4-dichlorophenyl 427phenoxy3-trifluoromethyl 4-fluorophenyl 376phenoxy3-trifluoromethyl 4-butylphenyl 414phenoxy3-trifluoromethyl 2-methylphenyl 372phenoxy3-trifluoromethyl phenyl 358phenoxy3-trifluoromethyl 4-ethylphenyl 386phenoxy3-trifluoromethyl 2,3-difluorophenyl 394phenoxy3-trifluoromethyl 2,6-dimethoxyphenyl 418phenoxy3-trifluoromethyl 3,4-difluorophenyl 394phenoxy3-trifluoromethyl 2,5-difluorophenyl 394phenoxy3-trifluoromethyl 4-ethoxyphenyl 402phenoxy3-trifluoromethyl 2,4,6-trichlorophenyl 462phenoxy3-trifluoromethyl 3-methylphenyl 372phenoxy3-trifluoromethyl 2-fluoro-5- 444phenoxy (trifluoromethyl)phenyl3-trifluoromethyl 3-methoxyphenyl 388phenoxy3-trifluoromethyl 2-bromophenyl 437phenoxy3-trifluoromethyl 4-bromophenyl 437phenoxy3-trifluoromethyl 4-fluoro-3- 444phenoxy (trifluoromethyl)phenyl3-trifluoromethyl 3-(trifluoromethoxy)phenyl 442phenoxy3-trifluoromethyl 9-fluorenon-4-yl 460phenoxy3-trifluoromethyl isoxazol-5-yl 349phenoxy3-trifluoromethyl benzofuroxan-5-yl 416phenoxy3-trifluoromethyl 2-chloropyrid-3-yl 394phenoxy3-trifluoromethyl 2-(4- 465phenoxy methylphenoxy)pyridin-3-yl3-trifluoromethyl pyridin-4-yl 359phenoxy3-trifluoromethyl anthraquinon-2-yl 488phenoxy3-trifluoromethyl 2-iodophenyl 484phenoxy3-trifluoromethyl 4-pentylphenyl 428phenoxy3-trifluoromethyl 2-(4-chlorophenylthio) 502phenoxy pyridin-3-yl3-trifluoromethyl 2,6-dimethylphenyl 386phenoxy3-trifluoromethyl 2,5-dimethoxyphenyl 418phenoxy3-trifluoromethyl 2,5-dichloropyridin-3-yl 428phenoxy3-trifluoromethyl 2-chloro-6-methoxypyridin- 424phenoxy 4-yl3-trifluoromethyl 2,3-dichloropyridin-5-yl 428phenoxy3-trifluoromethyl 1-naphthyl 422phenoxy3-trifluoromethyl 2,4-dimethoxyphenyl 418phenoxy3-trifluoromethyl 3,5- 494phenoxy bis(trifluoromethyl)phenyl3-trifluoromethyl 2-(4- 486phenoxy chlorophenoxy)pyridin-3-yl3-trifluoromethyl pentafluorophenyl 448phenoxy2,6-dichlorophenoxy 3,4-dimethoxyphenyl 4192,6-dichlorophenoxy 2-(trifluoromethyl)phenyl 4272,6-dichlorophenoxy 2,4-difluorophenyl 3952,6-dichlorophenoxy 3-(trifluoromethyl)phenyl 4272,6-dichlorophenoxy 2-naphthyl 4092,6-dichlorophenoxy 2-methoxyphenyl 3892,6-dichlorophenoxy 3,4,5-trimethylphenyl 4492,6-dichlorophenoxy 3,4-dichlorophenyl 4282,6-dichlorophenoxy 3-bromophenyl 4382,6-dichlorophenoxy 3-pyridyl 3612,6-dichlorophenoxy 2-ethoxynaphth-1-yl 4532,6-dichlorophendxy 2,3-dichlorophenyl 4282,6-dichlorophenoxy 6-chloropyrid-3-yl 3952,6-dichlorophenoxy 4-(trifluoromethoxy)phenyl 4432,6-dichlorophenoxy 2-fluoro-4- 445 (trifluoromethyl)phenyl2,6-dichlorophenoxy 3-bromothienyl 4442,6-dichlorophenoxy 2-acetoxyphenyl 4172,6-dichlorophenoxy 5-methylisoxazol-3-yl 3642,6-dichlorophenoxy 2-(phenylthio)pyrid-3-yl 4682,6-dichlorophenoxy 2-(trifluoromethoxy)phenyl 4432,6-dichlorophenoxy 1-phenyl-5-propylpyrazin- 467 4-yl2,6-dichlorophenoxy 2-ethoxyphenyl 4032,6-dichlorophenoxy 3-chlorothien-2-yl 4002,6-dichlorophenoxy 1-(2-(2-methyl)propyl)-3- 419 methylpyrazol-5-yl2,6-dichlorophenoxy 3,5-dichlorophenyl 4282,6-dichlorophenoxy 2-(propylthio)pyridin-3-yl 4342,6-dichlorophenoxy 2-(ethylthio)pyridin-3-yl 4202,6-dichlorophenoxy 3-bromopyridin-5-yl 4392,6-dichlorophenoxy 4-methyl-1,2,3-thiadiazol- 381 5-yl2,6-dichlorophenoxy 1-methyl-3-(2-(2- 419 methyl)propyl)pyrazol-5-yl2,6-dichlorophenoxy 3-chlorobenzo[b]thiophen- 450 2-yl2,6-dichlorophenoxy 4-chlorophenyl 3942,6-dichlorophenoxy 4-methyl-2-phenyl-1,2,3- 440 triazol-5-yl2,6-dichlorophenoxy benzo[b]thiophen-2-yl 4152,6-dichlorophenoxy 3,4-dimethylphenyl 3872,6-dichlorophenoxy 2-(phenoxy)pyridin-3-yl 4522,6-dichlorophenoxy 2-(methylthio)pyridin-3-yl 4062,6-dichlorophenoxy 5-methyl-3-phenylisoxazol- 440 4-yl2,6-dichlorophenoxy 4-chloro-1,3-dimethyl 463 pyrazolo[3,4-b]pyridin-3- yl2,6-dichlorophenoxy 2-chloro-6-methylpyridin- 409 4-yl2,6-dichlorophenoxy 3,5-dimethylisoxazol-4-yl 3782,6-dichlorophenoxy 1-naphthyl 4092,6-dichlorophenoxy 2-fluorophenyl 3772,6-dichlorophenoxy 4-propylphenyl 4012,6-dichlorophenoxy 3-fluorophenyl 3772,6-dichlorophenoxy 2,6-difluorophenyl 3952,6-dichlorophenoxy 2-chlorophenyl 3942,6-dichlorophenoxy 3-(chloromethyl)phenyl 4082,6-dichlorophenoxy 4-(2-(2-methyl)propyl) 415 phenyl2,6-dichlorophenoxy 3-chlorophenyl 6942,6-dichlorophenoxy 3,5-dimethoxyphenyl 4192,6-dichlorophenoxy 2,6-dichlorophenyl 4282,6-dichlorophenoxy 2,4-dichlorophenyl 4282,6-dichlorophenoxy 4-fluorophenyl 3772,6-dichlorophenoxy 4-butylphenyl 4152,6-dichlorophenoxy 2-methylphenyl 3732,6-dichlorophenoxy phenyl 3592,6-dichlorophenoxy 4-ethylphenyl 3872,6-dichlorophenoxy 2,3-difluorophenyl 3952,6-dichlorophenoxy 2,6-dimethoxyphenyl 4192,6-dichlorophenoxy 3,4-difluorophenyl 3952,6-dichlorophenoxy 2,5-difluorophenyl 3952,6-dichlorophenoxy 4-ethoxyphenyl 4032,6-dichlorophenoxy 2,4,6-trichlorophenyl 4632,6-dichlorophenoxy 3-methylphenyl 3732,6-dichlorophenoxy 2-fluoro-5- 445 (trifluoromethyl)phenyl2,6-dichlorophenoxy 3-methoxyphenyl 3892,6-dichlorophenoxy 2-bromophenyl 4382,6-dichlorophenoxy 4-bromophenyl 4382,6-dichlorophenoxy 4-fluoro-3- 445 (trifluoromethyl)phenyl2,6-dichlorophenoxy 3-(trifluoromethoxy)phenyl 4432,6-dichlorophenoxy 9-fluorenon-4-yl 4612,6-dichlorophenoxy isoxazol-5-yl 3502,6-dichlorophenoxy benzofuroxan-5-yl 4172,6-dichlorophenoxy 2-chloropyrid-3-yl 3952,6-dichlorophenoxy 2-(4- 466 methylphenoxy)pyridin-3-yl2,6-dichlorophenoxy pyridin-4-yl 3602,6-dichlorophenoxy anthraquinon-2-yl 4892,6-dichlorophenoxy 2-iodophenyl 4852,6-dichlorophenoxy 4-pentylphenyl 4292,6-dichlorophenoxy 2-(4-chlorophenylthio) 503 pyridin-3-yl2,6-dichlorophenoxy 2,6-dimethylphenyl 3872,6-dichlorophenoxy 2,5-dimethoxyphenyl 4192,6-dichlorophenoxy 2,5-dichloropyridin-3-yl 4292,6-dichlorophenoxy 2-chloro-6-methoxypyridin- 425 4-yl2,6-dichlorophenoxy 2,3-dichloropyridin-5-yl 4292,6-dichlorophenoxy 1-naphthyl 4132,6-dichlorophenoxy 2,4-dimethoxyphenyl 4192,6-dichlorophenoxy 3,5- 495 bis(trifluoromethyl)phenyl2,6-dichlorophenoxy 2-(4- 487 chlorophenoxy)pyridin-3-yl2,6-dichlorophenoxy pentafluorophenyl 4492,4-dichlorophenoxy 3,4-dimethoxyphenyl 4192,4-dichlorophenoxy 2-(trifluoromethyl)phenyl 4272,4-dichlorophenoxy 2,4-difluorophenyl 3952,4-dichlorophenoxy 3-(trifluoromethyl)phenyl 4272,4-dichlorophenoxy 2-naphthyl 4092,4-dichlorophenoxy 2-methoxyphenyl 3892,4-dichlorophenoxy 3,4,5-trimethylphenyl 4492,4-dichlorophenoxy 3,4-dichlorophenyl 4282,4-dichlorophenoxy 3-bromophenyl 4382,4-dichlorophenoxy 3-pyridyl 3612,4-dichlorophenoxy 2-ethoxynaphth-1-yl 4532,4-dichlorophenoxy 2,3-dichlorophenyl 4282,4-dichlorophenoxy 6-chloropyrid-3-yl 3952,4-dichlorophenoxy 4-(trifluoromethoxy)phenyl 4432,4-dichlorophenoxy 2-fluoro-4- 445 (trifluoromethyl)phenyl2,4-dichlorophenoxy 3-bromothienyl 4442,4-dichlorophenoxy 2-acetoxyphenyl 4172,4-dichlorophenoxy 5-methylisoxazol-3-yl 3642,4-dichlorophenoxy 2-(phenylthio)pyrid-3-yl 4682,4-dichlorophenoxy 2-(trifluoromethoxy)phenyl 4432,4-dichlorophenoxy 1-phenyl-5-propylpyrazin- 467 4-yl2,4-dichlorophenoxy 2-ethoxyphenyl 4032,4-dichlorophenoxy 3-chlorothien-2-yl 4002,4-dichlorophenoxy 1-(2-(2-methyl)propyl)-3- 419 methylpyrazol-5-yl2,4-dichlorophenoxy 3,5-dichlorophenyl 4282,4-dichlorophenoxy 2-(propylthio)pyridin-3-yl 4342,4-dichlorophenoxy 2-(ethylthio)pyridin-3-yl 4202,4-dichlorophenoxy 3-bromopyridin-5-yl 4392,4-dichlorophenoxy 4-methyl-1,2,3-thiadiazol- 381 5-yl2,4-dichlorophenoxy 1-methyl-3-(2-(2- 419 methyl)propyl)pyrazol-5-yl2,4-dichlorophenoxy 3-chlorobenzo[b]thiophen- 450 2-yl2,4-dichlorophenoxy 4-chlorophenyl 3942,4-dichlorophenoxy 4-methyl-2-phenyl-1,2,3- 440 triazol-5-yl2,4-dichlorophenoxy benzo[b]thiophen-2-yl 4152,4-dichlorophenoxy 3,4-dimethylphenyl 3872,4-dichlorophenoxy 2-(phenoxy)pyridin-3-yl 4522,4-dichlorophenoxy 2-(methylthio)pyridin-3-yl 4062,4-dichlorophenoxy 5-methyl-3-phenylisoxazol- 440 4-yl2,4-dichlorophenoxy 4-chloro-1,3-dimethyl 463 pyrazolo[3,4-b]pyridin-3- yl2,4-dichlorophenoxy 2-chloro-6-methylpyridin- 409 4-yl2,4-dichlorophenoxy 3,5-dimethylisoxazol-4-yl 3782,4-dichlorophenoxy 1-naphthyl 4092,4-dichlorophenoxy 2-fluorophenyl 3772,4-dichlorophenoxy 4-propylphenyl 4012,4-dichlorophenoxy 3-fluorophenyl 3772,4-dichlorophenoxy 2,6-difluorophenyl 3952,4-dichlorophenoxy 2-chlorophenyl 3942,4-dichlorophenoxy 3-(chloromethyl)phenyl 4082,4-dichlorophenoxy 4-(2-(2- 415 methyl)propyl)phenyl2,4-dichlorophenoxy 3-chlorophenyl 6942,4-dichlorophenoxy 3,5-dimethoxyphenyl 4192,4-dichlorophenoxy 2,6-dichlorophenyl 4282,4-dichlorophenoxy 2,4-dichlorophenyl 4282,4-dichlorophenoxy 4-fluorophenyl 3772,4-dichlorophenoxy 4-butylphenyl 4152,4-dichlorophenoxy 2-methylphenyl 3732,4-dichlorophenoxy phenyl 3592,4-dichlorophenoxy 4-ethylphenyl 3872,4-dichlorophenoxy 2,3-difluorophenyl 3952,4-dichlorophenoxy 2,6-dimethoxyphenyl 4192,4-dichlorophenoxy 3,4-difluorophenyl 3952,4-dichlorophenoxy 2,5-difluorophenyl 3952,4-dichlorophenoxy 4-ethoxyphenyl 4032,4-dichlorophenoxy 2,4,6-trichlorophenyl 4632,4-dichlorophenoxy 3-methylphenyl 3732,4-dichlorophenoxy 2-fluoro-5- 445 (trifluoromethyl)phenyl2,4-dichlorophenoxy 3-methoxyphenyl 3892,4-dichlorophenoxy 2-bromophenyl 4382,4-dichlorophenoxy 4-bromophenyl 4382,4-dichlorophenoxy 4-fluoro-3- 445 (trifluoromethyl)phenyl2,4-dichlorophenoxy 3-(trifluoromethoxy)phenyl 4432,4-dichlorophenoxy 9-fluorenon-4-yl 4612,4-dichlorophenoxy isoxazol-5-yl 3502,4-dichlorophenoxy benzofuroxan-5-yl 4172,4-dichlorophenoxy 2-chloropyrid-3-yl 3952,4-dichlorophenoxy 2-(4- 466 methylphenoxy)pyridin-3-yl2,4-dichlorophenoxy pyridin-4-yl 3602,4-dichlorophenoxy anthraquinon-2-yl 4892,4-dichlorophenoxy 2-iodophenyl 4852,4-dichlorophenoxy 4-pentylphenyl 4292,4-dichlorophenoxy 2-(4-chlorophenylthio) 503 pyridin-3-yl2,4-dichlorophenoxy 2,6-dimethylphenyl 3872,4-dichlorophenoxy 2,5-dimethoxyphenyl 4192,4-dichlorophenoxy 2,5-dichloropyridin-3-yl 4292,4-dichlorophenoxy 2-chloro-6-methoxypyridin- 425 4-yl2,4-dichlorophenoxy 2,3-dichloropyridin-5-yl 4292,4-dichlorophenoxy 1-naphthyl 4132,4-dichlorophenoxy 2,4-dimethoxyphenyl 4192,4-dichlorophenoxy 3,5- 495 bis(trifluoromethyl)phenyl2,4-dichlorophenoxy 2-(4- 487 chlorophenoxy)pyridin-3-yl2,4-dichlorophenoxy pentafluorophenyl 4494-chloro-3- 3,4-dimethoxyphenyl 319methylphenoxy4-chloro-3- 2-(trifluoromethyl)phenyl 407methylphenoxy4-chloro-3- 2,4-difluorophenyl 375methylphenoxy4-chloro-3- 3-(trifluoromethyl)phenyl 407methylphenoxy4-chloro-3- 2-naphthyl 389methylphenoxy4-chloro-3- 2-methoxyphenyl 369methylphenoxy4-chloro-3- 3,4,5-trimethylphenyl 429methylphenoxy4-chloro-3- 3,4-dichlorophenyl 408methylphenoxy4-chloro-3- 3-bromophenyl 418methylphenoxy4-chloro-3- 3-pyridyl 340methylphenoxy4-chloro-3- 2-ethoxynaphth-1-yl 433methylphenoxy4-chloro-3- 2,3-dichlorophenyl 408methylphenoxy4-chloro-3- 6-chloropyrid-3-yl 374methylphenoxy4-chloro-3- 4-(trifluoromethoxy)phenyl 423methylphenoxy4-chloro-3- 2-fluoro-4- 425methylphenoxy (trifluoromethyl)phenyl4-chloro-3- 3-bromothienyl 424methylphenoxy4-chloro-3- 2-acetoxyphenyl 397methylphenoxy4-chloro-3- 5-methylisoxazol-3-yl 344methylphenoxy4-chloro-3- 2-(phenylthio)pyrid-3-yl 448methylphenoxy4-chloro-3- 