Substituted pyridine compounds and methods of use

Abstract
Selected novel substituted pyridine compounds are effective for prophylaxis and treatment of diseases, such as TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseases, and other maladies, suchas pain and diabetes. The inventin 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 intermedates 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-α, IL-1β, 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 α (TNF-α) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflamatory stimuli (e.g., lipopolysacchride—LPS) or external cellular stress (e.g., osmotic shock and peroxide).




Elevated levels of TNF-α and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disesase; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic β 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-α.




It has been reported that TNF-α plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-α 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 cerebal artery was occluded, the levels of TNF-α mRNA of TNF-α increased (Feurstein et al.,


Neurosci. Lett.


164, 125 (1993)). Administration of TNF-α into the rat cortex has been reported to result insignificant neutrophil accumulation in capillaries an dadherence in small blood vessels. TNF-α promotes the infiltration of other cytokines (IL-1β, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein,


Stroke


25, 1481 (1994)). TNF-α has also been implicated to play a role intype II diabetes (Endocrinol. 130, 43-52, 1992; and Endocrinol. 136, 1474-1481, 1995).




TNF-α appears to play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-α 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-α in the HIV associated states of cachexia and muscle degradation.




TNF-α is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-α 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 syndrom (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-α inhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.




TNF-α and IL-1 appear to play a role in pancreatic β cell destruction and diabetes. Pancreatic β cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic β cells often accompanies type I diabetes. Pancreatic β 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 attenuatingplasma 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 intr-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-α (Firestein,


Am. J. Pathol.


140, 1309 (1992)). At sites of local injectin, netrophil, 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 appearts 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-α induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction witin the arthritic joints. In a model of arthritis (collagen-induced arthritis (CIA) in rats and mice), intra-articular administration of TNF-α either prior to or after the inductin 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 infilttration into sites of inflammatin or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflamatory 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-α. One approach involves using soluble receptors for TNF-α (e.g., TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-α-mediated disease states. A second approach to neutralizing TNF-α using a monoclonal antibody specific to TNF-α, 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-α 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-inducible proteins. Raf proteins are kinases activated in response to extracellular mitogenic stimuli such as PDG, EGF, acidic FDF, 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 antogonism 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). Substitued 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 described 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 terapeutically valuable compounds for use as antiphlogistic agents.




BRIEF DESCRIPTION OF THE INVENTION




The present invention comprises a new class of compunds useful in the prophylaxis and treatment of diseases, such as TNF-α, IL-1β, 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 inventin also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF-α, IL-1β, 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:











wherein R


1


, R


5


, R


6


, R


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:











or a pharmaceutically acceptable salt thereof, wherein




X is O, S, S(O), S(O)


2


or NR


2


; preferably, X is O, S or NR


2


; more preferably, X is O or NR


2


; most preferably, X is NR


2


;




Y is —C(O)—NR


3


R


4


or —NR


4


—C(O)—R


3


;




R


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


18


—Z


18


— or R


18


—Z


18


—alkyl;




preferably, R


1


is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of C


1


-C


6


alkyl, halo, C


1


-C


6


haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R


18


—Z


18


— or R


18


—Z


18


—C


1


-C


6


alkyl;




more preferably, R


1


is a cycloalkyl, aryl, heterocyclyl or heteraryl radical which is optionally substituted by 1-4 radicals of C


1


-C


4


alkyl, halo, C


1


-C


4


haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R


18


—Z


18


— or R


18


—Z


18


—C


1


-C


4


alkyl;




provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R


1


is 1-3, preferably, 1-2, and provided when Y is —NR


4


—C(O)—R


3


and X is O or S, R


1


is other than a 2-pyrimidinyl radical;




more preferably, R


1


is a radical of the formula











wherein R


22


, R


23


, R


24


, R


25


and R


26


are each independently a radical of hydrogen, C


1


-C


4


alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino, R


18


—Z


18


— or R


18


—Z


18


—C


1


-C


4


alkyl; provided at least one of R


21


, R


22


, R


23


, R


24


and R


25


is hydrogen; and provided that the combined total number of aryl and heteroaryl radicals in R


22


, R


23


, R


24


, R


25


and R


26


is 0-1;




R


2


is a hydrogen or alkyl radical; preferably, R


2


is a hydrogen or C


1


-C


4


alkyl radical; more preferably, R


2


is a hydrogen or C


1


-C


2


alkyl radical; more preferably, R


2


is a hydrogen or methyl radical; and most preferably, R


2


is a hydrogen radical;




R


3


is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R


19


—Z


19


— or R


19


—Z


19


—alkyl; preferably, R


3


is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C


1


-C


6


alkyl, halo, C


1


-C


6


haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R


19


—Z


19


— or R


19


—Z


19


—C


1


-C


6


alkyl; more preferably, R


3


is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C


1


-C


6


alkyl, halo, C


1


-C


4


haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R


19


—Z


19


— or R


19


—Z


19


—C


1


-C


4


alkyl;




provided that the total number of aryl and heteroaryl radicals in R


3


is 1-3, preferably, 1-2; and provided when Y is —C(O)—NR


3


R


4


, R


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


4


—;




more preferably, R


3


is a radical of the formula











wherein




U is C—R


13


or N;




V and W are each independently C—R


12


or N;




R


11


and R


13


are each independently a radical of hydrogen, C


1


-C


4


alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R


19


—Z


19


—; preferably, R


11


and R


13


are each independently a radical of hydrogen, methyl, ethyl, fluoro,chloro, trifluoromethyl, cyano, azido, nitro, amidino, R


19


—O—, R


19


—S(O)


2


—, R


19


—O—C(O)—, R


19


—C(O)—, R


19


—NR


21


—C(O)— or R


19


—NR


21


—S(O)


2


—;




each R


12


is independently a radical of hydrogen, C


1


-C


6


alkyl, halo, C


1


-C


4


haloalkyl of 1-3 halo radicals, R


31


—Z


31


— or R


31


—Z


31


—C


1


-C


4


alkyl; preferably, each R


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


11


, R


12


and R


13


is 0-1;




wherein each R


31


is independently a hydrogen, C


1


-C


4


alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C


1


-C


4


alkyl or heteroaryl-C


1


-C


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


31


is independently —O—, —NR


21


—, —NR


21


—C(O)—, —C(O)—NR


21


—, —NR


21


—S(O)


2


— or —S(O)


2


—NR


21


—;




R


4


is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R


20


—Z


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


4


is a radical of hydrogen, C


1


-C


6


alkyl, C


2


-C


6


alkenyl, C


1


-C


6


haloalkyl of 1-3 halo radicals, C


2


-C


6


haloalkenyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C


1


-C


4


alkyl, heteroaryl-C


1


-C


4


alkyl or R


20


—Z


20


—C


1


-C


6


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, C


1


-C


5


alkanoylamino, C


1


-C


4


alkylsulfonylamino, C


1


-C


4


alkylsulfinyl, C


1


-C


4


alkylsulfonyl, (C


1


-C


4


alkoxy)carbonylamino, (C


1


-C


4


alkoxy)carbonyl, cyano, halo, azido, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals or C


1


-C


4


haloalkoxy of 1-3 halo radicals;




more preferably, R


4


is a radical of hydrogen, C


1


-C


6


alkyl, aryl, heteroaryl, aryl-C


1


-C


4


alkyl, heteroaryl-C


1


-C


4


alkyl or R


20


—Z


20


—C


2


-C


4


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, acetylamino, halo, C


1


-C


4


alkyl, trifluoromethyl or trifluoromethoxy;




more preferably, R


4


is a radical of hydrogen, C


1


-C


6


alkyl, aryl, heteroaryl, aryl-C


1


-C


4


alkyl, heteroaryl-C


1


-C


4


alkyl or R


20


—Z


20


—C


2


-C


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


4


is a radical of hydrogen, methyl or ethyl radical;




wherein each R


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, R


18


is independently a hydrogen, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C


1


-C


4


alkyl or heteroaryl-C


1


-C


4


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, C


1


-C


5


alkanoylamino, C


1


-C


4


alkylsulfonylamino, C


1


-C


4


alkylsulfinyl, C


1


-C


4


alkylsulfonyl, (C


1


-C


4


alkoxy)carbonylamino, (C


1


-C


4


alkoxy)carbonyl, cyano, halo, azido, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals or C


1


-C


4


haloalkoxy of 1-3 halo radicals;




more preferably, each R


18


is independently a hydrogen, C


1


-C


4


alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C


1


-C


2


alkyl or heteroaryl-C


1


-C


2


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, acetylamino, cyano, halo, azido, C


1


-C


4


alkyl, trifluoromethyl or trifluoromethoxy;




each Z


18


is independently —O—, —S—, —S(O)—, —S(O)


2


—, —CO


2


—, —C(O)—, —NR


21


—, —NR


21


—C(O)—, —C(O)—NR


21


—, —NR


21


—S(O)


2


— or —S(O)


2


—NR


21


—; preferably, each Z


18


is independently —O—, —S—, —S(O)


2


—, —CO


2


—, —NR


21


—, —NR


21


—C(O)—, —C(O)—NR


21


—, —NR


21


—S(O)


2


— or —S(O)


2


—NR


21


—;




wherein each R


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


19


is independently a hydrogen, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C


1


-C


4


alkyl or heteroaryl-C


1


-C


4


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, C


1


-C


5


alkanoylamino, C


1


-C


4


alkylsulfonylamino, C


1


-C


4


alkylsulfinyl, C


1


-C


4


alkylsulfonyl, (C


1


-C


4


alkoxy)carbonylamino, (C


1


-C


4


alkoxy)carbonyl, cyano, halo, azido, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals or C


1


-C


4


haloalkoxy of 1-3 halo radicals;




more preferably, each R


19


is independently a hydrogen, C


1


-C


4


alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C


1


-C


4


alkyl or heteroaryl-C


1


-C


4


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, acetylamino, cyano, halo, C


1


-C


4


alkyl, trifluoromethyl or trifluoromethoxy;




more preferably, each R


19


is independently a hydrogen, C


1


-C


4


alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C


1


-C


4


alkyl or heteroaryl-C


1


-C


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


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


19


is independently —O—, —S—, —S(O)—, —S(O)


2


—, —CO


2


—, —C(O)—, —NR


21


—, —NR


21


—C(O)—, —C(O)—NR


21


—, —NR


21


—S(O)


2


— or —S(O)


2


—NR


21


—; preferably, each Z


19


is independently —O—, —S(O)


2


—, —CO


2


—, —C(O)—, —NR


21


—C(O)—, —C(O)—NR


21


—, —NR


21


—S(O)


2


— or —S(O)


2


—NR


21


—; more preferably, each Z


19


is independently —O—, —S(O)


2


—, —O—C(O)—, —C(O)—, —NR


21


—C(O)— or —NR


21


—S(O)


2


—;




wherein each R


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, R


20


is independently a hydrogen, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C


1


-C


4


alkyl or heteroaryl-C


1


-C


4


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, C


1


-C


5


alkanoylamino, C


1


-C


4


alkylsulfonylamino, C


1


-C


4


alkylsulfinyl, C


1


-C


4


alkylsulfonyl, (C


1


-C


4


alkoxy)carbonylamino, (C


1


-C


4


alkoxy)carbonyl, cyano, halo, azido, C


1


-C


4


alkyl, C


1


-C


4


haloalkyl of 1-3 halo radicals or C


1


-C


4


haloalkoxy of 1-3 halo radicals;




more preferably, each R


20


is independently a hydrogen, C


1


-C


4


alkyl, aryl, heteroaryl, aryl C


1


-C


2


alkyl or heteroaryl-C


1


-C


2


alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C


1


-C


4


alkoxy, C


1


-C


4


alkylthiol, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, acetylamino, halo, C


1


-C


4


alkyl, trifluoromethyl or trifluoromethoxy;




more preferably, each R


20


is independently a hydrogen, C


1


-C


4


alkyl, aryl, heteroaryl, aryl-C


1


-C


2


alkyl or heteroaryl-C


1


-C


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


20


is independently —O—, —S—, —S(O)—, —S(O)


2


—, —CO


2


—, —C(O)—, —NR


21


—, —NR


21


—C(O)—, —C(O)—NR


21


—, —NR


21


—S(O)


2


— or —S(O)


2


—NR


21


—; preferably, each Z


20


is independently —O— or —NR


21


—;




wherein each R


21


is independently a hydrogen or alkyl radical; preferably, each R


21


is independently a hydrogen or C


1


-C


4


alkyl radical; more preferably, each R


21


is independently a hydrogen or methyl radical;




R


5


and R


6


are each independently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkyaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;




preferably, R


5


or R


6


are each independently a hydrogen, C


1


-C


4


alkyl, halo, C


1


-C


4


haloalkyl of 1-3 halo radicals, C


1


-C


4


haloalkoxy of 1-3 halo radicals, C


1


-C


4


aminoalkyl, (C


1


-C


4


alkyl)amino-C


1


-C


4


alkyl, di(C


1


-C


4


alkyl)amino-C


1


-C


4


alkyl, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, C


1


-C


5


alkanoylamino, C


1


-C


4


alkylsulfonylamino, aminosulfonyl, C


1


-C


4


alkylaminosulfonyl, di(C


1


-C


4


alkyl)aminosulfonyl, hydroxy, C


1


-C


4


hydroxyalkyl, thiol, C


1


-C


4


alkylthiol, C


1


-C


4


alkylsulfinyl, C


1


-C


4


alkylsulfonyl, C


1


-C


4


alkoxy, (C


1


-C


4


alkoxy)C


1


-C


4


alkyl, cyano, azido, nitro, carboxy, (C


1


-C


4


alkoxy)carbonyl, aminocarbonyl, (C


1


-C


4


alkyl)aminocarbonyl or di(C


1


-C


4


alkyl)aminocarbonyl radical;




more preferably, R


5


or R


6


are each independently a hydrogen, C


1


-C


4


alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C


1


-C


4


alkylamino, di(C


1


-C


4


alkyl)amino, C


1


-C


5


alkanoylamino, hydroxy, C


1


-C


4


hydroxyalkyl, C


1


-C


4


alkoxy, cyano, azido, nitro, carboxy, (C


1


-C


4


alkoxy)carbonyl, aminocarbonyl, (C


1


-C


4


alkyl)aminocarbonyl or di(C


1


-C


4


alkyl)aminocarbonyl radical;




more preferably, R


5


or R


6


are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C


1


-C


2


alkylamino, di(C


1


-C


2


alkyl)amino, hydroxy, methoxy or ethoxy radical; more preferably, R


5


or R


6


are each a hydrogen radical;




R


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


7


is a hydrogen, C


1


-C


4


alkyl, halo, C


1


-C


4


haloalkyl of 1-3 halo radicals, C


1


-C


4


haloalkoxy of 1-3 halo radicals, C


1


-C


4


aminoalkyl, (C


1


-C


4


alkyl)amino-C


1


-C


4


alkyl, di(C


1


-C


4


alkyl)amino-C


1


-C


4


alkyl, aminosulfonyl, C


1


-C


4


alkylaminosulfonyl, di(C


1


-C


4


alkyl)aminosulfonyl, hydroxy, C


1


-C


4


hydroxyalkyl, thiol, C


1


-C


4


alkylthiol, C


1


-C


4


alkylsulfinyl, C


1


-C


4


alkylsulfonyl, C


1


-C


4


alkoxy, (C


1


-C


4


alkoxy)C


1


-C


4


alkyl, cyano, azido, nitro, carboxy, (C


1


-C


4


alkoxy)carbonyl, aminocarbonyl, (C


1


-C


4


alkyl)aminocarbonyl or di(C


1


-C


4


alkyl)aminocarbonyl radical;




more preferably, R


7


is a hydrogen, C


1


-C


4


alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C


1


-C


4


hydroxyalkyl, C


1


-C


4


alkoxy, carboxy, (C


1


-C


4


alkoxy)carbonyl, aminocarbonyl, (C


1


-C


4


alkyl)aminocarbonyl or di(C


1


-C


4


alkyl)aminocarbonyl radical;




more preferably, R


7


is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; more preferably, R


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


1


-C


15


), more preferably 1-8 carbon atoms (C


1


-C


8


), even more preferably 1-6 carbon atoms (C


1


-C


6


), yet more preferably 1-4 carbon atoms (C


1


-C


4


), still more preferably 1-3 carbon atoms (C


1


-C


3


), and most preferably 1-2 carbon atoms (C


1


-C


2


). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, 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


2


-C


15


), more preferably 2-8 carbon atoms (C


2


-C


8


), even more preferably 2-6 carbon atoms (C


2


-C


6


), yet more preferably 2-4 carbon atoms (C


2


-C


4


), and still more preferably 2-3 carbon atoms (C


2


-C


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—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 “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)


2


—” wherein “R” is an alkyl radical as defined above and “S(O)


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


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—O(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


6


H


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 β-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


5


-C


12


), more preferably 5-10 carbon atoms (C


5


-C


10


), even more preferably 5-7 carbon atoms (C


5


-C


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


3


-C


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, alicyclic 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-1β, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-α (tumor necrosis factor-α).




“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, orthomethylbenzyl, 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 sutiable 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 fluoride 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-buty-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:











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


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° C. to 120° C. to form 2-substituted-5-nitropyridines (3) (Scheme I). Reduction of the nitro group can be performed by treatment of (3) with hydrogen gas in the presence of palladium on carbon or Raney nickel, or alternatively, by treatment with SnCl


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


3


C(O)Cl or R


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


3


CO


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


2


in methanolic solvent. Subsequent acylation with an appropriate activated ester (i.e.: R


3


CO


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)


2


and K


2


CO


3


in DMF at 140° C. provides compounds of formula (1) where X═O.











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


7


or a precursor thereof (such as, HO





, RO





, AcS





, NC





, RS





and the like) provides (6). Subsequent reaction to form (7) (treatment with R


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° C. to 120° C.) and (8) (reduction of the nitro group and substitution with R


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











ester as shown in Scheme I to provide compounds of formula (1). Where R


7


═CN, compounds of formula (8) may be hydrolyzed to acids (R


7


═CO


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


7


═−CN, may be reduced to the primary amine (R


7


═−CH


2


NH


2


) using reagents such as BH


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


7


═−CH


2


NH


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


6


and/or R


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


2


, PhLi, NaH or the like at temperatures from −78° C. to 22° 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


3


R


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° C. to 120° 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


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° C. to 180° C. to form the final product (13).











Substituted halopyridines may be readily prepared from the corresponding pyridones using phosphorus oxychloride or pentachloride.




Amines of formula NHR


1


R


2


and NHR


3


R


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 presence 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, crylalkyl, 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. Frelfelder 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 acid, 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.




Thioester 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 modifications 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 administration 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. 21503 (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
















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° C., 2-chloro-5-nitropyridine (101 mg, 0.64 mmol) was added and the reaction mixture was heated to reflex for 1 hour. The solution was cooled to ambient temperature, quenched with saturated aqueous NH


4


Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2× with saturated NaHCO


3


, saturated NaCl, dried over anhydrous Na


2


SO


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 solvent was filtered through celite and concentrated in vacuo. MS (m/z): 234/236 (M+H)


+


; C


12


H


11


N


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




235







2-(4-Chloro-2,6-dimethylphenoxy)-5-amino-




249







pyridine







2-(2-Methyl-pyridin-3-yloxy)-5-amino-pyridine




201







2-(4-Fluoro-2-methylphenoxy)-5-amino-pyridine




218







2-(2-Isopropylphenoxy)-5-amino-pyridine




228







2-(1-Naphthyloxy)-5-amino-pyridine




236







2-(Cyclohexyloxy)-5-amino-pyridine




192







2-(2-Methylphenoxy)-5-amino-pyridine




200







2-(2,4-Dimethylphenoxy)-5-amino-pyridine




214







2-(4-Chlorophenoxy)-5-amino-pyridine




222







2-(Phenoxy)-5-amino-pyridine




186







2-(2-Methylcyclohexylamino)-5-amino-pyridine




205







2-(Cyclohexylamino)-5-amino-pyridine




191







2-(2-Methylanilino)-5-amino-pyridine




199







2-(4-Chloro-2-methylanilino)-5-amino-pyridine




233







2-(2,4-Dimethylanilino)-5-amino-pyridine




212







2-(4-Chloro-2-methylthiophenoxy)-5-amino-




251







pyridine















EXAMPLE 3
















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× 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× with saturated NaHCO


3







and saturated NaCl then dried over Na


2


SO


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


2


using 1:1 ethyl acetate/hexanes as eluant. MS (m/z): 248/250 (M+H)


+


; C


13


H


13


N


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-




249







pyridine







6-(4-Chloro-2-methyl-phenoxy)-2-methyl-3-amino-




249







pyridine







6-(4-Chloro-2-methyl-phenoxy)-2,3-diamino-




250







pyridine















EXAMPLE 5
















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° C. then saturated aqueous NaHCO


3


was added and the mixture was stirred for another hour. The organic layer was separated and washed 2× with 6% aqueous NaHCO


3


, dried over Na


2


SO


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)


+


; C


19


H


15


N


2


O


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-




340







pyridylcarbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




408







dichlorophenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-(4-




340







pyridylcarbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((4-




369







methoxyphenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((4-




409







pentylphenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-(2-




389







naphthylcarbonylamino) pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-(2-




345







thienylcarbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((3,5-dimethyl-




358







4-isoxazolyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((5-




383







benzo[1,3]dioxol-yl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((5-tert-butyl-




399







2-methyl-2H-pyrazol-3-yl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




395







benzo[b]thiophenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




369







methoxyphenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((3,5-




408







dichlorophenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




367







dimethylphenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




353







methylphenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




384







nitrophenyl)carbonylamino)pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




397







acetoxyphenyl)carbonylamino)pyridine







2-(4-chloro-2,6-dimethylphenoxy)-5-((2,6-




422







dichlorophenyl)carbonylamino)pyridine







2-(4-chloro-2,6-dimethylphenoxy)-5-((2,6-




381







dimethylphenyl)carbonylamino)pyridine







2-(2-methyl-pyridin-3-yloxy)-5-((2,6-




374







dichlorophenyl)carbonylamino)pyridine







2-(2-methyl-pyridin-3-yloxy)-5-((2,6-




333







dimethylphenyl)carbonylamino)pyridine







2-(2-methyl-pyridin-3-yloxy)-5-((2-




319







methylphenyl)carbonylamino)pyridine







2-(4-fluoro-2-methylphenoxy)-5-((2,6-




391







dichlorophenyl)carbonylamino)pyridine







2-(4-fluoro-2-methylphenoxy)-5-((2,6-




350







dimethylphenyl)carbonylamino)pyridine







2-(4-fluoro-2-methylphenoxy)-5-((2-




336







methylphenyl)carbonylamino)pyridine







2-(4-fluoro-2-methylphenoxy)-5-((2-




390







trifluoromethylphenyl)carbonylamino)pyridine







2-(4-fluoro-2-methylphenoxy)-5-((2-




340







fluorophenyl)carbonylamino)pyridine







2-(2-isopropylphenoxy)-5-((2,6-




401







dichlorophenyl)carbonylamino)pyridine







2-(2-isopropylphenoxy)-5-((2,6-




360







dimethylphenyl)carbonylamino)pyridine







2-(2-isopropylphenoxy)-5-((2-




346







methylphenyl)carbonylamino)pyridine







2-(1-naphthyloxy)-5-((2,6-




409







dichlorophenyl)carbonylamino)pyridine







2-(1-naphthyloxy)-5-((2,6-




368







dimethylphenyl)carbonylamino)pyridine







2-(1-naphthyloxy)-5-((2-




354







methylphenyl)carbonylamino)pyridine







2-(cyclohexyloxy)-5-((2,6-




365







dichlorophenyl)carbonylamino)pyridine







2-(cyclohexyloxy)-5-((2,6-




324







dimethylphenyl)carbonylamino)pyridine







2-(cyclohexyloxy)-5-((2-




331







chlorophenyl)carbonylamino)pyridine







2-(cyclohexyloxy)-5-((2-




310







methylphenyl)carbonylamino)pyridine







2-(2-methylphenoxy)-5-((2,6-




373







dichlorophenyl)carbonylamino)pyridine







2-(2-methylphenoxy)-5-((2,6-




332







dimethylphenyl)carbonylamino)pyridine







2-(2-methylphenoxy)-5-((2-




339







chlorophenyl)carbonylamino)pyridine







2-(2-methylphenoxy)-5-((2-




318







methylphenyl)carbonylamino)pyridine







2-(2,4-dimethylphenoxy)-5-((2,6-




387







dichlorophenyl)carbonylamino)pyridine







2-(2,4-dimethylphenoxy)-5-((2,6-




346







dimethylphenyl)carbonylamino)pyridine







2-(2,4-dimethylphenoxy)-5-((2-




353







chlorophenyl)carbonylamino)pyridine







2-(2,4-dimethylphenoxy)-5-((2-




332







methylphenyl)carbonylamino)pyridine







2-(4-chlorophenoxy)-5-((2,6-




394







dichlorophenyl)carbonylamino)pyridine







2-(4-chlorophenoxy)-5-((2,6-




353







dimethylphenyl)carbonylamino)pyridine







2-(2-methylcyclohexylamino)-5-((2,6-




378







dichlorophenyl)carbonylamino)pyridine







2-(2-methylcyclohexylamino)-5-((2-




323







methylphenyl)carbonylamino)pyridine







2-(cyclohexylamino)-5-((2,6-




364







dichlorophenyl)carbonylamino)pyridine







2-(cyclohexylamino)-5-((2,6-




323







dimethylphenyl)carbonylamino)pyridine







2-(cyclohexylamino)-5-((2-




309







methylphenyl)carbonylamino)pyridine







2-(2-methylanilino)-5-((2,6-




372







dichlorophenyl)carbonylamino)pyridine







2-(2-methylanilino)-5-((2,6-




331







dimethylphenyl)carbonylamino)pyridine







2-(2-methylanilino)-5-((2-




317







methylphenyl)carbonylamino)pyridine







2-(4-chloro-2-methylanilino)-5-((2,6-




407







dichlorophenyl)carbonylamino)pyridine







2-(4-chloro-2-methylanilino)-5-((2,6-




366







dimethylphenyl)carbonylamino)pyridine







2-(4-chloro-2-methylanilino)-5-((2-




352







methylphenyl)carbonylamino)pyridine







2-(2,4-dimethylanilino)-5-((2,6-




386







dichlorophenyl)carbonylamino)pyridine







2-(2,4-dimethylanilino)-5-((2,6-




345







dimethylphenyl)carbonylamino)pyridine







2-(2,4-dimethylanilino)-5-((2-




331







methylphenyl)carbonylamino)pyridine







2-(2,4-dimethylanilino)-5-((2-




352







chlorophenyl)carbonylamino)pyridine







2-(2,4-dimethylanilino)-5-((2-




335







fluorophenyl)carbonylamino)pyridine







2-(4-chloro-2-methyl-thiophenyl)-5-((2,6




424







dichlorophenyl)carbonylamino)pyridine







2-(4-chloro-2-methyl-thiophenyl)-5-((2,6-




383







dimethylphenyl)carbonylamino)pyridine







2-(4-chloro-2-methyl-thiophenyl)-5-((2-




369







methylphenyl)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-




422







dichlorophenyl)carbonylamino)-3-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




387







chlorophenyl)carbonylamino)-3-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




367







methylphenyl)carbonylamino)-3-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




332







dimethylphenyl)carbonylamino)-3-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




422







dichlorophenyl)carbonylamino)-4-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-fluoro-6-




439







trifluoromethylphenyl)carbonylamino)-4-methyl-







pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,4,6-




479







triisopropylphenyl)carbonylamino)-4-methyl-







pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




367







methylphenyl)carbonylamino)-6-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




387







chlorophenyl)carbonylamino)-6-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




422







dichlorophenyl)carbonylamino)-6-methyl-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




423







dichlorophenyl)carbonylamino)-6-amino-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




388







chlorophenyl)carbonylamino)-6-amino-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2,6-




382







dimethylphenyl)carbonylamino)-6-amino-pyridine







2-(4-Chloro-2-methyl-phenoxy)-5-((2-




368







methylphenyl)carbonylamino)-6-amino-pyridine















EXAMPLE 8
















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)


+


; C


19


H


16


N


3


O


2


Cl requires 353.8.




EXAMPLE 9
















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 hydrozide solution (1.0


M


, 3.8 mL, 3.8 mmol). The solution was stirred for 30 minutes at 22° C. then quenched with aqueous saturated NH


4


Cl. The mixture was diluted with ethyl acetate then the organics were washed with water, 2× saturated NaHCO


3


, saturated NaCl, dried over Na


2


SO


4


and concentrated in vacuo. MS (m/z): 354/356 (M+H)


+


; C


19


H


15


N


2


O


3


Cl requires 354.8.




EXAMPLE 10
















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× 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° 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


4


Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2× with saturated NaHCO


3


, saturated NaCl, dried over anhydrous Na


2


SO


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× 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° C., the reaction mixture was cooled to 0° C. and methyl iodide (0.55 mL, 8.9 mmol) was added. The solution was stirred for 1.5 hours at 0° C. followed by quenching with saturated aqueous NH


4


Cl. The reaction mixture was diluted with ethyl acetate and extracted 5× with water (200 mL), saturated NaCl, dried over Na


2


SO


4


and concentrated in vacuo oil was chromatographed on SiO


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


2


using 1:1 ethyl acetate/hexanes as eluent. MS (m/z): 206 (M+H)


+


; C


12


H


19


N


3


requires 205.3.




EXAMPLE 11
















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
















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° C. for 18 hours followed by quenching with saturated aqueous NH


4


Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na


2


SO


4


then concentrated in vacuo. The crude product was purified by chromatography on SiO


2


using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 378/380 (M+H)


+


; C


19


H


21


N


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-




378







dichlorophenyl)carbonylamino)pyridine







2-(N-cyclohexyl-N-methylamino)-5-((2-




344







chlorophenyl)carbonylamino)pyridine







2-(N-cyclohexyl-N-methylamino)-5-((2-




323







methylphenyl)carbonylamino)pyridine







2-(N-cyclohexyl-N-methylamino)-5-((2,6-




337







dimethylphenyl)carbonylamino)pyridine







2-(2,4-dimethylphenyl)-5-((2,6-




359







dimethylphenyl)carbonylamino)pyridine







2-(2,4-dimethylphenyl)-5-((2-




345







methylphenyl)carbonylamino)pyridine







2-(2,4-dimethylphenyl)-5-((2-




366







chlorophenyl)carbonylamino)pyridine







2-(2,4-dimethylphenyl)-5-((2-




349







fluorophenyl)carbonylamino)pyridine







2-(2,4-dimethylphenyl)-5-((2,6-




400







dichlorophenyl)carbonylamino)pyridine















EXAMPLE 14
















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° 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° 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


2


using 30% ethyl acetate/hexanes as eluent. MS (m/z): 248/250 (M+H)


+


; C


13


H


13


N


2


OCl requires 249.




EXAMPLE 15
















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° C. for 18 hours followed by quenching with saturated aqueous NH


4


Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na


2


SO


4


then concentrated in vacuo. The crude product was purified by chromatography on SiO


2


using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 422/424 (M+H)


+


; C


20


H


15


N


2


O


2


Cl


3


requires 422.




