# Patent

## Title
Oxazole and thiazole compounds as beta-catenin modulators and uses thereof

## Abstract

A series of oxazole and thiazole compounds are shown herein to be small molecule inhibitors of the Wnt pathway that specifically target the activity of the stabilized pool of β-cat oxazole and thiazole compounds are disclosed that have a formula represented by the following:




The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, cancer, and others.

## Background
RELATED APPLICATIONS
The present application claims the benefit under 35 U.S.C. §119 of U.S. Provisional Application Ser. Nos. 61/062,772 filed Jan. 28, 2008; Ser. No. 61/084,681 filed Jul. 30, 2008; and Ser. No. 61/147,715 filed Jan. 27, 2009. The contents of each of said provisional applications is hereby incorporated by reference in its entirety.


GOVERNMENT RIGHTS
This invention was made with government support under Grant No. W81XWH-04-1-0460 awarded by the Department of Defense. Accordingly, the United States Government has certain rights in the invention.


FIELD OF THE INVENTION
This invention relates to oxazole and thiazole compounds capable of modulating β-catenin activity and uses of such compounds to modulate the activity of the Wnt/wingless (wg) signaling pathway.
BACKGROUND OF THE INVENTION
Wnts/wingless (wg) are a family of conserved signaling molecules that have been shown to regulate a plethora of fundamental developmental and cell biological processes, including cell proliferation, differentiation and cell polarity [Miller et al. Oncogene 18, 7860-72 (1999); Polakis. Genes Dev 14, 1837-51 (2000); Wodarz et al. Annu Rev Cell Dev Biol 14, 59-88 (1998)]. Mutations in the Wnt genes or in those genes encoding regulators of the Wnt/wg signaling pathway can cause devastating birth defects, including debilitating abnormalities of the central nervous system, axial skeleton, limbs, and occasionally other organs [Ciruna et al. Nature 439, 220-4 (2006); Grove et al. Development 125, 2315-25 (1998); Jiang et al. Dev Dyn 235, 1152-66 (2006); Kokubu et al. Development 131, 5469-80 (2004); Miyoshi et al. Breast Cancer Res 5, 63-8 (2003); Shu et al. Development 129, 4831-42 (2002); Staal et al. Hematol J 1, 3-6 (2000)]. Aberrant Wnt signaling has also been linked to human disease, such as hepatic, colorectal, breast and skin cancers [Miyoshi et al. supra (2003); Miyoshi et al. Oncogene 21, 5548-56 (2002); Moon et al. Nat Rev Genet. 5, 691-701 (2004)].
Wnts/wg encode secreted glycoproteins that activate receptor-mediated pathways leading to numerous transcriptional and cellular responses [Wodarz et al. supra (1998); Moon et al. supra (2004); Nusse. Trends Genet. 15, 1-3 (1999)]. The main function of the canonical Wnt pathway is to stabilize the cytoplasmic pool of a key mediator, β-catenin (β-cat)/armadillo (arm), which is otherwise degraded by the proteosome pathway (See FIG. 1). Initially identified as a key player in stabilizing cell-cell adherens junctions, β-cat/arm is also known to act as a transcription factor by forming a complex with the LEF/TCF (Lymphoid Enhancer Factor/T Cell Factor) family of HMG-box (High mobility group) transcription factors. Upon Wnt stimulation, stabilized β-cat/arm translocates to the nucleus, wherein together with LEF/TCF transcription factors, it activates downstream target genes [Miller et al. supra (1999); Staal et al. supra (2000); Nusse. supra (1999); Schweizer et al. Proc Natl Acad Sci USA 100, 5846-51 (2003)]. Catenin responsive transcription (CRT), which is the activation of transcriptional targets of β-cat, has been shown to regulate many aspects of cell growth, proliferation, differentiation and death. The Wnt/wg pathway can also be activated by inhibiting negative regulators such as GSK-3β (Glycogen Synthase Kinase-3β), APC (Adenomatous Polyposis Coli) and Axin that promote β-cat/arm degradation, or by introducing activating mutations in β-cat that render it incapable of interacting with the degradation complex, thus stabilizing its cytosolic pool [Logan et al. Annu Rev Cell Dev Biol 20, 781-810 (2004); Nusse et al. Cell Res 15, 28-32 (2005)]. Wnt/wg signaling can also activate an alternative “non-canonical” pathway that may lead to PKC (Protein Kinase C) and JNK (c-Jun N-terminal Kinase) activation resulting in calcium release and cytoskeletal rearrangements [Miller et al. supra (1999)].
At the plasma membrane, Wnt proteins bind to their receptor, belonging to the Frizzled family of proteins and the co-receptor encoded by LDL-related-protein-5, 6 (LRP5, LRP6)/arrow (arr, in Drosophila) [Schweizer et al. BMC Cell Biol 4, 4 (2003); Tamai et al. Mol Cell 13, 149-56 (2004)]. In the absence of the Wnt stimulus, GSK-3β is known to phosphorylate β-cat/arm, which marks it for ubiquitination and subsequent proteosome-mediated degradation. Activation of the receptor/co-receptor complex upon Wnt binding initiates a signal transduction cascade, which results in phosphorylation and subsequent inactivation of GSK-3β24.
Recent evidence has uncovered a new branch in the canonical Wnt/wg pathway whereby β-cat/arm can be stabilized in a GSK-3β independent fashion suggesting that regulated degradation of β-cat/arm (by GSK-3β) is not necessary for Wnt/wg signaling [Tolwinski et al. Dev Cell 4, 407-18 (2003); Tolwinski et al. Trends Genet. 20, 177-81 (2004)]. Specifically, upon Wg binding, Arr directly recruits Axin (a scaffold protein which acts as a negative regulator) to the plasma membrane and causes its degradation. As a consequence, Arm no longer binds Axin or the degradation complex, resulting in nuclear accumulation and signaling by β-cat/Arm42.
A large number of oxazole and thiazole compounds are commercially available.
In view of the above, a need exists for therapeutic agents, and corresponding pharmaceutical compositions and related methods of treatment that address conditions causally related to aberrant Wnt pathway activity and CRT activity, and it is toward the fulfillment and satisfaction of that need, that the present invention is directed.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a method for preventing, treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the Wnt pathway in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula I:




    
    
        wherein A is A1, A2 or A3;
        A1 is
    
    






    
    
        A2 is
    
    






    
    
        A3 is
    
    






    
    
        x is 1, when A is A1 or A2; or x is 0, when A is A3;
        L1 is S, SO or SO2;
        m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5;
        L2 is substituted or unsubstituted C1-C7 alkylene or heteroalkylene;
        each R1, R2a, R2b, R2c, and R2d is independently selected from hydrogen, halo, and substituted or unsubstituted C1-C6 alkyl;
        R2 is selected from aryl or heteroaryl, unsubstituted or substituted with one or more R4;
        R3 is hydroxy, alkoxy, substituted or unsubstituted amino or cycloheteroalkyl; or when A is A3, R3 is R5;
        each R4 and R5, is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and
        R5 is selected from aryl or heteroaryl, unsubstituted or substituted with one or more R5a;
        or a pharmaceutically acceptable salt, solvate or prodrug thereof;
        and stereoisomers, isotopic variants and tautomers thereof.
    
    


In one particular embodiment, with respect to compounds of formula I, A1 is




In one particular embodiment, with respect to compounds of formula I, A2 is




In one particular embodiment, with respect to compounds of formula I, A3 is




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIa:




and wherein L1, m1, n, R1, R2a, R2b, R2c, R2d, R2, R3, and R4 are as described for formula I.

In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIb:




and wherein L2, R1, R2, R3, and R4 are as described for formula I.

In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIc:




and wherein R2a, R2b, R2, R4, and R5 are as described for formula I.

In a further aspect, the present invention provides pharmaceutical compositions comprising an oxazole or an thiazole compound of the invention, and a pharmaceutically acceptable carrier, excipient or diluent. In this aspect of the invention, the pharmaceutical composition can comprise one or more of the compounds described herein. Moreover, the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are all pharmaceutically acceptable as prepared and used.
In a further aspect, this invention provides the compounds of the invention and other agents for use in the treatment of mammals susceptible to or afflicted with a condition from those listed herein, and particularly, such conditions as may be associated with alterations or aberrations in Wnt/wg pathway signaling.
In addition to the methods of treatment set forth above, the present invention extends to the use of any of the compounds of the invention for the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified.
A further aspect and object of the invention, is to provide a method of treating a mammal susceptible to or afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with e.g. altered Wnt/wg pathway signaling, by administering to such mammal a an effective disease-treating or condition-treating amount of a compound or composition of the invention. Such conditions include, without limitation, a variety of hyperproliferative disorders and cancers, including hepatic, colorectal, breast and skin cancers. Additional support for this aspect of the invention is presented in the fact that most cancers of the skin, intestine, and breast epithelial tissue are a result of increased levels of the activated/signaling pool of β-catenin. A number of birth defects are also associated with altered Wnt/wg pathway signaling, including debilitating abnormalities of the central nervous system, axial skeleton, limbs, and occasionally other organs.
Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description, which proceeds with reference to the following illustrative drawings.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a bar graph depicting the activity of candidate inhibitors on TOP12-LF in Clone 8 cells.
FIG. 2 shows a bar graph depicting the results of genetic epistasis analyses.
FIG. 3 shows a bar graph depicting the activity of candidate inhibitors on S37A β-catenin mediated TOP12-LF in Clone 8 cells.
FIG. 4 shows a bar graph representation of the effect of several inhibitory compounds in mammalian HEK-293 cells.
FIG. 5 shows photomicrographs of Wnt3a transformed C57 mg cell phenotypes and rescue thereof by inhibitory compounds.
FIG. 6 shows a bar graph of quantitative analyses of Wnt3a transformed C57 mg cell phenotypes and rescue thereof by inhibitory compounds.
FIG. 7 shows Inhibition of Wnt-target accumulation in HCT116 cells.
FIG. 8 shows Transcription Inhibition of Wnt-targets in HCT116 cells.
FIG. 9 shows C3 & C14 cause G0/G1 arrest.
FIG. 10 shows Quantification of −αPH3 staining in compound treated HCT116 cells.



DETAILED DESCRIPTION OF THE INVENTION
General Introduction
As indicated above, the Wnt pathway is one of a core set of evolutionarily conserved signaling pathways that regulates many aspects of metazoan development. Misregulation or aberrant regulation of the Wnt pathway can lead to adverse effects as demonstrated by the causal relationship identified between mutations in several components of the pathway and tumorigenesis of the liver, colon, breast and the skin. One of the most important effectors of the Wnt pathway is encoded by β-catenin (β-cat)/armadillo (arm). Induction by Wnt ligands leads to stabilization of cytosolic β-cat, which subsequently translocates into the nucleus to activate target genes that regulate many aspects of cell proliferation, growth, differentiation and death.
Since Catenin Responsive Transcription (CRT) has been implicated in the genesis of many cancers, this effector step of the pathway provides a good target for developing therapeutics that could modulate Wnt pathway activity, and more particularly, the nuclear activity of β-cat. Notably, the family of compounds disclosed herein are inhibitors that specifically target the activity of the signaling pool of β-catenin.
Definitions
The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.
The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.
‘Acyl’ or ‘Alkanoyl’ refers to a radical —C(O)R20, where R20 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary ‘acyl’ groups are —C(O)H, —C(O)—C1-C8 alkyl, —C(O)—(CH2)t(C6-C10 aryl), —C(O)—(CH2)t(5-10 membered heteroaryl), —C(O)—(CH2)t(C3-C10 cycloalkyl), and —C(O)—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
‘Substituted Acyl’ or ‘Substituted Alkanoyl’ refers to a radical —C(O)R21, wherein R21 is independently

    
    
        C1-C8 alkyl, substituted with halo or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
    
    


‘Acylamino’ refers to a radical —NR22C(O)R23, where R22 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl and R23 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein. Exemplary ‘acylamino’ include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary ‘acylamino’ groups are —NR24C(O)—C1-C8 alkyl, —NR24C(O)—(CH2)t(C6-C10 aryl), —NR24C(O)—(CH2)t(5-10 membered heteroaryl), —NR24C(O)—(CH2)t(C3-C10 cycloalkyl), and —NR24C(O)—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R24 independently represents H or C1-C8 alkyl.
‘Substituted Acylamino’ refers to a radical —NR25C(O)R26, wherein:
R25 is independently

    
    
        H, C1-C8 alkyl, substituted with halo or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and
    
    


R26 is independently

    
    
        H, C1-C8 alkyl, substituted with halo or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl;
    
    


provided at least one of R25 and R26 is other than H.
‘Acyloxy’ refers to a radical —OC(O)R27, where R27 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary ‘acyl’ groups are —(O)H, —C(O)—C1-C8 alkyl, —C(O)—(CH2)t(C6-C10 aryl), —C(O)—(CH2)t(5-10 membered heteroaryl), —C(O)—(CH2)t(C3-C10 cycloalkyl), and —C(O)—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
‘Substituted Acyloxy’ refers to a radical —OC(O)R28, wherein R28 is independently

    
    
        C1-C8 alkyl, substituted with halo or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
    
    


‘Alkoxy’ refers to the group —OR29 where R29 is C1-C8 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
‘Substituted alkoxy’ refers to an alkoxy group substituted with one or more of those groups recited in the definition of “substituted” herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)2—. Exemplary ‘substituted alkoxy’ groups are —O—(CH2)t(C6-C10 aryl), —O—(CH2)t(5-10 membered heteroaryl), —O—(CH2)t(C3-C10 cycloalkyl), and —O—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are OCF3, OCH2CF3, OCH2Ph, OCH2-cyclopropyl, OCH2CH2OH, and OCH2CH2NMe2.
‘Alkoxycarbonyl’ refers to a radical —C(O)—OR30 where R30 represents an C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein. Exemplary “alkoxycarbonyl” groups are C(O)O—C1-C8 alkyl, —C(O)O—(CH2)t(C6-C10 aryl), —C(O)O—(CH2)t(5-10 membered heteroaryl), —C(O)O—(CH2)t(C3-C10 cycloalkyl), and —C(O)O—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
‘Substituted Alkoxycarbonyl’ refers to a radical —C(O)—OR31 where R31 represents:

    
    
        C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, or 4-10 membered heterocycloalkylalkyl, each of which is substituted with halo, substituted or unsubstituted amino, or hydroxy; or
        C6-C10 aralkyl, or 5-10 membered heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.
    
    


‘Aryloxycarbonyl’ refers to a radical —C(O)—OR32 where R32 represents an C6-C10 aryl, as defined herein. Exemplary “aryloxycarbonyl” groups is —C(O)O—(C6-C10 aryl).
‘Substituted Aryloxycarbonyl’ refers to a radical —C(O)—OR33 where R33 represents

    
    
        C6-C10 aryl, substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.
    
    


‘Heteroaryloxycarbonyl’ refers to a radical —C(O)—OR34 where R34 represents a 5-10 membered heteroaryl, as defined herein. An exemplary “aryloxycarbonyl” group is —C(O)O-(5-10 membered heteroaryl).
‘Substituted Heteroaryloxycarbonyl’ refers to a radical —C(O)—OR35 where R35 represents:

    
    
        5-10 membered heteroaryl, substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.
    
    


“Alkoxycarbonylamino” refers to the group —NR36C(O)OR37, where R36 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein, and R37 is C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
‘Alkyl’ means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms. Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms. Exemplary straight chained groups include methyl, ethyl n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.
‘Substituted alkyl’ refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of “substituted” herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (—O-acyl or —OC(O)R20), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (—NR′′-alkoxycarbonyl or —NH—C(O)—OR27), amino, substituted amino, aminocarbonyl (carbamoyl or amido or —C(O)—NR′′2), aminocarbonylamino (—NR′′—C(O)—NR′′2), aminocarbonyloxy (—O—C(O)—NR′′2), aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, heteroaryl, nitro, thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)2-alkyl, and —S(O)2-aryl. In a particular embodiment ‘substituted alkyl’ refers to a C1-C8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR′′′SO2R′′, —SO2NR′′R′′, —C(O)R′′, —C(O)OR′′, —OC(O)R′′, —NR′′′C(O)R′′, —C(O)NR′′R′′′, —NR′′R′′′, or —(CR′′′R′′′′)mOR′′′; wherein each R′′ is independently selected from H, C1-C8 alkyl, —(CH2)t(C6-C10 aryl), —(CH2)t(5-10 membered heteroaryl), —(CH2)t(C3-C10 cycloalkyl), and —(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Each of R′′′ and R′′′′ independently represents H or C1-C8 alkyl.
“Alkylene” refers to divalent saturated alkene radical groups having 1 to 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (—CH2—), ethylene (—CH2CH2—), the propylene isomers (e.g., —CH2CH2CH2— and —CH(CH3)CH2—) and the like.
‘Substituted alkylene’ refers to those groups recited in the definition of “substituted” herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)2—.
“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (—CH═CH2), n-propenyl (—CH2CH═CH2), isopropenyl (—C(CH3)═CH2), vinyl and substituted vinyl, and the like.
“Substituted alkenyl” refers to those groups recited in the definition of “substituted” herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)2—.
“Alkenylene” refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 11 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH═CHCH2— and —C(CH3)═CH— and —CH═C(CH3)—) and the like.
“Alkynyl” refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 11 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation. Particular non-limiting examples of alkynyl groups include acetylenic, ethynyl (—C≡CH), propargyl (—CH2C≡CH), and the like.
“Substituted alkynyl” refers to those groups recited in the definition of “substituted” herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)2—.
‘Amino’ refers to the radical —NH2.
‘Substituted amino’ refers to an amino group substituted with one or more of those groups recited in the definition of ‘substituted’ herein, and particularly refers to the group —N(R38)2 where each R38 is independently selected from:

    
    
        hydrogen, C1-C8 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-C10 cycloalkyl; or
        C1-C8 alkyl, substituted with halo or hydroxy; or
        —(CH2)t(C6-C10 aryl), —(CH2)t(5-10 membered heteroaryl), —(CH2)t(C3-C10 cycloalkyl) or —(CH2)t(4-10 membered heterocycloalkyl) wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or
        both R38 groups are joined to form an alkylene group.

