NZ714958B2 - 2,3-dihydrobenzofuran-5-yl compounds as dyrk kinase inhibitors - Google Patents

2,3-dihydrobenzofuran-5-yl compounds as dyrk kinase inhibitors Download PDF

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NZ714958B2
NZ714958B2 NZ714958A NZ71495814A NZ714958B2 NZ 714958 B2 NZ714958 B2 NZ 714958B2 NZ 714958 A NZ714958 A NZ 714958A NZ 71495814 A NZ71495814 A NZ 71495814A NZ 714958 B2 NZ714958 B2 NZ 714958B2
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c1alkyl
cancer
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Johann Leban
Mirko Zaja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Abstract

The present invention relates to compounds of below Formula (I), physiologically functional derivatives or salts thereof, where the groups R1, R2, R3, R4, RA, X1, and A, as well as the variables n, m and p are detailed further herein. In another aspect, the present invention provides methods for their preparation, their medical use and pharmaceutical compositions comprising said compounds, physiologically functional derivatives, solvates or salts thereof. ir preparation, their medical use and pharmaceutical compositions comprising said compounds, physiologically functional derivatives, solvates or salts thereof.

Description

/062774 2,3-dihydrobenzofuran~5wyl compounds as DYRK Kinase Inhibitors OUND OF THE INVENTION The final—Specificity Tyrosine—fiegulated Elnase 1B (DYRKlB, also referred to as Minibrain-Eegulated _Iginase MIRK) belongs to the DYRK family of serine/threonine kinases, which, based on sequence and structural homologies, can be divided into three subgroups: the YAK group with no members in the animal kingdom, the DYRKI and the DYRK2 subgroup. The two DYRKl subgroup members DYRKIA and DYRKlB share 85% l0 identity at the amino acid level, though expression and functional characteristics are distinct (Aranda et 3.1., FASEB J. 2011 Feb;25(2):449«462.).
The human DYRKIB gene encodes a 69kDa protein with 629 amino acids in length.
Alternative Splicing and ential promoter engagement can yield two additional, slightly shorter DYRKIB isoforms with differential expression patterns, the shorter of which lacking kinase activity (Leder et al., m J. 2003 Jun 15;372(Pt 3):88]-888.).
The regulation of DYRKIB catalytic activity and function is not entirely understood. Given the extensive sequence rity to DYRKIA, the intrinsic regulatory and catalytic properties of DYRKlB can w to a certain extent - be ed from studies of DYRKlA regulation.
DYRK family members are arginine—directed serine/threonine kinases, with DYRKlB phosphorylating either serine in the consensus substrate sequence SPSXXR (Friedman, J Cell Biochem. 2007 Oct 1;102(2):274~279.; Himpel et al, J Biol Chem. 2000 Jan 28;275(4):2431- . tion of DYRKlB involves an intramolecular tyrosine (Y) auto—phosphorylation of the second tyrosine of an YxY motif in the conserved kinase domain and activation loop, respectively (Becker et al, FEBS J. 2011 Jan;278(2):246—256.; Himpel et al., J‘ Biol Chem. 2000 Jan 28;275(4):2431—2438.; Nolen at 211., Mol Cell. 2004 Sep 5):661-675.).
Notably, this Y~phosphorylation—dependent activation step occurs only during translation of DYRK kinases, resulting in activated DYRK proteins with serine/threonine kinase activity (Locbhead et al., Cell. 2005 Jun l7;121(6):925—936.). This implies that additional processes ing protein—protein interactions, further post—translational modifications and/or subcellular localization control the response of DYRK kinases to extracellular signals. For instance, signaling via RAS/RAC/MKK3 is able to stimulate DYRKIB activity in n ar contexts such as in pancreatic cancer cells and interaction of DYRKlA with 14—3—3 proteins significantly enhances DYRK kinase activity (Deng et a1., J Biol Chem. 2003 Oct l7;278(42):4l347—41354.; Jin et 211., J Biol Chem. 2005 Dec 23;280(51):42097-42105.; Jin et 211., Cancer Res. 2007 Aug 1;67(15):7247—7255.; Kim et 8.1., Biochem s Res Commun. 2004 Oct 15;323(2):499—504.).
During normal development DYRKlB expression is preferentially restricted to testes and muscle cells (Leder et al., Biochem J. 2003 Jun 15;372(Pt 3):881—888.; Leder et a1, Biochem Biophys Res Commun. 1999 Jan 19;254(2):474—479.). ln muscle its expression is ted by RHO and basic Heliquoop-Helix transcription factors via binding to an E—box in the DYRKlB promoter (Deng et 31., J Biol Chem. 2003 Oct l7;278(42):41347-41354.; Friedman, J Cell Biochem. 2007 Oct l;102(2):274—279.). Inhibition and overexpression studies suggest a pro~differentiation activity of DYRKIB in myoblast differentiation by enhancing the expression of myogenic transcription factors such as Mei2 (Deng et al., J Biol Chem. 2005 Feb 11;280(6):4894-4905.). This effect is mediated by DYRKlB-dependent phosphorylation of class II histone deacetylases (HDAC) thereby freeing Mei2 from complexes with inhibitory HDACS and allowing Mef2 to exert its pro—myogenic function (Deng et al., J Biol Chem. 2005 Feb (6):4894—4905.). In addition to its role in myoblast differentiation, DYRKlB also ls cell cycle arrest by p110sphorylationudependent destabilization of D—type cyclins and stabilization of cell cycle tors including p27 and p21 (Deng et al., J Biol Chem. 2004 May 21 ;279(2l):22498—22504.; Ewton et a1, Mol Cancer Ther. 2011 Nov;10(11):2104- 2114.; Mercer et al, J Biol Chem. 2005 Jul 27):25788-25801.; Zou et a1, J Biol Chem. 2004 Jun (26)2779027798.). Like , for which a larger number of substrate proteins has already been identified, DYRKIB can act as co—activator of the FOXOla transcription factor, thereby regulating glucose-(S—phosphatase expression (von Groote— Bidlingmaier et a1, BiOchein s Res Commun. 2003 Jan l7;300(3):764—769.).
DYRKlB deficient mice do not display any evident pmental defects and survive several weeks post birth (Leder et a1, Biochem J. 2003 Jun 15;372(Pt 3):881-888.). Details of the DYRKlB mutant phenotype remain to be reported. By contrast, DYRKlA ncy in mice results in an embryonic lethal phenotype (Fotaki et a1., Mol Cell Biol. 2002 Sep;22(18):6636-6647.).
DYRKIB in cancer Several recent studies have implicated DYRKlB as a putative oncogenic factor in different cancer entities. DYRKlB localizes to the chromosomal region 19ql3, which is frequently amplified in pancreatic and n cancers (Friedman, J Cell Biochem. 2007 Oct l;102(2):274-279.; Karhu et al., Genes somes Cancer. 2006 Aug;45(8):72l—730.; Lee et al., Cancer Res. 2000 Jul l;60(13):3631—3637.). Accordingly, DYRKlB is strongly expressed in a fraction of atic and ovarian cancer cell lines (Friedman, J Cell Biochem. 2007 Oct l;102(2):274—279.; Hu and Friedman, Genes Cancer. 2010 Aug l;l(8):803—811.).
Notably, in pancreatic cancer DYRKIB acts as survival or kinase downstream of RAS- RACl to promote viability and clonal growth of cancer cells (Jin et al., Cancer Res. 2007 Aug l;67(15):7247-7255.). In addition, several in vitro studies suggest that DYRKIB has pro— oncogenic function in colon cancer, osteosarcoma and rhabdornyosarcoma (RMS). RNA interference and overexpression studies demonstrated a pro—survival role of DYRKlB in colon cancer, osteosarcoma, RMS and pancreatic cancer (Deng et al., Cancer Res. 2009 Apr 15;69(8):3317~3324.; Deng et al., Cancer Res. 2006 Apr 15;66(8):4l49-4158.; Friedman, Sarcoma. 2011;2011:260757, .l155/2011/260757.; lin et al., Cancer Res. 2007 Aug l;67(15):7247—7255.; Mercer et al., Cancer Res. 2006 May 15;66(10):5143-5150.; Yang et al., Carcinogenesis. 2010 Apr;3 l(4):552-558.). The pro—survival activity in sarcoma can «— at least in part — be ascribed to the role of DYRKIB in promoting the inactivation of reactive oxygen species (ROS). DYRKIB is able to increase the sion of ROS detoxifying enzymes including superoxide dismutases 2 and 3 (Deng et al., Cancer Res. 2009 Apr 15;69(8):33 17- 3324.; Hu and Friedman, Genes Cancer. 2010 Aug l;l(8):803-8ll.). This may also explain the enhanced sensitivity of DYRKlB—depleted cancer cells to certain chemotherapeutic drugs such as cisplatin known to increase toxic ROS levels (Hu and Friedman, Genes Cancer. 2010 Aug l;l(8):803~811.).
Hedgehog signaling in cancer therapy The Hedgehog (HH)/GLI signal transduction pathway is a key regulator of multiple developmental processes. Uncontrolled activation of HH/GLI ing is a common e of many human ancies including cancers of the brain, skin, gastro—intestinal tract, prostate, breast lung, muscle and bone (reviewed in {Beachy et al., . 2004 Sep (7007):402.; Beachy et al., Nature. 2004 Nov 18;432(7015)1324—331.; Epstein, Nat Rev Cancer. 2008 Oct;8(10):743—754.; Kasper et al., J Clin . 2012 Feb l;122(2):455—463.; Kasper et al., Eur J . 2006 Mar;42(4):437-445.; Merchant and Matsui, Clin Cancer Res. 2010 Jun 15;16(12):3130-3140.; Ng and Curran, Nat Rev Cancer. 2011 May 26;11(7):493—501.; Ruiz i Altaba et al., Trends Cell Biol. 2007 (9):438—447.; Ruiz i Altaba et al., Nat Rev Cancer. 2002 May;2(5):361—372.; Scales and de Sauvage, Trends Pharmacol Sci. 2009 Jun;30(6):303—312.; Teglund and rd, m Biophys Acta. 2010 Apr;1805(2):181—208.; Theunissen and de Sauvage, Cancer Res. 2009 Aug 1;69(15):6007— 6010.).
Precise reversible tion of Hedgehog signaling is a complex process and mandatory for proper normal development of both invertebrate and vertebrate organisms (for detailed s see (Huangfu and Anderson, Development. 2006 Jan;133(1):3~14.; lngham and McMahon, Genes Dev. 2001 Dec 1;15(23):3059—3087.; Teglund and Toftgard, Biochirn Biophys Acta. 2010 Apr;1805(2):181-208.)).
In the absence of HH ligand, HH signaling is repressed by the activity of the HE or Patched (PTCH), a —transmembrane domain protein Whose intracellular localization is concentrated at the base of the primary cilium, a single antenna—like cell surface compartment that coordinates I-lH signal transduction. Unliganded PTCH prevents the translocation of the G—protein coupled receptor—like protein and essential pathway effector Srnoothened into the primary cilium (Corbit et al., Nature. 2005 Oct 13;437(7061):1018-1021.; Rohatgi et al., e. 2007 Jul 20;317(5836):372-376.; Rohatgi and Scott, Nat Cell Biol. 2007 Sep;9(9]:1005—1009.). This leads to proteolytie cleavage of the latent zinc finger transcription s GLI3 - and to some extent also of GLIZ - into C—terminally truncated repressor forms (GLIR). GLIR formation involves preceding and tial phosphoryiation by protein kinase A (PKA), glycogen synthase kinase 3—beta (GSK) and casein kinase I (CKI) (Price and Kalderon, Cell. 2002 Mar 22;108(6):823-835.) as well as a functional primary cilium (Smith and Rohatgi, Sci Signal. 2011 Jan 11;4(155):1nr1.; Wang et at., Cell. 2000 Feb 18;100(4)2423— _434.; Wen et 311., Mol Cell Biol. 2010 Apr;30(8):1910-1922.; Wong et al., Nat Med. 2009 Sep;15(9):1055—106l.). Following processing, GrLlR translocates to the nucleus to bind to HH target gene ers and repress target gene expression (Aza—Blanc and Kornberg, Trends Genet. 1999 Nov;15(ll):458-462.; Aza—Blanc et al., Cell. 1997 Jun 27;89(7):1043-1053.).
GL1 signals are also negatively regulated by proteasomeminediated degradation of GL1 and by binding to Suppressor of Fused (SUFU), which sequesters GL1 ns in the cytoplasm and also contributes to GL1 sing in the primary cilium (Humke et a1., Genes Dev. 2010 Apr l;24(7):670—682.; Kogerman et al., Nat Cell Biol. 1999 Sep;l(5):312—3l9.).
The therapeutic relevance of targeting HH/GLI signaling in human cancers with genetic, —independent activation of HH/GLI signaling has ly been demonstrated for basal- cell carcinoma (ECG) and medulioblastoma. In both malignant entities, inhibition of the ial HH pathway effector Smoothened had a dramatic therapeutic benefit (Rudin et a1., N Engl J Med. 2009 Sep l7;361(12):1173~1178.; Skvara et al., I invest Dermatol. 2011 Aug;131(8):1735—l744.; Von Hoffet a1., N Engl J Med. 2009 Sep l7;361(12):1164-1172.). r Smocthened antagonists will display therapeutic efficacy in HH ligand dependent s s to be shown. Ongoing clinical trials with Smoothened antagonists from different pharmaceutical companies will eventually answer the question of the clinical efficacy of targeting Smoothened in og associated malignancies (Aberger et al., Vitam Horm. 2012;88:25-54.; Lin and Matsui, Onco Targets Ther. 2012;5:47-58.; Ng and Curran, Nat Rev Cancer. 2011 May 26;1 l(7):493—501.; Scales and de Sauvage, Trends Pharmacol Sci. 2009 Jun;30(6):303—312.). Clinical studies with small molecule Smoothened inhibitors to treat ts with metastatic colorectal cancer, ovarian cancer or pancreatic cancer failed to demonstrate therapeutic efficacy of Smoothened antagonists in combination with currents treatment regimens (Ng and Curran, Nat Rev Cancer. 201 1 May 26;l l(7):493—501.).
One of the reasons for the lack of therapeutic efficacy of Smocthened inhibitors may be explained by Smoothened—independent activation of GL1 ription factors in different cancer entities such as pancreatic , melanoma or s sarcoma. This nonical activation of GL1 transcription factors can be induced by a variety of s frequently hyperactive in malignant cells including SMAD, RAS—MEKJERK, Pl3K/AKT, EGFR signaling or the EWS-FLII oncogene (reviewed in (Aberger et al, Vitam Honn. 2012;88:25— 54.; Mangelberger et at, Front Biosci. 2012 Jan l;17:90—99.; Stecca and Ruiz, I M01 Cell Biol. 2010 Apr;2(2):84—95.).