EXAMPLE 16
















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
















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
















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











MS






R


1


X




R


3






(m/z)











4-chloro-2-




4-biphenyl




415






methylphenoxy






4-chloro-2-




3,4-dimethoxyphenyl




319






methylphenoxy






4-chloro-2-




2-(trifluoromethyl)phenyl




407






methylphenoxy






4-chloro-2-




2,4-difluorophenyl




375






methylphenoxy






4-chloro-2-




4-cyanophenyl




364






methylphenoxy






4-chloro-2-




3-(trifluoromethyl)phenyl




407






methylphenoxy






4-chloro-2-




3-cyanophenyl




364






methylphenoxy






4-chloro-2-




2-naphthyl




389






methylphenoxy






4-chloro-2-




2-methoxyphenyl




369






methylphenoxy






4-chloro-2-




3,4,5-trimethylphenyl




429






methylphenoxy






4-chloro-2-




4-nitrophenyl




384






methylphenoxy






4-chloro-2-




3,4-dichlorophenyl




408






methylphenoxy






4-chloro-2-




5-nitrofuran-2-yl




374






methylphenoxy






4-chloro-2-




3-bromophenyl




418






methylphenoxy






4-chloro-2-




3-pyridyl




340






methylphenoxy






4-chloro-2-




2-ethoxynaphth-1-yl




433






methylphenoxy






4-chloro-2-




2,3-dichlorophenyl




408






methylphenoxy






4-chloro-2-




3-nitrophenyl




384






methylphenoxy






4-chloro-2-




6-chloropyrid-3-yl




374






methylphenoxy






4-chloro-2-




4-(trifluoromethoxy)phenyl




423






methylphenoxy






4-chloro-2-




2-fluoro-4-




425






methylphenoxy




(trifluoromethyl)phenyl






4-chloro-2-




2-acetoxyphenyl




397






methylphenoxy






4-chloro-2-




5-methylisoxazol-3-yl




344






methylphenoxy






4-chloro-2-




2-(phenylthio)pyrid-3-yl




448






methylphenoxy






4-chloro-2-




2-(trifluoromethoxy)phenyl




423






methylphenoxy






4-chloro-2-




1-phenyl-5-propyl-pyrazin-




447






methylphenoxy




4-yl






4-chloro-2-




2-ethoxyphenyl




383






methylphenoxy






4-chloro-2-




3-chlorothien-2-yl




379






methylphenoxy






4-chloro-2-




3-bromothien-2-yl




424






methylphenoxy






4-chloro-2-




1-(2-(2-methyl)propyl)-3-




399






methylphenoxy




methylpyrazol-5-yl






4-chloro-2-




3,5-dichlorophenyl




408






methylphenoxy






4-chloro-2-




2-(propylthio)pyridin-3-yl




414






methylphenoxy






4-chloro-2-




2-(ethylthio)pyridin-3-yl




400






methylphenoxy






4-chloro-2-




3-bromopyridin-5-yl




419






methylphenoxy






4-chloro-2-




4-methyl-1,2,3-thiadiazol-




361






methylphenoxy




5-yl






4-chloro-2-




1-methyl-3-(2-(2-




399






methylphenoxy




methyl)propyl)pyrazol-5-yl






4-chloro-2-




3-chlorobenzo[b]thiophen-




429






methylphenoxy




2-yl






4-chloro-2-




4-chlorophenyl




373






methylphenoxy






4-chloro-2-




4-methyl-2-phenyl-1,2,3-




420






methylphenoxy




triazol-5-yl






4-chloro-2-




benzo[b]thiophen-2-yl




395






methylphenoxy






4-chloro-2-




3,4-dimethylphenyl




367






methylphenoxy






4-chloro-2-




2-(phenoxy)pyridin-3-yl




432






methylphenoxy






4-chloro-2-




2-(methylthio)pyridin-3-yl




386






methylphenoxy






4-chloro-2-




5-methyl-3-phenylisoxazol-




420






methylphenoxy




4-yl






4-chloro-2-




4-chloro-1,3-dimethyl




442






methylphenoxy




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-2-




2-chloro-6-methylpyridin-




388






methylphenoxy




4-yl






4-chloro-2-




3,5-dimethylisoxazol-4-yl




358






methylphenoxy






4-chloro-2-




1-naphthyl




389






methylphenoxy






4-chloro-2-




2-fluorophenyl




357






methylphenoxy






4-chloro-2-




4-propylphenyl




381






methylphenoxy






4-chloro-2-




4-(trifluoromethyl)phenyl




407






methylphenoxy






4-chloro-2-




3-fluorophenyl




357






methylphenoxy






4-chloro-2-




2,6-difluorophenyl




375






methylphenoxy






4-chloro-2-




2-chlorophenyl




373






methylphenoxy






4-chloro-2-




3-(chloromethyl)phenyl




387






methylphenoxy






4-chloro-2-




4-(2-(2-methyl)




395






methylphenoxy




propyl)phenyl






4-chloro-2-




3-chlorophenyl




373






methylphenoxy






4-chloro-2-




2-nitrophenyl




384






methylphenoxy






4-chloro-2-




3,5-dimethoxyphenyl




399






methylphenoxy






4-chloro-2-




2,6-dichlorophenyl




408






methylphenoxy






4-chloro-2-




2,4-dichlorophenyl




408






methylphenoxy






4-chloro-2-




4-fluorophenyl




357






methylphenoxy






4-chloro-2-




4-butylphenyl




395






methylphenoxy






4-chloro-2-




2-methylphenyl




353






methylphenoxy






4-chloro-2-




phenyl




339






methylphenoxy






4-chloro-2-




4-ethylphenyl




367






methylphenoxy






4-chloro-2-




2,3-difluorophenyl




375






methylphenoxy






4-chloro-2-




2,6-dimethoxyphenyl




399






methylphenoxy






4-chloro-2-




2,5-difluorophenyl




375






methylphenoxy






4-chloro-2-




4-ethoxyphenyl




383






methylphenoxy






4-chloro-2-




2,4,6-trichlorophenyl




442






methylphenoxy






4-chloro-2-




3-methylphenyl




353






methylphenoxy






4-chloro-2-




2-fluoro-5-




425






methylphenoxy




(trifluoromethyl)phenyl






4-chloro-2-




3-methoxyphenyl




369






methylphenoxy






4-chloro-2-




thien-2-yl




345






methylphenoxy






4-chloro-2-




2-bromophenyl




418






methylphenoxy






4-chloro-2-




4-bromophenyl




418






methylphenoxy






4-chloro-2-




4-fluoro-3-




425






methylphenoxy




(trifluoromethyl)phenyl






4-chloro-2-




3-(trifluoromethoxy)phenyl




423






methylphenoxy






4-chloro-2-




9-fluorenon-4-yl




441






methylphenoxy






4-chloro-2-




isoxazol-5-yl




330






methylphenoxy






4-chloro-2-




benzofuroxan-5-yl




397






methylphenoxy






4-chloro-2-




2-chloropyrid-3-yl




374






methylphenoxy






4-chloro-2-




3,5-difluorophenyl




375






methylphenoxy






4-chloro-2-




2-(4-




446






methylphenoxy




methylphenoxy)pyridin-3-yl






4-chloro-2-




pyridin-4-yl




340






methylphenoxy






4-chloro-2-




anthraquinon-2-yl




469






methylphenoxy






4-chloro-2-




2-iodophenyl




465






methylphenoxy






1-naphthoxy




4-biphenyl




416






1-naphthoxy




3,4-dimethoxyphenyl




400






1-naphthoxy




2-(trifluoromethyl)phenyl




408






1-naphthoxy




2,4-difluorophenyl




376






1-naphthoxy




4-cyanophenyl




365






1-naphthoxy




3-(trifluoromethyl)phenyl




408






1-naphthoxy




3-cyanophenyl




365






1-naphthoxy




2-naphthyl




390






1-naphthoxy




2-methoxyphenyl




370






1-naphthoxy




3,4,5-trimethylphenyl




430






1-naphthoxy




4-nitrophenyl




385






1-naphthoxy




3,4-dichlorophenyl




409






1-naphthoxy




5-nitrofuran-2-yl




375






1-naphthoxy




3-bromophenyl




419






1-naphthoxy




3-pyridyl




341






1-naphthoxy




2-ethoxynaphth-1-yl




334






1-naphthoxy




2,3-dichlorophenyl




409






1-naphthoxy




3-nitrophenyl




385






1-naphthoxy




6-chloropyrid-3-yl




376






1-naphthoxy




4-(trifluoromethoxy)phenyl




424






1-naphthoxy




2-fluoro-4-




426







(trifluoromethyl)phenyl






1-naphthoxy




3-bromothiophenyl




425






1-naphthoxy




2-acetoxyphenyl




398






1-naphthoxy




5-methylisoxazol-3-yl




345






1-naphthoxy




2-(phenylthio)pyrid-3-yl




449






1-naphthoxy




2-(trifluoromethoxy)phenyl




424






1-naphthoxy




1-phenyl-5-propylpyrazin-




448







4-yl






1-naphthoxy




2-ethoxyphenyl




384






1-naphthoxy




3-chlorothien-2-yl




381






1-naphthoxy




1-(2-(2-methyl)propyl)-3-




400







methylpyrazol-5-yl






1-naphthoxy




3,5-dichlorophenyl




409






1-naphthoxy




2-(propylthio)pyridin-3-yl




415






1-naphthoxy




2-(ethylthio)pyridin-3-yl




401






1-naphthoxy




3-bromopyridin-5-yl




420






1-naphthoxy




4-methyl-1,2,3-thiadiazol-




362







5-yl






1-naphthoxy




1-methyl-3-(2-(2-




400







methyl)propyl)pyrazol-5-yl






1-naphthoxy




3-chlorobenzo[b]thiophen-




431







2-yl






1-naphthoxy




4-chlorophenyl




375






1-naphthoxy




4-methyl-2-phenyl-1,2,3-




421







triazol-5-yl






1-naphthoxy




benzo[b]thiophen-2-yl




396






1-naphthoxy




3,4-dimethylphenyl




368






1-naphthoxy




2-(phenoxy)pyridin-3-yl




433






1-naphthoxy




2-(methylthio)pyridin-3-yl




387






1-naphthoxy




5-methyl-3-phenylisoxazol-




421







4-yl






1-naphthoxy




4-chloro-1,3-dimethyl




444







pyrazolo[3,4-b]pyridin-3-







yl






1-naphthoxy




2-chloro-6-methylpyridin-




390







4-yl






1-naphthoxy




3,5-dimethylisoxazol-4-yl




359






1-naphthoxy




1-naphthyl




390






1-naphthoxy




2-fluorophenyl




358






1-naphthoxy




4-propylphenyl




382






1-naphthoxy




4-(trifluoromethyl)phenyl




408






1-naphthoxy




3-fluorophenyl




358






1-naphthoxy




2,6-difluorophenyl




376






1-naphthoxy




2-chlorophenyl




375






1-naphthoxy




3-(chloromethyl)phenyl




389






1-naphthoxy




4-(2-(2-




396







methyl)propyl)phenyl






1-naphthoxy




3-chlorophenyl




375






1-naphthoxy




2-nitrophenyl




385






1-naphthoxy




3,5-dimethoxyphenyl




400






1-naphthoxy




2,6-dichlorophenyl




409






1-naphthoxy




2,4-dichlorophenyl




409






1-naphthoxy




4-fluorophenyl




358






1-naphthoxy




4-butylphenyl




396






1-naphthoxy




2-methylphenyl




354






1-naphthoxy




phenyl




340






1-naphthoxy




4-ethylphenyl




368






1-naphthoxy




2,3-difluorophenyl




376






1-naphthoxy




2,6-dimethoxyphenyl




400






1-naphthoxy




3,4-difluorophenyl




376






1-naphthoxy




2,5-difluorophenyl




376






1-naphthoxy




4-ethoxyphenyl




384






1-naphthoxy




2,4,6-trichlorophenyl




444






1-naphthoxy




3-methylphenyl




354






1-naphthoxy




2-fluoro-5-




426







(trifluoromethyl)phenyl






1-naphthoxy




3-methoxyphenyl




370






1-naphthoxy




thien-2-yl




346






1-naphthoxy




2-bromophenyl




419






1-naphthoxy




4-bromophenyl




419






1-naphthoxy




4-fluoro-3-




426







(trifluoromethyl)phenyl






1-naphthoxy




3-(trifluoromethoxy)phenyl




424






1-naphthoxy




9-fluorenon-4-yl




442






1-naphthoxy




isoxazol-5-yl




331






1-naphthoxy




benzofuroxan-5-yl




398






1-naphthoxy




2-chloropyrid-3-yl




376






1-naphthoxy




3,5-difluorophenyl




376






1-naphthoxy




2-(4-




447







methylphenoxy)pyridin-3-yl






1-naphthoxy




pyridin-4-yl




341






1-naphthoxy




anthraquinon-2-yl




470






1-naphthoxy




2-iodophenyl




466






2-(2-propyl)phenoxy




4-biphenyl




408






2-(2-propyl)phenoxy




3,4-dimethoxyphenyl




392






2-(2-propyl)phenoxy




2-(trifluoromethyl)phenyl




400






2-(2-propyl)phenoxy




2,4-difluorophenyl




368






2-(2-propyl)phenoxy




4-cyanophenyl




357






2-(2-propyl)phenoxy




3-(trifluoromethyl)phenyl




400






2-(2-propyl)phenoxy




3-cyanophenyl




357






2-(2-propyl)phenoxy




2-naphthyl




382






2-(2-propyl)phenoxy




2-methoxyphenyl




362






2-(2-propyl)phenoxy




3,4,5,-trimethylphenyl




422






2-(2-propyl)phenoxy




4-nitrophenyl




377






2-(2-propyl)phenoxy




3,4-dichlorophenyl




401






2-(2-propyl)phenoxy




5-nitrofuran-2-yl




367






2-(2-propyl)phenoxy




3-bromophenyl




411






2-(2-propyl)phenoxy




3-pyridyl




333






2-(2-propyl)phenoxy




2-ethoxynaphth-1-yl




426






2-(2-propyl)phenoxy




2,3-dichlorophenyl




401






2-(2-propyl)phenoxy




3-nitrophenyl




377






2-(2-propyl)phenoxy




6-chloropyrid-3-yl




368






2-(2-propyl)phenoxy




4-(trifluoromethoxy)phenyl




416






2-(2-propyl)phenoxy




2-fluoro-4-




418







(trifluoromethyl)phenyl






2-(2-propyl)phenoxy




3-bromothiophenyl




417






2-(2-propyl)phenoxy




2-acetoxyphenyl




390






2-(2-propyl)phenoxy




5-methylisoxazol-3-yl




337






2-(2-propyl)phenoxy




2-(phenylthio)pyrid-3-yl




442






2-(2-propyl)phenoxy




2-(trifluoromethoxy)phenyl




416






2-(2-propyl)phenoxy




1-phenyl-5-propylpyrazin-




441







4-yl






2-(2-propyl)phenoxy




2-ethoxyphenyl




376






2-(2-propyl)phenoxy




3-chlorothien-2-yl




373






2-(2-propyl)phenoxy




1-(2-(2-methyl)propyl)-3-




392







methylpyrazol-5-yl






2-(2-propyl)phenoxy




3,5-dichlorophenyl




401






2-(2-propyl)phenoxy




2-(propylthio)pyridin-3-yl




407






2-(2-propyl)phenoxy




2-(ethylthio)pyridin-3-yl




393






2-(2-propyl)phenoxy




3-bromopyridin-5-yl




412






2-(2-propyl)phenoxy




4-methyl-1,2,3-thiadiazol-




354







5-yl






2-(2-propyl)phenoxy




1-methyl-3-(2-(2-




392







methyl)propyl)pyrazol-5-yl






2-(2-propyl)phenoxy




3-chlorobenzo[b]thiophen-




423







2-yl






2-(2-propyl)phenoxy




4-chlorophenyl




367






2-(2-propyl)phenoxy




4-methyl-2-phenyl-1,2,3-




413







triazol-5-yl






2-(2-propyl)phenoxy




benzo[b]thiophen-2-yl




388






2-(2-propyl)phenoxy




3,4-dimethylphenyl




360






2-(2-propyl)phenoxy




2-(phenoxy)pyridin-3-yl




425






2-(2-propyl)phenoxy




2-(methylthio)pyridin-3-yl




379






2-(2-propyl)phenoxy




5-methyl-3-phenylisoxazol-




413







4-yl






2-(2-propyl)phenoxy




4-chloro-1,3-




436







dimethylpyrazolo[3,4-







b]pyridin-3-yl






2-(2-propyl)phenoxy




2-chloro-6-methylpyridin-




382







4-yl






2-(2-propyl)phenoxy




3,5-dimethylisoxazol-4-yl




351






2-(2-propyl)phenoxy




1-naphthyl




382






2-(2-propyl)phenoxy




2-fluorophenyl




350






2-(2-propyl)phenoxy




4-propylphenyl




374






2-(2-propyl)phenoxy




4-(trifluoromethyl)phenyl




400






2-(2-propyl)phenoxy




3-fluorophenyl




350






2-(2-propyl)phenoxy




2,6-difluorophenyl




368






2-(2-propyl)phenoxy




2-chlorophenyl




367






2-(2-propyl)phenoxy




3-(chloromethyl)phenyl




381






2-(2-propyl)phenoxy




4-(2-(2-




388







methyl)propyl)phenyl






2-(2-propyl)phenoxy




3-chlorophenyl




367






2-(2-propyl)phenoxy




2-nitrophenyl




377






2-(2-propyl)phenoxy




3,5-dimethoxyphenyl




392






2-(2-propyl)phenoxy




2,6-dichlorophenyl




401






2-(2-propyl)phenoxy




2,4-dichlorophenyl




401






2-(2-propyl)phenoxy




4-fluorophenyl




350






2-(2-propyl)phenoxy




4-butylphenyl




388






2-(2-propyl)phenoxy




2-methylphenyl




346






2-(2-propyl)phenoxy




phenyl




332






2-(2-propyl)phenoxy




4-ethylphenyl




360






2-(2-propyl)phenoxy




2,3-difluorophenyl




368






2-(2-propyl)phenoxy




2,6-dimethoxyphenyl




392






2-(2-propyl)phenoxy




3,4-difluorophenyl




368






2-(2-propyl)phenoxy




2,5-difluorophenyl




368






2-(2-propyl)phenoxy




4-ethoxyphenyl




376






2-(2-propyl)phenoxy




2,4,6-trichlorophenyl




436






2-(2-propyl)phenoxy




3-methylphenyl




346






2-(2-propyl)phenoxy




2-fluoro-5-




418







(trifluoromethyl)phenyl






2-(2-propyl)phenoxy




3-methoxyphenyl




362






2-(2-propyl)phenoxy




thien-2-yl




338






2-(2-propyl)phenoxy




2-bromophenyl




411






2-(2-propyl)phenoxy




4-bromophenyl




411






2-(2-propyl)phenoxy




4-fluoro-3-




418







(trifluoromethyl)phenyl






2-(2-propyl)phenoxy




3-(trifluoromethoxy)phenyl




416






2-(2-propyl)phenoxy




9-fluorenon-4-yl




434






2-(2-propyl)phenoxy




isoxazol-5-yl




323






2-(2-propyl)phenoxy




benzofuroxan-5-yl




390






2-(2-propyl)phenoxy




2-chloropyrid-3-yl




368






2-(2-propyl)phenoxy




3,5-difluorophenyl




368






2-(2-propyl)phenoxy




2-(4-




439







methylphenoxy)pyridin-3-yl






2-(2-propyl)phenoxy




pyridin-4-yl




333






2-(2-propyl)phenoxy




anthraquinon-2-yl




462






2-(2-propyl)phenoxy




2-iodophenyl




458






3-fluoro-5-




4-biphenyl




398






methylphenoxy






3-fluoro-5-




3,4-dimethoxyphenyl




382






methylphenoxy






3-fluoro-5-




2-(trifluoromethyl)phenyl




390






methylphenoxy






3-fluoro-5-




2,4-difluorophenyl




358






methylphenoxy






3-fluoro-5-




4-cyanophenyl




347






methylphenoxy






3-fluoro-5-




3-(trifluoromethyl)phenyl




390






methylphenoxy






3-fluoro-5-




3-cyanophenyl




347






methylphenoxy






3-fluoro-5-




2-naphthyl




372






methylphenoxy






3-fluoro-5-




2-methoxyphenyl




352






methylphenoxy






3-fluoro-5-




3,4,5,-trimethylphenyl




412






methylphenoxy






3-fluoro-5-




4-nitrophenyl




367






methylphenoxy






3-fluoro-5-




3,4-dichlorophenyl




391






methylphenoxy






3-fluoro-5-




5-nitrofuran-2-yl




357






methylphenoxy






3-fluoro-5-




3-bromophenyl




401






methylphenoxy






3-fluoro-5-




3-pyridyl




323






methylphenoxy






3-fluoro-5-




2-ethoxynaphth-1-yl




416






methylphenoxy






3-fluoro-5-




2,3-dichlorophenyl




391






methylphenoxy






3-fluoro-5-




3-nitrophenyl




367






methylphenoxy






3-fluoro-5-




6-chloropyrid-3-yl




358






methylphenoxy






3-fluoro-5-




4-(trifluoromethoxy)phenyl




406






methylphenoxy






3-fluoro-5-




2-fluoro-4-




408






methylphenoxy




(trifluoromethyl)phenyl






3-fluoro-5-




3-bromothienyl




407






methylphenoxy






3-fluoro-5-




2-acetoxyphenyl




380






methylphenoxy






3-fluoro-5-




5-methylisoxazol-3-yl




327






methylphenoxy






3-fluoro-5-




2-(phenylthio)pyrid-3-yl




431






methylphenoxy






3-fluoro-5-




2-(trifluoromethoxy)phenyl




406






methylphenoxy






3-fluoro-5-




1-phenyl-5-propylpyrazin-




430






methylphenoxy




4-yl






3-fluoro-5-




2-ethoxyphenyl




366






methylphenoxy






3-fluoro-5-




3-chlorothien-2-yl




363






methylphenoxy






3-fluoro-5-




1-(2-(2-methyl)propyl)-3-




382






methylphenoxy




methylpyrazol-5-yl






3-fluoro-5-




3,5-dichlorophenyl




391






methylphenoxy






3-fluoro-5-




2-(propylthio)pyridin-3-yl




397






methylphenoxy






3-fluoro-5-




2-(ethylthio)pyridin-3-yl




383






methylphenoxy






3-fluoro-5-




3-bromopyridin-5-yl




402






methylphenoxy






3-fluoro-5-




4-methyl-1,2,3-thiadiazol-




344






methylphenoxy




5-yl






3-fluoro-5-




1-methyl-3-(2-(2-




382






methylphenoxy




methyl)propyl)pyrazol-5-yl






3-fluoro-5-




3-chlorobenzo[b]thiophen-




413






methylphenoxy




2-yl






3-fluoro-5-




4-chlorophenyl




357






methylphenoxy






3-fluoro-5-




4-methyl-2-phenyl-1,2,3-




403






methylphenoxy




triazol-5-yl






3-fluoro-5-




benzo[b]thiophen-2-yl




378






methylphenoxy






3-fluoro-5-




3,4-dimethylphenyl




350






methylphenoxy






3-fluoro-5-




2-(phenoxy)pyridin-3-yl




415






methylphenoxy






3-fluoro-5-




2-(methylthio)pyridin-3-yl 369






methylphenoxy






3-fluoro-5-




5-methyl-3-phenylisoxazol-




403






methylphenoxy




4-yl






3-fluoro-5-




4-chloro-1,3-dimethyl




426






methylphenoxy




pyrazolo[3,4-b]pyridin-3-







yl






3-fluoro-5-




2-chloro-6-methylpyridin-




372






methylphenoxy




4-yl






3-fluoro-5-




3,5-dimethylisoxazol-4-yl




341






methylphenoxy






3-fluoro-5-




1-naphthyl




372






methylphenoxy






3-fluoro-5-




2-fluorophenyl




340






methylphenoxy






3-fluoro-5-




4-propylphenyl




364






methylphenoxy






3-fluoro-5-




4-(trifluoromethyl)phenyl




390






methylphenoxy






3-fluoro-5-




3-fluorophenyl




340






methylphenoxy






3-fluoro-5-




2,6-difluorophenyl




358






methylphenoxy






3-fluoro-5-




2-chlorophenyl




357






methylphenoxy






3-fluoro-5-




3-(chloromethyl)phenyl




371






methylphenoxy






3-fluoro-5-




4-(2-(2-




378






methylphenoxy




methyl)propyl)phenyl






3-fluoro-5-




3-chlorophenyl




357






methylphenoxy






3-fluoro-5-




2-nitrophenyl




367






methylphenoxy






3-fluoro-5-




3,5-dimethoxyphenyl




382






methylphenoxy






3-fluoro-5-




2,6-dichlorophenyl




391






methylphenoxy






3-fluoro-5-




2,4-dichlorophenyl




391






methylphenoxy






3-fluoro-5-




4-fluorophenyl




340






methylphenoxy






3-fluoro-5-




4-butylphenyl




378






methylphenoxy






3-fluoro-5-




2-methylphenyl




336






methylphenoxy






3-fluoro-5-




phenyl




322






methylphenoxy






3-fluoro-5-




4-ethylphenyl




350






methylphenoxy






3-fluoro-5-




2,3-difluorophenyl




358






methylphenoxy






3-fluoro-5-




2,6-dimethoxyphenyl




382






methylphenoxy






3-fluoro-5-




3,4-difluorophenyl




358






methylphenoxy






3-fluoro-5-




2,5-difluorophenyl




358






methylphenoxy






3-fluoro-5-




4-ethoxyphenyl




366






methylphenoxy






3-fluoro-5-




2,4,6-trichlorophenyl




426






methylphenoxy






3-fluoro-5-




3-methylphenyl




336






methylphenoxy






3-fluoro-5-




2-fluoro-5-




408






methylphenoxy




(trifluoromethyl)phenyl






3-fluoro-5-




3-methoxyphenyl




352






methylphenoxy






3-fluoro-5-




thien-2-yl




328






methylphenoxy






3-fluoro-5-




2-bromophenyl




401






methylphenoxy






3-fluoro-5-




4-bromophenyl




401






methylphenoxy






3-fluoro-5-




4-fluoro-3-




408






methylphenoxy




(trifluoromethyl)phenyl






3-fluoro-5-




3-(trifluoromethoxy)phenyl




406






methylphenoxy






3-fluoro-5-




9-fluorenon-4-yl




424






methylphenoxy






3-fluoro-5-




isoxazol-5-yl




313






methylphenoxy






3-fluoro-5-




benzofuroxan-5-yl




380






methylphenoxy






3-fluoro-5-




2-chloropyrid-3-yl




358






methylphenoxy






3-fluoro-5-




3,5-difluorophenyl




358






methylphenoxy






3-fluoro-5-




2-(4-




429






methylphenoxy




methylphenoxy)pyridin-3-yl






3-fluoro-5-




pyridin-4-yl




323






methylphenoxy






3-fluoro-5-




anthraquinon-2-yl




452






methylphenoxy






3-fluoro-5-




2-iodophenyl




448






methylphenoxy






2-methylpyrid-3-yloxy




4-biphenyl




381






2-methylpyrid-3-yloxy




3,4-dimethoxyphenyl




365






2-methylpyrid-3-yloxy




2-(trifluoromethyl)phenyl




373






2-methylpyrid-3-yloxy




2,4-difluorophenyl




341






2-methylpyrid-3-yloxy




4-cyanophenyl




330






2-methylpyrid-3-yloxy




3-(trifluoromethyl)phenyl




373






2-methylpyrid-3-yloxy




3-cyanophenyl




330






2-methylpyrid-3-yloxy




2-naphthyl




355






2-methylpyrid-3-yloxy




2-methoxyphenyl




335






2-methylpyrid-3-yloxy




3,4,5-trimethylphenyl




395






2-methylpyrid-3-yloxy




4-nitrophenyl




350






2-methylpyrid-3-yloxy




3,4-dichlorophenyl




374






2-methylpyrid-3-yloxy




5-nitrofuran-2-yl




340






2-methylpyrid-3-yloxy




3-bromophenyl




384






2-methylpyrid-3-yloxy




3-pyridyl




306






2-methylpyrid-3-yloxy




2-ethoxynaphth-1-yl




399






2-methylpyrid-3-yloxy




2,3-dichlorophenyl




374






2-methylpyrid-3-yloxy




3-nitrophenyl




350






2-methylpyrid-3-yloxy




6-chloropyrid-3-yl




341






2-methylpyrid-3-yloxy




4-(trifluoromethoxy)phenyl




389






2-methylpyrid-3-yloxy




2-fluoro-4-




391







(trifluoromethyl)phenyl






2-methylpyrid-3-yloxy




3-bromothienyl




390






2-methylpyrid-3-yloxy




2-acetoxyphenyl




363






2-methylpyrid-3-yloxy




5-methylisoxazol-3-yl




310






2-methylpyrid-3-yloxy




2-(phenylthio)pyrid-3-yl




414






2-methylpyrid-3-yloxy




2-(trifluoromethoxy)phenyl




389






2-methylpyrid-3-yloxy




1-phenyl-5-propylpyrazin-




413







4-yl






2-methylpyrid-3-yloxy




2-ethoxyphenyl




349






2-methylpyrid-3-yloxy




3-chlorothien-2-yl




346






2-methylpyrid-3-yloxy




1-(2-(2-methyl)propyl)-3-




365







methylpyrazol-5-yl






2-methylpyrid-3-yloxy




3,5-dichlorophenyl




374






2-methylpyrid-3-yloxy




2-(propylthio)pyridin-3-yl




380






2-methylpyrid-3-yloxy




2-(ethylthio)pyridin-3-yl




366






2-methylpyrid-3-yloxy




3-bromopyridin-5-yl




385






2-methylpyrid-3-yloxy




4-methyl-1,2,3-thiadiazol-




327







5-yl






2-methylpyrid-3-yloxy




1-methyl-3-(2-(2-




365







methyl)propyl)pyrazol-5-yl






2-methylpyrid-3-yloxy




3-chlorobenzo[b]thiophen-




396







2-yl






2-methylpyrid-3-yloxy




4-chlorophenyl




340






2-methylpyrid-3-yloxy




4-methyl-2-phenyl-1,2,3-




386







triazol-5-yl






2-methylpyrid-3-yloxy




benzo[b]thiophen-2-yl




361






2-methylpyrid-3-yloxy




3,4-dimethylphenyl




333






2-methylpyrid-3-yloxy




2-(phenoxy)pyridin-3-yl




398






2-methylpyrid-3-yloxy




2-(methylthio)pyridin-3-yl




352






2-methylpyrid-3-yloxy




5-methyl-3-phenylisoxazol-




386







4-yl






2-methylpyrid-3-yloxy




4-chloro-1,3-dimethyl




409







pyrazolo[3,4-b]pyridin-3-







yl






2-methylpyrid-3-yloxy




2-chloro-6-methylpyridin-




355







4-yl






2-methylpyrid-3-yloxy




3,5-dimethylisoxazol-4-yl




324






2-methylpyrid-3-yloxy




1-naphthyl




355






2-methylpyrid-3-yloxy




2-fluorophenyl




323






2-methylpyrid-3-yloxy




4-propylphenyl




347






2-methylpyrid-3-yloxy




4-(trifluoromethyl)phenyl




373






2-methylpyrid-3-yloxy




3-fluorophenyl




323






2-methylpyrid-3-yloxy




2,6-difluorophenyl




341






2-methylpyrid-3-yloxy




2-chlorophenyl




340






2-methylpyrid-3-yloxy




3-(chloromethyl)phenyl




354






2-methylpyrid-3-yloxy




4-(2-(2-




361







methyl)propyl)phenyl






2-methylpyrid-3-yloxy




3-chlorophenyl




340






2-methylpyrid-3-yloxy




2-nitrophenyl




350






2-methylpyrid-3-yloxy




3,5-dimethoxyphenyl




365






2-methylpyrid-3-yloxy




2,6-dichlorophenyl




374






2-methylpyrid-3-yloxy




2,4-dichlorophenyl




374






2-methylpyrid-3-yloxy




4-fluorophenyl




323






2-methylpyrid-3-yloxy




4-butylphenyl




361






2-methylpyrid-3-yloxy




2-methylphenyl




319






2-methylpyrid-3-yloxy




phenyl




305






2-methylpyrid-3-yloxy




4-ethylphenyl




333






2-methylpyrid-3-yloxy




2,3-difluorophenyl




341






2-methylpyrid-3-yloxy




2,6-dimethoxyphenyl




365






2-methylpyrid-3-yloxy




3,4-difluorophenyl




341






2-methylpyrid-3-yloxy




2,5-difluorophenyl




341






2-methylpyrid-3-yloxy




4-ethoxyphenyl




349






2-methylpyrid-3-yloxy




2,4,6-trichlorophenyl




409






2-methylpyrid-3-yloxy




3-methylphenyl




319






2-methylpyrid-3-yloxy




2-fluoro-5-




391







(trifluoromethyl)phenyl






2-methylpyrid-3-yloxy




3-methoxyphenyl




335






2-methylpyrid-3-yloxy




thien-2-yl




311






2-methylpyrid-3-yloxy




2-bromophenyl




384






2-methylpyrid-3-yloxy




4-bromophenyl




384






2-methylpyrid-3-yloxy




4-fluoro-3-




391







(trifluoromethyl)phenyl






2-methylpyrid-3-yloxy




3-(trifluoromethoxy)phenyl




389






2-methylpyrid-3-yloxy




9-fluorenon-4-yl




407






2-methylpyrid-3-yloxy




isoxazol-5-yl




296






2-methylpyrid-3-yloxy




benzofuroxan-5-yl




363






2-methylpyrid-3-yloxy




2-chloropyrid-3-yl




341






2-methylpyrid-3-yloxy




3,5-difluorophenyl




341






2-methylpyrid-3-yloxy




2-(4-




412







methylphenoxy)pyridin-3-yl






2-methylpyrid-3-yloxy




pyridin-4-yl




306






2-methylpyrid-3-yloxy




anthraquinon-2-yl




435






2-methylpyrid-3-yloxy




2-iodophenyl




431






4-chloro-2,5-




3,4-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-2,5-




2-(trifluoromethyl)phenyl




421






dimethylphenoxy






4-chloro-2,5-




2,4-difluorophenyl




389






dimethylphenoxy






4-chloro-2,5-




3-(trifluoromethyl)phenyl




421






dimethylphenoxy






4-chloro-2,5-




2-naphthyl




403






dimethylphenoxy






4-chloro-2,5-




2-methoxyphenyl




484






dimethylphenoxy






4-chloro-2,5-




3,4,5-trimethylphenyl




443






dimethylphenoxy






4-chloro-2,5-




3,4-dichlorophenyl




422






dimethylphenoxy






4-chloro-2,5-




3-bromophenyl




432






dimethylphenoxy






4-chloro-2,5-




3-pyridyl




354






dimethylphenoxy






4-chloro-2,5-




2-ethoxynaphth-1-yl




447






dimethylphenoxy






4-chloro-2,5-




2,3-dichlorophenyl




422






dimethylphenoxy






4-chloro-2,5-




6-chloropyrid-3-yl




388






dimethylphenoxy






4-chloro-2,5-




4-(trifluoromethoxy)phenyl




437






dimethylphenoxy






4-chloro-2,5-




2-fluoro-4-




439






dimethylphenoxy




(trifluoromethyl)phenyl






4-chloro-2,5-




3-bromothienyl




438






dimethylphenoxy






4-chloro-2,5-




2-acetoxyphenyl




411






dimethylphenoxy






4-chloro-2,5-




5-methylisoxazol-3-yl




358






dimethylphenoxy






4-chloro-2,5-




2-(phenylthio)pyrid-3-yl




462






dimethylphenoxy






4-chloro-2,5-




2-(trifluoromethoxy)phenyl




437






dimethylphenoxy






4-chloro-2,5-




1-phenyl-5-propylpyrazin-




461






dimethylphenoxy




4-yl






4-chloro-2,5-




2-ethoxyphenyl




397






dimethylphenoxy






4-chloro-2,5-




3-chlorothien-2-yl




393






dimethylphenoxy






4-chloro-2,5-




1-(2-(2-methyl)propyl)-3-




413






dimethylphenoxy




methylpyrazol-5-yl






4-chloro-2,5-




3,5-dichlorophenyl




422






dimethylphenoxy






4-chloro-2,5-




2-(propylthio)pyridin-3-yl




428






dimethylphenoxy






4-chloro-2,5-




2-(ethylthio)pyridin-3-yl




414






dimethylphenoxy






4-chloro-2,5-




3-bromopyridin-5-yl




433






dimethylphenoxy






4-chloro-2,5-




4-methyl-1,2,3-thiadiazol-




375






dimethylphenoxy




5-yl






4-chloro-2,5-




1-methyl-3-(2-(2-




413






dimethylphenoxy




methyl)propyl)pyrazol-5-yl






4-chloro-2,5-




3-chlorobenzo[b]thiophen-




443






dimethylphenoxy




2-yl






4-chloro-2,5-




4-chlorophenyl




387






dimethylphenoxy






4-chloro-2,5-




4-methyl-2-phenyl-1,2,3-




434






dimethylphenoxy




triazol-5-yl






4-chloro-2,5-




benzo[b]thiophen-2-yl




409






dimethylphenoxy






4-chloro-2,5-




3,4-dimethylphenyl




381






dimethylphenoxy






4-chloro-2,5-




2-(phenoxy)pyridin-3-yl




446






dimethylphenoxy






4-chloro-2,5-




2-(methylthio)pyridin-3-yl




400






dimethylphenoxy






4-chloro-2,5-




5-methyl-3-phenylisoxazol-




434






dimethylphenoxy




4-yl






4-chloro-2,5-




4-chloro-1,3-dimethyl




456






dimethylphenoxy




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-2,5-




2-chloro-6-methylpyridin-




402






dimethylphenoxy




4-yl






4-chloro-2,5-




3,5-dimethylisoxazol-4-yl




372






dimethylphenoxy






4-chloro-2,5-




1-naphthyl




403






dimethylphenoxy






4-chloro-2,5-




2-fluorophenyl




371






dimethylphenoxy






4-chloro-2,5-




4-propylphenyl




395






dimethylphenoxy






4-chloro-2,5-




3-fluorophenyl




371






dimethylphenoxy






4-chloro-2,5-




2,6-difluorophenyl




389






dimethylphenoxy






4-chloro-2,5-




2-chlorophenyl




387






dimethylphenoxy






4-chloro-2,5-




3-(chloromethyl)phenyl




401






dimethylphenoxy






4-chloro-2,5-




4-(2-(2-




409






dimethylphenoxy




methyl)propyl)phenyl






4-chloro-2,5-




3-chlorophenyl




387






dimethylphenoxy






4-chloro-2,5-




3,5-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-2,5-




2,6-dichlorophenyl




422






dimethylphenoxy






4-chloro-2,5-




2,4-dichlorophenyl




422






dimethylphenoxy






4-chloro-2,5-




4-fluorophenyl




371






dimethylphenoxy






4-chloro-2,5-




4-butylphenyl




409






dimethylphenoxy






4-chloro-2,5-




2-methylphenyl




367






dimethylphenoxy






4-chloro-2,5-




phenyl




353






dimethylphenoxy






4-chloro-2,5-




4-ethylphenyl




381






dimethylphenoxy






4-chloro-2,5-




2,3-difluorophenyl




389






dimethylphenoxy






4-chloro-2,5-




2,6-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-2,5-




3,4-difluorophenyl




389






dimethylphenoxy






4-chloro-2,5-




2,5-difluorophenyl




389






dimethylphenoxy






4-chloro-2,5-




4-ethoxyphenyl




397






dimethylphenoxy






4-chloro-2,5-




2,4,6-trichlorophenyl




456






dimethylphenoxy






4-chloro-2,5-




3-methylphenyl




367






dimethylphenoxy






4-chloro-2,5-




2-fluoro-5-




439






dimethylphenoxy




(trifluoromethyl)phenyl






4-chloro-2,5-




3-methoxyphenyl




383






dimethylphenoxy






4-chloro-2,5-




2-bromophenyl




432






dimethylphenoxy






4-chloro-2,5-




4-bromophenyl




432






dimethylphenoxy






4-chloro-2,5-




4-fluoro-3-




439






dimethylphenoxy




(trifluoromethyl)phenyl






4-chloro-2,5-




3-(trifluoromethoxy)phenyl




437






dimethylphenoxy






4-chloro-2,5-




9-fluorenon-4-yl




455






dimethylphenoxy






4-chloro-2,5-




isoxazol-5-yl




344






dimethylphenoxy






4-chloro-2,5-




benzofuroxan-5-yl




411






dimethylphenoxy






4-chloro-2,5-




2-chloropyrid-3-yl




388






dimethylphenoxy






4-chloro-2,5-




2-(4-




460






dimethylphenoxy




methylphenoxy)pyridin-3-yl






4-chloro-2,5-




pyridin-4-yl




354






dimethylphenoxy






4-chloro-2,5-




anthraquinon-2-yl




483






dimethylphenoxy






4-chloro-2,5-




2-iodophenyl




479






dimethylphenoxy






4-chloro-2,5-




4-pentylphenyl




423






dimethylphenoxy






4-chloro-2,5-




2-(4-chlorophenylthio)