When both R38 groups are hydrogen, —N(R38)2 is an amino group. Exemplary ‘substituted amino’ groups are —NR39—C1-C8 alkyl, —NR39—(CH2)t(C6-C10 aryl), —NR39—(CH2)t(5-10 membered heteroaryl), —NR39—(CH2)t(C3-C10 cycloalkyl), and —NR39—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R39 independently represents H or C1-C8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term “substituted amino” includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.

    
    


‘Alkylamino’ refers to the group —NHR40, wherein R40 is C1-C8 alkyl;
‘Substituted Alkylamino’ refers to the group —NHR41, wherein R41 is C1-C8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Alkylarylamino’ refers to the group —NR42R43, wherein R42 is aryl and R43 is C1-C8 alkyl.
‘Substituted Alkylarylamino’ refers to the group —NR44R45, wherein R44 is aryl and R45 is C1-C8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Arylamino’ means a radical —NHR46 where R46 is selected from C6-C10 aryl and 5-10 membered heteroaryl as defined herein.
‘Substituted Arylamino’ refers to the group —NHR47, wherein R47 is independently selected from C6-C10 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Dialkylamino’ refers to the group —NR48R49, wherein each of R48 and R49 are independently selected from C1-C8 alkyl.
‘Substituted Dialkylamino’ refers to the group —NR50R51, wherein each of R59 and R51 are independently selected from C1-C8 alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Diarylamino’ refers to the group —NR52R53, wherein each of R52 and R53 are independently selected from C6-C10 aryl.
“Aminosulfonyl” or “Sulfonamide” refers to the radical —S(O2)NH2.
“Substituted aminosulfonyl” or “substituted sulfonamide” refers to a radical such as —S(O2)N(R54)2 wherein each R548 is independently selected from:

    
    
        H, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
        C1-C8 alkyl substituted with halo or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy;

provided that at least one R54 is other than H.

    
    


Exemplary ‘substituted aminosulfonyl’ or ‘substituted sulfonamide’ groups are —S(O2)N(R55)—C1-C8 alkyl, —S(O2)N(R55)—(CH2)t(C6-C10 aryl), —S(O2)N(R55)—(CH2)t(5-10 membered heteroaryl), —S(O2)N(R55)—(CH2)t(C3-C10 cycloalkyl), and —S(O2)N(R55)—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R55 independently represents H or C1-C8 alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Aralkyl’ or ‘arylalkyl’ refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
‘Substituted Aralkyl’ or ‘substituted arylalkyl’ refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
‘Substituted Aryl’ refers to an aryl group substituted with one or more of those groups recited in the definition of ‘substituted’ herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent. Particularly, ‘Substituted Aryl’ refers to an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.
Examples of representative substituted aryls include the following




In these formulae one of R56 and R57 may be hydrogen and at least one of R56 and R57 is each independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R60, and R61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, substituted aryl, 5-10 membered heteroaryl.
“Fused Aryl” refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
‘Arylalkyloxy’ refers to an —O-alkylaryl radical where alkylaryl is as defined herein.
‘Substituted Arylalkyloxy’ refers to an —O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Azido’ refers to the radical —N3.
‘Carbamoyl or amido’ refers to the radical —C(O)NH2.
‘Substituted Carbamoyl or substituted amido’ refers to the radical —C(O)N(R62)2 wherein each R62 is independently

    
    
        H, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
        C1-C8 alkyl substituted with halo or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy;

provided that at least one R62 is other than H.

Exemplary ‘Substituted Carbamoyl’ groups are —C(O)NR64—C1-C8 alkyl, C(O)NR64—(CH2)t(C6-C10 aryl), —C(O)N64—(CH2)t(5-10 membered heteroaryl), —C(O)NR64—(CH2)t(C3-C10 cycloalkyl), and —C(O)NR64—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R64 independently represents H or C1-C9 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

    
    


‘Carboxy’ refers to the radical —C(O)OH.
‘Cycloalkyl’ refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
‘Substituted cycloalkyl’ refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of ‘substituted’ herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent
‘Cyano’ refers to the radical —CN.
‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
‘Heteroaryl’ means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
Examples of representative heteroaryls include the following:




wherein each Y is selected from carbonyl, N, NR65, O and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl.

Examples of representative aryl having hetero atoms containing substitution include the following:




wherein each W is selected from C(R66)2, NR66, O and S; and each Y is selected from carbonyl, NR66, and S; and R66 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl.

As used herein, the term ‘heterocycloalkyl’ refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine. Particular examples of heterocycloalkyl groups are shown in the following illustrative examples:




wherein each W is selected from CR67, C(R67)2, NR67, O and S; and each Y is selected from NR67, 0 and S; and R67 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)2-alkyl, and —S(O)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

‘Hydroxy’ refers to the radical —OH.
‘Nitro’ refers to the radical —NO2.
‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents may be selected from the group consisting of:

    
    
        halogen, —R68, —O—, ═O, —OR68, —SR68, —S−, ═S, —NR68R69, ═NR68, —CCl3, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)2O−, —S(O)2OH, —S(O)2R68, —OS(O2)O−, —OS(O)2R68, —P(O)(O−)2, —P(O)(OR68)(O−), —OP(O)(OR68)(OR69), —C(O)R68, —C(S)R68, —C(O)OR68, —C(O)NR68R69, —C(O)O−, —C(S)OR68—NR70C(O)NR68R69, —NR70C(S)NR68R69, —NR71C(NR70)NR68R69 and —C(NR70)NR68R69;
    
    


wherein each R68, R69, R70 and R71 are independently:

    
    
        hydrogen, C1-C8 alkyl, C6-C10 aryl, arylalkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, heteroarylalkyl; or
        C1-C8 alkyl substituted with halo or hydroxy; or
        C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 cycloalkyl or 4-10 membered heterocycloalkyl each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

In a particular embodiment, substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.

In a further particular embodiment the substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR72SO2R73, —SO2NR73R72, —C(O)R73, —C(O)OR73, —OC(O)R73, —NR72C(O)R73, —C(O)NR73R72, —NR73R72, (CR72R72)mOR72, wherein, each R73 is independently selected from H, C1-C8 alkyl, —(CH2)t(C6-C10 aryl), —(CH2)t(5-10 membered heteroaryl), —(CH2)t(C3-C10 cycloalkyl), and —(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; and

        any alkyl groups present, may themselves be substituted by halo or hydroxy; and
        any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Each R independently represents H or C1-C6alkyl.
    
    


‘Substituted sulfanyl’ refers to the group —SR74, wherein R74 is selected from:

    
    
        C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
        C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
    
    


Exemplary ‘substituted sulfanyl’ groups are —S—(C1-C8 alkyl) and —S—(C3-C10 cycloalkyl), —S—(CH2)t(C6-C10 aryl), —S—(CH2)t(5-10 membered heteroaryl), —S—(CH2)t(C3-C10 cycloalkyl), and —S—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term ‘substituted sulfanyl’ includes the groups ‘alkylsulfanyl’ or ‘alkylthio’, ‘substituted alkylthio’ or ‘substituted alkylsulfanyl’, ‘cycloalkylsulfanyl’ or ‘cycloalkylthio’, ‘substituted cycloalkylsulfanyl’ or ‘substituted cycloalkylthio’, ‘arylsulfanyl’ or ‘aryltbio’ and ‘heteroarylsulfanyl’ or ‘heteroarylthio’ as defined below.
‘Alkylthio’ or ‘Alkylsulfanyl’ refers to a radical —SR75 where R75 is a C1-C8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
‘Substituted Alkylthio’ or ‘substituted alkylsulfanyl’ refers to the group —SR76 where R76 is a C1-C8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
‘Cycloalkylthio’ or ‘Cycloalkylsulfanyl’ refers to a radical —SR77 where R77 is a C3-C10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
‘Substituted cycloalkylthio’ or ‘substituted cycloalkylsulfanyl’ refers to the group-SR78 where R78 is a C3-C10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
‘Arylthio’ or ‘Arylsulfanyl’ refers to a radical —SR79 where R79 is a C6-C10 aryl group as defined herein.
‘Heteroarylthio’ or ‘Heteroarylsulfanyl’ refers to a radical —SR80 where R80 is a 5-10 membered heteroaryl group as defined herein.
‘Substituted sulfinyl’ refers to the group —S(O)R81, wherein R81 is selected from:

    
    
        C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
        C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
    
    


Exemplary ‘substituted sulfinyl’ groups are —S(O)—(C1-C8 alkyl) and —S(O)—(C3-C10 cycloallyl), —S(O)—(CH2)t(C6-C10 aryl), —S(O)—(CH2)t(5-10 membered heteroaryl), —S(O)—(CH2)t(C3-C10 cycloalkyl), and —S(O)—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term substituted sulfinyl includes the groups ‘alkylsulfinyl’, ‘substituted alkylsulfinyl’, ‘cycloalkylsulfinyl’, ‘substituted cycloalkylsulfinyl’, ‘arylsulfinyl’ and ‘heteroarylsulfinyl’ as defined herein.
‘Alkylsulfinyl’ refers to a radical —S(O)R82 where R82 is a C1-C8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
‘Substituted Alkylsulfinyl’ refers to a radical —S(O)R83 where R83 is a C1-C8 alkyl group as defined herein. substituted with halo, substituted or unsubstituted amino, or hydroxy.
‘Cycloalkylsulfinyl’ refers to a radical —S(O)R84 where R84 is a C3-C10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfinyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary ‘cycloalkylsulfinyl’ groups are S(O)—C3-C10 cycloalkyl.
‘Substituted cycloalkylsulfinyl’ refers to the group —S(O)R85 where R85 is a C3-C10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
‘Arylsulfinyl’ refers to a radical —S(O)R86 where R86 is a C6-C10 aryl group as defined herein.
‘Heteroarylsulfinyl’ refers to a radical —S(O)R87 where R87 is a 5-10 membered heteroaryl group as defined herein.
‘Substituted sulfonyl’ refers to the group —S(O)2R88, wherein R88 is selected from:

    
    
        C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
        C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
    
    


Exemplary ‘substituted sulfonyl’ groups are —S(O)2—(C1-C8 alkyl) and —S(O)2—(C3-C10 cycloalkyl), —S(O)2—(CH2)t(C6-C10 aryl), —S(O)2—(CH2)t(5-10 membered heteroaryl), —S(O)2—(CH2)t(C3-C10 cycloalkyl), and —S(O)2—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
‘Alkylsulfonyl’ refers to a radical —S(O)2R89 where R89 is an C1-C8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
‘Substituted Alkylsulfonyl’ refers to a radical —S(O)2R90 where R90 is an C1-C8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
‘Cycloalkylsulfonyl’ refers to a radical —S(O)2R91 where R91 is a C3-C10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
‘Substituted cycloalkylsulfonyl’ refers to the group —S(O)2R92 where R92 is a C3-C10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
‘Arylsulfonyl’ refers to a radical —S(O)2R93 where R93 is an C6-C10 aryl group as defined herein.
‘Heteroarylsulfonyl’ refers to a radical —S(O)2R94 where R94 is an 5-10 membered heteroaryl group as defined herein.
‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as —SO3H.
‘Substituted sulfo’ or ‘sulfonic acid ester’ refers to the group —S(O)2OR95, wherein R95 is selected from:

    
    
        C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
        C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
        C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
    
    


Exemplary ‘Substituted sulfo’ or ‘sulfonic acid ester’ groups are —S(O)2—O—(C1-C8 alkyl) and —S(O)2—O—(C3-C10 cycloalkyl), —S(O)2—O—(CH2)t(C6-C10 aryl), —S(O)2—O—(CH2)t(5-10 membered heteroaryl), —S(O)2—O—(CH2)t(C3-C10 cycloalkyl), and —S(O)2—O—(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
‘Thiol’ refers to the group —SH.
‘Aminocarbonylamino’ refers to the group —NR96C(O)NR96R96 where each R96 is independently hydrogen C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R96 groups, when attached to the same N, are joined to form an alkylene group.
‘Bicycloaryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system. Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
‘Bicycloheteroaryl’ refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system. Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like. Preferably, the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred. Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
‘Compounds of the present invention’, and equivalent expressions, are meant to embrace the compounds as hereinbefore described, in particular compounds according to any of the formulae herein recited and/or described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
‘Cycloalkylalkyl’ refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
‘Heterocycloalkylalkyl’ refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
‘Cycloalkenyl’ refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
‘Substituted cycloalkenyl’ refers to those groups recited in the definition of “substituted” herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)2—.
‘Fused Cycloalkenyl’ refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
“Ethenyl” refers to substituted or unsubstituted —(C═C)—.
‘Ethylene’ refers to substituted or unsubstituted —(C—C)—.
‘Ethynyl’ refers to —(C≡C)—.
‘Hydrogen bond donor’ group refers to a group containing O—H, or N—H functionality. Examples of ‘hydrogen bond donor’ groups include —OH, —NH2, and —NH—R97 and wherein R97 is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.
‘Dihydroxyphosphoryl’ refers to the radical —PO(OH)2.
‘Substituted dihydroxyphosphoryl’ refers to those groups recited in the definition of “substituted” herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
‘Aminohydroxyphosphoryl’ refers to the radical —PO(OH)NH2.
‘Substituted aminohydroxyphosphoryl’ refers to those groups recited in the definition of “substituted” herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
‘Nitrogen-Containing Heterocycloalkyl’ group means a 4 to 7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
‘Thioketo’ refers to the group ═S.
One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutaric acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
‘Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
‘Therapeutically effective amount’ means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.
‘Compounds of the present invention’, and equivalent expressions, are meant to embrace compounds of the Formula (e) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
When ranges are referred to herein, for example but without limitation, C1-C8 alkyl, the citation of a range should be considered a representation of each member of said range.
Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
As used herein, the term ‘isotopic variant’ refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an ‘isotopic variant’ of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.
Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
As used herein and unless otherwise indicated, the term “enantiomerically pure R-compound” refers to at least about 80% by weight R-compound and at most about 20% by weight S-compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R-compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
As used herein and unless otherwise indicated, the term “enantiomerically pure S-compound” or “S-compound” refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R-compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.
In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
The Compounds
The present invention provides a method for preventing, treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the Wnt signaling pathway in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula I:




    
    
        wherein A is A1, A2 or A3;
        A1 is
    
    






    
    
        A2 is
    
    






    
    
        A3 is
    
    






    
    
        x is 1, when A is A1 or A2; or x is 0, when A is A3;
        L1 is S, SO or SO2;
        m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5;
        L2 is substituted or unsubstituted C1-C7 alkylene or heteroalkylene;
        each R1, R2a, R2b, R2c, and R2d is independently selected from hydrogen, halo, and substituted or unsubstituted C1-C6 alkyl;
        R2 is selected from aryl or heteroaryl, unsubstituted or substituted with one or more R4;
        R3 is hydroxy, alkoxy, substituted or unsubstituted amino or cycloheteroalkyl; or when A is A3, R3 is R5;
        each R4 and R5a is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and
        R5 is selected from aryl or heteroaryl, unsubstituted or substituted with one or more R5a;
        or a pharmaceutically acceptable salt, solvate or prodrug thereof,
        and stereoisomers, isotopic variants and tautomers thereof.
    
    


In one particular embodiment, with respect to compounds of formula I, A1 is




In one particular embodiment, with respect to compounds of formula I, A2 is




In one particular embodiment, with respect to compounds of formula I, A3 is




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIa:




and wherein L1, m1, n, R1, R2a, R2b, R2c, R2d, R2, R3, and R4 are as described for formula I.

In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIb:




and wherein L2, R1, R2, R3, and R4 are as described for formula I.

In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIc:




and wherein R2a, R2b, R2, R4, and R5 are as described for formula.