Regulation of HIDGLI signaling by DYRK family members The first regulatory interactions between DYRK family members and the HH/GLI pathway came from studies of DYRKIA and its impact 0n the transcriptional activity of the GL1 zinc finger transcription factors mediating the transcriptional output of HH pathway activation.
Using reporter gene based assays, Mao et al. have shown that DYRKIA is able to enhance the activity of the GL1] activator and stimulate HH target gene expression, respectively.
DYRKIA can phosphorylate GL1] in vitro and enhance the nuclear level of GLII. Direct modification of GLll and enhanced nuciear zation in response to DYRKIA ty are likely to t for the enhanced expression of HH target genes (Mao et at, J Biol Chem. 2002 Sep 20;277(38):35156—35161.).
While DYRKIA enhances GLI activity, the class II DYRK family member DYRK2 acts as negative regulator of GLI activity. DYRK2 can directly phosphorylate GLIZ and GLB resulting in destabilization of GL12/3 and enhanced proteasome-dependent degradation.
Mutation of the DYRKZ substrate phosphorylation sites 8384 and 81011 in GL12 rendered GLIZ resistant to DYRKZ mediated inhibition of transcriptional activity and proteasomal degradation (Varjosalo et al., Cell. 2008 May 2;l33(3):537-548.).
Analysis of DYRKIB on in HH~unresponsive RAS mutant pancreatic cancer cells revealed another regulatory mechanism by which DYRK kinases can affect the activity of HH signaling. Lauth et al. (Nat Struct Mol Biol. 2010 Jun;l7(6):718—725.) provide evidence that DYRKlB is involved in an autocrine—to-paracrine shifi of HH signaling triggered by mutant RAS. This study suggests that oncogenic RAS signaling in pancreatic cancer cells increases HH ligand expression though at the same time it also prevents autocrine HH y activation (Lauth et 31., Nat ' Struct Mol Biol. 2010 Jun;l7(6):718—725.). RAS signaling therefore contributes to paracrine HH signaling, with tumor cells representing the signal source and adjacent stroma cells the signal—receiving compartment (Yauch et al., . 2008 Sep l8;455(7211):406-410.). Like RAS, expression of the RAS effector DYRKlB in HH activated mouse asts inhibited HH signaling, suggesting that DYRKlB can act downstream of RAS to prevent autocrine HH signaling. Further, RNAi knockdown of RAS and DYRKIB in RAS mutant pancreatic cancer cells both led to a GLUE-dependent increase in GLIl mRNA expression (Lauth et 211., Nat Struct Mol Biol. 2010 Jun;l7(6):718~725.). The ed isms ofHH pathway tion by DYRKl B remain unknown.
Together, these reports show that DYRKZ and DYRKlB can have a repressive effect on HH/GLI signaling while DYRKIA functions as positive tor of GL1 transcriptional activity.
BRIEF SUMMARY OF THE INVENTION The compounds of the present invention interact with DYRK kinase, suggesting their ability in prevention and/or therapy of medical conditions wherein the function of Kinase plays a role.
In one aspect, the present invention provides nds of below Formula (I), logically functional derivatives or salts thereof, where the groups R1, R2, R3, R4, RA, X1, and A, as well as the variables n, m and p are detailed further herein below.
R3 R4 N (RA)p (Run\fflgfiiXi/g—ghrg K \\ (Rom In another aspect, the present invention provides methods for preparation of nds according to the present invention, physiologically functional derivatives, solvates or salts thereof, as detailed further herein below. in another aspect, the present ion provides methods for the treatment or tion of n medical conditions, said methods comprising the administration of compounds according to the present invention, physiologically functional derivatives, solvates or salts thereof, to a subject in need thereof, as detailed further herein below.
In another aspect, the present invention provides the use of compounds according to the present invention, physiologicaliy onal derivatives, solvates or salts thereof, in the cture of a medicament for the ent or prevention of certain medical conditions, as detailed further herein beiow.
In another , the present invention provides compounds according to the present invention, physiologically functional derivatives, solvates or salts thereof, for use in the ent or prevention of certain medical conditions, as detailed further herein below.
In another aspect, the present invention provides pharmaceutical compositions comprising compounds according to the t invention, physiologically functional derivatives, solvates or salts thereof and one or more pharmaceutically acceptable ents.
DESCRIPTION OF THE FIGURES Fig. 1 shows the results of a aft assay with L3.6pl cancer cells in Foxn1nu/nu nude mice, administration of the compound of example 5 (dashed line) versus vehicle control (solid line).
The x-axis reflects the time [in days], while the y-axis reflects the tumor volume [in mm3].
DETAILED DESCRIPTION OF THE INVENTION The t invention is particularly set out in the following items: 1. A compound of formula (I) or a solvate or salt thereof, wherein the X1-azol moiety is attached at the 5- or 6- position of the 2,3-dihydrobenzofuran moiety, n is an integer from 0 to 2; m is an integer from 0 to 3; p is an integer from 0 to 4; R1 is H; R2 is H; R3 is H; R4 is H; X1 is independently ed from the group comprising NRn, O and S; (followed by page 8A) Rn is independently selected from the group comprising H, alkyl, aralkyl, haloalkyl, koxy, OH, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CONH2, R’), -CO(R’), -COO(R’), and -SO2(R’); A is a monocyclic heteroaromatic ring system ting of 5 ring atoms, or a ic heteroaromatic ring system consisting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein optionally one to three further ring atoms are heteroatoms independently selected from the group comprising O, S and N and wherein the remaining ring atoms are carbon atoms; RA is ndently selected from the group comprising H, halogen, CN, NO2, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -OR’, -CO-R’, -COO-R’, -CONH-R’, -NHCOR ’, -CON(R’)2, -NR’CO-R’, -NR’-CONR’, -NR’-COOR’, -S-R’, -SO-R’, -SO2-R’, -NHSO2- R’, -SO2NH-R’, -O-CO-NHR’, -O-CO-R’, -R’-O-R’, -R’, -R’-NH-R’, NH-R’, CO-R’, -CONH-alkyl-O-R’, -CONH-alkyl-R’, -NHCO-alkyl-O-R’, -NHCO-alkyl- R’, -CO-R’-alkyl-R’, -CO-R’-alkyl, N(R’)2, -NHR’, NH2, -S-R’, yl-R’ and alkyl-R’; R’ is independently selected from the group comprising H, alkyl, haloalkyl, aryl, aryl, cycloalkyl and heterocycloalkyl; wherein any of the aforementioned alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may independently be substituted with one or more, particularly one to three, more particularly one or two substituents R’’, wherein R’’ independently selected from the group comprising C1 alkyl halogen, aloalkyl, OH, C1alkoxy, C1haloalkoxy, nitro, -NH2, -N(C1alkyl)2, - NH(C1alkyl), -NHCO(C1alkyl), , -CONH(C1alkyl), -CO(C1alkyl), -COH, - COO(C1alkyl), -COOH and –CN; wherein each alkyl group is independently a linear or branched C1-C6 alkanyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the total number of ring atoms in each aryl group is independently 6 to 14; wherein the total number of ring atoms in each heteroaryl group is independently 5 to 14; wherein each cycloalkyl group independently comprises 3 to 10 carbon atoms; wherein each heterocycloalkyl group is, independently, a 5- to 10-membered mono- or polycyclic ring system; wherein each haloalkyl group independently denotes an alkyl group wherein one or more of the hydrogen atoms on the hydrocarbon chain are replaced by halogen atoms; wherein each alkoxy group independently s an O-alkyl group, the alkyl group being as defined above; (followed by page 8B) wherein each alkylthio group independently denotes an yl group, the alkyl group being as defined above; n each haloalkoxy group independently denotes an O-haloalkyl group, haloalkyl group being as defined above; and wherein each alkylamino group independently denotes an NH-alkyl or N-dialkyI group, the alkyl group being as defined above. 2. A compound according to 1, wherein A is a monocyclic heteroaromatic ring system ting of 5 ring atoms, or a bicyclic aromatic ring system consisting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein optionally one or two further ring atoms are N atoms or one further ring atom is an O or S atom, or one further ring atom is an N atom and one ring atom is an O or S atom, and wherein the remaining ring atoms are carbon atoms, wherein A is optionally substituted with one or two substituents RA selected from the group comprising H, CN, NO2, NH2, N(alkyl)2, halogen OH, , haloalkyl, alkyl, haloalkoxy, alkoxyalkyl, heterocycloalkyl, -heterocycloalkyl-alkyl, -heterocycloalkyl-COO-alkyl, heteroaryl, -COOH, -COO-alkyl, aralkyl, aryl, -aryl-halogen, -CO-N(alkyl)2, -CONH-(alkyl), - lkyl-alkoxy, -CONH-cycloalkyl, -CONH-alkyl-heterocycloalkyl, -CO- heterocycloalkyl-alkyl-heterocycloalkyl, -CO-heterocycloalkyl, -CO-heteroaryl, -CO-aryl, - CO-alkyl, -SO2-alkyl, -S-alkyl, -S-alkyl-COO-alkyl, and -S-aralkyl, or a solvate or salt thereof. 3. A compound according to one of 1 or 2, wherein A is a monocyclic or ic heteroaromatic ring system selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazole, imidazole, le, thiadiazole, and oxadiazole, wherein A is optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, Br, OH, C1alkyl, C1alkoxy, CF3, OCF3, -COOH, -COO-(C1alkyl), , hyl, phenyl, fluorophenyl, -CO-N(C1alkyl)2, -CONH-(C1alkyl), -CONH-(C1 alkyl)-O(C1alkyl), (C3cycloalkyl), -CONH-(C1alkyl-tetrahydrofuryl), -CO- piperazinyl-(C1alkyl)-tetrahydrofuranyl, -CO-morholinyl, -CO-pyrrolidinyl, -CO-(methyl- (followed by page 8C) zinyl)-, -SO2(C1alkyl), -S-(C1alkyl), -S-benzyl, -S-(chlorophenylmethyl), -S- hyl, -CO-thienyl, -CO-pyrrolyl, -CO-piperidinyl, peridinyl-COO-(C1alkyl), morpholinyl, C1alkylpiperazinyl, C1alkylthiazolyl, pyridyl, -CO-phenyl, -S-(C1alkyl)- COO-(C1alkyl), NH2, N(C1alkyl)2, -CO-C1alkyl, and -(C1alkyl)-O(C1alkyl), and wherein, when A is benzoxazole, benzothiazole or benzimidazole, A may optionally further be substituted with a halogen atom, and wherein, when A is thiazole, A may optionally r be tuted with a methyl group, or a solvate or salt f. 4. A compound according to any one of 1 to 3, wherein the X1-azol moiety is attached at the 5- position of the hydrobenzofuran .
. A compound according to 1, wherein the X1-azol moiety is attached at the 5- position of the 2,3-dihydrobenzofuran moiety; X1 is independently selected from the group comprising NRn, O and S; Rn is independently selected from the group comprising H, methyl, ethyl, OH, -CONH2, -CONH-methyl, and -COO-methyl; R1 is H; R2 is H; R3 is H; R4 is H; A is independently selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazole, imidazole, triazole, thiadiazole, and oxadiazole; wherein A is optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, Br, OH, C1alkyl, C1alkoxy, CF3, OCF3, -COOH, -COO-(C1alkyl), benzyl, phenethyl, phenyl, fluorophenyl, C1alkyl)2, (C1alkyl), -CONH-(C1 alkyl)-O(C1alkyl), -CONH-(C3cycloalkyl), -CONH-(C1alkyl-tetrahydrofuryl), -CO- piperazinyl-(C1alkyl)-tetrahydrofuranyl, -CO-morholinyl, -CO-pyrrolidinyl, -CO-(methylpiperazinyl )-, -SO2(C1alkyl), -S-(C1alkyl), -S-benzyl, -S-(chlorophenylmethyl), -S- phenethyl, -CO-thienyl, -CO-pyrrolyl, -CO-piperidinyl, -CO-piperidinyl-COO-(C1alkyl), morpholinyl, C1alkylpiperazinyl, C1alkylthiazolyl, l, -CO-phenyl, -S-(C1alkyl)- COO-(C1alkyl), NH2, N(C1alkyl)2, -CO-C1alkyl, and -(C1alkyl)-O(C1alkyl); (followed by page 8D) and wherein, when A is benzoxazole, benzothiazole or benzimidazole, A may optionally further be substituted with a halogen atom, and wherein, when A is thiazole, A may optionally further be substituted with a methyl group, or a solvate or salt thereof. 6. A compound according to 1, wherein the X1-azol moiety is attached at the 5- position of the 2,3-dihydrobenzofuran moiety, X1 is S; A is a monocyclic or bicyclic aromatic ring system selected from the group comprising 1H-imidazolyl, 1H-1,2,4-triazolyl, 1H-benzo[d]imidazolyl, pyridinyl, 1,3,4- thiadiazolyl, 1H-pyrazolyl, 1,3-thiazolyl, and 1,2,4-thiadiazolyl; wherein A is optionally substituted with a tuent RA selected from the group comprising F, Cl, Br, CN, methyl, -SO2-Me, OMe, CF3, Me)2, -CO-N(Me)2, 5-(4-((tetrahydrofuran- 2-yl)methyl)piperazinecarbonyl, -COO-Et, linecarbonyl, OCF3, -COO-Me, OH, - CO-NHMe, -S-Me, pyrrolidincarbonyl, -CO-NH-C2H4-OMe, -S-iPr, ropylcarbamoyl, 4-methylpiperazinecarbonyl, -S-nPr, COOH, -S-benzyl, -S-(4- benzyl), -S-iBu, ((tetrahydrofuranyl)methyl)carbamoyl, phenethyl, -S-phenethyl, - CO-thienyl, -CO-pyrrolyl, peridinyl, -CO-(4ethoxycarbonyl-piperidinyl), linyl, 4-methyl-piperazinyl, 5-methyl-thiazolyl, pyridinyl, -CO-phenyl, -S- (CH2)-COOMe, NH2, -CO-C1alkyl, 3-fluorophenyl, acetyl, -methylthio, and methoxymethyl; and wherein, when A is 1H-benzo[d]imidazolyl, A may optionally further be substituted with a chlorine atom, and when A is 1,3-thiazolyl, A may optionally further be substituted with a methyl group, or a solvate or salt thereof. 7. A compound according to any one of 1 to 6, n said compound is selected from the group comprising (followed by page 8E) No. ure (followed by page 8F) wed by page 8G) wed by page 8H wed by page 8I wed by page 8J) wed by page 8K) wed by page 8L) wed by page 8M) N N 47 S N N N O H wed by page 8N) S HN 52 S N N wed by page 8O) wed by page 8P) wed by page 8Q) wed by page 8R) N O wed by page 8S) wed by page 8T) wed by page 8U) S HN 81 O or a e or salt thereof. (followed by page 8V) 8. A compound according to any one of 1 to 7, or a solvate or salt thereof for use in the treatment of a medical condition selected from the group comprising cancer of the , gus, gastrointestinal tract, gastro-intestinal stromal tumors, pancreas, prostate, y tract, bladder, basal cell oma, medulloblastoma, rhabdomyosarcoma, glioma, small-cell lung cancer, oral squamous cell carcinoma, melanoma, ctal cancer, non-small cell lung cancer, osteosarcoma, glioblastoma, c lymphacytic leukemia, chronic myeloid leukemia, multiple myeloma, acute myeloid leukemia, ovarian , meningioma, and liver cancer . 9. A pharmaceutical composition comprising a compound according to any one of 1 to 7 or a solvate or salt thereof and one or more pharmaceutically acceptable excipients.