496






dimethylphenoxy




pyridin-3-yl






4-chloro-2,5-




2,6-dimethylphenyl




381






dimethylphenoxy






4-chloro-2,5-




2,5-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-2,5-




2,5-dichloropyridin-3-yl




423






dimethylphenoxy






4-chloro-2,5-




2-chloro-6-methoxypyridin-




418






dimethylphenoxy




4-yl






4-chloro-2,5-




2,3-dichloropyridin-5-yl




423






dimethylphenoxy






4-chloro-2,5-




1-naphthyl




417






dimethylphenoxy






4-chloro-2,5-




2,4-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-2,5-




3,5-bis(trifluoromethyl)




489






dimethylphenoxy




phenyl






4-chloro-2,5-




2-(4-




480






dimethylphenoxy




chlorophenoxy)pyridin-3-yl






4-chloro-2,5-




pentafluorophenyl




443






dimethylphenoxy






4-methoxyphenoxy




3,4-dimethoxyphenyl




380






4-methoxyphenoxy




2-(trifluoromethyl)phenyl




388






4-methoxyphenoxy




2,4-difluorophenyl




356






4-methoxyphenoxy




3-(trifluoromethyl)phenyl




388






4-methoxyphenoxy




2-naphthyl




370






4-methoxyphenoxy




2-methoxyphenyl




350






4-methoxyphenoxy




3,4,5-trimethylphenyl




410






4-methoxyphenoxy




3,4-dichlorophenyl




389






4-methoxyphenoxy




3-bromophenyl




399






4-methoxyphenoxy




3-pyridyl




321






4-methoxyphenoxy




2-ethoxynaphth-1-yl




414






4-methoxyphenoxy




2,3-dichlorophenyl




389






4-methoxyphenoxy




6-chloropyrid-3-yl




356






4-methoxyphenoxy




4-(trifluoromethoxy)phenyl




404






4-methoxyphenoxy




2-fluoro-4-




406







(trifluoromethyl)phenyl






4-methoxyphenoxy




3-bromothienyl




405






4-methoxyphenoxy




2-acetoxyphenyl




378






4-methoxyphenoxy




5-methylisoxazol-3-yl




325






4-methoxyphenoxy




2-(phenylthio)pyrid-3-yl




429






4-methoxyphenoxy




2-(trifluoromethoxy)phenyl




404






4-methoxyphenoxy




1-phenyl-5-propylpyrazin-




428







4-yl






4-methoxyphenoxy




2-ethoxyphenyl




364






4-methoxyphenoxy




3-chlorothien-2-yl




361






4-methoxyphenoxy




1-(2-(2-methyl)propyl)-3-




380







methylpyrazol-5-yl






4-methoxyphenoxy




3,5-dichlorophenyl




389






4-methoxyphenoxy




2-(propylthio)pyridin-3-yl




395






4-methoxyphenoxy




2-(ethylthio)pyridin-3-yl




381






4-methoxyphenoxy




3-bromopyridin-5-yl




400






4-methoxyphenoxy




4-methyl-1,2,3-thiadiazol-




342







5-yl






4-methoxyphenoxy




1-methyl-3-(2-(2-




380







methyl)propyl)pyrazol-5-yl






4-methoxyphenoxy




3-chlorobenzo[b]thiophen-




411







2-yl






4-methoxyphenoxy




4-chlorophenyl




355






4-methoxyphenoxy




4-methyl-2-phenyl-1,2,3-




401







triazol-5-yl






4-methoxyphenoxy




benzo[b]thiophen-2-yl




376






4-methoxyphenoxy




3,4-dimethylphenyl




348






4-methoxyphenoxy




2-(phenoxy)pyridin-3-yl




413






4-methoxyphenoxy




2-(methylthio)pyridin-3-yl




367






4-methoxyphenoxy




5-methyl-3-phenylisoxazol-




401







4-yl






4-methoxyphenoxy




4-chloro-1,3-dimethyl




424







pyrazolo[3,4-b]pyridin-3-







yl






4-methoxyphenoxy




2-chloro-6-methylpyridin-




370







4-yl






4-methoxyphenoxy




3,5-dimethylisoxazol-4-yl




339






4-methoxyphenoxy




1-naphthyl




370






4-methoxyphenoxy




2-fluorophenyl




338






4-methoxyphenoxy




4-propylphenyl




362






4-methoxyphenoxy




3-fluorophenyl




338






4-methoxyphenoxy




2,6-difluorophenyl




356






4-methoxyphenoxy




2-chlorophenyl




355






4-methoxyphenoxy




3-(chloromethyl)phenyl




369






4-methoxyphenoxy




4-(2-(2-




376







methyl)propyl)phenyl






4-methoxyphenoxy




3-chlorophenyl




355






4-methoxyphenoxy




3,5-dimethoxyphenyl




380






4-methoxyphenoxy




2,6-dichlorophenyl




389






4-methoxyphenoxy




2,4-dichlorophenyl




389






4-methoxyphenoxy




4-fluorophenyl




338






4-methoxyphenoxy




4-butylphenyl




376






4-methoxyphenoxy




2-methylphenyl




334






4-methoxyphenoxy




phenyl




320






4-methoxyphenoxy




4-ethylphenyl




348






4-methoxyphenoxy




2,3-difluorophenyl




356






4-methoxyphenoxy




2,6-dimethoxyphenyl




380






4-methoxyphenoxy




3,4-difluorophenyl




356






4-methoxyphenoxy




2,5-difluorophenyl




356






4-methoxyphenoxy




4-ethoxyphenyl




364






4-methoxyphenoxy




2,4,6-trichlorophenyl




424






4-methoxyphenoxy




3-methylphenyl




334






4-methoxyphenoxy




2-fluoro-5-




406







(trifluoromethyl)phenyl






4-methoxyphenoxy




3-methoxyphenyl




350






4-methoxyphenoxy




2-bromophenyl




399






4-methoxyphenoxy




4-bromophenyl




399






4-methoxyphenoxy




4-fluoro-3-




406







(trifluoromethyl)phenyl






4-methoxyphenoxy




3-(trifluoromethoxy)phenyl




404






4-methoxyphenoxy




9-fluorenon-4-yl




422






4-methoxyphenoxy




isoxazol-5-yl




311






4-methoxyphenoxy




benzofuroxan-5-yl




378






4-methoxyphenoxy




2-chloropyrid-3-yl




356






4-methoxyphenoxy




2-(4-




427







methylphenoxy)pyridin-3-yl






4-methoxyphenoxy




pyridin-4-yl




321






4-methoxyphenoxy




anthraquinon-2-yl




450






4-methoxyphenoxy




2-iodophenyl




446






4-methoxyphenoxy




4-pentylphenyl




390






4-methoxyphenoxy




2-(4-chlorophenylthio)




464







pyridin-3-yl






4-methoxyphenoxy




2,6-dimethylphenyl




348






4-methoxyphenoxy




2,5-dimethoxyphenyl




380






4-methoxyphenoxy




2,5-dichloropyridin-3-yl




390






4-methoxyphenoxy




2-cloro-6-methoxypyridin-




386







4-yl






4-methoxyphenoxy




2,3-dichloropyridin-5-yl




390






4-methoxyphenoxy




1-naphthyl




384






4-methoxyphenoxy




2,4-dimethoxyphenyl




380






4-methoxyphenoxy




3,5-bis(trifluoromethyl)




456







phenyl






4-methoxyphenoxy




2-(4-




448







chlorophenoxy)pyridin-3-yl






4-methoxyphenoxy




pentafluorophenyl




410






2-(2-propoxy)phenoxy




3,4-dimethoxyphenyl




408






2-(2-propoxy)phenoxy




2-(trifluoromethyl)phenyl




416






2-(2-propoxy)phenoxy




2,4-difluorophenyl




384






2-(2-propoxy)phenoxy




3-(trifluoromethyl)phenyl




416






2-(2-propoxy)phenoxy




2-naphthyl




398






2-(2-propoxy)phenoxy




2-methoxyphenyl




378






2-(2-propoxy)phenoxy




3,4,5-trimethylphenyl




438






2-(2-propoxy)phenoxy




3,4-dichlorophenyl




417






2-(2-propoxy)phenoxy




3-bromophenyl




427






2-(2-propoxy)phenoxy




3-pyridyl




349






2-(2-propoxy)phenoxy




2-ethoxynaphth-1-yl




442






2-(2-propoxy)phenoxy




2,3-dichlorophenyl




417






2-(2-propoxy)phenoxy




6-chloropyrid-3-yl




384






2-(2-propoxy)phenoxy




4-(trifluoromethoxy)phenyl




432






2-(2-propoxy)phenoxy




2-fluoro-4-




434







(trifluoromethyl)phenyl






2-(2-propoxy)phenoxy




3-bromothienyl




433






2-(2-propoxy)phenoxy




2-acetoxyphenyl




406






2-(2-propoxy)phenoxy




5-methylisoxazol-3-yl




353






2-(2-propoxy)phenoxy




2-(phenylthio)pyrid-3-yl




458






2-(2-propoxy)phenoxy




2-(trifluoromethoxy)phenyl




432






2-(2-propoxy)phenoxy




1-phenyl-5-propylpyrazin-




457







4-yl






2-(2-propoxy)phenoxy




2-ethoxyphenyl




392






2-(2-propoxy)phenoxy




3-chlorothien-2-yl




389






2-(2-propoxy)phenoxy




1-(2-(2-methyl)propyl)-3-




408







methylpyrazol-5-yl






2-(2-propoxy)phenoxy




3,5-dichlorophenyl




417






2-(2-propoxy)phenoxy




2-(propylthio)pyridin-3-yl




423






2-(2-propoxy)phenoxy




2-(ethylthio)pyridin-3-yl




409






2-(2-propoxy)phenoxy




3-bromopyridin-5-yl




428






2-(2-propoxy)phenoxy




4-methyl-1,2,3-thiadiazol-




370







5-yl






2-(2-propoxy)phenoxy




1-methyl-3-(2-(2-




408







methyl)propyl)pyrazol-5-yl






2-(2-propoxy)phenoxy




3-chlorobenzo[b]thiophen-




439







2-yl






2-(2-propoxy)phenoxy




4-chlorophenyl




383






2-(2-propoxy)phenoxy




4-methyl-2-phenyl-1,2,3-




429







triazol-5-yl






2-(2-propoxy)phenoxy




benzo[b]thiophen-2-yl




404






2-(2-propoxy)phenoxy




3,4-dimethylphenyl




376






2-(2-propoxy)phenoxy




2-(phenoxy)pyridin-3-yl




441






2-(2-propoxy)phenoxy




2-(methylthio)pyridin-3-yl




395






2-(2-propoxy)phenoxy




5-methyl-3-phenylisoxazol-




429







4-yl






2-(2-propoxy)phenoxy




4-chloro-1,3-dimethyl




452







pyrazolo[3,4-b]pyridin-3-







yl






2-(2-propoxy)phenoxy




2-chloro-6-methylpyridin-




398







4-yl






2-(2-propoxy)phenoxy




3,5-dimethylisoxazol-4-yl




367






2-(2-propoxy)phenoxy




1-naphthyl




398






2-(2-propoxy)phenoxy




2-fluorophenyl




366






2-(2-propoxy)phenoxy




4-propylphenyl




390






2-(2-propoxy)phenoxy




3-fluorophenyl




366






2-(2-propoxy)phehoxy




2,6-difluorophenyl




384






2-(2-propoxy)phenoxy




2-chlorophenyl




383






2-(2-propoxy)phenoxy




3-(chloromethyl)phenyl




397






2-(2-propoxy)phenoxy




4-(2-(2-




404







methyl)propyl)phenyl






2-(2-propoxy)phenoxy




3-chlorophenyl




383






2-(2-propoxy)phenoxy




3,5-dimethoxyphenyl




408






2-(2-propoxy)phenoxy




2,6-dichlorophenyl




417






2-(2-propoxy)phenoxy




2,4-dichlorophenyl




417






2-(2-propoxy)phenoxy




4-fluorophenyl




366






2-(2-propoxy)phenoxy




4-butylphenyl




404






2-(2-propoxy)phenoxy




2-methylphenyl




362






2-(2-propoxy)phenoxy




phenyl




348






2-(2-propoxy)phenoxy




4-ethylphenyl




376






2-(2-propoxy)phenoxy




2,3-difluorophenyl




384






2-(2-propoxy)phenoxy




2,6-dimethoxyphenyl




408






2-(2-propoxy)phenoxy




3,4-difluorophenyl




384






2-(2-propoxy)phenoxy




2,5-difluorophenyl




384






2-(2-propoxy)phenoxy




4-ethoxyphenyl




392






2-(2-propoxy)phenoxy




2,4,6-trichlorophenyl




452






2-(2-propoxy)phenoxy




3-methylphenyl




362






2-(2-propoxy)phenoxy




2-fluoro-5-




434







(trifluoromethyl)phenyl






2-(2-propoxy)phenoxy




3-methoxyphenyl




378






2-(2-propoxy)phenoxy




2-bromophenyl




427






2-(2-propoxy)phenoxy




4-bromophenyl




427






2-(2-propoxy)phenoxy




4-fluoro-3-




434







(trifluoromethyl)phenyl






2-(2-propoxy)phenoxy




3-(trifluoromethoxy)phenyl




432






2-(2-propoxy)phenoxy




9-fluorenon-4-yl




450






2-(2-propoxy)phenoxy




isoxazol-5-yl




339






2-(2-propoxy)phenoxy




benzofuroxan-5-yl




406






2-(2-propoxy)phenoxy




2-chloropyrid-3-yl




384






2-(2-propoxy)phenoxy




2-(4-




455







methylphenoxy)pyridin-3-yl






2-(2-propoxy)phenoxy




pyridin-4-yl




349






2-(2-propoxy)phenoxy




anthraquinon-2-yl




478






2-(2-propoxy)phenoxy




2-iodophenyl




474






2-(2-propoxy)phenoxy




4-pentylphenyl




419






2-(2-propoxy)phenoxy




2-(4-chlorophenylthio)




492







pyridin-3-yl






2-(2-propoxy)phenoxy




2,6-dimethylphenyl




376






2-(2-propoxy)phenoxy




2,5-dimethoxyphenyl




408






2-(2-propoxy)phenoxy




2,5-dichloropyridin-3-yl




418






2-(2-propoxy)phenoxy




2-chloro-6-methoxypyridin-




414







4-yl






2-(2-propoxy)phenoxy




2,3-dichloropyridin-5-yl




418






2-(2-propoxy)phenoxy




1-naphthyl




412






2-(2-propoxy)phenoxy




2,4-dimethoxyphenyl




408






2-(2-propoxy)phenoxy




3,5-bis(trifluoromethyl)




484







phenyl






2-(2-propoxy)phenoxy




2-(4-




476







chlorophenoxy)pyridin-3-yl






2-(2-propoxy)phenoxy




pentafluorophenyl




438






4-fluorophenoxy




3,4-dimethoxyphenyl




368






4-fluorophenoxy




2-(trifluoromethyl)phenyl




376






4-fluorophenoxy




2,4-difluorophenyl




344






4-fluorophenoxy




3-(trifluoromethyl)phenyl




376






4-fluorophenoxy




2-naphthyl




358






4-fluorophenoxy




2-methoxyphenyl




338






4-fluorophenoxy




3,4,5-trimethylphenyl




398






4-fluorophenoxy




3,4-dichlorophenyl




377






4-fluorophenoxy




3-bromophenyl




387






4-fluorophenoxy




3-pyridyl




309






4-fluorophenoxy




2-ethoxynaphth-1-yl




402






4-fluorophenoxy




2,3-dichlorophenyl




377






4-fluorophenoxy




6-chloropyrid-3-yl




344






4-fluorophenoxy




4-(trifluoromethoxy)phenyl




392






4-fluorophenoxy




2-fluoro-4-




394







(trifluoromethyl)phenyl






4-fluorophenoxy




3-bromothienyl




393






4-fluorophenoxy




2-acetoxyphenyl




366






4-fluorophenoxy




5-methylisoxazol-3-yl




313






4-fluorophenoxy




2-(phenylthio)pyrid-3-yl




417






4-fluorophenoxy




2-(trifluoromethoxy)phenyl




392






4-fluorophenoxy




1-phenyl-5-propylpyrazin-




416







4-yl






4-fluorophenoxy




2-ethoxyphenyl




352






4-fluorophenoxy




3-chlorothien-2-yl




349






4-fluorophenoxy




1-(2-(2-methyl)propyl)-3-




368







methylpyrazol-5-yl






4-fluorophenoxy




3,5-dichlorophenyl




377






4-fluorophenoxy




2-(propylthio)pyridin-3-yl




383






4-fluorophenoxy




2-(ethylthio)pyridin-3-yl




369






4-fluorophenoxy




3-bromopyridin-5-yl




388






4-fluorophenoxy




4-methyl-1,2,3-thiadiazol




330







5-yl






4-fluorophenoxy




1-methyl-3-(2-(2-




368







methyl)propyl)pyrazol-5-yl






4-fluorophenoxy




3-chlorobenzo[b]thiophen-




399







2-yl






4-fluorophenoxy




4-chlorophenyl




343






4-fluorophenoxy




4-methyl-2-phenyl-1,2,3-




389







triazol-5-yl






4-fluorophenoxy




benzo[b]thiophen-2-yl




364






4-fluorophenoxy




3,4-dimethylphenyl




336






4-fluorophenoxy




2-(phenoxy)pyridin-3-yl




401






4-fluorophenoxy




2-(methylthio)pyridin-3-yl




355






4-fluorophenoxy




5-methyl-3-phenylisoxazol-




389







4-yl






4-fluorophenoxy




4-chloro-1,3-dimethyl




412







pyrazolo[3,4-b]pyridin-3-







yl






4-fluorophenoxy




2-chloro-6-methylpyridin-




358







4-yl






4-fluorophenoxy




3,5-dimethylisoxazol-4-yl




327






4-fluorophenoxy




1-naphthyl




358






4-fluorophenoxy




2-fluorophenyl




326






4-fluorophenoxy




4-propylphenyl




350






4-fluorophenoxy




3-fluorophenyl




326






4-fluorophenoxy




2,6-difluorophenyl




344






4-fluorophenoxy




2-chlorophenyl




343






4-fluorophenoxy




3-(chloromethyl)phenyl




357






4-fluorophenoxy




4-(2-(2




364







methyl)propyl)phenyl






4-fluorophenoxy




3-chlorophenyl




343






4-fluorophenoxy




3,5-dimethoxyphenyl




368






4-fluorophenoxy




2,6-dichlorophenyl




377






4-fluorophenoxy




2,4-dichlorophenyl




377






4-fluorophenoxy




4-fluorophenyl




326






4-fluorophenoxy




4-butylphenyl




364






4-fluorophenoxy




2-methylphenyl




322






4-fluorophenoxy




phenyl




308






4-fluorophenoxy




4-ethylphenyl




336






4-fluorophenoxy




2,3-difluorophenyl




344






4-fluorophenoxy




2,6-dimethoxyphenyl




368






4-fluorophenoxy




3,4-difluorophenyl




344






4-fluorophenoxy




2,5-difluorophenyl




344






4-fluorophenoxy




4-ethoxyphenyl




352






4-fluorophenoxy




2,4,6-trichlorophenyl




412






4-fluorophenoxy




3-methylphenyl




322






4-fluorophenoxy




2-fluoro-5-




394







(trifluoromethyl)phenyl






4-fluorophenoxy




3-methoxyphenyl




338






4-fluorophenoxy




2-bromophenyl




387






4-fluorophenoxy




4-bromophenyl




387






4-fluorophenoxy




4-fluoro-3-




394







(trifluoromethyl)phenyl






4-fluorophenoxy




3-(trifluoromethoxy)phenyl




392






4-fluorophenoxy




9-fluorenon-4-yl




410






4-fluorophenoxy




isoxazol-5-yl




299






4-fluorophenoxy




benzofuroxan-5-yl




366






4-fluorophenoxy




2-chloropyrid-3-yl




344






4-fiuorophenoxy




2-(4-




415







methylphenoxy)pyridin-3-yl






4-fluorophenoxy




pyridin-4-yl




309






4-fluorophenoxy




anthraquinon-2-yl




438






4-fluorophenoxy




2-iodophenyl




434






4-fluorophenoxy




4-pentylphenyl




378






4-fluorophenoxy




2-(4-chlorophenylthio)




452







pyridin-3-yl






4-fluorophenoxy




2,6-dimethylphenyl




336






4-fluorophenoxy




2,5-dimethoxyphenyl




368






4-fluorophenoxy




2,5-dichloropyridin-3-yl




378






4-fluorophenoxy




2-chloro-6-methoxypyridin-




374







4-yl






4-fluorophenoxy




2,3-dichloropyridin-5-yl




378






4-fluorophenoxy




1-naphthyl




372






4-fluorophenoxy




2,4-dimethoxyphenyl




368






4-fluorophenoxy




3,5-




444







bis(trifluoromethyl)phenyl






4-fluorophenoxy




2-(4-




436







chlorophenoxy)pyridin-3-yl






4-fluorophenoxy




pentafluorophenyl




398






4-chlorophenoxy




3,4-dimethoxyphenyl




385






4-chlorophenoxy




2-(trifluoromethyl)phenyl




393






4-chlorophenoxy




2,4-difluorophenyl




361






4-chlorophenoxy




3-(trifluoromethyl)phenyl




393






4-chlorophenoxy




2-naphthyl




375






4-chlorophenoxy




2-methoxypheny




355






4-chlorophenoxy




3,4,5-trimethylphenyl




415






4-chlorophenoxy




3,4-dichlorophenyl




394






4-chlorophenoxy




3-bromophenyl




404






4-chlorophenoxy




3-pyridyl




326






4-chlorophenoxy




2-ethoxynaphth-1-yl




419






4-chlorophenoxy




2,3-dichlorophenyl




394






4-chlorophenoxy




6-chloropyrid-3-yl




360






4-chlorophenoxy




4-(trifluoromethoxy)phenyl




409






4-chlorophenoxy




2-fluoro-4-




411







(trifluoromethyl)phenyl






4-chlorophenoxy




3-bromothienyl




410






4-chlorophenoxy




2-acetoxyphenyl




383






4-chlorophenoxy




5-methylisoxazol-3-yl




330






4-chlorophenoxy




2-(phenylthio)pyrid-3-yl




434






4-chlorophenoxy




2-(trifluoromethoxy)phenyl




409






4-chlorophenoxy




1-phenyl-5-propylpyrazin-




433







4-yl






4-chlorophenoxy




2-ethoxyphenyl




369






4-chlorophenoxy




3-chlorothien-2-yl




365






4-chlorophenoxy




1-(2-(2-methyl)propyl)-3-




385







methylpyrazol-5-yl






4-chlorophenoxy




3,5-dichlorophenyl




394






4-chlorophenoxy




2-(propylthio)pyridin-3-yl




400






4-chlorophenoxy




2-(ethylthio)pyridin-3-yl




386






4-chlorophenoxy




3 bromopyridin-5-yl




405






4-chlorophenoxy




4-methyl-1,2,3-thiadiazol-




347







5-yl






4-chlorophenoxy




1-methyl-3-(2-(2-




385







methyl)propyl)pyrazol-5-yl






4-chlorophenoxy




3-chlorobenzo[b]thiophen-




415







2-yl






4-chlorophenoxy




4-chlorophenyl




359






4-chlorophenoxy




4-methyl-2-phenyl-1,2,3-




406







triazol-5-yl






4-chlorophenoxy




benzo[b]thiophen-2-yl




381






4-chlorophenoxy




3,4-dimethylphenyl




353






4-chlorophenoxy




2-(phenoxy)pyridin-3-yl




418






4-chlorophenoxy




2-(methylthio)pyridin-3-yl




372






4-chlorophenoxy




5-methyl-3-phenylisoxazol-




406







4-yl






4-chlorophenoxy




4-chloro-1,3-dimethyl




428







pyrazolo[3,4-b]pyridin-3-







yl






4-chlorophenoxy




2-chloro-6-methylpyridin-




374







4-yl






4-chlorophenoxy




3,5-dimethylisoxazol-4-yl




344






4-chlorophenoxy




1-naphthyl




375






4-chlorophenoxy




2-fluorophenyl




343






4-chlorophenoxy




4-propylphenyl




367






4-chlorophenoxy




3-fluorophenyl




343






4-chlorophenoxy




2,6-difluorophenyl




361






4-chlorophenoxy




2-chlorophenyl




359






4-chlorophenoxy




3-(chloromethyl)phenyl




373






4-chlorophenoxy




4-(2-(2-




381







methyl)propyl)phenyl






4-chlorophenoxy




3-chlorophenyl




359






4-chlorophenoxy




3,5-dimethoxyphenyl




385






4-chlorophenoxy




2,6-dichlorophenyl




394






4-chlorophenoxy




2,4-dichlorophenyl




394






4-chlorophenoxy




4-fluorophenyl




343






4-chlorophenoxy




4-butylphenyl




381






4-chlorophenoxy




2-methylphenyl




339






4-chlorophenoxy




phenyl




325






4-chlorophenoxy




4-ethylphenyl




353






4-chlorophenoxy




2,3-difluorophenyl




361






4-chlorophenoxy




2,6-dimethoxyphenyl




385






4-chlorophenoxy




3,4-difluorophenyl




361






4-chlorophenoxy




2,5 -difluorophenyl




361






4-chlorophenoxy




4-ethoxyphenyl




369






4-chlorophenoxy




2,4,6-trichlorophenyl




428






4-chlorophenoxy




3-methylphenyl




339






4-chlorophenoxy




2-fluoro-5-




411







(trifluoromethyl)phenyl






4-chlorophenoxy




3-methoxyphenyl




355






4-chlorophenoxy




2-bromophenyl




404






4-chlorophenoxy




4-bromophenyl




404






4-chlorophenoxy




4-fluoro-3-




411







(trifluoromethyl)phenyl






4-chlorophenoxy




3-(trifluoromethoxy)phenyl




409






4-chlorophenoxy




9-fluorenon-4-yl




427






4-chlorophenoxy




isoxazol-5-yl




316






4-chlorophenoxy




benzofuroxan-5-yl




383






4-chlorophenoxy




2-chloropyrid-3-yl




360






4-chlorophenoxy




2-(4-




432







methylphenoxy)pyridin-3-yl






4-chlorophenoxy




pyridin-4-yl




326






4-chlorophenoxy




anthraquinon-2-yl




455






4-chlorophenoxy




2-iodophenyl




451






4-chlorophenoxy




4-pentylphenyl




395






4-chlorophenoxy




2-(4-chlorophenylthio)