In one particular embodiment, with respect to compounds of formula IIa; L1 is S.
In one particular embodiment, with respect to compounds of formula IIa; L1 is SO or SO2.
In one particular embodiment, with respect to compounds of formula IIa or IIc; each of R2a and R2b is H.
In one particular embodiment, with respect to compounds of formula IIa or IIc; one of R2a and R2b is independently Me and the other is H.
In one particular embodiment, with respect to compounds of formula IIa or IIc; each of R2a and R2b is Me.
In one particular embodiment with respect to compounds of formula IIa; the subscript m1 is 1 or 2; and each of R2c and R2d is H.
In one particular embodiment, with respect to compounds of formula IIa; the subscript m1 is 1 or 2; and each of R2c and R2d is independently Me and the other is H.
In one particular embodiment, with respect to compounds of formula IIa; the subscript m1 is 1 or 2; and each of R2c and R2d is Me.
In one particular embodiment, with respect to compounds of formula IIa; L1 is S; the subscript m1 is 1; and each of R2, R2b, R2c and R2d is H.
In one particular embodiment, with respect to compounds of formula IIb; L2 is —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, or —CH2—CH2—CH2—CH2—.
In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIc.
In one particular embodiment, with respect to compounds of formula IIb or IIc, R2 is phenyl, unsubstituted or substituted with one or more R4.
In one particular embodiment, with respect to compounds of formula IIb or IIc, R2 is heteroaryl, unsubstituted or substituted with one or more R4.
In one particular embodiment, with respect to compounds of formula IIb or IIc, R2 is pyridyl, furanyl, thiophenyl, or pyrrolidinyl, unsubstituted or substituted with one or more R4.
In one particular embodiment, with respect to compounds of formula IIc, R5 is phenyl, unsubstituted or substituted with one or more R4.
In one particular embodiment, with respect to compounds of formula IIc, R5 is heteroaryl, unsubstituted or substituted with one or more R4.
In one particular embodiment, with respect to compounds of formula IIc, R5 is pyridyl, furanyl, thiophenyl, or pyrrolidinyl, unsubstituted or substituted with one or more R4.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R5 is H or substituted or unsubstituted C1-C6 alkyl.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R1 is halo.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R1 is Me.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R3 is OH.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R3 is alkoxy.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R3 is substituted or unsubstituted amino.
In one particular embodiment, with respect to compounds of formula IIa or IIb; R3 is NR3aR3b; and each R3a and R3b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R3a and R3b join together to form a cycloheteroalkyl heteroaryl ring.
In one particular embodiment, with respect to compounds of formula I, the compound is according to formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf:







    
    
        wherein n and R4 are as described for formula I; R3a and R3b are as described above; and m is 0 or 1.
    
    


In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IVa, IVb, or IVc:




    
    
        wherein n, R4, and R5 as described for formula I; and R3a and R3b as described above.
    
    


In one particular embodiment, with respect to compounds of formula IIa-IVc, each of R4 is H.
In one particular embodiment, with respect to compounds of formula IIa-IVc, n, when present, is 1; and R4 is alkyl, alkoxy, haloalkyl, or halo.
In one particular embodiment, with respect to compounds of formula IIa-IVc, n, when present, is 1 or 2; and R4 is Me, Et, i-Pr, OMe, OEt, O-i-Pr, Cl, or F.
In one particular embodiment, with respect to compounds of formula IIa-IVc, n, when present, is 1 or 2; and R4 is Me, OMe, SMe, or Et.
In one particular embodiment, with respect to compounds of formula I, the compound is according to formulae Va, Vb, Vc, Vd, Ve or Vf:




    
    
        wherein R3a and R3b are as described above; and m is 0 or 1.
    
    


In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3a is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3a is substituted or unsubstituted alkyl.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3a is substituted or unsubstituted benzyl.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3, is substituted or unsubstituted phenethyl.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3a is substituted or unsubstituted cycloalkyl.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3a is cyclopropyl.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf; R3b is substituted or unsubstituted heteroaryl.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf; R3b is substituted or unsubstituted heterocycloalkyl.
In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, and each of R3a and R3b is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf; one of R3a and R3b is substituted or unsubstituted alkyl and the other is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, one of R3a and R3b is substituted or unsubstituted benzyl and the other is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, one of R3a and R3b is substituted or unsubstituted phenethyl and the other is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, one of R3a and R3b is substituted or unsubstituted cycloalkyl and the other is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, one of R3a and R3b is substituted or unsubstituted cyclopropyl and the other is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, one of R3a and R3b is substituted or unsubstituted cyclopentyl or cyclobutyl and the other is H.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, R3a and R3b join together to form a cycloheteroalkyl heteroaryl ring.
In one particular embodiment, with respect to compounds of formula IIIb, IIId, IIIf, IVa, Vb, Vd, or Vf, NR3aR3b is:




    
    
        and wherein R3c is H or alkyl.
    
    


In one particular embodiment, with respect to compounds of formula I, the compound is according to formula VIa, VIb, or VIc:




    
    
        and m is 0 or 1.
    
    


In one particular embodiment, with respect to compounds of formula IIIa-VIc, m, when present, is 0.
In one particular embodiment, with respect to compounds of formula IIIa-VIc, m, when present, is 1.
In one particular embodiment, with respect to compounds of formula IIIa-VIc, the compound is according to formula VIIa, VIIb, VIIc or VIId:




    
    
        wherein R3b is as described above.
    
    


In one particular embodiment, with respect to compounds of formula VIIa, VIIb, VIIc or VIId; R3b is substituted or unsubstituted cycloalkyl, phenyl, benzyl, or phenethyl.
In one particular embodiment, with respect to compounds of formula VIIa, VIIb, VIIc or VIId; R3b is substituted or unsubstituted heteroaryl, or heterocycloalkyl.
In one particular embodiment, with respect to compounds of formula I, the compound is according to formula VIIIa, VIIb, VIIc, or VIIId:




    
    
        wherein Cy is
    
    






    
    
         and wherein R3c is H or alkyl.
    
    


In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IXa, IXb, IXc or IXd:




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula Xa, Xb, Xc or Xd:




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula XIa, XIb, XIc or XId:




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula XIIa, XIIb, XIIc or XIId:




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula XIIIa, XIIIb, XIIIc or XIIId:




In one particular embodiment, with respect to compounds of formula I, the compound is according to formula XIVa, or XIVb:




    
    
        wherein each R4 and R5, is independently selected from alkyl, alkoxy, haloalkyl, halo, hydroxy, carboxy, carbalkoxy, or nitro; and each n and t is independently 0, 1 or 2.
    
    


In one particular embodiment, with respect to compounds of formula XIVa, or XIVb, each R4 is H.
In one particular embodiment, with respect to compounds of formula XIVa, or XIVb, n is 1 or 2; and each R4 is independently Me, Et, i-Pr, OMe, OEt, O-i-Pr, Cl, or F.
In one particular embodiment, with respect to compounds of formula XIVa, or XIVb, each R5a is H.
In one particular embodiment, with respect to compounds of formula XIVa, or XIVb, t is 1 or 2; and each R5a is independently Me, Et, i-Pr, OMe, OEt, O-i-Pr, Cl, or F.
In one particular embodiment, with respect to compounds of formula I, the compound is according to formula XVa or XVb:




In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 1.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 2.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 3.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 4.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 5.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 6.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 7.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 8.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 9.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 10.
In one particular embodiment, with respect to compounds of formula I, the compound is selected from Table 11.
In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Preferred are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
Pharmaceutical Compositions
When employed as pharmaceuticals, the compounds of this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound-administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
The compounds of this invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.
The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences. 
The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1—Tablets
A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
Formulation 2—Capsules
A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active amide compound per capsule).
Formulation 3—Liquid
A compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color would then be diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
Formulation 4—Tablets
A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
Formulation 5—Injection
A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
Formulation 6—Topical
Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75° C. and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
Methods of Treatment
The present compounds are used as therapeutic agents for the treatment of conditions in mammals that are causally related or attributable to aberrant activity of the Wnt/wg signaling pathway. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutics for preventing and/or treating a variety of cancers and hyperproliferative conditions in mammals, including humans. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for use in such methods, and for the preparation of medicaments useful for such methods.
In a method of treatment aspect, this invention provides a method of treating a mammal susceptible to or afflicted with a condition associated with cancer and/or a hyperproliferative disorder, which method comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
In yet another method of treatment aspect, this invention provides a method of treating a mammal susceptible to or afflicted with a condition that gives rise to increased cellular proliferation or a transformed phenotype, or that relates to dysregulation of Wnt/wg signaling. The present oxazoles and thiazoles have use as anti-proliferative agents that reduce proliferative levels (potentially to normal levels for a particular cell type), and/or anti-transformed phenotype agents that restore, at least in part, normal phenotypic properties of a particular cell type. Accordingly, the present oxazoles and thiazoles have use for the treatment of cancers and hyperproliferative disorders relating to aberrant Wnt/wg signaling.
In additional method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with a cancer causally related or attributable to aberrant activity of the Wnt/wg signaling pathway. Such cancers include, without limitation, those of the liver, colon, rectum, breast and skin. Such methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions just described.
As a further aspect of the invention there is provided the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
For the prevention and/or treatment of long-term conditions, such as psoriasis, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. Psoriasis, for example, has been linked to Wnt signaling. Several basic and clinical studies using patient samples revealed an increase in nuclear β-catenin staining in many psoriatic samples. It has been suggested that a sustained low-level increase in Wnt/β-catenin signaling could be responsible for skin psoriatic lesions. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
When used to prevent the onset of a hyperproliferative condition, the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
The compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to safe and efficacious for such combined administration.
General Synthetic Procedures
The compounds of this invention may be purchased from various commercial sources or can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
The following schemes are presented with details as to the preparation of representative compounds that have been listed hereinabove. The compounds of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.












EXAMPLE 1
Protocols/Methods for In Vitro Testing of Candidate Compounds
The present inventors employed a novel methodology that integrates a “sensitized” chemical genetic high-throughput screen (HTS) with RNA-interference (RNAi) screening technology in order to identify specific small molecule inhibitors of the Wnt pathway in Drosophila cells. As described herein, Drosophila Clone 8 cell-based assay systems developed by the present inventors to investigate the Wnt/wg pathway [DasGupta et al. Science 308, 826-33 (2005)] were used in a small molecule chemical genetic screen to identify specific inhibitors of the pathway. These cell-based assays, which are described in detail below, utilize a Wnt-responsive luciferase reporter dTF12, the activity of which can be determined using immunofluorescence-based visual detection means. The present inventors used the small-molecule library available from the Institute of Chemistry and Cellular Biology (ICCB-Longwood) at Harvard Medical School, Boston, for the screen.
More particularly, the method for testing and identifying compounds useful in the present invention begins with the activation of the signaling pathway by the introduction of dsRNAs specific for Axin, which is the scaffold protein that negatively regulates β-cat by promoting its GSK-3β-mediated degradation. The resultant activation of the Wnt signaling pathway is then detected by assessing the activity of the Wnt-responsive luciferase reporter gene in the cell-based assay system. Thereafter, candidate compounds are added to the cell-based assay system to assess their effect on the strongly induced Wg-reporter-gene (TOPFlash) activity that results from the dsRNA-mediated knockdown of Axin. This protocol significantly increases the specificity of the small-molecule inhibitors for CRT and serves to identify molecules that regulate Wnt signaling activity downstream of the Axin-mediated degradation complex. Although not wishing to be bound by theory, the prediction is that the candidate compounds act on the “activated” or stable pool of β-cat and potentially prevent its interaction with known components of the transcriptional-activator complex (such as pangolin (pan)/dTcf, pygopus (pygo), legless (lgs) or Bcl9, p300/CBP), or other proteins that may function to regulate the activity of stabilized cytosolic β-cat.
Methods and Materials
Primary small molecule screen for the Wingless signaling pathway in Drosophila Clone 8 cells
Day 1 (PM):

    Set up transfection with Wg-reporter (dTF12), Normalization vector (PolIII-RL) and dsRNA against DAxin (dsRNA is specific towards Drosophila Axin and lacks any predicted off-targets).
    1. Add 40,000 Drosophila Clone 8 cells (in 40 μL) in 384-well plate (white solid bottom, Corning Costar) using the multidrop.
    2. Add 20 μL of Transfection mix in each well of a 384-well plate (Corning Costar) using the multidrop.


Transfection Mix:

    TOP12x-Luc (DNA)=25 ng (0.25 μL of DNA @0.1 μg/μL)
    PolIII-RLuc (DNA)=25 ng (0.25 μL of DNA @0.1 μg/μL)
    dsRNA to DAxin=100 ng (5 μL of dsRNA @20 ng/μL)
    Buffer EC=13.5 μL
    Enhancer=0.8 μL
    Effectene=0.25 μL
    Total volume=20 μL
    Incubate at 25° C. for 4 days to ensure complete knockdown of Axin.


Day 5 (PM):

    Add small molecule library (Cybio Robot). Incubate 18 hrs.


Day 6 (AM):

    Assay luminescence from the samples using the “Dual-Glo” luciferase kit (Promega Inc.).
    Specifically, aspirate supernatant and add 20 μL media+20 μL luciferase buffer using the multidrop. Read Firefly Luciferase activity on the En Vision (Perkin Elmer plate reader). Add 20 μL of Stop&Glo using the multidrop. Read Renilla luciferase activity on the En Vision (Perkin Elmer plate reader).


Epistasis Analysis: Epistasis Analysis was conducted in a 96 well format following the protocol as described for the Primary Screen (above), except that, 80,000 Clone 8 cells were used per well. Small Molecule Compounds were used at a final concentration of 2.5 ng/ul.
Reporter Assay in Mammalian HEK 293 cells: HEK 293 cells were transfected with 50 ng each of the Wnt-responsive STF16 luciferase reporter and pCMV-RL normalization reporter using the Lipofectamine LTX (Invitrogen Inc.) in a 96 well plate format.
Transfection Mix Per Well

    STF16-FLuc (DNA): 50 ng (0.5 μL of DNA @0.1 μg/μL)
    CMV-RLuc (DNA): 50 ng (0.5 μL of DNA @0.1 μg/μL)
    Lipofectamine-LTX: 0.25 μL
    Serum Free Medium: 20 μL