. Use of a compound according to any of 1 to 7, or a solvate or salt thereof in the manufacture of a medicament for the treatment of a medical ion selected from the group comprising cancer of the breast, esophagus, gastrointestinal tract, gastrointestinal stromal tumors, pancreas, prostate, biliary tract, bladder, basal cell carcinoma, medulloblastoma, myosarcoma, glioma, small-cell lung cancer, oral squamous cell carcinoma, melanoma, colorectal cancer, all cell lung cancer, osteosarcoma, glioblastoma, chronic lymphacytic leukemia, chronic myeloid leukemia, multiple a, acute myeloid leukemia, ovarian cancer, meningioma, and liver cancer.
The present invention is further enumerated in the following items, certain embodiments of which are disclosed herein for teness: 1. A compound of formula (I) or a physiologically functional derivative, solvate or salt thereof, (followed by page 8W) wherein the X1-azol moiety is attached at the 5- or 6- position of the 2,3-dihydrobenzofuran mioety, n is an integer from 0 to 2; m is an integer from 0 to 3; p is an integer from 0 to 4; R1 is independently selected from the group comprising H, halogen, alkyl, aralkyl, haloalkyl, haloalkoxy, OH, alkoxy, -CN, aryl, aryl, cycloalkyl, cycloalkyl, -S-R’, -SO-R’, nitro, -NH2, -N(R’)2, -NH(R’), -NHCO(R’), -CONH2, -CONH(R’), -CO(R’), -COH, -COO(R’), -COOH, -SO2NH2, -SO2NH(R’), -SO2(R’), 2(R’) and -NHCOOR’; (followed by page 9) R2 is independently selected from the group comprising H, halogen, aikyl, l, haloalkyl, haloalkoxy, OH, alkoxy, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, «S—R’, —SO-R’, nitro, -NH2, —N(R’)2, —NH(R’), —NHCO(R’), —CONH2, —CONH(R’), -CO(R’), -COH, —COO(R’), —COOH, ~SOZNH2, (R’), —SOg(R’), “NH—802(R’) and ~NHCOOR’; R3 is independently selected from the group comprising H, halogen, alkyl, aralkyl, haloalkyl, haloalkcxy, OH, alkoxy, -CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —S—R’, ~SO-R’, nitro, —NH2, —N(R’)2, —NH(R’), -NHCO(R’), —CONH2, —CONH(R’), ~CO(R’), -COH, -COO(R’), -COOI—I, —SOgNl-Iz, —SOZNH(R’), “802(R’), -NH—SOZ(R’) and —NHCOOR’; R4 is independently selected from the group comprising H, alkyl, ai‘alkyi, haloalkyi, haloalkoxy, OH, alkoxy, aryl, heteroazryl, cycloalkyl, heterocycloalkyl, -CONH2, —CONI~I(R’), —CO(R’), —COO(R’), and —SO;(R’); X1 is ndently selected from the group comprising NR“, 0 or S; Rn is ndently selected from the group comprising H, alkyl, aralkyl, haloalkyl, haloalkoxy, OH, , aryl, heteroaryl, lkyl, heterocycloalkyl, ~CONH2, —CONH(R’), —CO(R’), —COO(R’), and -SO;(R’); A is a monocyclic or hicyclic heteroaromatic ring system consisting of 5 to 10 ring atoms, at least one of which is an N atom, n optionally one to three further ring atoms are heteroatoms independently selected from the group comprising 0, S and N and wherein the remaining ring atoms are carbon atoms; RA is independently selected from the group comprising H, halogen, CN, N02, alkyl, haloalkyl, aryl, heteroaryl, lkyl, heterocycloalkyi, —OR’, ~CO—R’, -COO~R’, —CONH—R’, uNHCO—R’, —CON(R’)2, uNR’CO—R’, —NR’—CONR’, —NR’wCOOR’, -S-R’, , ’, ~NHSOg—R’, —SOzNH—R’, —O—CO—NHR’, —O-CO-R’, —R’—0-R’, -R’-CO-R’, ~R’-N'H—R’, NH-R’, —R’-NHCO-R’, alkyl~O-R’, CONH-alkyl—R’, a1kyl—O-R’, —NHCO-alkyl—R’, —CO—R’—all<yl—R’, —CO—R’-alkyl, yl—R’ and alkyl—R’; or in an alternative embodiment of item 1, RA is independently selected from the group comprising H, halogen, CN, N02, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —OR’, , ’, CONE—R”, ~NHCO—R’, ~CON(R’)2, -NR’CO—R’, —NR’-CONR’, —NR’—COOR’, —S-R’, -SO-R’, —SOg—R’, ~NHSOg—R’, -SO;NH~R’, -O-CO—NHR’, mO—CO—R’, -R’wO-R’, —R’—CO-R’, ~R’—NH—R’, -R’—CONH—R’, -R’—NHCO—R’, -CONH—a1kyl-O~R’, -CONH—alkyl-R’, -NHCO—alkyl—O~R’, —NHCO-alky1-R°, ~CO*R’-alkyl—R’, ~CO—R’-alkyl, N(R’)2, «NHR’, NHg, -S—R’, -S—alkyl—R’ and alkyl-R’; R” is independently ed from the group comprising H, alkyl, haloalkyi, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; wherein any of the aforementioned alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may independently be substituted with one or more, particularly one to three, more particularly one or two substituents R”, wherein R” independently selected from the group comprising CM—alkyl halogen, C;_4—haloall<yl, OH, CM—alkoxy, C1_4—lialoalkoxy, nitro, -NH2, -N(C1.4—a}kyl)2, -NH(C1-4—alky1), lO -NHCO(C14—alkyl), —CONH2, -CONH(C14~alkyl), ~CO(Cla-alkyl), -COH, -COO(C;4~ , -COOH and «CN. 2. A compound according to item 1, wherein R1 is independently selected from the group comprising H, fluorine, ne, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, OH, y, ethoxy, «CN, nitro, -NH2, —N(methyl)2, ~NH~1nethyL —NHCO—mcthyl, ~CONH2, —CONH—1nethyl, acetyl, COO—methyl, and —COOH; and R2 is independently selected from the group comprising H, fluorine, chlorine, , ethyl, isopropyl, romethyl, triflnoromethoxy, OH, inethoxy, ethoxy, —CN, nitro, -NH2, ~N(methyl)g, -NH—methyl, ~NHCO-methyl, -CONH2, -CONH—methyl, acetyl, —COO—inethyl, and —COOH, or a physiologically functional derivative, solvate or salt thereof. 3. A compound according to any of items 1 or 2, n n is 0 and m is 0, or a logically functional derivative, solvate or salt thereof. 4. A compound according to any of items 1 to 3, wherein R3 is independently selected from the group comprising H, fluorine, chlorine, methyl, ethyl, isopropyl, trifluorornethyl, —OCF3, OH, y, ethoxy, ~CN, nitro, —NH2, thyl)2, —NH-inethyl, ~NHCO—1nethyl, -CONH2, —CONH-methy1, acetyl, —COO—methyl, and MCOOH, or a physiologically onal derivative, solvate or salt thereof.
. A compound according to any of items 1 to 4, wherein R3 is H, or a physiologically functional tive, solvate or salt thereof. 6. A compound according to any of items 1 to 5, wherein R4 is independently selected from the group comprising H, C1_3—alkyl, C1_4—haloa1kyi, OH, -CONH2, -CONH~C1_3-alkyl, —CO-C1_3—alkyl, and 1-3~alkyl, or a physiologically functional derivative, solvate or salt thereof. 7. A compound according to any of items 1 to 6, wherein R4 is H, or a physiologically functional derivative, e or salt thereof. 8. A compound according to any of items 1 to 7, wherein A is a monocyclic heteroaromatic ring system consisting of 5 or 6 ring atoms, or a bicyclic heteroaromatic ring system consisting of 9 ring atoms, n at least one of the ring atoms is an N atom, wherein optionally one or two further ring atoms are N atoms and wherein the remaining ring atoms are carbon atoms, or in an alternative embodiment of item 8, A is a monocyclic aromatic ring system ting of 5 or 6 ring atoms, or a bicyclic aromatic ring system consisting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein optionally one or two further ring atoms are N atoms, or one further ring atom is an O or S atom, or one further ring atom is an N atom and one ring atom is an O or S atom, and wherein the remaining ring atoms are carbon atoms; wherein A is optionally substituted with one or two substituents RA selected from the group comprising H, CN, N02, halogen OH, alkoxy, haloalkyl, alkyl, haloalkoxy, —COOH, lkyl, aralkyl, aryl, —CO—N(alkyl)2, —CONH-(alkyl), ~CONH-alkyl— alkoxy, —CONH-cycioalkyl, ~CONH—alkyl—heterocycloalkyl, —CO~heterocycloalkyl—alkyl- heterocycloalkyl, -CO-heterocycloalkyl, —SOg-alkyl, —S-alky1, and -S-aralkyl, or a physiologically functional tive, solvate or salt thereof, or in an alternative embodiment of item 8, A is optionally substituted with one or two substituents RA selected from the group sing H, CN, N02, NHg, N(alkyl)2, n OH, alkoxy, haloalkyi, alkyl, haloalkoxy, alkoxyalkyl, heterocycloalkyl, — heterocycloalkyi-alkyl, —heter0cycloalkyi—COO—aikyl, heteroaryl, -COOH, -COOmall<yl, aralkyl, aryl, -aryl—halogen, -CO~N(alkyl)g_, -CONH—(alkyl), —CONH—alkyl—alkoxy, - CONflncycloalkyl, —CONH—alkylnheterocycloalkyl, ~CO—heterocycloalkyl—alkyl- -11.. heterocyeloalkyl, —CO-heterooycloalkyl, -CO-heteroaryl, yl, -CO—all<yl, ~302— alkyl, —S~alkyl, «S-alkyl—Coonalkyl, and —S-aralky1.
A compound according to any of items 1 to 8, wherein A is a monocyclic or bicyclic heteroaromatic ring system selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazole, oie, triazole, pyrazine, triazine, pyrimidine and pyridine, or in an ative embodiment of item 9, A is a monocyclic or bicyclic heteroaromatic ring system selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazole, imidazole, le, pyrazine, triazine, pyrimidine, pyridine, azole, and oxadiazole, wherein A is Optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, 0H, lkoxy, CF3, OCFg, *COOH, ~COO-(C1_2-alkyl), benzyl, phenethyi, , —CO~N(C1_2—alkyl)2, -CONH-(C1.2—alkyl), -CONH-(C1_2—alkyl)— 0(C1.2-alkyl), ICONH—(CH—cycloalkyl), "CONH—(C;.2-alkyl~tetrahydrofuryl), —CO—piperazinyl—(C;.2~alkyl)-tetrahydrofuranyl, -CO-1norholinyl, —CO—pyrrolidinyl, -CO—(methyl—piperazinyl)~, —SO;(C1,2-aikyl), —S-(C1-4—a1kyl), -S—benzyl, —S-(chlorophenylmethyl), and ~S-phenethyl, or in an alternative embodiment of item 9, A is optionally substituted with a tuent RA selected from the group comprising H, CN, F, Cl, Br, OH, Cpl—alkyd, C1_2—alkoxy, CF3, 0GP}, «COOH, -COO—(C1.2—alkyl), , phenethyl, phenyl, fluorophenyl, —CO—N(Clt2—alkyi)2, (C1.g—aikyl), ~CONH-(C1.2—alkyl)—O(C1_2fi alkyl), -CONH—(C3.5—cycloalkyl), —CONH—(C1_2~alkyl-tetrahydrofuryl), -CO—piperazinyl- (C1.2~a1kyl)-tetrahydrofuranyl, ~CO—morholiny1, —CO-pyrrolidinyl, ethyl— piperazinyl)—, —SOZ(C;_2—alkyl), —S—(C1_4-alkyl), —S—benzyl, ~S—(chlorophenylmethyl), -S— phenethyl, -COnthienyl, «CO—pyrrolyl, peridinyl, ~CO-piperidinyl—COO—(C1.2— alkyl), morpholinyl, Cltg—alkylpiperazinyl, C1_2—alkylthiaz,oly1, pyridyl, -CO—phenyl, -S- (C1-2—alkyl)-COO—(C1a1kyl), NHg, N(C1tgma1kyi)2, ~CO-C1.2—alkyl, —(C1_2-alkyl)-O(C;_2» alkyl) and wherein, when A is benzoxazole, benzothiaizole or benzimidazole, A may optionally r be substituted with a halogen atom, or in an alternative embodiment of item 9, when A is benzoxazole, benzothiazole or benzimidazole, A may optionally further be substituted with a halogen atom, and wherein, when A is thiazole, A may Optionally further be substituted with a methyl group 2014/062774 or a physiologically functional derivative, e or salt thereof.