2-(trifluoromethoxy)phenyl 423methylphenoxy4-chloro-3- 1-phenyl-5-propylpyrazin- 447methylphenoxy 4-yl4-chloro-3- 2-ethoxyphenyl 383methylphenoxy4-chloro-3- 3-chlorothien-2-yl 379methylphenoxy4-chloro-3- 1-(2-(2-methyl)propyl)-3- 399methylphenoxy methylpyrazol-5-yl4-chloro-3- 3,5-dichlorophenyl 408methylphenoxy4-chloro-3- 2-(propylthio)pyridin-3-yl 414methylphenoxy4-chloro-3- 2-(ethylthio)pyridin-3-yl 400methylphenoxy4-chloro-3- 3-bromopyridin-5-yl 419methylphenoxy4-chloro-3- 4-methyl-1,2,3-thiadiazol- 361methylphenoxy 5-yl4-chloro-3- 1-methyl-3-(2-(2- 399methylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-3- 3-chlorobenzo[b]thiophen- 429methylphenoxy 2-yl4-chloro-3- 4-chlorophenyl 373methylphenoxy4-chloro-3- 4-methyl-2-phenyl-1,2,3- 420methylphenoxy triazol-5-yl4-chloro-3- benzo[b]thiophen-2-yl 395methylphenoxy4-chloro-3- 3,4-dimethylphenyl 367methylphenoxy4-chloro-3- 2-(phenoxy)pyridin-3-yl 432methylphenoxy4-chloro-3- 2-(methylthio)pyridin-3-yl 386methylphenoxy4-chloro-3- 5-methyl-3-phenylisoxazol- 420methylphenoxy 4-yl4-chloro-3- 4-chloro-1,3-dimethyl 442methylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-3- 2-chloro-6-methylpyridin- 388methylphenoxy 4-yl4-chloro-3- 3,5-dimethylisoxazol-4-yl 358methylphenoxy4-chloro-3- 1-naphthyl 389methylphenoxy4-chloro-3- 2-fluorophenyl 357methylphenoxy4-chloro-3- 4-propylphenyl 381methylphenoxy4-chloro-3- 4-(trifluoromethyl)phenyl 407methylphenoxy4-chloro-3- 3-fluorophenyl 357methylphenoxy4-chloro-3- 2,6-difluorophenyl 375methylphenoxy4-chloro-3- 2-chlorophenyl 373methylphenoxy4-chloro-3- 3-(chloromethyl)phenyl 387methylphenoxy4-chloro-3- 4-(2-(2- 395methylphenoxy methyl)propyl)phenyl4-chloro-3- 3-chlorophenyl 373methylphenoxy4-chloro-3- 3,5-dimethoxyphenyl 399methylphenoxy4-chloro-3- 2,6-dichlorophenyl 408methylphenoxy4-chloro-3- 2,4-dichlorophenyl 408methylphenoxy4-chloro-3- 4-fluorophenyl 357methylphenoxy4-chloro-3- 4-butylphenyl 395methylphenoxy4-chloro-3- 2-methylphenyl 353methylphenoxy4-chloro-3- phenyl 339methylphenoxy4-chloro-3- 4-ethylphenyl 367methylphenoxy4-chloro-3- 2,3-difluorophenyl 375methylphenoxy4-chloro-3- 2,6-dimethoxyphenyl 399methylphenoxy4-chloro-3- 3,4-difluorophenyl 375methylphenoxy4-chloro-3- 2,5-difluorophenyl 375methylphenoxy4-chloro-3- 4-ethoxyphenyl 383methylphenoxy4-chloro-3- 2,4,6-trichlorophenyl 442methylphenoxy4-chloro-3- 3-methylphenyl 353methylphenoxy4-chloro-3- 2-fluoro-5- 425methylphenoxy (trifluoromethyl)phenyl4-chloro-3- 3-methoxyphenyl 369methylphenoxy4-chloro-3- 2-bromophenyl 418methylphenoxy4-chloro-3- 4-bromophenyl 418methylphenoxy4-chloro-3- 4-fluoro-3- 425methylphenoxy (trifluoromethyl)phenyl4-chloro-3- 3-(trifluoromethoxy)phenyl 423methylphenoxy4-chloro-3- 9-fluorenon-4-yl 441methylphenoxy4-chloro-3- isoxazol-5-yl 330methylphenoxy4-chloro-3- benzofuroxan-5-yl 397methylphenoxy4-chloro-3- 2-chloropyrid-3-yl 374methylphenoxy4-chloro-3- 2-(4- 446methylphenoxy methylphenoxy)pyridin-3-yl4-chloro-3- pyridin-4-yl 340methylphenoxy4-chloro-3- anthraquinon-2-yl 469methylphenoxy4-chloro-3- 2-iodophenyl 465methylphenoxy4-chloro-3- 4-pentylphenyl 409methylphenoxy4-chloro-3- 2-(4-chlorophenylthio) 482methylphenoxy pyridin-3-yl4-chloro-3- 2,6-dimethylphenyl 367methylphenoxy4-chloro-3- 2,5-dimethoxyphenyl 399methylphenoxy4-chloro-3- 2,5-dichloropyridin-3-yl 409methylphenoxy4-chloro-3- 2-chloro-6-methoxypyridin- 404methylphenoxy 4-yl4-chloro-3- 2,3-dichloropyridin-5-yl 409methylphenoxy4-chloro-3- 1-naphthyl 403methylphenoxy4-chloro-3- 2,4-dimethoxyphenyl 399methylphenoxy4-chloro-3- 3,5- 475methylphenoxy bis(trifluoromethyl)phenyl4-chloro-3- 2-(4- 466methylphenoxy chlorophenoxy)pyridin-3-yl4-chloro-3- pentafluorophenyl 429methylphenoxy4-chloro-2- 3,4-dimethoxyphenyl 467cyclohexylphenoxy4-chloro-2- 2-(trifluoromethyl)phenyl 475cyclohexylphenoxy4-chloro-2- 2,4-difluorophenyl 443cyclohexylphenoxy4-chloro-2- 3-(trifluoromethyl)phenyl 475cyclohexylphenoxy4-chloro-2- 2-naphthyl 457cyclohexylphenoxy4-chloro-2- 2-methoxyphenyl 437cyclohexylphenoxy4-chloro-2- 3,4,5-trimethylphenyl 497cyclohexylphenoxy4-chloro-2- 3,4-dichlorophenyl 176cyclohexylphenoxy4-chloro-2- 3-bromophenyl 486cyclohexylphenoxy4-chloro-2- 3-pyridyl 408cyclohexylphenoxy4-chloro-2- 2-ethoxynaphth-1-yl 501cyclohexylphenoxy4-chloro-2- 2,3-dichlorophenyl 476cyclohexylphenoxy4-chloro-2- 6-chloropyrid-3-yl 442cyclohexylphenoxy4-chloro-2- 4-(trifluoromethoxy)phenyl 491cyclohexylphenoxy4-chloro-2- 2-fluoro-4- 493cyclohexylphenoxy (trifluoromethyl)phenyl4-chloro-2- 3-bromothienyl 492cyclohexylphenoxy4-chloro-2- 2-acetoxyphenyl 465cyclohexylphenoxy4-chloro-2- 5-methylisoxazol-3-yl 412cyclohexylphenoxy4-chloro-2- 2-(phenylthio)pyrid-3-yl 516cyclohexylphenoxy4-chloro-2- 2-(trifluoromethoxy)phenyl 491cyclohexylphenoxy4-chloro-2- 1-phenyl-5-propylpyrazin- 515cyclohexylphenoxy 4-yl4-chloro-2- 2-ethoxyphenyl 451cyclohexylphenoxy4-chloro-2- 3-chlorothien-2-yl 447cyclohexylphenoxy4-chloro-2- 1-(2-(2-methyl)propyl)-3- 467cyclohexylphenoxy methylpyrazol-5-yl4-chloro-2- 3,5-dichlorophenyl 476cyclohexylphenoxy4-chloro-2- 2-(propylthio)pyridin-3-yl 482cyclohexylphenoxy4-chloro-2- 2-(ethylthio)pyridin-3-yl 468cyclohexylphenoxy4-chloro-2- 3-bromopyridin-5-yl 487cyclohexylphenoxy4-chloro-2- 4-methyl-1,2,3-thiadiazol- 429cyclohexylphenoxy 5-yl4-chloro-2- 1-methyl-3-(2-(2- 467cyclohexylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-2- 3-chlorobenzo[b]thiophen- 497cyclohexylphenoxy 2-yl4-chloro-2- 4-chlorophenyl 441cyclohexylphenoxy4-chloro-2- 4-methyl-2-phenyl-1,2,3- 488cyclohexylphenoxy triazol-5-yl4-chloro-2- benzo[b]thiophen-2-yl 463cyclohexylphenoxy4-chloro-2- 3,4-dimethylphenyl 435cyclohexylphenoxy4-chloro-2- 2-(phenoxy)pyridin-3-yl 500cyclohexylphenoxy4-chloro-2- 2-(methylthio)pyridin-3-yl 454cyclohexylphenoxy4-chloro-2- 5-methyl-3-phenylisoxazol- 488cyclohexylphenoxy 4-yl4-chloro-2- 4-chloro-1,3-dimethyl 510cyclohexylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 456cyclohexylphenoxy 4-yl4-chloro-2- 3,5-dimethylisoxazol-4-yl 426cyclohexylphenoxy4-chloro-2- 1-naphthyl 457cyclohexylphenoxy4-chloro-2- 2-fluorophenyl 425cyclohexylphenoxy4-chloro-2- 4-propylphenyl 449cyclohexylphenoxy4-chloro-2- 3-fluorophenyl 425cyclohexylphenoxy4-chloro-2- 2,6-difluorophenyl 443cyclohexylphenoxy4-chloro-2- 2-chlorophenyl 441cyclohexylphenoxy4-chloro-2- 3-(chloromethyl)phenyl 455cyclohexylphenoxy4-chloro-2- 4-(2-(2- 463cyclohexylphenoxy methyl)propyl)phenyl4-chloro-2- 3-chlorophenyl 441cyclohexylphenoxy4-chloro-2- 3,5-dimethoxyphenyl 467cyclohexylphenoxy4-chloro-2- 2,6-dichlorophenyl 476cyclohexylphenoxy4-chloro-2- 2,4-dichlorophenyl 476cyclohexylphenoxy4-chloro-2- 4-fluorophenyl 425cyclohexylphenoxy4-chloro-2- 4-butylphenyl 463cyclohexylphenoxy4-chloro-2- 2-methylphenyl 421cyclohexylphenoxy4-chloro-2- phenyl 407cyclohexylphenoxy4-chloro-2- 4-ethylphenyl 435cyclohexylphenoxy4-chloro-2- 2,3-difluorophenyl 443cyclohexylphenoxy4-chloro-2- 2,6-dimethoxyphenyl 467cyclohexylphenoxy4-chloro-2- 3,4-difluorophenyl 443cyclohexylphenoxy4-chloro-2- 2,5-difluorophenyl 443cyclohexylphenoxy4-chloro-2- 4-ethoxyphenyl 451cyclohexylphenoxy4-chloro-2- 2,4,6-trichlorophenyl 510cyclohexylphenoxy4-chloro-2- 3-methylphenyl 421cyclohexylphenoxy4-chloro-2- 2-fluoro-5- 493cyclohexylphenoxy (trifluoromethyl)phenyl4-chloro-2- 3-methoxyphenyl 437cyclohexylphenoxy4-chloro-2- 2-bromophenyl 486cyclohexylphenoxy4-chloro-2- 4-bromophenyl 486cyclohexylphenoxy4-chloro-2- 4-fluoro-3- 493cyclohexylphenoxy (trifluoromethyl)phenyl4-chloro-2- 3-(trifluoromethoxy)phenyl 491cyclohexylphenoxy4-chloro-2- 9-fluorenon-4-yl 503cyclohexylphenoxy4-chloro-2- isoxazol-5-yl 398cyclohexylphenoxy4-chloro-2- benzofuroxan-5-yl 465cyclohexylphenoxy4-chloro-2- 2-chloropyrid-3-yl 442cyclohexylphenoxy4-chloro-2- 2-(4- 514cyclohexylphenoxy methylphenoxy)pyridin-3-yl4-chloro-2- pyridin-4-yl 408cyclohexylphenoxy4-chloro-2- anthraquinon-2-yl 537cyclohexylphenoxy4-chloro-2- 2-iodophenyl 533cyclohexylphenoxy4-chloro-2- 4-pentylphenyl 477cyclohexylphenoxy4-chloro-2- 2-(4-chlorophenylthio) 550cyclohexylphenoxy pyridin-3-yl4-chloro-2- 2,6-dimethylphenyl 435cyclohexylphenoxy4-chloro-2- 2,5-dimethoxyphenyl 467cyclohexylphenoxy4-chloro-2- 2,5-dichloropyridin-3-yl 477cyclohexylphenoxy4-chloro-2- 2-chloro-6-methoxypyridin- 472cyclohexylphenoxy 4-yl4-chloro-2- 2,3-dichloropyridin-5-yl 477cyclohexylphenoxy4-chloro-2- 1-naphthyl 471cyclohexylphenoxy4-chloro-2- 2,4-dimethoxyphenyl 467cyclohexylphenoxy4-chloro-2- 3,5- 546cyclohexylphenoxy bis(trifluoromethyl)phenyl4-chloro-2- 2-(4- 534cyclohexylphenoxy chlorophenoxy)pyridin-3-yl4-chloro-2- pentafluorophenyl 497cyclohexylphenoxy4-chloro-3,5- 3,4-dimethoxyphenyl 413dimethylphenoxy4-chloro-3,5- 2-(trifluoromethyl)phenyl 421dimethylphenoxy4-chloro-3,5- 2,4-difluorophenyl 389dimethylphenoxy4-chloro-3,5- 3-(trifluoromethyl)phenyl 421dimethylphenoxy4-chloro-3,5- 2-naphthyl 403dimethylphenoxy4-chloro-3,5- 2-methoxyphenyl 484dimethylphenoxy4-chloro-3,5- 3,4,5-trimethylphenyl 443dimethylphenoxy4-chloro-3,5- 3,4-dichlorophenyl 422dimethylphenoxy4-chloro-3,5- 3-bromophenyl 432dimethylphenoxy4-chloro-3,5- 3-pyridyl 354dimethylphenoxy4-chloro-3,5- 2-ethoxynaphth-1-yl 447dimethylphenoxy4-chloro-3,5- 2,3-dichlorophenyl 422dimethylphenoxy4-chloro-3,5- 6-chloropyrid-3-yl 388dimethylphenoxy4-chloro-3,5- 4-(trifluoromethoxy)phenyl 437dimethylphenoxy4-chloro-3,5- 2-fluoro-4- 439dimethylphenoxy (trifluoromethyl)phenyl4-chloro-3,5- 3-bromothienyl 438dimethylphenoxy4-chloro-3,5- 2-acetoxyphenyl 411dimethylphenoxy4-chloro-3,5- 5-methylisoxazol-3-yl 358dimethylphenoxy4-chloro-3,5- 2-(phenylthio)pyrid-3-yl 462dimethylphenoxy4-chloro-3,5- 2-(trifluoromethoxy)phenyl 437dimethylphenoxy4-chloro-3,5- 1-phenyl-5-propylpyrazin- 461dimethylphenoxy 4-yl4-chloro-3,5- 2-ethoxyphenyl 397dimethylphenoxy4-chloro-3,5- 3-chlorothien-2-yl 393dimethylphenoxy4-chloro-3,5- 1-(2-(2-methyl)propyl)-3- 413dimethylphenoxy methylpyrazol-5-yl4-chloro-3,5- 3,5-dichlorophenyl 422dimethylphenoxy4-chloro-3,5- 2-(propylthio)pyridin-3-yl 428dimethylphenoxy4-chloro-3,5- 2-(ethylthio)pyridin-3-yl 414dimethylphenoxy4-chloro-3,5- 3-bromopyridin-5-yl 433dimethylphenoxy4-chloro-3,5- 4-methyl-1,2,3-thiadiazol- 375dimethylphenoxy 5-yl4-chloro-3,5- 1-methyl-3-(2-(2- 413dimethylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-3,5 3-chlorobenzo[b]thiophen- 443dimethylphenoxy 2-yl4-chloro-3,5- 4-chlorophenyl 387dimethylphenoxy4-chloro-3,5- 4-methyl-2-phenyl-1,2,3- 434dimethylphenoxy triazol-5-yl4-chloro-3,5- benzo[b]thiophen-2-yl 409dimethylphenoxy4-chloro-3,5- 3,4-dimethylphenyl 381dimethylphenoxy4-chloro-3,5- 2-(phenoxy)pyridin-3-yl 446dimethylphenoxy4-chloro-3,5- 2-(methylthio)pyridin-3-yl 400dimethylphenoxy4-chloro-3,5- 5-methyl-3-phenylisoxazol- 434dimethylphenoxy 4-yl4-chloro-3,5- 4-chloro-1,3-dimethyl 456dimethylphenoxy pyrazolo[3 ,4-b]pyridin-3- yl4-chloro-3,5- 2-chloro-6-methylpyridin- 402dimethylphenoxy 4-yl4-chloro-3,5- 3,5-dimethylisoxazol-4-yl 372dimethylphenoxy4-chloro-3,5- 1-naphthyl 403dimethylphenoxy4-chloro-3,5- 