Cells were cultured in DMEM/10% FBS at 37° C. for 2 days following which, they were induced with Wnt3a conditioned media for 1 day and then treated with small molecule compounds to a final concentration of 2.5 ng/μl for approximately 18 hours. Luciferase reporter activity was then measured using the Dual-Glo system (Promega Inc.) on the Envision Plate Reader. Normalized luciferase activity in response to treatment with candidate small molecule compounds was compared to that obtained from cells treated with DMSO.
C57 mg transformation Assay: The transformation assay was carried out in a 96 well format. C57 mg cells were cultured in DMEM/10% FBS supplemented with purified Wnt3a protein (R&D Systems) to a final concentration of 100 ng/μl. Small molecule compounds dissolved in DMSO were added to a final concentration of 10 ng/μl and 0.01% DMSO. Following incubation at 37° C. for 5 days, cells were fixed with 4% Formaldehyde in 1×PBS at RT for 30 min and washed subsequently with 1×PBS at room temperature (RT) for 5 minutes (x3). Cells were then permeabilized in Blocking buffer (0.1% Triton-X/1×PBS/5% Normal Goat Serum) at RT for 20 min, subsequent to which, cells were incubated with anti-β-cat at RT for 1 hour (diluted to 1:1000 in blocking buffer). Subsequently, cells were washed with 1×PBS at RT for 10 minutes (x3) and then incubated with secondary antibody and Alexa-Fluor 488 conjugated phalloidin in Blocking buffer at RT for 1 hour. Following a brief wash in 1×PBS, cells were imaged in PBS buffer using the Array-Scan imaging system.
Molecular validation of C57 mg transformation assay was performed by qPCR analysis of the Wnt-target gene, WISP1. First strand cDNA was prepared from C57 mg cells treated as above using Cells-to-cDNA kit (Ambion, Inc.) as directed by the manufacturer. Equal amounts of cDNA were used for qPCR analysis using primers specific for WISP1 and GAPDH (the endogenous control). Comparison of amplification kinetics of WISP1 from samples treated with compounds to those treated with DMSO (ddCt method) was used to study changes in Wnt-directed transcriptional activity in response to treatment with candidate small molecule compounds.
Unless otherwise indicated, all experiments described herein that call for supplemental Wnt3a utilize Wnt3a conditioned media prepared by harvesting media from L-cells stably transfected with a Wnt3a coding construct (available from ATCC #CRL-2647). The cells are cultured in DMEM containing 10% fetal bovine serum (FBS). The medium, harvested from adherent cells cultured to about 80% confluency over 4 days, is purified through a 0.2 μm filter and stored at 4° C. over several months without an appreciable loss in activity [Willert et al. Nature 423, 448-52 (2003)].
Results
The Wnt signaling pathway was induced by the introduction of dsRNAs specific for Axin into Clone 8 cells comprising the Wg-responsive luciferase reporter-gene (dTF12). As described herein, Axin is a scaffold protein that negatively regulates Arm/β-cat by promoting its degradation. Thereafter, a selected set of a small molecule library was added to the Clone 8 cell-based assay system to assess the effect of individual compounds on (Axin dsRNA-mediated) activated CRT by monitoring the activity of the Wg-responsive luciferase reporter-gene (dTF12). The primary screen identified molecules that have a statistically significant effect on the activity of the dTF12-luciferase reporter gene, wherein a minimum of a 2.5-fold change in reporter activity was considered “significant” as a cut-off for hit-picking compounds for secondary screens. As shown in FIG. 1, addition of these compounds to the cells strongly repressed dTF12-reporter activity (>70-90%). Six of the strongest inhibitors are identified herein and, as indicated, share significant structural similarities suggesting that they constitute a family of compounds (i.e., a subset of oxazoles and thiazoles) that regulate a common aspect of the Wnt-pathway activity by potentially binding to the same target protein.
Epistatic Analyses:
Small molecule inhibitors identified in the primary screen may modulate Wnt signaling by affecting intermolecular interactions at any point downstream of Axin in the signaling cascade. Given that the oncogenic character of β-cat and therefore the Wnt pathway itself is caused by aberrant CRT (Park et al. Cancer Res 59, 4257-60 (1999); Lin et al. Proc Natl Acad Sci USA 97, 4262-6 (2000), a major focus of the present invention is to study those compounds which affect Wnt-responsiveness by regulating the transcriptional complex involved in CRT. The use of dsRNAs targeted to specific components of the Wnt pathway elucidates the level at which the compounds exert their inhibitory effect on the Wnt/Wg signaling pathway. This objective can be achieved by activating the Wnt pathway in Clone 8 cells using dsRNAs targeting other known negative regulators of the Wnt pathway, such as Slimb/βTrCP and SkpA, and assaying the effect of the compounds on the dTF12 reporter activity in these cells. Each of the aforementioned biomolecules functions to negatively regulate Wnt signaling downstream of Axin, so these analyses further delineate the stage in the Wnt pathway wherein the compound in question exerts its effect. The results of this experimental approach are presented in FIG. 2.
To gain further evidence that the compounds exert their inhibitory effect in the nucleus, they have been tested in Clone 8 cells transfected with a construct coding for a degradation resistant form of β-cat, S37A β-cat [Orford et al. J Biol Chem 272, 24735-8 (1997)]. This mutant form of β-cat bears a Serine to Alanine mutation, thus rendering it refractory to GSK3β mediated phosphorylation and hence proteosome degradation. An inhibitory effect of the compounds on the activity of S37A β-cat thus provides further proof that the compounds exert their effect on Wnt responsiveness at the level of CRT. The concentration of the compounds for all of the above assays is kept constant at 2.5 ng/μl, which is the same as that used for the primary screen. As shown in FIG. 3, most of the compounds exert an inhibitory effect on Wnt signaling on the transcriptional level. Data depicted in FIG. 3 show that a majority of the compounds inhibit S37A-mediated reporter activity, thus lending further support to the notion that these putative inhibitors do indeed function by abrogating the activity of stabilized β-cat in the nucleus.
Reproducibility of Inhibitory Effect of Small Molecules in Mammalian Cells:
In order to confirm and corroborate the activity of CRT inhibitor compounds in a mammalian context, the present inventors have tested a subset of the inhibitors identified in the context of established mammalian cell lines. To this end, the present inventors have optimized culture conditions for screening for Wnt signaling modulators in mammalian HEK 293 cells in a 96-well plate format. Briefly, HEK 293 cells were transfected with pSTF16-LF along with the normalization reporter, pCMV-RL and the effect of the compounds on reporter activity in such cells was determined by quantifying the luminescence from the luciferase reporter gene as described in Dasgupta et al. [supra (2005)]. As shown in FIG. 6, the present inventors have been able to recapitulate the inhibitory effect of several candidate inhibitors in these cells using the Wnt responsive luciferase reporter, STF16-LF.
In that Wnt signaling has been shown to have a profound influence on both cell fate and cell proliferation in various developmental and pathogenic contexts [Clevers. Cell 127, 469-80 (2006)], the present inventors have begun to investigate the activity of a subset of the CRT inhibitors identified in the primary screen in the context of other available Wnt responsive cell lines. Such cell lines can be used to ascertain further the inhibitory activity of the putative small molecule inhibitors in a phenotypic context. Such Wnt responsive cell-specific phenotypes include an assessment of transformation of the C57 mg mammary epithelial cell line, neural differentiation capacity of G-Olig2 ES cells, E-cadherin expression in the HT-29 colon cancer cell line, and Wnt induced invasive capacity of the MCF-7 breast adenocarcinoma cell line.
The C57 mg cell line, which was isolated from mouse mammary epithelial tissue [Wong et al. Mol Cell Biol 14, 6278-86 (1994)], has previously been shown to undergo transformation when cultured in Wnt-conditioned media. Transformation of the cell line is evidenced by pronounced changes in morphology, typified by formation of chord-like bundles of cells or foci-forming colonies that break off and float in the media [Wong et al. supra, 1994]. This Wnt responsive phenotype provides a mammalian assay in which to evaluate the inhibitory effect of the small molecule inhibitors identified in the primary screen. Briefly, cells are cultured in Wnt3a conditioned media in the presence or absence of a small molecule inhibitor and morphological analysis conducted using automated microscopy.
The present inventors have established a phenotypic assay using the Wnt-responsive C57 mg mouse mammary epithelial cell line to ascertain the validity of the inhibitory compounds identified in the primary screen. Specifically, addition of Wnt3a conditioned media or purified Wnt3a protein results in cellular transformation, manifested by a pronounced change from an epithelial-cell like morphology to those resembling spindle shaped cells with chord like bundles. Addition of candidate small molecule compounds to such cells in the presence of Wnt3a results in significant inhibition of the transformation phenotype. The Array-Scan imagining system (Cellomics Inc.) is used to image such phenotypic changes in a 96-well plate format so as to gain a quantitative estimate of the degree of the inhibitory effect of the compounds on Wnt3a induced transformation in C57 mg cells. Quantitative analysis of the transformation phenotype is measured by the degree of actin fiber alignment (defined as anisotropy), which is expressed as the standard deviation (SD) of the angles projected by the actin fibers relative to the normal; low SD numbers reflect an increase in Wnt-responsive transformation. This approach allows for objective inferences on the cellular effects of the candidate inhibitors. See FIG. 5.
As depicted in FIG. 5, compounds 10 and 14 show a significant inhibition of Wnt3a induced C57 mg transformation, whereas compounds 1, 5, 8, 11, 12, 13, 18 and 22 show a partial reduction in the degree of transformation. It should be noted that the degree of inhibitory effect of the compounds on Wnt-induced phenotypes may vary with different cellular types. For example, compounds 10 and 14 are poor inhibitors of TOP12-LF activity in HEK-293 cells (see FIG. 4), and yet seem to be potent inhibitors of Wnt3a-induced transformation in C57 mg cells. This could perhaps be due to their effect on the interaction of β-cat with different transcriptional co-factors in the nucleus that drive transcription of different targets. However to further validate the efficacy of candidate compounds in inhibiting Wnt-induced C57 mg transformation, the present inventors monitored changes in the expression of WISP1 mRNA by qRT-PCR. WISP1 is the key β-catenin target responsible for C57 mg transformation in response to Wnt signaling [Xu et al. Genes Dev. 14, 585-95 (2000)]. Reduction in the level of WISP1 mRNA correlates highly with the observed phenotypic rescue in response to Wnt exposure (FIG. 6).
The HT-29 colon cancer cell line has been shown to undergo β-cat/TCF dependent Epithelial Mesenchymal Transition (EMT) which can be monitored by changes in both morphology and downregulation of E-cadherin expression levels and upregulation of vimentin [Yang et al. Cell 127, 139-55 (2006)]. The HT-29 cell line, therefore, provides a model system for analysis of the candidate small molecule inhibitors in the context of a transformed colon cancer cell. Accordingly, the present inventors will treat HT-29 cells with candidate small molecules and assay E-cadherin and vimentin levels by western blotting as well as immunochemistry using commercially available antibodies. Furthermore, morphological analysis by compound differential contrast (DIC) microscopy will also be used to determine the effect of the compounds in inhibiting β-cat dependent EMT.
The MCF-7 breast cancer cell line exhibits a pronounced invasive capacity in response to Wnt signaling [Yook et al. Nat Cell Biol 8, 1398-406 (2006)]. To utilize this cell line to assess the activity of Wnt inhibitor compounds identified, MCF-7 cells can be transduced with recombinant retroviral vectors coding for Wnt3a or β-cat-S33Y, a constitutively active form of β-cat [as described in Yook et al. supra, (2006)]. The retroviral vectors will be prepared from pPGS-β-cateninS33Y- or pPGS-Wnt3a-transfected 293 packaging cells. MCF-7 cells transduced with these retroviral vectors can be loaded onto the upper chamber of Matrigel (prepared in serum-free DMEM culture media) containing Transwells, which are subsequently cultured in complete media with inhibitory compounds or DMSO. The cultures will be incubated at 37° C. in a humidified chamber for 24-72 hrs. Following incubation of the cell-loaded Matrigel, non-invasive cells are scraped off and the invaded cells counted by simple light microscopy by fixing and staining with Trypan Blue [Valster et al. Methods 37, 208-15 (2005)]. Results derived from this assay will provide insights into the use of compounds as inhibitors of the metastatic potential of malignant cells in general and malignant breast cancer cells in particular.
G-Olig2 ES cells (available from ATCC) contain a GFP insertion in the gene for Olig 2, a neural lineage specific transcription factor. Neural differentiation, therefore, results in the upregulation of GFP-positive cells. Neural differentiation of G-Olig2 ES cells can be induced by treating these cells with synthetic Retinoic Acid (RA) following the appearance of Embryoid bodies in culture. It has previously been shown that Wnt signaling inhibits neural differentiation of ES cells [Bouhon et al. Brain Res Bull 68, 62-75 (2005)]. To assay the inhibitory effect of the candidate compounds, the present inventors will culture the above ES cells in Wnt3a conditioned media containing RA and individual compounds and determine the number of GFP positive cells by Flow Cytometry. The inhibitory effect on Wnt signaling will be reflected by a reduction in the number of GFP positive differentiated cells in cultures treated with DMSO+RA as compared to those treated with compound+RA.
Although the present Example is directed to screening in the context of an “activated” Wnt pathway, it will be appreciated that other components of the pathway that promote Wnt signaling can be targeted for RNAi mediated ablation and the result of such an approach would be an “inhibited” Wnt pathway. In either event, the cellular milieu of an “activated” or an “inhibited” Wnt pathway can be used as a genetic background in which to perform small molecule/compound chemical screens directed to the identification of small molecules/compounds such as those of the present invention, that modulate the activity of a specific component of a signaling pathway.
EXAMPLE 2
Protocols/Methods for In Vitro and In Vivo Testing
Preliminary in vivo tests to assay the efficacy of the compounds will be performed in the zebrafish, Danio rerio, wherein increased Wnt signaling during zebrafish embryonic development results in axial specification defects and loss of anterior fates. This is commonly manifested by loss of or reduced eye-structures. To test the effectiveness of the compounds in inhibiting Wnt-signaling in a whole organismal context, one-cell embryos will be injected with synthetic Wnt8 mRNA and cultured in the presence of DMSO or individual compounds. Inhibitory activity of the compounds will be assayed by quantifying the penetrance of the Wnt8 induced phenotype.
Upon successful in vivo validation of the compounds in an animal model system, their efficacy will be further tested in the clinically relevant mouse model system, viz. the APCmin mouse. Loss of APC function results in an increase in the level of signaling competent β-catenin, which has been shown to be the causative factor in the induction of colon cancer in the above mouse model. Such mice will be administered candidate compounds and assayed for the regression of tumors resulting from increased Wnt signaling in the APCmin mouse. Standardized protocols for tail-vein and/or tissue injections will be used.
EXAMPLE 3
The colon carcinoma cell line, HCT-116 offers a pathologically-relevant system to examine the effects of candidate Wnt-inhibitors. HCT-116 cells bear a deletion of the S45 residue in β-cat, making it refractory to phosphorylation and degradation, thereby resulting in constitutive CRT. Wnt targets such as CycD1 and c-myc are thus overexpressed in this cell-type.
In order to test the inhibitory effect of candidate compounds on the transcription of endogenous Wnt/β-cat target genes in HCT116 cells, lysates were prepared from cells that were either treated with candidate small molecules or DMSO control. As shown in FIG. 7, the protein levels of CycD1 and c-myc were markedly reduced upon the addition of increasing concentrations of candidate compounds. qRT-PCR assays for the CycD1 and c-myc locus confirmed that the changes in their protein level reflected a change in their mRNA transcription (FIG. 8), further corroborating the effect of the candidate small molecules at the level of modulating CRT. Taken together, our analyses suggest a common theme of CRT-inhibition by these candidate compounds in a wide variety of Wnt-responsive heterologous cell types, thus making them ideal lead compounds for drug development for Wnt/CRT-related human disease. Finally, as predicted for the inhibition of target genes involved in cell cycle and cell proliferation, flow cytometry analyses of HCT116 cells treated with candidate compounds showed a G0/G1 arrest of the cell cycle (FIG. 9). Cell cycle arrest of compound treated HCT116 cells was further confirmed by the reduced number of phosphorylated Histone3 (PH3) positive cells, when cultured in the presence of candidate compounds (FIG. 10).

    C3: Oxazole
    C5: Thiazole


EXAMPLE 4
Additional Protocols
HCT116 cells were obtained from ATCC(CCL-247) and cultured in McCoy's 5A medium supplemented with 10% Fetal Bovine Serum (FBS) at 37° C. with 5% CO2. Target accumulation validations were performed by qPCR following treatment with the lead compounds. Briefly, cells were treated specified concentrations of compounds for 1 day, and lysed in 50 ul of Cell Lysis Buffer (Ambion #AM8723) at 75° C./10′. First-strand cDNA was prepared using High-Capacity Reverse Transcription Kit (Applied Biosystems # 4368814) as per manufacturer's instructions. Real-time qPCR was carried out for CycD1, c-Myc and GAPDH2 (endogenous control) using pre-validated gene-specific primer pairs from Qiagen and the SYBr green PCR master mix from Applied Biosystems. Data analysis was performed using the MxPro-Mx3005P system from Stratagene using the ddCt method.
Flow Cytometry analysis was performed on HCT116 cells treated with candidate compounds for 16 hrs per standard protocols. Briefly, compound treated cells were harvested and washed in 1×PBS followed by fixation in 70% Ethanol at 4° C. for 16 hrs. Cells were then washed in 1×PBS and treated with RNAse at 37° C. for 30′. Following extensive washes in 1×PBS, cellular DNA was stained with 500 ug/ml of Propidium Iodide at room temperature for 10′. Cells were washed again in 1×PBS and analysed by flow cytometry on a FACScalibur machine (Beckson Dickinson) at the NYU flow cytometry core facility.
EXAMPLE 5
Exemplary Compounds of the Invention
The following compounds, as exemplified in Tables 1-10, have been purchased, or can be purchased, or can be prepared according to the synthetic schemes described herein, or can be prepared according to the synthetic methods known to one skilled in the art.







TABLE 1







Oxazole amides (R3 = NH-benzyl)








 









ID
Structure
MW





IIa-1




421.35


 


IIa-2




400.93


 


IIa-3




452.62


 


IIa-4




466.65


 


IIa-5




456.58


 


IIa-6




484.68


 


IIa-7




414.50


 


IIa-8




410.54


 


IIa-9




430.96


 


IIa-10




430.96


 


IIa-11




396.51


 


IIa-12




440.52


 


IIa-13




468.62


 


IIa-14




414.50


 


IIa-15




396.51


 


IIa-16




426.54


 


IIa-17




426.54


 


IIa-18




410.54


 


IIa-19




436.58


 


IIa-20




410.54


 


IIa-21




430.96


 


IIa-22




430.96


 


IIa-23




382.49


 


IIa-24




416.93


 


IIa-25




412.51


 


IIa-26




396.51


 


IIa-27




426.50


 


IIa-28




396.51


 


IIa-29




412.51


 


IIa-30




422.55


 


IIa-31




382.49


 


IIa-32




416.93


 


IIa-33




396.51


 


IIa-34




412.51


 


IIa-35




412.51


 


IIa-36




446.96


 


IIa-37




446.96


 


IIa-38




442.54


 


IIa-39




456.52


 


IIa-40




426.54


 


IIa-41




442.54


 


IIa-42




430.50


 


IIa-43




452.58


 


IIa-44




386.90


 


IIa-45




421.35


 


IIa-46




400.93


 


IIa-47




400.93


 


IIa-48




396.51


 


IIa-49




380.51


 


IIa-50




410.50


 


IIa-51




396.51


 


IIa-52




438.55


 


IIa-53




421.35


 


IIa-54




400.93


 


IIa-55




430.91


 


IIa-56




416.93


 


IIa-57




404.89


 


IIa-58




398.55


 


IIa-59




432.99


 


IIa-60




432.99


 


IIa-61




428.58


 


IIa-62




412.58


 


IIa-63




442.56


 


IIa-64




428.58


 


IIa-65




470.61


 


IIa-66




380.51


 


IIa-67




414.96


 


IIa-68




414.96


 


IIa-69




410.54


 


IIa-70




394.54


 


IIa-71




424.52


 


IIa-72




410.54


 


IIa-73




386.90


 


IIa-74




421.35


 


IIa-75




421.35


 


IIa-76




416.93


 


IIa-77




404.89


 


IIa-78




370.45


 


IIa-79




404.89


 


IIa-80




400.48


 


IIa-81




384.48


 


IIa-82




414.46


 


IIa-83




400.48


 


IIa-84




366.49


 


IIa-85




400.93


 


IIa-86




400.93


 


IIa-87




396.51


 


IIa-88




380.51


 


IIa-89




396.51


 


IIa-90




366.49


 


IIa-91




400.93


 


IIa-92




400.93


 


IIa-93




396.51


 


IIa-94




380.51


 


IIa-95




410.50


 


IIa-96




380.51


 


IIa-97




396.51


 


IIa-98




398.48


 


IIa-99




432.93


 


IIa-100




432.93


 


IIa-101




428.51


 


IIa-102




412.51


 


IIa-103




442.49


 


IIa-104




428.51


 


IIa-105




416.47


 


IIa-106




437.35


 


IIa-107




386.45


 


IIa-108




420.89


 