. A compound according to any of items 1 to 9, wherein the Xl—azol moiety is ed at the 5— position of the 2,3 —dihydrobenzofuran rnioety. 11. A compound according to item 1, wherein the l moiety is attached at the 5— position of the 2,3-dihydrobenzofi1ran mioety', n is 0 or 1; 1n is 0 0r 1; X1 is independently selected from the group comprising NRn, O or S; R“ is independently selected from the group comprising H, methyl, ethyl, OH, —CONH2, 1nethy1, and «COO—methyl; R1 is independently ed from the group comprising H, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, OH, methoxy, ethoxy, —CN, nitro, ~NH2, —N(rnethyl)2, -NH~1nethyl, —NHCO—methyl, -CONH2, —CONH—methyl, acetyl, COO—methyl, and MCOOH; R2 is independently selected from the group comprising H, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, OH, methoxy, ethoxy, -CN, nitro, —NH2, —N(methyl)2, -NH—rnethyl, -NHCO-1nethyl, —CONH2, -CONH~methyl, 2O , COO—methyl, and MCOOH; R3 is independently seiected from the group comprising H, fluorine, ne, methyl, ethyl, isopropyl, trifluorornethyl, trifluoromethoxy, OH, methoxy, , —CN, nitro, -NH2, —N(niethyl)g, -NH-methyl, -NHCO—methyl, ~CONH2, -CONH—1nethyl, acetyl, —COO—rnethyi, and ~COOH; R4 is independently selected from the group comprising H, C1_3—alkyl, C1_4—haloalkyl, OH, ~CONH2, ~CONH—C1-3—alkyl, -COmC1_3~a1kyl, and -COO—C1,3wall<yl; A is independently selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazzole, imidazole, triazole, pyrazine, triazine, pyrimidine and ne; or in an alternative embodiment of item 11, A is independently selected from the group sing thiazole, oxazole, pyrazole, e, henzoxazole, benzothiazole, henziinidazole, ole, triazole, pyrazine, triazine, pyrimidine, pyridine, thiadiazole, and oxadiazole; wherein A is optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, OH, C1_2-alkoxy, CFg,7 OCF3, -COOH, -COO-(Cl_g—alkyl), benzyl, phenethyl, phenyl, —CO—N(C1i2—alkyl)2, (C1.g—alkyl), -CONI-I-(C;_2-alkyl)— —alkyl), —CONH—(C3_5—Cycioalkyl), (C1.2—alkyl—tetrahydrofiiryl), -CO—piperazinyl-(C1-2—alkyl)—tetrahydrofuranyl, —C0~morholiny1, ~CO-pyrrolidinyl, —C0- (methy1~piperazi11yl)—, —SOz{C1_2—alkyl), —S—(C1_4-all(yl), ~S—benzy1, «S—(chlorophenyhnethyl), and -S-phenethyl; or in an alternative embodiment of item 11, A is optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, Br, OH, Clog—alkyl, lkoxy, CF3, OCF3, —COOH, —COO—(C1_2~alkyl), benzyl, phenethyl, phenyl, fluorophenyl, ~CO-N(C1_2—alkyl)2, -CONH~(C]_2—alkyl), -CONH—(C1_2—alky1)—O(C1.2— alkyl), -CONH—(C3_5—cycloalkyl), —CONH—(C1-2—a1kyl—tetrahydrofi1ryl), -CO—piperazinyl- (Cg.z—alkyl)—tetrahydrofuranyl, ~CO-1norholinyl, -CO—pyrrolidinyl, ~CO-(1nethyl— piperazinyl)—, ~SOg(C1_2—allcyl), —S-(C1_4-alkyl), -S—benzyl, -S~(chlorophenylmethyl), -S— phenethyl, ~CO~thienyl, irolyl, —C0~piperidinyl, —CO—piperidiny1—COO*(C1-2— , morpholinyl, C1,2~all(ylpiperazinyl, Clwg—alkylthiazolyl, pyiidyl, —CO—pheny1, -S- (C1.2—allcyl)—COO-(C1-3—alkyl), NHg, N(C1_2-alkyl)2, .2—a1kyi, and {Cm—alkyd)- 0(C1.2-a1ky1); and wherein, when A is benzoxazoie, benzothiazole 0r henzimidazole, A may optionally further be substituted with a halogen atom, or in an alternative ment of item 11, when A is benzoxazole, benzothiazole or benzimidazole, A may optionally fiirther be substituted with a halogen atom> and wherein, when A is thiazole, A may optionally further be tuted with a methyl group, or a physiologically functional derivative, solvate or salt f. 12. A compound acCOrding to item 1, wherein the Xl—azol moiety is attached at the 5‘ position of the 2,3 —dihydrobenzofuran mioety, nis 0;mis 0;X1 is S,R3is H; R4isH; A is a monocyclic or bicyclie heteroaromatic ring system selected from the group comprising lH-imidazol-Z-yl, lH—l,2,4—triazoi~5—yl, 1H—benzo[d]imidazol~2-yl and pyridin—Z—yl; or in an alternative embodiment of item 12, A is a monocyclic or bicyclic heteroaromatic ring system selected from the group sing idazol—2-yl, 1H—1,2,4—triazoiy1, lH-benzo[d}imidazol—2—yl, pyridin-Z-yl, 1,3,4—thiadiazolyl, lH~pyrazol—3—yl, l,3~ thiazol—Z-yl, and 1,2,4—thiadiazolyl; wherein A is ally substituted with a substituent RA selected from the group comprising F, Cl, CN, ~SOg—Me, OMe, CF3, —CO—N(Me)2, ~CO—N(Me)2, 5-(4— ((terrahydrofuran—2—yl)methyl)piperazine-I~carbonyl, -COO—Et, line—4-carbonyl, OCFg, e, OH, Me, —S—Me, pyirolidin—l—carbonyl, -CO—NH—C2H4wOMe, —S—iPr, cyc10propylcarbamoyl, 4—methylpiperazine—1—carbony1, , COOH, —S~benzyl, -S—(4-chlorobenzyl), ~S—iBu, ((tetrahydrofuran—2—yl)methyl)carbamoyl, phenethyl and vS—phenethyl; or in an alternative embodiment of item 12, A is optionally substituted with a substituent RA selected from the group comprising F, Cl, Br, CN, methyl, —SOz-Me, OMe, CF3, ~CO- N(Me)2, -CO-N(Me)2, 5—(4—((tetrahydrofiiran-Z—yl)methyl)piperazine—1—carbonyl, —COO— Et, morpholine—4-carbonyl, OCF3, , OH, -CO-NHMe, ~S-Me, pyrrolidin-lcarbonyl , »CO~NH-C2H4—OMe, -S—iPr, cyclopropylcarbamoyl, 4-methylpiperazine—1- carbonyl, -S-nPr, COOH, -S—benzyl, -S—(4—chlorobenzyl), ~S-iBu, ((tetrahydrofitran~2~ yl)methyl)carbamoyl, phenethyl, »S-phenethyl, —CO—thien—2-y1, -CO—pyrrol—2—yl, —CO— din~l-yl, —CO—(4ethoxycarbonyl-piperidin—l—yl), morpholinyl, 4—inethyl- piperazin—l—yl, 5-methyl—thiazol-2—yl, pyridin—4~yl, -CO—phenyi, -S—(CH2)—C00Me, NHg, —CO—C;_2—alkyl, 3—fluorophenyl, acetyl, —methy]thio, and methoxymethyl; and wherein, when A is lH—benzo[d}imidazol—2—yl, A may optionally further be substituted with a chlorine atom, or in an alternative embodiment of item 12, when A is lH—benzoEfliinidazol-Z—yl, A may optionally further be substituted with a chlorine atom, and when A is 1,3vthiazolyl, A may optionally further be substituted with a methyl group, or a physiologically functional derivative, e or salt thereof. 13. A compound according to any of items 1 to 12, wherein said compound is selected from the group comprising the compounds 1 to 47, or in an ative ment of item 13 compounds I to 82, as shown below in the example section, or a logically functional derivative, solvate or salt thereof. 14. A compound ing to any of items 1 to 13, or a logically fiinctional derivative, solvate or salt thereof for use in the treatment of a medical condition selected from the group comprising cancer of the breast, esophagus, intestinal tract, gastro-intestinal stromal tumors, pancreas, prostate, biliary tract, bladder, basal cell carcinoma, medulloblastoma, myosarcoma, glioma, small—cell lung cancer, oral squamous cell carcinoma, melanoma, colorectal cancer, all cell lung , arcoma, glioblastoma, chronic lymphacytic ia, chronic myeloid leukemia, multiple myeloma, acute myeloid leukemia, ovarian cancer, meningiorna, and liver cancer .
. A pharmaceutical composition comprising a compound according to any of items 1 to 13 or a physiologically functional derivative, solvate or salt thereof and one or more pharmaceutically acceptable excipients. 16. A method of treatment of a medical condition selected from the group comprising cancer of the breast, esophagus, gastrointestinal tract, gastro-intestinal stromal , pancreas, prostate, biliary tract, r, basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, glioma, small-cell lung cancer, oral squamous cell carcinoma, melanoma, colorectal cancer, non~small cell lung , osteosarcoma, glioblastoma, chronic lymphacytic leukemia, chronic 1nyeloid leukemia, multiple myeloma, acute myeloid leukemia, n cancer, meningioma, and liver cancer, which comprises the administration of an effective amount of a compound according to any of items 1 to 13, or a physiologically functional derivative, solvate or salt thereof to a subject in need thereof. 17. Use of a compound according to any of items 1 to 13, or a physiologically onal derivative, solvate or salt thereof in the cture of a medicament for the treatment of a l condition selected from the group comprising cancer of the breast, esophagus, gastrointestinal tract, gastro—intestinal stromal tumors, pancreas, prostate, biliary tract, bladder, basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, glioma, small—cell lung , oral squamous cell carcinoma, melanoma, colorectal cancer, non—small cell lung , osteosarcoma, glioblastoma, chronic lymphacytic leukemia, chronic myeloid leukemia, multiple 1nyeloma, acute myeloid ia, ovarian cancer, meningiorna, and liver cancer.
In certain embodiments, n is an integer from 0 to I, more particularly n is 0.
In certain embodiments, m is an integer from 0 to 2, more particularly 0 to 1, even more particularly 0.
In certain embodiments, p is an integer from 0 to 3, more particularly 0 to 2, even more particularly 0 to 1, yet even more particularly 1.
In certain embodiments, R1 is independently selected from the group comprising H, n, 014—alkyl, , C1_4-haloalkyl, C gw4—haloalkoxy, OH, C1-4—alkoxy, —CN, phenyl, naphthyl, l, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, piperidyl, piperazinyl, inorpholinyl, idinyl, —S—C1.4alkyl, mSO-Cinalkyi, nitro, —NH2, -N(C1.4alkyl)2, —NH—C1_4alkyl, -NHCO~C14alkyl, , ~CONH—C1-4alkyl, —CO—C]_4alkyl, -COH, 1_4alkyl, “COOH, —SOgNH2, —SOgNH-C1.4alkyl, ~SOZ-C14fllle, -NH—SOQ—Cli4alkyl and —NHCOO—C1_ 4611le. in more particular embodiments, R1 is independently selected from the group comprising H, n, C1.4—a1kyl, benzyl, Cla—lialoalkyl, CM—haloalkoxy, OH, C1_4—alkoxy, ~CN, phenyl, cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, mS-C1_4alkyl, —SO—C1_4alky1, nitro, -NH2, -N(C;_4alkyl)2, —NH—C1_4alkyl, —NHCO-C1_4alkyl, —CONH2, -CONH—Cl-4alkyl, —CO-C1-4alkyl, ~COO—C1_4alkyl, —COOH, —SOZNH2, ~SOgNH—C14alkyl, —SOz—C;"4all<yl, -NH—SOg-C1_4alkyl and wNHCOO—C;_4alkyl.
In even more particular embodiments, R] is independently selected from the group comprising H, halogen, Clot-alkyl, aloalkyl, CM-haloalkoxy, OH, C1_4-alkoxy, -CN, cyclopropyl, cyclobutyl, nitro, —NH2, -N(C1_4alkyl)p_, -4alkyl, —NHCO~C1_4alkyl, — CONHg, nCONH~C1_4alkyl, —CO-—C1_4alkyl, —COO—C;.4alkyl, and ~COOH.
In yet even more particular embodiments, R1 is independently ed from the group comprising H, halogen, C;_4—alkyl, 01.4-haloalkyl, C;_4-haloalkoxy, OH, Clot—alkoxy, —CN, nitro, -NH2, —N(C1_2alkyl)2, -NH—Cg.2alkyl, ~NHCO-Cl.2alkyl, —CONH2, —CONH~C;_;alkyl, _zalkyl, —COO—C1_2alkyl, and -COOH.
In yet even more particular embodiments, R1 is independently selected from the group comprising H, e, chlorine, bromine, C]_3alkyl, trifluoromethyl, difluoromethyl, -17o trifluoromethoxy, OH, Clog-alkoxy, -CN, nitro, ~NH2, 2alkyl)g, ~NH-Cl_galkyl, C1_2alkyl, —CONH2, —CONH-C1_galkyl, —CO-C;,2a1kyl, -COO-C;.2alky1, and -COOH.
In yet even more particular embodiments, R1 is independently selected from the group comprising H, e, chlorine, methyl, ethyl, pyl, trifluoromethyl, trifluoromethoxy, OH, methoxy, ethoxy, -CN, nitro, —NH2, —N(methy1)2, -NH—methyl, -NHCO-methyl, —CONH2, -CONH—methy1, acetyl, COO-methyl, and -COOH.
In yet even more particular embodiments, R1 is independently selected from the group comprising H, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, OH, and methoxy.
In yet even more particular embodiments, R1 is independently selected from the group comprising H, fluorine, chlorine, methyl, trifluoromethyl, trifluoromethoxy, OH, and methoxy.
Most particularly, R1 is independently H. in n embodiments, R2 is independently selected from the group comprising H, halogen, lky1, benzyl, CM—haloalkyl, C;.4—haloalkoxy, OH, Cli-alkoxy, -CN, phenyl, naphthyl, 2O pyridyl, pyrrolyl, furanyl, l, thiazolyl, oxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, tetrahydrofuryl, ydropyranyl, tetrahydrothienyl, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, ~S~C1_4alkyl, —SO-Cl_4alkyl, nitro, —NH2, —N(C1_4alkyl)g, -NH—C1_4alkyl, -NHCO—C1_4alky1, —CONH2, -CONH—C1_4alkyl, aalkyl, —COH, -COO—C1_4aikyl, -COOH, ~802NH2, -SOgNH—C1_4alkyl, —SOg-Cl4alkyl, —NH-SOz-Ci-4alkyl and —NHCOO-C;.galky1.
