WO2017152032A1 - Nouveaux composés oxazoles et thiazoles pouvant être utilisés comme modulateurs de la β-caténine et leurs utilisations - Google Patents

Nouveaux composés oxazoles et thiazoles pouvant être utilisés comme modulateurs de la β-caténine et leurs utilisations Download PDF

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WO2017152032A1
WO2017152032A1 PCT/US2017/020631 US2017020631W WO2017152032A1 WO 2017152032 A1 WO2017152032 A1 WO 2017152032A1 US 2017020631 W US2017020631 W US 2017020631W WO 2017152032 A1 WO2017152032 A1 WO 2017152032A1
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substituted
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cancer
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Ramanuj Dasgupta
Gavara Govinda Rajulu
John K. Dickson
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New York University NYU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to oxazole and thiazole compounds capable of modulating ⁇ -catenin activity and uses of such compounds to modulate the activity of the W t/wingless (wg) signaling pathway.
  • nts/wingless 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
  • the main function of the canonical Wnt pathway is to stabilize the cytoplasmic pool of a key mediator, B-catenin (R-cat)l armadillo (arm), which is otherwise degraded by the proteosome pathway (See Fig. 1).
  • R-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.
  • LEF/TCF Lymphoid Enhancer Factor/T Cell Factor
  • HMG-box High mobility group
  • CRT Catenin responsive transcription
  • 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)].
  • PKC Protein Kinase C
  • JNK c-Jun N-terminal Kinase
  • LRP5, KP6/arrow a co-receptor encoded by LDL-related-protein-5, 6
  • GSK-3B is known to phosphorylate B-cat/arw, 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-3B24.
  • U.S. Patent No. 8,252,823 discloses substituted mercaptomethyl-oxazole compounds as B-catenin modulators.
  • 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:
  • Y is -S-, -S(O)- or -S(0) 2 -, one of A or B is -L 1 -X-L 2 -C(0)-NR 2a R 2b or - ⁇ ⁇ - ⁇ ⁇ )- OR 2a , and the other is R 1 ;
  • Y is -0-
  • B is -L 1 -X-L 2 -C(0)-NR 2a R 2b or -L 1 -X-L 2 -C(0)-OR 2a
  • A is R 1 ;
  • X is a single bond, -C(R 4a R 4b )-, -0-, -S-, -S(O)- or -S(0) 2 -;
  • Cy is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • each of L 1 and L 2 is independently substituted or unsubstituted C 1 -C7 alkylene or heteroalkylene;
  • R 1 is hydrogen, halo, or substituted or unsubstituted C 1 -C5 alkyl
  • each R 2a and R 2b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 2a and R 2b are joined together to form a substituted or unsubstituted heterocycloalkyl or a heteroaryl ring;
  • each R 4a and R 4b is independently selected from H, substituted or unsubstituted alkyl, and halo;
  • the present invention provides a composition of a compound according to formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or stereoisomers, isotopic variants or tautomers thereof.
  • the present invention provides a composition of a compound according to formula I, provided that:
  • 5-oxazolebutanoic acid 2-(2-methoxyphenyl)-4-methyl-, methyl ester; or 5-thiazolebutanoic acid, 4-methyl-P-oxo-2 -phenyl-, ethyl ester; or a pharmaceutically acceptable salt, solvate or prodrug thereof;
  • R 1 is substituted or unsubstituted alkyl or halo.
  • R 1 is Me, Et, i-Pr, n-Pr, n-Bu, F, CI, Br, or I.
  • R 1 is Me.
  • the present invention provides a composition of a compound according to formula IVa, IVb, IVc, IVd, IVe, or IVf
  • R 1 , R 2a , and R 2b are as in claim 1 ; n is 1, 2, 3, 4, or 5; and
  • each R 3c 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 un
  • the present invention provides pharmaceutical compositions comprising a oxazole and/or thiazole compound of the invention, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein are all pharmaceutically acceptable as prepared and used.
  • 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.
  • 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 an effective disease-treating or condition-treating amount of a compound or composition of the invention.
  • Such conditions include, without limitation ⁇ variety of hyperproliferative disorders, fibrotic diseases (e.g., pulmonary fibrosis), and cancers, including prostate cancer, colorectal cancer, breast cancer, skin cancer (e.g., melanoma), hepatic cancer (e.g., hepatocellular cancer and hepatoblastoma), head and neck cancer, lung cancer (e.g., non- small cell lung cancer), gastric cancer, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer, endometrial ovarian cancer, Wilm's tumor, bladder cancer and leukemia.
  • fibrotic diseases e.g., pulmonary fibrosis
  • cancers including prostate cancer, colorectal cancer, breast cancer, skin cancer (e.g., melanoma), hepatic cancer (e.g., hepatocellular cancer and hepatoblastoma), head and neck cancer, lung cancer (e.
  • Figure 1 shows a plasmid map of Super 8X Topflash.
  • Figure 2 shows a plasmid map of pPGK-mWnt3 A.
  • FIG. 3 is a graph showing dose dependent inhibition of the Wnt reporter by
  • Figure 4 depicts a graph showing dose dependent inhibition of the Wnt reporter by iCRT3 analog A45 in FEK293 cells stimulated with either exogenous (STF) or endogenous Wnt 3a (STF3a).
  • Compound A45 is Example 1 (Table 1).
  • Figure 5 depicts a graph showing dose dependent inhibition of the Wnt reporter by iCRT3 analog, A48 in FEK293 cells stimulated with either exogenous (STF) or endogenous Wnt 3a (STF3a).
  • Compound A48 is Example 2 (Table 1).
  • Figure 6 shows a histogram depicting iCRT3 mediated inhibition of proliferation of HCT116 colorectal cells.
  • CCD-I8C0 cells control cell line for normal colon cells
  • 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
  • CRT catenin responsive transcription
  • the family of compounds disclosed herein comprises inhibitors that specifically target the activity of the signaling pool of B-catenin.
  • Wnt signaling has been linked to or causally related with a variety of cancers, including: prostate cancer, colon cancer, rectal cancer, breast cancer, skin cancer (e.g., melanoma), liver cancer (e.g., hepatocellular cancer and hepatoblastoma), head and neck cancer, lung cancer (e.g., non-small cell lung cancer), gastric cancer, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer, endometrial ovarian cancer, Wilm's tumor, bladder cancer and leukemia. See, for example, Luu et al.
  • a breakthrough in understanding recurring, resistant disease was the finding that prostate cancer cells become addicted to the AR pathway, and up-regulation of the AR is the major determinate in aggressive castration-resistant prostate cancer [Chen et al, Nat Med, 2004. 10(1): 33-39].
  • recent studies show that even under conditions of androgen ablation therapy, prostate cancer cells are able to synthesize androgens locally, through upregulation of androgen synthetic enzymes that direct de novo androgen synthesis or convert adrenal androgens to higher affinity ligands, testosterone and dihydrotestosterone [Titus et al, Clin Cancer Res, 2005. 11(13): 4653-7;
  • treatment approaches to develop more effective drugs include agents that block androgen binding to the AR (AR antagonists) such as the MDV3100 compound [Tran et al, Science, 2009. 324(5928): 787-90; Scher et al, Lancet, 2010. 375(9724): 1437-46] or inhibit synthetic enzymes in the androgen synthesis pathway such as abiraterone acetate [Attard et al, Cancer Res, 2009. 69(12): 4937-40].
  • AR antagonists such as the MDV3100 compound [Tran et al, Science, 2009. 324(5928): 787-90; Scher et al, Lancet, 2010. 375(9724): 1437-46] or inhibit synthetic enzymes in the androgen synthesis pathway such as abiraterone acetate [Attard et al, Cancer Res, 2009. 69(12): 4937-40].
  • the present inventors have investigated further the role of the Wnt signaling pathway in prostate cancer by testing small molecule inhibitors of nuclear ⁇ -catenin to evaluate to evaluate their ability to repress prostate cancer growth by inhibiting AR function.
  • this approach takes advantage of the fact that the AR interacts with, and is transcriptionally regulated by ⁇ -catenin.
  • ⁇ -catenin is an effector of the Wnt family of proteins, an evolutionarily conserved group of signaling molecules that regulates developmental and biological processes [Wodarz et al, Annu Rev Cell Dev Biol, 1998. 14: 59-88; Miller et al, Oncogene, 1999.
  • Wnt signaling results in stabilization and activation of ⁇ -catenin, which translocates to the nucleus and together with the T-cell Factor (TCF) family of transcription factors, regulates expression of target genes.
  • TCF T-cell Factor
  • Aberrant Wnt/ ⁇ -catenin signaling has been linked to a number of human cancers [Miyoshi et al, Breast Cancer Res, 2003. 5(2): 63- 8; Moon et al, Nat Rev Genet, 2004. 5(9): 691-701] including prostate cancer [Wang et al, Cancer Res, 2008. 68(23): 9918-27; Beildeck et al, Exp Cell Res, 2010. 316(11): 1763-72; Yu et al, Prostate, 2009. 69(3): 249-62].
  • the AR gene itself is a target of nuclear ⁇ -catenin action through TCF binding sites in the AR promoter [Yang et al, Oncogene, 2006. 25(24): 3436-44]. Further, crosstalk between the AR and ⁇ -catenin pathways occurs in castration-resistant prostate cancer [Wang et al, Cancer Res, 2008. 68(23): 9918-27]. Therefore, in theory, ⁇ -catenin inhibitors would modulate AR and its target genes as well as direct targets of ⁇ -catenin such as c-myc [He et al, Science, 1998. 281(5382): 1509-12], which acts as an oncogene in prostate cancer [Ellwood-Yen et al, Cancer Cell, 2003. 4(3): 223- 38; Zhang et al, Prostate, 2000. 43(4): 278-85; Koh et al, Am J Pathol, 2011. 178(4): 1824-34].