IIa-109




400.48


 


IIa-110




430.46


 


IIa-111




404.44


 


IIa-112




382.49


 


IIa-113




416.93


 


IIa-114




416.93


 


IIa-115




412.51


 


IIa-116




396.51


 


IIa-117




396.51


 


IIa-118




412.51


 


IIa-119




400.48


 


IIa-120




382.49


 


IIa-121




416.93


 


IIa-122




416.93


 


IIa-123




412.51


 


IIa-124




396.51


 


IIa-125




426.50


 


IIa-126




412.51


 


IIa-127




400.48


 


IIa-128




422.55


 


IIa-129




402.90


 


IIa-130




437.35


 


IIa-131




437.35


 


IIa-132




416.93


 


IIa-133




446.91


 


IIa-134




416.93


 


IIa-135




420.89


 


IIa-136




442.97


 


IIa-137




382.49


 


IIa-138




416.93


 


IIa-139




412.51


 


IIa-140




396.51


 


IIa-141




426.50


 


IIa-142




412.51


 


IIa-143




402.90


 


IIa-144




437.35


 


IIa-145




437.35


 


IIa-146




416.93


 


IIa-147




446.91


 


IIa-148




432.93


 


IIa-149




420.89


 


IIa-150




398.48


 


IIa-151




432.93


 


IIa-152




432.93


 


IIa-153




442.49


 


IIa-154




416.47


 


IIa-155




428.51


 


IIa-156




462.96


 


IIa-157




462.96


 


IIa-158




458.54


 


IIa-159




442.54


 


IIa-160




472.52


 


IIa-161




442.54


 


IIa-162




458.54


 


IIa-163




446.50


 


IIa-164




468.58


 


IIa-165




368.46


 


IIa-166




402.90


 


IIa-167




402.90


 


IIa-168




398.48


 


IIa-169




448.93


 


IIa-170




432.47


 


IIa-171




432.93


 


IIa-172




398.48


 


IIa-173




432.93


 


IIa-174




432.93


 


IIa-175




428.51


 


IIa-176




412.51


 


IIa-177




442.49


 


IIa-178




412.51


 


IIa-179




438.55


 


IIa-180




470.55


 


IIa-181




414.48


 


IIa-182




448.93


 


IIa-183




444.51


 


IIa-184




458.49


 


IIa-185




444.51


 


IIa-186




448.93


 


IIa-187




414.48


 


IIa-188




448.93


 


IIa-189




448.93


 


IIa-190




444.51


 


IIa-191




428.51


 


IIa-192




458.49


 


IIa-193




428.51


 


IIa-194




444.51


 


IIa-195




454.55


 


IIa-196




432.93


 


IIa-197




398.48


 


IIa-198




432.93


 


IIa-199




432.93


 


IIa-200




428.51


 


IIa-201




412.51


 


IIa-202




442.49


 


IIa-203




412.51


 


IIa-204




428.51


 


IIa-205




416.47


 


IIa-206




436.89


 


IIa-207




416.47


 


IIa-208




418.90


 


IIa-209




436.89


 


IIa-210




453.35


 


IIa-211




448.93


 


IIa-212




453.35


 


IIa-213




453.35


 


IIa-214




436.89


 


IIa-215




432.93


 


IIa-216




453.35


 


IIa-217




448.93


 


IIa-218




462.91


 


IIa-219




418.90


 


IIa-220




432.93


 


IIa-221




448.93


 


IIa-222




432.93


 


IIa-223




442.54


 


IIa-224




462.96


 


IIa-225




446.50


 


IIa-226




458.54


 


IIa-227




477.38


 


IIa-228




477.38


 


IIa-229




412.51


 


IIa-230




456.57


 


IIa-231




456.57


 


IIa-232




416.47


 


IIa-233




507.41


 


IIa-234




442.54


 


IIa-235




474.54


 


IIa-236




493.38


 


IIa-237




493.38


 


IIa-238




428.51


 


IIa-239




472.56


 


IIa-240




472.56


 


IIa-241




432.47


 


IIa-242




523.41


 


IIa-243




458.54


 


IIa-244




477.38


 


IIa-245




477.38


 


IIa-246




442.54


 


IIa-247




412.51


 


IIa-248




456.57


 


IIa-249




456.57


 


IIa-250




416.47


 


IIa-251




507.41


 


IIa-252




442.54


 


IIa-253




400.48


 


IIa-254




426.97


 


IIa-255




410.50


 


IIa-256




426.50


 


IIa-257




400.48


 


IIa-258




432.93
















TABLE 2







Oxazole amides (R3 = NH-phenethyl)








 









ID
Structure
MW





IIa-301




416.93


 


IIa-302




444.98


 


IIa-303




424.57


 


IIa-304




410.54


 


IIa-305




470.59


 


IIa-306




410.54


 


IIa-307




424.57


 


IIa-308




444.98


 


IIa-309




498.65


 


IIa-310




456.57


 


IIa-311




442.60


 


IIa-312




440.57


 


IIa-313




430.96


 


IIa-314




456.57


 


IIa-315




396.51


 


IIa-316




430.96


 


IIa-317




410.54


 


IIa-318




460.98


 


IIa-319




486.59


 


IIa-320




440.57


 


IIa-321




426.54


 


IIa-322




514.65


 


IIa-323




394.54


 


IIa-324




468.62


 


IIa-325




435.38


 


IIa-326




414.96


 


IIa-327




447.02


 


IIa-328




472.63


 


IIa-329




426.60


 


IIa-330




412.58


 


IIa-331




428.98


 


IIa-332




454.50


 


IIa-333




394.54


 


IIa-334




482.65


 


IIa-335




444.53


 


IIa-336




384.48


 


IIa-337




414.96


 


IIa-338




440.57


 


IIa-339




380.51


 


IIa-340




468.62


 


IIa-341




394.54


 


IIa-342




380.51


 


IIa-343




446.96


 


IIa-344




472.56


 


IIa-345




412.51


 


IIa-346




500.62


 


IIa-347




434.92


 


IIa-348




460.53


 


IIa-349




414.50


 


IIa-350




488.58


 


IIa-351




430.96


 


IIa-352




410.54


 


IIa-353




396.51


 


IIa-354




484.62


 


IIa-355




430.96


 


IIa-356




456.57


 


IIa-357




410.54


 


IIa-358




396.51


 


IIa-359




484.62


 


IIa-360




451.38


 


IIa-361




476.98


 


IIa-362




430.96


 


IIa-363




505.04


 


IIa-364




430.96


 


IIa-365




410.54


 


IIa-366




396.51


 


IIa-367




484.62


 


IIa-368




451.38


 


IIa-369




476.98


 


IIa-370




430.96


 


IIa-371




416.93


 


IIa-372




505.04


 


IIa-373




472.56


 


IIa-374




426.54


 


IIa-375




412.51


 


IIa-376




476.98


 


IIa-377




502.59


 


IIa-378




456.57


 


IIa-379




442.54


 


IIa-380




530.65


 


IIa-381




442.54


 


IIa-382




446.96


 


IIa-383




472.56


 


IIa-384




412.51


 


IIa-385




426.54


 


IIa-386




426.54


 


IIa-387




440.57


 


IIa-388




456.57


 


IIa-389




472.56


 


IIa-390




458.60


 


IIa-391




462.96


 


IIa-392




428.51


 


IIa-393




442.54


 


IIa-394




456.57


 


IIa-395




472.56


 


IIa-396




488.56


 


IIa-397




474.60


 


IIa-398




462.96


 


IIa-399




488.56


 


IIa-400




428.51


 


IIa-401




442.54


 


IIa-402




442.54


 


IIa-403




456.57


 


IIa-404




488.56


 


IIa-405




472.56


 


IIa-406




488.56


 


IIa-407




446.96


 


IIa-408




412.51


 


IIa-409




426.54


 


IIa-410




426.54


 


IIa-411




440.57


 


IIa-412




456.57


 


IIa-413




472.56


 


IIa-414




458.60


 


IIa-415




450.92


 


IIa-416




460.53


 


IIa-417




462.57


 


IIa-418




476.98


 


IIa-419




432.93


 


IIa-420




467.37


 


IIa-421




460.98


 


IIa-422




492.98


 


IIa-423




476.98


 


IIa-424




492.98


 


IIa-425




432.93


 


IIa-426




467.37


 


IIa-427




446.96


 


IIa-428




492.98


 


IIa-429




492.98
















TABLE 3







Oxazole amides (R3 = NH-Phenyl)








 









ID
Structure
MW





IIa-501




443.48


 


IIa-502




461.38


 


IIa-503




396.51


 


IIa-504




456.57


 


IIa-505




404.44


 


IIa-506




382.49


 


IIa-507




440.52


 


IIa-508




396.51


 


IIa-509




393.47


 


IIa-510




413.46


 


IIa-511




452.46


 


IIa-512




414.48


 


IIa-513




414.48


 


IIa-514




463.35


 


IIa-515




418.90


 


IIa-516




418.90


 


IIa-517




478.96


 


IIa-518




412.51


 


IIa-519




412.51


 


IIa-520




456.52


 


IIa-521




442.49


 


IIa-522




428.51


 


IIa-523




481.34


 


IIa-524




398.48


 


IIa-525




432.93


 


IIa-526




432.93


 


IIa-527




412.51


 


IIa-528




412.51


 


IIa-529




456.52


 


IIa-530




444.51


 


IIa-531




432.93


 


IIa-532




412.51


 


IIa-533




426.54


 


IIa-534




420.44


 


IIa-535




416.47


 


IIa-536




486.90


 


IIa-537




453.35


 


IIa-538




434.90


 


IIa-539




442.49


 


IIa-540




442.49


 


IIa-541




468.46


 


IIa-542




479.35


 


IIa-543




434.90


 


IIa-544




434.90


 


IIa-545




469.35


 


IIa-546




436.44


 


IIa-547




428.51


 


IIa-548




428.51


 


IIa-549




472.52


 


IIa-550




458.49


 


IIa-551




497.34


 


IIa-552




414.48


 


IIa-553




448.93


 


IIa-554




448.93


 


IIa-555




428.51


 


IIa-556




428.51


 


IIa-557




472.52


 


IIa-558




460.51


 


IIa-559




448.93


 


IIa-560




442.54


 


IIa-561




428.51


 


IIa-562




442.49


 


IIa-563




493.38


 


IIa-564




442.54


 


IIa-565




436.44


 


IIa-566




464.93


 


IIa-567




432.47


 


IIa-568




469.35


 


IIa-569




452.46


 


IIa-570




418.90


 


IIa-571




418.90


 


IIa-572




453.35


 


IIa-573




412.51


 


IIa-574




456.52


 


IIa-575




481.34


 


IIa-576




398.48


 


IIa-577




432.93


 


IIa-578




412.51


 


IIa-579




412.51


 


IIa-580




456.52


 


IIa-581




444.51


 


IIa-582




432.93


 


IIa-583




412.51


 


IIa-584




420.44


 


IIa-585




416.47


 


IIa-586




486.90


 


IIa-587




453.35


 


IIa-588




380.51


 


IIa-589




382.49


 


IIa-590




421.35


 


IIa-591




380.51


 


IIa-592




431.35
















TABLE 4







Oxazole amides (R3 = NH—C3-C7cycloalkyl)








 









ID
Structure
MW





IIa-601




402.56


 


IIa-602




388.53


 


IIa-603




388.53


 


IIa-604




418.56


 


IIa-605




392.95


 


IIa-606




372.53


 


IIa-607




404.60


 


IIa-608




386.56


 


IIa-609




392.95


 


IIa-610




376.50


 


IIa-611




372.53


 


IIa-612




404.53


 


IIa-613




388.53


 


IIa-614




408.95


 


IIa-615




388.53


 


IIa-616




374.51


 


IIa-617




404.53


 


IIa-618




420.53


 


IIa-619




420.53


 


IIa-620




416.59


 


IIa-621




402.56


 


IIa-622




416.59


 


IIa-623




402.56


 


IIa-624




374.51


 


IIa-625




388.53


 


IIa-626




402.56


 


IIa-627




418.56


 


IIa-628




418.56


 


IIa-629




432.59


 


IIa-630




406.98


 


IIa-631




386.56


 


IIa-632




358.51


 


IIa-633




392.95


 


IIa-634




406.98


 


IIa-635




378.92


 


IIa-636




404.60


 


IIa-637




404.60


 


IIa-638




418.62


 


IIa-639




390.57


 


IIa-640




386.56


 


IIa-641




376.50


 


IIa-642




390.52


 


IIa-643




362.47


 


IIa-644




372.53


 


IIa-645




372.53


 


IIa-646




386.56


 


IIa-647




358.51


 


IIa-648




372.53


 


IIa-649




372.53


 


IIa-650




404.53


 


IIa-651




418.56


 


IIa-652




390.51


 


IIa-653




378.47


 


IIa-654




402.56


 


IIa-655




374.51


 


IIa-656




388.53


 


IIa-657




402.56


 


IIa-658




374.51


 


IIa-659




408.95


 


IIa-660




422.98


 


IIa-661




394.92


 


IIa-662




388.53


 


IIa-663




402.56


 


IIa-664




374.51


 


IIa-665




390.51


 


IIa-666




434.56


 


IIa-667




434.56


 


IIa-668




448.59


 


IIa-669




420.53


 


IIa-670




404.53


 


IIa-671




404.53


 


IIa-672




418.56


 


IIa-673




420.53


 


IIa-674




420.53


 


IIa-675




434.56


 


IIa-676




420.53


 


IIa-677




420.43


 


IIa-678




434.56


 


IIa-679




404.53


 


IIa-680




418.56


 


IIa-681




422.52


 


IIa-682




424.95


 


IIa-683




438.98


 


IIa-684




424.95


 


IIa-685




438.98


 


IIa-686




374.51


 


IIa-687




374.51


 


IIa-688




360.48


 


IIa-689




390.51


 


IIa-690




364.90


 


IIa-691




376.54


 


IIa-692




358.51


 


IIa-693




364.90


 


IIa-694




348.44


 


IIa-695




344.48


 


IIa-696




376.48


 


IIa-697




364.44


 


IIa-698




360.48


 


IIa-699




360.48


 


IIa-700




380.90


 


IIa-701




360.48


 


IIa-702




376.48


 


IIa-703




406.50


 


IIa-704




346.45


 


IIa-705




376.48


 


IIa-706




392.48


 


IIa-707




376.48


 


IIa-708




380.44


 


IIa-709




396.90


 


IIa-710




396.90


 


IIa-711




352.84


 


IIa-712




346.45


 


IIa-713




346.45


 


IIa-714




362.45


 


IIa-715




336.84


 


IIa-716




316.43


 


IIa-717




336.84


 


IIa-718




348.49


 


IIa-719




330.45


 


IIa-720




320.39


 


IIa-721




316.43


 


IIa-722




316.43


 


IIa-723




348.42


 


IIa-724




336.39


 


IIa-725




332.42


 


IIa-726




332.42


 


IIa-727




352.84


 


IIa-728




348.42


 


IIa-729




348.42


 


IIa-730




364.42


 


IIa-731




348.42


 


IIa-732




368.84


 


IIa-733




336.84
















TABLE 5







Oxazole amides (R3 = NH-misc)








 









ID
Structure
MW





IIa-1001




387.89


 


IIa-1002




368.89


 


IIa-1003




400.88


 


IIa-1004




461.58


 


IIa-1005




416.59


 


IIa-1006




445.63


 


IIa-1007




431.60


 


IIa-1008




376.52


 


IIa-1009




394.49


 


IIa-1010




348.47


 


IIa-1011




433.57


 


IIa-1012




403.55


 


IIa-1013




397.50


 


IIa-1014




362.49


 


IIa-1015




378.49


 


IIa-1016




386.47


 


IIa-1017




362.49


 


IIa-1018




434.67


 


IIa-1019




508.69


 


IIa-1020




449.62


 


IIa-1021




470.04


 


IIa-1022




529.11


 


IIa-1023




436.64


 


IIa-1024




462.68


 


IIa-1025




508.69


 


IIa-1026




461.58


 


IIa-1027




362.49


 


IIa-1028




348.47


 


IIa-1029




403.55


 


IIa-1030




529.11


 


IIa-1031




433.57


 


IIa-1032




397.50


 


IIa-1033




362.49


 


IIa-1034




386.47


 


IIa-1035




406.55


 


IIa-1036




376.52


 


IIa-1037




431.56


 


IIa-1038




419.55


 


IIa-1039




414.57


 


IIa-1040




394.49


 


IIa-1041




402.54


 


IIa-1042




438.59


 


IIa-1043




422.55


 


IIa-1044




417.57


 


IIa-1045




348.47


 


IIa-1046




390.51


 


IIa-1047




508.69


 


IIa-1048




392.52


 


IIa-1049




495.65


 


IIa-1050




446.62


 


IIa-1051




364.47


 


IIa-1052




479.65


 


IIa-1053




453.61


 


IIa-1054




375.47


 


IIa-1055




369.45


 


IIa-1056




410.54


 


IIa-1057




500.71


 


IIa-1058




522.72


 


IIa-1059




447.56


 


IIa-1060




408.52


 


IIa-1061




383.47


 


IIa-1062




348.47


 


IIa-1063




372.45


 


IIa-1064




380.47


 


IIa-1065




419.55


 


IIa-1066




362.49


 


IIa-1067




376.48


 


IIa-1068




417.53


 


IIa-1069




350.44


 