468







pyridin-3-yl






4-chlorophenoxy




2,6-dimethylphenyl




353






4-chlorophenoxy




2,5-dimethoxyphenyl




385






4-chlorophenoxy




2,5-dichloropyridin-3-yl




395






4-chlorophenoxy




2-chloro-6-methoxypyridin-




390







4-yl






4-chlorophenoxy




2,3-dichloropyridin-5-yl




395






4-chlorophenoxy




1-naphthyl




389






4-chlorophenoxy




2,4-dimethoxyphenyl




385






4-chlorophenoxy




3,5-




461







bis(trifluoromethyl)phenyl






4-chlorophenoxy




2-(4-




452







chlorophenoxy)pyridin-3-yl






4-chlorophenoxy




pentafluorophenyl




415






2,4-difluorophenoxy




3,4-dimethoxyphenyl




386






2,4-difluorophenoxy




2-(trifluoromethyl)phenyl




394






2,4-difluorophenoxy




2,4-difluorophenyl




362






2,4-difluorophenoxy




3-(trifluoromethyl)phenyl




394






2,4-difluorophenoxy




2-naphthyl




376






2,4-difluorophenoxy




2-methoxyphenyl




356






2,4-difluorophenoxy




3,4,5-trimethylphenyl




416






2,4-difluorophenoxy




3,4-dichlorophenyl




395






2,4-difluorophenoxy




3-bromophenyl




405






2,4-difluorophenoxy




3-pyridyl




327






2,4-difluorophenoxy




2-ethoxynaphth-1-yl




420






2,4-difluorophenoxy




2,3-dichlorophenyl




395






2,4-difluorophenoxy




6-chloropyrid-3-yl




362






2,4-difluorophenoxy




4-(trifluoromethoxy)phenyl




410






2,4-difluorophenoxy




2-fluoro-4-




412







(trifluoromethyl)phenyl






2,4-difluorophenoxy




3-bromothienyl




411






2,4-difluorophenoxy




2-acetoxyphenyl




384






2,4-difluorophenoxy




5-methylisoxazol-3-yl




331






2,4-difluorophenoxy




2-(phenylthio)pyrid-3-yl




435






2,4-difluorophenoxy




2-(trifluoromethoxy)phenyl




410






2,4-difluorophenoxy




1-phenyl-5-propylpyrazin-




434







4-yl






2,4-difluorophenoxy




2-ethoxyphenyl




370






2,4-difluorophenoxy




3-chlorothien-2-yl




367






2,4-difluorophenoxy




1-(2-(2-methyl)propyl)-3-




386







methylpyrazol-5-yl






2,4-difluorophenoxy




3,5-dichlorophenyl




395






2,4-difluorophenoxy




2-(propylthio)pyridin-3-yl




401






2,4-difluorophenoxy




2-(ethylthio)pyridin-3-yl




387






2,4-difluorophenoxy




3-bromopyridin-5-yl




406






2,4-difluorophenoxy




4-methyl-1,2,3-thiadiazol




348







5-yl






2,4-difluorophenoxy




1-methyl-3-(2-(2-




386







methyl)propyl)pyrazol-5-yl






2,4-difluorophenoxy




3-chlorobenzo[b]thiophen-




417







2-yl






2,4-difluorophenoxy




4-chlorophenyl




361






2,4-difluorophenoxy




4-methyl-2-phenyl-1,2,3-




407







triazol-5-yl






2,4-difluorophenoxy




benzo[b]thiophen-2-yl




382






2,4-difluorophenoxy




3,4-dimethylphenyl




354






2,4-difluorophenoxy




2-(phenoxy)pyridin-3-yl




409






2,4-difluorophenoxy




2-(methylthio)pyridin-3-yl




373






2,4-difluorophenoxy




5-methyl-3-phenylisoxazol-




407







4-yl






2,4-difluorophenoxy




4-chloro-1,3-dimethyl




430







pyrazolo[3,4-b]pyridin-3







yl






2,4-difluorophenoxy




2-chloro-6-methylpyridin-




376







4-yl






2,4-difluorophenoxy




3,5-dimethylisoxazol-4-yl




345






2,4-difluorophenoxy




1-naphthyl




376






2,4-difluorophenoxy




2-fluorophenyl




344






2,4-difluorophenoxy




4-propylphenyl




368






2,4-difluorophenoxy




3-fluorophenyl




344






2,4-difluorophenoxy




2,6-difluorophenyl




362






2,4-difluorophenoxy




2-chlorophenyl




361






2,4-difluorophenoxy




3-(chloromethyl)phenyl




375






2,4-difluorophenoxy




4-(2-(2-




382







methyl)propyl)phenyl






2,4-difluorophenoxy




3-chlorophenyl




361






2,4-difluorophenoxy




3,5-dimethoxyphenyl




386






2,4-difluorophenoxy




2,6-dichlorophenyl




395






2,4-difluorophenoxy




2,4-dichlorophenyl




392






2,4-difluorophenoxy




4-fluorophenyl




344






2,4-difluorophenoxy




4-butylphenyl




382






2,4-difluorophenoxy




2-methylphenyl




340






2,4-difluorophenoxy




phenyl




326






2,4-difluorophenoxy




4-ethylphenyl




354






2,4-difluorophenoxy




2,3-difluorophenyl




362






2,4-difluorophenoxy




2,6-dimethoxyphenyl




386






2,4-difluorophenoxy




3,4-difluorophenyl




362






2,4-difluorophenoxy




2,5-difluorophenyl




362






2,4-difluorophenoxy




4-ethoxyphenyl




370






2,4-difluorophenoxy




2,4,6-trichlorophenyl




430






2,4-difluorophenoxy




3-methylphenyl




340






2,4-difluorophenoxy




2-fluoro-5-




412







(trifluoromethyl)phenyl






2,4-difluorophenoxy




3-methoxyphenyl




356






2,4-difluorophenoxy




2-bromophenyl




405






2,4-difluorophenoxy




4-bromophenyl




405






2,4-difluorophenoxy




4-fluoro-3-




412







(trifluoromethyl)phenyl






2,4-difluorophenoxy




3-(trifluoromethoxy)phenyl




410






2,4-difluorophenoxy




9-fluorenon-4-yl




428






2,4-difluorophenoxy




isoxazol-5-yl




317






2,4-difluorophenoxy




benzofuroxan-5-yl




384






2,4-difluorophenoxy




2-chloropyrid-3-yl




362






2,4-difluorophenoxy




2-(4-




433







methylphenoxy)pyridin-3-yl






2,4-difluorophenoxy




pyridin-4-yl




327






2,4-difluorophenoxy




anthraquinon-2-yl




456






2,4-difluorophenoxy




2-iodophenyl




452






2,4-difluorophenoxy




4-pentylphenyl




396






2,4-difluorophenoxy




2-(4-chlorophenylthio)




470







pyridin-3-yl






2,4-difluorophenoxy




2,6-dimethylphenyl




354






2,4-difluorophenoxy




2,5-dimethoxyphenyl




386






2,4-difluorophenoxy




2,5-dichloropyridin-3-yl




396






2,4-difluorophenoxy




2-chloro-6-methoxypyridin-




392







4-yl






2,4-difluorophenoxy




2,3-dichloropyridin-5-yl




396






2,4-difluorophenoxy




1-naphthyl




390






2,4-difluorophenoxy




2,4-dimethoxyphenyl




386






2,4-difluorophenoxy




3,5-




462







bis(trifluoromethyl)phenyl






2,4-difluorophenoxy




2-(4-




454







chlorophenoxy)pyridin-3-yl






2,4-difluorophenoxy




pentafluorophenyl




416






4-thiomethylphenoxy




3,4-dimethoxyphenyl




396






4-thiomethylphenoxy




2-(trifluoromethyl)phenyl




404






4-thiomethylphenoxy




2,4-difluorophenyl




372






4-thiomethylphenoxy




3-(trifluoromethyl)phenyl




404






4-thiomethylphenoxy




2-naphthyl




386






4-thiomethylphenoxy




2-methoxyphenyl




366






4-thiomethylphenoxy




3,4,5,-trimethylphenyl




426






4-thiomethylphenoxy




3,4-dichlorophenyl




405






4-thiomethylphenoxy




3-bromophenyl




415






4-thiomethylphenoxy




3-pyridyl




337






4-thiomethylphenoxy




2-ethoxynaphth-1-yl




430






4-thiomethylphenoxy




2,3-dichlorophenyl




405






4-thiomethylphenoxy




6-chloropyrid-3-yl




372






4-thiomethylphenoxy




4-(trifluoromethoxy)phenyl




420






4-thiomethylphenoxy




2-fluoro-4-




422







(trifluoromethyl)phenyl






4-thiomethylphenoxy




3-bromothienyl




421






4-thiomethylphenoxy




2-acetoxyphenyl




394






4-thiomethylphenoxy




5-methylisoxazol-3-yl




341






4-thiomethylphenoxy




2-(phenylthio)pyrid-3-yl




446






4-thiomethylphenoxy




2-(trifluoromethoxy)phenyl




420






4-thiomethylphenoxy




1-phenyl-5-propylpyrazin-




445







4-yl






4-thiomethylphenoxy




2-ethoxyphenyl




380






4-thiomethylphenoxy




3-chlorothien-2-yl




377






4-thiomethylphenoxy




1-(2-(2-methyl)propyl)-3-




396







methylpyrazol-5-yl






4-thiomethylphenoxy




3,5-dichlorophenyl




405






4-thiomethylphenoxy




2-(propylthio)pyridin-3-yl




412






4-thiomethylphenoxy




2-(ethylthio)pyridin-3-yl




397






4-thiomethylphenoxy




3-bromopyridin-5-yl




416






4-thiomethylphenoxy




4-methyl-1,2,3-thiadiazol-




358







5-yl






4-thiomethylphenoxy




1-methyl-3-(2-(2-




396







methyl)propyl)pyrazol-5-yl






4-thiomethylphenoxy




3-chlorobenzo[b]thiophen-




427







2-yl






4-thiomethylphenoxy




4-chlorophenyl




371






4-thiomethylphenoxy




4-methyl-2-phenyl-1,2,3-




417







triazol-5-yl






4-thiomethylphenoxy




benzo[b]thiophen-2-yl




392






4-thiomethylphenoxy




3,4-dimethylphenyl




364






4-thiomethylphenoxy




2-(phenoxy)pyridin-3-yl




429






4-thiomethylphenoxy




2-(methylthio)pyridin-3-yl




383






4-thiomethylphenoxy




5-methyl-3-phenylisoxazol-




417







4-yl






4-thiomethylphenoxy




4-chloro-1,3-dimethyl




440







pyrazolo[3,4-b]pyridin-3-







yl






4-thiomethylphenoxy




2-chloro-6-methylpyridin-




386







4-yl






4-thiomethylphenoxy




3,5-dimethylisoxazol-4-yl




355






4-thiomethylphenoxy




1-naphthyl




386






4-thiomethylphenoxy




2-fluorophenyl




354






4-thiomethylphenoxy




4-propylphenyl




378






4-thiomethylphenoxy




3-fluorophenyl




354






4-thiomethylphenoxy




2,6-difluorophenyl




372






4-thiomethylphenoxy




2-chlorophenyl




371






4-thiomethylphenoxy




3-(chloromethyl)phenyl




385






4-thiomethylphenoxy




4-(2-(2-




392







methyl)propyl)phenyl






4-thiomethylphenoxy




3-chlorophenyl




371






4-thiomethylphenoxy




3,5-dimethoxyphenyl




396






4-thiomethylphenoxy




2,6-dichlorophenyl




405






4-thiomethylphenoxy




2,4-dichlorophenyl




405






4-thiomethylphenoxy




4-fluorophenyl




354






4-thiomethylphenoxy




4-butylphenyl




392






4-thiomethylphenoxy




2-methylphenyl




350






4-thiomethylphenoxy




phenyl




336






4-thiomethylphenoxy




4-ethylphenyl




364






4-thiomethylphenoxy




2,3-difluorophenyl




372






4-thiomethylphenoxy




2,6-dimethoxyphenyl




396






4-thiomethylphenoxy




3,4-difluorophenyl




372






4-thiomethylphenoxy




2,5-difluorophenyl




372






4-thiomethylphenoxy




4-ethoxyphenyl




380






4-thiomethylphenoxy




2,4,6-trichlorophenyl




440






4-thiomethylphenoxy




3-methylphenyl




350






4-thiomethylphenoxy




2-fluoro-5-




422







(trifluoromethyl)phenyl






4-thiomethylphenoxy




3-methoxyphenyl




366






4-thiomethylphenoxy




2-bromophenyl




415






4-thiomethylphenoxy




4-bromophenyl




415






4-thiomethylphenoxy




4-fluoro-3-




422







(trifluoromethyl)phenyl






4-thiomethylphenoxy




3-(trifluoromethoxy)phenyl




420






4-thiomethylphenoxy




9-fluorenon-4-yl




438






4-thiomethylphenoxy




isoxazol-5-yl




327






4-thiomethylphenoxy




benzofuroxan-5-yl




394






4-thiomethylphenoxy




2-chloropyrid-3-yl




372






4-thiomethylphenoxy




2-(4-




443







methylphenoxy)pyridin-3-yl






4-thiomethylphenoxy




pyridin-4-yl




337






4-thiomethylphenoxy




anthraquinon-2-yl




466






4-thiomethylphenoxy




2-iodophenyl




462






4-thiomethylphenoxy




4-pentylphenyl




407






4-thiomethylphenoxy




2-(4-chlorophenylthio)




480







pyridin-3-yl






4-thiomethylphenoxy




2,6-dimethylphenyl




364






4-thiomethylphenoxy




2,5-dimethoxyphenyl




396






4-thiomethylphenoxy




2,5-dichloropyridin-3-yl




406






4-thiomethylphenoxy




2-chloro-6-methoxypyridin-




402







4-yl






4-thiomethylphenoxy




2,3-dichloropyridin-5-yl




406






4-thiomethylphenoxy




1-naphthyl




400






4-thiomethylphenoxy




2,4-dimethoxyphenyl




396






4-thiomethylphenoxy




3,5-




372







bis(trifluoromethyl)phenyl






4-thiomethylphenoxy




2-(4-




464







chlorophenoxy)pyridin-3-yl






4-thiomethylphenoxy




pentafluorophenyl




426






4-(2-(2-




3,4-dimethoxyphenyl




406






methyl)propyl)phenoxy






4-(2-(2-




2-(trifluoromethyl)phenyl




414






methyl)propyl)phenoxy






4-(2-(2-




2,4-difluorophenyl




382






methyl)propyl)phenoxy






4-(2-(2-




3-(trifluoromethyl)phenyl




414






methyl)propyl)phenoxy






4-(2-(2-




2-naphthyl




396






methyl)propyl)phenoxy






4-(2-(2-




2-methoxyphenyl




376






methyl)propyl)phenoxy






4-(2-(2-




3,4,5-trimethylphenyl




436






methyl)propyl)phenoxy






4-(2-(2-




3,4-dichlorophenyl




415






methyl)propyl)phenoxy






4-(2-(2-




3-bromophenyl




425






methyl)propyl)phenoxy






4-(2-(2-




3-pyridyl




347






methyl)propyl)phenoxy






4-(2-(2-




2-ethoxynaphth-1-yl




441






methyl)propyl)phenoxy






4-(2-(2-




2,3-dichlorophenyl




415






methyl)propyl)phenoxy






4-(2-(2-




6-chloropyrid-3-yl




382






methyl)propyl)phenoxy






4-(2-(2-




4-(trifluoromethoxy)phenyl




430






methyl)propyl)phenoxy






4-(2-(2-




2-fluoro-4-




432






methyl)propyl)phenoxy




(trifluoromethyl)phenyl






4-(2-(2-




3-bromothienyl




431






methyl)propyl)phenoxy






4-(2-(2-




2-acetoxyphenyl




404






methyl)propyl)phenoxy






4-(2-(2-




5-methylisoxazol-3-yl




351






methyl)propyl)phenoxy






4-(2-(2-




2-(phenylthio)pyrid-3-yl




456






methyl)propyl)phenoxy






4-(2-(2-




2-(trifluoromethoxy)phenyl




430






methyl)propyl)phenoxy






4-(2-(2-




1-phenyl-5-propylpyrazin-




455






methyl)propyl)phenoxy




4-yl






4-(2-(2-




2-ethoxyphenyl




390






methyl)propyl)phenoxy






4-(2-(2-




3-chlorothien-2-yl




387






methyl)propyl)phenoxy






4-(2-(2-




1-(2-(2-methyl)propyl)-3-




406






methyl)propyl)phenoxy




methylpyrazol-5-yl






4-(2-(2-




3,5-dichlorophenyl




415






methyl)propyl)phenoxy






4-(2-(2-




2-(propylthio)pyridin-3-yl




422






methyl)propyl)phenoxy






4-(2-(2-




2-(ethylthio)pyridin-3-yl




407






methyl)propyl)phenoxy






4-(2-(2-




3-bromopyridin-5-yl




426






methyl)propyl)phenoxy






4-(2-(2-




4-methyl-1,2,3-thiadiazol-




368






methyl)propyl)phenoxy




5-yl






4-(2-(2-




1-methyl-3-(2-(2-




406






methyl)propyl)phenoxy




methyl)propyl)pyrazol-5-yl






4-(2-(2-




3-chlorobenzo[b]thiophen-




437






methyl)propyl)phenoxy




2-yl






4-(2-(2-




4-chlorophenyl




381






methyl)propyl)phenoxy






4-(2-(2-




4-methyl-2-phenyl-1,1,2,3-




427






methyl)propyl)phenoxy




triazol-5-yl






4-(2-(2-




benzo[b]thiophen-2-yl




402






methyl)propyl)phenoxy






4-(2-(2-




3,4-dimethylphenyl




374






methyl)propyl)phenoxy






4-(2-(2-




2-(phenoxy)pyridin-3-yl




439






methyl)propyl)phenoxy






4-(2-(2-




2-(methylthio)pyridin-3-yl




393






methyl)propyl)phenoxy






4-(2-(2-




5-methyl-3-phenylisoxazol-




427






methyl)propyl)phenoxy




4-yl






4-(2-(2-




4-chloro-1,3-dimethyl




450






methyl)propyl)phenoxy




pyrazolo[3,4-b]pyridin-3-







yl






4-(2-(2-




2-chloro-6-methylpyridin




396






methyl)propyl)phenoxy




4-yl






4-(2-(2-




3,5-dimethylisoxazol-4-yl




365






methyl)propyl)phenoxy






4-(2-(2-




1-naphthyl




396






methyl)propyl)phenoxy






4-(2-(2-




2-fluorophenyl




364






methyl)propyl)phenoxy






4-(2-(2-




4-propylphenyl




388






methyl)propyl)phenoxy






4-(2-(2-




3-fluorophenyl




364






methyl)propyl)phenoxy






4-(2-(2-




2,6-difluorophenyl




382






methyl)propyl)phenoxy






4-(2-(2-




2-chlorophenyl




381






methyl)propyl)phenoxy






4-(2-(2-




3-(chloromethyl)phenyl




395






methyl)propyl)phenoxy






4-(2-(2-




4-(2-(2-




402






methyl)propyl)phenoxy




methyl)propyl)phenoxy






4-(2-(2-




3-chlorophenyl




381






methyl)propyl)phenoxy






4-(2-(2-




3,5-dimethoxyphenyl




406






methyl)propyl)phenoxy






4-(2-(2-




2,6-dichlorophenyl




415






methyl)propyl)phenoxy






4-(2-(2-




2,4-dichlorophenyl




415






methyl)propyl)phenoxy






4-(2-(2-




4-fluorophenyl




364






methyl)propyl)phenoxy






4-(2-(2-




4-butylphenyl




402






methyl)propyl)phenoxy






4-(2-(2-




2-methylphenyl




360






methyl)propyl)phenoxy






4-(2-(2-




phenyl




346






methyl)propyl)phenoxy






4-(2-(2-




4-ethylphenyl




374






methyl)propyl)phenoxy






4-(2-(2-




2,3-difluorophenyl




382






methyl)propyl)phenoxy






4-(2-(2-




2,6-dimethoxyphenyl




406






methyl)propyl)phenoxy






4-(2-(2-




3,4-difluorophenyl




382






methyl)propyl)phenoxy






4-(2-(2-




2,5-difluorophenyl




382






methyl)propyl)phenoxy






4-(2-(2-




4-ethoxyphenyl




390






methyl)propyl)phenoxy






4-(2-(2-




2,4,6-trichlorophenyl




450






methyl)propyl)phenoxy






4-(2-(2-




3-methylphenyl




360






methyl)propyl)phenoxy






4-(2-(2-




2-fluoro-5-




432






methyl)propyl)phenoxy




(trifluoromethyl)phenyl






4-(2-(2-




3-methoxyphenyl




376






methyl)propyl)phenoxy






4-(2-(2-




2-bromophenyl




425






methyl)propyl)phenoxy






4-(2-(2-




4-bromophenyl




425






methyl)propyl)phenoxy






4-(2-(2-




4-fluoro-3-




432






methyl)propyl)phenoxy




(trifluoromethyl)phenyl






4-(2-(2-




3-(trifluoromethoxy)phenyl




430






methyl)propyl)phenoxy






4-(2-(2-




9-fluorenon-4-yl




448






methyl)propyl)phenoxy






4-(2-(2-




isoxazol-5-yl




338






methyl)propyl)phenoxy






4-(2-(2-




benzofuroxan-5-yl




404






methyl)propyl)phenoxy






4-(2-(2-




2-chloropyrid-3-yl




382






methyl)propyl)phenoxy






4-(2-(2-




2-(4-




454






methyl)propyl)phenoxy




methylphenoxy)pyridin-3-yl






4-(2-(2-




pyridin-4-yl




347






methyl)propyl)phenoxy






4-(2-(2-




anthraquinon-2-yl




476






methyl)propyl)phenoxy






4-(2-(2-




2-iodophenyl




472






methyl)propyl)phenoxy






4-(2-(2-




4-pentylphenyl




417






methyl)propyl)phenoxy






4-(2-(2-




2-(4-chlorophenylthio)




490






methyl)propyl)phenoxy




pyridin-3-yl






4-(2-(2-




2,6-dimethylphenyl




374






methyl)propyl)phenoxy






4-(2-(2-




2,5-dimethoxyphenyl




406






methyl)propyl)phenoxy






4-(2-(2-




2,5-dichloropyridin-3-yl




416






methyl)propyl)phenoxy






4-(2-(2-




2-chloro-6-methoxypyridin-




412






methyl)propyl)phenoxy




4-yl






4-(2-(2-




2,3-dichloropyridin-5-yl




416






methyl)propyl)phenoxy






4-(2-(2-




1-naphthyl




410






methyl)propyl)phenoxy






4-(2-(2-




2,4-dimethoxyphenyl




406






methyl)propyl)phenoxy






4-(2-(2-




3,5-bis(trifluoromethyl)




482






methyl)propyl)phenoxy




phenyl






4-(2-(2-




2-(4-




474






methyl)propyl)phenoxy




chlorophenoxy)pyridin-3-yl






4-(2-(2-




pentafluorophenyl




436






methyl)propyl)phenoxy






2,3-dimethylphenoxy




3,4-dimethoxyphenyl




378






2,3-dimethylphenoxy




2-(trifluoromethyl)phenyl




386






2,3-dimethylphenoxy




2,4-difluorophenyl




354






2,3-dimethylphenoxy




3-(trifluoromethyl)phenyl




386






2,3-dimethylphenoxy




2-naphthyl




368






2,3-dimethylphenoxy




2-methoxyphenyl




348






2,3-dimethylphenoxy




3,4,5-trimethylphenyl




408






2,3-dimethylphenoxy




3,4-dichlorophenyl




387






2,3-dimethylphenoxy




3-bromophenyl




397






2,3-dimethylphenoxy




3-pyridyl




319






2,3-dimethylphenoxy




2-ethoxynaphth-1-yl




412






2,3-dimethylphenoxy




2,3-dichlorophenyl




387






2,3-dimethylphenoxy




6-chloropyrid-3-yl




354






2,3-dimethylphenoxy




4-(trifluoromethoxy)phenyl




402






2,3-dimethylphenoxy




2-fluoro-4-




404







(trifluoromethyl)phenyl






2,3-dimethylphenoxy




3-bromothienyl




403






2,3-dimethylphenoxy




2-acetoxyphenyl




376






2,3-dimethylphenoxy




5-methylisoxazol-3-yl




323






2,3-dimethylphenoxy




2-(phenylthio)pyrid-3-yl




427






2,3-dimethylphenoxy




2-(trifluoromethoxy)phenyl




402






2,3-dimethylphenoxy




1-phenyl-5-propylpyrrazin-




426







4-yl






2,3-dimethylphenoxy




2-ethoxyphenyl




362






2,3-dimethylphenoxy




3-chlorothien-2-yl




359






2,3-dimethylphenoxy




1-(2-(2-methyl)propyl)-3-




378







methylpyrazol-5-yl






2,3-dimethylphenoxy




3,5-dichlorophenyl




387






2,3-dimethylphenoxy




2-(propylthio)pyridin-3-yl




393






2,3-dimethylphenoxy




2-(ethylthio)pyridin-3-yl




379






2,3-dimethylphenoxy




3-bromopyridin-5-yl




398






2,3-dimethylphenoxy




4-methyl-1,2,3-thiadiazol-




340







5-yl






2,3-dimethylphenoxy




1-methyl-3-(2-(2-




378







methyl)propyl)pyrazol-5-yl






2,3-dimethylphenoxy




3-chlorobenzo[b]thiophen-




409







2-yl






2,3-dimethylphenoxy




4-chlorophenyl




353






2,3-dimethylphenoxy




4-methyl-2-phenyl-1,2,3-




399







triazol-5-yl






2,3-dimethylphenoxy




benzo[b]thiophen-2-yl




374






2,3-dimethylphenoxy




3,4-dimethylphenyl




346






2,3-dimethylphenoxy




2-(phenoxy)pyridin-3-yl




411






2,3-dimethylphenoxy




2-(methylthio)pyridin-3-yl




365






2,3-dimethylphenoxy




5-methyl-3-phenylisoxazol-




399







4-yl






2,3-dimethylphenoxy




4-chloro-1,3-dimethyl




422







pyrazolo[3,4-b]pyridin-3-







yl






2,3-dimethylphenoxy




2-chloro-6-methylpyridin-




368







4-yl






2,3-dimethylphenoxy




3,5-dimethylisoxazol-4-yl




337






2,3-dimethylphenoxy




1-naphthyl




368






2,3-dimethylphenoxy




2-fluorophenyl




336






2,3-dimethylphenoxy




4-propylphenyl




360






2,3-dimethylphenoxy




3-fluorophenyl




336






2,3-dimethylphenoxy




2,6-difluorophenyl




354






2,3-dimethylphenoxy




2-chlorophenyl




353






2,3-dimethylphenoxy




3-(chloromethyl)phenyl




368






2,3-dimethylphenoxy




4-(2-(2-methyl)propyl)




374







phenyl






2,3-dimethylphenoxy




3-chlorophenyl




353






2,3-dimethylphenoxy




3,5-dimethoxyphenyl




378






2,3-dimethylphenoxy




2,6-dichlorophenyl




387






2,3-dimethylphenoxy




2,4-dichlorophenyl




387






2,3-dimethylphenoxy




4-fluorophenyl




336






2,3-dimethylphenoxy




4-butylphenyl




374






2,3-dimethylphenoxy




2-methylphenyl




332






2,3-dimethylphenoxy




phenyl




318






2,3-dimethylphenoxy




4-ethylphenyl




346






2,3-dimethylphenoxy




2,3-difluorophenyl




354






2,3-dimethylphenoxy




2,6-dimethoxyphenyl




378






2,3-dimethylphenoxy




3,4-difluorophenyl




354






2,3-dimethylphenoxy




2,5-difluorophenyl




354






2,3-dimethylphenoxy




4-ethoxyphenyl




362






2,3-dimethylphenoxy




2,4,6-trichlorophenyl




422






2,3-dimethylphenoxy




3-methylphenyl




332






2,3-dimethylphenoxy




2-fluoro-5-




404







(trifluoromethyl)phenyl






2,3-dimethylphenoxy




3-methoxyphenyl




348






2,3-dimethylphenoxy




2-bromophenyl




397






2,3-dimethylphenoxy




4-bromophenyl




397






2,3-dimethylphenoxy




4-fluoro-3-




404







(trifluoromethyl)phenyl






2,3-dimethylphenoxy




3-(trifluoromethoxy)phenyl




402






2,3-dimethylphenoxy




9-fluorenon-4-yl




420






2,3-dimethylphenoxy




isoxazol-5-yl




609






2,3-dimethylphenoxy




benzofuroxan-5-yl




376






2,3-dimethylphenoxy




2-chloropyrid-3-yl




354






2,3-dimethylphenoxy




2-(4-




425







methylphenoxy)pyridin-3-yl






2,3-dimethylphenoxy




pyridin-4-yl




319






2,3-dimethylphenoxy




anthraquinon-2-yl




448






2,3-dimethylphenoxy




2-iodophenyl




444






2,3-dimethylphenoxy




4-pentylphenyl




388






2,3-dimethylphenoxy




2-(4-chlorophenylthio)




462







pyridin-3-yl






2,3-dimethylphenoxy




2,6-dimethylphenyl




346






2,3-dimethylphenoxy




2,5-dimethoxyphenyl




378






2,3-dimethylphenoxy




2,5-dichloropyridin-3-yl




388






2,3-dimethylphenoxy




2-chloro-6-methoxypyridin-




384







4-yl






2,3-dimethylphenoxy




2,3-dichloropyridin-5-yl




388






2,3-dimethylphenoxy




1-naphthyl




382






2,3-dimethylphenoxy




2,4-dimethoxyphenyl




378






2,3-dimethylphenoxy




3,5-bis(trifluoromethyl)




454







phenyl






2,3-dimethylphenoxy




2-(4-




446







chlorophenoxy)pyridin-3-yl






2,3-dimethylphenoxy




pentafluorophenyl




408






3,5-(bis-2-




3,4-dimethoxyphenyl




434






propyl)phenoxy






3,5-(bis-2-




2-(trifluoromethyl)phenyl




442






propyl)phenoxy






3,5-(bis-2-




2,4-difluorophenyl




410






propyl)phenoxy






3,5-(bis-2-




3-(trifluoromethyl)phenyl




442






propyl)phenoxy






3,5-(bis-2-




2-naphthyl




425






propyl)phenoxy






3,5-(bis-2-




2-methoxyphenyl




404






propyl)phenoxy






3,5-(bis-2-




3,4,5-trimethylphenyl




465






propyl)phenoxy






3,5-(bis-2-




3,4-dichlorophenyl




443






propyl)phenoxy






3,5-(bis-2-




3-bromophenyl




453






propyl)phenoxy






3,5-(bis-2-




3-pyridyl




375






propyl)phenoxy






3,5-(bis-2-




2-ethoxynaphth-1-yl




469






propyl)phenoxy






3,5-(bis-2-




2,3-dichlorophenyl




443






propyl)phenoxy






3,5-(bis-2-




6-chloropyrid-3-yl




410






propyl)phenoxy






3,5-(bis-2-




4-(trifluoromethoxy)phenyl




458






propyl)phenoxy






3,5-(bis-2-




2-fluoro-4-




460






propyl)phenoxy




(trifluoromethyl)phenyl






3,5-(bis-2-




3-bromothienyl




459






propyl)phenoxy






3,5-(bis-2-




2-acetoxyphenyl




432






propyl)phenoxy






3,5-(bis-2-




5-methylisoxazol-3-yl




379






propyl)phenoxy






3,5-(bis-2-




2-(phenylthio)pyrid-3-yl




484






propyl)phenoxy






3,5-(bis-2-




2-(trifluoromethoxy)phenyl




458






propyl)phenoxy






3,5-(bis-2-




1-phenyl-5-propylpyrazin-




483






propyl)phenoxy




4-yl






3,5-(bis-2-




2-ethoxyphenyl




418






propyl)phenoxy






3,5-(bis-2-




3-chlorothiophen-2-yl




415






propyl)phenoxy






3,5-(bis-2-




1-(2-(2-methyl)propyl)-3-




435






propyl)phenoxy




methylpyrazol-5-yl






3,5-(bis-2-




3,5-dichlorophenyl




443






propyl)phenoxy






3,5-(bis-2-




2-(propylthio)pyridin-3-yl




450






propyl)phenoxy






3,5-(bis-2-




2-(ethylthio)pyridin-3-yl




436






propyl)phenoxy






3,5-(bis-2-




3-bromopyridin-5-yl




454






propyl)phenoxy






3,5-(bis-2-




4-methyl-1,2,3-thiadiazol-




396






propyl)phenoxy




5-yl






3,5-(bis-2-




1-methyl-3-(2-(2-




435






propyl)phenoxy




methyl)propyl)pyrazol-5-yl






3,5-(bis-2-




3-chlorobenzo[b]thiophen-




465






propyl)phenoxy




2-yl






3,5-(bis-2-




4-chlorophenyl




409






propyl)phenoxy






3,5-(bis-2-




4-methyl-2-phenyl-1,2,3




456






propyl)phenoxy




triazol-5-yl






3,5-(bis-2-




benzo[b]thiophen-2-yl




431






propyl)phenoxy






3,5-(bis-2-




3,4-dimethylphenyl




402






propyl)phenoxy






3,5-(bis-2-




2-(phenoxy)pyridin-3-yl




468






propyl)phenoxy






3,5-(bis-2-




2-(methylthio)pyridin-3-yl




422






propyl)phenoxy






3,5-(bis-2-




5-methyl-3-phenylisoxazol-




456






propyl)phenoxy




4-yl






3,5-(bis-2-




4-chloro-1,3-dimethyl




478






propyl)phenoxy




pyrazolo[3,4-b]pyridin-3-







yl






3,5-(bis-2-




2-chloro-6-methylpyridin-




424






propyl)phenoxy




4-yl






3,5-(bis-2-




3,5-dimethylisoxazol-4-yl




393






propyl)phenoxy






3,5-(bis-2-




1-naphthyl




425






propyl)phenoxy






3,5-(bis-2-




2-fluorophenyl




392






propyl)phenoxy






3,5-(bis-2-




4-propylphenyl




417






propyl)phenoxy






3,5-(bis-2-




3-fluorophenyl




392






propyl)phenoxy






3,5-(bis-2-




2,6-difluorophenyl




410






propyl)phenoxy






3,5-(bis-2-




2-chlorophenyl




409






propyl)phenoxy






3,5-(bis-2-




3-(chloromethyl)phenyl




423






propyl)phenoxy






3,5-(bis-2-




4-(2-(2-methyl)propyl)




431






propyl)phenoxy




phenyl






3,5-(bis-2-




3-chlorophenyl




409






propyl)phenoxy






3,5-(bis-2-




3,5-dimethoxyphenyl




434






propyl)phenoxy






3,5-(bis-2-




2,6-dichlorophenyl




443






propyl)phenoxy






3,5-(bis-2-




2,4-dichlorophenyl




443






propyl)phenoxy






3,5-(bis-2-




4-fluorophenyl




392






propyl)phenoxy






3,5-(bis-2-




4-butylphenyl




431






propyl)phenoxy






3,5-(bis-2-




2-methylphenyl




388






propyl)phenoxy






3,5-(bis-2-




phenyl




374






propyl)phenoxy






3,5-(bis-2-




4-ethylphenyl




402






propyl)phenoxy






3,5-(bis-2-




2,3-difluorophenyl




410






propyl)phenoxy






3,5-(bis-2-




2,6-dimethoxyphenyl




434






propyl)phenoxy






3,5-(bis-2-




3,4-difluorophenyl




410






propyl)phenoxy






3,5-(bis-2-




2,5-difluorophenyl




410






propyl)phenoxy






3,5-(bis-2-




4-ethoxyphenyl




418






propyl)phenoxy






3,5-(bis-2-




2,4,6-trichlorophenyl




478






propyl)phenoxy






3,5-(bis-2-




3-methylphenyl




388






propyl)phenoxy






3,5-(bis-2-




2-fluoro-5-




460






propyl)phenoxy




(trifluoromethyl)phenyl






3,5-(bis-2-




3-methoxyphenyl




404






propyl)phenoxy






3,5-(bis-2-




2-bromophenyl




453






propyl)phenoxy






3,5-(bis-2-




4-bromophenyl




453






propyl)phenoxy






3,5-(bis-2-




4-fluoro-3-




460






propyl)phenoxy




(trifluoromethyl)phenyl






3,5-(bis-2-




3-(trifluoromethoxy)phenyl




458






propyl)phenoxy






3,5-(bis-2-




9-fluorenon-4-yl




477






propyl)phenoxy






3,5-(bis-2-




isoxazol-5-yl




365






propyl)phenoxy






3,5-(bis-2-




benzofuroxan-5-yl




432






propyl)phenoxy






3,5-(bis-2-




2-chloropyrid-3-yl




410






propyl)phenoxy






3,5-(bis-2-




2-(4-




482






propyl)phenoxy




methylphenoxy)pyridin-3-yl






3,5-(bis-2-




pyridin-4-yl




375






propyl)phenoxy






3,5-(bis-2-




anthraquinon-2-yl




505






propyl)phenoxy






3,5-(bis-2-




2-iodophenyl




500






propyl)phenoxy






3,5-(bis-2-




4-pentylphenyl




445






propyl)phenoxy






3,5-(bis-2-




2-(4-chlorophenylthio)