  • cancer stem cells small subpopulations of cancer cells, termed “cancer stem cells (CSCs)” or “tumor-initiating cells” based on their ability to self-renew as well as differentiate to a daughter cell type, play a critical role in both initiation and maintenance of tumors. It has been suggested that these cells are resistant to conventional chemotherapy and radiation, making it important to develop new therapeutic approaches to selectively target them [Chandler et al, Stem Cell Res Ther, 2010. 1(2): p. 13; Korkaya et al, Nat Cell Biol, 2010.
  • an analogue means one analogue or more than one analogue.
  • 'Acyl' or 'Alkanoyl' refers to a radical -C(0)R 20 , where R 20 is hydrogen, Ci-C 8 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(0)H, -C(0)-Ci-C 8 alkyl, -C(0)-(CH 2 ) t (C 6 -Cio aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), - C(0)-(CH 2 ) t (C 3 -Cio cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • Substituted Acyl' or ' Substituted Alkanoyl' refers to a radical -C(0)R 21 , wherein
  • R 21 is independently
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • 'Acylamino' refers to a radical - R 22 C(0)R 23 , where R 22 is hydrogen, Ci-C 8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R 23 is hydrogen, Ci-C 8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio 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 - R 24 C(0)-Ci-C 8 alkyl, - R 24 C(0)-(CH 2 ) t (C 6 -Cio aryl), - R 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), - R 24 C(0)- (CH 2 ) t (C 3 -Cio cycloalkyl), and - R 24 C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R 24 independently represents H or Ci-C 8 alkyl.
  • Substituted Acylamino' refers to a radical - R 25 C(0)R 26 , wherein:
  • R 25 is independently
  • R 26 is independently
  • R 25 and R 26 is other than H.
  • 'Acyloxy' refers to a radical -OC(0)R 27 , where R 27 is hydrogen, Ci-C 8 alkyl, C 3 -
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyl' groups are -C(0)H, -C(0)-Ci-C 8 alkyl, -C(0)-(CH 2 ) t (C 6 -Cio aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -C(O)- (CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted Acyloxy' refers to a radical -OC(0)R 28 , wherein R 28 is independently
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • alkoxy' refers to the group -OR 29 where R 29 is Ci-C 8 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, see-but oxy, 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, C 6 -Cio 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(0) 2 - and aryl-S(0) 2 -.
  • Exemplary 'substituted alkoxy' groups are -0-(CH 2 ) t (C 6 -Cio aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -0-(CH 2 ) t (C 3 -Cio cycloalkyl), and -O-(CH 2 ) 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 OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 - cyclopropyl, OCH 2 CH 2 OH, and OCH 2 CH 2 Me 2 .
  • 'Alkoxycarbonyl' refers to a radical -C(0)-OR 30 where R 30 represents an Ci-C 8 alkyl, C 3 -Cio cycloalkyl, C 3 -Cio cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein.
  • alkoxycarbonyl groups are C(0)0-Ci-C 8 alkyl, -C(0)0-(CH 2 ) t (C 6 -Cio aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), - C(0)0-(CH 2 ) t (C 3 -Cio cycloalkyl), and -C(O)O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
  • Substituted Alkoxycarbonyl' refers to a radical -C(0)-OR 31 where R 31 represents:
  • heterocycloalkylalkyl each of which is substituted with halo, substituted or unsubstituted amino, or hydroxy; or
  • Aryloxycarbonyl' refers to a radical -C(0)-OR 32 where R 32 represents an C 6 -Cio aryl, as defined herein.
  • R 32 represents an C 6 -Cio aryl, as defined herein.
  • aryloxycarbonyl groups is -C(0)0-(C6-Cio aryl).
  • Substituted Aryloxycarbonyl' refers to a radical -C(0)-OR 33 where R 33 represents
  • Heteroaryloxycarbonyl' refers to a radical -C(0)-OR 34 where R 34 represents a 5-
  • aryloxycarbonyl is -C(0)0- (5-10 membered heteroaryl).
  • Substituted Heteroaryloxycarbonyl' refers to a radical -C(0)-OR where R represents:
  • Alkoxycarbonylamino refers to the group - R 36 C(0)OR 37 , where R 36 is hydrogen, Ci-C 8 alkyl, C 3 -C10 cycloalkyl, C 3 -C10 cycloalkylmethyl, 4-10 membered
  • R 37 is Ci-C 8 alkyl, C 3 -C10 cycloalkyl, C 3 -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(0)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (- R -alkoxycarbonyl or -NH-C(0)-OR 27 ), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(0)- R 2 ), aminocarbonylamino (- R -C(0)- R 2 ), aminocarbonyloxy (-O-C(O)- R 2) , aminosulfonyl, sulfonyla
  • each R " is independently selected from H, Ci-C 8 alkyl, -(CH 2 ) t (C 6 -Cio aryl), -(CH 2 ) t (5-10 membered heteroaryl), - (CH 2 ) t (C 3 -Cio cycloalkyl), and -(CH 2 ) 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
  • Alkylene refers to divalent saturated alkene radical groups having 1 to 1 1 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 (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) 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(0) 2 - and aryl-S(0) 2 -.
  • substituents for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consist
  • alkenyl refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 1 1 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.
  • 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(0) 2 - and aryl-S(0) 2 -.
  • 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.
  • alkynyl groups include acetylenic, ethynyl (- C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • 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(0) 2 - and aryl-S(0) 2 -.
  • 'Amino' refers to the radical - H 2 .
  • 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(R 38 ) 2 where each R 38 is independently selected from:
  • heterocycloalkyl or C3-C 10 cycloalkyl
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • R 38 groups When both R 38 groups are hydrogen, -N(R 38 ) 2 is an amino group.
  • exemplary ' substituted amino' groups are - R 39 -Ci-C 8 alkyl, - R 39 -(CH 2 ) t (C 6 -Cio aryl), - R 39 -(CH 2 ) t (5-10 membered heteroaryl), - R 39 -(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and - R 39 -(CH 2 ) t (4-10 membered
  • heterocycloalkyl wherein t is an integer from 0 to 4, each R 39 independently represents H or Ci- C 8 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 C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 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 - HR 40 , wherein R 40 is Ci-C 8 alkyl;
  • Substituted Alkylamino' refers to the group -NHR 41 , wherein R 41 is Ci-C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Alkylarylamino' refers to the group -NR 42 R 43 , wherein R 42 is aryl and R 43 is Ci-
  • Substituted Alkylarylamino' refers to the group -NR 44 R 45 , wherein R 44 is aryl and
  • R 45 is Ci-C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Arylamino' means a radical -NHR 46 where R 46 is selected from C 6 -Cio aryl and
  • Substituted Arylamino' refers to the group -NHR 47 , wherein R 47 is
  • any aryl or heteroaryl groups present may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Dialkylamino' refers to the group -NR 48 R 49 , wherein each of R 48 and R 49 are independently selected from Ci-C 8 alkyl.
  • Dialkylamino refers to the group -NR 50 R 51 , wherein each of R 59 and
  • R 51 are independently selected from Ci-C 8 alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered
  • heterocycloalkyl C 6 -Cio 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 - R 52 R 53 , wherein each of R 52 and R 53 are independently selected from C 6 -Cio aryl.
  • Aminosulfonyl or “Sulfonamide” refers to the radical -S(0 2 ) H 2 .
  • Substituted aminosulfonyl or “substituted sulfonamide” refers to a radical such as -S(0 2 )N(R 54 ) 2 wherein each R 548 is independently selected from:
  • Ci-C 8 alkyl C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • 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 R 54 is other than H.
  • '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.
  • 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, hexalene, 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
  • '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.
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, Ci-C 8 alkyl, Ci-C 8 haloalkyl, cyano, hydroxy, Ci-C 8 alkoxy, and amino.
  • one of R and R may be hydrogen and at least one of R and
  • R 57 is each independently selected from Ci-C 8 alkyl, Ci-C 8 haloalkyl, 4-10 membered
  • heterocycloalkyl alkanoyl, Ci-C 8 alkoxy, heteroaryloxy, alkylamino, arylamino,
  • R 60 , and R 61 are independently hydrogen, Ci-C 8 alkyl, C 1 -C4 haloalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio 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 Ci- C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci- 4 haloalkyl, unsubstituted Ci-
  • 'Azido' refers to the radical -N 3 .
  • Carbamoyl or amido' refers to the radical -C(0)NH 2 .
  • Substituted Carbamoyl or substituted amido' refers to the radical -C(0)N(R 62 ) 2 wherein each R 62 is independently
  • Ci-Cg alkyl C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • heteroaryl or heteroaralkyl, each of which is substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy; provided that at least one R 62 is other than H.
  • Exemplary ' Substituted Carbamoyl' groups are -C(O) R 64 -Ci-C 8 alkyl, -C(0) R 64 -(CH 2 ) t (C 6 - C10 aryl), -C(O)N 64 -(CH 2 ) t (5-10 membered heteroaryl), -C(0) R 64 -(CH 2 ) t (C 3 -Cio cycloalkyl), and -C(O) R 64 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 64 independently represents H or Ci-C 8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalky
  • '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
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I).
  • 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.
  • cycloalkenyl e.g. cycloheteroalkenyl, and the like having from 1 to 5, and
  • 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.
  • 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.
  • 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.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • 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.
  • 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.