2-fluorophenyl 371dimethylphenoxy4-chloro-3,5- 4-propylphenyl 395dimethylphenoxy4-chloro-3,5- 3-fluorophenyl 371dimethylphenoxy4-chloro-3,5- 2,6-difluorophenyl 389dimethylphenoxy4-chloro-3,5- 2-chlorophenyl 387dimethylphenoxy4-chloro-3,5- 3-(chloromethyl)phenyl 401dimethylphenoxy4-chloro-3,5- 4-(2-(2- 409dimethylphenoxy methyl)propyl)phenyl4-chloro-3,5- 3-chlorophenyl 387dimethylphenoxy4-chloro-3,5- 3,5-dimethoxyphenyl 413dimethylphenoxy4-chloro-3,5- 2,6-dichlorophenyl 422dimethylphenoxy4-chloro-3,5- 2,4-dichlorophenyl 422dimethylphenoxy4-chloro-3,5- 4-fluorophenyl 371dimethylphenoxy4-chloro-3,5- 4-butylphenyl 409dimethylphenoxy4-chloro-3,5- 2-methylphenyl 367dimethylphenoxy4-chloro-3,5- phenyl 353dimethylphenoxy4-chloro-3,5- 4-ethylphenyl 381dimethylphenoxy4-chloro-3,5- 2,3-difluorophenyl 389dimethylphenoxy4-chloro-3,5- 2,6-dimethoxyphenyl 413dimethylphenoxy4-chloro-3,5- 3,4-difluorophenyl 389dimethylphenoxy4-chloro-3,5- 2,5-difluorophenyl 389dimethylphenoxy4-chloro-3,5- 4-ethoxyphenyl 397dimethylphenoxy4-chloro-3,5- 2,4,6-trichlorophenyl 456dimethylphenoxy4-chloro-3,5- 3-methylphenyl 367dimethylphenoxy4-chloro-3,5- 2-fluoro-5- 439dimethylphenoxy (trifluoromethyl)phenyl4-chloro-3,5- 3-methoxyphenyl 383dimethylphenoxy4-chloro-3,5- 2-bromophenyl 432dimethylphenoxy4-chloro-3,5- 4-bromophenyl 432dimethylphenoxy4-chloro-3,5- 4-fluoro-3- 439dimethylphenoxy (trifluoromethyl)phenyl4-chloro-3,5- 3-(trifluoromethoxy)phenyl 437dimethylphenoxy4-chloro-3,5- 9-fluorenon-4-yl 455dimethylphenoxy4-chloro-3,5- isoxazol-5-yl 344dimethylphenoxy4-chloro-3,5- benzofuroxan-5-yl 411dimethylphenoxy4-chloro-3,5- 2-chloropyrid-3-yl 388dimethylphenoxy4-chloro-3,5- 2-(4- 460dimethylphenoxy methylphenoxy)pyridin-3-yl4-chloro-3,5- pyridin-4-yl 354dimethylphenoxy4-chloro-3,5- anthraquinon-2-yl 483dimethylphenoxy4-chloro-3,5- 2-iodophenyl 479dimethylphenoxy4-chloro-3,5- 4-pentylphenyl 423dimethylphenoxy4-chloro-3,5- 2-(4-chlorophenylthio) 496dimethylphenoxy pyridin-3-yl4-chloro-3,5- 2,6-dimethylphenyl 381dimethylphenoxy4-chloro-3,5- 2,5-dimethoxyphenyl 413dimethylphenoxy4-chloro-3,5- 2,5-dichloropyridin-3-yl 423dimethylphenoxy4-chloro-3,5- 2-chloro-6-methoxypyridin- 418dimethylphenoxy 4-yl4-chloro-3,5- 2,3-dichloropyridin-5-yl 423dimethylphenoxy4-chloro-3,5- 1-naphthyl 417dimethylphenoxy4-chloro-3,5- 2,4-dimethoxyphenyl 413dimethylphenoxy4-chloro-3,5- 3,5- 489dimethylphenoxy bis(trifluoromethyl)phenyl4-chloro-3,5- 2-(4- 480dimethylphenoxy chlorophenoxy)pyridin-3-yl4-chloro-3,5- pentafluorophenyl 443dimethylphenoxypyrid-3-yloxy 3,4-dimethoxyphenyl 351pyrid-3-yloxy 2-(trifluoromethyl)phenyl 359pyrid-3-yloxy 2,4-difluorophenyl 327pyrid-3-yloxy 3-(trifluoromethyl)phenyl 359pyrid-3-yloxy 2-naphthyl 341pyrid-3-yloxy 2-methoxyphenyl 321pyrid-3-yloxy 3,4,5-trimethylphenyl 381pyrid-3-yloxy 3,4-dichlorophenyl 360pyrid-3-yloxy 3-bromophenyl 370pyrid-3-yloxy 3-pyridyl 292pyrid-3-yloxy 2-ethoxynaphth-1-yl 385pyrid-3-yloxy 2,3-dichlorophenyl 360pyrid-3-yloxy 6-chloropyrid-3-yl 327pyrid-3-yloxy 4-(trifluoromethoxy)phenyl 375pyrid-3-yloxy 2-fluoro-4- 377 (trifluoromethyl)phenylpyrid-3-yloxy 3-bromothienyl 376pyrid-3-yloxy 2-acetoxyphenyl 349pyrid-3-yloxy 5-methylisoxazol-3-yl 296pyrid-3-yloxy 2-(phenylthio)pyrid-3-yl 400pyrid-3-yloxy 2-(trifluoromethoxy)phenyl 375pyrid-3-yloxy 1-phenyl-5-propylpyrazin- 399 4-ylpyrid-3-yloxy 2-ethoxyphenyl 335pyrid-3-yloxy 3-chlorothien-2-yl 332pyrid-3-yloxy 1-(2-(2-methyl)propyl)-3- 351 methylpyrazol-5-ylpyrid-3-yloxy 3,5-dichlorophenyl 360pyrid-3-yloxy 2-(propylthio)pyridin-3-yl 366pyrid-3-yloxy 2-(ethylthio)pyridin-3-yl 352pyrid-3-yloxy 3-bromopyridin-5-yl 371pyrid-3-yloxy 4-methyl-1,2,3-thiadiazol- 313 5-ylpyrid-3-yloxy 1-methyl-3-(2-(2- 351 methyl)propyl)pyrazol-5-ylpyrid-3-yloxy 3-chlorobenzo[b]thiophen- 382 2-ylpyrid-3-yloxy 4-chlorophenyl 326pyrid-3-yloxy 4-methyl-2-phenyl-1,2,3- 372 triazol-5-ylpyrid-3-yloxy benzo[b]thiophen-2-yl 347pyrid-3-yloxy 3,4-dimethylphenyl 319pyrid-3-yloxy 2-(phenoxy)pyridin-3-yl 384pyrid-3-yloxy 2-(methylthio)pyridin-3-yl 338pyrid-3-yloxy 5-methyl-3-phenylisoxazol- 372 4-ylpyrid-3-yloxy 4-chloro-1,3-dimethyl 395 pyrazolo[3,4-b]pyridin-3- ylpyrid-3-yloxy 2-chloro-6-methylpyridin- 341 4-ylpyrid-3-yloxy 3,5-dimethylisoxazol-4-yl 310pyrid-3-yloxy 1-naphthyl 341pyrid-3-yloxy 2-fluorophenyl 309pyrid-3-yloxy 4-propylphenyl 333pyrid-3-yloxy 3-fluorophenyl 309pyrid-3-yloxy 2,6-difluorophenyl 327pyrid-3-yloxy 2-chlorophenyl 326pyrid-3-yloxy 3-(chloromethyl)phenyl 340pyrid-3-yloxy 4-(2-(2- 347 methyl)propyl)phenylpyrid-3-yloxy 3-chlorophenyl 326pyrid-3-yloxy 3,5-dimethoxyphenyl 351pyrid-3-yloxy 2,6-dichlorophenyl 360pyrid-3-yloxy 2,4-dichlorophenyl 360pyrid-3-yloxy 4-fluorophenyl 309pyrid-3-yloxy 4-butylphenyl 347pyrid-3-yloxy 2-methylphenyl 305pyrid-3-yloxy phenyl 291pyrid-3-yloxy 4-ethylphenyl 319pyrid-3-yloxy 2,3-difluorophenyl 327pyrid-3-yloxy 2,6-dimethoxyphenyl 351pyrid-3-yloxy 3,4-difluorophenyl 327pyrid-3-yloxy 2,5-difluorophenyl 327pyrid-3-yloxy 4-ethoxyphenyl 335pyrid-3-yloxy 2,4,6-trichlorophenyl 395pyrid-3-yloxy 3-methylphenyl 305pyrid-3-yloxy 2-fluoro-5- 377 (trifluoromethyl)phenylpyrid-3-yloxy 3-methoxyphenyl 321pyrid-3-yloxy 2-bromophenyl 370pyrid-3-yloxy 4-bromophenyl 370pyrid-3-yloxy 4-fluoro-3- 377 (trifluoromethyl)phenylpyrid-3-yloxy 3-(trifluoromethoxy)phenyl 375pyrid-3-yloxy 9-fluorenon-4-yl 393pyrid-3-yloxy isoxazol-5-yl 282pyrid-3-yloxy benzofuroxan-5-yl 349pyrid-3-yloxy 2-chloropyrid-3-yl 327pyrid-3-yloxy 2-(4- 398 methylphenoxy)pyridin-3-ylpyrid-3-yloxy pyridin-4-yl 292pyrid-3-yloxy anthraquinon-2-yl 421pyrid-3-yloxy 2-iodophenyl 417pyrid-3-yloxy 4-pentylphenyl 361pyrid-3-yloxy 2-(4-chlorophenylthio) 435 pyridin-3-ylpyrid-3-yloxy 2,6-dimethylphenyl 319pyrid-3-yloxy 2,5-dimethoxyphenyl 354pyrid-3-yloxy 2,5-dichloropyridin-3-yl 361pyrid-3-yloxy 2-chloro-6-methoxypyridin- 357 4-ylpyrid-3-yloxy 2,3-dichloropyridin-5-yl 361pyrid-3-yloxy 1-naphthyl 355pyrid-3-yloxy 2,4-dimethoxyphenyl 351pyrid-3-yloxy 3,5- 427 bis(trifluoromethyl)phenylpyrid-3-yloxy 2-(4- 419 chlorophenoxy)pyridin-3-ylpyrid-3-yloxy pentafluorophenyl 3814-bromophenoxy 3,4-dimethoxyphenyl 4294-bromophenoxy 2-(trifluoromethyl)phenyl 4374-bromophenoxy 2,4-difluorophenyl 4054-bromophenoxy 3-(trifluoromethyl)phenyl 4374-bromophenoxy 2-naphthyl 4194-bromophenoxy 2-methoxyphenyl 3994-bromophenoxy 3,4,5-trimethylphenyl 4594-bromophenoxy 3,4-dichlorophenyl 4384-bromophenoxy 3-bromophenyl 4484-bromophenoxy 3-pyridyl 3704-bromophenoxy 2-ethoxynaphth-1-yl 4634-bromophenoxy 2,3-dichlorophenyl 4384-bromophenoxy 6-chloropyrid-3-yl 4054-bromophenoxy 4-(trifluoromethoxy)phenyl 4534-bromophenoxy 2-fluoro-4- 455 (trifluoromethyl)phenyl4-bromophenoxy 3-bromothienyl 4544-bromophenoxy 2-acetoxyphenyl 4274-bromophenoxy 5-methylisoxazol-3-yl 3744-bromophenoxy 2-(phenylthio)pyrid-3-yl 4784-bromophenoxy 2-(trifluoromethoxy)phenyl 4534-bromophenoxy 1-phenyl-5-propylpyrazin- 477 4-yl4-bromophenoxy 2-ethoxyphenyl 4134-bromophenoxy 3-chlorothien-2-yl 4104-bromophenoxy 1-(2-(2-methyl)propyl)-3- 429 methylpyrazol-5-yl4-bromophenoxy 3,5-dichlorophenyl 4384-bromophenoxy 2-(propylthio)pyridin-3-yl 4444-bromophenoxy 2-(ethylthio)pyridin-3-yl 4304-bromophenoxy 3-bromopyridin-5-yl 4494-bromophenoxy 4-methyl-1,2,3-thiadiazol- 391 5-yl4-bromophenoxy 1-methyl-3-(2-(2- 429 methyl)propyl)pyrazol-5-yl4-bromophenoxy 3-chlorobenzo[b]thiophen- 460 2-yl4-bromophenoxy 4-chlorophenyl 4044-bromophenoxy 4-methyl-2-phenyl-1,2,3- 450 triazol-5-yl4-bromophenoxy benzo[b]thiophen-2-yl 4254-bromophenoxy 3,4-dimethylphenyl 3974-bromophenoxy 2-(phenoxy)pyridin-3-yl 4624-bromophenoxy 2-(methylthio)pyridin-3-yl 4164-bromophenoxy 5-methyl-3-phenylisoxazol- 450 4-yl4-bromophenoxy 4-chloro-1,3-dimethyl 473 pyrazolo[3,4-b]pyridin-3- yl4-bromophenoxy 2-chloro-6-methylpyridin- 419 4-yl4-bromophenoxy 3,5-dimethylisoxazol-4-yl 3884-bromophenoxy 1-naphthyl 4194-bromophenoxy 2-fluorophenyl 3874-bromophenoxy 4-propylphenyl 4114-bromophenoxy 3-fluorophenyl 3874-bromophenoxy 2,6-difluorophenyl 4054-bromophenoxy 2-chlorophenyl 4144-bromophenoxy 3-(chloromethyl)phenyl 4184-bromophenoxy 4-(2-(2- 425 methyl)propyl)phenyl4-bromophenoxy 3-chlorophenyl 4044-bromophenoxy 3,5-dimethoxyphenyl 4294-bromophenoxy 2,6-dichlorophenyl 4384-bromophenoxy 2,4-dichlorophenyl 4384-bromophenoxy 4-fluorophenyl 3874-bromophenoxy 4-butylphenyl 4254-bromophenoxy 2-methylphenyl 3834-bromophenoxy phenyl 3694-bromophenoxy 4-ethylphenyl 3974-bromophenoxy 2,3-difluorophenyl 4054-bromophenoxy 2,6-dimethoxyphenyl 4294-bromophenoxy 3,4-difluorophenyl 4054-bromophenoxy 2,5-difluorophenyl 4054-bromophenoxy 4-ethoxyphenyl 4134-bromophenoxy 2,4,6-trichlorophenyl 4734-bromophenoxy 3-methylphenyl 3834-bromophenoxy 2-fluoro-5- 455 (trifluoromethyl)phenyl4-bromophenoxy 3-methoxyphenyl 3994-bromophenoxy 2-bromophenyl 4484-bromophenoxy 4-bromophenyl 4484-bromophenoxy 4-fluoro-3- 455 (trifluoromethyl)phenyl4-bromophenoxy 3-(trifluoromethoxy)phenyl 4534-bromophenoxy 9-fluorenon-4-yl 4714-bromophenoxy isoxazol-5-yl 3604-bromophenoxy benzofuroxan-5-yl 4274-bromophenoxy 2-chloropyrid-3-yl 3604-bromophenoxy 2-(4- 476 methylphenoxy)pyridin-3-yl4-bromophenoxy pyridin-4-yl 3704-bromophenoxy anthraquinon-2-yl 4994-bromophenoxy 2-iodophenyl 4954-bromophenoxy 4-pentylphenyl 4394-bromophenoxy 2-(4- 513 chlorophenylthio)pyridin- 3-yl4-bromophenoxy 2,6-dimethylphenyl 3974-bromophenoxy 2,5-dimethoxyphenyl 4294-bromophenoxy 2,5-dichloropyridin-3-yl 4394-bromophenoxy 2-chloro-6-methoxypyridin- 435 4-yl4-bromophenoxy 2,3-dichloropyridin-5-yl 4394-bromophenoxy 1-naphthyl 4334-bromophenoxy 2,4-dimethoxyphenyl 4294-bromophenoxy 3,5- 505 bis(trifluoromethyl)phenyl4-bromophenoxy 2-(4- 497 chlorophenoxy)pyridin-3-yl4-bromophenoxy pentafluorophenyl 4594-chloro-2- 4-biphenyl 431methylphenylthio4-chloro-2- 3,4-dimethoxyphenyl 415methylphenylthio4-chloro-2- 2-(trifluoromethyl)phenyl 423methylphenylthio4-chloro-2- 2,4-difluorophenyl 391methylphenylthio4-chloro-2- 4-cyanophenyl 380methylphenylthio4-chloro-2- 3-(trifluoromethyl)phenyl 423methylphenylthio4-chloro-2- 3-cyanophenyl 380methylphenylthio4-chloro-2- 2-naphthyl 405methylphenylthio4-chloro-2- 2-methoxyphenyl 385methylphenylthio4-chloro-2- 3,4,5-trimethylphenyl 445methylphenylthio4-chloro-2- 4-nitrophenyl 400methylphenylthio4-chloro-2- 3,4-dichlorophenyl 424methylphenylthio4-chloro-2- 5-nitrofuran-2-yl 390methylphenylthio4-chloro-2- 3-bromophenyl 434methylphenylthio4-chloro-2- 3-pyridyl 356methylphenylthio4-chloro-2- 2-ethoxynaphth-1-yl 449methylphenylthio4-chloro-2- 2,3-dichlorophenyl 424methylphenylthio4-chloro-2- 3-nitrophenyl 400methylphenylthio4-chloro-2- 6-chloropyrid-3-yl 390methylphenylthio4-chloro-2- 4-(trifluoromethoxy)phenyl 439methylphenylthio4-chloro-2- 2-fluoro-4- 441methylphenylthio (trifluoromethyl)phenyl4-chloro-2- 3-bromothienyl 440methylphenylthio4-chloro-2- 2-acetoxyphenyl 413methylphenylthio4-chloro-2- 5-methylisoxazol-3-yl 360methylphenylthio4-chloro-2- 2-(phenylthio)pyrid-3-yl 464methylphenylthio4-chloro-2- 