In more specific embodiments, R2 is independently selected from the group comprising H, halogen, Clea-alkyl, benzyl, CH—haloalkyl, CM-haloalkoxy, OH, C1-4—alkoxy, —CN, phenyl, cyciopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkyl, -SO-C14alkyl, nitro, —NH2, —N(C;_4alkyl)2, -NH—C1_4alkyl, ~NHCO—C14alkyl, —CONH2, C14alkyl, ~COmC1_4alky1, —COO—C1_4alkyl, «COOH, ~SOZNH2, -C1_4aikyl, nSOZ-Cmalkyl, ~NH—SOg—C14alkyl and —NHCOO-C 1-4alkyi. ~18— in even more particular embodiments, R2 is independently selected from the group comprising H, halogen, C1_4-alkyl, C1_4—haloalkyl, Ct_4-haloalkoxy, OH, CM—alkoxy, —CN, cyclopropyl, cyclobutyl, nitro, —NH2, alkyl)2, 4alkyl, —NHCO—C1_4alkyl, — CONHZ, —CONH-C1_4alkyl, ~CO—C14alkyl, —COO—C;_4alkyl, and —COOH.
In yet even more particular embodiments, R2 is independently selected from the group comprising H, halogen, C1_4-alkyl, C1_4—haloalkyl, C1_4-haloalkoxy, OH, C]_4-alkexy, -CN, nitro, «NHZ, ~N(C;_2alkyl)2, —NH-Ci_2alkyl, -NHCO—Cl_2alkyl, —CONH2, ~CONH—C1_2alkyl, «COowalkyl, ~COO—Cllzalkyl, and —COOH. in yet even more particular embodiments, R2 is independently selected from the group comprising H, fluorine, chlorine, bromine, kyl, trifluoromethyl, omethyl, trifluoromethoxy, OH, C1_3-alkoxy, —CN, nitro, -NH2, -N(C3_2alkyl);_, —NI-l-C1_2alkyl, —NHCO-C1_;_alkyl, —CONI—I2, —CONH—C1.2alkyl, —CO—C1,23H<yl, —COO—C1_2alkyl, and -COOH. in yet even more particular embodiments, R2 is independently selected from the group comprising H, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, OH, methoxy, ethoxy, ~CN, nitro, —NH2, —N(1nethy1)2, ~NH—methyl, —NHCO—1nethyl, —CONH2, -CONH-methyl, acetyl, COO-methyl, and —COOH. in yet even more ular embodiments, R2 is independently selected from the group comprising H, fluorine, chlorine, methyl, ethyl, pyl, trifluoromethyl, trifluoromethoxy, OH, and methoxy.
In yet even more particular embodiments, R2 is independently selected from the group comprising H, fluorine, chlorine, methyl, trifluoromethyl, romethoxy, OH, and methoxy.
Most particularly, R2 is ndently H.
In certain embodiments, R3 is ndently selected from the group comprising H, halogen, lky1, benzyl, C;_4—haloalkyl, CM—haloalkoxy, OH, lkoxy, —CN, phenyl, naphthyl, pyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, lyl, cyclopi'opyl, cyclobutyl, cyclopentyl, exyl, cycloheptyl, decalinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, —S-C,_4alkyl, -SO-Cl_4alky1, nitro, "NHQ, alky1)2, -NH-C1,4alkyl, C14alkyl, ~CONH2, -CONH-C;_4alkyl, —CO—C14alky1, ~COH, —COO~C14alkyl, -COOH, —SOZNH2, -SO;NH~C1-4alkyl, ~SOZ-C14alky1, —NH—SOg—C14alkyl and ~NHCOO—C1-4alkyl.
In more particular ments, R3 is independently selected from the group comprising H, halogen, lky1, benzyl, C1_4—haloalkyl, Ola-haloalkoxy, OH, Cla-alkoxy, ~CN, phenyl, cyclopropyl, utyl, entyl, cyclohexyl, —S—C]W4alkyl, -SO—C1_4a1ky1, nitro, —NH2, ~N(C;.4all<yl)2, —N’H—C1_4alkyl, —NHCOnC1_4alkyl, —CONH2, —CONH~C1.4a1kyl, -CO—C1,4alkyl, -COO-C1-4alkyl, —COOH, —SO;NH2, —SOgNH-C1_4alkyl, —SOg—C1_4alkyl, —NH—SOz—C1_4alkyl and —NHCOO—C1_4alkyl.
In even more particular embodiments, R3 is independently selected from the group comprising H, halogen, C1_4-a1kyl, oalkyl, C1_4—haloalkoxy, OH, C1_4—all<oxy, —CN, cyclopropyl, utyl, nitro, —NH2, -N(C1,4a1kyl)2, _4alkyl, —NHCO—C1-4alkyl, - CONHz, —CONH—CMalkyl, -CO—C1,4all<yl, -COO—C1_4alkyl, and -COOH. in yet even more particular embodiments, R3 is independently selected from the group comprising H, halogen, C1.4-alkyl, Ola-haloalkyl, C1_4‘haloalkoxy, OH, CIA—alkoxy, —CN, nitro, —NH2, —N(C1_2alkyl)p_, ~NH—C1.2alkyl, -NHCO—C1,2alkyl, -CONH2, —CONH-C1.2alkyl, ~CO—C1.2alkyl, ~COO—C1_2alkyl, and —COOH.
In yet even more particular embodiments, R3 is ndently selected from the group comprising H, fluorine, chlorine, bromine, C1_3alkyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, OH, C1_3-alkoxy, -CN, nitro, ~NH2, -N(Ci_2alkyl)2, -NH-C1_2all<yl, —NHCO-Cl_zalkyl, —CONH2, —CONH—C1.2alkyl, ,2alky1, -COO—C1-2alkyl, and ~COOH.
In yet even more particular embodiments, R3 is independently selected from the group comprising H, e, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroniethoxy, OH, methoxy, ethoxy, —CN, nitro, —NH2, —N(methyl)2, “NH—methyl, -NHCO«1nethyl, —CONH2, —CONH—1nethyl, acetyl, COO—methyl, and —COOI—l.
In yet even more particular embodiments, R3 is independently selected from the group comprising H, fluorine, chlorine, methyl, ethyl, pyl, trifluoromethyl, romethoxy, OH, and methoxy.
In yet even more particular embodiments, R3 is independently selected from the group comprising H, fluorine, chlorine, methyl, trifluoromethyl, trifluoremethoxy, OH, and methoxy.
Most particularly, R3 is independently H.
In certain embodiments, R4 is independently selected from the group comprising H, Cln-alkyl, benzyl, Chit—haloalkyl, C1_4—haloalkoxy, OH, CM-alkoxy, , naphthyl, pyridyl, pyrrolyl, fiiranyl, thienyl, lyl, oxazolyl, pyrazclyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, nyl, tetrahydrofnryl, tetrahydropyranyl, IS tetrahydrothienyl, piperidyl, piperazinyl, morpholinyl, pmolidinyl, —CONH2, —CONH—C1_4-alkyl, —CO—C1_4—alkyl, —COO—C14~alkyl, and —SOz-C14-alkyl.
In more particular embodiments, R4 is independently selected fiom the group comprising H, CM—alkyl, benzyl, C1_4—haloalkyl, CM—haloalkoxy, OH, C]alkoxy, phenyl, ~CONH2, —CONH-C1_4-alkyl, —CO—C1_4-aikyl, —COO—C1_4-alkyl, and —SOg—C]_4-alkyl.
In more ular embodiments, R4 is independently selected from the group comprising H, lkyl, Cln-haloalkyl, OH, —CONH2, -CONH—C1-3—alkyl, —CO—C§_3~alkyl, and —COO—C1_3—alkyl.
In even more particular embodiments, R4 is independently selected from the group comprising H, , ethyl, OH, ~CONH2, —CONH—methyl, and —COO~1nethyl.
In yet even more ular embodiments, R4 is independently selected from the group comprising H, and methyl.
Most particularly, R4 is independently H.
In certain embodiments, XE is O or S. In more c embodiments, X1 is S. -21, In certain embodiments, R" is independently selected from the group comprising H, C1_4-alkyl, benzyl, Cla-lialoalkyl, C1,4~haloalkoxy, OH, C;_4—alkoxy, phenyl, naphthyl, pyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazolyl, cyclopropyl, utyl, entyl, exyl, eptyl, decalinyl, ydrofuryl, tetrahydropyranyl, tetrahydrothienyl, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, —CONH2, ~CONH-C1_4—alkyl, ~CO—C1_4-alkyl, -COO—C1,4—alkyl, and —SOg—C1.4—alkyl.
In more particular embodiments, Rn is independently selected from the group cmnprising H, C14-alkyl, benzyl, Ola—haloalkyl, C1_4nhaloalkoxy, OH, C1-4—alkoxy, phenyl, —CONH2, ~CONH-C14—alkyl, -CO—C1_4-alkyl, -COO-C14-alkyl, and -SOg—C1_4-all<yl.
In more particular embodiments, R1‘ is ndently selected from the group sing H, C;_3-alkyl, C1,4—haloalkyl, OH, ~CONH2, —CONH—C1_3-alkyl, -CO-C1.3—alkyl, and ~COO~C§-3—alkyl.
In even more particular embodiments, Rn is independently selected from the group comprising H, methyl, ethyl, OH, —CONH2, —CONH—methyl, and —COO~methyl.
In yet even more particular embodiments, Rn is independently selected from the group comprising H, and methyl.
Most particularly, R“ is independently H.
In certain embodiments, A is a monocyclic or bicyclic heteroaromatic ring system consisting of 5 to 9 ring atoms, at least one of which is an N atom, wherein optionally one or two further ring atoms are atoms independently selected from the group comprising 0, S and N, particularly N, and wherein the remaining ring atoms are carbon atoms.
In more particular embodiments, A is a clic heteroaromatic ring system consisting of 5 or 6 ring atoms, or a bicyclic heteroaromatic ring system ting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein optionally one or two further ring atoms are atoms independently selected from the group comprising 0, S and N and wherein the remaining ring atoms are carbon atoms. ,22_ In other more particular embodiments, A is a 5-membered monocyclic heteroaromatic ring which is ally fused to a phenyl ring, wherein at least one of the ring atoms is an N atom, wherein optionally one or two further ring atoms are N atoms and wherein the ing ring atoms are carbon atoms.
In other more particular embodiments, A is a 5—membered monocyclic heteroaromatic ring which is optionally fused to a phenyl ring, wherein at least one of the ring atoms is an N atom, wherein optionally one further ring atom is an N atom and/or one further ring atom is an O or S atom, and wherein the remaining ring atoms are carbon atoms. in even more particular embodiments, A is a monocyclic heteroaromatic ring system consisting of 5 or 6 ring atOms, or a bicyclic heteroaromatic ring system consisting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein optionally one or two further ring atoms are N atoms and wherein the remaining ring atoms are carbon atoms. in other even more particular embodiments, A is a monocyclic heteroaromatic ring system consisting of 5 or 6 ring atoms, or a bicyclic heteroaromatic ring system ting of 9 ring atoms, n at least one of the ring atoms is an N atom, wherein ally one or two further ring atoms are N atoms, or one further ring atom is an O or S atom, or one further ring atom is an N atom and one ring atom is an O or S atom, and wherein the remaining ring atoms are carbon atoms In other more particular embodiments, A is independently selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, azole, benzothiazole, benzimidazole, imidazole, triazole, ne, triazine, pyrimidine and pyridine, even more particularly i—Z—yl, oxazol—Z—yl, pyrazol—Z-yl, pyrrol—Z-yl, benzoxazol—Z-yl, benzothiazol—Z—yl, benzimidazol—Znyl, imidazol—Z-yl, triazol—S-yl, pyrazin—Z—yl, triazin-Z—yl, pyrimidin—2—yl and pyridin—Z—yl.
In other more particular embodiments, A is independently seiected from the group comprising le, e, pyrazole, e, benzoxazole, benzothiazole, idazole, imidazole, triazole, pyrazine, triazine, pyrimidine, thiadiazole, oxadiazole, and pyridine, even more particularly thiazol—Z—yl, oxazol-Z—yl, pyrazol-Z—yl, pyirol—Z-yl, benzoxazol—Zuyi, benzothiazoi—Z—yt, benzimidazol—Z—yl, imidazol—Z—yl, triazol-S—yl, pyrazin-Z—yl, triazin-Z-yl, pyrimidin—Z—yl, thiadiazol—Z—yl, thiadiazoI-3—yl, thiadiazol—S—yl, zol—Z—yl, oxadiazol—B— yl, oxadiazol—Snyl, and pyridin—Znyl.
In yet even more particular embodiments, A is independently selected from the group comprising imidazolyl, triazolyl, benzoimidazol and pyridinyl, In other yet even more ular embodiments, A is independently ed from the group comprising imidazolyl, triazolyl, benzoimidazoiyl, hiazolyl, thiadiazolyl, pyrazolyl, thiazoiyl, oxazolyl, oxadiazolyl and pyridinyl.
In yet even more particular embodiments, A is independently selected from the group comprising dazolyl, lH~1,2,4—triazol—5—yl, lH—benzo[d]imidazol—2-yl and pyridin—Z— In other yet even more ular embodiments, A is independently selected from the group comprising 1H-imidazol~2—yl, lH—l,2,4—triazol—5—yl, 1H—benzo[d]imidazol—2-y1, pyridin—Z—yl, 1,3,4—thiadiazolw2-yl, lepyrazol—3—yl, 1,3—thiazol—2—yl, 1,2,4—thiadiazolm3-yl, 1,3,4— thiadiazol—Z—yl, 1,2,4-thiadiazol—5—yl, 1,3—oxazol—2—yl and 1,2,4uoxadiazolyl.
In yet even more particular embodiments, A is independently selected from the group comprising benzimidazolHZ—yl and imidazol—Z—yl.
In other yet even more particular embodiments, A is independently selected from the group comprising benzimidazol—Z—yl, imidazoi-Z-yl, l,3,4—tbiadiazol—2~yl, IH—pyrazol—3-yl, 1,3- thiazol—Z—yl, and 1,2,4—thiadiazoly1.
Most particularly, A is independently benzimidazol-Z—yi.
In other embodiments, most particularly, A is independently ndently selected from the group comprising benzimidazol—Z-yl, 1,3,4—thiadiazolyl, lH—pyrazol—S—yl, and 1,3—thiazol- 2—yl.