  • each Y is selected from carbonyl, N, NR , O and S; and R is independently hydrogen, Ci-Cg alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • each W is selected from C(R ) 2 , NR , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, Ci-C 8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • 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.
  • heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • 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.
  • heterocycloalkyl groups are shown in the following illustrative examples:
  • each W is selected from CR , C(R ) 2 , NR , O and S; and each Y is selected from
  • R 67 O and S; and R 67 is independently hydrogen, Ci-C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio 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,
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
  • 'Nitro' refers to the radical -N0 2 .
  • '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:
  • R 68 , R 69 , R 70 and R 71 are independently:
  • heterocycloalkyl 5-10 membered heteroaryl, heteroarylalkyl; or
  • heterocycloalkyl each of which is substituted by unsubstituted C 1 -C4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR 72 S0 2 R 73 , -S0 2 R 73 R 72 , -C(0)R 73 , - C(0)OR 73 , -OC(0)R 73 , - R 72 C(0)R 73 , -C(0) R 73 R 72 , - R 73 R 72 , -(CR 72 R 72 ) m OR 72 , wherein, each R 73 is independently selected from H, Ci-C 8 alkyl, -(CH 2 ) t (C 6 -Cio aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -Cio cycloalkyl), and -(CH 2 ) t (4-10 membered
  • heterocycloalkyl wherein t is an integer from 0 to 4.
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted Ci- C 4 haloalkoxy or hydroxy.
  • Each R independently represents H or Ci-Cealkyl.
  • Substituted sulfanyl refers to the group -SR 74 , wherein R 74 is selected from:
  • Ci-C 8 alkyl C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • heteroaryl or heteroaralkyl, each of which is substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Exemplary 'substituted sulfanyl' groups are -S-(Ci-C 8 alkyl) and -S-(C 3 -Cio cycloalkyl), -S-(CH 2 ) t (C 6 -Cio aryl), -S-(CH 2 ) t (5-10 membered heteroaryl), -S-(CH 2 ) t (C 3 -Cio cycloalkyl), and -S-(CH 2 ) 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 C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C
  • 'substituted sulfanyl' includes the groups 'alkylsulfanyl' or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl', 'cycloalkylsulfanyl' or 'cycloalkylthio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or 'arylthio' and
  • 'heteroarylsulfanyl' or 'heteroarylthio' refers to a radical -SR" where R is a Ci-C 8 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 -SR 76 where R 76 is a Ci-C 8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR 77 where R 77 is a
  • Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
  • R 78 is a C 3 -C 10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • Arylthio' or 'Arylsulfanyl' refers to a radical -SR 79 where R 79 is a C 6 -Ci 0 aryl group as defined herein.
  • 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR 80 where R 80 is a 5-
  • Substituted sulfinyl' refers to the group -S(0)R 81 , wherein R 81 is selected from:
  • Ci-C 8 alkyl C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • heteroaryl or heteroaralkyl, each of which is substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Exemplary 'substituted sulfinyl' groups are -S(0)-(Ci-C 8 alkyl) and -S(0)-(C 3 -
  • C 10 cycloalkyl C 10 cycloalkyl), -S(0)-(CH 2 ) t (C 6 -Cio aryl), -S(O)-(CH 2 ) t (5-10 membered heteroaryl), -S(O)- (CH 2 ) t (C 3 -Cio cycloalkyl), and -S(O)-(CH 2 ) 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 C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloal
  • substituted sulfinyl includes the groups 'alkyl sulfinyl', 'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfinyl', 'arylsulfinyl' and 'heteroarylsulfinyl' as defined herein.
  • 'Alkylsulfinyl' refers to a radical -S(0)R s where is a Ci-C 8 alkyl group as defined herein. Representative examples include, but are not limited to, methyl sulfinyl, ethylsulfinyl, propyl sulfinyl and butylsulfinyl.
  • Substituted Alkylsulfinyl refers to a radical -S(0)R 83 where R 83 is a Ci-C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfinyl' refers to a radical -S(0)R 84 where R 84 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(0)-C 3 -Cio cycloalkyl.
  • Substituted cycloalkylsulfinyl' refers to the group -S(0)R 85 where R 85 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • Aryl sulfinyl' refers to a radical -S(0)R 86 where R 86 is a C 6 -Cio aryl group as defined herein.
  • Heteroarylsulfinyl' refers to a radical -S(0)R 87 where R 87 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfonyl' refers to the group -S(0) 2 R 88 , wherein R 88 is selected from:
  • Ci-C 8 alkyl C 3 -Cio cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • 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(0) 2 -(Ci-C 8 alkyl) and -S(0) 2 -(C 3 -
  • substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
  • 'Alkylsulfonyl' refers to a radical -S(0) 2 R where R 9 is an Ci-C 8 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(0) 2 R 90 where R 90 is an Ci-C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfonyl' refers to a radical -S(0) 2 R 91 where R 91 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(0) 2 R 92 where R 92 is a C 3 -
  • Cio cycloalkyl substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfonyl' refers to a radical -S(0) 2 R 93 where R 93 is an C 6 -Cio aryl group as defined herein.
  • Heteroarylsulfonyl' refers to a radical -S(0) 2 R 94 where R 94 is an 5-10 membered heteroaryl group as defined herein.
  • 'Sulfo' or 'sulfonic acid' refers to a radical such as -S0 3 H.
  • 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(0) 2 OR 95 , wherein
  • R 95 is selected from:
  • Ci-C 8 alkyl C 3 -Cio cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • 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(0) 2 -0-(Ci-C 8 alkyl) and -S(O) 2 -O-(C 3 -Ci 0 cycloalkyl), -S(0) 2 -0-(CH 2 ) t (C 6 -Cio aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -S(O) 2 -O-(CH 2 ) 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
  • 'Thiol' refers to the group -SH.
  • 'Aminocarbonylamino' refers to the group -NR C(0)NR R where each R yb is independently hydrogen Ci-C 8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R 96 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.
  • 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.
  • 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.
  • '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
  • 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,
  • 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.
  • 'Ethylene' refers to substituted or unsubstituted -(C-C)-.
  • 'Hydrogen bond donor' group refers to a group containg O-H, or N-H
  • Examples of 'hydrogen bond donor' groups include -OH, - H 2 , and - H-R 97 and wherein R 97 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) H 2 .
  • '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.
  • 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.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • '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.
  • prophylactic measures may include the administration of vaccines; the
  • '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).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • '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.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • cancer refers to any cellular malignancy characterized by unregulated proliferation, lack of differentiation or dedifferentiation and the ability to invade local tissues and metastasize. Cancer can develop in any tissue of any organ. More specifically, cancer is intended to include, without limitation, prostate cancer, colon cancer, rectal cancer, breast cancer, skin cancer (e.g., melanoma), liver cancer (e.g., hepatocellular cancer and hepatoblastoma), head and neck cancer, lung cancer (e.g., non-small cell lung cancer), gastric cancer, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer, endometrial ovarian cancer, Wilm's tumor, bladder cancer and leukemia.
  • prostate cancer colon cancer
  • rectal cancer breast cancer
  • breast cancer e.g., melanoma
  • liver cancer e.g., hepatocellular cancer and hepatoblastoma
  • head and neck cancer e.g., non-
  • Prostate cancer is used herein to refer to an uncontrolled (malignant) growth of cells in the prostate gland, which is located at the base of the urinary bladder and is responsible for forming part of the semen. Prostate cancer is typically classified by a Gleason score, a histological analysis of the grade or severity of the cancer.
  • metastasis is used herein to refer to a cancer that has spread beyond the tissue of origin, for example, the prostate. "Metastasis” is also intended to mean the process by which cancer spreads from one part of the body to another, the way it travels from the place at which it first arose as a primary tumor to distant locations in the body.
  • 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.
  • double ester type prodrugs such as (acyloxy)alkyl esters or
  • ((alkoxycarbonyl)oxy)alkylesters Particularly the Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention.
  • 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.
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
  • the following atoms, where present, may vary, so that for example, any hydrogen may be 2 H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • 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. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as U C, 18 F, 15 0 and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • 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 ⁇ electrons and an atom (usually H).
  • 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.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • 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.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80%> by weight, more than 85%o 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%o 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%o by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • 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.
  • the weights are based upon total weight of compound.
  • 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.
  • the weights are based upon total weight of compound.
  • an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10%) enantiomerically pure R-compound.
  • 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.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • 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.
  • 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.
  • 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:
  • Y is -S-, -S(O)- or -S(0) 2 -, one of A or B is -L 1 -X-L 2 -C(0)-NR 2a R 2b or - ⁇ ⁇ - ⁇ ⁇ ( ⁇ )- OR 2a , and the other is R 1 ;
  • Y is -0-
  • B is -L 1 -X-L 2 -C(0)-NR 2a R 2b or -L 1 -X-L 2 -C(0)-OR 2a
  • A is R 1 ;
  • X is a single bond, -C(R 4a R 4b )-, -0-, -S-, -S(O)- or -S(0) 2 -;
  • Cy is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • each of L 1 and L 2 is independently substituted or unsubstituted C 1 -C7 alkylene or heteroalkylene;
  • R 1 is hydrogen, halo, or substituted or unsubstituted C 1 -C5 alkyl
  • each R 2a and R 2b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 2a and R 2b are joined together to form a substituted or unsubstituted heterocycloalkyl or a heteroaryl ring;
  • each R 4a and R 4b is independently selected from H, substituted or unsubstituted alkyl, and halo;
  • the present invention provides a composition of a compound according to formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or stereoisomers, isotopic variants or tautomers thereof.