2-(trifluoromethoxy)phenyl 439methylphenylthio4-chloro-2- 1-phenyl-5-propylpyrazin- 463methylphenylthio 4-yl4-chloro-2- 2-ethoxyphenyl 399methylphenylthio4-chloro-2- 3-chlorothien-2-yl 395methylphenylthio4-chloro-2- 1-(2-(2-methyl)propyl)-3- 415methylphenylthio methylpyrazol-5-yl4-chloro-2- 3,5-dichlorophenyl 424methylphenylthio4-chloro-2- 2-(propylthio)pyridin-3-yl 430methylphenylthio4-chloro-2- 2-(ethylthio)pyridin-3-yl 416methylphenylthio4-chloro-2- 3-bromopyridin-5-yl 435methylphenylthio4-chloro-2- 4-methyl-1,2,3-thiadiazol- 377methylphenylthio 5-yl4-chloro-2- 1-methyl-3-(2-(2- 415methylphenylthio methyl)propyl)pyrazol-5-yl4-chloro-2- 3-chlorobenzo[b]thiophen- 445methylphenylthio 2-yl4-chloro-2- 4-chlorophenyl 389methylphenylthio4-chloro-2- 4-methyl-2-phenyl-1,2,3- 436methylphenylthio triazol-5-yl4-chloro-2- benzo[b]thiophen-2-yl 411methylphenylthio4-chloro-2- 3,4-dimethylphenyl 383methylphenylthio4-chloro-2- 2-(phenoxy)pyridin-3-yl 448methylphenylthio4-chloro-2- 2-(methylthio)pyridin-3-yl 402methylphenylthio4-chloro-2- 5-methyl-3-phenylisoxazol- 436methylphenylthio 4-yl4-chloro-2- 4-chloro-1,3-dimethyl 458methylphenylthio pyrazolo[3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 404methylphenylthio 4-yl4-chloro-2- 3,5-dimethylisoxazol-4-yl 374methylphenylthio4-chloro-2- 1-naphthyl 405methylphenylthio4-chloro-2- 2-fluorophenyl 373methylphenylthio4-chloro-2- 4-propylphenyl 397methylphenylthio4-chloro-2- 4-(trifluoromethyl)phenyl 423methylphenylthio4-chloro-2- 3-fluorophenyl 373methylphenylthio4-chloro-2- 2,6-difluorophenyl 391methylphenylthio4-chloro-2- 2-chlorophenyl 389methylphenylthio4-chloro-2- 3-(chloromethyl)phenyl 403methylphenylthio4-chloro-2- 4-(2-(2- 411methylphenylthio methyl)propyl)phenyl4-chloro-2- 3-chlorophenyl 389methylphenylthio4-chloro-2- 2-nitrophenyl 400methylphenylthio4-chloro-2- 3,5-dimethoxyphenyl 415methylphenylthio4-chloro-2- 2,6-dichlorophenyl 424methylphenylthio4-chloro-2- 2,4-dichlorophenyl 424methylphenylthio4-chloro-2- 4-fluorophenyl 373methylphenylthio4-chloro-2- 4-butylphenyl 411methylphenylthio4-chloro-2- 2-methylphenyl 369methylphenylthio4-chloro-2- phenyl 355methylphenylthio4-chloro-2- 4-ethylphenyl 383methylphenylthio4-chloro-2- 2,3-difluorophenyl 391methylphenylthio4-chloro-2- 2,6-dimethoxyphenyl 415methylphenylthio4-chloro-2- 3,4-difluorophenyl 391methylphenylthio4-chloro-2- 2,5-difluorophenyl 391methylphenylthio4-chloro-2- 4-ethoxyphenyl 399methylphenylthio4-chloro-2- 2,4,6-trichlorophenyl 458methylphenylthio4-chloro-2- 3-methylphenyl 369methylphenylthio4-chloro-2- 2-fluoro-5- 441methylphenylthio (trifluoromethyl)phenyl4-chloro-2- 3-methoxyphenyl 385methylphenylthio4-chloro-2- thien-2-yl 361methylphenylthio4-chloro-2- 2-bromophenyl 434methylphenylthio4-chloro-2- 4-bromophenyl 434methylphenylthio4-chloro-2- 4-fluoro-3- 441methylphenylthio (trifluoromethyl)phenyl4-chloro-2- 3-(trifluoromethoxy)phenyl 439methylphenylthio4-chloro-2- 9-fluorenon-4-yl 457methylphenylthio4-chloro-2- isoxazol-5-yl 346methylphenylthio4-chloro-2- benzofuroxan-5-yl 413methylphenylthio4-chloro-2- 2-chloropyrid-3-yl 390methylphenylthio4-chloro-2- 3,5-difluorophenyl 391methylphenylthio4-chloro-2- 2-(4- 462methylphenylthio methylphenoxy)pyridin-3-yl4-chloro-2- pyridin-4-yl 356methylphenylthio4-chloro-2- anthraquinon-2-yl 485methylphenylthio4-chloro-2- 2-iodophenyl 481methylphenylthio4-chloro-2- 4-biphenyl 414methylanilino4-chloro-2- 3,4-dimethoxyphenyl 398methylanilino4-chloro-2- 2-(trifluoromethyl)phenyl 406methylanilino4-chloro-2- 2,4-difluorophenyl 374methylanilino4-chloro-2- 4-cyanophenyl 363methylanilino4-chloro-2- 3-(trifluoromethyl)phenyl 406methylanilino4-chloro-2- 3-cyanophenyl 363methylanilino4-chloro-2- 2-naphthyl 388methylanilino4-chloro-2- 2-methoxyphenyl 368methylanilino4-chloro-2- 3,4,5-trimethylphenyl 428methylanilino4-chloro-2- 4-nitrophenyl 383methylanilino4-chloro-2- 3,4-dichlorophenyl 407methylanilino4-chloro-2- 5-nitrofuran-2-yl 373methylanilino4-chloro-2- 3-bromophenyl 417methylanilino4-chloro-2- 3-pyridyl 339methylanilino4-chloro-2- 2-ethoxynaphth-1-yl 432methylanilino4-chloro-2- 2,3-dichlorophenyl 407methylanilino4-chloro-2- 3-nitrophenyl 383methylanilino4-chloro-2- 6-chloropyrid-3-yl 373methylanilino4-chloro-2- 4-(trifluoromethoxy)phenyl 422methylanilino4-chloro-2- 2-fluoro-4- 424methylanilino (trifluoromethyl)phenyl4-chloro-2- 3-bromothienyl 423methylanilino4-chloro-2- 2-acetoxyphenyl 396methylanilino4-chloro-2- 5-methylisoxazol-3-yl 343methylanilino4-chloro-2- 2-(phenylthio)pyrid-3-yl 447methylanilino4-chloro-2- 2-(trifluoromethoxy)phenyl 422methylanilino4-chloro-2- 1-phenyl-5-propylpyrazin- 446methylanilino 4-yl4-chloro-2- 2-ethoxyphenyl 382methylanilino4-chloro-2- 3-chlorothien-2-yl 378methylanilino4-chloro-2- 1-(2-(2-methyl)propyl)-3- 398methylanilino methylpyrazol-5-yl4-chloro-2- 3,5-dichlorophenyl 407methylanilino4-chloro-2- 2-(propylthio)pyridin-3-yl 413methylanilino4-chloro-2- 2-(ethylthio)pyridin-3-yl 399methylanilino4-chloro-2- 3-bromopyridin-5-yl 418methylanilino4-chloro-2- 4-methyl-1,2,3-thiadiazol- 360methylanilino 5-yl4-chloro-2- 1-methyl-3-(2-(2- 398methylanilino methyl)propyl)pyrazol-5-yl4-chloro-2- 3-chlorobenzo[b]thiophen- 428methylanilino 2-yl4-chloro-2- 4-chlorophenyl 372methylanilino4-chloro-2- 4-methyl-2-phenyl-1,2,3- 419methylanilino triazol-5-yl4-chloro-2- benzo[b]thiophen-2-yl 394methylanilino4-chloro-2- 3,4-dimethylphenyl 366methylanilino4-chloro-2- 2-(phenoxy)pyridin-3-yl 431methylanilino4-chloro-2- 2-(methylthio)pyridin-3-yl 385methylanilino4-chloro-2- 5-methyl-3-phenylisoxazol- 419methylanilino 4-yl4-chloro-2- 4-chloro-1,3-dimethyl 441methylanilino pyrazolo[3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 387methylanilino 4-yl4-chloro-2- 3,5-dimethylisoxazol-4-yl 357methylanilino4-chloro-2- 1-naphthyl 388methylanilino4-chloro-2- 2-fluorophenyl 356methylanilino4-chloro-2- 4-propylphenyl 380methylanilino4-chloro-2- 4-(trifluoromethyl)phenyl 406methylanilino4-chloro-2- 3-fluorophenyl 356methylanilino4-chloro-2- 2,6-difluorophenyl 374methylanilino4-chloro-2- 2-chlorophenyl 372methylanilino4-chloro-2- 3-(chloromethyl)phenyl 386methylanilino4-chloro-2- 4-(2-(2- 394methylanilino methyl)propyl)phenyl4-chloro-2- 3-chlorophenyl 372methylanilino4-chloro-2- 2-nitrophenyl 383methylanilino4-chloro-2- 3,5-dimethoxyphenyl 398methylanilino4-chloro-2- 2,6-dichlorophenyl 407methylanilino4-chloro-2- 2,4-dichlorophenyl 407methylanilino4-chloro-2- 4-fluorophenyl 356methylanilino4-chloro-2- 4-butylphenyl 394methylanilino4-chloro-2- 2-methylphenyl 352methylanilino4-chloro-2- phenyl 338methylanilino4-chloro-2- 4-ethylphenyl 366methylanilino4-chloro-2- 2,3-difluorophenyl 374methylanilino4-chloro-2- 2,6-dimethoxyphenyl 398methylanilino4-chloro-2- 3,4-difluorophenyl 374methylanilino4-chloro-2- 2,5-difluorophenyl 374methylanilino4-chloro-2- 4-ethoxyphenyl 382methylanilino4-chloro-2- 2,4,6-trichlorophenyl 441methylanilino4-chloro-2- 3-methylphenyl 352methylanilino4-chloro-2- 2-fluoro-5- 424methylanilino (trifluoromethyl)phenyl4-chloro-2- 3-methoxyphenyl 368methylanilino4-chloro-2- thien-2-yl 344methylanilino4-chloro-2- 2-bromophenyl 417methylanilino4-chloro-2- 4-bromophenyl 417methylanilino4-chloro-2- 4-fluoro-3- 424methylanilino (trifluoromethyl)phenyl4-chloro-2- 3-(trifluoromethoxy)phenyl 422methylanilino4-chloro-2- 9-fluorenon-4-yl 440methylanilino4-chloro-2- isoxazol-5-yl 329methylanilino4-chloro-2- benzofuroxan-5-yl 396methylanilino4-chloro-2- 2-chloropyrid-3-yl 373methylanilino4-chloro-2- 3,5-difluorophenyl 374methylanilino4-chloro-2- 2-(4- 445methylanilino methylphenoxy)pyridin-3-yl4-chloro-2- pyridin-4-yl 339methylanilino4-chloro-2- anthraquinon-2-yl 468methylanilino4-chloro-2- 2-iodophenyl 464methylanilino______________________________________
The compounds listed in Table 7 can be prepared from substituted 5-aminopyridine compounds and the appropriate acid chloride according to the general procedure above.
TABLE 7______________________________________R.sup.1 X R.sup.3______________________________________4-chloro-2-methylphenoxy 3,4-difluorphenyl4-chloro-2-methylphenoxy 4-pentylphenyl4-chloro-2-methylphenoxy 2-(4-chlorophenylthio) pyridin-3-yl4-chloro-2-methylphenoxy 2,6-dimethylphenyl4-chloro-2-methylphenoxy 2,5-dimethoxyphenyl4-chloro-2-methylphenoxy 2,5-dichloropyridin-3-yl4-chloro-2-methylphenoxy 2-chloro-6-methoxypyridin- 4-yl4-chloro-2-methylphenoxy 2,3-dichloropyridin-5-yl4-chloro-2-methylphenoxy 1-naphthyl4-chloro-2-methylphenoxy 2,4-dimethoxyphenyl4-chloro-2-methylphenoxy 3,5- bis(trifluoromethyl)phenyl4-chloro-2-methylphenoxy 2-(4- chlorophenoxy)pyridin-3-yl4-chloro-2-methylphenoxy pentafluorophenyl1-naphthoxy 4-pentylphenyl1-naphthoxy 2-(4-chlorophenylthio) pyridin-3-yl1-naphthoxy 2,6-dimethylphenyl1-naphthoxy 2,5-dimethoxyphenyl1-naphthoxy 2,5-dichloropyridin-3-yl1-naphthoxy 2-chloro-6-methoxypyridin- 4-yl1-naphthoxy 2,3-dichloropyridin-5-yl1-naphthoxy 1-naphthyl1-naphthoxy 2,4-dimethoxyphenyl1-naphthoxy 3,5-bis(trifluoromethyl) phenyl1-naphthoxy 2-(4- chlorophenoxy) pyridin-3 -yl1-naphthoxy pentafluorophenyl2-(2-propyl)phenoxy 4-pentylphenyl2-(2-propyl)phenoxy 2-(4-chlorophenylthio) pyridin-3-yl2-(2-propyl)phenoxy 2,6-dimethylphenyl2-(2-propyl)phenoxy 2,5-dimethoxyphenyl2-(2-propyl)phenoxy 2,5-dichloropyridin-3-yl2-(2-propyl)phenoxy 2-chloro-6-methoxypyridin- 4-yl2-(2-propyl)phenoxy 2,3-dichloropyridin-5-yl2-(2-propyl)phenoxy 1-naphthyl2-(2-propyl)phenoxy 2,4-dimethoxyphenyl2-(2-propyl)phenoxy 3,5-bis (trifluoromethyl) phenyl2-(2-propyl)phenoxy 2-(4- chlorophenoxy)pyridin-3-yl2-(2-propyl)phenoxy pentafluorophenyl3-fluoro-5-methylphenoxy 4-pentylphenyl3-fluoro-5-methylphenoxy 2-(4-chlorophenylthio) pyridin-3-yl3-fluoro-5-methylphenoxy 2,6-dimethylphenyl3-fluoro-5-methylphenoxy 2,5-dimethoxyphenyl3-fluoro-5-methylphenoxy 2,5-dichloropyridin-3-yl3-fluoro-5-methylphenoxy 2-chloro-6-methoxypyridin- 4-yl3-fluoro-5-methylphenoxy 2,3-dichloropyridin-5-yl3-fluoro-5-methylphenoxy 1-naphthyl3-fluoro-5-methylphenoxy 2,4-dimethoxyphenyl3-fluoro-5-methylphenoxy 3,5-bis(trifluoromethyl) phenyl3-fluoro-5-methylphenoxy 2-(4- chlorophenoxy) pyridin-3-yl3-fluoro-5-methylphenoxy pentafluorophenyl2-methylpyrid-3-yloxy 4-pentylphenyl2-methylpyrid-3-yloxy 2-(4-chlorophenylthio) pyridin-3-yl2-methylpyrid-3-yloxy 2,6-dimethylphenyl2-methylpyrid-3-yloxy 2,5-dimethoxyphenyl2-methylpyrid-3-yloxy 2,5-dichloropyridin-3-yl2-methylpyrid-3-yloxy 2-chloro-6-methoxypyridin- 4-yl2-methylpyrid-3-yloxy 2,3-dichloropyridin-5-yl2-methylpyrid-3-yloxy 1-naphthyl2-methylpyrid-3-yloxy 2,4-dimethoxyphenyl2-methylpyrid-3-yloxy 3,5-bis(trifluoromethyl) phenyl2-methylpyrid-3-yloxy 2-(4- chlorophenoxy)pyridin-3-yl2-methylpyrid-3-yloxy pentafluorophenyl4-methoxyphenoxy 4-biphenyl4-methoxyphenoxy 4-cyanophenyl4-methoxyphenoxy 3-cyanophenyl4-methoxyphenoxy 4-nitrophenyl4-methoxyphenoxy 5-nitrofuran-2-yl4-methoxyphenoxy 3-nitrophenyl4-methoxyphenoxy 4-(trifluoromethyl)phenyl4-methoxyphenoxy 2-nitrophenyl4-methoxyphenoxy