In all ments bed herein, A may be tuted, where appropriate and chemically feasible, with 0 to 4, particularly, 0 to 2, more particularly 0 to 2, even more particularly 1 or WO 02638 2 substituents RA, n RA is independently selected as detailed in the embodiments as described herein. In certain particular ments, In certain particular embodiments, the thiazole, oxazole, pyrazole, pyrrole, or imidazole group A is particularly optionally substituted with one RA tuent in position 4, the triazole group A is optionally substituted with RA in position 3, the pyrazine, triazine, pyrimidine or pyridine group A is optionally substituted with RA in position 5, and the benzoxazole, henzothiazole, or benzimidazole group A is optionally substituted with RA in position 5 and/or 6, even more particularly optionally substituted with RA in position 5 and further ally substituted in position 6 with a group ed from the group comprising halogen, methyl, ethyl, CF3, CN, N02, COOl—l, OH, NHz, NMeg, and COOMe, more particularly selected from the group comprising halogen, methyl, CFg, CN, and OH, even more particularly selected from the group comprising fluorine, ne, bromine, CF3, CN and OH, yet even more particularly selected from the group comprising fluorine and chlorine, most particularly chlorine.
In other certain particular embodiments, the le, oxazole, pyrazole, pyrrole, or imidazole group A is particularly optionally substituted with one RA substituent in position 4 or 5, the triazole group A is optionally substituted with RA in position 3, the pyrazine, triazine, pyrimidine or pyridine group A is optionally substituted with RA in position 5, and the benzoxazole, benzothiazole, or benzimidazole group A is optionally substituted with RA in position 5 and/or 6, or alternatively in position 1, and r optionally substituted in position or 6 (whichever one is available) with a group selected from the group comprising halogen, methyl, ethyl, CF3, CN, N02, COOH, OH, , NMeg, and COOMe, more particularly selected from the group comprising halogen, methyl, CF3, CN, and OH, even more particularly selected from the group comprising fluorine, chlorine, bromine, CF3, CN and OH, yet even more particularly selected from the group comprising fluorine and ne, most ularly chlorine. For sake of completeness, it is mentioned that thiadiazole and oxadiazole groups are optionally substituted at the ring carbon atom available for binding.
In other more particular embodiments, A is a group of a (la) -E / x3 (Ia), wherein X2 is a group selected from the group comprising N and ethenylene, which may optionally be substituted by one or two RA; X3 is an atom selected from the group comprising C and N which may optionally be substituted by RA; R5 is a substituent group selected from the groups as defined herein for RA, or R5, together with X3 forms a clic 5— or 6 membered aryl or heteroaryl ring, particularly a benzene ring, which may ally be tuted by one or more RA.
In other more particular embodiments, A is an aromatic grOup of formula (Ia) (la), wherein X2 is selected from the group comprising N, S, O, NH, CH, CRA and ethenylene optionally substituted by one or two RA, particularly selected from the group comprising N, S, O, NH, CH and CRA; X3 is ed from the group comprising N, S, NH, CH and CRA; X6 is selected from the group comprising N, S, O, NH, CH and CR5, wherein R5 is a substituent group selected from the groups as defined herein for RA, or R5, together with X3 forms a monocyclic 5— or 6 membered aryl or heteroaryl ring, particularly a benzene ring, which may optionally be substituted by one or more RA, particularly in positon 5 or 6 of a resulting benzazole derivative, wherein ularly said group A comprises not more than one atom selected from O and S and not more than three heteroatoms in total.
In yet other more particular embodiments, A is a group of formula (lb) /N X3 wv-‘E’X/ (Ia), wherein X4 is selected fiom the group comprising CH and NH; X4 is selected from the group comprising CH and a single bond; X3 is an atom selected from the group comprising C and N which may ally be substituted by RA; R.5 is a substituent group ed from the groups as defined herein for RA, or R5, er with X3 forms a monocyclic 5— or 6 membered aryl or heteroaryl ring, particularly a benzene ring, which may optionally be substituted by one or more R". —26- In yet other more particular embodiments, A is an aromatic group of formula (Ia) X4~—~X5 (la), wherein X4 is ed from the group comprising N, S, O, NH, CH and CRA; X5 is selected from the X35 is ed from the group comprising CH and a single bond, particularly a single bond; group comprising N, S, NH, CH and CRA; X6 is selected from the group comprising N, S, O, NH, CH and CR5, wherein R5 is a substituent group selected from the groups as defined herein for RA, or R5, together with X3 forms a monocyclic S- or 6 membered aryl or heteroaryl ring, particularly a benzene ring, which may ally be substituted by one or more RA, particularly in positon 5 or 6 of a resulting benzazole derivative, wherein particularly said group A comprises not more than one atom selected from O and S and not more than three atoms in total.
For ation, when R5, er with X3 forms a tnonocyclic 5— or 6 membered aryl or heteroaryl ring, particularly a benzene ring, which may optionally be substituted by one or more RA, particularly in positon S or 6 of a resulting benzazole derivative, said positon 5 or 6 of a resulting benzazole tive is as shown in the below structure: E /:N 6 In certain embodiments, RA is independently selected from the group comprising H, CN, N02, halogen OH, alkoxy, haloalkyl, alkyl, haloalkoxy, —COOH, lkyl, aralkyl, aryl, —CO—N(alky1)g, —CONH—(alkyl), —CONH—all<yl—alkoxy, —CONH—cycloalkyl, -CONH—all<yl— heterocycloalkyl, —NHCO—(alkyl), — NHCO—alkyl—alkoxy, - NHCO—cycloalkyl, - NHCO-alkyl~ heterocycloalkyl, —CO-heterocycloalkyl—alkyl-heterocycloalky1, -CO-heterocycloalkyl, $02- alkyl, —S—a1kyl, —S—aralkyl, —CO—heteroaryl, heteroaryl, —heterocycloalkyl—alkoxycarbonyl, — CO—aryl, yleOOvalkyl, halophenyl, NHQ, NH(alky1), N(alkyl), —CO-alkyl, and ~alkylu O—alkyh In certain embodiments, RA is independently selected from the group comprising H, CN, N02, halogen OH, , haloalkyl, alkyl, haloalkoxy, -COOH, ~COO—a1kyl, aralkyl, aryl, ~CO-N(alky1)2, -CONH-(alkyl), -CONH-alkyl-alkoxy, -CONH—cycloalkyl, -CONH—alky1— cycloalkyl, (alkyl), - NHCO—alkyl—alkoxy, - ycloalkyl, - NHCO-alkyl— heterocycloalkyl, —CO—heterocycloalkyl—alkyl—heterocycloalkyl, —CO~heterocycloalkyl, -SO;;- alkyl, —S-alkyl, and -S—aralkyl.
In r embodiments, RA is independently selected from the group comprising H, CN, N02, halogen OH, alkcxy, haloalkyl, alkyl, koxy, -COOH, ~COO-alkyl, araikyl, aryl, -CO— N(alkyl)2, —CONH—(alkyl), —CONH—alky1—alkoxy, ¢CONH—cycloalkyl, —CONH—alkyl- heterocycloalkyl, ~CO-heterocycloalkyl—alkyl—heterocycloalkyl, ~CO~heterocycloalkyL —SOz—a1kyl, —S—all<y1, and —S—ara1kyl.
In more particular embodiments, RA is independently selected from the group comprising H, CN, N02, halogen, OH, alkoxy, haloalkyl, alkyl, haloalkoxy, —COOH, -COO~alky1, aralkyl, aryl, a1kyl)2, —CONH—(alky1), —CONH—alkyl»alkoxy, ~CONH-cycloalkyl, wCONH- alkyl-heterocycloalkyl, ~CO-heterocycloalkyl—alkylwheterocycloalkyl, -CO—heterocycioalkyl, ~SOg-alkyl, -S-alkyl, -S—aralkyl, -CO—heteroaryl, heteroaryl, ~11eterocycloalkyl— alkoxycarbonyl, «CO—aryl, yl—COO—alkyl, halophenyl, NHZ, NH(alkyl), N(alky1), —CO— alkyl, and —O—a1kyl.
In more particular embodiments, RA is ndently selected from the group comprising H, CN, N02, halogen OH, alkoxy, haloalkyl, alkyl, haloalkoxy, —COOH, “COO-alkyl, aralkyl, aryl, -CO—N(alkyl);_, -CONH-(alky1), —CONH—a1ky1-alkoxy, —CONH—cycloalkyl, -CONH— alkyl—heterocycloalkyl, terocyeloalkyl~alkyl~heterocycloalkyl, —CO—heterocycloalkyl, lkyl, —S—alkyl, and -S—aralkyl.
In even more particular embodiments, RA is independently selected from the group comprising H, CN, halogen, OH, Cmnalkoxy, C1.4—alky1, C1_4—haloalky1, Clii-haloalkoxy, - COOH, —COO—(C1,4-alky1), benzyl, hyl, phenyl, C1_3—alkyl)2, -CONH—(C1_3~ alkyl), -CONH—(C1.3—alkyl)—O(C1_3—alky1), -CONH—(C3,5-cycloalky1), —CONH—(C1alkyl)—(C5, 6-heterocycloalkyl), -CO—(C5-6—heterocyeloalkyl)-(Cg-3—alkyD—(Cmnheterocycloalkyl), —CO— (C5,6—heterocycloalkyl), —SOg(C;_4—alkyl), —S-(C14-alkyl), —S-benzyl, -S~(chlorophenylmethyl), —S—phenethy1, ~CO—(C5-5uheteroary1), C5.5—heteroaryl, -C5,5—heterocycloalkyl-(C 1.4— alkoxycarbonyl), «CO-phenyl, -S-(C;,4-alkyl)—COO~(C1_4~alkyl), halOphenyl, NI-Ig, NH(C1_4» alkyl), N(C1.4—alkyl)2, —CO-(Cg_4-alkyl), and —(C1-4malkyl)~O-(C1-4nalkyl).
WO 02638 In even more particular embodiments, RA is independently selected from the group comprising H, CN, halogen OH, (31alkoxy, C]_4—alkyl, C1_4-haloalkyl, loalkoxy, - COOH, -COO—(C14—alkyl), , hyl, phenyi, —CO-N(C1_3—alkyl)2, ~CONH—(C1_3— alkyl), "CONE—(C1-3—alkyl)-O(C1,3—alkyl), —CONH~(C3_5—cycloalkyl), -CONH-(C1_3~a1kyl)—(C5- 6—heterocycloalkyl), —CO—(C5.6—hcterocycloalkyl)—(C1,3—alkyl)-(C5_6—heterocycloalkyl), -CO- (C5_6-heterocycloalkyl), ~SOg(C14—alkyl), —S-(C1_4-alky1), 'S—benzyl, —S-(chlorophenylrnethyl), and —S—phenethyl.
In yet even more particular embodiments, RA is independently ed from the group comprising H, CN, F, Cl, OH, C1_2—alkoxy, CF3, OCF3, ~COOH, —COO~(C1.2—alkyl), , phenethyl, phenyl, -CO—N(C]-g-alkyl)2, ~CONH~(C1_2—alky1), —CONH—(C1_2~alkyl)—O(C1_2— alkyl), -CONH-(C3_5-cycloalkyl), —CONH—(Cgmz—alkyl—tetrahydrofinyl), -CO—piperazinyl-(C1_2— —tetrahydrofi1ranyl, rholinyl, —CO-pyrrolidinyl, ~CO—(methyl-piperazinyl)—, -SOg(C1_2~alkyl), nS—(C1_4~alkyl), -S-benzyl, —S—(chlorophenylmethyl), ~S-phenethy1, -CO- thienn2—y1, -CO—pyrrol—2—yl, -CO-morpholin—4—yl, piperidin—l—yl—, 4~(C1,2~alkoxycarbonyl)— piperidin—l—yl, C1_2-alkyl, C1_2-alkoxyearbony1, morphoiin—4—yl, 4—py1idyl, -CO—phenyl, "S- (C1alkyl)-COO—(C1.g-alkyl), Br, 3—fluorophenyl, NHg, -CO-(C1,g—alkyl), -S-(C1_2—alkyl), and —(Cl_2—alkyl)~0w(C1-2walkyl).
In yet even more ular embodiments, RA is independently selected from the group comprising H, CN, F, Cl, OH, C1_2-alkoxy, CF3, OCF3, -COOI—I, —COO—(C1_2-alkyl), benzyl, phenethyl, phenyl, —CO—N(C1-2—alky1)2, -CONH—(C1.3—alkyl), «CONE—(C1-2—alkyl)-O(C1,2- alkyl), —CONH-(C3_5—cycloalkyl), ~CONH-(C1.2—alkyl—tetrahydrofi1ryl), —CO~piperazinyl—(Cl,2- alkyl)ntetrahydrofuranyl, —CO—niorholinyi, -CO~pyrrolidinyl, ethyl—piperazinyl)—, -SOg(C1,2—alkyl), _4—alkyl), -S—benzyl, —S—(chlorophenylrnethyl), and nethyl.
In yet even more particular embodiments, RA is independently selected from the group comprising H, CN, F, Cl, —SOgMe, »OMe, CFg, —CO~NMe2, —CO—piperazine—l,4-yl-CH2- tetrahydrofurane—Zwyl, "COO—Et, —CO—morholine—l-yl, 3-methoxyphenyl, OCFg, -CO0Me, OH, —CONH—Me, —SMe, -CO-pyrrolidine—l~yl, -CONH-CH2—CH2-0Me, -S—iPr, -CONH— cyclopropyl, —CO—(4-1nethyl-piperazine—l—yl)—, ~S~nPr, -COOH, -S-benzyl, -S-(4— chlorophenylmethyl), —S—iBu, «CONH-CHz—tetrahydrofinane-Z—yl, hyl, ~S-phenethy1, - CO—thien—Z—yl, —CO-pyrrolyl, mCO-morpholin—4—yl, piperidin—l-yl—, 4-ethoxycarbonyl— "29.. piperidin—l—yl, methyl, ethoxyoarbonyl, morpholin—4-yl, 4—pyridyl, -CO—phenyl, —S—CI-I2— COO-Et, Br, S—fluor0phenyl, NHZ, acetyl, -S-Me, and -CHg-OM€.
In yet even more ular embodiments, RA is independently selected from the group comprising H, CN, F, C1, -SOgMe, —0Me, CF3, -CO-NM62, ~CO-piperazine—1,4—yl-CH2— tetrahydrofurane—2-y1, —COO-Et, ~CO-morholine—1-yl, 3—methoxyphenyl, OCF3, -COOMe, OH, —CONH~Me, -SMe, —CO—pyrrolidine-l~yl, ~CONH—CH2—CH2—OMe, -S—iPr, —CONH— cyclopropyl, —CO—(4—rnethyl-piperazine—l-yl)-, ~S—nPr, -COOH, -S-benzy1, -S—(4- chlorophenylmethyl), —S—iBu, -CONH-CH2-tetrahydrofurane—2—yl, phenethyl, and —S—phenethyl.