  • the present invention provides a composition of a compound according to formula I, provided that:
  • Y is -S-, -S(O)- or -S(0) 2 -, one of A or B is -L ⁇ X-L ⁇ QC - R ⁇ R 215 or - ⁇ ⁇ - ⁇ ⁇ )- OR 2a , and the other is R 1 ;
  • Y is -0-
  • B is -L 1 -X-L 2 -C(0)-NR 2a R 2b or -L 1 -X-L 2 -C(0)-OR 2a
  • A is R 1 ;
  • X is a single bond, -C(R 4a R 4b )-, -0-, -S-, -S(O)- or -S(0) 2 -;
  • Cy is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • each of L 1 and L 2 is independently substituted or unsubstituted C1-C7 alkylene or heteroalkylene;
  • R 1 is hydrogen, halo, or substituted or unsubstituted C1-C5 alkyl
  • each R 2a and R 2b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 2a and R 2b are joined together to form a substituted or unsubstituted heterocycloalkyl or a heteroaryl ring;
  • each R 4a and R 4b is independently selected from H, substituted or unsubstituted alkyl, and halo;
  • R 1 is substituted or unsubstituted alkyl or halo.
  • R 1 is Me, Et, i-Pr, n-Pr, n-Bu, F, CI, Br, or I.
  • R 1 is Me.
  • the present invention provides a composition of a compound according to formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or stereoisomers, isotopic variants or tautomers thereof.
  • Y is -0-.
  • Y is -S-, -S(O)- or -S(0) 2 -.
  • Y is -S-.
  • the compound is according to formula Ila or lib:
  • A is R 1 ; and B is - ⁇ ⁇ - ⁇ ⁇ - ⁇ 2 ⁇ or - ⁇ ⁇ - ⁇ ⁇ ( ⁇ )-
  • the compound is according to formula Ilia, Illb, IIIc, Hid,
  • L 1 is methylene, ethylene, propylene, or butylene, each of which unsubstituted or substituted with one or more groups selected from C 1 -C 4 alkyl, halo, and hydroxyl.
  • L 1 is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, or -CH 2 -CH 2 -
  • L 1 is -CH 2 -, -C(H)Me-, or C(Me) 2 -.
  • L 2 is methylene, ethylene, propylene, or butylene, each of which unsubstituted or substituted with one or more groups selected from C 1 -C 4 alkyl, halo, and hydroxyl.
  • L 2 is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, or -CH 2 -CH 2 - CH 2 -CH 2
  • L 2 is -CH 2 -, -C(H)Me-, or C(Me) 2 -.
  • each L 1 and L 2 is -CH 2 -.
  • Cy is unsubstituted aryl.
  • Cy is unsubstituted phenyl.
  • Cy is unsubstituted naphthyl.
  • Cy is unsubstituted heteroaryl.
  • Cy is unsubstituted pyridyl.
  • Cy is unsubstituted pyrimidinyl.
  • Cy is substituted aryl.
  • Cy is substituted phenyl.
  • Cy is substituted naphthyl.
  • Cy is substituted heteroaryl.
  • Cy is substituted pyridyl.
  • Cy is substituted pyrimidinyl.
  • the substitution is independently selected from one to three alkyl, alkoxy, haloalkyl, halo and cyano.
  • the substitution is independently selected from one to three Me, Et, i-Pr, t-Bu, OMe, OEt, O-i-Pr, CN, Br, CI, or F.
  • the compound is according to formula IVa, IVb, IVc,
  • R 1 , R 2a , and R 2b are as described for formula I; n is 1, 2, 3, 4, or 5; and each R 3c 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 amino
  • 5-thiazolebutanoic acid 4-methyl-P-oxo-2 -phenyl-, ethyl ester.
  • R 1 is H or substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 is halo
  • R 1 is Me.
  • the compound is according to formula Va, Vb, Vc, Vd,
  • each of R 3c is H.
  • n is 1; and R 3c is alkyl, alkoxy, haloalkyl, or halo.
  • n is 1 or 2; and each R 3c is independently Me, Et, i-Pr, t-
  • n is 1 or 2; and each R 3c is independently Me, CF 3 , OMe, or Et.
  • n 1; and R 3c is Et.
  • n is 1; and R 3c is i-Pr.
  • n is 1; and R 3c is t-Bu.
  • n is 1; and R 3c is CF 3 .
  • the compound is according to formula Via, VIb, Vic,
  • R 2b is H. In certain embodiments, R 2b is Me.
  • each of R 2a and R 2b is H.
  • the compound is according to formula Vila, Vllb, VIIc,
  • R 3c is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, haloalkyl, substituted or unsubstituted acyl,or halo.
  • R 3c is Me, Et, i-Pr, t-Bu, OMe, OEt, O-i-Pr, CN, -
  • R 3c is Me, CF 3 , OMe, or Et.
  • R 3c is Me.
  • R 3c is Et.
  • R 3c is i-Pr.
  • R 3c is t-Bu.
  • R 3c is CF 3 .
  • R 2a is H.
  • R 2a is substituted or unsubstituted alkyl.
  • R 2a is substituted or unsubstituted aryl.
  • R 2a is substituted or unsubstituted phenyl.
  • R 2a is substituted or unsubstituted benzyl.
  • R 2a is substituted or unsubstituted phenethyl.
  • R 2a is substituted or unsubstituted phenylpropyl.
  • R 2a is substituted or unsubstituted cycloalkyl.
  • R 2a is cyclopropyl, cyclopentyl or cyclobutyl.
  • R 2a is substituted or unsubstituted heteroaryl.
  • R 2a is substituted or unsubstituted pyridyl, pyrimidyl, or pyrazinyl.
  • R 2a is substituted or unsubstituted heterocycloalkyl.
  • R 2a is substituted or unsubstituted pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.
  • R 2a is alkyl substituted with aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
  • R 2a is methyl, ethyl, or n-propyl substituted with phenyl, pyridyl, cycloalkyl or heterocycloalkyl.
  • R 2a is methyl, ethyl, or n-propyl each of which substituted with substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morphlinyl or substituted or unsubstituted piperazinyl.
  • R a is substituted or unsubstituted phenylmethyl, substituted or unsubstituted pyridylmethyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted cyclohexylmethyl, substituted or unsubstituted cyclopentylmethyl, substituted or unsubstituted cyclobutylmethyl, substituted or unsubstituted piperidinylmethyl, substituted or unsubstituted morphlinylmethyl, or substituted or unsubstituted piperazinylmethyl.
  • R 2a is substituted or unsubstituted phenylethyl, substituted or unsubstituted pyridylethyl, substituted or unsubstituted cyclopropylethyl, substituted or unsubstituted cyclohexylethyl, substituted or unsubstituted cyclopentylethyl, substituted or unsubstituted cyclobutylethyl, substituted or unsubstituted piperidinylethyl, substituted or unsubstituted morphlinylethyl, or substituted or unsubstituted piperazinylethyl.
  • R 2a is substituted or unsubstituted phenylpropyl, substituted or unsubstituted pyridylpropyl, substituted or unsubstituted cyclopropylpropyl, substituted or unsubstituted cyclohexylpropyl, substituted or unsubstituted cyclopentylpropyl, substituted or unsubstituted cyclobutylpropyl, substituted or unsubstituted piperidinylpropyl, substituted or unsubstituted morphlinylpropyl, or substituted or unsubstituted piperazinylpropyl.
  • the substitution is independently selected from one to three alkyl, alkoxy, haloalkyl, halo and cyano.
  • the substitution is selected from one to three Me, Et, i-Pr, t-Bu, OMe, OEt, O-i-Pr, CN, Br, CI, or F.
  • R 2a is substituted or unsubstituted pyridyl, or pyrimidinyl.
  • R 2a is substituted or unsubstituted pyridylmethyl, or pyrimidinylmethyl.
  • R 2a is substituted or unsubstituted pyridylethyl, or pyrimidinylethyl.
  • R 2a is phenyl, benzyl, phenethyl, or phenpropyl each unsubstituted or substituted with halo, alkyl, haloalkyl, or cyano.
  • R 2a is phenyl, benzyl, phenethyl, or phenpropyl each unsubstituted or substituted with CI, Br, F, Me, Et, CF 3 , or cyano.
  • R 2a is pyridyl, pyridylmethyl, or pyridylethyl each unsubstituted or substituted with halo, alkyl, haloalkyl, or cyano.
  • R 2a is pyridyl, pyridylmethyl, or pyridylethyl each unsubstituted or substituted with CI, Br, F, Me, Et, CF 3 , or cyano.
  • R 2a is pyrimidinyl, pyrimidinylmethyl, or
  • R a is pyrimidinyl, pyrimidinylmethyl, or
  • pyrimidinylethyl each unsubstituted or substituted with CI, Br, F, Me, Et, CF 3 , or cyano.
  • R 2a is phenyl, benzyl, 4-fluorophenyl, pyrid-3-yl ethyl, cyclopropyl, cyclopentyl, cyclohexylethyl, 2-chloro-5-pyridyl, 2-fluoro-5-pyridyl, 2-methyl-5- pyridyl, phenylpropyl, 4-fluorobenzyl, 4-fluorophenethyl, 2-(pyrrolidin-l-yl)ethyl, or 2- (morpholin- 1 -yl)ethyl.
  • R 2a and R 2b join together to form a heterocycloalkyl or a heteroaryl ring.
  • R 2a R 2b is:
  • R 2c isH or alkyl
  • X is -0-.
  • X is -S-, -S(O)-, -S(0) 2 -.
  • X is -S-.
  • X is -CH 2 -.
  • each of R 3c is H.
  • R 3c is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, haloalkyl, or halo.