518






propyl)phenoxy




pyridin-3-yl






3,5-(bis-2-




2,6-dimethylphenyl




402






propyl)phenoxy






3,5-(bis-2-




2,5-dimethoxyphenyl




434






propyl)phenoxy






3,5-(bis-2-




2,5-dichloropyridin-3-yl




444






propyl)phenoxy






3,5-(bis-2-




2-chloro-6-methoxypyridin-




440






propyl)phenoxy




4-yl






3,5-(bis-2-




2,3-dichloropyridin-5-yl




444






propyl)phenoxy






3,5-(bis-2-




1-naphthyl




439






propyl)phenoxy






3,5-(bis-2-




2,4-dimethoxyphenyl




434






propyl)phenoxy






3,5-(bis-2-




3,5-bis(trifluoromethyl)




510






propyl)phenoxy




phenyl






3,5-(bis-2-




2-(4-




502






propyl)phenoxy




chlorophenoxy)pyridin-3-yl






3,5-(bis-2-




pentafluorophenyl




464






propyl)phenoxy






3-trifluoromethyl




3,4-dimethoxyphenyl




418






phenoxy






3-trifluoromethyl




2-(trifluoromethyl)phenyl




426






phenoxy






3-trifluoromethyl




2,4-difluorophenyl




394






phenoxy






3-trifluoromethyl




3-(trifluoromethyl)phenyl




426






phenoxy






3-trifluoromethyl




2-naphthyl




408






phenoxy






3-trifluoromethyl




2-methoxyphenyl




388






phenoxy






3-trifluoromethyl




3,4,5-trimethylphenyl




448






phenoxy






3-trifluoromethyl




3,4-dichlorophenyl




427






phenoxy






3-trifluoromethyl




3-bromophenyl




437






phenoxy






3-trifluoromethyl




3-pyridyl




359






phenoxy






3-trifluoromethyl




2-ethoxynaphth-1-yl




452






phenoxy






3-trifluoromethyl




2,3-dichlorophenyl




427






phenoxy






3-trifluoromethyl




6-chloropyrid-3-yl




394






phenoxy






3-trifluoromethyl




4-(trifluoromethoxy)phenyl




442






phenoxy






3-trifluoromethyl




2-fluoro-4-




444






phenoxy




(trifluoromethyl)phenyl






3-trifluoromethyl




3-bromothienyl




443






phenoxy






3-trifluoromethyl




2-acetoxyphenyl




416






phenoxy






3-trifluoromethyl




5-methylisoxazol-3-yl




363






phenoxy






3-trifluoromethyl




2-(phenylthio)pyrid-3-yl




467






phenoxy






3-trifluoromethyl




2-(trifluoromethoxy)phenyl




442






phenoxy






3-trifluoromethyl




1-phenyl-5-propylpyrazin-




466






phenoxy




4-yl






3-trifluoromethyl




2-ethoxyphenyl




402






phenoxy






3-trifluoromethyl




3-chlorothien-2-yl




399






phenoxy






3-trifluoromethyl




1-(2-(2-methyl)propyl)-3-




418






phenoxy




methylpyrazol-5-yl






3-trifluoromethyl




3,5-dichlorophenyl




427






phenoxy






3-trifluoromethyl




2-(propylthio)pyridin-3-yl




433






phenoxy






3-trifluoromethyl




2-(ethylthio)pyridin-3-yl




419






phenoxy






3-trifluoromethyl




3-bromopyridin-5-yl




438






phenoxy






3-trifluoromethyl




4-methyl-1,2,3-thiadiazol-




380






phenoxy




5-yl






3-trifluoromethyl




1-methyl-3-(2-(2-




418






phenoxy




methyl)propyl)pyrazol-5-yl






3-trifluoromethyl




3-chlorobenzo[b]thiophen-




449






phenoxy




2-yl






3-trifluoromethyl




4-chlorophenyl




393






phenoxy






3-trifluoromethyl




4-methyl-2-phenyl-1,2,3-




439






phenoxy




triazol-5-yl






3-trifluoromethyl




benzo[b]thiophen-2-yl




414






phenoxy






3-trifluoromethyl




3,4-dimethylphenyl




386






phenoxy






3-trifluoromethyl




2-(phenoxy)pyridin-3-yl




451






phenoxy






3-trifluoromethyl




2-(methylthio)pyridin-3-yl




405






phenoxy






3-trifluoromethyl




5-methyl-3-phenylisoxazol-




439






phenoxy




4-yl






3-trifluoromethyl




4-chloro-1,3-dimethyl




462






phenoxy




pyrazolo[3,4-b]pyridin-3-







yl






3-trifluoromethyl




2-chloro-6-methylpyridin-




408






phenoxy




4-yl






3-trifluoromethyl




3,5-dimethylisoxazol-4-yl




377






phenoxy






3-trifluoromethyl




1-naphthyl




408






phenoxy






3-trifluoromethyl




2-fluorophenyl




476






phenoxy






3-trifluoromethyl




4-propylphenyl




400






phenoxy






3-trifluoromethyl




3-fluorophenyl




376






phenoxy






3-trifluoromethyl




2,6-difluorophenyl




394






phenoxy






3-trifluoromethyl




2-chlorophenyl




393






phenoxy






3-trifluoromethyl




3-(chloromethyl)phenyl




407






phenoxy






3-trifluoromethyl




4-(2-(2-methyl)propyl)




414






phenoxy




phenyl






3-trifluoromethyl




3-chlorophenyl




393






phenoxy






3-trifluoromethyl




3,5-dimethoxyphenyl




418






phenoxy






3-trifluoromethyl




2,6-dichlorophenyl




427






phenoxy






3-trifluoromethyl




2,4-dichlorophenyl




427






phenoxy






3-trifluoromethyl




4-fluorophenyl




376






phenoxy






3-trifluoromethyl




4-butylphenyl




414






phenoxy






3-trifluoromethyl




2-methylphenyl




372






phenoxy






3-trifluoromethyl




phenyl




358






phenoxy






3-trifluoromethyl




4-ethylphenyl




386






phenoxy






3-trifluoromethyl




2,3-difluorophenyl




394






phenoxy






3-trifluoromethyl




2,6-dimethoxyphenyl




418






phenoxy






3-trifluoromethyl




3,4-difluorophenyl




394






phenoxy






3-trifluoromethyl




2,5-difluorophenyl




394






phenoxy






3-trifluoromethyl




4-ethoxyphenyl




402






phenoxy






3-trifluoromethyl




2,4,6-trichlorophenyl




462






phenoxy






3-trifluoromethyl




3-methylphenyl




372






phenoxy






3-trifluoromethyl




2-fluoro-5-




444






phenoxy




(trifluoromethyl)phenyl






3-trifluoromethyl




3-methoxyphenyl




388






phenoxy






3-trifluoromethyl




2-bromophenyl




437






phenoxy






3-trifluoromethyl




4-bromophenyl




437






phenoxy






3-trifluoromethyl




4-fluoro-3-




444






phenoxy




(trifluoromethyl)phenyl






3-trifluoromethyl




3-(trifluoromethoxy)phenyl




442






phenoxy






3-trifluoromethyl




9-fluorenon-4-yl




460






phenoxy






3-trifluoromethyl




isoxazol-5-yl




349






phenoxy






3-trifluoromethyl




benzofuroxan-5-yl




416






phenoxy






3-trifluoromethyl




2-chloropyrid-3-yl




394






phenoxy






3-trifluoromethyl




2-(4-




465






phenoxy




methylphenoxy)pyridin-3-yl






3-trifluoromethyl




pyridin-4-yl




359






phenoxy






3-trifluoromethyl




anthraquinon-2-yl




488






phenoxy






3-trifluoromethyl




2-iodophenyl




484






phenoxy






3-trifluoromethyl




4-pentylphenyl




428






phenoxy






3-trifluoromethyl




2-(4-chlorophenylthio)




502






phenoxy




pyridin-3-yl






3-trifluoromethyl




2,6-dimethylphenyl




386






phenoxy






3-trifluoromethyl




2,5-dimethoxyphenyl




418






phenoxy






3-trifluoromethyl




2,5-dichloropyridin-3-yl




428






phenoxy






3-trifluoromethyl




2-chloro-6-methoxypyridin-




424






phenoxy




4-yl






3-trifluoromethyl




2,3-dichloropyridin-5-yl




428






phenoxy






3-trifluoromethyl




1-naphthyl




422






phenoxy






3-trifluoromethyl




2,4-dimethoxyphenyl




418






phenoxy






3-trifluoromethyl




3,5-




494






phenoxy




bis(trifluoromethyl)phenyl






3-trifluoromethyl




2-(4-




486






phenoxy




chlorophenoxy)pyridin-3-yl






3-trifluoromethyl




pentafluorophenyl




448






phenoxy






2,6-dichlorophenoxy




3,4-dimethoxyphenyl




419






2,6-dichlorophenoxy




2-(trifluoromethyl)phenyl




427






2,6-dichlorophenoxy




2,4-difluorophenyl




395






2,6-dichlorophenoxy




3-(trifluoromethyl)phenyl




427






2,6-dichlorophenoxy




2-naphthyl




409






2,6-dichlorophenoxy




2-methoxyphenyl




389






2,6-dichlorophenoxy




3,4,5-trimethylphenyl




449






2,6-dichlorophenoxy




3,4-dichlorophenyl




428






2,6-dichlorophenoxy




3-bromophenyl




438






2,6-dichlorophenoxy




3-pyridyl




361






2,6-dichlorophenoxy




2-ethoxynaphth-1-yl




453






2,6-dichlorophenoxy




2,3-dichlorophenyl




428






2,6-dichlorophenoxy




6-chloropyrid-3-yl




395






2,6-dichlorophenoxy




4-(trifluoromethoxy)phenyl




443






2,6-dichlorophenoxy




2-fluoro-4-




445







(trifluoromethyl)phenyl






2,6-dichlorophenoxy




3-bromothienyl




444






2,6-dichlorophenoxy




2-acetoxyphenyl




417






2,6-dichlorophenoxy




5-methylisoxazol-3-yl




364






2,6-dichlorophenoxy




2-(phenylthio)pyrid-3-yl




468






2,6-dichlorophenoxy




2-(trifluoromethoxy)phenyl




443






2,6-dichlorophenoxy




1-phenyl-5-propylpyrazin-




467







4-yl






2,6-dichlorophenoxy




2-ethoxyphenyl




403






2,6-dichlorophenoxy




3-chlorothien-2-yl




400






2,6-dichlorophenoxy




1-(2-(2-methyl)propyl)-3-




419







methylpyrazol-5-yl






2,6-dichlorophenoxy




3,5-dichlorophenyl




428






2,6-dichlorophenoxy




2-(propylthio)pyridin-3-yl




434






2,6-dichlorophenoxy




2-(ethylthio)pyridin-3-yl




420






2,6-dichlorophenoxy




3-bromopyridin-5-yl




439






2,6-dichlorophenoxy




4-methyl-1,2,3-thiadiazol-




381







5-yl






2,6-dichlorophenoxy




1-methyl-3-(2-(2-




419







methyl)propyl)pyrazol-5-yl






2,6-dichlorophenoxy




3-chlorobenzo[b]thiophen-




450







2-yl






2,6-dichlorophenoxy




4-chlorophenyl




394






2,6-dichlorophenoxy




4-methyl-2-phenyl-1,2,3-




440







triazol- 5-yl






2,6-dichlorophenoxy




benzo[b]thiophen-2-yl




415






2,6-dichlorophenoxy




3,4-dimethylphenyl




387






2,6-dichlorophenoxy




2-(phenoxy)pyridin-3-yl




452






2,6-dichlorophenoxy




2-(methylthio)pyridin-3-yl




406






2,6-dichlorophenoxy




5-methyl-3-phenylisoxazol-




440







4-yl






2,6-dichlorophenoxy




4-chloro-1,3-dimethyl




463







pyrazolo[3,4-b]pyridin-3-







yl






2,6-dichlorophenoxy




2-chloro-6-methylpyridin-




409







4-yl






2,6-dichlorophenoxy




3,5-dimethylisoxazol-4-yl




378






2,6-dichlorophenoxy




1-naphthyl




409






2,6-dichlorophenoxy




2-fluorophenyl




377






2,6-dichlorophenoxy




4-propylphenyl




401






2,6-dichlorophenoxy




3-fluorophenyl




377






2,6-dichlorophenoxy




2,6-difluorophenyl




395






2,6-dichlorophenoxy




2-chlorophenyl




394






2,6-dichlorophenoxy




3-(chloromethyl)phenyl




408






2,6-dichlorophenoxy




4-(2-(2-methyl)propyl)




415







phenyl






2,6-dichlorophenoxy




3-chlorophenyl




694






2,6-dichlorophenoxy




3,5-dimethoxyphenyl




419






2,6-dichlorophenoxy




2,6-dichlorophenyl




428






2,6-dichlorophenoxy




2,4-dichlorophenyl




428






2,6-dichlorophenoxy




4-fluorophenyl




377






2,6-dichlorophenoxy




4-butylphenyl




415






2,6-dichlorophenoxy




2-methylphenyl




373






2,6-dichlorophenoxy




phenyl




359






2,6-dichlorophenoxy




4-ethylphenyl




387






2,6-dichlorophenoxy




2,3-difluorophenyl




395






2,6-dichlorophenoxy




2,6-dimethoxyphenyl




419






2,6-dichlorophenoxy




3,4-difluorophenyl




395






2,6-dichlorophenoxy




2,5-difluorophenyl




395






2,6-dichlorophenoxy




4-ethoxyphenyl




403






2,6-dichlorophenoxy




2,4,6-trichlorophenyl




463






2,6-dichlorophenoxy




3-methylphenyl




373






2,6-dichlorophenoxy




2-fluoro-5-




445







(trifluoromethyl)phenyl






2,6-dichlorophenoxy




3-methoxyphenyl




389






2,6-dichlorophenoxy




2-bromophenyl




438






2,6-dichlorophenoxy




4-bromophenyl




438






2,6-dichlorophenoxy




4-fluoro-3-




445







(trifluoromethyl)phenyl






2,6-dichlorophenoxy




3-(trifluoromethoxy)phenyl




443






2,6-dichlorophenoxy




9-fluorenon-4-yl




461






2,6-dichlorophenoxy




isoxazol-5-yl




350






2,6-dichlorophenoxy




benzofuroxan-5-yl




417






2,6-dichlorophenoxy




2-chloropyrid-3-yl




395






2,6-dichlorophenoxy




2-(4-




466







methylphenoxy)pyridin-3-yl






2,6-dichlorophenoxy




pyridin-4-yl




360






2,6-dichlorophenoxy




anthraquinon-2-yl




489






2,6-dichlorophenoxy




2-iodophenyl




485






2,6-dichlorophenoxy




4-pentylphenyl




429






2,6-dichlorophenoxy




2-(4-chlorophenylthio)




503







pyridin-3 -yl






2,6-dichlorophenoxy




2,6-dimethylphenyl




387






2,6-dichlorophenoxy




2,5-dimethoxyphenyl




419






2,6-dichlorophenoxy




2,5-dichloropyridin-3-yl




429






2,6-dichlorophenoxy




2-chloro-6-methoxypyridin-




425







4-yl






2,6-dichlorophenoxy




2,3-dichloropyridin-5-yl




429






2,6-dichlorophenoxy




1-naphthyl




413






2,6-dichlorophenoxy




2,4-dimethoxyphenyl




419






2,6-dichlorophenoxy




3,5-




495







bis(trifluoromethyl)phenyl






2,6-dichlorophenoxy




2-(4-




487







chlorophenoxy)pyridin-3-yl






2,6-dichlorophenoxy




pentafluorophenyl




449






2,4-dichlorophenoxy




3,4-dimethoxyphenyl




419






2,4-dichlorophenoxy




2-(trifluoromethyl)phenyl




427






2,4-dichlorophenoxy




2,4-difluorophenyl




395






2,4-dichlorophenoxy




3-(trifluoromethyl)phenyl




427






2,4-dichlorophenoxy




2-naphthyl




409






2,4-dichlorophenoxy




2-methoxyphenyl




389






2,4-dichlorophenoxy




3,4,5-trimethylphenyl




449






2,4-dichlorophenoxy




3,4-dichlorophenyl




428






2,4-dichlorophenoxy




3-bromophenyl




438






2,4-dichlorophenoxy




3-pyridyl




361






2,4-dichlorophenoxy




2-ethoxynaphth-1-yl




453






2,4-dichlorophenoxy




2,3-dichlorophenyl




428






2,4-dichlorophenoxy




6-chloropyrid-3-yl




395






2,4-dichlorophenoxy




4-(trifluoromethoxy)phenyl




443






2,4-dichlorophenoxy




2-fluoro-4-




445







(trifluoromethyl)phenyl






2,4-dichlorophenoxy




3-bromothienyl




444






2,4-dichlorophenoxy




2-acetoxyphenyl




417






2,4-dichlorophenoxy




5-methylisoxazol-3-yl




364






2,4-dichlorophenoxy




2-(phenylthio)pyrid-3-yl




468






2,4-dichlorophenoxy




2-(trifluoromethoxy)phenyl




443






2,4-dichlorophenoxy




1-phenyl-5-propylpyrazin-




467







4-yl






2,4-dichlorophenoxy




2-ethoxyphenyl




403






2,4-dichlorophenoxy




3-chlorothien-2-yl




400






2,4-dichlorophenoxy




1-(2-(2-methyl)propyl)-3-




419







methylpyrazol-5-yl






2,4-dichlorophenoxy




3,5-dichlorophenyl




428






2,4-dichlorophenoxy




2-(propylthio)pyridin-3-yl




434






2,4-dichlorophenoxy




2-(ethylthio)pyridin-3-yl




420






2,4-dichlorophenoxy




3-bromopyridin-5-yl




439






2,4-dichlorophenoxy




4-methyl-1,2,3-thiadiazol-




381







5-yl






2,4-dichlorophenoxy




1-methyl-3-(2-(2-




419







methyl)propyl)pyrazol-5-yl






2,4-dichlorophenoxy




3-chlorobenzo[b]thiophen-




450







2-yl






2,4-dichlorophenoxy




4-chlorophenyl




394






2,4-dichlorophenoxy




4-methyl-2-phenyl-1,2,3-




440







triazol-5-yl






2,4-dichlorophenoxy




benzo[b]thiophen-2-yl




415






2,4-dichlorophenoxy




3,4-dimethylphenyl




387






2,4-dichlorophenoxy




2-(phenoxy)pyridin-3-yl




452






2,4-dichlorophenoxy




2-(methylthio)pyridin-3-yl




406






2,4-dichlorophenoxy




5-methyl-3-phenylisoxazol-




440







4-yl






2,4-dichlorophenoxy




4-chloro-1,3-dimethyl




463







pyrazolo[3,4-b]pyridin-3-







yl






2,4-dichlorophenoxy




2-chloro-6-methylpyridin-




409







4-yl






2,4-dichlorophenoxy




3,5-dimethylisoxazol-4-yl




378






2,4-dichlorophenoxy




1-naphthyl




409






2,4-dichlorophenoxy




2-fluorophenyl




377






2,4-dichlorophenoxy




4-propylphenyl




401






2,4-dichlorophenoxy




3-fluorophenyl




377






2,4-dichlorophenoxy




2,6-difluorophenyl




395






2,4-dichlorophenoxy




2-chlorophenyl




394






2,4-dichlorophenoxy




3-(chloromethyl)phenyl




408






2,4-dichlorophenoxy




4-(2-(2-




415







methyl)propyl)phenyl






2,4-dichlorophenoxy




3-chlorophenyl




694






2,4-dichlorophenoxy




3,5-dimethoxyphenyl




419






2,4-dichlorophenoxy




2,6-dichlorophenyl




428






2,4-dichlorophenoxy




2,4-dichlorophenyl




428






2,4-dichlorophenoxy




4-fluorophenyl




377






2,4-dichlorophenoxy




4-butylphenyl




415






2,4-dichlorophenoxy




2-methylphenyl




373






2,4-dichlorophenoxy




phenyl




359






2,4-dichlorophenoxy




4-ethylphenyl




387






2,4-dichlorophenoxy




2,3-difluorophenyl




395






2,4-dichlorophenoxy




2,6-dimethoxyphenyl




419






2,4-dichlorophenoxy




3,4-difluorophenyl




395






2,4-dichlorophenoxy




2,5-difluorophenyl




395






2,4-dichlorophenoxy




4-ethoxyphenyl




403






2,4-dichlorophenoxy




2,4,6-trichlorophenyl




463






2,4-dichlorophenoxy




3-methylphenyl




373






2,4-dichlorophenoxy




2-fluoro-5-




445







(trifluoromethyl)phenyl






2,4-dichlorophenoxy




3-methoxyphenyl




389






2,4-dichlorophenoxy




2-bromophenyl




438






2,4-dichlorophenoxy




4-bromophenyl




438






2,4-dichlorophenoxy




4-fluoro-3-




445







(trifluoromethyl)phenyl






2,4-dichlorophenoxy




3-(trifluoromethoxy)phenyl




443






2,4-dichlorophenoxy




9-fluorenon-4-yl




461






2,4-dichlorophenoxy




isoxazol-5-yl




350






2,4-dichlorophenoxy




benzofuroxan-5-yl




417






2,4-dichlorophenoxy




2-chloropyrid-3-yl




395






2,4-dichlorophenoxy




2-(4-




466







methylphenoxy)pyridin-3-yl






2,4-dichlorophenoxy




pyridin-4-yl




360






2,4-dichlorophenoxy




anthraquinon-2-yl




489






2,4-dichlorophenoxy




2-iodophenyl




485






2,4-dichlorophenoxy




4-pentylphenyl




429






2,4-dichlorophenoxy




2-(4-chlorophenylthio)




503







pyridin-3-yl






2,4-dichlorophenoxy




2,6-dimethylphenyl




387






2,4-dichlorophenoxy




2,5-dimethoxyphenyl




419






2,4-dichlorophenoxy




2,5-dichloropyridin-3-yl




429






2,4-dichlorophenoxy




2-chloro-6-methoxypyridin-




425







4-yl






2,4-dichlorophenoxy




2,3-dichloropyridin-5-yl




429






2,4-dichlorophenoxy




1-naphthyl




413






2,4-dichlorophenoxy




2,4-dimethoxyphenyl




419






2,4-dichlorophenoxy




3,5-




495







bis(trifluoromethyl)phenyl






2,4-dichlorophenoxy




2-(4-




487







chlorophenoxy)pyridin-3-yl






2,4-dichlorophenoxy




pentafluorophenyl




449






4-chloro-3-




3,4-dimethoxyphenyl




319






methylphenoxy






4-chloro-3-




2-(trifluoromethyl)phenyl




407






methylphenoxy






4-chloro-3-




2,4-difluorophenyl




375






methylphenoxy






4-chloro-3-




3-(trifluoromethyl)phenyl




407






methylphenoxy






4-chloro-3-




2-naphthyl




389






methylphenoxy






4-chloro-3-




2-methoxyphenyl




369






methylphenoxy






4-chloro-3-




3,4,5-trimethylphenyl




429






methylphenoxy






4-chloro-3-




3,4-dichlorophenyl




408






methylphenoxy






4-chloro-3-




3-bromophenyl




418






methylphenoxy






4-chloro-3-




3-pyridyl




340






methylphenoxy






4-chloro-3-




2-ethoxynaphth-1-yl




433






methylphenoxy






4-chloro-3-




2,3-dichlorophenyl




408






methylphenoxy






4-chloro-3-




6-chloropyrid-3-yl




374






methylphenoxy






4-chloro-3-




4-(trifluoromethoxy)phenyl




423






methylphenoxy






4-chloro-3-




2-fluoro-4-




425






methylphenoxy




(trifluoromethyl)phenyl






4-chloro-3-




3-bromothienyl




424






methylphenoxy






4-chloro-3-




2-acetoxyphenyl




397






methylphenoxy






4-chloro-3-




5-methylisoxazol-3-yl




344






methylphenoxy






4-chloro-3-




2-(phenylthio)pyrid-3-yl




448






methylphenoxy






4-chloro-3-




2-(trifluoromethoxy)phenyl




423






methylphenoxy






4-chloro-3-




1-phenyl-5-propylpyrazin-




447






methylphenoxy




4-yl






4-chloro-3-




2-ethoxyphenyl




383






methylphenoxy






4-chloro-3-




3-chlorothien-2-yl




379






methylphenoxy






4-chloro-3-




1-(2-(2-methyl)propyl)-3-




399






methylphenoxy




methylpyrazol-5-yl






4-chloro-3-




3,5-dichlorophenyl




408






methylphenoxy






4-chloro-3-




2-(propylthio)pyridin-3-yl




414






methylphenoxy






4-chloro-3-




2-(ethylthio)pyridin-3-yl




400






methylphenoxy






4-chloro-3-




3-bromopyridin-5-yl




419






methylphenoxy






4-chloro-3-




4-methyl-1,2,3-thiadiazol-




361






methylphenoxy




5-yl






4-chloro-3-




1-methyl-3-(2-(2-




399






methylphenoxy




methyl)propyl)pyrazol-5-yl






4-chloro-3-




3-chlorobenzo[b]thiophen-




429






methylphenoxy




2-yl






4-chloro-3-




4-chlorophenyl




373






methylphenoxy






4-chloro-3-




4-methyl-2-phenyl-1,2,3-




420






methylphenoxy




triazol-5-yl






4-chloro-3-




benzo[b]thiophen-2-yl




395






methylphenoxy






4-chloro-3-




3,4-dimethylphenyl




367






methylphenoxy






4-chloro-3-




2-(phenoxy)pyridin-3-yl




432






methylphenoxy






4-chloro-3-




2-(methylthio)pyridin-3-yl




386






methylphenoxy






4-chloro-3-




5-methyl-3-phenylisoxazol-




420






methylphenoxy




4-yl






4-chloro-3-




4-chloro-1,3-dimethyl




442






methylphenoxy




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-3-




2-chloro-6-methylpyridin-




388






methylphenoxy




4-yl






4-chloro-3-




3,5-dimethylisoxazol-4-yl




358






methylphenoxy






4-chloro-3-




1-naphthyl




389






methylphenoxy






4-chloro-3-




2-fluorophenyl




357






methylphenoxy






4-chloro-3-




4-propylphenyl




381






methylphenoxy






4-chloro-3-




4-(trifluoromethyl)phenyl




407






methylphenoxy






4-chloro-3-




3-fluorophenyl




357






methylphenoxy






4-chloro-3-




2,6-difluorophenyl




375






methylphenoxy






4-chloro-3-




2-chlorophenyl




373






methylphenoxy






4-chloro-3-




3-(chloromethyl)phenyl




387






methylphenoxy






4-chloro-3-




4-(2-(2-




395






methylphenoxy




methyl)propyl)phenyl






4-chloro-3-




3-chlorophenyl




373






methylphenoxy






4-chloro-3-




3,5-dimethoxyphenyl




399






methylphenoxy






4-chloro-3-




2,6-dichlorophenyl




408






methylphenoxy






4-chloro-3-




2,4-dichlorophenyl




408






methylphenoxy






4-chloro-3-




4-fluorophenyl




357






methylphenoxy






4-chloro-3-




4-butylphenyl




395






methylphenoxy






4-chloro-3-




2-methylphenyl




353






methylphenoxy






4-chloro-3-




phenyl




339






methylphenoxy






4-chloro-3-




4-ethylphenyl




367






methylphenoxy






4-chloro-3-




2,3-difluorophenyl




375






methylphenoxy






4-chloro-3-




2,6-dimethoxyphenyl




399






methylphenoxy






4-chloro-3-




3,4-difluorophenyl




375






methylphenoxy






4-chloro-3-




2,5-difluorophenyl




375






methylphenoxy






4-chloro-3-




4-ethoxyphenyl




383






methylphenoxy






4-chloro-3-




2,4,6-trichlorophenyl




442






methylphenoxy






4-chloro-3-




3-methylphenyl




353






methylphenoxy






4-chloro-3-




2-fluoro-5-




425






methylphenoxy




(trifluoromethyl)phenyl






4-chloro-3-




3-methoxyphenyl




369






methylphenoxy






4-chloro-3-




2-bromophenyl




418






methylphenoxy






4-chloro-3-




4-bromophenyl




418






methylphenoxy






4-chloro-3-




4-fluoro-3-




425






methylphenoxy




(trifluoromethyl)phenyl






4-chloro-3-




3-(trifluoromethoxy)phenyl




423






methylphenoxy






4-chloro-3-




9-fluorenon-4-yl




441






methylphenoxy






4-chloro-3-




isoxazol-5-yl




330






methylphenoxy






4-chloro-3-




benzofuroxan-5-yl




397






methylphenoxy






4-chloro-3-




2-chloropyrid-3-yl




374






methylphenoxy






4-chloro-3-




2-(4-




446






methylphenoxy




methylphenoxy)pyridin-3-yl






4-chloro-3-




pyridin-4-yl




340






methylphenoxy






4-chloro-3-




anthraquinon-2-yl




469






methylphenoxy






4-chloro-3-




2-iodophenyl




465






methylphenoxy






4-chloro-3-




4-pentylphenyl




409






methylphenoxy






4-chloro-3-




2-(4-chlorophenylthio)




482






methylphenoxy




pyridin-3-yl






4-chloro-3-




2,6-dimethylphenyl




367






methylphenoxy






4-chloro-3-




2,5-dimethoxyphenyl




399






methylphenoxy






4-chloro-3-




2,5-dichloropyridin-3-yl




409






methylphenoxy






4-chloro-3-




2-chloro-6-methoxypyridin




404






methylphenoxy




4-yl






4-chloro-3-




2,3-dichloropyridin-5-yl




409






methylphenoxy






4-chloro-3-




1-naphthyl




403






methylphenoxy






4-chloro-3-




2,4-dimethoxyphenyl




399






methylphenoxy






4-chloro-3-




3,5-




475






methylphenoxy




bis(trifluoromethyl)phenyl






4-chloro-3-




2-(4-




466






methylphenoxy




chlorophenoxy)pyridin-3-yl






4-chloro-3-




pentafluorophenyl




429






methylphenoxy






4-chloro-2-




3,4-dimethoxyphenyl




467






cyclohexylphenoxy






4-chloro-2-




2-(trifluoromethyl)phenyl




475






cyclohexylphenoxy






4-chloro-2-




2,4-difluorophenyl




443






cyclohexylphenoxy






4-chloro-2-




3-(trifluoromethyl)phenyl




475






cyclohexylphenoxy






4-chloro-2-




2-naphthyl




457






cyclohexylphenoxy






4-chloro-2-




2-methoxyphenyl




437






cyclohexylphenoxy






4-chloro-2-




3,4,5-trimethylphenyl




497






cyclohexylphenoxy






4-chloro-2-




3,4-dichlorophenyl




176






cyclohexylphenoxy






4-chloro-2-




3-bromophenyl




486






cyclohexylphenoxy






4-chloro-2-




3-pyridyl




408






cyclohexylphenoxy






4-chloro-2-




2-ethoxynaphth-1-yl




501






cyclohexylphenoxy






4-chloro-2-




2,3-dichlorophenyl




476






cyclohexylphenoxy






4-chloro-2-




6-chloropyrid-3-yl




442






cyclohexylphenoxy






4-chloro-2-




4-(trifluoromethoxy)phenyl




491






cyclohexylphenoxy






4-chloro-2-




2-fluoro-4-




493






cyclohexylphenoxy




(trifluoromethyl)phenyl






4-chloro-2-




3-bromothienyl




492






cyclohexylphenoxy






4-chloro-2-




2-acetoxyphenyl




465






cyclohexylphenoxy






4-chloro-2-




5-methylisoxazol-3-yl




412






cyclohexylphenoxy






4-chloro-2-




2-(phenylthio)pyrid-3-yl




516






cyclohexylphenoxy






4-chloro-2-




2-(trifluoromethoxy)phenyl




491






cyclohexylphenoxy






4-chloro-2-




1-phenyl-5-propylpyrazin-




515






cyclohexylphenoxy




4-yl






4-chloro-2-




2-ethoxyphenyl




451






cyclohexylphenoxy






4-chloro-2-




3-chlorothien-2-yl




447






cyclohexylphenoxy






4-chloro-2-




1-(2-(2-methyl)propyl)-3-




467






cyclohexylphenoxy




methylpyrazol-5-yl






4-chloro-2-




3,5-dichlorophenyl




476






cyclohexylphenoxy






4-chloro-2-




2-(propylthio)pyridin-3-yl




482






cyclohexylphenoxy






4-chloro-2-




2-(ethylthio)pyridin-3-yl




468






cyclohexylphenoxy






4-chloro-2-




3-bromopyridin-5-yl




487






cyclohexylphenoxy






4-chloro-2-




4-methyl-1,2,3-thiadiazol-




429






cyclohexylphenoxy




5-yl






4-chloro-2-




1-methyl-3-(2-(2-




467






cyclohexylphenoxy




methyl)propyl)pyrazol-5-yl






4-chloro-2-




3-chlorobenzo[b]thiophen-




497






cyclohexylphenoxy




2-yl






4-chloro-2-




4-chlorophenyl




441






cyclohexylphenoxy






4-chloro-2-




4-methyl-2-phenyl-1,2,3-




488






cyclohexylphenoxy




triazol-5-yl






4-chloro-2-




benzo[b]thiophen-2-yl




463






cyclohexylphenoxy






4-chloro-2-




3,4-dimethylphenyl




435






cyclohexylphenoxy






4-chloro-2-




2-(phenoxy)pyridin-3-yl




500






cyclohexylphenoxy






4-chloro-2-




2-(methylthio)pyridin-3-yl




454






cyclohexylphenoxy






4-chloro-2-




5-methyl-3-phenylisoxazol-




488






cyclohexylphenoxy




4-yl






4-chloro-2-




4-chloro-1,3-dimethyl




510






cyclohexylphenoxy




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-2-




2-chloro-6-methylpyridin-




456






cyclohexylphenoxy




4-yl






4-chloro-2-




3,5-dimethylisoxazol-4-yl




426






cyclohexylphenoxy






4-chloro-2-




1-naphthyl




457






cyclohexylphenoxy






4-chloro-2-




2-fluorophenyl




425






cyclohexylphenoxy






4-chloro-2-




4-propylphenyl




449






cyclohexylphenoxy






4-chloro-2-




3-fluorophenyl




425






cyclohexylphenoxy






4-chloro-2-




2,6-difluorophenyl




443






cyclohexylphenoxy






4-chloro-2-




2-chlorophenyl




441






cyclohexylphenoxy






4-chloro-2-




3-(chloromethyl)phenyl




455






cyclohexylphenoxy






4-chloro-2-




4-(2-(2-




463






cyclohexylphenoxy




methyl)propyl)phenyl






4-chloro-2-




3-chlorophenyl




441






cyclohexylphenoxy






4-chloro-2-




3,5-dimethoxyphenyl




467






cyclohexylphenoxy






4-chloro-2-




2,6-dichlorophenyl




476






cyclohexylphenoxy






4-chloro-2-




2,4-dichlorophenyl




476






cyclohexylphenoxy






4-chloro-2-




4-fluorophenyl




425






cyclohexylphenoxy






4-chloro-2-




4-butylphenyl




463






cyclohexylphenoxy






4-chloro-2-




2-methylphenyl




421






cyclohexylphenoxy






4-chloro-2-




phenyl




407






cyclohexylphenoxy






4-chloro-2-




4-ethylphenyl




435






cyclohexylphenoxy






4-chloro-2-




2,3-difluorophenyl




443






cyclohexylphenoxy






4-chloro-2-




2,6-dimethoxyphenyl




467






cyclohexylphenoxy






4-chloro-2-




3,4-difluorophenyl




443






cyclohexylphenoxy






4-chloro-2-




2,5-difluorophenyl




443






cyclohexylphenoxy






4-chloro-2-




4-ethoxyphenyl




451






cyclohexylphenoxy






4-chloro-2-




2,4,6-trichlorophenyl




510






cyclohexylphenoxy






4-chloro-2-




3-methylphenyl




421






cyclohexylphenoxy






4-chloro-2-




2-fluoro-5-




493






cyclohexylphenoxy




(trifluoromethyl)phenyl






4-chloro-2-




3-methoxyphenyl




437






cyclohexylphenoxy






4-chloro-2-




2-bromophenyl




486






cyclohexylphenoxy






4-chloro-2-




4-bromophenyl




486






cyclohexylphenoxy






4-chloro-2-




4-fluoro-3-




493






cyclohexylphenoxy




(trifluoromethyl)phenyl






4-chloro-2-




3-(trifluoromethoxy)phenyl




491






cyclohexylphenoxy






4-chloro-2-




9-fluorenon-4-yl




503






cyclohexylphenoxy






4-chloro-2-




isoxazol-5-yl




398






cyclohexylphenoxy






4-chloro-2-




benzofuroxan-5-yl




465






cyclohexylphenoxy






4-chloro-2-




2-chloropyrid-3-yl




442






cyclohexylphenoxy






4-chloro-2-




2-(4-




514






cyclohexylphenoxy




methylphenoxy)pyridin-3-yl






4-chloro-2-




pyridin-4-yl




408






cyclohexylphenoxy






4-chloro-2-




anthraquinon-2-yl




537






cyclohexylphenoxy






4-chloro-2-




2-iodophenyl




533






cyclohexylphenoxy






4-chloro-2-




4-pentylphenyl




477






cyclohexylphenoxy






4-chloro-2-




2-(4-chlorophenylthio)