thien-2-yl2-(2-propoxy)phenoxy 4-biphenyl2-(2-propoxy)phenoxy 4-cyanophenyl2-(2-propoxy)phenoxy 3-cyanophenyl2-(2-propoxy)phenoxy 4-nitrophenyl2-(2-propoxy)phenoxy 5-nitrofuran-2-yl2-(2-propoxy)phenoxy 3-nitrophenyl2-(2-propoxy)phenoxy 2-nitrophenyl2-(2-propoxy)phenoxy thien-2-yl2-(2-propoxy)phenoxy 3,5-difluorophenyl4-fluorophenoxy 4-biphenyl4-fluorophenoxy 4-cyanophenyl4-fluorophenoxy 3-cyanophenyl4-fluorophenoxy 4-nitrophenyl4-fluorophenoxy 5-nitrofuran-2-yl4-fluorophenoxy 3-nitrophenyl4-fluorophenoxy 2-nitrophenyl4-fluorophenoxy 4-(trifluoromethyl)phenyl4-fluorophenoxy thien-2-yl4-fluorophenoxy 3,5-difluorophenyl4-chlorophenoxy 4-biphenyl4-chlorophenoxy 4-cyanophenyl4-chlorophenoxy 3-cyanophenyl4-chlorophenoxy 4-nitrophenyl4-chlorophenoxy 5-nitrofuran-2-yl4-chlorophenoxy 3-nitrophenyl4-chlorophenoxy 2-nitrophenyl4-chlorophenoxy 4-(trifluoromethyl)phenyl4-chlorophenoxy thien-2-yl4-chlorophenoxy 3,5-difluorophenyl2,4-difluorophenoxy 4-biphenyl2,4-difluorophenoxy 4-cyanophenyl2,4-difluorophenoxy 3-cyanophenyl2,4-difluorophenoxy 4-nitrophenyl2,4-difluorophenoxy 5-nitrofuran-2-yl2,4-difluorophenoxy 3-nitrophenyl2,4-difluorophenoxy 4-(trifluoromethyl)phenyl2,4-difluorophenoxy 2-nitrophenyl4-chloro-2,5- 4-biphenyldimethylphenoxy4-chloro-2,5- 4-cyanophenyldimethylphenoxy4-chloro-2,5- 3-cyanophenyldimethylphenoxy4-chloro-2,5- 4-nitrophenyldimethylphenoxy4-chloro-2,5- 5-nitrofuran-2-yldimethylphenoxy4-chloro-2,5- 3-nitrophenyldimethylphenoxy4-chloro-2,5- 4-(trifluoromethyl)phenyldimethylphenoxy4-chloro-2,5- 2-nitrophenyldimethylphenoxy4-chloro-2,5- thien-2-yldimethylphenoxy4-chloro-2,5- 3,5-difluorophenyldimethylphenoxy4-methoxyphenoxy 3,5-difluorophenyl2-(2-propoxy)phenoxy 4-(trifluoromethyl)phenyl2,4-difluorophenoxy thien-2-yl2,4-difluorophenoxy 3,5-difluorophenyl4-thiomethylphenoxy 4-biphenyl4-thiomethylphenoxy 4-cyanophenyl4-thiomethylphenoxy 3-cyanophenyl4-thiomethylphenoxy 4-nitrophenyl4-thiomethylphenoxy 5-nitrofuran-2-yl4-thiomethylphenoxy 3-nitrophenyl4-thiomethylphenoxy 4-(trifluoromethyl)phenyl4-thiomethylphenoxy 2-nitrophenyl4-thiomethylphenoxy thien-2-yl4-thiomethylphenoxy 3,5-difluorophenyl4-(2-(2-methyl)propyl) 4-biphenylphenoxy4-(2-(2-methyl)propyl) 4-cyanophenylphenoxy4-(2-(2-methyl)propyl) 3-cyanophenylphenoxy4-(2-(2-methyl)propyl) 4-nitrophenylphenoxy4-(2-(2-methyl)propyl) 5-nitrofuran-2-ylphenoxy4-(2-(2-methyl)propyl) 3-nitrophenylphenoxy4-(2-(2-methyl)propyl) 4-(trifluoromethyl)phenylphenoxy4-(2-(2-methyl)propyl) 2-nitrophenylphenoxy4-(2-(2-methyl)propyl) thien-2-ylphenoxy4-(2-(2-methyl)propyl) 3,5-difluorophenylphenoxy2,3-dimethylphenoxy 4-biphenyl2,3-dimethylphenoxy 4-cyanophenyl2,3-dimethylphenoxy 3-cyanophenyl2,3-dimethylphenoxy 4-nitrophenyl2,3-dimethylphenoxy 5-nitrofuran-2-yl2,3-dimethylphenoxy 3-nitrophenyl2,3-dimethylphenoxy 4-(trifluoromethyl)phenyl2,3-dimethylphenoxy 2-nitrophenyl2,3-dimethylphenoxy thien-2-yl2,3-dimethylphenoxy 3,5-difluorophenyl3,5-(bis-2-propyl)phenoxy 4-biphenyl3,5-(bis-2-propyl)phenoxy 4-cyanophenyl3,5-(bis-2-propyl)phenoxy 3-cyanophenyl3,5-(bis-2-propyl)phenoxy 4-nitrophenyl3,5-(bis-2-propyl)phenoxy 5-nitrofuran-2-yl3,5-(bis-2-propyl)phenoxy 3-nitrophenyl3,5-(bis-2-propyl)phenoxy 4-(trifluoromethyl)phenyl3,5-(bis-2-propyl)phenoxy 2-nitrophenyl3,5-(bis-2-propyl)phenoxy thien-2-yl3,5-(bis-2-propyl)phenoxy 3,5-difluorophenyl3-trifluoromethyl phenoxy 4-biphenyl3-trifluoromethyl phenoxy 4-cyanophenyl3-trifluoromethyl phenoxy 3-cyanophenyl3-trifluoromethyl phenoxy 4-nitrophenyl3-trifluoromethyl phenoxy 5-nitrofuran-2-yl3-trifluoromethyl phenoxy 3-nitrophenyl3-trifluoromethyl phenoxy 4-(trifluoromethyl)phenyl3-trifluoromethyl phenoxy 2-nitrophenyl3-trifluoromethyl phenoxy thien-2-yl3-trifluoromethyl phenoxy 3,5-difluorophenyl2,6-dichlorophenoxy 4-biphenyl2,6-dichlorophenoxy 4-cyanophenyl2,6-dichlorophenoxy 3-cyanophenyl2,6-dichlorophenoxy 4-nitrophenyl2,6-dichlorophenoxy 5-nitrofuran-2-yl2,6-dichlorophenoxy 3-nitrophenyl2,6-dichlorophenoxy 4-(trifluoromethyl)phenyl2,6-dichlorophenoxy 2-nitrophenyl2,6-dichlorophenoxy thien-2-yl2,6-dichlorophenoxy 3,5-difluorophenyl2,4-dichlorophenoxy 4-biphenyl2,4-dichlorophenoxy 4-cyanophenyl2,4-dichlorophenoxy 3-cyanophenyl2,4-dichlorophenoxy 4-nitrophenyl2,4-dichlorophenoxy 5-nitrofuran-2-yl2,4-dichlorophenoxy 3-nitrophenyl2,4-dichlorophenoxy 4-(trifluoromethyl)phenyl2,4-dichlorophenoxy 2-nitrophenyl2,4-dichlorophenoxy thien-2-yl2,4-dichlorophenoxy 3,5-difluorophenyl4-chloro-3-methylphenoxy 4-biphenyl4-chloro-3-methylphenoxy 4-cyanophenyl4-chloro-3-methylphenoxy 3-cyanophenyl4-chloro-3-methylphenoxy 4-nitrophenyl4-chloro-3-methylphenoxy 5-nitrofuran-2-yl4-chloro-3-methylphenoxy 3-nitrophenyl4-chloro-3-methylphenoxy 2-nitrophenyl4-chloro-3-methylphenoxy thien-2-yl4-chloro-3-methylphenoxy 3,5-difluorophenyl4-chloro-2- 4-biphenylcyclohexylphenoxy4-chloro-2- 4-cyanophenylcyclohexylphenoxy4-chloro-2 - 3 -cyanophenylcyclohexylphenoxy4-chloro-2- 4-nitrophenylcyclohexylphenoxy4-chloro-2- 5-nitrofuran-2-ylcyclohexylphenoxy4-chloro-2- 3-nitrophenylcyclohexylphenoxy4-chloro-2- 4-(trifluoromethyl)phenylcyclohexylphenoxy4-chloro-2- 2-nitrophenylcyclohexylphenoxy4-chloro-2- thien-2-ylcyclohexylphenoxy4-chloro-2- 3,5-difluorophenylcyclohexylphenoxy4-chloro-3,5- 4-biphenyldimethylphenoxy4-chloro-3,5- 4-cyanophenyldimethylphenoxy4-chloro-3,5- 3-cyanophenyldimethylphenoxy4-chloro-3,5- 4-nitrophenyldimethylphenoxy4-chloro-3,5- 5-nitrofuran-2-yldimethylphenoxy4-chloro-3,5- 3-nitrophenyldimethylphenoxy4-chloro-3,5- 4-(trifluoromethyl)phenyldimethylphenoxy4-chloro-3,5- 2-nitrophenyldimethylphenoxy4-chloro-3,5- thien-2-yldimethylphenoxy4-chloro-3,5- 3,5-difluorophenyldimethylphenoxypyrid-3-yloxy 4-biphenylpyrid-3-yloxy 4-cyanophenylpyrid-3-yloxy 3-cyanophenylpyrid-3-yloxy 4-nitrophenylpyrid-3-yloxy 5-nitrofuran-2-ylpyrid-3-yloxy 3-nitrophenylpyrid-3-yloxy 4-(trifluoromethyl)phenylpyrid-3-yloxy 2-nitrophenylpyrid-3-yloxy thien-2-ylpyrid-3-yloxy 3,5-difluorophenyl4-bromophenoxy 4-biphenyl4-bromophenoxy 4-cyanophenyl4-bromophenoxy 3-cyanophenyl4-bromophenoxy 4-nitrophenyl4-bromophenoxy 5-nitrofuran-2-yl4-bromophenoxy 3-nitrophenyl4-bromophenoxy 4-(trifluoromethyl)phenyl4-bromophenoxy 2-nitrophenyl4-bromophenoxy thien-2-yl4-bromophenoxy 3,5-difluorophenyl4-chloro-2- 4-pentylphenylmethylphenylthio4-chloro-2- 2-(4-chlorophenylthio)methylphenylthio pyridin-3-yl4-chloro-2- 2,6-dimethylphenylmethylphenylthio4-chloro-2- 2,5-dimethoxyphenylmethylphenylthio4-chloro-2- 2,5-dichloropyridin-3-ylmethylphenylthio4-chloro-2- 2-chloro-6-methoxypyridin-methylphenylthio 4-yl4-chloro-2- 2,3-dichloropyridin-5-ylmethylphenylthio4-chloro-2- 1-naphthylmethylphenylthio4-chloro-2- 2,4-dimethoxyphenylmethylphenylthio4-chloro-2- 3,5-bis(trifluoromethyl)methylphenylthio phenyl4-chloro-2- 2-(4-methylphenylthio chlorophenoxy)pyridin-3-yl4-chloro-2- pentafluorophenylmethylphenylthio4-chloro-2-methylanilino 4-pentylphenyl4-chloro-2-methylanilino 2-(4-chlorophenylthio) pyridin-3-yl4-chloro-2-methylanilino 2,6-dimethylphenyl4-chloro-2-methylanilino 2,5-dimethoxyphenyl4-chloro-2-methylanilino 2,5-dichloropyridin-3-yl4-chloro-2-methylanilino 2-chloro-6-methoxypyridin- 4-yl4-chloro-2-methylanilino 2,3-dichloropyridin-5-yl4-chloro-2-methylanilino 1-naphthyl4-chloro-2-methylanilino 2,4-dimethoxyphenyl4-chloro-2-methylanilino 3,5- bis(trifluoromethyl)phenyl4-chloro-2-methylanilino 2-(4- chlorophenoxy)pyridin-3-yl4-chloro-2-methylanilino pentafluorophenyl______________________________________
EXAMPLE 19 ##STR22## General procedure for the synthesis of 6-(substituted-amino)-N-substituted nicotinamides
Step A. General procedure for the preparation of 6-chloro-N-substituted nicotinamide
To a suspension of 6-chloronicotinoyl chloride (1.76 g, 10.0 mmol) in dry dichloromethane (10 mL) was added the amine (R.sup.3 R.sup.4 NH) (10.0 mmol) followed by the dropwise addition of triethylamine (1.7 mL, 12.2 mmol). After stirring for 40 min. at room temperature, the mixture was diluted with dichloromethane, washed with aqueous 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water, dried over sodium sulfate and concentrated to dryness under reduce pressure to afford the desired nicotinamide.
The following compounds were prepared according to this procedure using the appropriate substituted amine:
6-Chloro-N-o-tolylnicotinamide: MS (m/z): 247/249 (M+H).sup.+ ; C.sub.13 H.sub.11 Cl.sub.1 N.sub.2 O.sub.1 requires 246.5.
6-Chloro-N-(2-fluorophenyl)nicotinamide: MS (m/z): 251/253 (M+H).sup.+ ; C.sub.12 H.sub.8 Cl.sub.1 F.sub.1 N.sub.2 O.sub.1 requires 250.7.
6-Chloro-N-(2,6-dimethylphenyl)nicotinamide: MS (m/z): 261/263 (M+H).sup.+ ; C.sub.14 H.sub.13 Cl.sub.1 N.sub.2 O.sub.1 requires 260.7.
6-Chloro-N-(2-phenoxyphenyl)nicotinamide: MS (m/z): 325/327 (M+H).sup.+ ; C.sub.18 H.sub.13 Cl.sub.1 N.sub.2 O.sub.1 requires 324.8.
6-Chloro-N-phenylnicotinamide: MS (m/z): 233/235 (M+H).sup.+ ; C.sub.12 H.sub.8 Cl.sub.1 N.sub.2 O.sub.1 requires 232.7.
6-Chloro-N-(2,4-difluorophenyl)nicotinamide: MS (m/z): 269/271 (M+H).sup.+ ; C.sub.12 H.sub.7 Cl.sub.1 F.sub.2 N.sub.2 O.sub.1 requires 268.6.
6-Chloro-N-(2,6-diisopropylphenyl)nicotinamide: MS (m/z): 317/319 (M+H).sup.+ ; C.sub.18 H.sub.21 Cl.sub.1 N.sub.2 O.sub.1 requires 316.8.
6-Chloro-N-(4-chlorophenyl)-N-methylnicotinamide: MS (m/z): 281/283 (M+H).sup.+ ; C.sub.13 H.sub.10 Cl.sub.2 N.sub.2 O.sub.1 requires 281.1.
6-Chloro-N-(2,4-dimethoxyphenyl)nicotinamide: MS (m/z): 293/295 (M+H).sup.+ ; C.sub.14 H.sub.13 Cl.sub.1 N.sub.2 O.sub.3 requires 292.7.
6-Chloro-N-(3-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H).sup.+ ; C.sub.13 H.sub.11 Cl.sub.1 N.sub.2 O.sub.2 requires 262.7.
6-Chloro-N-(4-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H).sup.+ ; C.sub.13 H.sub.11 Cl.sub.1 N.sub.2 O.sub.2 requires 262.7.
6-Chloro-N-(2-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H).sup.+ ; C.sub.13 H.sub.11 Cl.sub.1 N.sub.2 O.sub.2 requires 262.7.
6-Chloro-N-methyl-N-phenylnicotinamide: MS (m/z): 247/249 (M+H).sup.+ ; C.sub.13 H.sub.11 Cl.sub.2 N.sub.2 O.sub.1 requires 246.7.
N-Benzyl-6-chloronicotinamide: MS (m/z): 247/249 (M+H).sup.+ ; C.sub.13 H.sub.11 Cl.sub.1 N.sub.2 O.sub.1 requires 246.7.
Step B. General procedure for the preparation of 6-(substituted-amino)-N-substituted nicotinamides
A mixture of the 6-chloro-N-substituted nicotinamide (12.5 mmol) and amine (R.sup.1 NH.sub.2 or R.sup.1 NHCH.sub.3) (20 mmol) in ethylene glycol (50 mL) or pyridine (alkylamines) (50 mL) was heated to 140.degree. C. for 20 hours. After cooling to room temperature, the mixture was diluted with dichloromethane/methanol (9:1, 250 mL) and filtered through a plug of silica gel, washing with additional dichloromethane/methanol (9:1, 250 mL). Concentration under reduced pressure afforded the desired 6-(substituted-amino)-N-substituted nicotinamide.
The compounds listed in Tables 8-11 were prepared from 6-chloro-N-substituted nicotinamides compounds and the appropriate amine according to the general procedure above.