  • R 3c is Me, Et, i-Pr, t-Bu, OMe, OEt, O-i-Pr, CN, CI, or F
  • R 3c is Me, CF 3 , OMe, SMe, or Et.
  • R 3c is Me.
  • R 3c is Et.
  • R 3c is i-Pr.
  • R 3c is t-Bu.
  • R 3c is CF 3 .
  • the compound is according to formula Villa, VHIb, VIIIc, VHId, or Vllle:
  • the compound is according to formula IXa, IXb, IXc, IXd, IXe, or IXf:
  • each R 4 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 unsub
  • the compound is according to formula Xa, Xb, Xc, Xd, Xe, or Xf:
  • each R 4 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 unsub
  • m is 1 or 2; and each R 4 is independently Me, Et, i-Pr, OMe,
  • each R 4 is H.
  • m is 1 ; and R 4 is Me, Et, i-Pr, OMe, OEt, O-i-Pr, CN, CI, or F.
  • m is 1 ; and R 4 is 4-Cl, or 4-F.
  • the compound is according to formula XIa, Xlb, or Xlc:
  • each R 4 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 unsub
  • the compound is according to formula Xlla, Xllb, or XIIc:
  • each R 4 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 unsub
  • the compound is according to formula XHIa, XHIb, or XIIIc:
  • each R 4 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 unsub
  • the compound is according to formula XlVa, XlVb, or XIVc:
  • each R 4 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 unsub
  • the compound is according to formula XVa, XVb, XVc, XVd, XVe, XVf, XVg, or XVh:
  • the compound is according to formula XVIa, XVIb, XVIc, XVId, XVIe, or XVIf:
  • each R 4 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 unsub
  • m is 1 or 2; and each R 4 is independently Me, Et, i-Pr, OMe,
  • each R 4 is H.
  • m is 1 ; and R 4 is Me, Et, i-Pr, OMe, OEt, O-i-Pr, CN, CI, or F.
  • X is -0-.
  • X is -CH 2 -.
  • X is -S-, -S(O)-, -S(0) 2 -.
  • m is 1 and R 4 is 4-F or 4-CF 3 .
  • n is 1 and R 4 is 4-F. In another particular embodiment, m is 1 and R 4 is 4-CF 3 .
  • R 3c is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, haloalkyl, substituted or unsubstituted acyl, or halo.
  • R 3c is Me, Et, i-Pr, t-Bu, OMe, OEt, O-i-Pr, CN, -C(0)Me, CF 3 , -C(OH)HMe, -C(Me) 2 OH, - OC(H)F 2 , CI, or F.
  • R 3c is Me, CF 3 , OMe, SMe, or Et.
  • R 3c is Me.
  • R 3c is Et.
  • R 3c is i-Pr.
  • R 3c is t-Bu.
  • R 3c is CF 3 .
  • the present invention provides a composition of a compound according to formula I-XVIf.
  • the present invention provides a composition of a compound according to formula IVa-XVIf.
  • the present invention provides a composition of a compound according to formula
  • R 1 , R 2a , R 3c , L 1 , L 2 , and n are as described herein;
  • R 1 is substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, or halo.
  • R 1 is H.
  • R 3c is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, haloalkyl, substituted or unsubstituted acyl, or halo.
  • R 3c is
  • R 3c is
  • R 3c is
  • R 3c is
  • R 3c is i-
  • R 3c is t-
  • R 3c is
  • R 3c is
  • R 3c is
  • R 3c is at 3- position. In another embodiment, R 3c is at 4-position.
  • L 1 and L 2 is independently -CH 2 -, -C(H)Me-, or -C(Me) 2 -. In one embodiment, one of L 1 and L 2 is -C(H)Me- and the other is -CH 2 -. In another embodiment, one of L 1 and L 2 is -C(Me) 2 - and the other is -CH 2 -. In a particular embodiment, each of L 1 and L 2 is -CH 2 -.
  • X is -S-. In a particular embodiment, X is -0-.
  • R 2a is H or substituted or unsubstituted alkyl. In a particular embodiment, R 2a is H.
  • the compound is selected from:
  • the compound is selected from Table 1.
  • 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- alkylmorp/zo/z ' we esters and the like.
  • 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.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Preferred are the Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention.
  • 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.
  • 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.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • 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.
  • the active ingredients 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.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • the present oxazoles and thiazoles have use for the treatment of cancers and hyperproliferative disorders relating to aberrant Wnt/wg signaling.
  • 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.
  • cancers include, without limitation, those of the prostate cancer, colon cancer, rectal cancer, breast cancer, skin cancer (e.g., melanoma), liver cancer (e.g., hepatocellular cancer and hepatoblastoma), head and neck cancer, lung cancer (e.g., non-small cell lung cancer), gastric cancer, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer, endometrial ovarian cancer, Wilm's tumor, bladder cancer and leukemia.
  • Such methods comprise administering an effective condition-treating or condition- preventing amount of one or more of the pharmaceutical compositions just described.
  • compounds and compositions thereof and methods described herein are also envisioned as useful for targeting cancerous prostate cells that remain following radical prostatectomy, including micrometastases and thus, are useful for treating prostate cancer patients following surgical intervention.
  • compounds and compositions thereof and methods described herein are envisioned as being useful in advance of surgical intervention to delay or prevent the need for surgery.
  • direct delivery of the compounds or compositions thereof to the prostate tumor or in the vicinity of the tumor is envisioned as a particular delivery mode suitable for such an application.
  • combination therapies that comprise administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with therapeutic regimens (e.g., local and/or systemic therapeutic modalities) implemented for treating patients afflicted with diseases or conditions that are causally related to the aberrant activity of the Wnt pathway in vivo.
  • therapeutic regimens e.g., local and/or systemic therapeutic modalities
  • Such diseases include, without limitation, pulmonary fibrosis; and cancers, including: without limitation, prostate cancer, colon cancer, rectal cancer, breast cancer, skin cancer (e.g., melanoma), liver cancer (e.g., hepatocellular cancer and hepatoblastoma), head and neck cancer, lung cancer (e.g., non-small cell lung cancer), gastric cancer, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer, endometrial ovarian cancer, Wilm's tumor, bladder cancer and leukemia.
  • prostate cancer e.g., melanoma
  • liver cancer e.g., hepatocellular cancer and hepatoblastoma
  • head and neck cancer e.g., lung cancer (e.g., non-small cell lung cancer)
  • gastric cancer mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer,
  • Such combination therapies can boost the therapeutic activity of each of the therapeutic modalities with the potential for synergistic therapeutic benefit.
  • Combination therapy furthermore, has the potential to improve therapeutic benefit with no significant increase in morbidity relative to that typically achieved using the individual therapeutic modalities (monotherapies) separately. Under some circumstances, the doses of each of the individual therapeutic modalities can be reduced, which may result in an overall decrease in morbidity when combination therapy is implemented.
  • combination therapies may involve administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, at the same time, before, and/or after a second therapeutic modality of the combination therapy.
  • the timing of administration of the, e.g., first and second therapeutic modalities of a combination therapy may be determined based on the experience of the attending physician and the manner in which therapeutic modalities known in the art are typically administered.
  • a combination therapy comprises administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with a systemic therapeutic modality, such as, for example, one or more of a systemic inhibitor of immune system down regulation, such as anti-CTLA-4 (including but not limited to ipilimumab and tremelimumab), PD-1, and PD-L1 antibodies.
  • a systemic therapeutic modality such as, for example, one or more of a systemic inhibitor of immune system down regulation, such as anti-CTLA-4 (including but not limited to ipilimumab and tremelimumab), PD-1, and PD-L1 antibodies.
  • combination therapy may comprise administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with one or more of a systemic immune upregulating agent, including: non-specific cytokines, such as interleukin-1, -2, or -6 (IL-1, IL-2 or IL-6) and aldesleukin; interferon-alpha or gamma (IFN-a and IFN- ⁇ ), interferon alfa-2b and pegylated interferon (including pegylated interferon alfa-2a and pegylated interferon alfa-2b); granulocyte macrophage colony stimulating factor (GM-CSF, molgramostim or sargramostim); dendritic cell vaccines and other allogeneic or autologous therapeutic cancer vaccines, including intralesional vaccines containing an oncolytic herpes virus encoding GM-CSF (ONCOVEX®) or
  • combination therapy may comprise administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with one or more systemic targeted therapy agent, including: drugs that target protein kinases and the receptors that activate them, including but not limited to afatinib (BIBW 2992), bevacizumab, cetuximab, dasatinib, E7080, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, sorafenib, sunitinib, trastuzumab and vandetanib; serine/threonine-selective protein kinase inhibitors, including but not limited to those targeting the B-Raf/MEKIERK pathway, such as vemurafenib (also known
  • COX-2 inhibitors including but not limited to celecoxib, valdecoxib and rofecoxib
  • angiogenesis blockers including IFN-a, IL-12, suramin, and thrombospondin (including thrombospondin 1, ABT-510 and ABT-898)
  • immune cell therapy including but not limited to adoptive T-cell transfer and autologous immune cell therapy.
  • a combination therapy comprises administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with a local therapeutic modality, such as, for example, a local immunomodulative therapy: including, but not limited to, intralesional (IL) chemoablation using an IL chemoablative agent consisting primarily of rose bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) or another halogenated xanthene, including erythrosin B, phloxine B, 4,5,6,7-tetrabromo-2',4',5',7'- tetraiodofluorescein, 2',4,5,6,7-pentachloro-4',5',7'-triiodofluorescein, 4,4',5,6,7-pentachloro- 2'
  • a physiologically acceptable salt of the halogenated xanthene may be used in this composition.