In other particular embodiments, RA is independently ed from the group comprising H, — SOg(C1_4-alkyl), —CO—N(C]-4—alkyl)2, (C14—alkyl), —CO—NH2, ~CO—(Cs_6- cyeloalkyl)-C1-4—alky1—(C5_5—heterocycloalkyl), —COO—(C1_4—alkyl), —CO—(C5_5~ heteroeyeloalkyl), ~CONH-C14—alkyl-O(C1,4—alkyl), ~CONI—I-C1-4—alkyl—(C5_6—heteroa1'yl), halogen, C1_4-lialoalky1, 3-(C1M4—alkoxy)—aryl, C;_4-haloalkoxy, «CONH—(C1_4—alkyl), -CONH— (C3_5—cycloalkyl), —(Cs_6-heterocycloalkyl)-(C[-4—alkyl), C5_6—11eteroaryl, and —CO-(C1_4—alkyl)- (C5.5—heter0eycloalkyl), -CO—(C5.6—heteroaryi), —CO—(C5.6-heteroeyoloalkyl), {€5.6- heterocyeloalkyl)»(C;_4-alkoxyearbonyl), C l, C1_4-alkoxycarbonyl, .—CO-phenyl, _ 4—alkyleneJ—COO-(C1,4—alkyl), and Cln—alkoxy.
In other particular embodiments, RA is independently selected from the group comprising H, — 802(CM—alky1), —CO—N(C1_4—alkyl)2, -CO~NH(C1_4—alkyl), -CO—NH2, —CO-(C5_5— heterocycloalkyl)—C1 l—(C5_6—heterocycloalkyl), ~COO—(CHualkyl), —CO—(C5,6— heterocyeioalkyl), C1.4-alkyl—O(C1_4—alkyl), CONE-Cg.4—alkyl—(Csfimheteroaryl), halogen, C1_4-haloalkyl, 3—(C1i4-alkoxy).-ary1, CIA—haloalkoxy, —CONH—(C1,4—alkyl), —CONH- (C3_5—cycloalkyl), (C5_6—heterocycloalkyl)~(C1-4ualkyl), Cgé—lieteroaryl, and —CO—(C1,4—alkyl)— (C5_6—heteroeyeloalkyl).
In other more particular embodiments, RA is independently selected from the group sing H, —SOg(Cl.4—alkyl), -CO—N(C1_4—alkyl)2, “CO-piperazine—l,4nyl—C1_4—alkyl- tetrahydrofilrane—Z-yl, COO-(CM—alkyl), ‘CO—morholine—l—yl, rrolidine~1-yl, - CONE-C1.4—alky1uO(C1_4-alkyl), —CONH—C14—alkyl-tetrahydrofi1rane—2~yl, halogen, C14— haloalkyl, 3~(C14-alkoxy)—pher1yl, C1_4—haloalkoxy, -CONH—(Cg.4—alkyl), ~CONH—(C3.5~ cycloalkyl), 4—(C1_4~alkyi)-piperazine—l—yl, 3—pyridyl, 2—fhranyl, —CO—(4—[C;_4—alkyl}- piperazine—l-yl), —CO—thienyl, -CO~pyrrol-2vy1, —CO~morpholin—4—yl, piperidin—l—yl—, 4-C;_ 4-alkoxycarbonyl—piperidinyl, C1_4-alky1, C1_4—alkoxycarbonyl, morpholin—4-yl, 4-pyridyl, - CO—phenyl, —S—(C14~alky1ene)—COO—(C14—alkyl), and C1.4~alkoxy.
In other more particular ments, RA is independently seiected from the group comprising H, —SOZ(C1_4-alkyl), -CO-N(C1.4—alkyl)2, -CO—piperazine—l,4—yl-C1_4-alkyl— tetrahydrofiirane-Z—yl, C14-alkyl), ~CO—morholine—1—y1, -CO—pyrrolidine-l~yi, — CONH—C1_4-allcyl-O(C1,4—aikyl), -CONH—C1.4na1kyl—tetrahydrofinaneyl, halogen, €1 haioalkyl, 3—(C1_4—alkoxy)—phenyl, (31.4-haloalkoxy, —CONH—(C1_4—alkyl}, (C3-5— cycloalkyl), 4—(C1-4—alkyl)—piperazine—l-yl, 3—pyridyl, Z—fin‘anyl and —{C1-4—a1kyl]- zine—l-yl).
In other even more particular ments, RA is independently selected from the group comprising H, —SOg(C;_2-alkyl), -_CO—N(C1.2-alkyl)2, perazine-l,4~y1-C1-p_-alkyl- tetrahydrofurane-Z—yl, «COO—(C;_2-alkyl), -CO—morholineul—yl, —CO-pyrrolidine-l—yl, » CONH—C1alkyl-O(C1-2—aikyl), -CONI-l—C14—alkyl—tetrahydrofurane—Z-yl, halogen, CL? haloalkyl, 3~(C1_2-all<oxy)—phenyl, oalkoxy, —CONH-(C1_4—alkyl), —CONH—(C3_5- cycloalkyl), 4—(C1.4—alky1)-piperazine—1-y], 3—pyridyl, Z—fiiranyl, --CC)—(4—[("31.4—alkyl]~ piperazine-l-yl), wCO-thien-Z-yl, «CO-pyrrol-Z—yl, ~QO-morpholin—4—yl, piperidin—l—ylu, 4—C1. 2—alkoxycarbonyl—piperidin—l-yl, Cmmalkyl, C1_2—a1koxycarbony1, morpholinyl, dyl, ~ CO-phenyl, —S-(C1.3—a1kylene)-COO-(C1.g—alkyl), and C1.2—alkoxy.
In other even more particular embodiments, RA is independently selected from the group comprising H, ~SOz(C1_2—alkyl), C1.2-alkyl)2, ~CO—piperazine-1,4—yl—C1_2~alkyl~ tetrahydrofurane—Zvyl, "COO—(Clhg-alkyl), «CO-morholine-l-yl, -CO—pyrrolidine-1—yl, m CONH—C1-2—alkyl—O(C1_;-alkyl), -CONH—C1-2—alky1—tetrahydrofi1rane—2—yl, halogen, C1-2— haloalkyl, 3-(C1_2-alkoxy)—phenyl, C1_4-haloalkoxy, —CONH—(C]_4—alkyl), —CONH—(C3_5— cycloalkyl), 4—(C14—a1kyl)—piperazine—l—yl, 3—pyridyl, nyl and —CO-(4-[C14—alkyl]- piperazine-l—yl).
In other yet even more particular embodiments, RA is independently selected from the group comprising ~802Me, ~CO-NMeg, —CO-piperazine—1,4—y1—CH2~tetrahydrofiirane—2-yl, ~COO— Et, ~CO—morholine—1—yl, —CO-pyrrolidine-l—yl, -CONH-(CH2)2—OMe, -CONH—CH2- tetrahydrofurane—Z-yi, Cl, CF3, H, 3—1nethoxyphenyl, OCF3, ~CONH—Me, —CONH- cyclopropyl, 4—methyl—piperazinehl—yl, 3—pyridyl, 2—fi1ranyl, —CO—(4~ethyl—piperazine—l—yl), — CO-thien—Z—yl, —CO—pyrrol—2—yl, ~CO—morpholin-4~yl, din-l—yl-, 4—ethoxycarbonyl~ piperidin—l—yl, methyl, ethoxycarbonyl, morpholin-4—yl, 4~pyridyl, -CO-phenyl, ~S~CH2~ COO—E’s, and methoxy.
In other yet even more particular embodiments, RA is independently selected from the group comprising —SOzMe, e2, —CO-piperazine—l,4—ylCH;—tetrahydrofurane—2—yl, —COO— Et, ~CO-morholine-l—yl, —CO—pyrrolidine—l~yl, ~CONH—(CH2h—0Me, ~CONH—CH2— tetrahydrofiirane—Z—yl, Ci, CF3, H, 3—methoxyphenyl, OCF3, —CONH—Me, ~CONH~ cyclopropyl, 4-methyl—piperazine-l—yl, 3-pyridyl, 2-furanyl and -CO—(4—ethyi—piperazine~l~ yl).
In other particular embodiments, RA is independently selected from the group comprising — 802(CM—alkyl), ~CO-N(C1_4~alkyl)2, —CO-NH(Cl_4—alkyl), —CO—NH2, (SO—(CM— heterocycloalkyl)~C 1 4-alkyl-(C5-5—heterocycloalkyl), —COO-(C1_4-alkyl), —CO—(C5.6- heterocycloalkyl), —CONH—C1.4-alkyl—O(C1,4~alkyl), “CONH—C]alkyl-(C5-5—heteroaryl), H, ~ _6-lieteroaryl), {Csheterocycloalkyl), C14-alkyloxycarbonyl—substituted C54; heterocycloalkyl, and C1alkyl.
In other particular embodiments, RA is independently selected from the group comprising - SOg(C14-alkyl), C[_4—alkyl)2, ~CO—NH(C1_4-alkyl), -CO-NH2, (IO—((35-6— cycloalkyl)-C1-4—alkyl-(C5.6—heterccycloalkyl), ~COO—(C1_4-all<yl), 5 heterocycloalkyl), —CONH—C1.4—alkyl—O(C1_4-alkyl), and —CONH—C1alkyl—(€5-6—heter0aryl). 425 in other more Particular embodiments, RA is ndently selected from the grouP —CO—N(Cl,4—alky1)2, ~COupiperazine— 1 ,4—y1-C1_4nalkyl— A comprising -SOZ(CM-aikyl), tetrahydrofiirane—2-yl, —COO—(C1_4—alkyl), ’CO-rnorholine—l—yl, rrolidine—1—y1, - CONH—C1_4—alkyl—O(C1.4—alkyl), «CONH—C1-4—alkyl-tetrahydrofuraneAZ—yl, H, ~CO—thien—2—yl, rrol-2—yl, —CO—rnorpholin'4—yl, piperidin—l—yl— 4—C1-4—alkyloxycarbonyl~piperidin—l—yl, and 01-4—alkyl.
In other more ular embodiments, RA is independently selected from the gronP comprising —SOg(C1-4—alkyl), -CO—N(C1_4-all<yl)2, —CO-piperazine—1,4-yl—C1.4—alkyl- tetrahydrofilrane—Z—yl, —COO-[C14malkyl), -CO—morholineH1—yl, «Gonpmoiidine—l—yi, — CONH-Cll4-alkyl-O(C1_4—alkyl), and —CONH-C1.4—alkyl—tetrahydrofiirane-2—yl.
In other even more particular embodiments, RA is independently ed from the group comprising —SOZ(C1_2~alkyl), -CO-N(C;_2-alkyl)2, perazine~1,4—yl—C;_2—alkylm tetrahydrofuranemZHyl, Cl_3-alkyl), -CO-morholine-1—yl, ~CO-p3urolidine—1—yl, — CONH—C;.2—alkyl—O(C1t2—alkyl), ~CONH—C;-2—alkyl~tetrahydrofurane—Z-yl, H, -CO—thien—2—yi, -CO~pyrrolAZ—y1, —CO—morphoiin—4nyl, piperidin—l—yi— 4~C1.2—alkyloxycarbonyi—piperidin—l-yl, and C1_2~alkyi.
In other even more particular embodiments, RA is independently selected from the group comprising —SOg(C]alkyl), ~CO—N(C1-2—alkyl)2, ~CO-piperazine—1,4—y1—Cl_2-alky1— tetrahydrofiirane~2~yL —COO—(Cl_3—alky1), ~CO-morholine-l—yl, —CO—pyrroiidine—l—yi, — CONH-C;.2—alkyl—O(C1_2—alkyl), and ~CONH—C1.z-alkyl—tetrahydrofurane-Z-yl.
In other yet even more particular embodiments, RA is independently selected from the group comprising ~802Me, —CO—NMe2, —Cpriperazine—l,4—yl—CHz—tetrahydrofurane-2~yl, —COO- Et, orholine-l-yl, «CO—pyrrolidine—l-yl, —CONH—(CH2)2-0Me, -C0NH-CH2— tetrahydrofiirane—2—yl, 1-1, —CO-thien-2—yl, —CO-pyrrol-2myi, -C0—morpholin—4—yl, piperidin-l— yl- 4—ethoxycarbonyl-pipeiidin—1—yl, and .
In other yet even more particular embodiments, RA is independently selected from the group comprising —SOgMe, -COmNMe2, —CO—piperazine—l,4—yl-CHz-tetrahydrofurane—Z—yl, ~COO- Et, —CO—morholine—l-yl, "CO—pmoiidine-l—yl, ~CONHH(CH2)2-0Me, and ~CONI-LCH2- ydrofurane—Z—yl.
In certain embodiments, R” is independently selected from the group comprising H, Cm— alkyl, C;-6—haloalkyl, phenyl, naphthyl, C5_6-heteroaryl, C3t7~eycloalkyl and C44— cycloalkyli In certain embodiments, R” is independently selected from the group comprising H, CH— alkyl, C1_6~11aloalkyi, phenyl, naphthyi, eteroaryl, C3_7—cyeloalkyl and €4.7— heterocycloalkyl.
In more particular embodiments, R’ is independently ed from the group comprising H, (31-4—alkyl, C;-4—haloalkyl, phenyl, C5_5—heteroaryl comprising 1 to 3 heteroatoms independently selected from the group comprising N, O and S, ycloaikyl and (34 heterocycloalkyl comprising 1 or 2 heteroatoms independently Selected from the group comprising N, O and S.
In even more particular embodiments, R’ is independently selected from the group comprising H, C]_4—all{y1, Cl_3—haloalkyl, phenyl, C5,5—heter0ary1 comprising 1 or 2 heteroatoms independently selected from the group comprising N, O and S, C3_6-cycloalkyl and C5_6-heterocycloa1l<yl sing 1 or 2 heteroatoms independently selected from the group comprising N, O and S.
In even more particular embodiments, R’ is independently selected from the group comprising H, methyl, ethyl, yl, n—propyl, l, n-butyl, t—butyl, CF3, phenyl, pyridine, pyrimidine, pyrrol, furane, thiphene, , pyrazol, imidazol, isothiazol, isoxazol, thiazol, oxazol, C3_6-cycloalkyl, thiomorpholine, morpholine, dine, piperazine, tetrahydrofurane, tetrahydropyrane, pyrrolidine, pyrroline, dihydrofurane, dihydrothiphene, tetrahydrothiphene, dihydropyrane, pyrazoline, pyrazolidine, imidazoline, imidazolidine, isothiazoline, isothiazolidine, oline, isoxazolidine, thiazcline, thiazolidine, ine, 2O oxazoline, and oxazolidine.