IIa-1070




388.51


 


IIa-1071




378.49


 


IIa-1072




400.54


 


IIa-1073




424.57


 


IIa-1074




364.47


 


IIa-1075




392.52


 


IIa-1076




348.47


 


IIa-1077




515.08


 


IIa-1078




439.58


 


IIa-1079




447.56


 


IIa-1080




334.44


 


IIa-1081




334.44


 


IIa-1082




376.48


 


IIa-1083




378.49


 


IIa-1084




400.54


 


IIa-1085




424.57


 


IIa-1086




364.47


 


IIa-1087




405.52


 


IIa-1088




348.47


 


IIa-1089




389.52


 


IIa-1090




597.74


 


IIa-1091




439.58


 


IIa-1092




477.58


 


IIa-1093




438.55


 


IIa-1094




413.50


 


IIa-1095




378.49


 


IIa-1096




364.47


 


IIa-1097




364.47


 


IIa-1098




410.49


 


IIa-1099




449.57


 


IIa-1100




392.52


 


IIa-1101




447.56


 


IIa-1102




380.47


 


IIa-1103




408.52


 


IIa-1104




430.57


 


IIa-1105




394.49


 


IIa-1106




435.55


 


IIa-1107




378.49


 


IIa-1108




475.66


 


IIa-1109




461.63


 


IIa-1110




475.66


 


IIa-1111




447.60


 


IIa-1112




462.62


 


IIa-1113




542.68


 


IIa-1114




545.11


 


IIa-1115




469.61


 


IIa-1116




524.69


 


IIa-1117




469.61


 


IIa-1118




452.64


 


IIa-1119




412.94


 


IIa-1120




352.89


 


IIa-1121




409.98


 


IIa-1122




338.86


 


IIa-1123




338.86


 


IIa-1124




384.88


 


IIa-1125




423.97


 


IIa-1126




366.91


 


IIa-1127




380.90


 


IIa-1128




354.86


 


IIa-1129




382.91


 


IIa-1130




368.89


 


IIa-1131




396.94


 


IIa-1132




409.94


 


IIa-1133




407.97


 


IIa-1134




519.50


 


IIa-1135




444.00


 


IIa-1136




453.07


 


IIa-1137




367.47


 


IIa-1138




332.47


 


IIa-1139




334.44


 


IIa-1140




387.55


 


IIa-1141




372.51


 


IIa-1142




362.49


 


IIa-1143




348.47


 


IIa-1144




376.52


 


IIa-1145




373.52


 


IIa-1146




499.08


 


IIa-1147




451.98


 


IIa-1148




387.89


 


IIa-1149




352.89


 


IIa-1150




376.86


 


IIa-1151




392.93


 


IIa-1152




368.89


 


IIa-1153




352.89


 


IIa-1154




427.03


 


IIa-1155




463.62


 


IIa-1156




399.54


 


IIa-1157




364.53


 


IIa-1158




364.53


 


IIa-1159




379.55


 


IIa-1160




388.51


 


IIa-1161




350.51


 


IIa-1162




350.51


 


IIa-1163




396.53


 


IIa-1164




435.61


 


IIa-1165




378.56


 


IIa-1166




392.54


 


IIa-1167




433.60


 


IIa-1168




366.50


 


IIa-1169




419.61


 


IIa-1170




404.58


 


IIa-1171




394.56


 


IIa-1172




416.61


 


IIa-1173




440.63


 


IIa-1174




380.53


 


IIa-1175




364.53


 


IIa-1176




419.61


 


IIa-1177




405.59


 


IIa-1178




455.65


 


IIa-1179




510.73


 


IIa-1180




464.72


 


IIa-1181




346.50


 


IIa-1182




346.50


 


IIa-1183




361.51


 


IIa-1184




370.47


 


IIa-1185




378.49


 


IIa-1186




415.56


 


IIa-1187




386.54


 


IIa-1188




362.49


 


IIa-1189




390.55


 


IIa-1190




346.50


 


IIa-1191




513.11


 


IIa-1192




420.64


 


IIa-1193




446.68


 


IIa-1194




384.88


 


IIa-1195




366.91


 


IIa-1196




392.93


 


IIa-1197




371.44


 


IIa-1198




351.45


 


IIa-1199




360.41


 


IIa-1200




350.46


 


IIa-1201




364.44


 


IIa-1202




405.49


 


IIa-1203




338.40


 


IIa-1204




366.46


 


IIa-1205




352.43


 


IIa-1206




377.48


 


IIa-1207




410.58


 


IIa-1208




367.47


 


IIa-1209




332.47


 


IIa-1210




403.55


 


IIa-1211




334.44


 


IIa-1212




372.51


 


IIa-1213




362.49


 


IIa-1214




332.47


 


IIa-1215




401.58


 


IIa-1216




499.08


 


IIa-1217




431.56


 


IIa-1218




392.52


 


IIa-1219




367.47


 


IIa-1220




332.47


 


IIa-1221




356.45


 


IIa-1222




318.44


 


IIa-1223




364.47


 


IIa-1224




403.55


 


IIa-1225




346.50


 


IIa-1226




360.48


 


IIa-1227




334.44


 


IIa-1228




372.51


 


IIa-1229




362.49


 


IIa-1230




408.57


 


IIa-1231




348.47


 


IIa-1232




376.52


 


IIa-1233




389.52


 


IIa-1234




332.47


 


IIa-1235




373.52


 


IIa-1236




499.08


 


IIa-1237




478.66


 


IIa-1238




423.58


 


IIa-1239




432.65


 


IIa-1240




463.56


 


IIa-1241




424.52


 


IIa-1242




399.47


 


IIa-1243




399.47


 


IIa-1244




388.45


 


IIa-1245




350.44


 


IIa-1246




350.44


 


IIa-1247




396.47


 


IIa-1248




392.48


 


IIa-1249




366.44


 


IIa-1250




416.54


 


IIa-1251




380.47


 


IIa-1252




408.52


 


IIa-1253




364.47


 


IIa-1254




531.08


 


IIa-1255




354.86


 


IIa-1256




384.88


 


IIa-1257




368.89


 


IIa-1258




451.52


 


IIa-1259




387.44


 


IIa-1260




387.44


 


IIa-1261




352.43


 


IIa-1262




338.40


 


IIa-1263




384.43


 


IIa-1264




392.47


 


IIa-1265




368.43


 


IIa-1266




396.48


 


IIa-1267




421.54


 


IIa-1268




383.47


 


IIa-1269




348.47


 


IIa-1270




363.48


 


IIa-1271




372.45


 


IIa-1272




334.44


 


IIa-1273




334.44


 


IIa-1274




380.47


 


IIa-1275




362.49


 


IIa-1276




376.48


 


IIa-1277




350.44


 


IIa-1278




388.51


 


IIa-1279




378.49


 


IIa-1280




424.57


 


IIa-1281




364.47


 


IIa-1282




348.47


 


IIa-1283




515.08


 


IIa-1284




467.64


 


IIa-1285




453.61


 


IIa-1286




422.61


 


IIa-1287




448.65


 


IIa-1288




447.56


 


IIa-1289




408.52


 


IIa-1290




383.47


 


IIa-1291




348.47


 


IIa-1292




372.45


 


IIa-1293




334.44


 


IIa-1294




391.54


 


IIa-1295




380.47


 


IIa-1296




362.49


 


IIa-1297




376.48


 


IIa-1298




350.44


 


IIa-1299




388.51


 


IIa-1300




378.49


 


IIa-1301




400.54


 


IIa-1302




424.57


 


IIa-1303




364.47


 


IIa-1304




392.52


 


IIa-1305




405.52


 


IIa-1306




348.47


 


IIa-1307




431.60


 


IIa-1308




417.57


 


IIa-1309




419.59


 


IIa-1310




389.52


 


IIa-1311




445.63


 


IIa-1312




417.57


 


IIa-1313




432.59


 


IIa-1314




507.70


 


IIa-1315




447.64


 


IIa-1316




422.61


 


IIa-1317




448.65


 


IIa-1318




467.98


 


IIa-1319




428.94


 


IIa-1320




403.89


 


IIa-1321




392.86


 


IIa-1322




354.86


 


IIa-1323




411.95


 


IIa-1324




439.96


 


IIa-1325




396.90


 


IIa-1326




370.86


 


IIa-1327




408.93


 


IIa-1328




398.91


 


IIa-1329




420.96


 


IIa-1330




384.88


 


IIa-1331




412.94


 


IIa-1332




425.94


 


IIa-1333




452.02


 


IIa-1334




437.99


 


IIa-1335




409.94


 


IIa-1336




466.05


 


IIa-1337




453.01


 


IIa-1338




452.02


 


IIa-1339




466.05


 


IIa-1340




447.56


 


IIa-1341




408.52


 


IIa-1342




383.47


 


IIa-1343




348.47


 


IIa-1344




334.44


 


IIa-1345




334.44


 


IIa-1346




380.47


 


IIa-1347




419.55


 


IIa-1348




362.49


 


IIa-1349




350.44


 


IIa-1350




388.51


 


IIa-1351




378.49


 


IIa-1352




400.54


 


IIa-1353




424.57


 


IIa-1354




364.47


 


IIa-1355




405.52


 


IIa-1356




348.47


 


IIa-1357




403.55


 


IIa-1358




515.08


 


IIa-1359




494.66


 


IIa-1360




439.58


 


IIa-1361




403.89


 


IIa-1362




392.86


 


IIa-1363




411.95


 


IIa-1364




400.88


 


IIa-1365




382.91


 


IIa-1366




370.86


 


IIa-1367




408.93


 


IIa-1368




368.89


 


IIa-1369




466.05


 


IIa-1370




463.56


 


IIa-1371




424.52


 


IIa-1372




364.47


 


IIa-1373




350.44


 


IIa-1374




350.44


 


IIa-1375




396.47


 


IIa-1376




366.44


 


IIa-1377




440.57


 


IIa-1378




380.47


 


IIa-1379




408.52


 


IIa-1380




364.47


 


IIa-1381




493.58


 


IIa-1382




454.55


 


IIa-1383




429.50


 


IIa-1384




394.49


 


IIa-1385




418.47


 


IIa-1386




437.56


 


IIa-1387




426.49


 


IIa-1388




465.57


 


IIa-1389




408.52


 


IIa-1390




396.47


 


IIa-1391




449.57


 


IIa-1392




434.54


 


IIa-1393




424.52


 


IIa-1394




446.57


 


IIa-1395




470.59


 


IIa-1396




410.49


 


IIa-1397




438.55


 


IIa-1398




394.49


 


IIa-1399




491.65


 


IIa-1400




477.63


 


IIa-1401




479.64


 


IIa-1402




449.57


 


IIa-1403




463.60


 


IIa-1404




465.62


 


IIa-1405




435.55


 


IIa-1406




479.64


 


IIa-1407




491.65


 


IIa-1408




463.60


 


IIa-1409




478.62


 


IIa-1410




465.62


 


IIa-1411




477.63


 


IIa-1412




553.73


 


IIa-1413




507.70


 


IIa-1414




541.72


 


IIa-1415




561.10


 


IIa-1416




493.67


 


IIa-1417




485.61


 


IIa-1418




468.64


 


IIa-1419




494.68


 


IIa-1420




394.49


 


IIa-1421




369.45


 


IIa-1422




334.44


 


IIa-1423




349.46


 


IIa-1424




358.42


 


IIa-1425




415.47


 


IIa-1426




404.45


 


IIa-1427




412.47


 


IIa-1428




394.49


 


IIa-1429




382.44


 


IIa-1430




432.54


 


IIa-1431




396.47


 


IIa-1432




380.47


 


IIa-1433




463.56


 


IIa-1434




399.47


 


IIa-1435




399.47


 


IIa-1436




364.47


 


IIa-1437




421.56


 


IIa-1438




379.48


 


IIa-1439




426.54


 


IIa-1440




350.44


 


IIa-1441




435.55


 


IIa-1442




378.49


 


IIa-1443




392.48


 


IIa-1444




366.44


 


IIa-1445




419.55


 


IIa-1446




451.55


 


IIa-1447




394.49


 


IIa-1448




416.54


 


IIa-1449




440.57


 


IIa-1450




380.47


 


IIa-1451




408.52


 


IIa-1452




421.52


 


IIa-1453




470.64


 


IIa-1454




448.59


 


IIa-1455




469.61


 


IIa-1456




449.62


 


IIa-1457




419.55


 


IIa-1458




435.59


 


IIa-1459




405.52


 


IIa-1460




461.63


 


IIa-1461




462.62


 


IIa-1462




433.57


 


IIa-1463




448.59


 


IIa-1464




477.67


 


IIa-1465




477.67


 


IIa-1466




447.60


 


IIa-1467




463.64


 


IIa-1468




455.58


 


IIa-1469




497.66


 


IIa-1470




424.59


 


IIa-1471




464.65


 


IIa-1472




489.68


 


IIa-1473




479.56


 


IIa-1474




440.52


 


IIa-1475




380.47


 


IIa-1476




395.48


 


IIa-1477




442.54


 


IIa-1478




423.54


 


IIa-1479




451.55


 


IIa-1480




408.48


 


IIa-1481




449.53


 


IIa-1482




424.52


 


IIa-1483




464.59


 


IIa-1484




479.56


 


IIa-1485




415.47


 


IIa-1486




380.47


 


IIa-1487




437.56


 


IIa-1488




395.48


 


IIa-1489




442.54


 


IIa-1490




366.44


 


IIa-1491




423.54


 


IIa-1492




451.55


 


IIa-1493




394.49


 


IIa-1494




449.53


 


IIa-1495




382.44


 


IIa-1496




420.51


 


IIa-1497




410.49


 


IIa-1498




456.57


 


IIa-1499




396.47


 


IIa-1500




424.52


 


IIa-1501




437.52


 


IIa-1502




486.64


 


IIa-1503




464.59


 


IIa-1504




485.61


 


IIa-1505




477.63


 


IIa-1506




463.60


 


IIa-1507




465.62


 


IIa-1508




449.57


 


IIa-1509




451.59


 


IIa-1510




477.63


 


IIa-1511




478.62


 


IIa-1512




493.67


 


IIa-1513




477.63


 


IIa-1514




497.62


 


IIa-1515




479.64


 


IIa-1516




479.64


 


IIa-1517




471.58


 


IIa-1518




440.58


 


IIa-1519




480.65


 


IIa-1520




463.56


 


IIa-1521




364.47


 


IIa-1522




421.56


 


IIa-1523




379.48


 


IIa-1524




388.45


 


IIa-1525




426.54


 


IIa-1526




350.44


 


IIa-1527




407.54


 


IIa-1528




435.55


 


IIa-1529




378.49


 


IIa-1530




392.48


 


IIa-1531




433.53


 


IIa-1532




366.44


 


IIa-1533




419.55


 


IIa-1534




440.57


 


IIa-1535




380.47


 


IIa-1536




408.52


 


IIa-1537




421.52


 


IIa-1538




364.47


 


IIa-1539




448.59


 


IIa-1540




419.55


 


IIa-1541




405.52


 


IIa-1542




461.63


 


IIa-1543




462.62


 


IIa-1544




477.67


 


IIa-1545




461.63


 


IIa-1546




424.59


 


IIa-1547




383.44


 


IIa-1548




392.41


 


IIa-1549




430.50


 


IIa-1550




400.43


 


IIa-1551




439.51


 


IIa-1552




444.53


 


IIa-1553




452.55


 


IIa-1554




439.55


 


IIa-1555




409.48


 


IIa-1556




465.59


 


IIa-1557




465.59


 


IIa-1558




485.58


 


IIa-1559




451.56


 


IIa-1560




467.61


 


IIa-1561




428.55


 


IIa-1562




468.61


 


IIa-1563




408.59


 


IIa-1564




485.07


 


IIa-1565




386.86


 


IIa-1566




414.91


 


IIa-1567




446.96


 


IIa-1568




408.86


 


IIa-1569




384.88


 


IIa-1570




561.10


 


IIa-1571




400.88


 


IIa-1572




441.94


 


IIa-1573




460.98


 


IIa-1574




483.97


 


IIa-1575




436.96


 


IIa-1576




370.86


 


IIa-1577




483.97


 


IIa-1578




446.96


 


IIa-1579




400.88


 


IIa-1580




428.94


 


IIa-1581




441.94


 


IIa-1582




460.98


 


IIa-1583




386.86


 


IIa-1584




425.94


 


IIa-1585




436.96


 


IIa-1586




455.96


 


IIa-1587




408.86


 


IIa-1588




551.50


 


IIa-1589




559.13


 


IIa-1590




428.94


 


IIa-1591




334.44


 


IIa-1592




507.70


 


IIa-1593




427.03


 


IIa-1594




447.56


 


IIa-1595




403.89


 


IIa-1596




436.94


 


IIa-1597




408.31


 


IIa-1598




377.85


 


IIa-1599




391.85


 


IIa-1600




361.40


 


IIa-1601




357.43


 


IIa-1602




387.89


 


IIa-1603




478.04
















TABLE 6







Oxazole amides (R3 = N-cyclo)








 









ID
Structure
MW





IIa- 2001




330.45


 


IIa- 2002




387.50


 


IIa- 2003




392.52


 


IIa- 2004




372.53


 


IIa- 2005




437.57


 


IIa- 2006




463.65


 


IIa- 2007




479.60


 


IIa- 2008




511.67


 