  • the aforementioned local immunomodulative therapies are known in the art and are described in, for example, U.S. 2015/0290318 and U.S. Application Ser. No. 12/315,781, the entire content of each of which is incorporated herein by reference.
  • a combination therapy comprises administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with intralesional (IL) chemoablation with PV-10 or another halogenated xanthene agent.
  • IL intralesional
  • IL chemoablation using a specific class of agent can elicit not only highly specific ablation of the injected lesion but also an antitumor immune response (“bystander effect") that augments local efficacy in the injected tumor and leads to spontaneous regression of uninjected tumors.
  • PV-10 is, for example, undergoing clinical testing for treatment of metastatic melanoma, breast carcinoma and hepatocellular carcinoma.
  • IL chemoablation can lead to rapid reduction in tumor burden, thereby reducing the potential for tumor-induced immune suppression and potentially minimizing the extent and severity of the disease. Chemoablation of entire tumors or
  • substantially all of the tumors, and especially chemoablation of multiple tumors, enhances exposure of the patient's immune system to distinct clonal subpopulations of tumor cells that may be present, and thus maximizes overall immune response to the tumor .
  • combination therapy can be heightened by repeated administration. Since IL chemoablation is well suited to repeat treatment, continued therapeutic intervention by ongoing administration of the oxazole and/or thiazole compounds described herein, or a composition thereof, alongside repeated IL chemoablation is envisioned.
  • the timing of administration may be varied and combination therapy may be performed with concurrent administration of either therapy, or delayed administration of one or another of the therapies.
  • IL chemoablative agent use of additional complementary therapeutic modalities may offer additive or synergistic benefit, particularly when they promote immunologic stimulation (i. e., immunodulation).
  • Complementary immunomodulative therapies may be used to advantage to promote additive or synergistic immunologic interactions that allow one or multiple therapies to be used at reduced doses relative to those used when administered individually as monotherapies, while retaining high efficacy and potentially reducing undesirable adverse effects.
  • immunomodulative therapies elicit immune system upregulation or counter tumor-induced immune system down regulation.
  • Monotherapy dose schedules are set by determining the maximum tolerated dose (MTD) in early-stage clinical trials.
  • MTD maximum tolerated dose
  • the MTD (or a close variation thereof) is then applied to later-stage clinical trials that optimize efficacy and further assess issues pertaining to safety.
  • Examplary dosing schedules for a number of systemic agents that may be combined with administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, are provided in Table 7.
  • thronibospondm (ABT-51 if ) J 20 mg daily to 100 mg twice daily
  • the combination therapies and methods for treatment described herein will generally permit administration of a systemic agent at a level at or below the typical dose schedule for the systemic agent when used as a monotherapy (as described in Table 7). This may also apply to dosing parameters for the oxazole and/or thiazole compounds described herein or a composition thereof. Lower doses of the oxazole and/or thiazole compounds described herein, or a composition thereof, may confer benefit when used in combination with either systemic or a local therapeutic modality, such as, for example, a local immunomodulative therapy.
  • combination therapies that comprise administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with therapeutic regimens directed to promoting immune responses are envisioned.
  • Such therapeutic regimens may be directed to promoting immune responses systemically and/or in a localized manner.
  • effective systemic immunotherapeutic approaches have been developed and implemented for the treatment of a variety of cancers, including melanoma, lung cancer, and prostate cancer. These approaches include blockade of immune-inhibitory receptors on activated T cells.
  • Monoclonal antibodies against CTLA-4, PD-1, and PD-L1, for example, have been used to advantage to promote immune responses. See, for example, Kaufman et al.
  • combination therapy comprising administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with at least one of antibodies against CTLA-4, PD-1, and/or PD-L1 is envisioned herein.
  • combination therapies comprise administration of one or more of the oxazole and/or thiazole compounds described herein, or a composition thereof, in conjunction with a therapeutic regimen used for the treatment of a cancer, such as those understood in the art and listed, for example, herein below.
  • Cancer drugs approved by the Food and Drug Administration (FDA) for treating breast cancer include, without limitation: Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin- stabilized Nanoparticle Formulation) Ado-Trastuzumab Emtansine, Adrucil
  • Emtansine Lapatinib Ditosylate, Letrozole, Megace (Megestrol Acetate), Megestrol Acetate, Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate), Mexate-AQ
  • Neosar (Cyclophosphamide), Nolvadex (Tamoxifen Citrate), Paclitaxel,
  • Paclitaxel Albumin-stabilized Nanoparticle Formulation Palbociclib, Pamidronate Disodium, Perjeta (Pertuzumab), Pertuzumab, Tamoxifen Citrate, Taxol (Paclitaxel), Taxotere (Docetaxel), Thiotepa, Toremifene, Trastuzumab, Tykerb (Lapatinib Ditosylate), Velban (Vinblastine
  • Velsar Vinblastine Sulfate
  • Vinblastine Sulfate Vinblastine Sulfate
  • Xeloda Capecitabine
  • Zoladex Goserelin Acetate
  • Drug combinations used for treating breast include, without limitation: AC:
  • Doxorubicin Hydrochloride (Adriamycin) (A); and Cyclophosphamide (C); AC-T: Doxorubicin Hydrochloride (Adriamycin) (A); Cyclophosphamide (C); Paclitaxel (Taxol) (T); CAF:
  • Cancer drugs approved by the FDA for treating prostate cancer include, without limitation: Abiraterone Acetate; Bicalutamide; Cabazitaxel; Casodex (Bicalutamide); Degarelix; Docetaxel; Enzalutamide; Goserelin Acetate; Jevtana (Cabazitaxel); Leuprolide Acetate; Lupron (Leuprolide Acetate); Lupron Depot (Leuprolide Acetate); Lupron Depot-3 Month (Leuprolide Acetate); Lupron Depot-4 Month (Leuprolide Acetate); Lupron Depot-Ped (Leuprolide Acetate); Mitoxantrone Hydrochloride; Prednisone; Provenge (Sipuleucel-T); Radium 223 Dichloride; Sipuleucel-T; Taxotere (Docetaxel); Viadur (Leuprolide Acetate); Xofigo (Radium 223
  • Cancer drugs approved by the FDA for treating colon cancer include, without limitation: Adrucil (Fluorouracil); Avastin (Bevacizumab); Bevacizumab; Camptosar (Irinotecan Hydrochloride); Capecitabine; Cetuximab; Cyramza (Ramucirumab); Efudex (Fluorouracil); Eloxatin (Oxaliplatin); Erbitux (Cetuximab); 5-FU (Fluorouracil); Fluoroplex (Fluorouracil); Fluorouracil; Irinotecan Hydrochloride; Leucovorin Calcium; Lonsurf (Trifluridine and Tipiracil Hydrochloride); Oxaliplatin; Panitumumab; Ramucirumab; Regorafenib; Stivarga (Regorafenib); Trifluridine and Tipiracil Hydrochloride; Vectibix (Panitumumab).
  • Drug combinations used for treating colon cancer include, without limitation:
  • CAPOX Capecitabine (CAP); Oxaliplatin (OX); FOLFIRI: Leucovorin Calcium (Folinic Acid) (FOL); Fluorouracil (F); Irinotecan Hydrochloride (IRI); FOLFIRI-BEVACIZUMAB: Leucovorin Calcium (Folinic Acid) (FOL); Fluorouracil (F); Irinotecan Hydrochloride (IRI); Bevacizumab; FOLFIRI-CETUXIMAB: Leucovorin Calcium (Folinic Acid) (FOL);
  • Fluorouracil F
  • IRI Irinotecan Hydrochloride
  • Cetuximab FOLFOX: Leucovorin Calcium (Folinic Acid) (FOL); Fluorouracil (F); Oxaliplatin (OX); FU-LV: Fluorouracil (FU);
  • LV Leucovorin Calcium
  • XELIRI Capecitabine (Xeloda) (XEL); Irinotecan
  • Cancer drugs approved by the FDA for treating rectal cancer include, without limitation: Adrucil (Fluorouracil); Avastin (Bevacizumab); Bevacizumab; Camptosar (Irinotecan Hydrochloride); Capecitabine; Cetuximab; Cyramza (Ramucirumab); Efudex (Fluorouracil); Eloxatin (Oxaliplatin); Erbitux (Cetuximab); 5-FU (Fluorouracil); Fluoroplex (Fluorouracil); Fluorouracil; Irinotecan Hydrochloride; Leucovorin Calcium; Lonsurf (Trifluridine and Tipiracil Hydrochloride); Oxaliplatin; Panitumumab; Ramucirumab; Regorafenib; Stivarga (Regorafenib); Trifluridine and Tipiracil Hydrochloride; Vectibix (Panitumumumum
  • Drug combinations used for treating rectal cancer include, without limitation:
  • CAPOX Capecitabine (CAP); Oxaliplatin (OX); FOLFIRI: Leucovorin Calcium (Folinic Acid) (FOL); Fluorouracil (F); Irinotecan Hydrochloride (IRI); FOLFIRI-BEVACIZUMAB: Leucovorin Calcium (Folinic Acid) (FOL); Fluorouracil (F); Irinotecan Hydrochloride (IRI); Bevacizumab; FOLFIRI-CETUXIMAB: Leucovorin Calcium (Folinic Acid) (FOL);
  • Fluorouracil F
  • IRI Irinotecan Hydrochloride
  • Cetuximab FOLFOX: Leucovorin Calcium (Folinic Acid) (FOL); Fluorouracil (F); Oxaliplatin (OX); FU-LV: Fluorouracil (FU);
  • LV Leucovorin Calcium
  • XELIRI Capecitabine (Xeloda) (XEL); Irinotecan Hydrochloride (IRI); XELOX: Capecitabine (Xeloda) (XEL); and Oxaliplatin (OX).