TABLE 8______________________________________ ##STR23## MSR.sup.3 R.sup.1 (m/z)______________________________________o-tolyl phenyl 303o-tolyl o-tolyl 317o-tolyl 4-chloro-2-methylphenyl 352o-tolyl 2-fluorophenyl 321o-tolyl 3-fluorophenyl 321o-tolyl 4-fluorophenyl 321o-tolyl 2,4-difluorophenyl 339o-tolyl 2-methoxyphenyl 333o-tolyl 3-methoxyphenyl 333o-tolyl 4-methoxyphenyl 333o-tolyl 2,4-dimethoxyphenyl 363o-tolyl 2-phenoxyphenyl 395o-tolyl 3-phenoxyphenyl 395o-tolyl 4-phenoxyphenyl 395o-tolyl 4-biphenyl 379o-tolyl 4-benzylphenyl 393o-tolyl 4-(trifluoromethoxy)phenyl 387o-tolyl cyclohexyl 309o-tolyl 2-methylcyclohexyl 323o-tolyl cycloheptyl 323o-tolyl indan-1-yl 343o-tolyl 2-dicyclohexyl 4922-fluorophenyl phenyl 3072-fluorophenyl o-tolyl 3212-fluorophenyl 4-chloro-2-methylphenyl 3562-fluorophenyl 2-fluorophenyl 3252-fluorophenyl 3-fluorophenyl 3252-fluorophenyl 4-fluorophenyl 3252-fluorophenyl 2,4-difluorophenyl 3432-fluorophenyl 2-methoxyphenyl 3372-fluorophenyl 3-methoxyphenyl 3372-fluorophenyl 4-methoxyphenyl 3372-fluorophenyl 2,4-dimethoxyphenyl 3672-fluorophenyl 2-phenoxyphenyl 3992-fluorophenyl 3-phenoxyphenyl 3992-fluorophenyl 4-phenoxyphenyl 3992-fluorophenyl 4-biphenyl 3832-fluorophenyl 4-benzylphenyl 3972-fluorophenyl 4-(trifluoromethoxy)phenyl 3912-fluorophenyl cyclohexyl 3132-fluorophenyl 2-methylcyclohexyl 3272-fluorophenyl cycloheptyl 3272-fluorophenyl indan-1-yl 3472-fluorophenyl 2-dicyclohexyl 3952,6-dimethylphenyl phenyl 3172,6-dimethylphenyl o-tolyl 3312,6-dimethylphenyl 4-chloro-2-methylphenyl 3662,6-dimethylphenyl 2-fluorophenyl 3352,6-dimethylphenyl 3-fluorophenyl 3352,6-dimethylphenyl 4-fluorophenyl 3352,6-dimethylphenyl 2,4-difluorophenyl 3532,6-dimethylphenyl 2-methoxyphenyl 3472,6-dimethylphenyl 3-methoxyphenyl 3472,6-dimethylphenyl 4-methoxyphenyl 3472,6-dimethylphenyl 2,4-dimethoxyphenyl 3772,6-dimethylphenyl 2-phenoxyphenyl 4092,6-dimethylphenyl 3-phenoxyphenyl 4092,6-dimethylphenyl 4-phenoxyphenyl 4092,6-dimethylphenyl 4-biphenyl 3932,6-dimethylphenyl 4-benzylphenyl 4072,6-dimethylphenyl 4-(trifluoromethoxy)phenyl 4012,6-dimethylphenyl cyclohexyl 3232,6-dimethylphenyl 2-methylcyclohexyl 3372,6-dimethylphenyl cycloheptyl 6672,6-dimethylphenyl indan-1-yl 3572,6-dimethylphenyl 2-dicyclohexyl 4062-phenoxyphenyl phenyl 3812-phenoxyphenyl o-tolyl 3952-phenoxyphenyl 4-chloro-2-methylphenyl 4302-phenoxyphenyl 2-fluorophenyl 3992-phenoxyphenyl 3-fluorophenyl 3992-phenoxyphenyl 4-fluorophenyl 3992-phenoxyphenyl 2,4-difluorophenyl 4172-phenoxyphenyl 2-methoxyphenyl 4112-phenoxyphenyl 3-methoxyphenyl 4112-phenoxyphenyl 4-methoxyphenyl 4112-phenoxyphenyl 2,4-dimethoxyphenyl 4412-phenoxyphenyl 2-phenoxyphenyl 4732-phenoxyphenyl 3-phenoxyphenyl 4732-phenoxyphenyl 4-phenoxyphenyl 4732-phenoxyphenyl 4-biphenyl 4572-phenoxyphenyl 4-benzylphenyl 4722-phenoxyphenyl 4-(trifluoromethoxy)phenyl 4652-phenoxyphenyl cyclohexyl 3872-phenoxyphenyl 2-methylcyclohexyl 4012-phenoxyphenyl cycloheptyl 4012-phenoxyphenyl indan-1-yl 4212-phenoxyphenyl 2-dicyclohexyl 470phenyl phenyl 289phenyl o-tolyl 303phenyl 4-chloro-2-methylphenyl 338phenyl 2-fluorophenyl 307phenyl 3-fluorophenyl 307phenyl 4-fluorophenyl 307phenyl 2,4-difluorophenyl 325phenyl 2-methoxyphenyl 319phenyl 3-methoxyphenyl 319phenyl 4-methoxyphenyl 319phenyl 2,4-dimethoxyphenyl 349phenyl 2-phenoxyphenyl 381phenyl 3-phenoxyphenyl 381phenyl 4-phenoxyphenyl 381phenyl 4-biphenyl 365phenyl 4-benzylphenyl 379phenyl 4-(trifluoromethoxy)phenyl 373phenyl cyclohexyl 295phenyl 2-methylcyclohexyl 309phenyl cycloheptyl 309phenyl indan-1-yl 329phenyl 2-dicyclohexyl 3772,4-difluorophenyl phenyl 3252,4-difluorophenyl o-tolyl 3392,4-difluorophenyl 4-chloro-2-methylphenyl 3742,4-difluorophenyl 2-fluorophenyl 3432,4-difluorophenyl 3-fluorophenyl 3432,4-difluorophenyl 4-fluorophenyl 3432,4-difluorophenyl 2,4-difluorophenyl 3612,4-difluorophenyl 2-methoxyphenyl 3552,4-difluorophenyl 3-methoxyphenyl 3552,4-difluorophenyl 4-methoxyphenyl 3552,4-difluorophenyl 2,4-dimethoxyphenyl 3852,4-difluorophenyl 2-phenoxyphenyl 4172,4-difluorophenyl 3-phenoxyphenyl 4172,4-difluorophenyl 4-phenoxyphenyl 4172,4-difluorophenyl 4-biphenyl 4012,4-difluorophenyl 4-benzylphenyl 4152,4-difluorophenyl 4-(trifluoromethoxy)phenyl 4092,4-difluorophenyl cyclohexyl 3312,4-difluorophenyl 2-methylcyclohexyl 3452,4-difluorophenyl cycloheptyl 3452,4-difluorophenyl indan-1-yl 3652,4-difluorophenyl 2-dicyclohexyl 4132,6-diisopropylphenyl phenyl 3732,6-diisopropylphenyl o-tolyl 3872,6-diisopropylphenyl 4-chloro-2-methylphenyl 4222,6-diisopropylphenyl 2-fluorophenyl 3912,6-diisopropylphenyl 3-fluorophenyl 3912,6-diisopropylphenyl 4-fluorophenyl 3912,6-diisopropylphenyl 2,4-difluorophenyl 4092,6-diisopropylphenyl 2-methoxyphenyl 4032,6-diisopropylphenyl 3-methoxyphenyl 4032,6-diisopropylphenyl 4-methoxyphenyl 4032,6-diisopropylphenyl 2,4-dimethoxyphenyl 4342,6-diisopropylphenyl 2-phenoxyphenyl 4662,6-diisopropylphenyl 3-phenoxyphenyl 4662,6-diisopropylphenyl 4-phenoxyphenyl 4662,6-diisopropylphenyl 4-biphenyl 4502,6-diisopropylphenyl 4-benzylphenyl 4642,6-diisopropylphenyl 4-(trifluoromethoxy)phenyl 4572,6-diisopropylphenyl cyclohexyl 3802,6-diisopropylphenyl 2-methylcyclohexyl 3942,6-diisopropylphenyl cycloheptyl 3942,6-diisopropylphenyl indan-1-yl 4142,6-diisopropylphenyl 2-dicyclohexyl 4622,4-dimethoxyphenyl phenyl 3492,4-dimethoxyphenyl o-tolyl 3632 4-dimethoxyphenyl 4-chloro-2-methylphenyl 3982,4-dimethoxyphenyl 2-fluorophenyl 3672,4-dimethoxyphenyl 3-fluorophenyl 3672,4-dimethoxyphenyl 4-fluorophenyl 3672,4-dimethoxyphenyl 2,4-difluorophenyl 3852,4-dimethoxyphenyl 2-methoxyphenyl 3792,4-dimethoxyphenyl 3-methoxyphenyl 3792,4-dimethoxyphenyl 4-methoxyphenyl 3792,4-dimethoxyphenyl 2,4-dimethoxyphenyl 4092,4-dimethoxyphenyl 2-phenoxyphenyl 4412,4-dimethoxyphenyl 3-phenoxyphenyl 4412,4-dimethoxyphenyl 4-phenoxyphenyl 4412,4-dimethoxyphenyl 4-biphenyl 4252,4-dimethoxyphenyl 4-benzylphenyl 4392,4-dimethoxyphenyl 4-(trifluoromethoxy)phenyl 4332,4-dimethoxyphenyl 3-trifluoromethylphenyl 4172,4-dimethoxyphenyl cyclohexyl 3552,4-dimethoxyphenyl 2-methylcyclohexyl 3693-methoxyphenyl phenyl 3193-methoxyphenyl o-tolyl 3333-methoxyphenyl 4-chloro-2-methylphenyl 3683-methoxyphenyl 2-fluorophenyl 3373-methoxyphenyl 3-fluorophenyl 3373-methoxyphenyl 4-fluorophenyl 3373-methoxyphenyl 2,4-difluorophenyl 3553-methoxyphenyl 2-methoxyphenyl 3493-methoxyphenyl 3-methoxyphenyl 3493-methoxyphenyl 4-methoxyphenyl 3493-methoxyphenyl 2,4-dimethoxyphenyl 3793-methoxyphenyl 2-phenoxyphenyl 4113-methoxyphenyl 3-phenoxyphenyl 4113-methoxyphenyl 4-phenoxyphenyl 4113-methoxyphenyl 4-biphenyl 3953-methoxyphenyl 4-benzylphenyl 4093-methoxyphenyl 4-(trifluoromethoxy)phenyl 4033-methoxyphenyl 3-trifluoromethylphenyl 3873-methoxyphenyl cyclohexyl 6253-methoxyphenyl 2-methylcyclohexyl 3394-methoxyphenyl phenyl 3194-methoxyphenyl o-tolyl 3334-methoxyphenyl 4-chloro-2-methylphenyl 3684-methoxyphenyl 2-fluorophenyl 3374-methoxyphenyl 3-fluorophenyl 3374-methoxyphenyl 4-fluorophenyl 3374-methoxyphenyl 2,4-difluorophenyl 3554-methoxyphenyl 2-methoxyphenyl 3494-methoxyphenyl 3-methoxyphenyl 3494-methoxyphenyl 4-methoxyphenyl 3494-methoxyphenyl 2,4-dimethoxyphenyl 3794-methoxyphenyl 2-phenoxyphenyl 4114-methoxyphenyl 3-phenoxyphenyl 4114-methoxyphenyl 4-phenoxyphenyl 4114-methoxyphenyl 4-biphenyl 3954-methoxyphenyl 4-benzylphenyl 4094-methoxyphenyl 4-(trifluoromethoxy)phenyl 4034-methoxyphenyl 3-trifluoromethylphenyl 3874-methoxyphenyl cyclohexyl 6254-methoxyphenyl 2-methylcyclohexyl 3392-methoxyphenyl phenyl 3192-methoxyphenyl o-tolyl 3332-methoxyphenyl 4-chloro-2-methylphenyl 3682-methoxyphenyl 2-fluorophenyl 3372-methoxyphenyl 3-fluorophenyl 3372-methoxyphenyl 4-fluorophenyl 3372-methoxyphenyl 2,4-difluorophenyl 3552-methoxyphenyl 2-methoxyphenyl 3492-methoxyphenyl 3-methoxyphenyl 3492-methoxyphenyl 4-methoxyphenyl 3492-methoxyphenyl 2,4-dimethoxyphenyl 3792-methoxyphenyl 2-phenoxyphenyl 4112-methoxyphenyl 3-phenoxyphenyl 4112-methoxyphenyl 4-phenoxyphenyl 4112-methoxyphenyl 4-biphenyl 3952-methoxyphenyl 4-benzylphenyl 4092-methoxyphenyl 4-(trifluoromethoxy)phenyl 4032-methoxyphenyl 3-trifluoromethylphenyl 3872-methoxyphenyl cyclohexyl 6252-methoxyphenyl 2-methylcyclohexyl 339______________________________________
TABLE 9______________________________________ ##STR24## MSR.sup.3 R.sup.1 (m/z)______________________________________4-chlorophenyl phenyl 3384-chlorophenyl o-tolyl 3524-chlorophenyl 4-chloro-2-methylphenyl 3864-chlorophenyl 2-fluorophenyl 3564-chlorophenyl 3-fluorophenyl 3564-chlorophenyl 4-fluorophenyl 3564-chlorophenyl 2,4-difluorophenyl 3744-chlorophenyl 2-methoxyphenyl 3684-chlorophenyl 3-methoxyphenyl 3684-chlorophenyl 4-methoxyphenyl 3684-chlorophenyl 2,4-dimethoxyphenyl 3984-chlorophenyl 2-phenoxyphenyl 4304-chlorophenyl 3-phenoxyphenyl 4304-chlorophenyl 4-phenoxyphenyl 4304-chlorophenyl 4-biphenyl 4144-chlorophenyl 4-benzylphenyl 4284-chlorophenyl 4-(trifluoromethoxy)phenyl 4224-chlorophenyl cyclohexyl 3444-chlorophenyl 2-methylcyclohexyl 358phenyl phenyl 303phenyl o-tolyl 317phenyl 4-chloro-2-methylphenyl 352phenyl 2-fluorophenyl 321phenyl 3-fluorophenyl 321phenyl 4-fluorophenyl 321phenyl 2,4-difluorophenyl 339phenyl 2-methoxyphenyl 333phenyl 3-methoxyphenyl 333phenyl 4-methoxyphenyl 333phenyl 2,4-dimethoxyphenyl 363phenyl 2-phenoxyphenyl 395phenyl 3-phenoxyphenyl 395phenyl 4-phenoxyphenyl 395phenyl 4-biphenyl 379phenyl 4-benzylphenyl 393phenyl 4-(trifluoromethoxy)phenyl 387phenyl 3-trifluoromethylphenyl 371phenyl cyclohexyl 309phenyl 2-methylcyclohexyl 323______________________________________
TABLE 10______________________________________ ##STR25## MSR.sup.3 R.sup.1 (m/z)______________________________________o-tolyl N-methylphenyl 317o-tolyl 4-chloro-N-methylphenyl 352o-tolyl N-methylcyclohexyl 3232-fluorophenyl N-methylphenyl 3212-fluorophenyl 4-chloro-N-methylphenyl 3562-fluorophenyl N-methylcyclohexyl 3272,6-dimethylphenyl N-methylphenyl 3312,6-dimethylphenyl 4-chloro-N-methylphenyl 3662,6-dimethylphenyl N-methylcyclohexyl 3372-phenoxyphenyl N-methylphenyl 3952-phenoxyphenyl 4-chloro-N-methylphenyl 4302-phenoxyphenyl N-methylcyclohexyl 401phenyl N-methylphenyl 303phenyl 4-chloro-N-methylphenyl 338phenyl N-methylcyclohexyl 3092,4-difluorophenyl N-methylphenyl 3392,4-difluorophenyl 4-chloro-N-methylphenyl 3742,4-difluorophenyl N-methylcyclohexyl 3452,6-diisopropylphenyl N-methylphenyl 3872,6-diisopropylphenyl 4-chloro-N-methylphenyl 4222,6-diisopropylphenyl N-methylcyclohexyl 3942,4-dimethoxyphenyl N-methylphenyl 3632,4-dimethoxyphenyl 4-chloro-N-methylphenyl 3982,4-dimethoxyphenyl N-methylcyclohexyl 3693-methoxyphenyl N-methylphenyl 3333-methoxyphenyl 4-chloro-N-methylphenyl 3683-methoxyphenyl N-methylcyclohexyl 3394-methoxyphenyl N-methylphenyl 3334-methoxyphenyl 4-chloro-N-methylphenyl 3684-methoxyphenyl N-methylcyclohexyl 3392-methoxyphenyl N-methylphenyl 3332-methoxyphenyl 4-chloro-N-methylphenyl 3682-methoxyphenyl N-methylcyclohexyl 339______________________________________
TABLE 11______________________________________ ##STR26## MSR.sup.3 R.sup.1 (m/z)______________________________________4-chlorophenyl phenyl 3384-chlorophenyl 4-chlorophenyl 3864-chlorophenyl cyclohexyl 358phenyl phenyl 317phenyl 4-chlorophenyl 352phenyl cyclohexyl 323______________________________________
The compounds listed in Tables 12-13 can be prepared from 6-chloro-N-substituted nicotinamides compounds and the appropriate amine according to the general procedure above.
TABLE 12______________________________________ ##STR27##R.sup.1 X R.sup.3______________________________________o-tolyl 3-trifluoromethylphenyl2-fluorophenyl 3-trifluoromethylphenyl2,6-dimethylphenyl 3-trifluoromethylphenyl2-phenoxyphenyl 3-trifluoromethylphenylphenyl 3-trifluoromethylphenyl2,4-difluorophenyl 3-trifluoromethylphenyl2,6-diisopropylphenyl 3-trifluoromethylphenyl2,4-dimethoxyphenyl cycloheptyl2,4-dimethoxyphenyl indan-1-yl2,4-dimethoxyphenyl 2-dicyclohexyl3-methoxyphenyl cycloheptyl3-methoxyphenyl indan-1-yl3-methoxyphenyl 2-dicyclohexyl4-methoxyphenyl cycloheptyl4-methoxyphenyl indan-1-yl4-methoxyphenyl 2-dicyclohexyl2-methoxyphenyl cycloheptyl2-methoxyphenyl indan-1-yl2-methoxyphenyl 2-dicyclohexyl______________________________________
TABLE 13______________________________________ ##STR28##R.sup.1 X R.sup.3______________________________________4-chlorophenyl 3-trifluoromethylphenyl4-chlorophenyl cycloheptyl4-chlorophenyl indan-1-yl4-chlorophenyl 2-dicyclohexylphenyl cycloheptylphenyl indan-1-ylphenyl 2-dicyclohexyl______________________________________
EXAMPLE 20
The following assays were used to characterize the ability of compounds of the invention to inhibit the production of TNF-.alpha. and IL-1-.beta.. The second assay measured the inhibition of TNF-.alpha. and/or IL-1-.beta. in mice after oral administration of the test compounds. The third assay, a glucagon binding inhibition in vitro assay, can be used to characterize the ability of compounds of the invention to inhibit glucagon binding. The fourth assay, a Cyclooxygenase enzyme (COX-1 and COX-2) inhibition activity in vitro assay, can be used to characterize the ability of compounds of the invention to inhibit COX-1 and/or COX-2. The fifth assay, a Raf-kinase inhibition assay, can be used to characterize the compounds of the invention to inhibit phosphorylation of MEK by activated Raf-kinase.
Lipopolysaccharide-activated monocyte TNF production assay
Isolation of monocytes
Test compounds were evaluated in vitro for the ability to inhibit the production of tumor necrosis factor (TNF) by monocytes activated with bacterial lipopolysaccharide (LPS). Fresh residual source leukocytes (a byproduct of plateletpheresis) were obtained from a local blood bank, and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation on Ficol-Paque Plus (Pharmacia). PBMCs were suspended at 2.times.10.sup.6 /ml in DMEM supplemented to contain 2% FCS, 10 mM, 0.3 mg/ml glutamate, 100 U/ml penicillin G and 100 mg/ml streptomycin sulfate (complete media). Cells were plated into Falcon flat bottom, 96 well culture plates (200 .mu.l/well) and cultured overnight at 37.degree. C. and 6% CO.sub.2. Non-adherent cells were removed by washing with 200 .mu.l/well of fresh medium. Wells containing adherent cells (.about.70% monocytes) were replenished with 100 .mu.l of fresh medium.