IIa- 2009




376.48


 


IIa- 2010




495.60


 


IIa- 2011




465.62


 


IIa- 2012




449.62


 


IIa- 2013




424.59


 


IIa- 2014




404.60


 


IIa- 2015




387.50


 


IIa- 2016




509.98


 


IIa- 2017




525.98


 


IIa- 2018




521.56


 


IIa- 2019




525.98


 


IIa- 2020




505.56


 


IIa- 2021




432.54


 


IIa- 2022




417.53


 


IIa- 2023




446.57


 


IIa- 2024




408.52


 


IIa- 2025




432.54


 


IIa- 2026




469.56


 


IIa- 2027




376.48


 


IIa- 2028




360.48


 


IIa- 2029




489.56


 


IIa- 2030




433.53


 


IIa- 2031




473.64


 


IIa- 2032




535.59


 


IIa- 2033




495.65


 


IIa- 2034




472.01


 


IIa- 2035




439.54


 


IIa- 2036




457.64


 


IIa- 2037




469.58


 


IIa- 2038




388.53


 


IIa- 2039




519.59


 


IIa- 2040




481.62


 


IIa- 2041




388.53


 


IIa- 2042




486.04


 


IIa- 2043




523.61


 


IIa- 2044




437.57


 


IIa- 2045




346.45


 


IIa- 2046




472.01


 


IIa- 2047




465.62


 


IIa- 2048




486.04


 


IIa- 2049




362.45


 


IIa- 2050




451.59


 


IIa- 2051




455.56


 


IIa- 2052




467.59


 


IIa- 2053




455.56


 


IIa- 2054




394.50


 


IIa- 2055




346.45


 


IIa- 2056




465.62


 


IIa- 2057




426.54


 


IIa- 2058




463.56


 


IIa- 2059




424.52


 


IIa- 2060




376.48


 


IIa- 2061




516.06


 


IIa- 2062




438.55


 


IIa- 2063




495.65


 


IIa- 2064




405.52


 


IIa- 2065




392.48


 


IIa- 2066




480.63


 


IIa- 2067




485.56


 


IIa- 2068




419.55


 


IIa- 2069




398.91


 


IIa- 2070




350.87


 


IIa- 2071




490.46


 


IIa- 2072




436.96


 


IIa- 2073




380.51


 


IIa- 2074




417.53


 


IIa- 2075




421.57


 


IIa- 2076




392.52


 


IIa- 2077




359.49


 


IIa- 2078




346.45


 


IIa- 2079




435.59


 


IIa- 2080




422.55


 


IIa- 2081




372.53


 


IIa- 2082




398.91


 


IIa- 2083




486.98


 


IIa- 2084




441.98


 


IIa- 2085




350.87


 


IIa- 2086




472.01


 


IIa- 2087




412.58


 


IIa- 2088




498.63


 


IIa- 2089




375.51


 


IIa- 2090




362.52


 


IIa- 2091




488.07


 


IIa- 2092




481.68


 


IIa- 2093




502.10


 


IIa- 2094




424.59


 


IIa- 2095




391.56


 


IIa- 2096




378.52


 


IIa- 2097




467.66


 


IIa- 2098




466.67


 


IIa- 2099




471.62


 


IIa- 2100




471.62


 


IIa- 2101




431.56


 


IIa- 2102




392.52


 


IIa- 2103




480.59


 


IIa- 2104




435.59


 


IIa- 2105




463.65


 


IIa- 2106




484.06


 


IIa- 2107




406.55


 


IIa- 2108




373.52


 


IIa- 2109




360.48


 


IIa- 2110




449.62


 


IIa- 2111




436.58


 


IIa- 2112




453.58


 


IIa- 2113




430.57


 


IIa- 2114




387.55


 


IIa- 2115




350.87


 


IIa- 2116




490.46


 


IIa- 2117




459.97


 


IIa- 2118




421.49


 


IIa- 2119




470.53


 


IIa- 2120




455.56


 


IIa- 2121




425.53


 


IIa- 2122




334.42


 


IIa- 2123




474.00


 


IIa- 2124




443.52


 


IIa- 2125




455.56


 


IIa- 2126




425.53


 


IIa- 2127




421.57


 


IIa- 2128




392.52


 


IIa- 2129




359.49


 


IIa- 2130




346.45


 


IIa- 2131




434.61


 


IIa- 2132




422.55


 


IIa- 2133




439.56


 


IIa- 2134




373.52


 


IIa- 2135




358.51


 


IIa- 2136




378.50


 


IIa- 2137




330.45


 


IIa- 2138




449.62


 


IIa- 2139




346.45


 


IIa- 2140




422.55


 


IIa- 2141




402.52


 


IIa- 2142




439.54


 


IIa- 2143




392.52


 


IIa- 2144




449.53


 


IIa- 2145




390.51


 


IIa- 2146




362.45


 


IIa- 2147




424.52


 


IIa- 2148




391.49


 


IIa- 2149




378.45


 


IIa- 2150




434.52


 


IIa- 2151




405.52


 


IIa- 2152




376.48


 


IIa- 2153




441.53


 


IIa- 2154




376.52


 


IIa- 2155




433.53


 


IIa- 2156




374.51


 


IIa- 2157




394.50


 


IIa- 2158




359.45


 


IIa- 2159




437.57


 


IIa- 2160




346.45


 


IIa- 2161




486.04


 


IIa- 2162




408.52


 


IIa- 2163




375.49


 


IIa- 2164




438.55


 


IIa- 2165




388.53


 


IIa- 2166




389.52


 


IIa- 2167




360.48


 


IIa- 2168




433.53


 


IIa- 2169




437.57


 


IIa- 2170




472.01


 


IIa- 2171




408.52


 


IIa- 2172




465.62


 


IIa- 2173




362.45


 


IIa- 2174




451.59


 


IIa- 2175




418.52


 


IIa- 2176




388.53


 


IIa- 2177




455.56


 


IIa- 2178




453.95


 


IIa- 2179




438.93


 


IIa- 2180




433.53


 


IIa- 2181




437.57


 


IIa- 2182




486.04


 


IIa- 2183




362.45


 


IIa- 2184




418.52


 


IIa- 2185




455.54


 


IIa- 2186




389.52


 


IIa- 2187




360.48


 


IIa- 2188




394.92


 


IIa- 2189




457.98


 


IIa- 2190




434.52


 


IIa- 2191




479.56


 


IIa- 2192




440.52


 


IIa- 2193




511.65


 


IIa- 2194




532.06


 


IIa- 2195




511.65


 


IIa- 2196




421.52


 


IIa- 2197




408.48


 


IIa- 2198




497.62


 


IIa- 2199




435.55


 


IIa- 2200




513.62


 


IIa- 2201




382.49


 


IIa- 2202




362.49


 


IIa- 2203




380.47


 


IIa- 2204




423.54


 


IIa- 2205




394.50


 


IIa- 2206




348.42


 


IIa- 2207




375.49


 


IIa- 2208




394.45


 


IIa- 2209




412.51


 


IIa- 2210




392.52


 


IIa- 2211




449.53


 


IIa- 2212




404.53


 


IIa- 2213




390.51


 


IIa- 2214




410.50


 


IIa- 2215




375.45


 


IIa- 2216




453.56


 


IIa- 2217




362.45


 


IIa- 2218




481.62


 


IIa- 2219




481.62


 


IIa- 2220




424.52


 


IIa- 2221




481.62


 


IIa- 2222




391.49


 


IIa- 2223




378.45


 


IIa- 2224




467.59


 


IIa- 2225




404.53


 


IIa- 2226




405.52


 


IIa- 2227




428.51


 


IIa- 2228




408.52


 


IIa- 2229




465.53


 


IIa- 2230




406.50


 


IIa- 2231




426.50


 


IIa- 2232




391.45


 


IIa- 2233




469.56


 


IIa- 2234




378.45


 


IIa- 2235




475.61


 


IIa- 2236




497.62


 


IIa- 2237




497.62


 


IIa- 2238




440.52


 


IIa- 2239




497.62


 


IIa- 2240




380.47


 


IIa- 2241




407.49


 


IIa- 2242




394.45


 


IIa- 2243




483.59


 


IIa- 2244




435.55


 


IIa- 2245




470.55


 


IIa- 2246




394.49


 


IIa- 2247




420.53


 


IIa- 2248




421.52


 


IIa- 2249




499.59


 


IIa- 2250




392.48


 


IIa- 2251




412.51


 


IIa- 2252




449.53


 


IIa- 2253




390.51


 


IIa- 2254




410.50


 


IIa- 2255




375.45


 


IIa- 2256




453.56


 


IIa- 2257




362.45


 


IIa- 2258




424.52


 


IIa- 2259




404.53


 


IIa- 2260




481.62


 


IIa- 2261




391.49


 


IIa- 2262




378.45


 


IIa- 2263




467.59


 


IIa- 2264




466.60


 


IIa- 2265




405.52


 


IIa- 2266




376.48


 


IIa- 2267




491.97


 


IIa- 2268




408.50


 


IIa- 2269




453.49


 


IIa- 2270




394.47


 


IIa- 2271




414.46


 


IIa- 2272




457.53


 


IIa- 2273




428.49


 


IIa- 2274




485.58


 


IIa- 2275




382.41


 


IIa- 2276




471.55


 


IIa- 2277




470.57


 


IIa- 2278




522.45


 


IIa- 2279




430.91


 


IIa- 2280




468.96


 


IIa- 2281




398.87


 


IIa- 2282




480.03


 


IIa- 2283




578.09


 


IIa- 2284




475.52


 


IIa- 2285




506.00


 


IIa- 2286




525.53


 


IIa- 2287




514.62


 


IIa- 2288




374.46


 


IIa- 2289




441.60


 


IIa- 2290




392.52


 


IIa- 2291




433.57
















TABLE 7







Phenmethylene-Thiazole Alkanoic Acids (R3 = OH)









ID
Structure
MW





IIb- 1




402.3


 


IIb- 2




409.5


 


IIb- 3




372.8


 


IIb- 4




395.5


 


IIb- 5




456.5


 


IIb- 6




337.4


 


IIb- 7




423.6


 


IIb- 8




442.5


 


IIb- 9




426.5


 


IIb- 10




343.4


 


IIb- 11




412.5


 


IIb- 12




336.4


 


IIb- 13




353.4


 


IIb- 14




359.4


 


IIb- 15




397.5


 


IIb- 16




353.4


 


IIb- 17




341.8


 


IIb- 18




466.6


 


IIb- 19




335.4


 


IIb- 20




372.3


 


IIb- 21




362.3


 


IIb- 22




362.3


 


IIb- 23




337.4


 


IIb- 24




311.4


 


IIb- 25




341.8


 


IIb- 26




421.6


 


IIb- 27




349.5


 


IIb- 28




443.5


 


IIb- 29




365.5


 


IIb- 30




369.5


 


IIb- 31




338.4


 


IIb- 32




337.4


 


IIb- 33




399.5


 


IIb- 34




339.5


 


IIb- 35




335.4


 


IIb- 36




397.4


 


IIb- 37




396.4


 


IIb- 38




309.4


 


IIb- 39




383.4


 


IIb- 40




307.4


 


IIb- 41




399.5


 


IIb- 42




369.4


 


IIb- 43




421.6


 


IIb- 44




362.3


 


IIb- 45




367.4


 


IIb- 46




366.4


 


IIb- 47




386.3


 


IIb- 48




413.5


 


IIb- 49




351.4


 


IIb- 50




413.5


 


IIb- 51




363.5


 


IIb- 52




353.5


 


IIb- 53




413.5


 


IIb- 54




457.6


 


IIb- 55




443.5


 


IIb- 56




411.5


 


IIb- 57




410.5


 


IIb- 58




397.5


 


IIb- 59




383.4


 


IIb- 60




435.6


 


IIb- 61




353.4


 


IIb- 62




338.4


 


IIb- 63




460.5


 


IIb- 64




435.6


 


IIb- 65




323.4


 


IIb- 66




349.4


 


IIb- 67




363.5


 


IIb- 68




448.5


 


IIb- 69




376.3


 


IIb- 70




376.3


 


IIb- 71




434.5


 


IIb- 72




448.6


 


IIb- 73




448.6


 


IIb- 74




448.6


 


IIb- 75




353.4


 


IIb- 76




364.5


 


IIb- 77




478.9


 


IIb- 78




344.4


 


IIb- 79




358.4


 


IIb- 80




344.4


 


IIb- 81




345.4


 


IIb- 82




358.4


 


IIb- 83




359.4


 


IIb- 84




339.4


 


IIb- 85




362.3


 


IIb- 86




350.5


 


IIb- 87




365.5


 


IIb- 88




309.4


 


IIb- 89




351.4


 


IIb- 90




446.5


 


IIb- 91




477.0


 


IIb- 92




451.6


 


IIb- 93




349.4


 


IIb- 94




413.5


 


IIb- 95




433.9


 


IIb- 96




433.9


 


IIb- 97




413.5


 


IIb- 98




433.9


 


IIb- 99




413.5


 


IIb- 100




433.9


 


IIb- 101




433.9


 


IIb- 102




464.0


 


IIb- 103




464.0


 


IIb- 104




478.0


 


IIb- 105




478.0


 


IIb- 106




395.5


 


IIb- 107




409.5


 


IIb- 108




465.6


 


IIb- 109




363.5


 


IIb- 110




427.5


 


IIb- 111




448.0


 


IIb- 112




448.0


 


IIb- 113




427.5


 


IIb- 114




448.0


 


IIb- 115




427.5


 


IIb- 116




448.0


 


IIb- 117




448.0


 


IIb- 118




478.0


 


IIb- 119




478.0


 


IIb- 120




492.0


 


IIb- 121




492.0


 


IIb- 122




418.3


 


IIb- 123




432.3


 


IIb- 124




395.5


 


IIb- 125




446.3


 


IIb- 126




465.3


 


IIb- 127




387.5


 


IIb- 128




343.8


 


IIb- 129




352.4


 


IIb- 130




351.4


 


IIb- 131




367.4


 


IIb- 132




351.4


 


IIb- 133




446.3


 


IIb- 134




354.4


 


IIb- 135




432.3


 


IIb- 136




460.4


 


IIb- 137




460.4


 


IIb- 138




381.4


 


IIb- 139




416.3


 


IIb- 140




337.4


 


IIb- 141




432.3


 


IIb- 142




467.2


 


IIb- 143




367.4


 


IIb- 144




381.5


 


IIb- 145




372.3


 


IIb- 146




466.6


 


IIb- 147




381.5


 


IIb- 148




367.4


 


IIb- 149




375.4


 


IIb- 150




359.8


 


IIb- 151




351.4


 


IIb- 152




359.4


 


IIb- 153




365.4


 


IIb- 154




491.0


 


IIb- 155




379.5


 


IIb- 156




393.5


 


IIb- 157




363.5


 


IIb- 158




442.5


 


IIb- 159




368.4


 


IIb- 160




352.4


 


IIb- 161




309.4


 


IIb- 162




352.4


 


IIb- 163




351.4


 


IIb- 164




442.5


 


IIb- 165




442.5


 


IIb- 166




323.4


 


IIb- 167




412.5


 


IIb- 168




412.5


 


IIb- 169




337.4


 


IIb- 170




337.4


 


IIb- 171




338.4


 


IIb- 172




349.4


 


IIb- 173




325.4


 


IIb- 174




456.5


 


IIb- 175




456.5


 


IIb- 176




456.5


 


IIb- 177




430.5


 


IIb- 178




430.5


 


IIb- 179




430.5


 


IIb- 180




446.5


 


IIb- 181




446.5


 


IIb- 182




472.5


 


IIb- 183




440.5


 


IIb- 184




440.5


 


IIb- 185




440.5


 


IIb- 186




456.5


 


IIb- 187




456.5


 


IIb- 188




456.5


 


IIb- 189




456.5


 


IIb- 190




456.5


 


IIb- 191




456.5


 


IIb- 192




456.5


 


IIb- 193




488.5


 


IIb- 194




488.5


 


IIb- 195




472.5


 


IIb- 196




472.5


 


IIb- 197




472.5


 


IIb- 198




444.5


 


IIb- 199




446.9


 


IIb- 200




446.9


 


IIb- 201




446.9


 


IIb- 202




446.9


 


IIb- 203




462.9


 


IIb- 204




462.9


 


IIb- 205




442.5


 


IIb- 206




442.5


 


IIb- 207




442.5


 


IIb- 208




458.5


 


IIb- 209




458.5


 


IIb- 210




486.6


 


IIb- 211




486.6


 


IIb- 212




486.6


 


IIb- 213




484.6


 


IIb- 214




484.6


 


IIb- 215




470.5


 


IIb- 216




470.5


 


IIb- 217




486.5


 


IIb- 218




442.5


 


IIb- 219




357.5


 


IIb- 220




321.4


 


IIb- 221




321.4


 


IIb- 222




465.6


 


IIb- 223




479.7


 


IIb- 224




465.6


 


IIb- 225




479.7


 


IIb- 226




479.7


 


IIb- 227




493.7


 


IIb- 228




325.4


 


IIb- 229




349.5


 


IIb- 230




345.8


 


IIb- 231




350.4


 


IIb- 232




364.4


 


IIb- 233




378.5


 


IIb- 234




406.5


 


IIb- 235




476.7


 


IIb- 236




364.4


 


IIb- 237




378.5


 


IIb- 238




392.5


 