  • Cancer drugs approved by the FDA for treating gastroenteropancreatic neuroendocrine tumors include, without limitation: Lanreotide Acetate; and Somatuline Depot (Lanreotide Acetate).
  • Cancer drugs approved by the FDA for treating ovarian cancer, fallopian tube cancer, and primary peritoneal cancer include, without limitation: Avastin (Bevacizumab);
  • Bevacizumab Carboplatin; Clafen; (Cyclophosphamide); Cisplatin; Cyclophosphamide; Cytoxan (Cyclophosphamide); Doxorubicin Hydrochloride; Dox-SL (Doxorubicin Hydrochloride Liposome); DOXIL (Doxorubicin Hydrochloride Liposome); Doxorubicin Hydrochloride Liposome; Evacet (Doxorubicin Hydrochloride Liposome); Gemcitabine Hydrochloride; Gemzar (Gemcitabine Hydrochloride); Hycamtin (Topotecan Hydrochloride); LipoDox (Doxorubicin Hydrochloride Liposome); Lynparza (Olaparib); Neosar (Cyclophosphamide); Olaparib;
  • Paclitaxel Paraplat (Carboplatin); Paraplatin (Carboplatin); Platinol (Cisplatin); Platinol-AQ (Cisplatin); Taxol (Paclitaxel); Thiotepa; and Topotecan Hydrochloride.
  • Drug combinations used for treating ovarian cancer, fallopian tube cancer, and primary peritoneal cancer include, without limitation: BEP: Bleomycin (B); Etoposide (E); Cisplatin (Platinol) (P); Carboplatin-Taxol: Carboplatin (C); Paclitaxel (Taxol); Gemcitabine- Cisplatin: Gemcitabine Hydrochloride, Cisplatin; and VelP: Vinblastine Sulfate (Velban) (Ve); Ifosfamide (I); Cisplatin (Platinol).
  • Cancer drugs approved by the FDA for treating liver cancer include, without limitation: Nexavar (Sorafenib Tosylate); and Sorafenib Tosylate.
  • Cancer drugs approved by the FDA for treating cancer that arises in the head or neck region include, without limitation: Abitrexate (Methotrexate); Adrucil (Fluorouracil); Blenoxane (Bleomycin); Bleomycin; Cetuximab; Cisplatin; Docetaxel; Efudex (Fluorouracil); Erbitux (Cetuximab); 5-FU (Fluorouracil); Fluoroplex (Fluorouracil); Fluorouracil; Folex
  • Taxotere Docetaxel
  • Drug combinations used for treating head and neck cancer include, without limitation: TPF: Docetaxel (Taxotere) (T); Cisplatin (Platinol) (P); and Fluorouracil (F).
  • Cancer drugs approved by the FDA for treating acute lymphoblastic leukemia include, without limitation: Abitrexate (Methotrexate); Arranon (Nelarabine);
  • Drug combinations used for treating ALL include, without limitation: Hyper-
  • CVAD Cyclophosphamide (C); Vincristine Sulfate (V); and Doxorubicin Hydrochloride (Adriamycin).
  • Cancer drugs approved by the FDA for treating acute myeloid leukemia include, without limitation: Arsenic Trioxide; Cerubidine (Daunorubicin Hydrochloride); Clafen (Cyclophosphamide); Cyclophosphamide; Cytarabine; Cytosar-U (Cytarabine); Cytoxan
  • Drug combinations used for treating AML include, without limitation: ADE:
  • Cytarabine (Ara-C); Daunorubicin Hydrochloride (D); and Etoposide (E).
  • CLL include, without limitation: Alemtuzumab; Ambochlorin (Chlorambucil); Amboclorin (Chlorambucil); Arzerra (Ofatumumab); Bendamustine Hydrochloride; Campath
  • Linfolizin Chlorambucil
  • Mechlorethamine Hydrochloride Mustargen (Mechlorethamine Hydrochloride); Neosar (Cyclophosphamide); Obinutuzumab; Ofatumumab; Prednisone; Rituxan (Rituximab); Rituximab; Treanda (Bendamustine Hydrochloride); and Zydelig (Idelalisib).
  • Drug combinations used for treating CLL include, without limitation:
  • Chlorambucil-Prednisone; and CVP Cyclophosphamide (C); Vincristine Sulfate (V); and Prednisone (P).
  • CML include, without limitation: Bosulif (Bosutinib); Bosutinib; Busulfan; Busulfex
  • Cancer drugs approved by the FDA for treating hairy cell leukemia include, without limitation: Intron A (Recombinant Interferon Alfa-2b); and Recombinant Interferon Alfa-2b.
  • Cancer drugs approved by the FDA for treating meningeal leukemia include, without limitation: Cytarabine; Cytosar-U (Cytarabine); and Tarabine PFS (Cytarabine).
  • Cancer drugs approved by the FDA for treating non-small cell lung cancer include, without limitation: Abitrexate (Methotrexate); Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation); Afatinib Dimaleate; Alimta (Pemetrexed Disodium); Avastin (Bevacizumab); Bevacizumab; Carboplatin; Ceritinib; Cisplatin; Crizotinib; Cyramza
  • Mexate-AQ Metalhotrexate
  • Mustargen Mechanism of the Mexate
  • Pembrolizumab Pemetrexed Disodium
  • Platinol Ciplatin
  • Platinol-AQ Ciplatin
  • Ramucirumab ; Tarceva (Erlotinib Hydrochloride); Taxol (Paclitaxel); Taxotere (Docetaxel); Vinorelbine Tartrate; Xalkori (Crizotinib); and Zykadia (Ceritinib).
  • Drug combinations used for treating non-small cell lung cancer include, without limitation: Carboplatin-Taxol and Gemcitabine-Cisplatin.
  • Cancer drugs approved by the FDA for treating small cell lung cancer include, without limitation: Abitrexate (Methotrexate); Doxorubicin Hydrochloride; Etopophos
  • Etoposide Phosphate Etoposide; Etoposide Phosphate; Folex (Methotrexate); Folex PFS (Methotrexate); Hycamtin (Topotecan Hydrochloride); Mechlorethamine Hydrochloride;
  • Methotrexate Methotrexate; Methotrexate LPF (Methotrexate); Mexate (Methotrexate); Mexate-AQ
  • Cancer drugs approved by the FDA for treating basal cell carcinoma include, without limitation: Adrucil (Fluorouracil); Aldara (Imiquimod); Efudex (Fluorouracil); Erivedge (Vismodegib); 5-FU (Fluorouracil); Fluoroplex (Fluorouracil); Fluorouracil; Imiquimod;
  • Cancer drugs approved by the FDA for treating melanoma include, without limitation: Aldesleukin; Dabrafenib; dacarbazine; DTIC-Dome (Dacarbazine); IL-2
  • Aldesleukin Imlygic (Talimogene Laherparepvec); Interleukin-2 (Aldesleukin); Intron A (Recombinant Interferon Alfa-2b); Ipilimumab; Keytruda (Pembrolizumab); Mekinist (Trametinib); Nivolumab; Opdivo (Nivolumab); Peginterferon Alfa-2b; Pembrolizumab;
  • Proleukin (Aldesleukin); Recombinant Interferon Alfa-2; Sylatron (Peginterferon Alfa-2b);
  • Tafinlar (Dabrafenib); Talimogene Laherparepvec; Trametinib; Vemurafenib; Yervoy
  • Cancer drugs approved by the FDA for treating melanoma include, without limitation: Adrucil (Fluorouracil); Cyramza (Ramucirumab); Docetaxel; Doxorubicin
  • Drug combinations used for treating gastric cancer include, without limitation:
  • Cancer drugs approved by the FDA for treating malignant mesothelioma include, without limitation: Alimta (Pemetrexed Disodium); Cisplatin; Pemetrexed Disodium; Platinol (Cisplatin); and Platinol- AQ (Cisplatin).
  • Drug combinations used for treating malignant mesothelioma include, without limitation: GEMCITABINE-CISPLATIN.
  • Cancer drugs approved by the FDA for treating esophageal cancer include, without limitation: Cyramza (Ramucirumab); Docetaxel; Herceptin (Trastuzumab);
  • Drug combinations used for treating malignant esophageal cancer include, without limitation: FU-LV and XELIRI.
  • Drug combinations used for treating synovial sarcoma include, without limitation:
  • Doxorubicin and/or Ifosfamide are administered to synovial sarcoma.
  • the primary treatment for synovial sarcoma is surgical resection, preferably with clear margins.
  • Cancer drugs approved by the FDA for treating cervical cancer include, without limitation: Avastin (Bevacizumab); Bevacizumab; Blenoxane (Bleomycin); Bleomycin;
  • Drug combinations used for treating cervical cancer include, without limitation:
  • Cancer drugs approved by the FDA for treating bladder cancer include, without limitation: Cisplatin; Doxorubicin Hydrochloride; Platinol (Cisplatin); Platinol-AQ (Cisplatin); and Thiotepa.
  • Drug combinations used for treating bladder cancer include, without limitation:
  • Drugs used for treating Wilms Tumor include, without limitation: actinomycin D, vincristine, doxorubicin, cyclophosphamide, etoposide, carboplatin, mesna (to protect the bladder from the effects of the cyclophosphamide), and irinotecan, and combinations thereof.
  • oxazole and/or thiazole compounds described herein, or a composition thereof may be administered in conjunction with a therapeutic regimen that calls for radiation and/or surgery.
  • a therapeutic regimen that calls for radiation and/or surgery.