Preparation of test compound stock solutions
Test compounds were dissolved in DMSO. Compound stock solutions were prepared to an initial concentration of 10-50 .mu.M. Stocks were diluted initially to 20-200 .mu.M in complete media. Nine two-fold serial dilutions of each compound were then prepared in complete medium.
Treatment of cells with test compounds and activation of TNF production with lipopolysaccharide
One hundred microliters of each test compound dilution were added to microtiter wells containing adherent monocytes and 100 .mu.l complete medium. Monocytes were cultured with test compounds for 60 min at which time 25 .mu.l of complete medium containing 30 ng/ml lipopolysaccharide from E. coli K532 were added to each well. Cells were cultured an additional 4 hrs. Culture supernatants were then removed and TNF presence in the supernatants was quantified using an ELISA.
TNF ELISA
Flat bottom, 96 well Corning High Binding ELISA plates were coated overnight (4.degree. C.) with 150 .mu.L/well of 3 .mu.g/ml murine anti-human TNF-.alpha. MAb (R&D Systems #MAB210). Wells were then blocked for 1 hr at room temperature with 200 .mu.L/well of CaCl.sub.2 -free ELISA buffer supplemented to contain 20 mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM CaCl.sub.2, 0.15 mM thimerosal, pH 7.4). Plates were washed and replenished with 100 .mu.l of test supernatants (diluted 1:3) or standards. Standards consisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/ml recombinant human TNF (R&D Systems). Plates were incubated at room temperature for 1 hr on orbital shaker (300 rpm), washed and replenished with 100 .mu.l/well of 0.5 .mu.g/ml goat anti-human TNF-.alpha. (R&D systems #AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40 min, washed and replenished with 100 .mu.l/well of alkaline phosphatase-conjugated streptavidin (Jackson ImmunoResearch #016-050-084) at 0.02 .mu.g/ml. Plates were incubated 30 min, washed and replenished with 200 .mu.l/well of 1 mg/ml of p-nitrophenyl phosphate. After 30 min, plates were read at 405 nm on a V.sub.max plate reader.
Data analysis
Standard curve data were fit to a second order polynomial and unknown TNF-.alpha. concentrations determined from their OD by solving this equation for concentration. TNF concentrations were then plotted vs. test compound concentration using a second order polynomial. This equation was then used to calculate the concentration of test compounds causing a 50% reduction in TNF production.
The following compounds had an IC.sub.50 of less than 15 .mu.M:
2-cyclohexyloxy-5-(2-chlorophenylcarbonylamino)pyridine;
2-cyclohexyloxy-5-(2-methylphenylcarbonylamino)pyridine;
2-cyclohexyloxy-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-cyclohexyloxy-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2,4-dimethylphenoxy)-5-(2-methylphenylcarbonylamino) pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2-chlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2-fluorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenoxy)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(1-naphthyloxy)-5-(2-methylphenylcarbonylamino) pyridine;
2-(1-naphthyloxy)-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-((3,5-dimethyl-4-isoxazolyl)carbonylamino)pyridine;
2-cyclohexylamino-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-cyclohexylamino-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methylcyclohexylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methylcyclohexylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl carbonylamino)pyridine; and
2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl aminocarbonyl)pyridine.
Compounds of the invention can also be shown to inhibit LPS-induced release of IL-1.beta., IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-1.beta., IL-6 and/or IL-8 by methods well known to those skilled in the art. In a similar manner to the above described assay involving the LPS induced release of TNF-.alpha. from monocytes, compounds of this invention can also be shown to inhibit LPS induced release of IL-1.beta., IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-1.beta., IL-6 and/or IL-8 by methods well known to those skilled in the art. Thus, the compounds of the invention may lower elevated levels of TNF-.alpha., IL-1, IL-6, and IL-8 levels. Reducing elevated levels of these inflammatory cytokines to basal levels or below is favorable in controlling, slowing progression, and alleviating many disease states. All of the compounds are useful in the methods of treating disease states in which TNF-.alpha., IL-1.beta., IL-6, and IL-8 play a role to the full extent of the definition of TNF-.alpha.-mediated diseases described herein.
Inhibition of LPS-Induced TNF-.alpha. production in mice
Male DBA/1LACJ mice are dosed with vehicle or test compounds in a vehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30 minutes prior to lipopolysaccharide (2 mg/kg, I.V.) injection. Ninety minutes after LPS injection, blood are collected and the serum is analyzed by ELISA for TNF levels.
Selected compounds from the class have shown in vivo activity in a LPS mouse model in which serum levels of TNF-.alpha. were reduced in the presence of compounds of this invention.
Compounds of the invention may be shown to have anti-inflammatory properties in animal models of inflammation, including carageenan paw edema, collagen induced arthritis and adjuvant arthritis, such as the carageenan paw edema model (C. A. Winter et al Proc. Soc. Exp. Biol. Med. (1962) vol 111, p 544; K. F. Swingle, in R. A. Scherrer and M. W. Whitehouse, Eds., Antiinflammatory Agents, Chemistry and Pharmacology, Vol. 13-II, Academic, New York, 1974, p. 33) and collagen induced arthritis (D. E. Trentham et al J. Exp. Med. (1977) vol. 146, p 857; J. S. Courtenay, Nature (New Biol.) (1980), Vol 283, p 666).
.sup.125 I-Glucagon Binding Screen with CHO/hGLUR Cells
The assay is described in WO 97/16442, which is incorporated herein by reference in its entirety.
Reagents
The reagents can be prepared as follows: (a) prepare fresh 1M o-Phenanthroline (Aldrich) (198.2 mg/ml ethanol); (b) prepare fresh 0.5M DTT (Sigma); (c) Protease Inhibitor Mix (1000.times.): 5 mg leupeptin, 10 mg benzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per ml DMSO and store aliquots at -20.degree. C.; (d) 250 .mu.M human glucagon (Peninsula): solubilize 0.5 mg vial in 575 .mu.l 0.1N acetic acid (1 .mu.l yields 1 .mu.M final concentration in assay for non-specific binding) and store in aliquots at -20.degree. C.; (e) Assay Buffer: 20 mM Tris (pH 7.8), 1 mM DTT and 3 mM o-phenanthroline; (f) Assay Buffer with 0.1% BSA (for dilution of label only; 0.01% final in assay): 10 .mu.l 10% BSA (heat-inactivated) and 990 .mu.l Assay Buffer; (g) .sup.125 I-Glucagon (NEN, receptor-grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 .mu.l in assay buffer with BSA (about 50 pM final concentration in assay).
Harvesting of CHO/hGLUR Cells for Assay
1. Remove media from confluent flask then rinse once each with PBS (Ca, Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media, Inc.).
2. Add 10 ml Enzyme-free Dissoc. Fluid and hold for about 4 min. at 37.degree. C.
3. Gently tap cells free, triturate, take aliquot for counting and centrifuge remainder for 5 min. at 1000 rpm.
4. Resuspend pellet in Assay Buffer at 75000 cells per 100 .mu.l.
Membrane preparations of CHO/hGLUR cells can be used in place of whole cells at the same assay volume. Final protein concentration of a membrane preparation is determined on a per batch basis.
Assay
The determination of inhibition of glucagon binding can be carried out by measuring the reduction of I.sup.125 -glucagon binding in the presence of compounds of Formula I. The reagents are combined in 120 .mu.L of assay buffer as follows:
______________________________________ Compound/ 250 .mu.M .sup.125 I- CHO/hGLUR Vehicle Glucagon Glucagon Cells______________________________________Total --/5 .mu.l -- 25 .mu.l 100 .mu.lBinding+ 5 .mu.l/-- -- 25 .mu.l 100 .mu.lCompoundNonspecif --/5 .mu.l 1 .mu.l 25 .mu.l 100 .mu.licBinding______________________________________
The mixture is incubated for 60 min. at 22.degree. C. on a shaker at 275 rpm. The mixture is filtered over pre-soaked (0.5% polyethylimine (PEI)) GF/C filtermat using an Innotech Harvester or Tomtec Harvester with four washes of ice-cold 20 mM Tris buffer (pH 7.8). The radioactivity in the filters is determined by a gamma-scintillation counter.
Thus, compounds of the invention may also be shown to inhibit the binding of glucagon to glucagon receptors.
Cyclooxygenase Enzyme Activity Assay
The human monocytic leukemia cell line, THP-1, differentiated by exposure to phorbol esters expresses only COX-1; the human osteosarcoma cell line 143B expresses predominantly COX-2. THP-1 cells are routinely cultured in RPMI complete media supplemented with 10% FBS and human osteosarcoma cells (HOSC) are cultured in minimal essential media supplemented with 10% fetal bovine serum (MEM-10%FBS); all cell incubations are at 37.degree. C. in a humidified environment containing 5% CO.sub.2.
COX-1 Assay
In preparation for the COX-1 assay, THP-1 cells are grown to confluency, split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate 13-acetate (TPA), and incubated for 48 hours on a shaker to prevent attachment. Cells are pelleted and resuspended in Hank's Buffered Saline (HBS) at a concentration of 2.5.times.10.sup.6 cells/mL and plated in 96-well culture plates at a density of 5.times.10.sup.5 cells/mL. Test compounds are diluted in HBS and added to the desired final concentration and the cells are incubated for an additional 4 hours. Arachidonic acid is added to a final concentration of 30 mM, the cells incubated for 20 minutes at 37.degree. C., and enzyme activity determined as described below.
COX-2 Assay
For the COX-2 assay, subconfluent HOSC are trypsinized and resuspended at 3.times.10.sup.6 cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in 96-well tissue culture plates at a density of 3.times.10.sup.4 cells per well, incubated on a shaker for 1 hour to evenly distribute cells, followed by an additional 2 hour static incubation to allow attachment. The media is then replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng human IL-1b/mL, and the cells incubated for 18-22 hours. Following replacement of media with 190 mL MEM, 10 mL of test compound diluted in HBS is added to achieve the desired concentration and the cells incubated for 4 hours. The supernatants are removed and replaced with MEM containing 30 mM arachidonic acid, the cells incubated for 20 minutes at 37.degree. C., and enzyme activity determined as described below.
COX Activity Determined
After incubation with arachidonic acid, the reactions are stopped by the addition of 1 N HCl, followed by neutralization with 1 N NaOH and centrifugation to pellet cell debris. Cyclooxygenase enzyme activity in both HOSC and THP-1 cell supernatants is determined by measuring the concentration of PGE.sub.2 using a commercially available ELISA (Neogen #404110). A standard curve of PGE.sub.2 is used for calibration, and commercially available COX-1 and COX-2 inhibitors are included as standard controls.
The following compound exhibits activities in the Cyclooxygenase assay with IC.sub.50 values of 10 .mu.M or less: 2-(2,4-dimethylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine.
Raf Kinase assay
In vitro Raf kinase activity is measured by the extent of phosphorylation of the substrate MEK (Map kinase/ERK kinase) by activated Raf kinase. Phosphorylated MEK is trapped on a filter and incorporation of radiolabeled phosphate is quantified by scintillation counting.
MATERIALS
Activated Raf is produced by triple transfection of Sf9 cells with baculoviruses expressing "Glu--Glu"-epitope tagged Raf,val.sup.12 -H-Ras, and Lck. The "Glu--Glu"-epitope, Glu-Try-Met-Pro-Met-Glu, was fused to the carboxy-terminus of full length c-Raf.
Catalytically inactive MEK (K97A mutation) is produced in Sf9 cells transfected with a baculovirus expressing c-terminus "Glu--Glu" epitope-tagged K97A MEK1.
Anti "Glu--Glu" antibody was purified from cells grown as described in: Grussenmeyer, et al., Proceedings of the National Academy of Science, U.S.A. pp 7952-7954, 1985.
Column buffer: 20 mM Tris pH=8, 100 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10 mM MgCl.sub.2, 2 mM DTT, 0.4 mM AEBSF, 0.1% n-octylglucopyranoside, 1 mM okadeic acid, and 10 .mu.g/mL each of benzamidine, leupeptin, pepstatin, and aprotinin.
5.times. Reaction buffer: 125 mM HEPES pH=8, 25 mM MgCl.sub.2, 5 mM EDTA, 5 mM Na.sub.3 VO.sub.4, 100 .mu.g/mL BSA.
Enzyme dilution buffer: 25 mM HEPES pH=8, 1 mM EDTA, 1 mM Na.sub.3 VO.sub.4, 400 .mu.g/mL BSA.
Stop solution: 100 mM EDTA, 80 mM sodium pyrophosphate.
Filter plates: Milipore multiscreen # SE3MO78E3, Immobilon-P (PVDF).
METHODS
Protein purification: Sf9 cells were infected with baculovirus and grown as described in Williams, et al., Proceedings of the National Academy of Science, U.S.A. pp 2922-2926, 1992. All subsequent steps were preformed on ice or at 4.degree. C. Cells were pelleted and lysed by sonication in column buffer. Lysates were spun at 17,000.times.g for 20 min, followed by 0.22 .mu.m filtration. Epitope tagged proteins were purified by chromatography over GammaBind Plus affinity column to which the "Glu--Glu" antibody was coupled. Proteins were loaded on the column followed by sequential washes with two column volumes of column buffer, and eluted with 50 .mu.g/mL Glu-Tyr-Met-Pro-Met-Glu in column buffer.
Raf kinase assay: Test compounds were evaluated using ten 3-fold serial dilutions starting at 10-100 .mu.M. 10 .mu.L of the test inhibitor or control, dissolved in 10% DMSO, was added to the assay plate followed by the addition of 30 .mu.L of the a mixture containing 10 .mu.L 5.times. reaction buffer, 1 mM .sup.33 P-.gamma.-ATP (20 .mu.Ci/mL), 0.5 .mu.L MEK (2.5 mg/mL), 1 .mu.L 50 mM .beta.-mercaptoethanol. The reaction was started by the addition of 10 .mu.L of enzyme dilution buffer containing 1 mM DTT and an amount of activated Raf that produces linear kinetics over the reaction time course. The reaction was mixed and incubated at room temperature for 90 min. and stopped by the addition of 50 .mu.L stop solution. 90 .mu.L aliquots of this stopped solution were transferred onto GFP-30 cellulose microtiter filter plates (Polyfiltronics), the filter plates washed in four well volumes of 5% phosphoric acid, allowed to dry, and then replenished with 25 .mu.l scintillation cocktail. The plates were counted for .sup.33 P gamma emission using a TopCount Scintillation Reader.
Accordingly, the compounds of the invention or a pharmaceutical composition thereof are useful for prophylaxis and treatment of rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic .beta. cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; Alzheimer's disease; stroke; myocardial infarction; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster, all of which are sensitive to TNF-.alpha. and/or IL-1 inhibition or glucagon antagonism, will also be positively effected by the compounds and methods of the invention.
The compounds of the present invention may also possess oncolytic characteristics and may be useful for the treatment of cancer. The compounds of the present invention may also block signal transduction by extracellular mitogenic stimuli and oncoproteins through inhibition of Raf kinase.
The compounds of the present invention also may possess analgesic properties and may be useful for the treatment of pain disorders, such as hyperalgesia due to excessive IL-1. The compounds of the present invention may also prevent the production of prostaglandins by inhibition of enzymes in the human arachidonic acid/prostaglandin pathway, including cyclooxygenase (WO 96/03387, incorporated herein by reference in its entirety).
Because of their ability to lower TNF-.alpha. and IL-1 concentrations or inhibit glucagon binding to its receptor, the compounds of the invention are also useful research tools for studying the physiology associated with blocking these effects.
The methods of the invention comprise administering an effective dose of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either, to a subject (i.e., an animal, preferably a mammal, most preferably a human) in need of a reduction in the level of TNF-.alpha., IL-1, IL-6, and/or IL-8 levels and/or reduction in plasma glucose levels and/or which subject may be suffering from rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic .beta. cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; cancer; bone resorption diseases; graft vs. host reaction; Alzheimer's disease; stroke; myocardial infarction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection, or which subject is infected by HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), or herpes zoster.
In another aspect, this invention comprises the use of a compound of the invention, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment either acutely or chronically of a TNF-.alpha., IL-1.beta., IL-6, and/or IL-8 mediated disease state, including those described previously. The compounds of the present are also useful in the manufacture of an anti-cancer medicant. The compounds of the present invention are also useful in the manufacture of a medicant to attenuate or prevent signal transduction by extracellular mitogenic stimuli and oncoproteins through inhibition of Raf kinase. Also, the compounds of this invention are useful in the manufacture of a analgesic medicament and a medicament for treating pain disorders, such as hyperalgesia. The compounds of the present invention also are useful in the manufacture of a medicament to prevent the production of prostaglandins by inhibition of enzymes in the human arachidonic acid/prostaglandin pathway.
In still another aspect, this invention provides a pharmaceutical composition comprising an effective TNF-.alpha., IL-1.beta., IL-6, and/or IL-8 lowering amount and/or effective plasma glucose level lowering amount, and/or effective tumor supressing amount of a compound of the invention and a pharmaceutically acceptable carrier or diluent, and if desired other active ingredients. The compounds of the invention are administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to arrest the progress or prevent tissue damage associated with the disease are readily ascertained by one of ordinary skill in the art using standard methods.
For the treatment of TNF-.alpha., IL-1.beta., IL-6, and IL-8 mediated diseases, cancer, and/or hyperglycemia, the compounds of the present invention may be administered orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitoneally.
The dosage regimen for treating a TNF-.alpha., IL-1, IL-6, and IL-8 mediated diseases, cancer, and/or hyperglycemia with the compounds of this invention and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. Dosage levels of the order from about 0.01 mg to 30 mg per kilogram of body weight per day, preferably from about 0.1 mg to 10 mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.