550






cyclohexylphenoxy




pyridin-3-yl






4-chloro-2-




2,6-dimethylphenyl




435






cyclohexylphenoxy






4-chloro-2-




2,5-dimethoxyphenyl




467






cyclohexylphenoxy






4-chloro-2-




2,5-dichloropyridin-3-yl




477






cyclohexylphenoxy






4-chloro-2-




2-chloro-6-methoxypyridin-




472






cyclohexylphenoxy




4-yl






4-chloro-2-




2,3-dichloropyridin-5-yl




477






cyclohexylphenoxy






4-chloro-2-




1-naphthyl




471






cyclohexylphenoxy






4-chloro-2-




2,4-dimethoxyphenyl




467






cyclohexylphenoxy






4-chloro-2-




3,5-




546






cyclohexylphenoxy




bis(trifluoromethyl)phenyl






4-chloro-2-




2-(4-




534






cyclohexylphenoxy




chlorophenoxy)pyridin-3-yl






4-chloro-2-




pentafluorophenyl




497






cyclohexylphenoxy






4-chloro-3,5-




3,4-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-3,5-




2-(trifluoromethyl)phenyl




421






dimethylphenoxy






4-chloro-3,5-




2,4-difluorophenyl




389






dimethylphenoxy






4-chloro-3,5-




3-(trifluoromethyl)phenyl




421






dimethylphenoxy






4-chloro-3,5-




2-naphthyl




403






dimethylphenoxy






4-chloro-3,5-




2-methoxyphenyl




484






dimethylphenoxy






4-chloro-3,5-




3,4,5-trimethylphenyl




443






dimethylphenoxy






4-chloro-3,5-




3,4-dichlorophenyl




422






dimethylphenoxy






4-chloro-3,5-




3-bromophenyl




432






dimethylphenoxy






4-chloro-3,5-




3-pyridyl




354






dimethylphenoxy






4-chloro-3,5-




2-ethoxynaphth-1-yl




447






dimethylphenoxy






4-chloro-3,5-




2,3-dichlorophenyl




422






dimethylphenoxy






4-chloro-3,5-




6-chloropyrid-3-yl




388






dimethylphenoxy






4-chloro-3,5-




4-(trifluoromethoxy)phenyl




437






dimethylphenoxy






4-chloro-3,5-




2-fluoro-4-




439






dimethylphenoxy




(trifluoromethyl)phenyl






4-chloro-3,5-




3-bromothienyl




438






dimethylphenoxy






4-chloro-3,5-




2-acetoxyphenyl




411






dimethylphenoxy






4-chloro-3,5-




5-methylisoxazol-3-yl




358






dimethylphenoxy






4-chloro-3,5-




2-(phenylthio)pyrid-3-yl




462






dimethylphenoxy






4-chloro-3,5-




2-(trifluoromethoxy)phenyl




437






dimethylphenoxy






4-chloro-3,5-




1-phenyl-5-propylpyrazin-




461






dimethylphenoxy




4-yl






4-chloro-3,5-




2-ethoxyphenyl




397






dimethylphenoxy






4-chloro-3,5-




3-chlorothien-2-yl




393






dimethylphenoxy






4-chloro-3,5-




1-(2-(2-methyl)propyl)-3-




413






dimethylphenoxy




methylpyrazol-5-yl






4-chloro-3,5-




3,5-dichlorophenyl




422






dimethylphenoxy






4-chloro-3,5-




2-(propylthio)pyridin-3-yl




428






dimethylphenoxy






4-chloro-3,5-




2-(ethylthio)pyridin-3-yl




414






dimethylphenoxy






4-chloro-3,5-




3-bromopyridin-5-yl




433






dimethylphenoxy






4-chloro-3,5-




4-methyl-1,2,3-thiadiazol-




375






dimethylphenoxy




5-yl






4-chloro-3,5-




1-methyl-3-(2-(2-




413






dimethylphenoxy




methyl)propyl)pyrazol-5-yl






4-chloro-3,5-




3-chlorobenzo[b]thiophen-




443






dimethylphenoxy




2-yl






4-chloro-3,5-




4-chlorophenyl




387






dimethylphenoxy






4-chloro-3,5-




4-methyl-2-phenyl-1,2,3-




434






dimethylphenoxy




triazol-5-yl






4-chloro-3,5-




benzo[b]thiophen-2-yl




409






dimethylphenoxy






4-chloro-3,5-




3,4-dimethylphenyl




381






dimethylphenoxy






4-chloro-3,5-




2-(phenoxy)pyridin-3-yl




446






dimethylphenoxy






4-chloro-3,5-




2-(methylthio)pyridin-3-yl




400






dimethylphenoxy






4-chloro-3,5-




5-methyl-3-phenylisoxazol-




434






dimethylphenoxy




4-yl






4-chloro-3,5-




4-chloro-1,3-dimethyl




456






dimethylphenoxy




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-3,5-




2-chloro-6-methylpyridin-




402






dimethylphenoxy




4-yl






4-chloro-3,5-




3,5-dimethylisoxazol-4-yl




372






dimethylphenoxy






4-chloro-3,5-




1-naphthyl




403






dimethylphenoxy






4-chloro-3,5-




2-fluorophenyl




371






dimethylphenoxy






4-chloro-3,5-




4-propylphenyl




395






dimethylphenoxy






4-chloro-3,5-




3-fluorophenyl




371






dimethylphenoxy






4-chloro-3,5-




2,6-difluorophenyl




389






dimethylphenoxy






4-chloro-3,5-




2-chlorophenyl




387






dimethylphenoxy






4-chloro-3,5-




3-(chloromethyl)phenyl




401






dimethylphenoxy






4-chloro-3,5-




4-(2-(2-




409






dimethylphenoxy




methyl)propyl)phenyl






4-chloro-3,5-




3-chlorophenyl




387






dimethylphenoxy






4-chloro-3,5-




3,5-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-3,5-




2,6-dichlorophenyl




422






dimethylphenoxy






4-chloro-3,5-




2,4-dichlorophenyl




422






dimethylphenoxy






4-chloro-3,5-




4-fluorophenyl




371






dimethylphenoxy






4-chloro-3,5-




4-butylphenyl




409






dimethylphenoxy






4-chloro-3,5-




2-methylphenyl




367






dimethylphenoxy






4-chloro-3,5-




phenyl




353






dimethylphenoxy






4-chloro-3,5-




4-ethylphenyl




381






dimethylphenoxy






4-chloro-3,5-




2,3-difluorophenyl




389






dimethylphenoxy






4-chloro-3,5-




2,6-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-3,5-




3,4-difluorophenyl




389






dimethylphenoxy






4-chloro-3,5-




2,5-difluorophenyl




389






dimethylphenoxy






4-chloro-3,5-




4-ethoxyphenyl




397






dimethylphenoxy






4-chloro-3,5-




2,4,6-trichlorophenyl




456






dimethylphenoxy






4-chloro-3,5-




3-methylphenyl




367






dimethylphenoxy






4-chloro-3,5-




2-fluoro-5-




439






dimethylphenoxy




(trifluoromethyl)phenyl






4-chloro-3,5-




3-methoxyphenyl




383






dimethylphenoxy






4-chloro-3,5-




2-bromophenyl




432






dimethylphenoxy






4-chloro-3,5-




4-bromophenyl




432






dimethylphenoxy






4-chloro-3,5-




4-fluoro-3-




439






dimethylphenoxy




(trifluoromethyl)phenyl






4-chloro-3,5-




3-(trifluoromethoxy)phenyl




437






dimethylphenoxy






4-chloro-3,5-




9-fluorenon-4-yl




455






dimethylphenoxy






4-chloro-3,5-




isoxazol-5-yl




344






dimethylphenoxy






4-chloro-3,5-




benzofuroxan-5-yl




411






dimethylphenoxy






4-chloro-3,5-




2-chloropyrid-3-yl




388






dimethylphenoxy






4-chloro-3,5-




2-(4-




460






dimethylphenoxy




methylphenoxy)pyridin-3-yl






4-chloro-3,5-




pyridin-4-yl




354






dimethylphenoxy






4-chloro-3,5-




anthraquinon-2-yl




483






dimethylphenoxy






4-chloro-3,5-




2-iodophenyl




479






dimethylphenoxy






4-chloro-3,5-




4-pentylphenyl




423






dimethylphenoxy






4-chloro-3,5-




2-(4-chlorophenylthio)




496






dimethylphenoxy




pyridin-3-yl






4-chloro-3,5-




2,6-dimethylphenyl




381






dimethylphenoxy






4-chloro-3,5-




2,5-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-3,5-




2,5-dichloropyridin-3-yl




423






dimethylphenoxy






4-chloro-3,5-




2-chloro-6-methoxypyridin-




418






dimethylphenoxy




4-yl






4-chloro-3,5-




2,3-dichloropyridin-5-yl




423






dimethylphenoxy






4-chloro-3,5-




1-naphthyl




417






dimethylphenoxy






4-chloro-3,5-




2,4-dimethoxyphenyl




413






dimethylphenoxy






4-chloro-3,5-




3,5-




489






dimethylphenoxy




bis(trifluoromethyl)phenyl






4-chloro-3,5-




2-(4-




480






dimethylphenoxy




chlorophenoxy)pyridin-3-yl






4-chloro-3,5-




pentafluorophenyl




443






dimethylphenoxy






pyrid-3-yloxy




3,4-dimethoxyphenyl




351






pyrid-3-yloxy




2-(trifluoromethyl)phenyl




359






pyrid-3-yloxy




2,4-difluorophenyl




327






pyrid-3-yloxy




3-(trifluoromethyl)phenyl




359






pyrid-3-yloxy




2-naphthyl




341






pyrid-3-yloxy




2-methoxyphenyl




321






pyrid-3-yloxy




3,4,5-trimethylphenyl




381






pyrid-3-yloxy




3,4-dichlorophenyl




360






pyrid-3-yloxy




3-bromophenyl




370






pyrid-3-yloxy




3-pyridyl




292






pyrid-3-yloxy




2-ethoxynaphth-1-yl




385






pyrid-3-yloxy




2,3-dichlorophenyl




360






pyrid-3-yloxy




6-chloropyrid-3-yl




327






pyrid-3-yloxy




4-(trifluoromethoxy)phenyl




375






pyrid-3-yloxy




2-fluoro-4-




377







(trifluoromethyl)phenyl






pyrid-3-yloxy




3-bromothienyl




376






pyrid-3-yloxy




2-acetoxyphenyl




349






pyrid-3-yloxy




5-methylisoxazol-3-yl




296






pyrid-3-yloxy




2-(phenylthio)pyrid-3-yl




400






pyrid-3-yloxy




2-(trifluoromethoxy)phenyl




375






pyrid-3-yloxy




1-phenyl-5-propylpyrazin




399







4-yl






pyrid-3-yloxy




2-ethoxyphenyl




335






pyrid-3-yloxy




3-chlorothien-2-yl




332






pyrid-3-yloxy




1-(2-(2-methyl)propyl)-3




351







methylpyrazol-5-yl






pyrid-3-yloxy




3,5-dichlorophenyl




360






pyrid-3-yloxy




2-(propylthio)pyridin-3-yl




366






pyrid-3-yloxy




2-(ethylthio)pyridin-3-yl




352






pyrid-3-yloxy




3-bromopyridin-5-yl




371






pyrid-3-yloxy




4-methyl-1,2,3-thiadiazol-




313







5-yl






pyrid-3-yloxy




1-methyl-3-(2-(2-




351







methyl)propyl)pyrazol-5-yl






pyrid-3-yloxy




3-chlorobenzo[b]thiophen-




382







2-yl






pyrid-3-yloxy




4-chlorophenyl




326






pyrid-3-yloxy




4-methyl-2-phenyl-1,2,3-




372







triazol-5-yl






pyrid-3-yloxy




benzo[b]thiophen-2-yl




347






pyrid-3-yloxy




3,4-dimethylphenyl




319






pyrid-3-yloxy




2-(phenoxy)pyridin-3-yl




384






pyrid-3-yloxy




2-(methylthio)pyridin-3-yl




338






pyrid-3-yloxy




5-methyl-3-phenylisoxazol-




372







4-yl






pyrid-3-yloxy




4-chloro-1,3-dimethyl




395







pyrazolo[3,4-b]pyridin-3-







yl






pyrid-3-yloxy




2-chloro-6-methylpyridin-




341







4-yl






pyrid-3-yloxy




3,5-dimethylisoxazol-4-yl




310






pyrid-3-yloxy




1-naphthyl




341






pyrid-3-yloxy




2-fluorophenyl




309






pyrid-3-yloxy




4-propylphenyl




333






pyrid-3-yloxy




3-fluorophenyl




309






pyrid-3-yloxy




2,6-difluorophenyl




327






pyrid-3-yloxy




2-chlorophenyl




326






pyrid-3-yloxy




3-(chloromethyl)phenyl




340






pyrid-3-yloxy




4-(2-(2-




347







methyl)propyl)phenyl






pyrid-3-yloxy




3-chlorophenyl




326






pyrid-3-yloxy




3,5-dimethoxyphenyl




351






pyrid-3-yloxy




2,6-dichlorophenyl




360






pyrid-3-yloxy




2,4-dichlorophenyl




360






pyrid-3-yloxy




4-fluorophenyl




309






pyrid-3-yloxy




4-butylphenyl




347






pyrid-3-yloxy




2-methylphenyl




305






pyrid-3-yloxy




phenyl




291






pyrid-3-yloxy




4-ethylphenyl




319






pyrid-3-yloxy




2,3-difluorophenyl




327






pyrid-3-yloxy




2,6-dimethoxyphenyl




351






pyrid-3-yloxy




3,4-difluorophenyl




327






pyrid-3-yloxy




2,5-difluorophenyl




327






pyrid-3-yloxy




4-ethoxyphenyl




335






pyrid-3-yloxy




2,4,6-trichlorophenyl




395






pyrid-3-yloxy




3-methylphenyl




305






pyrid-3-yloxy




2-fluoro-5-




377







(trifluoromethyl)phenyl






pyrid-3-yloxy




3-methoxyphenyl




321






pyrid-3-yloxy




2-bromophenyl




370






pyrid-3-yloxy




4-bromophenyl




370






pyrid-3-yloxy




4-fluoro-3-




377







(trifluoromethyl)phenyl






pyrid-3-yloxy




3-(trifluoromethoxy)phenyl




375






pyrid-3-yloxy




9-fluorenon-4-yl




393






pyrid-3-yloxy




isoxazol-5-yl




282






pyrid-3-yloxy




benzofuroxan-5-yl




349






pyrid-3-yloxy




2-chloropyrid-3-yl




327






pyrid-3-yloxy




2-(4-




398







methylphenoxy)pyridin-3-yl






pyrid-3-yloxy




pyridin-4-yl




292






pyrid-3-yloxy




anthraquinon-2-yl




421






pyrid-3-yloxy




2-iodophenyl




417






pyrid-3-yloxy




4-pentylphenyl




361






pyrid-3-yloxy




2-(4-chlorophenylthio)