  • oxazole and/or thiazole compounds described herein, or a composition thereof may, for example, be
  • Idiopathic pulmonary fibrosis is a progressive disease with a high mortality rate.
  • Dysregulation of the Wnt/p-catenin pathway has been implicated in lung fibrosis. See, for example, Lam et al, (2014, Am J Resp Crit Care Med 190: 185); Selman et al. (2008, PLoS Med 5:e62); Henderson et al.
  • combination therapies for the treatment of IPF comprise administration of at least one of the present oxazole and/or thiazoles in combination with a therapeutic regimen currently applied to the care of patients suffering from pulmonary fibrosis.
  • Guidelines for the care of IPF are known in the art and provided by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and the Latin American Thoracic Association.
  • nintedanib a tyrosine kinase inhibitor that targets multiple tyrosine kinases, including vascular endothelial growth factor, fibroblast growth factor, and PDGF receptors
  • pirfenidone a tyrosine kinase inhibitor that targets multiple tyrosine kinases, including vascular endothelial growth factor, fibroblast growth factor, and PDGF receptors
  • pirfenidone pirfenidone
  • antacid therapy even in patients without symptoms of gastroesophageal reflux (GER), are conditionally recommended.
  • Pirfenidone Esbriet
  • Oxidanib available from Boehringer Ingelheim GmbH, received FDA approval for treating IPF in 2014.
  • the guidelines also provide a conditional recommendation against using N-acetylcysteine monotherapy, sildenafil, macitentan, and bosentan.
  • the guidelines further recommend against the use of anticoagulation agents (warfarin); imatinib, a selective tyrosine kinase inhibitor against platelet-derived growth factor (PDGF) receptors; combination prednisone, azathioprine, and N-acetylcysteine; and selective endothelin receptor antagonist (ambrisentan).
  • the combination therapy encompassed herein may comprise administration of at least one of the present oxazole and/or thiazoles in combination with a corticosteroid alone or in combination with an
  • Combination therapy encompassed herein may also comprise administration of at least one of the present oxazole and/or thiazoles in combination with oxygen therapy, pulmonary rehabilitation, and/or surgery. All of the above therapeutic interventions are known in the art to be implemented for treating pulmonary fibrosis and are described in various websites, including that provided by the Mayo Clinic.
  • 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.
  • 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.
  • 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.
  • the compounds of this invention 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.
  • 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.
  • Thiazoles and oxazoles of the invention may be prepared according to Scheme 1.
  • Ketones 1 containing the appropriate A and B substituents may be transformed into 2 containing a suitable leaving group E, such as a halide or sulfonate, in the a-position, which may be further transformed directly into compounds of formula I by treatment with an appropriately
  • certain compounds of the invention may be prepared according to Scheme 4.
  • Thiazoles or oxazoles of structure 13 may be coupled with the appropriate partner 14 to provide 15.
  • Compounds of structure 15 may also be prepared by coupling halide-substituted heterocycles 16 with the appropriate partner 17.
  • M is a functional group capable of coupling, such as a boronic acid ester or a trialkylstannane. Coupling may also be carried out between 16 and an appropriate alkyne to provide 18.
  • Intermediates 15 and 18 may be reduced to provide compounds 19, which may also be made directly from 13 by treatment with a strong base, such as «-butyllithium, and reaction with an appropriate alkylating agent. In certain cases, protection of the carbonyl-containing functionality may be necessary.
  • intermediates 20 may be transformed into thiazoles 21.
  • the residue obtained was partitioned between water (250 mL) and ethyl acetate (250 mL), and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound as a brownish solid.
  • the crude product obtained was purified by silica gel (230-400) column chromatography (10% ethyl acetate in hexane) to obtain ethyl 2-bromo-4-methylthiazole- 5-carboxylate (800 mg, 59%) as a yellow solid.
  • the crude product obtained was purified by silica gel (230- 400) column chromatography (10% ethyl acetate in hexane) to obtain pure ethyl 2-(4- ethylphenyl)-4-methylthiazole-5-carboxylate (275 mg, 55%) as an off-white solid.
  • the separated ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a pale brown solid.
  • the crude product obtained was purified by silica gel (230-400) column chromatography (10% ethyl acetate in hexane) to obtain pure 5-(chloromethyl)-2-(4-ethylphenyl)-4-methylthiazole (1.2 g, 75%) as an off-white solid.
  • reaction mixture was diluted with water (250 mL), extracted with ethyl acetate (2 x 150 mL), and the combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ethyl 2-((2-(4-ethylphenyl)-4-methylthiazol-5-yl)methylthio)acetate (1.2 g, 56%) as an off-white solid.
  • the solid obtained from filtration was dissolved in water, acidified to pH 1 with aqueous HC1 (1.5N), and extracted with ethyl acetate (200 mL). The combined ethyl acetate layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-((2-(4-ethylphenyl)-4-methylthiazol- 5-yl)methylthio)acetic acid (1.6 g, 87 %) as a white solid.
  • the organic layers were washed with aqueous sodium bicarbonate solution (10%, 50 mL), aqueous HCl (1.5N, 50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product as a white solid.
  • the crude product obtained was purified by silica gel (230-400) column chromatography (30% ethyl acetate in hexane) to obtain the title compound (500 mg, 48%) as an off-white solid.
  • Example 1 Step 4 (50 mg, 0.214 mmol, 1 eq) in DMF (2 mL) was added sodium hydride (60% in mineral oil) (12.8 mg, 0.32 mmol, 1.5 eq) at 0 °C, and the reaction mixture was stirred at the same temperature for 5 min. To the resulting suspension was added bromoacetic acid tert-butyl ester (50 mg, 0.25 mmol, 1.2 eq) at 0 °C, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with aqueous ammonium chloride solution (10%) and extracted with ethyl acetate (50 mL).
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product.
  • the crude product obtained was purified by silica gel (230-400) column chromatography (40% ethyl acetate in hexane) to obtain pure tert-butyl 2-((2-(4-ethylphenyl)-4-methylthiazol-5-yl)methoxy)acetate (32 mg, 43%) as an off-white solid.
  • reaction mixture was evaporated under reduced pressure to remove formic acid, and the residue was dissolved in ethyl acetate (200 mL), washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-((2-(4-ethylphenyl)-4-methylthiazol-5-yl)methoxy)acetic acid (300 mg, 71%) as a white solid.
  • the resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate, and the ethyl acetate layer was washed with aqueous sodium bicarbonate solution (10%, 50 mL) and aqueous HC1 (1.5N, 50 mL), and then dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product.
  • the crude product obtained was purified by silica gel (230-400) column chromatography (40% ethyl acetate in hexane) to obtain the title compound (35 mg, 33%) as an off-white solid.

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Abstract

Des composés hétérocycliques selon la formule I : dans laquelle A, B, Y et Cy sont tels que décrits dans l'invention, sont utilisés en tant qu'inhibiteurs de la voie Wnt qui ciblent spécifiquement l'activité du pool stabilisé de B-cat Lesdits composés peuvent être préparés sous forme de compositions pharmaceutiques et peuvent être utilisés dans la prévention et le traitement de divers états chez les mammifères, notamment les hommes, comprenant et de manière non restrictive le cancer et d'autres états liés à un dysfonctionnement de la voie Wnt, notamment divers cancers et la fibrose pulmonaire.
PCT/US2017/020631 2016-03-04 2017-03-03 Nouveaux composés oxazoles et thiazoles pouvant être utilisés comme modulateurs de la β-caténine et leurs utilisations Ceased WO2017152032A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115785018A (zh) * 2022-12-26 2023-03-14 湖北广济药业股份有限公司 一种非布司他脱羧杂质的制备方法
US11680054B2 (en) 2018-07-06 2023-06-20 Arcede Pharma Ab Bronchodilating hetero-linked amides
WO2023120452A1 (fr) * 2021-12-20 2023-06-29 国立大学法人筑波大学 Inhibiteur de srebp-1 et composition pharmaceutique pour le traitement de l'hypertriglycéridémie

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110251103A1 (en) * 2008-09-10 2011-10-13 Ramanuj Dasgupta Targeted chemical high-throughput screening method
US20110251144A1 (en) * 2008-09-16 2011-10-13 Massachusetts Institute Of Technology Molecular modulators of the wnt/beta-catenin pathway
US8252823B2 (en) * 2008-01-28 2012-08-28 New York University Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
WO2016081451A1 (fr) * 2014-11-17 2016-05-26 New York University Nouveaux composés oxazoles pouvant être utilisés comme modulateurs de la β-caténine et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8252823B2 (en) * 2008-01-28 2012-08-28 New York University Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
US20110251103A1 (en) * 2008-09-10 2011-10-13 Ramanuj Dasgupta Targeted chemical high-throughput screening method
US20110251144A1 (en) * 2008-09-16 2011-10-13 Massachusetts Institute Of Technology Molecular modulators of the wnt/beta-catenin pathway
WO2016081451A1 (fr) * 2014-11-17 2016-05-26 New York University Nouveaux composés oxazoles pouvant être utilisés comme modulateurs de la β-caténine et leurs utilisations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11680054B2 (en) 2018-07-06 2023-06-20 Arcede Pharma Ab Bronchodilating hetero-linked amides
WO2023120452A1 (fr) * 2021-12-20 2023-06-29 国立大学法人筑波大学 Inhibiteur de srebp-1 et composition pharmaceutique pour le traitement de l'hypertriglycéridémie
CN115785018A (zh) * 2022-12-26 2023-03-14 湖北广济药业股份有限公司 一种非布司他脱羧杂质的制备方法

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