The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, a suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg, more preferably from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known are using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
The pharmaceutical compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids that may be employed to from pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims
  • 1. A compound of the formula ##STR29## or a pharmaceutically acceptable salt thereof, wherein X is O, S, S(O), S(O).sub.2 or NR.sup.2 ;
  • Y is --C(O)--NR.sup.3 R.sup.4 or --NR.sup.4 --C(O)--R.sup.3 ;
  • R.sup.1 is a cycloalkyl or aryl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 -alkyl;
  • provided that the total number of aryl and cycloalkyl radicals in R.sup.1 is 1-3;
  • R.sup.2 is a hydrogen or alkyl radical;
  • R.sup.3 is an aryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 -alkyl; provided that the total number of aryl radicals in R.sup.3 is 1-3; and provided when Y is --C(O)--NR.sup.3 R.sup.4, then R.sup.3 is other than an optionally substituted phenyl or naphthyl having an amino, nitro, cyano or --CO.sub.2 R.sup.19 substituent bonded to the ring carbon atom adjacent to the ring carbon atom bonded to --NR.sup.4 --; when Y is --NR.sup.4 --C(O)--R.sup.3 and X is O or S, then R.sup.3 is other than an optionally substituted 2-hydroxyphenyl or 2-(alkylcarbonyloxy)phenyl radical; and when R.sup.4 is a hydrogen radical and X is O or S, then R.sup.3 is other than a tert-butylphenyl radical;
  • R.sup.4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or R.sup.20 --Z.sup.20 -alkyl radical;
  • wherein R.sup.18, R.sup.19 and R.sup.20 are each independently a hydrogen, alkyl, haloalkyl, aryl or arylalkyl radical; wherein the aryl radicals of R.sup.4, R.sup.18, R.sup.19 and R.sup.20 are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy; and
  • Z.sup.18, Z.sup.19 and Z.sup.20 are each independently --O--, --S--, --S(O)--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --; wherein each R.sup.21 is independently a hydrogen or alkyl radical;
  • R.sup.5 and R.sup.6 are each independently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical; and
  • R.sup.7 is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical; provided when Y is --C(O)--NR.sup.3 R.sup.4 and X is O or S, then R.sup.7 is other than an aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical; and
  • wherein cycloalkyl is a monocyclic, bicyclic or tricyclic carbocyclic alkyl radical of 5-12 ring members, which is optionally partially unsaturated or benzo fused; and aryl is a phenyl or biphenyl radical which is optionally benzo fused.
  • 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.1 is a cycloalkyl or aryl radical which is optionally substituted by 1-4 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.6 alkyl; provided that the total number of aryl and cycloalkyl radicals in R.sup.1 is 1-3;
  • R.sup.2 is a hydrogen or C.sub.1 -C.sub.4 alkyl radical;
  • R.sup.3 is an aryl radical which is optionally substituted by 1-5 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 --C.sub.1 -C.sub.6 alkyl; provided that the total number of aryl radicals in R.sup.3 is 1-3;
  • R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 --C.sub.6 alkenyl, C.sub.1 -C.sub.6 haloalkyl of 1-3 halo radicals, C.sub.2 -C.sub.6 haloalkenyl of 1-3 halo radicals, aryl, aryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.1 -C.sub.6 alkyl radical; and
  • wherein R.sup.18, R.sup.19 and R.sup.20 are each independently a hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals of R.sup.4, R.sup.18, R.sup.19 and R.sup.20 are optionally substituted by 1-3 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, (C.sub.1 -C.sub.4 alkoxy)carbonylamino, (C.sub.1 -C.sub.4 alkoxy)carbonyl, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals or C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals; and
  • each R.sup.21 is independently a hydrogen or C.sub.1 -C.sub.4 alkyl radical;
  • R.sup.5 and R.sup.6 are each independently a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals, C.sub.1 -C.sub.4 aminoalkyl, (C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, di(C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, C.sub.1 -C.sub.4 alkylsulfonylamino, aminosulfonyl, C.sub.1 -C.sub.4 alkylaminosulfonyl, di(C.sub.1 -C.sub.4 alkyl)aminosulfonyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkylthiol, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkoxy)C.sub.1 -C.sub.4 alkyl, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical; and
  • R.sup.7 is a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, C.sub.1 -C.sub.4 haloalkoxy of 1-3 halo radicals, C.sub.1 -C.sub.4 aminoalkyl, (C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, di(C.sub.1 -C.sub.4 alkyl)amino-C.sub.1 -C.sub.4 alkyl, aminosulfonyl, C.sub.1 -C.sub.4 alkylaminosulfonyl, di(C.sub.1 -C.sub.4 alkyl)aminosulfonyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkylthiol, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.1 -C.sub.4 alkoxy, (C.sub.1 -C.sub.4 alkoxy)C.sub.1 -C.sub.4 alkyl, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical.
  • 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Y is --NR.sup.4 --C(O)--R.sup.3.
  • 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein
  • X is O or NR.sup.2 ;
  • R.sup.1 is a cycloalkyl or aryl radical which is optionally substituted by 1-4 radicals of C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.4 alkyl; provided that the total number of aryl and cycloalkyl radicals in R.sup.1 is 1-2;
  • wherein each R.sup.18 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.2 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy; and
  • R.sup.2 is a hydrogen or C.sub.1 -C.sub.2 alkyl radical;
  • R.sup.3 is an aryl radical which is optionally substituted by 1-5 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 --C.sub.1 -C.sub.4 alkyl; provided that the total number of aryl radicals in R.sup.3 is 1-2; and
  • wherein each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, cyano, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy; and
  • R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, aryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.2 -C.sub.4 alkyl radical; and
  • wherein R.sup.20 is a hydrogen, C.sub.1 -C.sub.4 alkyl, aryl or aryl-C.sub.1 -C.sub.2 alkyl radical; wherein the aryl radicals of R.sup.4 and R.sup.20 are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy; and
  • Z.sup.20 is --O--, --NH-- or --N(CH.sub.3)--;
  • R.sup.5 and R.sup.6 are each independently a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical; and
  • R.sup.7 is a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di (C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical; and
  • wherein cycloalkyl is a monocyclic or bicyclic carbocyclic alkyl radical of 5-12 ring members, which is optionally partially unsaturated or benzo fused.
  • 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.3 is a radical of the formula ##STR30## R.sup.11 and R.sup.13 are each independently a radical of hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R.sup.19 --Z.sup.19 --; and each R.sup.12 is independently a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, R.sup.31 --Z.sup.31 -- or R.sup.31 --Z.sup.31 --C.sub.1 -C.sub.4 alkyl; provided that the combined total number of aryl radicals in R.sup.11, R.sup.12 and R.sup.13 is 0-1;
  • wherein each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy; and
  • each Z.sup.19 is independently --O--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
  • wherein each R.sup.31 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy; and
  • each Z.sup.31 is independently --O--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
  • wherein R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, aryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.2 -C.sub.4 alkyl radical;
  • wherein R.sup.20 is a hydrogen, C.sub.1 -C.sub.4 alkyl, aryl or aryl-C.sub.1 -C.sub.2 alkyl radical; wherein the aryl radicals of R.sup.4 and R.sup.20 are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy; and
  • R.sup.5 and R.sup.6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C.sub.1 -C.sub.2 alkylamino, di(C.sub.1 -C.sub.2 alkyl)amino, hydroxy, methoxy or ethoxy radical; and
  • R.sup.7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; and
  • wherein cycloalkyl is a monocyclic or bicyclic carbocyclic alkyl radical of 5-10 ring members, which is optionally partially unsaturated with one double bond or benzo fused.
  • 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.1 is a radical of the formula ##STR31## wherein R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are each independently a radical of hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.4 alkyl; provided at least one of R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 is hydrogen; and provided that the combined total number of aryl radicals in R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 is 0-1; and
  • wherein each Z.sup.18 is independently --O--, --S--, --S(O).sub.2 --, --CO.sub.2 --, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 or --S(O).sub.2 --NR.sup.21 --.
  • 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
  • X is NR.sup.2 ;
  • R.sup.2 is a hydrogen or methyl radical;
  • R.sup.4 is a radical of hydrogen, methyl or ethyl radical; and
  • R.sup.5, R.sup.6 and R.sup.7 are each independently a hydrogen radical; and
  • wherein aryl is a phenyl, biphenyl or naphthyl radical.
  • 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.11 and R.sup.13 are each independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, azido, nitro, amidino, R.sup.19 --O--, R.sup.19 --S(O).sub.2 --, R.sup.19 --O--C(O)--, R.sup.19 --C(O)--, R.sup.19 --NR.sup.21 --C(O)-- or R.sup.19 --NR.sup.21 --S(O).sub.2 --; provided that the combined total number of aryl radicals in R.sup.11 and R.sup.13 is 0-1;
  • each R.sup.12 is independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl, (methylamino)methyl or (dimethylamino)methyl; and
  • wherein each R.sup.19 is independently a hydrogen, methyl, ethyl, trifluoromethyl, phenyl or phenylmethyl radical; wherein the phenyl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl or trifluoromethoxy.
  • 9. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Y is --C(O)--NR.sup.3 R.sup.4.
  • 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein
  • X is O or NR.sup.2 ;
  • R.sup.1 is a cycloalkyl or aryl radical which is optionally substituted by 1-4 radicals of C.sub.1 -C.sub.4 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.4 alkyl; provided that the total number of aryl and cycloalkyl radicals in R.sup.1 is 1-2;
  • wherein each R.sup.18 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.2 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, cyano, halo, azido, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy; and
  • R.sup.2 is a hydrogen or C.sub.1 -C.sub.2 alkyl radical;
  • R.sup.3 is an aryl radical which is optionally substituted by 1-5 radicals of C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R.sup.19 --Z.sup.19 -- or R.sup.19 --Z.sup.19 --C.sub.1 -C.sub.4 alkyl; provided that the total number of aryl radicals in R.sup.3 is 1-2;
  • wherein each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, cyano, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy; and
  • R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, aryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 --Z.sup.20 --C.sub.2 -C.sub.4 alkyl radical;
  • wherein R.sup.20 is a hydrogen, C.sub.1 -C.sub.4 alkyl, aryl or aryl-C.sub.1 -C.sub.2 alkyl radical; wherein the aryl radicals of R.sup.4 and R.sup.20 are optionally substituted by 1-2 radicals of hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthiol, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, acetylamino, halo, C.sub.1 -C.sub.4 alkyl, trifluoromethyl or trifluoromethoxy; and
  • Z.sup.20 is --O--, --NH-- or --N(CH.sub.3)--;
  • R.sup.5 and R.sup.6 are each independently a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.5 alkanoylamino, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, cyano, azido, nitro, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di(C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical; and
  • R.sup.7 is a hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, carboxy, (C.sub.1 -C.sub.4 alkoxy)carbonyl, aminocarbonyl, (C.sub.1 -C.sub.4 alkyl)aminocarbonyl or di (C.sub.1 -C.sub.4 alkyl)aminocarbonyl radical; and
  • wherein cycloalkyl is a monocyclic or bicyclic carbocyclic alkyl radical of 5-12 ring members, which is optionally partially unsaturated or benzo fused.
  • 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.3 is a radical of the formula ##STR32## R.sup.11 and R.sup.13 are each independently a radical of hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R.sup.19 --Z.sup.19 --; and each R.sup.12 is independently a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, halo, C.sub.1 -C.sub.4 haloalkyl of 1-3 halo radicals, R.sup.31 --Z.sup.31 -- or R.sup.31 --Z.sup.31 --C.sub.1 -C.sub.4 alkyl; provided that the combined total number of aryl radicals in R.sup.11, R.sup.12 and R.sup.13 is 0-1;
  • wherein each R.sup.19 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy; and
  • each Z.sup.19 is independently --O--, --S(O).sub.2 --, --CO.sub.2 --, --C(O)--, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --; wherein each R.sup.21 is independently a hydrogen or methyl radical;
  • wherein each R.sup.31 is independently a hydrogen, C.sub.1 -C.sub.4 alkyl, trifluoromethyl, aryl or aryl-C.sub.1 -C.sub.4 alkyl radical; wherein the aryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy; and
  • each Z.sup.31 is independently --O--, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --;
  • R.sup.4 is a radical of hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, aryl-C.sub.1 -C.sub.4 alkyl or R.sup.20 -Z.sup.20 --C.sub.2 -C.sub.4 alkyl radical; and
  • wherein R.sup.20 is a hydrogen, C.sub.1 -C.sub.4 alkyl, aryl or aryl-C.sub.1 -C.sub.2 alkyl radical; wherein the aryl radicals of R.sup.4 and R.sup.20 are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy; and
  • R.sup.5 and R.sup.6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C.sub.1 --C.sub.2 alkylamino, di(C.sub.1 -C.sub.2 alkyl)amino, hydroxy, methoxy or ethoxy radical; and
  • R.sup.7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; and
  • wherein cycloalkyl is a monocyclic or bicyclic carbocyclic alkyl radical of 5-10 ring members, which is optionally partially unsaturated with one double bond or benzo fused.
  • 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.1 is a radical of the formula ##STR33## wherein R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are each independently a radical of hydrogen, C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino, R.sup.18 --Z.sup.18 -- or R.sup.18 --Z.sup.18 --C.sub.1 -C.sub.4 alkyl; provided at least one of R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 is hydrogen; and provided that the combined total number of aryl radicals in R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 is 0-1; and
  • each Z.sup.18 is independently --O--, --S--, --S(O).sub.2 --, --CO.sub.2 --, --NR.sup.21 --, --NR.sup.21 --C(O)--, --C(O)--NR.sup.21 --, --NR.sup.21 --S(O).sub.2 -- or --S(O).sub.2 --NR.sup.21 --.
  • 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein
  • X is NR.sup.2 ;
  • R.sup.2 is a hydrogen or methyl radical;
  • R.sup.4 is a radical of hydrogen, methyl or ethyl radical; and
  • R.sup.5, R.sup.6 and R.sup.7 are each independently a hydrogen radical; and
  • wherein aryl is a phenyl, biphenyl or naphthyl radical.
  • 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein
  • R.sup.11 and R.sup.13 are each independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, azido, nitro, amidino, R.sup.19 --O--, R.sup.19 --S(O).sub.2 --, R.sup.19 --O--C(O)--, R.sup.19 --C(O)--, R.sup.19 --NR.sup.21 --C(O)-- or R.sup.19 --NR.sup.21 --S(O).sub.2 --; provided when U is C--R.sup.13 and V and W are each C--R.sup.12, R.sup.11 and R.sup.13 are each other than a nitro, cyano, carboxy or alkoxycarbonyl radical; and provided that the combined total number of aryl radicals in R.sup.11 and R.sup.13 is 0-1;
  • each R.sup.12 is independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl, (methylamino)methyl or (dimethylamino)methyl; and
  • wherein each R.sup.19 is independently a hydrogen, methyl, ethyl, trifluoromethyl, phenyl or phenylmethyl radical; wherein the phenyl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl or trifluoromethoxy.
  • 15. The compound of claim 1 which is:
  • 2-cyclohexyloxy-5-(2-chlorophenylcarbonylamino)pyridine;
  • 2-cyclohexyloxy-5-(2-methylphenylcarbonylamino)pyridine;
  • 2-cyclohexyloxy-5-(2,6-dichlorophenylcarbonylamino) pyridine;
  • 2-cyclohexyloxy-5-(2,6-dimethylphenylcarbonylamino) pyridine;
  • 2-(2,4-dimethylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;
  • 2-(2,4-dimethylphenoxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
  • 2-(2,4-dimethylphenoxy)-5-(2-methylphenylcarbonylamino) pyridine;
  • 2-(2,6-dimethyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino) pyridine;
  • 2-(2-methyl-4-fluorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2-methyl-4-chlorophenoxy)-5-(2-chlorophenylcarbonyl amino)pyridine;
  • 2-(2-methyl-4-chlorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2-methylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;
  • 2-(2-methylphenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
  • 2-(2-methylphenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2-methyl-4-chlorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
  • 2-(2-methyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
  • 2-(4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
  • 2-(2-methyl-4-fluorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
  • 2-(2-methyl-4-fluorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
  • 2-(2-methylphenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
  • 2-(2-methyl-4-fluorophenoxy)-5-(2-fluorophenylcarbonyl amino)pyridine;
  • 2-(2,4-dimethylphenoxy)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
  • 2-(1-naphthyloxy)-5-(2-methylphenylcarbonylamino) pyridine;
  • 2-(1-naphthyloxy)-5-(2,6-dichlorophenylcarbonylamino) pyridine;
  • 2-(1-naphthyloxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
  • 2-(2-methyl-4-chlorophenylthiol)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2-methyl-4-chlorophenylthiol)-5-(2,6-dimethylphenylcarbonylamino)pyridine;
  • 2-cyclohexylamino-5-(2,6-dichlorophenylcarbonylamino) pyridine;
  • 2-cyclohexylamino-5-(2,6-dimethylphenylcarbonylamino) pyridine;
  • 2-(2-methylcyclohexylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
  • 2-(2-methylcyclohexylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2,4-dimethylphenylamino)-5-(2-fluorophenylcarbonyl amino)pyridine;
  • 2-(2,4-dimethylphenylamino)-5-(2-chlorophenylcarbonyl amino)pyridine;
  • 2-(2,4-dimethylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
  • 2-(2-methyl-4-chlorophenylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;
  • 2-(2,4-dimethylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2-methylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
  • 2-(2-methylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
  • 2-(2-methylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
  • 2-(2,4-dimethylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
  • 2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl carbonylamino)pyridine;
  • 2-(2-methyl-4-chlorophenylamino)-5-(2,6-dimethylphenyl carbonylamino)pyridine; or
  • 2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl aminocarbonyl)pyridine.
  • 16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15 and a pharmaceutically acceptable carrier.
  • 17. A method for prophylaxis or treatment of inflammation comprising administering an effective amount of a compound of any one of claims 1 to 15.
  • 18. A method for prophylaxis or treatment of inflammation comprising administering an effective amount of a composition of claim 16.
Parent Case Info

This application claims priority from Provisional Application number 60/064,953, filed Nov. 7, 1997.

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