IIb- 239




406.5


 


IIb- 240




406.5


 


IIb- 241




406.5


 


IIb- 242




392.5


 


IIb- 243




440.5


 


IIb- 244




424.6


 


IIb- 245




421.5


 


IIb- 246




407.5


 


IIb- 247




479.6


 


IIb- 248




364.4


 


IIb- 249




378.5


 


IIb- 250




392.5


 


IIb- 251




420.6


 


IIb- 252




490.7


 


IIb- 253




378.5


 


IIb- 254




392.5


 


IIb- 255




406.5


 


IIb- 256




420.6


 


IIb- 257




420.6


 


IIb- 258




420.6


 


IIb- 259




454.6


 


IIb- 260




406.5


 


IIb- 261




438.6


 


IIb- 262




435.5


 


IIb- 263




421.5


 


IIb- 264




493.6


 


IIb- 265




380.4


 


IIb- 266




394.5


 


IIb- 267




408.5


 


IIb- 268




436.6


 


IIb- 269




394.5


 


IIb- 270




408.5


 


IIb- 271




422.5


 


IIb- 272




436.6


 


IIb- 273




436.6


 


IIb- 274




436.6


 


IIb- 275




422.5


 


IIb- 276




470.6


 


IIb- 277




454.6


 


IIb- 278




451.5


 


IIb- 279




437.5


 


IIb- 280




410.5


 


IIb- 281




424.5


 


IIb- 282




438.5


 


IIb- 283




424.5


 


IIb- 284




438.5


 


IIb- 285




452.6


 


IIb- 286




466.6


 


IIb- 287




466.6


 


IIb- 288




466.6


 


IIb- 289




452.6


 


IIb- 290




484.6


 


IIb- 291




481.6


 


IIb- 292




467.5


 


IIb- 293




424.5


 


IIb- 294




438.5


 


IIb- 295




452.6


 


IIb- 296




480.6


 


IIb- 297




438.5


 


IIb- 298




452.6


 


IIb- 299




466.6


 


IIb- 300




480.6


 


IIb- 301




480.6


 


IIb- 302




480.6


 


IIb- 303




466.6


 


IIb- 304




498.6


 


IIb- 305




495.6


 


IIb- 306




321.4


 


IIb- 307




335.4


 


IIb- 308




442.5


 


IIb- 309




354.4


 


IIb- 310




442.5


 


IIb- 311




422.5


 


IIb- 312




428.5


 


IIb- 313




446.5


 


IIb- 314




339.4


 


IIb- 315




448.6


 


IIb- 316




446.5


 


IIb- 317




325.4


 


IIb- 318




446.5


 


IIb- 319




428.5


 


IIb- 320




434.5


 


IIb- 321




442.5


 


IIb- 322




434.5


 


IIb- 323




428.5


 


IIb- 324




377.5


 


IIb- 325




363.5


 


IIb- 326




373.4


 


IIb- 327




378.5


 


IIb- 328




376.3


 


IIb- 329




353.4


 


IIb- 330




352.4


 


IIb- 331




484.6


 


IIb- 332




486.5


 


IIb- 333




466.6


 


IIb- 334




323.4


 


IIb- 335




367.4


 


IIb- 336




321.4


 


IIb- 337




418.3


 


IIb- 338




367.4


 


IIb- 339




399.5


 


IIb- 340




429.5


 


IIb- 341




422.5


 


IIb- 342




457.6


 


IIb- 343




338.4


 


IIb- 344




338.4


 


IIb- 345




383.4


 


IIb- 346




307.4


 


IIb- 347




337.4


 


IIb- 348




491.4


 


IIb- 349




491.4


 


IIb- 350




491.4


 


IIb- 351




456.5


 


IIb- 352




472.5


 


IIb- 353




444.5


 


IIb- 354




323.4


 


IIb- 355




323.4


 


IIb- 356




323.4


 


IIb- 357




426.5


 


IIb- 358




351.4


 


IIb- 359




426.5


 


IIb- 360




456.5


 


IIb- 361




456.5


 


IIb- 362




321.4


 


IIb- 363




472.5


 


IIb- 364




311.4


 


IIb- 365




325.4


 


IIb- 366




327.8


 


IIb- 367




293.4


 


IIb- 368




381.5


 


IIb- 369




393.5


 


IIb- 370




407.5


 


IIb- 371




393.5


 


IIb- 372




454.6


 


IIb- 373




454.6


 


IIb- 374




381.5


 


IIb- 375




339.4


 


IIb- 376




426.5


 


IIb- 377




353.4


 


IIb- 378




461.0


 


IIb- 379




426.5


 


IIb- 380




462.9


 


IIb- 381




426.5


 


IIb- 382




470.5


 


IIb- 383




454.6


 


IIb- 384




353.4


 


IIb- 385




440.5


 


IIb- 386




367.4


 


IIb- 387




446.9


 


IIb- 388




337.4


 


IIb- 389




327.8


 


IIb- 390




367.4


 


IIb- 391




372.3


 


IIb- 392




351.4


 


IIb- 393




440.5


 


IIb- 394




446.9


 


IIb- 395




351.4


 


IIb- 396




307.4


 


IIb- 397




440.5


 


IIb- 398




311.4


 


IIb- 399




385.5


 


IIb- 400




386.3


 


IIb- 401




461.0


 


IIb- 402




307.4


 


IIb- 403




462.9


 


IIb- 404




325.4


 


IIb- 405




461.0


 


IIb- 406




378.5


 


IIb- 407




343.4


 


IIb- 408




373.5


 


IIb- 409




446.9


 


IIb- 410




430.3


 


IIb- 411




386.3


 


IIb- 412




402.3


 


IIb- 413




339.4


 


IIb- 414




429.5


 


IIb- 415




444.5
















TABLE 8







Pyridyl And Quinolinyl Methylenyl Alkanoic Acids (R3 = OH)









ID
Structure
MW





IIb-416




294.4


 


IIb-417




308.4


 


IIb-418




344.4


 


IIb-419




358.4


 


IIb-420




374.4


 


IIb-421




374.4


 


IIb-422




378.9


 


IIb-423




388.5


 


IIb-424




388.5


 


IIb-425




392.9


 


IIb-426




388.5


 


IIb-427




402.5


 


IIb-428




408.9


 


IIb-429




422.9
















TABLE 9







Thiophenylmethylenyl Alkanoic Acids And Amides (R3 = O— And NH— )









ID
Structure
MW





IIb-430




327.4


 


IIb-431




446.6


 


IIb-432




404.5


 


IIb-433




404.5


 


IIb-434




418.5


 


IIb-435




430.6


 


IIb-436




456.5


 


IIb-437




396.5


 


IIb-438




434.5


 


IIb-439




449.5


 


IIb-440




439.6


 


IIb-441




418.5


 


IIb-442




313.4


 


IIb-443




327.4


 


IIb-444




446.6


 


IIb-445




458.6


 


IIb-446




494.7


 


IIb-447




480.6


 


IIb-448




476.0


 


IIb-449




438.6


 


IIb-450




395.5


 


IIb-451




458.7


 


IIb-452




410.6


 


IIb-453




424.6


 


IIb-454




428.6


 


IIb-455




418.6


 


IIb-456




420.6


 


IIb-457




487.6


 


IIb-458




457.6


 


IIb-459




398.6


 


IIb-460




380.6


 


IIb-461




412.6


 


IIb-462




456.5


 


IIb-463




432.6


 


IIb-464




432.6


 


IIb-465




472.7


 


IIb-466




442.5


 


IIb-467




416.5


 


IIb-468




430.5


 


IIb-469




388.5


 


IIb-470




446.6


 


IIb-471




370.5


 


IIb-472




418.5


 


IIb-473




352.5


 


IIb-474




368.5


 


IIb-475




381.5


 


IIb-476




383.5


 


IIb-477




379.5


 


IIb-478




375.5


 


IIb-479




375.5


 


IIb-480




432.6


 


IIb-481




341.5


 


IIb-482




404.5


 


IIb-483




418.6


 


IIb-484




432.5


 


IIb-485




441.0


 


IIb-486




494.7


 


IIb-487




410.6


 


IIb-488




467.4


 


IIb-489




381.5


 


IIb-490




439.6


 


IIb-491




380.6


 


IIb-492




380.6


 


IIb-493




416.6


 


IIb-494




354.5


 


IIb-495




384.5


 


IIb-496




380.6


 


IIb-497




477.6


 


IIb-498




445.6


 


IIb-499




416.6


 


IIb-500




406.5


 


IIb-501




439.0


 


IIb-502




397.6


 


IIb-503




457.6


 


IIb-504




416.6


 


IIb-505




430.6


 


IIb-506




432.5


 


IIb-507




406.5


 


IIb-508




424.6


 


IIb-509




478.7


 


IIb-510




402.6


 


IIb-511




402.6


 


IIb-512




416.6


 


IIb-513




452.6


 


IIb-514




395.5


 


IIb-515




389.5


 


IIb-516




446.7


 


IIb-517




434.5


 


IIb-518




430.6


 


IIb-519




416.6


 


IIb-520




444.6


 


IIb-521




448.5


 


IIb-522




444.6


 


IIb-523




441.6


 


IIb-524




434.5


 


IIb-525




430.6


 


IIb-526




414.5


 


IIb-527




418.6


 


IIb-528




406.6


 


IIb-529




407.0


 


IIb-530




428.6


 


IIb-531




392.5


 


IIb-532




392.5


 


IIb-533




424.9


 


IIb-534




414.6


 


IIb-535




480.7


 


IIb-536




421.0


 


IIb-537




431.6


 


IIb-538




409.0


 


IIb-539




448.5


 


IIb-540




453.6


 


IIb-541




467.4


 


IIb-542




423.0


 


IIb-543




370.5


 


IIb-544




432.6


 


IIb-545




402.6


 


IIb-546




416.6


 


IIb-547




299.4


 


IIb-548




374.5


 


IIb-549




418.6


 


IIb-550




464.6


 


IIb-551




341.5


 


IIb-552




404.5


 


IIb-553




388.5


 


IIb-554




407.0


 


IIb-555




313.4


 


IIb-556




388.5


 


IIb-557




388.5


 


IIb-558




404.5


 


IIb-559




369.5


 


IIb-560




355.5


 


IIb-561




432.5


 


IIb-562




355.5


 


IIb-563




394.6


 


IIb-564




425.6


 


IIb-565




452.6


 


IIb-566




354.5


 


IIb-567




395.5


 


IIb-568




394.6


 


IIb-569




402.6


 


IIb-570




416.5


 


IIb-571




442.5


 


IIb-572




448.5


 


IIb-573




313.4


 


IIb-574




418.6


 


IIb-575




366.5


 


IIb-576




382.5


 


IIb-577




384.5


 


IIb-578




408.6


 


IIb-579




432.6


 


IIb-580




471.6


 


IIb-581




366.5


 


IIb-582




418.6


 


IIb-583




418.5


 


IIb-584




421.0


 


IIb-585




380.6


 


IIb-586




327.4


 


IIb-587




402.6


 


IIb-588




389.5


 


IIb-589




410.6


 


IIb-590




453.4


 


IIb-591




390.5


 


IIb-592




404.5


 


IIb-593




390.5


 


IIb-594




369.5


 


IIb-595




366.5


 


IIb-596




394.6


 


IIb-597




444.6


 


IIb-598




409.6


 


IIb-599




390.5


 


IIb-600




418.6


 


IIb-601




445.6


 


IIb-602




368.5


 


IIb-603




313.4


 


IIb-604




438.6


 


IIb-605




402.6


 


IIb-606




393.5


 


IIb-607




395.6


 


IIb-608




424.6


 


IIb-609




459.6


 


IIb-610




491.7


 


IIb-611




383.6


 


IIb-612




432.5


 


IIb-613




471.6


 


IIb-614




452.6


 


IIb-615




409.6


 


IIb-616




407.0


 


IIb-617




421.0
















TABLE 10







5-[[2,5-Dimethyl-1H-Pyrrol-3-Yl]Methylene]-


2,4-Thiazolidinediones








ID
Structure





IIc-1






 


IIc-2






 


IIc-3






 


IIc-4






 


IIc-5






 


IIc-6






 


IIc-7






 


IIc-8






 


IIc-9






 


IIc-10






 


IIc-11






 


IIc-12






 


IIc-13






 


IIc-14






 


IIc-15






 


IIc-16






 


IIc-17






 


IIc-18






 


IIc-19






 


IIc-20






 


IIc-21






 


IIc-22






 


IIc-23






 


IIc-24






 


IIc-25






 


IIc-26






 


IIc-27






 


IIc-28






 


IIc-29






 


IIc-30






 


IIc-31






 


IIc-32






 


IIc-33






 


IIc-34






 


IIc-35






 


IIc-36






 


IIc-37






 


IIc-38






 


IIc-39






 


IIc-40






 


IIc-41






 


IIc-42






 


IIc-43






 


IIc-44






 


IIc-45






 


IIc-46






 


IIc-47






 


IIc-48






 


IIc-49






 


IIc-50






 


IIc-51






 


IIc-52






 


IIc-53






 


IIc-54






 


IIc-55






 


IIc-56






 


IIc-57






 


IIc-58






 


IIc-59






 


IIc-60






 


IIc-61






 


IIc-62






 


IIc-63






 


IIc-64






 


IIc-65






 


IIc-66






 


IIc-67






 


IIc-68






 


IIc-69






 


IIc-70






 


IIc-71






 


IIc-72






 


IIc-73






 


IIc-74






 


IIc-75






 


IIc-76






 


IIc-77






 


IIc-78






 


IIc-79






 


IIc-80






 


IIc-81






 


IIc-82






 


IIc-83






 


IIc-84






 


IIc-85






 


IIc-86






 


IIc-87






 


IIc-88






 


IIc-89






 


IIc-90






 


IIc-91






 


IIc-92






 


IIc-93






 


IIc-94






 


IIc-95






 


IIc-96






 


IIc-97






 


IIc-98






 


IIc-99






 


IIc-100






 


IIc-101






 


IIc-102






 


IIc-103






 


IIc-104






 


IIc-105






 


IIc-106






 


IIc-107






 


IIc-108






 


IIc-109






 


IIc-110






 


IIc-111






 


IIc-112






 


IIc-113













A number of representative oxazoles and thiazole derivatives of this invention, as listed below in Table 11, were tested for their inhibitory activity and IC50s were calculated. For the purpose of Table 11 below, activity of each compound is determined using the luciferase assay method in Drosophila Clone 8 cells.







TABLE 11







IC50 Values of Exemplary Compounds















IC50


ID
C#*
Structure
MW
(μM)














IIa-66
C6




380.51
3.51


 


IIa-333
C3




394.54
4.18


 


IIa-719
C1




330.45
1.58


 


IIa-722
C13




316.43
1259.72


 


IIa-2102
C8




392.52
1.10


 


IIb-143
C5




367.4
3.06


 


IIb-432
C10




404.5
4.76


 


IIc-3
C14




375.4
3.24





see FIG.S 3-12






From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
At least some of the chemical names of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control. Chemical structures shown herein were prepared using either ChemDraw® or ISIS®/DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

## Claims

1. A method for treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the Wnt signaling pathway in vivo, wherein the disease or condition is a cancer of the liver, colon, rectum, breast, or skin, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula I:



wherein A is A1;
A1 is




x is 1, when A is A1;
L1 is S, SO or SO2; 
m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5;
each R1,R2a,R2b, R2c, and R2d is independently selected from hydrogen, halo, and substituted or unsubstituted C1-C6 alkyl;
R3 is hydroxy, alkoxy, substituted or unsubstituted amino or cycloheteroalkyl;
and each R4 is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol;
or a pharmaceutically acceptable salt, thereof;
and stereoisomers, isotopic variants and tautomers thereof.

2. The method according to claim 1, wherein the compound is according to formula IIa:



and wherein L1, m1, n, R1, R2a, R2b, R2c, R2d, R3 , and R4, are as in claim 1.

3. The method according to claim 1, wherein the compound is according to formula IVa:



wherein n, and R4 are as in claim 1, and each R3a and R3b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R3a and R3b join together to form a cycloheteroalkyl heteroaryl ring.

4. The method according to claim 1, wherein the compound is according to formula VIIa, VIIb, VIIc or VIId:



wherein R3b is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R3b is joined together with R3a to form a cycloheteroalkyl heteroaryl ring.

5. The method according to claim 1, wherein the compound is according to formula VIIIa, VIIIb, VIIIc, or VIIId:



wherein Cy is




and wherein R3c is H or alkyl.

6. The method according to claim 1, wherein the compound is according to formula IXa, IXb, IXc or IXd:

7. The method according to claim 1, wherein the compound is according to formula Xa, Xb, Xc or Xd:

8. The method according to claim 1, wherein the compound is according to formula XIa, XIb, XIc or XId:

9. The method according to claim 1, wherein the compound is according to formula XIIa, XIIb, XIIc or XIId:

10. The method according to claim 1, wherein the compound is according to formula XIIIa, XIIIb, XIIIc or XIII&

11. The method according to claim 1, wherein the compound is selected from Tables 1-6.

12. The method of claim 1, wherein the cancer is hepatic cancer, colorectal cancer, or breast cancer.

13. The method according to claim 1, wherein the compound is according to formula VIIb, VIIc or VIId:



wherein R3b is selected trom H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R3b is joined together with R3a to form a cycloheteroalkyl heteroaryl ring.