435







pyridin-3-yl






pyrid-3-yloxy




2,6-dimethylphenyl




319






pyrid-3-yloxy




2,5-dimethoxyphenyl




354






pyrid-3-yloxy




2,5-dichloropyridin-3-yl




361






pyrid-3-yloxy




2-chloro-6-methoxypyridin-




357







4-yl






pyrid-3-yloxy




2,3-dichloropyridin-5-yl




361






pyrid-3-yloxy




1-naphthyl




355






pyrid-3-yloxy




2,4-dimethoxyphenyl




351






pyrid-3-yloxy




3,5-




427







bis(trifluoromethyl)phenyl






pyrid-3-yloxy




2-(4-




419







chlorophenoxy)pyridin-3-yl






pyrid-3-yloxy




pentafluorophenyl




381






4-bromophenoxy




3,4-dimethoxyphenyl




429






4-bromophenoxy




2-(trifluoromethyl)phenyl




437






4-bromophenoxy




2,4-difluorophenyl




405






4-bromophenoxy




3-(trifluoromethyl)phenyl




437






4-bromophenoxy




2-naphthyl




419






4-bromophenoxy




2-methoxyphenyl




399






4-bromophenoxy




3,4,5-trimethylphenyl




459






4-bromophenoxy




3,4-dichlorophenyl




438






4-bromophenoxy




3-bromophenyl




448






4-bromophenoxy




3-pyridyl




370






4-bromophenoxy




2-ethoxynaphth-1-yl




463






4-bromophenoxy




2,3-dichlorophenyl




438






4-bromophenoxy




6-chloropyrid-3-yl




405






4-bromophenoxy




4-(trifluoromethoxy)phenyl




453






4-bromophenoxy




2-fluoro-4-




455







(trifluoromethyl)phenyl






4-bromophenoxy




3-bromothienyl




454






4-bromophenoxy




2-acetoxyphenyl




427






4-bromophenoxy




5-methylisoxazol-3-yl




374






4-bromophenoxy




2-(phenylthio)pyrid-3-yl




478






4-bromophenoxy




2-(trifluoromethoxy)phenyl




453






4-bromophenoxy




1-phenyl-5-propylpyrazin-




477







4-yl






4-bromophenoxy




2-ethoxyphenyl




413






4-bromophenoxy




3-chlorothien-2-yl




410






4-bromophenoxy




1-(2-(2-methyl)propyl)-3-




429







methylpyrazol-5-yl






4-bromophenoxy




3,5-dichlorophenyl




438






4-bromophenoxy




2-(propylthio)pyridin-3-yl




444






4-bromophenoxy




2-(ethylthio)pyridin-3-yl




430






4-bromophenoxy




3-bromopyridin-5-yl




449






4-bromophenoxy




4-methyl-1,2,3-thiadiazol-




391







5-yl






4-bromophenoxy




1-methyl-3-(2-(2-




429







methyl)propyl)pyrazol-5-yl






4-bromophenoxy




3-chlorobenzo[b]thiophen-




460







2-yl






4-bromophenoxy




4-chlorophenyl




404






4-bromophenoxy




4-methyl-2-phenyl-1,2,3-




450







triazol-5-yl






4-bromophenoxy




benzo[b]thiophen-2-yl




425






4-bromophenoxy




3,4-dimethylphenyl




397






4-bromophenoxy




2-(phenoxy)pyridin-3-yl




462






4-bromophenoxy




2-(methylthio)pyridin-3-yl




416






4-bromophenoxy




5-methyl-3-phenylisoxazol-




450







4-yl






4-bromophenoxy




4-chloro-1,3-dimethyl




473







pyrazolo[3,4-b]pyridin-3-







yl






4-bromophenoxy




2-chloro-6-methylpyridin-




419







4-yl






4-bromophenoxy




3,5-dimethylisoxazol-4-yl




388






4-bromophenoxy




1-naphthyl




419






4-bromophenoxy




2-fluorophenyl




387






4-bromophenoxy




4-propylphenyl




411






4-bromophenoxy




3-fluorophenyl




387






4-bromophenoxy




2,6-difluorophenyl




405






4-bromophenoxy




2-chlorophenyl




414






4-bromophenoxy




3-(chloromethyl)phenyl




418






4-bromophenoxy




4-(2-(2-




425







methyl)propyl)phenyl






4-bromophenoxy




3-chlorophenyl




404






4-bromophenoxy




3,5-dimethoxyphenyl




429






4-bromophenoxy




2,6-dichlorophenyl




438






4-bromophenoxy




2,4-dichlorophenyl




438






4-bromophenoxy




4-fluorophenyl




387






4-bromophenoxy




4-butylphenyl




425






4-bromophenoxy




2-methylphenyl




383






4-bromophenoxy




phenyl




369






4-bromophenoxy




4-ethylphenyl




397






4-bromophenoxy




2,3-difluorophenyl




405






4-bromophenoxy




2,6-dimethoxyphenyl




429






4-bromophenoxy




3,4-difluorophenyl




405






4-bromophenoxy




2,5-difluorophenyl




405






4-bromophenoxy




4-ethoxyphenyl




413






4-bromophenoxy




2,4,6-trichlorophenyl




473






4-bromophenoxy




3-methylphenyl




383






4-bromophenoxy




2-fluoro-5




455







(trifluoromethyl)phenyl






4-bromophenoxy




3-methoxyphenyl




399






4-bromophenoxy




2-bromophenyl




448






4-bromophenoxy




4-bromophenyl




448






4-bromophenoxy




4-fluoro-3-




455







(trifluoromethyl)phenyl






4-bromophenoxy




3-(trifluoromethoxy)phenyl




453






4-bromophenoxy




9-fluorenon-4-yl




471






4-bromophenoxy




isoxazol-5-yl




360






4-bromophenoxy




benzofuroxan-5-yl




427






4-bromophenoxy




2-chloropyrid-3-yl




360






4-bromophenoxy




2-(4-




476







methylphenoxy)pyridin-3-yl






4-bromophenoxy




pyridin-4-yl




370






4-bromophenoxy




anthraquinon-2-yl




499






4-bromophenoxy




2-iodophenyl




495






4-bromophenoxy




4-pentylphenyl




439






4-bromophenoxy




2-(4-




513







chlorophenylthio)pyridin-







3-yl






4-bromophenoxy




2,6-dimethylphenyl




397






4-bromophenoxy




2,5-dimethoxyphenyl




429






4-bromophenoxy




2,5-dichloropyridin-3-yl




439






4-bromophenoxy




2-chloro-6-methoxypyridin-




435







4-yl






4-bromophenoxy




2,3-dichloropyridin-5-yl




439






4-bromophenoxy




1-naphthyl




433






4-bromophenoxy




2,4-dimethoxyphenyl




429






4-bromophenoxy




3,5-




505







bis(trifluoromethyl)phenyl






4-bromophenoxy




2-(4-




497







chlorophenoxy)pyridin-3-yl






4-bromophenoxy




pentafluorophenyl




459






4-chloro-2-




4-biphenyl




431






methylphenylthio






4-chloro-2-




3,4-dimethoxyphenyl




415






methylphenylthio






4-chloro-2-




2-(trifluoromethyl)phenyl




423






methylphenylthio






4-chloro-2-




2,4-difluorophenyl




391






methylphenylthio






4-chloro-2-




4-cyanophenyl




380






methylphenylthio






4-chloro-2-




3-(trifluoromethyl)phenyl




423






methylphenylthio






4-chloro-2-




3-cyanophenyl




380






methylphenylthio






4-chloro-2-




2-naphthyl




405






methylphenylthio






4-chloro-2-




2-methoxyphenyl




385






methylphenylthio






4-chloro-2-




3,4,5-trimethylphenyl




445






methylphenylthio






4-chloro-2-




4-nitrophenyl




400






methylphenylthio






4-chloro-2-




3,4-dichlorophenyl




424






methylphenylthio






4-chloro-2-




5-nitrofuran-2-yl




390






methylphenylthio






4-chloro-2-




3-bromophenyl




434






methylphenylthio






4-chloro-2-




3-pyridyl




356






methylphenylthio






4-chloro-2-




2-ethoxynaphth-1-yl




449






methylphenylthio






4-chloro-2-




2,3-dichlorophenyl




424






methylphenylthio






4-chloro-2-




3-nitrophenyl




400






methylphenylthio






4-chloro-2-




6-chloropyrid-3-yl




390






methylphenylthio






4-chloro-2-




4-(trifluoromethoxy)phenyl




439






methylphenylthio






4-chloro-2-




2-fluoro-4-




441






methylphenylthio




(trifluoromethyl)phenyl






4-chloro-2-




3-bromothienyl




440






methylphenylthio






4-chloro-2-




2-acetoxyphenyl




413






methylphenylthio






4-chloro-2-




5-methylisoxazol-3-yl




360






methylphenylthio






4-chloro-2-




2-(phenylthio)pyrid-3-yl




464






methylphenylthio






4-chloro-2-




2-(trifluoromethoxy)phenyl




439






methylphenylthio






4-chloro-2-




1-phenyl-5-propylpyrazin-




463






methylphenylthio




4-yl






4-chloro-2-




2-ethoxyphenyl




399






methylphenylthio






4-chloro-2-




3-chlorothien-2-yl




395






methylphenylthio






4-chloro-2-




1-(2-(2-methyl)propyl)-3-




415






methylphenylthio




methylpyrazol-5-yl






4-chloro-2-




3-5-dichlorophenyl




424






methylphenylthio






4-chloro-2-




2-(propylthio)pyridin-3-yl




430






methylphenylthio






4-chloro-2-




2-(ethylthio)pyridin-3-yl




416






methylphenylthio






4-chloro-2-




3-bromopyridin-5-yl




435






methylphenylthio






4-chloro-2-




4-methyl-1,2,3-thiadiazol-




377






methylphenylthio




5-yl






4-chloro-2-




1-methyl-3-(2-(2-




415






methylphenylthio




methyl)propyl)pyrazol-5-yl






4-chloro-2




3-chlorobenzo[b]thiophen-




445






methylphenylthio




2-yl






4-chloro-2-




4-chlorophenyl




389






methylphenylthio






4-chloro-2-




4-methyl-2-phenyl-1,2,3-




436






methylphenylthio




triazol-5-yl






4-chloro-2-




benzo[b]thiophen-2-yl




411






methylphenylthio






4-chloro-2-




3,4-dimethylphenyl




383






methylphenylthio






4-chloro-2-




2-(phenoxy)pyridin-3-yl




448






methylphenylthio






4-chloro-2-




2-(methylthio)pyridin-3-yl




402






methylphenylthio






4-chloro-2-




5-methyl-3-phenylisoxazoi-




436






methylphenylthio




4-yl






4-chloro-2-




4-chloro-1,3-dimethyl




458






methylphenylthio




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-2-




2-chloro-6-methylpyridin-




404






methylphenylthio




4-yl






4-chloro-2-




3,5-dimethylisoxazol-4-yl




374






methylphenylthio






4-chloro-2-




1-naphthyl




405






methylphenylthio






4-chloro-2-




2-fluorophenyl




373






methylphenylthio






4-chloro-2-




4-propylphenyl




397






methylphenylthio






4-chloro-2-




4-(trifluoromethyl)phenyl




423






methylphenylthio






4-chloro-2-




3-fluorophenyl




373






methylphenylthio






4-chloro-2-




2,6-difluorophenyl




391






methylphenylthio






4-chloro-2-




2-chlorophenyl




389






methylphenylthio






4-chloro-2-




3-(chloromethyl)phenyl




403






methylphenylthio






4-chloro-2-




4-(2-(2-




411






methylphenylthio




methyl)propyl)phenyl






4-chloro-2-




3-chlorophenyl




389






methylphenylthio






4-chloro-2-




2-nitrophenyl




400






methylphenylthio






4-chloro-2-




3,5-dimethoxyphenyl




415






methylphenylthio






4-chloro-2-




2,6-dichlorophenyl




424






methylphenylthio






4-chloro-2-




2,4-dichlorophenyl




424






methylphenylthio






4-chloro-2-




4-fluorophenyl




373






methylphenylthio






4-chloro-2-




4-butylphenyl




411






methylphenylthio






4-chloro-2-




2-methylphenyl




369






methylphenylthio






4-chloro-2-




phenyl




355






methylphenylthio






4-chloro-2-




4-ethylphenyl




383






methylphenylthio






4-chloro-2-




2,3-difluorophenyl




391






methylphenylthio






4-chloro-2-




2,6-dimethoxyphenyl




415






methylphenylthio






4-chloro-2-




3,4-difluorophenyl




391






methylphenylthio






4-chloro-2-




2,5-difluorophenyl




391






methylphenylthio






4-chloro-2-




4-ethoxyphenyl




399






methylphenylthio






4-chloro-2-




2,4,6-trichlorophenyl




458






methylphenylthio






4-chloro-2-




3-methylphenyl




369






methylphenylthio






4-chloro-2-




2-fluoro-5-




441






methylphenylthio




(trifluoromethyl)phenyl






4-chloro-2-




3-methoxyphenyl




385






methylphenylthio






4-chloro-2-




thien-2-yl




361






methylphenylthio






4-chloro-2-




2-bromophenyl




434






methylphenylthio






4-chloro-2-




4-bromophenyl




434






methylphenylthio






4-chloro-2-




4-fluoro-3-




441






methylphenylthio




(trifluoromethyl)phenyl






4-chloro-2-




3-(trifluoromethoxy)phenyl




439






methylphenylthio






4-chloro-2-




9-fluorenon-4-yl




457






methylphenylthio






4-chloro-2-




isoxazol-5-yl




346






methylphenylthio






4-chloro-2-




benzofuroxan-5-yl




413






methylphenylthio






4-chloro-2-




2-chloropyrid-3-yl




390






methylphenylthio






4-chloro-2-




3,5-difluorophenyl




391






methylphenylthio






4-chloro-2-




2-(4-




462






methylphenylthio




methylphenoxy)pyridin-3-yl






4-chloro-2-




pyridin-4-yl




356






methylphenylthio






4-chloro-2-




anthraquinon-2-yl




485






methylphenylthio






4-chloro-2-




2-iodophenyl




481






methylphenylthio






4-chloro-2-




4-biphenyl




414






methylanilino






4-chloro-2-




3,4-dimethoxyphenyl




398






methylanilino






4-chloro-2-




2-(trifluoromethyl)phenyl




406






methylanilino






4-chloro-2-




2,4-difluorophenyl




374






methylanilino






4-chloro-2-




4-cyanophenyl




363






methylanilino






4-chloro-2-




3-(trifluoromethyl)phenyl




406






methylanilino






4-chloro-2-




3-cyanophenyl




363






methylanilino






4-chloro-2-




2-naphthyl




388






methylanilino






4-chloro-2-




2-methoxyphenyl




368






methylanilino






4-chloro-2-




3,4,5-trimethylphenyl




428






methylanilino






4-chloro-2-




4-nitrophenyl




383






methylanilino






4-chloro-2-




3,4-dichlorophenyl




407






methylanilino






4-chloro-2-




5-nitrofuran-2-yl




373






methylanilino






4-chloro-2-




3-bromophenyl




417






methylanilino






4-chloro-2-




3-pyridyl




339






methylanilino






4-chloro-2-




2-ethoxynaphth-1-yl




432






methylanilino






4-chloro-2-




2,3-dichlorophenyl




407






methylanilino






4-chloro-2-




3-nitrophenyl




383






methylanilino






4-chloro-2-




6-chloropyrid-3-yl




373






methylanilino






4-chloro-2-




4-(trifluoromethoxy)phenyl 422






methylanilino






4-chloro-2-




2-fluoro-4-




424






methylanilino




(trifluoromethyl)phenyl






4-chloro-2-




3-bromothienyl




423






methylanilino






4-chloro-2-




2-acetoxyphenyl




396






methylanilino






4-chloro-2-




5-methylisoxazol-3-yl




343






methylanilino






4-chloro-2-




2-(phenylthio)pyrid-3-yl




447






methylanilino






4-chloro-2-




2-(trifluoromethoxy)phenyl 422






methylanilino






4-chloro-2-




1-phenyl-5-propylpyrazin-




446






methylanilino




4-yl






4-chloro-2-




2-ethoxyphenyl




382






methylanilino






4-chloro-2-




3-chlorothien-2-yl




378






methylanilino






4-chloro-2-




1-(2-(2-methyl)propyl)-3-




398






methylanilino




methylpyrazol-5-yl






4-chloro-2-




3,5-dichlorophenyl




407






methylanilino






4-chloro-2-




2-(propylthio)pyridin-3-yl




413






methylanilino






4-chloro-2-




2-(ethylthio)pyridin-3-yl




399






methylanilino






4-chloro-2-




3-bromopyridin-5-yl




418






methylanilino






4-chloro-2-




4-methyl-1,2,3-thiadiazol-




360






methylanilino




5-yl






4-chloro-2-




1-methyl-3-(2-(2-




398






methylanilino




methyl)propyl)pyrazol-5-yl






4-chloro-2-




3-chlorobenzo[b]thiophen-




428






methylanilino




2-yl






4-chloro-2-




4-chlorophenyl




372






methylanilino






4-chloro-2-




4-methyl-2-phenyl-1,2,3-




419






methylanilino




triazol-5-yl






4-chloro-2-




benzo[b]thiophen-2-yl




394






methylanilino






4-chloro-2-




3,4-dimethylphenyl




366






methylanilino






4-chloro-2-




2-(phenoxy)pyridin-3-yl




431






methylanilino






4-chloro-2-




2-(methylthio)pyridin-3-yl




385






methylanilino






4-chloro-2-




5-methyl-3-phenylisoxazol-




419






methylanilino




4-yl






4-chloro-2-




4-chloro-1,3-dimethyl




441






methylanilino




pyrazolo[3,4-b]pyridin-3-







yl






4-chloro-2-




2-chloro-6-methylpyridin-




387






methylanilino




4-yl






4-chloro-2-




3,5-dimethylisoxazol-4-yl




357






methylanilino






4-chloro-2-




1-naphthyl




388






methylanilino






4-chloro-2-




2-fluorophenyl




356






methylanilino






4-chloro-2-




4-propylphenyl




380






methylanilino






4-chloro-2-




4-(trifluoromethyl)phenyl




406






methylanilino






4-chloro-2-




3-fluorophenyl




356






methylanilino






4-chloro-2-




2,6-difluorophenyl




374






methylanilino






4-chloro-2-




2-chlorophenyl




372






methylanilino






4-chloro-2-




3-(chloromethyl)phenyl




386






methylanilino






4-chloro-2-




4-(2-(2-




394






methylanilino




methyl)propyl)phenyl






4-chloro-2-




3-chlorophenyl




372






methylanilino






4-chloro-2-




2-nitrophenyl




383






methylanilino






4-chloro-2-




3,5-dimethoxyphenyl




398






methylanilino






4-chloro-2-




2,6-dichlorophenyl




407






methylanilino






4-chloro-2-




2,4-dichlorophenyl




407






methylanilino






4-chloro-2-




4-fluorophenyl




356






methylanilino






4-chloro-2-




4-butylphenyl




394






methylanilino






4-chloro-2-




2-methylphenyl




352






methylanilino






4-chloro-2-




phenyl




338






methylanilino






4-chloro-2-




4-ethylphenyl




366






methylanilino






4-chloro-2-




2,3-difluorophenyl




374






methylanilino






4-chloro-2-




2,6-dimethoxyphenyl




398






methylanilino






4-chloro-2-




3,4-difluorophenyl




374






methylanilino






4-chloro-2-




2,5-difluorophenyl




374






methylanilino






4-chloro-2-




4-ethoxyphenyl




382






methylanilino






4-chloro-2-




2,4,6-trichlorophenyl




441






methylanilino






4-chloro-2-




3-methylphenyl




352






methylanilino






4-chloro-2-




2-fluoro-5-




424






methylanilino




(trifluoromethyl)phenyl






4-chloro-2-




3-methoxyphenyl




368






methylanilino






4-chloro-2-




thien-2-yl




344






methylanilino






4-chloro-2-




2-bromophenyl




417






methylanilino






4-chloro-2-




4-bromophenyl




417






methylanilino






4-chloro-2-




4-fluoro-3-




424






methylanilino




(trifluoromethyl)phenyl






4-chloro-2-




3-(trifluoromethoxy)phenyl




422






methylanilino






4-chloro-2-




9-fluorenon-4-yl




440






methylanilino






4-chloro-2-




isoxazol-5-yl




329






methylanilino






4-chloro-2-




benzofuroxan-5-yl




396






methylanilino






4-chloro-2-




2-chloropyrid-3-yl




373






methylanilino






4-chloro-2-




3,5-difluorophenyl




374






methylanilino






4-chloro-2-




2-(4-




445






methylanilino




methylphenoxy)pyridin-3-yl






4-chloro-2-




pyridin-4-yl




339






methylanilino






4-chloro-2-




anthraquinon-2-yl




468






methylanilino






4-chloro-2-




2-iodophenyl




464






methylanilino














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


1


X




R


3















4-chloro-2-methylphenoxy




3,4-difluorphenyl







4-chloro-2-methylphenoxy




4-pentylphenyl







4-chloro-2-methylphenoxy




2-(4-Chlorophenylthio)








pyridin-3-yl







4-chloro-2-methylphenoxy




2,6-dimethylphenyl







4-chloro-2-methylphenoxy




2,5-dimethoxyphenyl







4-chloro-2-methylphenoxy




2,5-dichloropyridin-3-yl







4-chloro-2-methylphenoxy




2-chloro-6-methoxypyridin-








4-yl







4-chloro-2-methylphenoxy




2,3-dichloropyridin-5-yl







4-chloro-2-methylphenoxy




1-naphthyl







4-chloro-2-methylphenoxy




2,4-dimethoxyphenyl







4-chloro-2-methylphenoxy




3,5-








bis(trifluoromethyl)phenyl







4-chloro-2-methylphenoxy




2-(4-








chlorophenoxy)pyridin-3-yl







4-chloro-2-methylphenoxy




pentafluorophenyl







1-naphthoxy




4-pentylphenyl







1-naphthoxy




2-(4-chlorophenylthio)








pyridin-3-yl







1-naphthoxy




2,6-dimethylphenyl







1-naphthoxy




2,5-dimethoxyphenyl







1-naphthoxy




2,5-dichloropyridin-3-yl







1-naphthoxy




2-chloro-6-methoxypyridin-








4-yl







1-naphthoxy




2,3-dichloropyridin-5-yl







1-naphthoxy




1-naphthyl







1-naphthoxy




2,4-dimethoxyphenyl







1-naphthoxy




3,5-bis(trifluoromethyl)








phenyl







1-naphthoxy




2-(4-








chlorophenoxy)pyridin-3-yl







1-naphthoxy




pentafluorophenyl







2-(2-propyl)phenoxy




4-pentylphenyl







2-(2-propyl)phenoxy




2-(4-chlorophenylthio)








pyridin-3-yl







2-(2-propyl)phenoxy




2,6-dimethylphenyl







2-(2-propyl)phenoxy




2,5-dimethoxyphenyl







2-(2-propyl)phenoxy




2,5-dichloropyridin-3-yl







2-(2-propyl)phenoxy




2-chloro-6-methoxypyridin-








4-yl







2-(2-propyl)phenoxy




2,3-dichloropyridin-5-yl







2-(2-propyl)phenoxy




1-naphthyl







2-(2-propyl)phenoxy




2,4-dimethoxyphenyl







2-(2-propyl)phenoxy




3,5-bis(trifluoromethyl)








phenyl







2-(2-propyl)phenoxy




2-(4-








chlorophenoxy)pyridin-3-yl







2-(2-propyl)phenoxy




pentafluorophenyl







3-fluoro-5-methylphenoxy




4-pentylphenyl







3-fluoro-5-methylphenoxy




2-(4-chlorophenylthio)








pyridin-3-yl







3-fluoro-5-methylphenoxy




2,6-dimethylphenyl







3-fluoro-5-methylphenoxy




2,5-dimethoxyphenyl







3-fluoro-5-methylphenoxy




2,5-dichloropyridin-3-yl







3-fluoro-5-methylphenoxy




2-chloro-6-methoxypyridin-








4-yl







3-fluoro-5-methylphenoxy




2,3-dichloropyridin-5-yl







3-fluoro-5-methylphenoxy




1-naphthyl







3-fluoro-5-methylphenoxy




2,4-dimethoxyphenyl







3-fluoro-5-methylphenoxy




3,5-bis(trifluoromethyl)








phenyl







3-fluoro-5-methylphenoxy




2-(4-








chlorophenoxy)pyridin-3-yl







3-fluoro-5-methylphenoxy




pentafluorophenyl







2-methylpyrid-3-yloxy




4-pentylphenyl







2-methylpyrid-3-yloxy




2-(4-chlorophenylthio)








pyridin-3-yl







2-methylpyrid-3-yloxy




2,6-dimethylphenyl







2-methylpyrid-3-yloxy




2,5-dimethoxyphenyl







2-methylpyrid-3-yloxy




2,5-dichloropyridin-3-yl







2-methylpyrid-3-yloxy




2-chloro-6-methoxypyridin-








4-yl







2-methylpyrid-3-yloxy




2,3-dichloropyridin-5-yl







2-methylpyrid-3-yloxy




1-naphthyl







2-methylpyrid-3-yloxy




2,4-dimethoxyphenyl







2-methylpyrid-3-yloxy




3,5-bis(trifluoromethyl)








phenyl







2-methylpyrid-3-yloxy




2-(4-








chlorophenoxy)pyridin-3-yl







2-methylpyrid-3-yloxy




pentafluorophenyl







4-methoxyphenoxy




4-biphenyl







4-methoxyphenoxy




4-cyanophenyl







4-methoxyphenoxy




3-cyanophenyl







4-methoxyphenoxy




4-nitrophenyl







4-methoxyphenoxy




5-nitrofuran-2-yl







4-methoxyphenoxy




3-nitrophenyl







4-methoxyphenoxy




4-(trifluoromethyl)phenyl







4-methoxyphenoxy




2-nitrophenyl







4-methoxyphenoxy




thien-2-yl







2-(2-propoxy)phenoxy




4-biphenyl







2-(2-propoxy)phenoxy




4-cyanophenyl







2-(2-propoxy)phenoxy




3-cyanophenyl







2-(2-propoxy)phenoxy




4-nitrophenyl







2-(2-propoxy)phenoxy




5-nitrofuran-2-yl







2-(2-propoxy)phenoxy




3-nitrophenyl







2-(2-propoxy)phenoxy




2-nitrophenyl







2-(2-propoxy)phenoxy




thien-2-yl







2-(2-propoxy)phenoxy




3,5-difluorophenyl







4-fluorophenoxy




4-biphenyl







4-fluorophenoxy




4-cyanophenyl







4-fluorophenoxy




3-cyanophenyl







4-fluorophenoxy




4-nitrophenyl







4-fluorophenoxy




5-nitrofuran-2-yl







4-fluorophenoxy




3-nitrophenyl







4-fluorophenoxy




2-nitrophenyl







4-fluorophenoxy




4-(trifluoromethyl)phenyl







4-fluorophenoxy




thien-2-yl







4-fluorophenoxy




3,5-difluorophenyl







4-chlorophenoxy




4-biphenyl







4-chlorophenoxy




4-cyanophenyl







4-chlorophenoxy




3-cyanophenyl







4-chlorophenoxy




4-nitrophenyl







4-chlorophenoxy




5-nitrofuran-2-yl







4-chlorophenoxy




3-nitrophenyl







4-chlorophenoxy




2-nitrophenyl







4-chlorophenoxy




4-(trifluoromethyl)phenyl







4-chlorophenoxy




thien-2-yl







4-chlorophenoxy




3,5-difluorophenyl







2,4-difluorophenoxy




4-biphenyl







2,4-difluorophenoxy




4-cyanophenyl







2,4-difluorophenoxy




3-cyanophenyl







2,4-difluorophenoxy




4-nitrophenyl







2,4-difluorophenoxy




5-nitrofuran-2-yl







2,4-difluorophenoxy




3-nitrophenyl







2,4-difluorophenoxy




4-(trifluoromethyl)phenyl







2,4-difluorophenoxy




2-nitrophenyl







4-chloro-2,5-




4-biphenyl







dimethylphenoxy







4-chloro-2,5-




4-cyanophenyl







dimethylphenoxy







4-chloro-2,5-




3-cyanophenyl







dimethylphenoxy







4-chloro-2,5-




4-nitrophenyl







dimethylphenoxy







4-chloro-2,5-




5-nitrofuran-2-yl







dimethylphenoxy







4-chloro-2,5-




3-nitrophenyl







dimethylphenoxy







4-chloro-2,5-




4-(trifluoromethyl)phenyl







dimethylphenoxy







4-chloro-2,5-




2-nitrophenyl







dimethylphenoxy







4-chloro-2,5-




thien-2-yl







dimethylphenoxy







4-chloro-2,5-




3,5-difluorophenyl







dimethylphenoxy







4-methoxyphenoxy




3,5-difluorophenyl







2-(2-propoxy)phenoxy




4-(trifluoromethyl)phenyl







2,4-difluorophenoxy




thien-2-yl







2,4-difluorophenoxy




3,5-difluorophenyl







4-thiomethylphenoxy




4-biphenyl







4-thiomethylphenoxy




4-cyanophenyl







4-thiomethylphenoxy




3-cyanophenyl







4-thiomethylphenoxy




4-nitrophenyl







4-thiomethylphenoxy




5-nitrofuran-2-yl







4-thiomethylphenoxy




3-nitrophenyl







4-thiomethylphenoxy




4-(trifluoromethyl)phenyl







4-thiomethylphenoxy




2-nitrophenyl







4-thiomethylphenoxy




thien-2-yl







4-thiomethylphenoxy




3,5-difluorophenyl







4-(2-(2-methyl)propyl)




4-biphenyl







phenoxy







4-(2-(2-methyl)propyl)




4-cyanophenyl







phenoxy







4-(2-(2-methyl)propyl)




3-cyanophenyl







phenoxy







4-(2-(2-methyl)propyl)




4-nitrophenyl







phenoxy







4-(2-(2-methyl)propyl)




5-nitrofuran-2-yl







phenoxy







4-(2-(2-methyl)propyl)




3-nitrophenyl







phenoxy







4-(2-(2-methyl)propyl)




4-(trifluoromethyl)phenyl







phenoxy







4-(2-(2-methyl)propyl)




2-nitrophenyl







phenoxy







4-(2-(2-methyl)propyl)




thien-2-yl







phenoxy







4-(2-(2-methyl)propyl)




3,5-difluorophenyl







phenoxy







2,3-dimethylphenoxy




4-biphenyl







2,3-dimethylphenoxy




4-cyanophenyl







2,3-dimethylphenoxy




3-cyanophenyl







2,3-dimethylphenoxy




4-nitrophenyl







2,3-dimethylphenoxy




5-nitrofuran-2-yl







2,3-dimethylphenoxy




3-nitrophenyl







2,3-dimethylphenoxy




4-(trifluoromethyl)phenyl







2,3-dimethylphenoxy




2-nitrophenyl







2,3-dimethylphenoxy




thien-2-yl







2,3-dimethylphenoxy




3,5-difluorophenyl







3,5-(bis-2-propyl)phenoxy




4-biphenyl







3,5-(bis-2-propyl)phenoxy




4-cyanophenyl







3,5-(bis-2-propyl)phenoxy




3-cyanophenyl







3,5-(bis-2-propyl)phenoxy




4-nitrophenyl







3,5-(bis-2-propyl)phenoxy




5-nitrofuran-2-yl







3,5-(bis-2-propyl)phenoxy




3-nitrophenyl







3,5-(bis-2-propyl)phenoxy




4-(trifluoromethyl)phenyl







3,5-(bis-2-propyl)phenoxy




2-nitrophenyl







3,5-(bis-2-propyl)phenoxy




thien-2-yl







3,5-(bis-2-propyl)phenoxy




3,5-difluorophenyl







3-trifluoromethyl phenoxy




4-biphenyl







3-trifluoromethyl phenoxy




4-cyanophenyl







3-trifluoromethyl phenoxy




3-cyanophenyl







3-trifluoromethyl phenoxy




4-nitrophenyl







3-trifluoromethyl phenoxy




5-nitrofuran-2-yl







3-trifluoromethyl phenoxy




3-nitrophenyl







3-trifluoromethyl phenoxy




4-(trifluoromethyl)phenyl







3-trifluoromethyl phenoxy




2-nitrophenyl







3-trifluoromethyl phenoxy




thien-2-yl







3-trifluoromethyl phenoxy




3,5-difluorophenyl







2,6-dichlorophenoxy




4-biphenyl







2,6-dichlorophenoxy




4-cyanophenyl







2,6-dichlorophenoxy




3-cyanophenyl







2,6-dichlorophenoxy




4-nitrophenyl







2,6-dichlorophenoxy




5-nitrofuran-2-yl







2,6-dichlorophenoxy




3-nitrophenyl







2,6-dichlorophenoxy




4-(trifluoromethyl)phenyl







2,6-dichlorophenoxy




2-nitrophenyl







2,6-dichlorophenoxy




thien-2-yl







2,6-dichlorophenoxy




3,5-difluorophenyl







2,4-dichlorophenoxy




4-biphenyl







2,4-dichlorophenoxy




4-cyanophenyl







2,4-dichlorophenoxy




3-cyanophenyl







2,4-dichlorophenoxy




4-nitrophenyl







2,4-dichlorophenoxy




5-nitrofuran-2-yl







2,4-dichlorophenoxy




3-nitrophenyl







2,4-dichlorophenoxy




4-(trifluoromethyl)phenyl







2,4-dichlorophenoxy




2-nitrophenyl







2,4-dichlorophenoxy




thien-2-yl







2,4-dichlorophenoxy




3,5-difluorophenyl







4-chloro-3-methylphenoxy




4-biphenyl







4-chloro-3-methylphenoxy




4-cyanophenyl







4-chloro-3-methylphenoxy




3-cyanophenyl







4-chloro-3-methylphenoxy




4-nitrophenyl







4-chloro-3-methylphenoxy




5-nitrofuran-2-yl







4-chloro-3-methylphenoxy




3-nitrophenyl







4-chloro-3-methylphenoxy




2-nitrophenyl







4-chloro-3-methylphenoxy




thien-2-yl







4-chloro-3-methylphenoxy




3,5-difluorophenyl







4-chloro-2-




4-biphenyl







cyclohexylphenoxy







4-chloro-2-




4-cyanophenyl







cyclohexylphenoxy







4-chloro-2-




3-cyanophenyl







cyclohexylphenoxy







4-chloro-2-




4-nitrophenyl







cyclohexylphenoxy







4-chloro-2-




5-nitrofuran-2-yl







cyclohexylphenoxy







4-chloro-2-




3-nitrophenyl







cyclohexylphenoxy







4-chloro-2-




4-(trifluoromethyl)phenyl







cyclohexylphenoxy







4-chloro-2-




2-nitrophenyl







cyclohexylphenoxy







4-chloro-2-




thien-2-yl







cyclohexylphenoxy







4-chloro-2-




3,5-difluorophenyl







cyclohexylphenoxy







4-chloro-3,5-




4-biphenyl







dimethylphenoxy







4-chloro-3,5-




4-cyanophenyl







dimethylphenoxy







4-chloro-3,5-




3-cyanophenyl







dimethylphenoxy







4-chloro-3,5-




4-nitrophenyl







dimethylphenoxy







4-chloro-3,5-




5-nitrofuran-2-yl







dimethylphenoxy







4-chloro-3,5-




3-nitrophenyl







dimethylphenoxy







4-chloro-3,5-




4-(trifluoromethyl)phenyl







dimethylphenoxy







4-chloro-3,5-




2-nitrophenyl







dimethylphenoxy







4-chloro-3,5-




thien-2-yl







dimethylphenoxy







4-chloro-3,5-




3,5-difluorophenyl







dimethylphenoxy







pyrid-3-yloxy




4-biphenyl







pyrid-3-yloxy




4-cyanophenyl







pyrid-3-yloxy




3-cyanophenyl







pyrid-3-yloxy




4-nitrophenyl







pyrid-3-yloxy




5-nitrofuran-2-yl







pyrid-3-yloxy




3-nitrophenyl







pyrid-3-yloxy




4-(trifluoromethyl)phenyl







pyrid-3-yloxy




2-nitrophenyl







pyrid-3-yloxy




thien-2-yl







pyrid-3-yloxy




3,5-difluorophenyl







4-bromophenoxy




4-biphenyl







4-bromophenoxy




4-cyanophenyl







4-bromophenoxy




3-cyanophenyl







4-bromophenoxy




4-nitrophenyl







4-bromophenoxy




5-nitrofuran-2-yl







4-bromophenoxy




3-nitrophenyl







4-bromophenoxy




4-(trifluoromethyl)phenyl







4-bromophenoxy




2-nitrophenyl







4-bromophenoxy




thien-2-yl







4-bromophenoxy




3,5-difluorophenyl







4-chloro-2-




4-pentylphenyl







methylphenylthio







4-chloro-2-




2-(4-chlorophenylthio)







methylphenylthio




pyridin-3-yl







4-chloro-2-




2,6-dimethylphenyl







methylphenylthio







4-chloro-2-




2,5-dimethoxyphenyl







methylphenylthio







4-chloro-2-




2,5-dichloropyridin-3-yl







methylphenylthio







4-chloro-2-




2-chloro-6-methoxypyridin-







methylphenylthio




4-yl







4-chloro-2-




2,3-dichloropyridin-5-yl







methylphenylthio







4-chloro-2-




1-naphthyl







methylphenylthio







4-chloro-2-




2,4-dimethoxyphenyl







methylphenylthio







4-chloro-2-




3,5-bis(trifluoromethyl)







methylphenylthio




phenyl







4-chloro-2-




2-(4-







methylphenylthio




chlorophenoxy)pyridin-3-yl







4-chloro-2-




pentafluorophenyl







methylphenylthio







4-chloro-2-methylanilino




4-pentylphenyl







4-chloro-2-methylanilino




2-(4-chlorophenylthio)








pyridin-3-yl







4-chloro-2-methylanilino




2,6-dimethylphenyl







4-chloro-2-methylanilino




2,5-dimethoxyphenyl







4-chloro-2-methylanilino




2,5-dichloropyridin-3-yl







4-chloro-2-methylanilino




2-chloro-6-methoxypyridin-








4-yl







4-chloro-2-methylanilino




2,3-dichloropyridin-5-yl







4-chloro-2-methylanilino




1-naphthyl







4-chloro-2-methylanilino




2,4-dimethoxyphenyl







4-chloro-2-methylanilino




3,5-








bis(trifluoromethyl)phenyl







4-chloro-2-methylanilino




2-(4-








chlorophenoxy)pyridin-3-yl







4-chloro-2-methylanilino




pentafluorophenyl















EXAMPLE 19
















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


3


R


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)


+


; C


13


H


11


Cl


1


N


2


O


1


requires 246.5.




6-Chloro-N-(2-fluorophenyl)nicotinamide: MS (m/z): 251/253 (M+H)


+


; C


12


H


8


Cl


1


F


1


N


2


O


1


requires 250.7.




6-Chloro-N-(2,6-dimethylphenyl)nicotinamide: MS (m/z): 261/263 (M+H)


+


; C


14


H


13


Cl


1


N


2


O


1


requires 260.7.




6-Chloro-N-(2-phenoxyphenyl)nicotinamide: MS (m/z): 325/327 (M+H)


+


; C


18


H


13


Cl


1


N


2


O


1


requires (324.8.




6-Chloro-N-phenylnicotinamide: MS (m/z): 233/235 (M+H)


+


; C


12


H


8


Cl


1


N


2


O


1


requires 232.7.




6-Chloro-N-(2,4-difluorophenyl)nicotinamide: MS (m/z): 269/271 (M+H)


+


; C


12


H


7


Cl


1


F


2


N


2


O


1


requires 268.6.




6-Chloro-N-(2,6-diisopropylphenyl)nicotinamide: MS (m/z): 317/319 (M+H)


+


; C


18


H


21


Cl


1


N


2


O


1


requires 316.8.




6-Chloro-N-(4-chlorophenyl)-N-methylnicotinamide: MS (m/z): 281/283 (M+H)


+


; C


13


H


10


Cl


2


N


2


O


1


requires 281.1.




6-Chloro-N-(2,4-dimethoxyphenyl)nicotinamide: MS (m/z): 293/295 (M+H)


+


; C


14


H


13


Cl


1


N


2


O


3


requires 292.7.




6-Chloro-N-(3-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H)


+


; C


13


H


11


Cl


1


N


2


O


2


requires 262.7.




6-Chloro-N-(4-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H)


+


; C


13


H


11


Cl


1


N


2


O


2


requires 262.7.




6-Chloro-N-(2-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H)


+


; C


13


H


11


Cl


1


N


2


O


2


requires 262.7.




6-Chloro-N-methyl-N-phenylnicotinamide: MS (m/z): 247/249 (M+H)


+


; C


13


H


11


Cl


1


N


2


O


1


requires 246.7.




N-Benzyl-6-chloronicotinamide: MS (m/z): 247/249 (M+H)


+


; C


13


H


11


Cl


1


N


2


O


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


1


NH


2


or R


1


NHCH


3


) (20 mmol) in ethylene glycol (50 mL) or pyridine (alkylamines) (50 mL) was heated to 140° 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











































MS







R


3






R


1






(m/z)











o-tolyl




phenyl




303







o-tolyl




o-tolyl




317







o-tolyl




4-chloro-2-methylphenyl




352







o-tolyl




2-fluorophenyl




321







o-tolyl




3-fluorophenyl




321







o-tolyl




4-fluorophenyl




321







o-tolyl




2,4-difluorophenyl




339







o-tolyl




2-methoxyphenyl




333







o-tolyl




3-methoxyphenyl




333







o-tolyl




4-methoxyphenyl




333







o-tolyl




2,4-dimethoxyphenyl




363







o-tolyl




2-phenoxyphenyl




395







o-tolyl




3-phenoxyphenyl




395







o-tolyl




4-phenoxyphenyl




395







o-tolyl




4-biphenyl




379







o-tolyl




4-benzylphenyl




393







o-tolyl




4-(trifluoromethoxy)phenyl




387







o-tolyl




cyclohexyl




309







o-tolyl




2-methylcyclohexyl




323







o-tolyl




cycloheptyl




323







o-tolyl




indan-1-yl




343







o-tolyl




2-dicyclohexyl




492







2-fluorophenyl




phenyl




307







2-fluorophenyl




o-tolyl




321







2-fluorophenyl




4-chloro-2-methylphenyl




356







2-fluorophenyl




2-fluorophenyl




325







2-fluorophenyl




3-fluorophenyl




325







2-fluorophenyl




4-fluorophenyl




325







2-fluorophenyl




2,4-difluorophenyl




343







2-fluorophenyl




2-methoxyphenyl




337







2-fluorophenyl




3-methoxyphenyl




337







2-fluorophenyl




4-methoxyphenyl




337







2-fluorophenyl




2,4-dimethoxyphenyl




367







2-fluorophenyl




2-phenoxyphenyl




399







2-fluorophenyl




3-phenoxyphenyl




399







2-fluorophenyl




4-phenoxyphenyl




399







2-fluorophenyl




4-biphenyl




383







2-fluorophenyl




4-benzylphenyl




397







2-fluorophenyl




4-(trifluoromethoxy)phenyl




391







2-fluorophenyl




cyclohexyl




313







2-fluorophenyl




2-methylcyclohexyl




327







2-fluorophenyl




cycloheptyl




327







2-fluorophenyl




indan-1-yl




347







2-fluorophenyl




2-dicyclohexyl




395







2,6-dimethylphenyl




phenyl




317







2,6-dimethylphenyl




o-tolyl




331







2,6-dimethylphenyl




4-chloro-2-methylphenyl




366







2,6-dimethylphenyl




2-fluorophenyl




335







2,6-dimethylphenyl




3-fluorophenyl




335







2,6-dimethylphenyl




4-fluorophenyl




335







2,6-dimethylphenyl




2,4-difluorophenyl




353







2,6-dimethylphenyl




2-methoxyphenyl




347







2,6-dimethylphenyl




3-methoxyphenyl




347







2,6-dimethylphenyl




4-methoxyphenyl




347







2,6-dimethylphenyl




2,4-dimethoxyphenyl




377







2,6-dimethylphenyl




2-phenoxyphenyl




409







2,6-dimethylphenyl




3-phenoxyphenyl




409







2,6-dimethylphenyl




4-phenoxyphenyl




409







2,6-dimethylphenyl




4-biphenyl




393







2,6-dimethylphenyl




4-benzylphenyl




407







2,6-dimethylphenyl




4-(trifluoromethoxy)phenyl




401







2,6-dimethylphenyl




cyclohexyl




323







2,6-dimethylphenyl




2-methylcyclohexyl




337







2,6-dimethylphenyl




cycloheptyl




667







2,6-dimethylphenyl




indan-1-yl




357







2,6-dimethylphenyl




2-dicyclohexyl




406







2-phenoxyphenyl




phenyl




381







2-phenoxyphenyl




o-tolyl




395







2-phenoxyphenyl




4-chloro-2-methylphenyl




430







2-phenoxyphenyl




2-fluorophenyl




399







2-phenoxyphenyl




3-fluorophenyl




399







2-phenoxyphenyl




4-fluorophenyl




399







2-phenoxyphenyl




2,4-difluorophenyl




417







2-phenoxyphenyl




2-methoxyphenyl




411







2-phenoxyphenyl




3-methoxyphenyl




411







2-phenoxyphenyl




4-methoxyphenyl




411







2-phenoxyphenyl




2,4-dimethoxyphenyl




441







2-phenoxyphenyl




2-phenoxyphenyl




473







2-phenoxyphenyl




3-phenoxyphenyl




473







2-phenoxyphenyl




4-phenoxyphenyl




473







2-phenoxyphenyl




4-biphenyl




457







2-phenoxyphenyl




4-benzylphenyl




472







2-phenoxyphenyl




4-(trifluoromethoxy)phenyl




465







2-phenoxyphenyl




cyclohexyl




387







2-phenoxyphenyl




2-methylcyclohexyl




401







2-phenoxyphenyl




cycloheptyl




401







2-phenoxyphenyl




indan-1-yl




421







2-phenoxyphenyl




2-dicyclohexyl




470







phenyl




phenyl




289







phenyl




o-tolyl




303







phenyl




4-chloro-2-methylphenyl




338







phenyl




2-fluorophenyl




307







phenyl




3-fluorophenyl




307







phenyl




4-fluorophenyl




307







phenyl




2,4-difluorophenyl




325







phenyl




2-methoxyphenyl




319







phenyl




3-methoxyphenyl




319







phenyl




4-methoxyphenyl




319







phenyl




2,4-dimethoxyphenyl




349







phenyl




2-phenoxyphenyl




381







phenyl




3-phenoxyphenyl




381







phenyl




4-phenoxyphenyl




381







phenyl




4-biphenyl




365







phenyl




4-benzylphenyl




379







phenyl




4-(trifluoromethoxy)phenyl




373







phenyl




cyclohexyl




295







phenyl




2-methylcyclohexyl




309







phenyl




cycloheptyl




309







phenyl




indan-1-yl




329







phenyl




2-dicyclohexyl




377







2,4-difluorophenyl




phenyl




325







2,4-difluorophenyl




o-tolyl




339







2,4-difluorophenyl




4-chloro-2-methylphenyl




374







2,4-difluorophenyl




2-fluorophenyl




343







2,4-difluorophenyl




3-fluorophenyl




343







2,4-difluorophenyl




4-fluorophenyl




343







2,4-difluorophenyl




2,4-difluorophenyl




361







2,4-difluorophenyl




2-methoxyphenyl




355







2,4-difluorophenyl




3-methoxyphenyl




355







2,4-difluorophenyl




4-methoxyphenyl




355







2,4-difluorophenyl




2,4-dimethoxyphenyl




385







2,4-difluorophenyl




2-phenoxyphenyl




417







2,4-difluorophenyl




3-phenoxyphenyl




417







2,4-difluorophenyl




4-phenoxyphenyl




417







2,4-difluorophenyl




4-biphenyl




401







2,4-difluorophenyl




4-benzylphenyl




415







2,4-difluorophenyl




4-(trifluoromethoxy)phenyl




409







2,4-difluorophenyl




cyclohexyl




331







2,4-difluorophenyl




2-methylcyclohexyl




345







2,4-difluorophenyl




cycloheptyl




345







2,4-difluorophenyl




indan-1-yl




365







2,4-difluorophenyl




2-dicyclohexyl




413







2,6-diisopropylphenyl




phenyl




373







2,6-diisopropylphenyl




o-tolyl




387







2,6-diisopropylphenyl




4-chloro-2-methylphenyl




422







2,6-diisopropylphenyl




2-fluorophenyl




391







2,6-diisopropylphenyl




3-fluorophenyl




391







2,6-diisopropylphenyl




4-fluorophenyl




391







2,6-diisopropylphenyl




2,4-difluorophenyl




409







2,6-diisopropylphenyl




2-methoxyphenyl




403







2,6-diisopropylphenyl




3-methoxyphenyl




403







2,6-diisopropylphenyl




4-methoxyphenyl




403







2,6-diisopropylphenyl




2,4-dimethoxyphenyl




434







2,6-diisopropylphenyl




2-phenoxyphenyl




466







2,6-diisopropylphenyl




3-phenoxyphenyl




466







2,6-diisopropylphenyl




4-phenoxyphenyl




466







2,6-diisopropylphenyl




4-biphenyl




450







2,6-diisopropylphenyl




4-benzylphenyl




464







2,6-diisopropylphenyl




4-(trifluoromethoxy)phenyl




457







2,6-diisopropylphenyl




cyclohexyl




380







2,6-diisopropylphenyl




2-methylcyclohexyl




394







2,6-diisopropylphenyl




cycloheptyl




394







2,6-diisopropylphenyl




indan-1-yl




414







2,6-diisopropylphenyl




2-dicyclohexyl




462







2,4-dimethoxyphenyl




phenyl




349







2,4-dimethoxyphenyl




o-tolyl




363







2,4-dimethoxyphenyl




4-chloro-2-methylphenyl




398







2,4-dimethoxyphenyl




2-fluorophenyl




367







2,4-dimethoxyphenyl




3-fluorophenyl




367







2,4-dimethoxyphenyl




4-fluorophenyl




367







2,4-dimethoxyphenyl




2,4-difluorophenyl




385







2,4-dimethoxyphenyl




2-methoxyphenyl




379







2,4-dimethoxyphenyl




3-methoxyphenyl




379







2,4-dimethoxyphenyl




4-methoxyphenyl




379







2,4-dimethoxyphenyl




2,4-dimethoxyphenyl




409







2,4-dimethoxyphenyl




2-phenoxyphenyl




441







2,4-dimethoxyphenyl




3-phenoxyphenyl




441







2,4-dimethoxyphenyl




4-phenoxyphenyl




441







2,4-dimethoxyphenyl




4-biphenyl




425







2,4-dimethoxyphenyl




4-benzylphenyl




439







2,4-dimethoxyphenyl




4-(trifluoromethoxy)phenyl




433







2,4-dimethoxyphenyl




3-trifluoromethylphenyl




417







2,4-dimethoxyphenyl




cyclohexyl




355







2,4-dimethoxyphenyl




2-methylcyclohexyl




369







3-methoxyphenyl




phenyl




319







3-methoxyphenyl




o-tolyl




333







3-methoxyphenyl




4-chloro-2-methylphenyl




368







3-methoxyphenyl




2-fluorophenyl




337







3-methoxyphenyl




3-fluorophenyl




337







3-methoxyphenyl




4-fluorophenyl




337







3-methoxyphenyl




2,4-difluorophenyl




355







3-methoxyphenyl




2-methoxyphenyl




349







3-methoxyphenyl




3-methoxyphenyl




349







3-methoxyphenyl




4-methoxyphenyl




349







3-methoxyphenyl




2,4-dimethoxyphenyl




379







3-methoxyphenyl




2-phenoxyphenyl




411







3-methoxyphenyl




3-phenoxyphenyl




411







3-methoxyphenyl




4-phenoxyphenyl




411







3-methoxyphenyl




4-biphenyl




395







3-methoxyphenyl




4-benzylphenyl




409







3-methoxyphenyl




4-(trifluoromethoxy)phenyl




403







3-methoxyphenyl




3-trifluoromethylphenyl




387







3-methoxyphenyl




cyclohexyl




625







3-methoxyphenyl




2-methylcyclohexyl




339







4-methoxyphenyl




phenyl




319







4-methoxyphenyl




o-tolyl




333







4-methoxyphenyl




4-chloro-2-methylphenyl




368







4-methoxyphenyl




2-fluorophenyl




337







4-methoxyphenyl




3-fluorophenyl




337







4-methoxyphenyl




4-fluorophenyl




337







4-methoxyphenyl




2,4-difluorophenyl




355







4-methoxyphenyl




2-methoxyphenyl




349







4-methoxyphenyl




3-methoxyphenyl




349







4-methoxyphenyl




4-methoxyphenyl




349







4-methoxyphenyl




2,4-dimethoxyphenyl




379







4-methoxyphenyl




2-phenoxyphenyl




411







4-methoxyphenyl




3-phenoxyphenyl




411







4-methoxyphenyl




4-phenoxyphenyl




411







4-methoxyphenyl




4-biphenyl




395







4-methoxyphenyl




4-benzylphenyl




409







4-methoxyphenyl




4-(trifluoromethoxy)phenyl




403







4-methoxyphenyl




3-trifluoromethylphenyl




387







4-methoxyphenyl




cyclohexyl




625







4-methoxyphenyl




2-methylcyclohexyl




339







2-methoxyphenyl




phenyl




319







2-methoxyphenyl




o-tolyl




333







2-methoxyphenyl




4-chloro-2-methylphenyl




368







2-methoxyphenyl




2-fluorophenyl




337







2-methoxyphenyl




3-fluorophenyl




337







2-methoxyphenyl




4-fluorophenyl




337







2-methoxyphenyl




2,4-difluorophenyl




355







2-methoxyphenyl




2-methoxyphenyl




349







2-methoxyphenyl




3-methoxyphenyl




349







2-methoxyphenyl




4-methoxyphenyl




349







2-methoxyphenyl




2,4-dimethoxyphenyl




379







2-methoxyphenyl




2-phenoxyphenyl




411







2-methoxyphenyl




3-phenoxyphenyl




411







2-methoxyphenyl




4-phenoxyphenyl




411







2-methoxyphenyl




4-biphenyl




395







2-methoxyphenyl




4-benzylphenyl




409







2-methoxyphenyl




4-(trifluoromethoxy)phenyl)




403







2-methoxyphenyl




3-trifluoromethylphenyl




387







2-methoxyphenyl




cyclohexyl




625







2-methoxyphenyl




2-methylcyclohexyl




339























TABLE 9











































MS







R


3






R


1






(m/z)











4-chlorophenyl




phenyl




338







4-chlorophenyl




o-tolyl




352







4-chlorophenyl




4-chloro-2-methylphenyl




386







4-chlorophenyl




2-fluorophenyl




356







4-chlorophenyl




3-fluorophenyl




356







4-chlorophenyl




4-fluorophenyl




356







4-chlorophenyl




2,4-difluorophenyl




374







4-chlorophenyl




2-methoxyphenyl




368







4-chlorophenyl




3-methoxyphenyl




368







4-chlorophenyl




4-methoxyphenyl




368







4-chlorophenyl




2,4-dimethoxyphenyl




398







4-chlorophenyl




2-phenoxyphenyl




430







4-chlorophenyl




3-phenoxyphenyl




430







4-chlorophenyl




4-phenoxyphenyl




430







4-chlorophenyl




4-biphenyl




414







4-chlorophenyl




4-benzylphenyl




428







4-chlorophenyl




4-(trifluoromethoxy)phenyl




422







4-chlorophenyl




cyclohexyl




344







4-chlorophenyl




2-methylcyclohexyl




358







phenyl




phenyl




303







phenyl




o-tolyl




317







phenyl




4-chloro-2-methylphenyl




352







phenyl




2-fluorophenyl




321







phenyl




3-fluorophenyl




321







phenyl




4-fluorophenyl




321







phenyl




2,4-difluorophenyl




339







phenyl




2-methoxyphenyl




333







phenyl




3-methoxyphenyl




333







phenyl




4-methoxyphenyl




333







phenyl




2,4-dimethoxyphenyl




363







phenyl




2-phenoxyphenyl




395







phenyl




3-phenoxyphenyl




395







phenyl




4-phenoxyphenyl




395







phenyl




4-biphenyl




379







phenyl




4-benzylphenyl




393







phenyl




4-(trifluoromethoxy)phenyl




387







phenyl




3-trifluoromethylphenyl




371







phenyl




cyclohexyl




309







phenyl




2-methylcyclohexyl




323























TABLE 10











































MS







R


3






R


1






(m/z)











o-tolyl




N-methylphenyl




317







o-tolyl




4-chloro-N-methylphenyl




352







o-tolyl




N-methylcyclohexyl




323







2-fluorophenyl




N-methylphenyl




321







2-fluorophenyl




4-chloro-N-methylphenyl




356







2-fluorophenyl




N-methylcyclohexyl




327







2,6-dimethylphenyl




N-methylphenyl




331







2,6-dimethylphenyl




4-chloro-N-methylphenyl




366







2,6-dimethylphenyl




N-methylcyclohexyl




337







2-phenoxyphenyl




N-methylphenyl




395







2-phenoxyphenyl




4-chloro-N-methylphenyl




430







2-phenoxyphenyl




N-methylcyclohexyl




401







phenyl




N-methylphenyl




303







phenyl




4-chloro-N-methylphenyl




338







phenyl




N-methylcyclohexyl




309







2,4-difluorophenyl




N-methylphenyl




339







2,4-difluorophenyl




4-chloro-N-methylphenyl




374







2,4-difluorophenyl




N-methylcyclohexyl




345







2,6-diisopropylphenyl




N-methylphenyl




387







2,6-diisopropylphenyl




4-chloro-N-methylphenyl




422







2,6-diisopropylphenyl




N-methylcyclohexyl




394







2,4-dimethoxyphenyl




N-methylphenyl




363







2,4-dimethoxyphenyl




4-chloro-N-methylphenyl




398







2,4-dimethoxyphenyl




N-methylcyclohexyl




369







3-methoxyphenyl




N-methylphenyl




333







3-methoxyphenyl




4-chloro-N-methylphenyl




368







3-methoxyphenyl




N-methylcyclohexyl




339







4-methoxyphenyl




N-methylphenyl




333







4-methoxyphenyl




4-chloro-N-methylphenyl




368







4-methoxyphenyl




N-methylcyclohexyl




339







2-methoxyphenyl




N-methylphenyl




333







2-methoxyphenyl




4-chloro-N-methylphenyl




368







2-methoxyphenyl




N-methylcyclohexyl




339























TABLE 11











































MS







R


3






R


1






(m/z)











4-chlorophenyl




phenyl




352







4-chlorophenyl




4-chlorophenyl




386







4-chlorophenyl




cyclohexyl




358







phenyl




phenyl




317







phenyl




4-chlorophenyl




352







phenyl




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








































R


1


X




R


3













o-tolyl




3-trifluoromethylphenyl







2-fluorophenyl




3-trifluoromethylphenyl







2,6-dimethylphenyl




3-trifluoromethylphenyl







2-phenoxyphenyl




3-trifluoromethylphenyl







phenyl




3-trifluoromethylphenyl







2,4-difluorophenyl




3-trifluoromethylphenyl







2,6-diisopropylphenyl




3-trifluoromethylphenyl







2,4-dimethoxyphenyl




cycloheptyl







2,4-dimethoxyphenyl




indan-1-yl







2,4-dimethoxyphenyl




2-dicyclohexyl







3-methoxyphenyl




cycloheptyl







3-methoxyphenyl




indan-1-yl







3-methoxyphenyl




2-dicyclohexyl







4-methoxyphenyl




cycloheptyl







4-methoxyphenyl




indan-1-yl







4-methoxyphenyl




2-dicyclohexyl







2-methoxyphenyl




cycloheptyl







2-methoxyphenyl




indan-1-yl







2-methoxyphenyl




2-dicyclohexyl























TABLE 13








































R


1


X




R


3













4-chlorophenyl




3-trifluoromethylphenyl







4-chlorophenyl




cycloheptyl







4-chlorophenyl




indan-1-yl







4-chlorophenyl




2-dicyclohexyl







phenyl




cycloheptyl







phenyl




indan-1-yl







phenyl




2-dicyclohexyl















EXAMPLE 20




The following assays were used to characterize the ability of compounds of the invention to inhibit the production of TNF-α and IL-1-β. The second assay measured the inhibition of TNF-α and/or IL-1-β 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 2×10


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 μl/well) and cultured overnight at 37° C. and 6% CO


2


. Non-adherent cells were removed by washing with 200 μl/well of fresh medium. Wells containing adherent cells (˜70% monocytes) were replenished with 100 μl 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 μM. Stocks were diluted initially to 20-200 μM 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 μl complete medium. Monocytes were cultured with test compounds for 60 min at which time 25 μl 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° C.) with 150 μL/well of 3 μg/ml murine anti-human TNF-α MAb (R&D Systems #MAB210). Wells were then blocked for 1 hr at room temperature with 200 μL/well of CaCl


2


-free ELISA buffer supplemented to contain 20 mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM CaCl


2


, 0.15 mM thimerosal, pH 7.4). Plates were washed and replenished with 100 μl 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 μl/well of 0.5 μg/ml goat anti-human TNF-α (R&D systems #AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40 min, washed and replenished with 100 μl/well of alkaline phosphatase-conjugated streptavidin (Jackson ImmunoResearch #016-050-084) at 0.02 μg/ml. Plates were incubated 30 min, washed and replenished with 200 μl/well of 1 mg/ml of p-nitrophenyl phosphate. After 30 min, plates were read at 405 nm on a V


max


plate reader.




Data analysis




Standard curve data were fit to a second order polynomial and unknown TNF-α 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


50


of less than 15 μM:




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-1β, IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-1β, 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-α from monocytes, compounds of this invention can also be shown to inhibit LPS induced release of IL-1β, IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-1β, 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-β, 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-α, IL-1β, IL-6, and IL-8 play a role to the full extent of the definition of TNF-α-mediated diseases described herein.




Inhibition of LPS-Induced TNF-α 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-α 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).






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 (1000X): 5 mg leupeptin, 10 mg benzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per ml DMSO and store aliquots at −20° C.; (d) 250 μM human glucagon (Peninsula): solubilize 0.5 mg vial in 575 μl 0.1N acetic acid (1 μl yields 1 μM final concentration in assay for non-specific binding) and store in aliquots at −20° 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 μl 10% BSA (heat-inactivated) and 990 μl Assay Buffer; (g)


125


I-Glucagon (NEN, receptor-grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 μl 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° 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 μl.




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


125


-glucagon binding in the presence of compounds of Formula I. The reagents are combined in 120 μL of assay buffer as follows:





















Compound/




250 μM






125


I-




CHO/hGLUR







Vehicle




Glucagon




Glucagon




Cells




























Total




 —/5 μl









25 μl




100 μl






Binding






+




5 μl/— 









25 μl




100 μl






Compound






Nonspecific




 —/5 μl




1 μl




25 μl




100 μl






Binding














The mixture is incubated for 60 min. at 22° 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° C. in a humidified environment containing 5% CO


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 2.5×10


6


cells/mL and plated in 96-well culture plates at a density of 5×10


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° C., and enzyme activity determined as described below.




COX-2 Assay




For the COX-2 assay, subconfluent HOSC are trypsinized and resuspended at 3×10


6


cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in 96-well tissue culture plates at a density of 3×10


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° 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


2


using a commercially available ELISA (Neogen #404110). A standard curve of PGE


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


50


values of 10 μM 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


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


2


, 2 mM DTT, 0.4 mM AEBSF, 0.1% n-octylglucopyranoside, 1 nM okadeic acid, and 10 μg/mL each of benzamidine, leupeptin, pepstatin, and aprotinin.




5x Reaction buffer: 125 mM HEPES pH=8, 25 mM MgCl


2


, 5 mM EDTA, 5 mM Na


3


VO


4


, 100 μg/mL BSA.




Enzyme dilution buffer: 25 mM HEPES pH=8, 1 mM EDTA, 1 mM Na


3


VO


4


, 400 μg/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° C. Cells were pelleted and lysed by sonication in column buffer. Lysates were spun at 17,000×g for 20 min, followed by 0.22 μm 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 μg/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 μM. 10 μL of the test inhibitor or control, dissolved in 10% DMSO, was added to the assay plate followed by the addition of 30 μL of the a mixture containing 10 μL 5x reaction buffer, 1 mM


33


P-γ-ATP (20 μCi/mL), 0.5 μL MEK (2.5 mg/mL), 1 μL 50 mM β-mercaptoethanol. The reaction was started by the addition of 10 μL 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 μL stop solution. 90 μL 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 μl scintillation cocktail. The plates were counted for


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 β 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-α 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-α 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-α, 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 β 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-α, IL-1β, 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-α, IL-1β, 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-α, IL-1β, 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-α, 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 preservations, 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-hyroxy-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 or a pharmaceutically acceptable salt thereof, whereinX is O, S, S(O), S(O)2 or NR2; Y is —C(O)—NR3R4 or —NR4—C(O)—R3; R1 is a pyridyl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18-alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-3; R2 is a hydrogen or alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19-alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-3; and provided when Y is —C(O)—NR3R4, R3 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 —NR4—; and R4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R20—Z20-alkyl radical; wherein R18, R19 and R20 are each independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical; wherein the aryl and heteroaryl radicals of R4, R18, R19 and R20 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 Z18, Z19 and Z20 are each independently —O—, —S—, —S(O)—, —S(O)2—, —CO2—, —C(O)—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R21 is independently a hydrogen or alkyl radical; R5 and R6 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 R7 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; wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused; and provided when X is O or S and R4 is a hydrogen radical, then R3 is other than a tert-butylphenyl radical; and when Y is —NR4—C(O)—R3, then R3 is other than an optionally substituted 1-indolinyl radical.
  • 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinR1 is a pyridyl radical which is optionally substituted by 1-4 radicals of C1-C6 alkyl, halo, C1-C6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—C1-C6 alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-3; R2 is a hydrogen or C1-C4 alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19—C1-C6 alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-3; and provided when Y is —C(O)—NR3R4, R3 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 —NR4—; and R4 is a radical of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl of 1-3 halo radicals, C2-C6 haloalkenyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C1-C6 alkyl radical; and wherein R18, R19 and R20 are each independently a hydrogen, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals of R4, R18, R19 and R20 are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; and each R21 is independently a hydrogen or C1-C4 alkyl radical; R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, C1-C4 aminoalkyl, (C1-C4 alkyl)amino-C1-C4 alkyl, di(C1-C4 alkyl)amino-C1-C4 alkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, aminosulfonyl, C1-C4 alkylaminosulfonyl, di(C1-C4 alkyl)aminosulfonyl, hydroxy, C1-C4 hydroxyalkyl, thiol, C1-C4 alkylthiol, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, (C1-C4 alkoxy)C1-C4 alkyl, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and R7 is a hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, C1-C4 aminoalkyl, (C1-C4 alkyl)amino-C1-C4 alkyl, di(C1-C4 alkyl)amino-C1-C4 alkyl, aminosulfonyl, C1-C4 alkylaminosulfonyl, di(C1-C4 alkyl)aminosulfonyl, hydroxy, C1-C4 hydroxyalkyl, thiol, C1-C4 alkylthiol, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, (C1-C4 alkoxy)C1-C4 alkyl, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused.
  • 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Y is —NR4—C(O)—R3.
  • 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, whereinX is O or NR2; R1 is a pyridyl radical which is optionally substituted by 1-4 radicals of C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-2; wherein each R18 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, azido, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and R2 is a hydrogen or C1-C2 alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-2; and wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and R4 is a radical of hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; and wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and Z20 is —O— or —NR21—; wherein each R21 is independently a hydrogen or methyl radical; R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and R7 is a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused.
  • 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, whereinR3 is a radical of the formula wherein U is C—R13 or N; V and W are each independently C—R12 or N; R11 and R13 are each independently a radical of hydrogen, C1-C4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R19—Z19—; and each R12 is independently a radical of hydrogen, C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, R31—Z31— or R31—Z31—C1-C4 alkyl; provided that the combined total number of aryl and heteroaryl radicals in R11, R12 and R13 is 0-1; wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z19 is independently —O—, —S(O)2—, —CO2—, —C(O)—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R31 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z31 is independently —O—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 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 R5 and R6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C2 alkylamino, di(C1-C2 alkyl)amino, hydroxy, methoxy or ethoxy radical; and R7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused.
  • 6. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Y is —C(O)—NR3R4.
  • 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, whereinX is O or NR2; R1 is a pyridyl radical which is optionally substituted by 1-4 radicals of C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-2; wherein each R18 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, azido, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and each Z18 is independently —O—, —S—, —S(O)—, —S(O)2—, —CO2—, —C(O)—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R21 is independently a hydrogen or C1-C4 alkyl radical; R2 is a hydrogen or C1-C2 alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-2; and provided R3 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 —NR4—; and wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; and wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and Z20 is —O— or —NR21—; wherein each R21 is independently a hydrogen or methyl radical; R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, cyano, azido, nitro, carboxy; (C1-C4 alkoxy)carbonyl aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and R7 is a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused.
  • 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, whereinR3 is a radical of the formula whereinU is C—R13 or N; V and W are each independently C—R12 or N; R11 and R13 are each independently a radical of hydrogen, C1-C4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino, or R19—Z19—; and each R12 is independently a radical of hydrogen, C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, R31—Z31— or R31—Z31—C1-C4 alkyl; provided that the combined total number of aryl and heteroaryl radicals in R11, R12 and R13 is 0-1; provided when U is C—R13 and V and W are each C—R12, R11 and R13 are each other than a nitro, cyano, carboxy or alkoxycarbonyl radical; wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z19 is independently —O—, —S(O)2—, —CO2—, —C(O)—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R21 is independently a hydrogen or methyl radical; wherein each R31 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z31 is independently —O—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; and wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 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 R5 and R6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C2 alkylamino, di(C1-C2 alkyl)amino, hydroxy, methoxy or ethoxy radical; and R7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused.
  • 9. The compound of claim 1 which is 2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonylamino)pyridine.
  • 10. A pharmaceutical composition comprising a compound according to any of claims 1-9 and a pharmaceutically acceptable carrier.
  • 11. A method for prophylaxis or treatment of inflammation comprising administering an effective amount of a composition of claim 10.
  • 12. A method for prophylaxis or treatment of inflammation comprising administering an effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof, whereinX is O, S, S(O), S(O)2 or NR2; Y is —C(O)—NR3R4 or —NR4—C(O)—R3; R1 is a pyridyl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-3; R2 is a hydrogen or alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19-alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-3; and provided when Y is —C(O)—NR3R4, R3 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 —NR4—; and R4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R20—Z20-alkyl radical; wherein R18, R19 and R20 are each independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical; wherein the aryl and heteroaryl radicals of R4, R18, R19 and R20 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 Z18, Z19 and Z20 are each independently —O—, —S—, —S(O)—, —S(O)2—, —CO2—, —C(O)—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R21 is independently a hydrogen or alkyl radical; R5 and R6 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 R7 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; wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused.
  • 13. The method of claim 12, whereinR1 is a pyridyl radical which is optionally substituted by 1-4 radicals of C1-C6 alkyl, halo, C1-C6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—C1-C6 alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-3; R2 is a hydrogen or C1-C4 alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C6 haloalkyl or 1-3 halo radicals, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19—C1-C6 alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-3; and provided when Y is —C(O)—NR3R4, R3 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 —NR4—; and R4 is a radical of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl of 1-3 halo radicals, C2-C6 haloalkenyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C1-C6 alkyl radical; and wherein R18, R19 and R20 are each independently a hydrogen, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals of R4, R18, R19 and R20 are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; and each R21 is independently a hydrogen or C1-C4 alkyl radical; R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, C1-C4 aminoalkyl, (C1-C4 alkyl)amino-C1-C4 alkyl, di(C1-C4 alkyl)amino-C1-C4 alkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, aminosulfonyl, C1-C4 alkylaminosulfonyl, di(C1-C4 alkyl)aminosulfonyl, hydroxy, C1-C4 hydroxyalkyl, thiol, C1-C4 alkylthiol, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, (C1-C4 alkoxy)C1-C4 alkyl, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and R7 is a hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, C1-C4 aminoalkyl, (C1-C4 alkyl)amino-C1-C4 alkyl, di(C1-C4 alkyl)amino-C1-C4 alkyl, aminosulfonyl, C1-C4 alkylaminosulfonyl, di(C1-C4 alkyl)aminosulfonyl, hydroxy, C1-C4 hydroxyalkyl, thiol, C1-C4 alkylthiol, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, (C1-C4 alkoxy)C1-C4 alkyl, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused; or a pharmaceutically acceptable salt thereof.
  • 14. The method of claim 13, wherein Y is —NR4 —C(O)—R3.
  • 15. The method of claim 14, whereinX is O or NR2; R1 is a pyridyl radical which is optionally substituted by 1-4 radicals or C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-2; wherein each R18 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, azido, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and R2 is a hydrogen or C1-C2 alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-2; and wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; and wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and Z20 is —O— or —NR21—; wherein each R21 is independently a hydrogen or methyl radical; R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and R7 is a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused; or a pharmaceutically acceptable salt thereof.
  • 16. The method of claim 15, whereinR3 is a radical of the formula whereinU is C—R13 or N; V and W are each independently C—R12 or N; R11 and R13 are each independently a radical of hydrogen, C1-C4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R19—Z19—; and each R12 is independently a radical of hydrogen, C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, R31—Z31— or R31—Z31—C1-C4 alkyl; provided that the combined total number of aryl and heteroaryl radicals in R11, R12 and R13 is 0-1; wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z19 is independently —O—, —S(O)2—, —CO2—, —C(O)—, —NR21—C(O)—, —C(O)—NR21−, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R31 is independently a hydrogen, C1-C4 alkyl;. trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z31 is independently —O—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 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 R5 and R6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C2 alkylamino, di(C1-C2 alkyl)amino, hydroxy, methoxy or ethoxy radical; and R7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused; or a pharmaceutically acceptable salt thereof.
  • 17. The method of claim 13, wherein Y is —C(O)—NR3R4.
  • 18. The method of claim 17, whereinX is O or NR2; R1 is a pyridyl radical which is optionally substituted by 1-4 radicals of C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18—Z18— or R18—Z18—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R1 is 1-2; wherein each R18 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, azido, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and each Z18 is independently —O—, —S—, —S(O)—, —S(O)2—, —CO2—, —C(O)—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R21 is independently a hydrogen or C1-C4 alkyl radical; R2 is a hydrogen or C1-C2 alkyl radical; R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19—Z19— or R19—Z19—C1-C4 alkyl; provided that the total number of aryl and heteroaryl radicals in R3 is 1-2; and provided R3 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 —NR4—; and wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; and wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy; and Z20 is —O— or —NR21—; wherein each R21 is independently a hydrogen or methyl radical; R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and R7 is a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused; or a pharmaceutically acceptable salt thereof.
  • 19. The method of claim 18, whereinR3 is a radical of the formula whereinU is C—R13 or N; V and W are each independently C—R12 or N; R11 and R13 are each independently a radical of hydrogen, C1-C4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R19—Z19—; and each R12 is independently a radical of hydrogen, C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, R31—Z31— or R31—Z31—C1-C4 alkyl; provided that the combined total number of aryl and heteroaryl radicals in R11, R12 and R13 is 0-1; provided when U is C—R13 and V and W are each C—R12, R11 and R13 are each other than a nitro, cyano, carboxy or alkoxycarbonyl radical; wherein each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each Z19 is independently —O—, —S(O)2—, —CO2—, —C(O)—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; wherein each R21 is independently a hydrogen or methyl radical; wherein each R31 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 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; and each R31 is independently —O—, —NR21—, —NR21—C(O)—, —C(O)—NR21—, —NR21—S(O)2— or —S(O)2—NR21—; R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20—Z20—C2-C4 alkyl radical; and wherein R20 is a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical; wherein the aryl and heteroaryl radicals of R4 and R20 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 R5 and R6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C2 alkylamino, di(C1-C2 alkyl)amino, hydroxy, methoxy or ethoxy radical; and R7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; and wherein aryl is a phenyl or biphenyl radical which is optionally benzo fused or heterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally saturated C3-C4-carbocyclic-fused; or a pharmaceutically acceptable salt thereof.
  • 20. The method of claim 12 wherein the compound is 2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine.
Parent Case Info

This application is a division of application Ser. No. 09/185,119 filed Nov. 3, 1998 now U.S. Pat. No. 6,022,884 Feb. 8, 2000, which claims the benefit of Provisional Application Serial No. 60/064,953, Filed Nov. 7, 1997, which are hereby incorporated by reference.

US Referenced Citations (22)
Number Name Date Kind
3375257 Thiele et al. Mar 1968
3513171 Thiele et al. May 1970
3539639 Mrozik et al. Nov 1970
3712900 Thiele et al. Jan 1973
3819639 Delarge et al. Jun 1974
3929807 Fitzi Dec 1975
3980652 Delarge et al. Sep 1976
3991057 Delarge et al. Nov 1976
4002629 Delarge et al. Jan 1977
4094982 Morisawa et al. Jun 1978
4149872 Pilgram Apr 1979
4241068 Schromm et al. Dec 1980
4888047 Milano et al. Dec 1989
4983600 Ward et al. Jan 1991
5236948 Waterson Aug 1993
5312820 Ashton et al. May 1994
5380734 Hsu et al. Jan 1995
5593992 Adams et al. Jan 1997
5596008 Lee Jan 1997
5610320 Yoshino et al. Mar 1997
5665724 Sanfilippo et al. Sep 1997
5990133 Gaster et al. Nov 1999
Foreign Referenced Citations (38)
Number Date Country
2052894 Apr 1992 CA
1810162 Aug 1969 DE
2655144 Jun 1978 DE
3633485 Apr 1988 DE
3737748 May 1989 DE
38 04 346 A1 Aug 1989 DE
3804346 Aug 1989 DE
039051 Jul 1985 EP
0283762 Sep 1988 EP
0424848 May 1991 EP
0480258 Apr 1992 EP
0799825 Oct 1997 EP
1189188 Apr 1970 GB
4-364168 Dec 1992 JP
6-135934 May 1994 JP
7-285962 Oct 1995 JP
8-175993 Jul 1996 JP
8-175995 Jul 1996 JP
WO 9104027 Apr 1991 WO
WO 9314081 Jul 1993 WO
WO 9526957 Oct 1995 WO
WO 9603387 Feb 1996 WO
WO 9611930 Apr 1996 WO
WO 9618626 Jun 1996 WO
WO 9618617 Jun 1996 WO
WO 9618616 Jun 1996 WO
WO 9621654 Jul 1996 WO
WO 9621452 Jul 1996 WO
WO 9624584 Aug 1996 WO
WO 9640143 Dec 1996 WO
WO 9641795 Dec 1996 WO
WO 9705877 Feb 1997 WO
WO 9705878 Feb 1997 WO
WO 9709315 Mar 1997 WO
WO 9716426 May 1997 WO
WO 9716441 May 1997 WO
WO 9716442 May 1997 WO
WO 9718626 Jun 1997 WO
Non-Patent Literature Citations (39)
Entry
Baracos, et al., The New England Journal of Medicine, vol. 308, p. 553 (1983).
Berge et al., Journal of Pharmaceutical Sciences, vol. 66, No. 1, pp. 1 (1977).
Beutler et al., Journal of Immunology, vol. 135, p. 3969 (1985).
Brahn et al., Lymphokine and Cytokine Research, vol. 11, pp. 253 (1992).
Brunner et al., Eur. J. Med. Chem., vol. 25, pp. 35 (1990).
Bundgaard et al., J. Med. Chem., vol. 32, p. 2503 (1989).
Chandrasekhar et al., Clinical Immunology and Immunopathology, vol. 55, pp. 382-400 (1990).
Clouse et al., Journal of Immunology, vol. 142 pp. 431-438 (1989).
Colbry et al., J. Heterocyclic Chem., vol. 21, pp. 1521 (1984).
Cooper et al., Clin. Exp. Immunol., vol. 89, pp. 244 (1992).
Courtenay et al., Nature, vol. 283, pp. 666 (1980).
Davies et al., J. Chem. Soc., Chem. Commun., pp. 1153 (1993).
Dinarello, Eur. Cytokine Netw., vol. 5, pp. 517-531 (1994).
Dornow et al., Chem. Ber 87, pp. 985 (1954).
Firestein et al., American Journal of Pathology, vol. 140, p. 1309 (1992).
Folks et al., Journal of Immunology, vol. 136, pp. 4049 (1986).
Freifelder et al., J. Am. Chem. Soc., vol. 82, pp. 696 (1959).
Grussenmeyer et al., PNAS USA, vol. 82, pp. 7952-7954 (1985).
Kaiser, Tetrahedron, vol. 39, pp. 2055 (1983).
Kojima et al., Bull. Chem. Soc. Jpn., vol. 55, pp. 1454 (1992).
Lahdevirta et al., The American Journal of Medicine, vol. 85, p. 289 (1988).
Lang et al., Endocrinology, vol. 130, p. 43 (1992).
Liu et al., Stroke, vol. 25, p. 1481 (1994).
Maini et al., Immunological Reviews, vol. 144, p. 195 (1995).
Matsumoto et al., J. Heterocyclic Chem., vol. 21, pp. 673 (1984).
Nishigaki et al., Chem. Pharm. Bull, vol. 17:9, pp. 1827 (1969).
Shohami et al., J. Cereb. Blood Flow Metab., vol. 14, No. 4, p. 615 (1994).
Svensson et al., Drug Metabolism Reviews, vol. 19(2), pp. 165 (1988).
Swingle, Antiinflammatory Agents, Edited by Robert Scherrer and Michael Whitehouse, vol. II, Ch. 2, pp. 33-122 (1974).
Szalkowski et al., Endocrinology, vol. 136, p. 1474 (1995).
Trentham et al., Journal of Experimental Medicine, vol. 146, p. 857 (1977).
Wheeler et al., Journal of Labelled Compounds and Radiopharmaceuticals, vol. XXXI, No. 4, pp. 305 (1992).
Williams et al., PNAS USA, vol. 89, pp. 2922-2926 (1992).
Winter et al., Proc. Soc. Exp. Biol. Med., vol. 111, pp. 544 (1962).
Liu et al., Neuroscience Letters, vol. 164, pp. 125-128 (1993).
Lee et al., Circulatory Shock, vol. 44, pp. 97-103 (1995).
Beyaert et al., EMBO Journal, vol. 15, pp. 1914-1923 (1996).
Joosten et al., Arthritis & Rheumatism, vol. 39, pp. 797-809 (1996).
Delarge, Farmaco-Ed. Sc., vol. 29, pp. 101-108 (1974).
Provisional Applications (1)
Number Date Country
60/064953 Nov 1997 US