In yet even more particular embodiments, R’ is independently selected from the group comprising H, methyl, ethyl, n—propyl, impropyl, n—butyl, i-butyl, tetrahydrofiirane, tetrahydrothiphene, phenyl, pyrrolidine, piperazine, piperidine, morpholine, cyclopropyl, cyclobutyl, cy010pentyl, CFg, thienyl, pyrrol and piperidine.
In yet even more ular ments, R’ is independently selected from the group comprising H, methyl, ethyl, n-propyl, i-propyl, n—butyl, i-butyl, tetrahydrofurane, tetrahydrothiphene, phenyl, pyrrolidine, piperazine, piperidine, line, cyclopropyl, cyclobutyl, cyclopentyl, and CF3.
In yet even more particular embodiments, R’ is ndently ed from the group comprising H, methyl, ethyl, n—propyl, i~propyl, i-butyl, tetrahydrofurane, phenyl, pyrrolidine, piperazine, morpholine, cyclopropyl, CF3, thienyl, pyrrole and piperidine.
In yet even more particular ments, R’ is independently ed from the group comprising H, methyl, ethyi, n—propyl, impropyl, i—butyl, tetrahydrofiirane, phenyl, pyrrolidine, piperazine, morpholine, cyclopropyl, and CF3.
Any of the entioned alkyl, aryl, heteroaryl, lkyl and heterocycloalkyl, including any particular or otherwise further specified embodiments thereof (e. g. for alkyl: C1,6~alkyl, isopropyl, methyl etc), may independently be substituted with one or more, particularly one to three, more particularly one or two substituents R”, wherein R” is independently selected from the group comprising C1_4-a1kyl, halogen, (EM—haioalkyl, OH, C}_4—alkoxy, C14- haloalkoxy, -N02, —CN, —NH2, —N(CM—all(yl)2, _4—alkyl), —NHCO(C1alkyl), —CONH2, C1i4—alkyl), —CO(C14—alkyl), —COH, -COO(_C1,4-a1kyl), -COOI—I and -CN.
In certain embodiments, R” is ndently selected from the group comprising H, C1_3~ alkyl, chlorine, fluorine, bromine, C1_3—haloalkyl, OH, ll<oxy, C1_3—haloalkoxy, -NH2, ~N(C1_3—aikyl)2, -NH(C1,3-alkyl), -NHCO(C1_3—alkyl), —CONH2, ~CONH(C1alkyl), —CO(C1_3- aikyl), —COH, -COO(C1,3—alkyl}, -COOH and —CN. in more particular embodiments, R” is independently selected from the group comprising C1- 3—alkyl, ne, fluorine, bromine, CF3, OH, OMe, OEt, OCF3, -NH2, -N(Me)2, -N(Et)2, «NH-Me, -NH—Et, r, ~NHCO—Me, —CONH2, —CONH—Me, -CONH-Et, «CONH-ii’r, acetyi, —COO-Me, —COO—Et, -COOH and ~CN. in even more particular embodiments, R” is ndently selected from the group comprising , chlorine, fluorine, CF3, OH, OMe, OCFg, -NH2, 2, -N(Et)g, —NHCO~Me, acetyl, ~COO~Me, —COOH and -COOEt.
In even more particular embodiments, R” is independently selected from the group comprising methyl, chlorine, fluorine, CF3, OH, OMe, OCF}, -NH2, —N(Me)2, —N(Et)2, —NHCO—Me, acetyl, -COO~Me, and —COOH.
In yet even more particular embodiments, R” is independently selected from the group comprising chlorine, fluorine, CF3, OH, OMe, OCFg, —NH2, -N(Me)2, —NHCO—Me, acetyl, (ZOO—Me, —COOH, ~COOEt and methyl.
In yet even more ular embodiments, R” is ndently selected from the group comprising chlorine, fluorine, CF3, OH, OMe, OCFg, -NH2, —N(Me)2, -NHCO~Me, acetyl, ~COO~Me, and —COOH.
In yet even more particular embodiments, R” is independently selected from the group comprising H, ne, e, CF3, OH, OMe, OCFg, —NH2, -N(Me)2, —COOEt and .
In yet even more particular embodiments, R” is independently selected from the group comprising chlorine, e, CF3, OH, OMe, OCFg, —NH2, and -N(M6)2.
Particularly, the substituent R” is not further substituted. in a specific embodiment, the nds of the present invention are selected from the group comprising compounds 1 to 48 as described herein in the example section.
In a specific ment, the compounds of the present invention are selected from the group comprising compounds 1 to 82 as described herein in the example section.
In a specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, 14, l7, 18, 19, 2], 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 34, 35, 37, 38, 39, 40, 41, 42, 44, 45, 46, 47, and 48 to 71 as described herein in the example section. in a more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 2, 3, 4, 6, 7, 8, 9, 10, 14, 17, 18, 19, 21, 22, 23, 24, 25, 27, 28, 30, 34, 35, 38, 39, 40, 41, 42, 45, 46 47, and 48 to 65 as described herein in the example section.
In an even more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 3, 6, 7, 8, 9, 10, 19, 22, 23, 25, 30, 35, 38, 42, 45 47 and 48 to 51 as described herein in the example section.
In another specific embodiment, the compounds of the t invention are selected from the group comprising compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, I4, 15, 16, 18, 19, 20, 2i, 22,23, 24, 25,30, 31, 33, 34, 35, 36, 37,38, 39, 40, 41, 45, 46 and 47 as described herein in the example section.
In r more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19,22, 23, 25, , 41, 45, 46 and 47 as described herein in the example section.
In r even more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 3, 7, 8, 9, 10, 22, 23 and 35 as described herein in the e section.
In another yet even more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 11, 42, 45, 46, 47, 50, 54, 55 and 62 as described herein in the e section.
In a specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 2, 3, 5,6, 7, 8, 9, 10, 11, 14, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 34, 35, 37, 38, 39, 40, 41, 42, 44, 45, 46, and 47 as described herein in the example section.
In a more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 2, 3, 6, 7, 8, 9, 10, 14, 17, 18, 19, 21, 22, 23, 24, 25, 27, 28, 30, 34, 35, 38, 39, 40, 41, 42, 45, 46 and 47 as described herein in the example section.
In an even more specific embodiment, the compounds of the present invention are selected from the group comprising compounds 1, 3, 6, 7, 8, 9, 10, 19, 22, 23, 25, 30, 35, 38, 42, 45 and 47 as bed herein in the example section.
In another specific embodiment, the compounds of the present invention are selected from the group comprising nds 1, 2, 3, 5, 6, 7, 8, 9, 10, ii, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23,24, 25, 30, 31, 33, 34, 35, 36, 37, 38, 39,40, 41,45, 46 and 47 as bed herein in the example section. in another more Specific embodiment, the compounds of the present ion are selected from the group comprising compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19, 22, 23, 25, , 41, 45, 46 and 47 as bed herein in the example section.
In another even more c embodiment, the compounds of the present ion are selected from the group comprising compounds 3, 7, 8, 9, 10, 22, 23 and 35 as described herein in the example section.
As used herein, a “ring atom” represents an atom which is part of the cyclic ure of a ring or ring system, wherein this ion does not include hydrogen atoms or tuents bound to the ring 0r ring system. For example, a pyridine group comprises 6 ring atoms, i.e. one N atom and five C atoms; The following definitions are meant to further define certain terms used in the context of the present invention. If a particular term used herein is not specifically defined, the term should not be considered to be ite. Rather, such terms are to be ued in accordance with their meaning as regularly understood by the skilled artisan in the field of art to which the invention is directed, particularly in the field of organic chemistry, pharmaceutical sciences and medicine.
In the context of the present invention, and for reasons of legibility, chemical group names such as “alkyl”, “aryl”, “phenyl”, “heteroaryl”, alkyl”, “heterocyclyl”, etc, depending on the respective particular t, are meant to include terminal groups and connecting 6‘ groups which are often referred to as ...ene” groups, such as for example “alkylene”, “arylene”, etc. Moreover, in the context of the present invention, the suffix “-yl” is in many cases omitted, which is not to be understood to delimit chemical names comprising said suffix from chemical names not comprising said suffix; for example “furyl”, “furanyl” and “furane” are meant to be used interchangeably.
As used herein, the term “XI—31201 moiety” refers to the below chemical entitY which is art , P of formular (1') according to the present invention: X/ 2% gm As used herein, an alkyl group particularly encompasses alkanyl, alkenyl, alkynyl, wherein alkanyl means a completely saturated hydrocarbon chain, alkenyl means a hydrocarbon chain comprising at least one carbon—carbon double bond, alkynyl means a hydrocarbon chain comprising at least one carbon—carbon triple bond (including a arbon chain comprising one or more carbonwcarbon double bonds and at least one carbon—carbon triple bond). In the context of the present invention, an alkanyl group, if not stated otherwise, particularly denotes a linear or branched C1—C6-alkanyl, more particularly a linear or branched C1-C5—alkanyl, even more particularly a linear or branched C1-C4~alkanyl; an alkenyl group, if not stated ise, particularly denotes a linear or branched Cz—Cé—alkenyl, more particularly a linear or branched Cg—C4—alkenyl, even more particularly ethenyl; and an l group, if not stated otherwise, particularly denotes a linear or branched C2—C6—alkynyl group, more particularly a linear or branched C1—C4—alkynyl, even more particularly ethynyl. In certain ular embodiments the alkyl group is selected from the group sing , ethyl, n—propyl, isopropyl, n—butyl, isohutyl, tyl, utyl, pentyl, hexyl, ethenyl, ethynyl, propen—l—yl, propen—2—yl, propen—S—yl, —CEC-CH3, and —CH2—CECH. The alkyl, alkanyl, aikenyl, and alkynyl groups as defined above, including the groups enumerated as examples and particular or otherwise further defined embodiments thereof, are optionally substituted by one or more substituents R’ ’.
As used herein, the term “aryl” particularly denotes an aromatic r polycyclic hydrocarbon ring system, which may optionally be fused to one or more cycloalkyl or cycloalkyl rings, and wherein the total number of ring atoms in the aryl group is 6 to 14, ularly 6 to 10, more particularly 6. The point of attachment of said aryl group to the central moiety may be located on the aromatic mono—or polycyclic hydrocarbon ring system or on the optionally fused cycloalkyl or heterocycloalkyl ring. Examples of the aryl group are , naphthyl, indenyl, yl, fiuorenyl, 1,2-dihydronaphthyl, 1,25,4— tetrahydronaphthyl, 2,3—dihydroindenyl, 1,5-dihydro—s-indacenyl, l,6—dihydro—as-indacenyl, lH—cyclopenta[a]naphthyl and lH—cyclopenta[b]naphthyl, phenalenyl, phenanthrenyl, anthracenyl, 1,6—dihydropentalenyl, 1,6a—dihydropentalenyl, l,2,3,4-tetrahydroanthracenyl, l,2,3,4—tetrahydrophenanthrenyl, 2,3wdihydro-lH—cyclopentala]naphthalenyl, 2,3~dihydro—1H— cyclopenta[b]naphthalenyl, 2,3—dihydro~1H—phenalenyl, 2,3ndihydrobenzo[b]thiophenyl~l,l- dioxide, 1 ,2,3 ,4-tetrahydroisoquinolinyl, l ,2,3 ,4—tetrahydroquinolinyl, 2,3— dihydrobenzo[b][l,4]dioxinyl, 2,3—dihydrobenzo[b]thiophenyl, 2,3-dihydrobenzofurany1, henzo[d][l,3]dioxolyl, chromanyl, indazolinyl and indolinyl. In particular embodiments, the aryl group is , 2,3-dihydrobenzo[b][l,4]dioxiny1, 2,3—dihydrobenzofi1ranyl or d][l,3]dioxolyl, more particularly phenyl. The aryl groups as defined above, including the groups enumerated as examples and particular or otherwise further defined embodiments thereof, are optionally substituted by one or more substituents R”.
As used herein, the term henyl” particularly denotes a phenyl group substituted with one or more n atoms, particularly with one halogen atom.
As used herein, the term “heteroaryl” particularly s an aromatic r polycyclic hydrocarbon ring system wherein one or more carbon atoms are replaced by heteroatoms independently selected fiom the group comprising 0, N and S, wherein the ic mono—or polycyclic hydrocarbon ring system may optionally be fused to one or more cycloalkyl or heterocycloalkyl rings, and wherein the total number of ring atoms in the heteroaryl group is 5 to 14, particularly 5 to 10, more particularly 5 or 6. The point of attachment of said heteroaryl group to the central moiety may be located on the mono-or polycyclic aromatic hydrocarbon ring system or on the optionally fused cycloalkyl or heterocycloalkyl ring. Examples of the heteroaryl group are furan—Z-yl, furan-B-yl, thiophen~2~yl, en—S-yl, thiazol—4-yl, pyrazol—S—yl, pyrazol~4uyl, oxazol-4—yl, oxazol—S—yl, isoxazol—4—yl, isoxazol~5—yl, pyrazin—Z- yl, n—Z—yl, pyridin—3—y1, pyridin—4-yl, —Z-yl, 1,2,3—thiadiazolyl, l,2,4—thiadiazol~ 3-yl, benzothiophen—S—yl, 1,2,3—triazol—4—yl, 1,2,4-triazol—5—yl, quinolin—Z-yl, , l—Z-yl, thiazol~5—yl, isothiazol—3-yl, isothiazol-4—yl, isothiazol—5~yl, -Z-yl, isoxazol—3~yl, 1,2,4- oxadiazol—3nyl, 1,2,4—oxadiazolyl, 1,2,5-oxadiazol—3—yl, oxadiazol—4-yl, 1,2,3— oxacliazol—4—yl, 1,2,3-oxadiazol—5—yl, 1,3,4noxadiazol—2-yl, 1,2,4-thiadiazol-S-yl, 1,2,55 thiadiazol—3—yl, 1,2,5mthiadiazol—4-yl, 1,3,4—thiadiazol-2—yl, 1,2,3—thiadiazol—4-yl, pyrrol—l—yl, pyrrol-B—yl, pyrazol—l—yl, purin-Z‘yl , purin—é—yl, purin—S—yl, purin—9-yl, pyrimidin—Z—yl, pyrimidin—4—yl, pyrimidin—S—yl, pyrimidin—6-yl, imidazol—l-yl, ol—Z-yl, imidazol—4—yl, 1,2,3—triazolnfi-yl, 1,2,4—triazol-3—yl, furan-Z—yl, benzo[b]furanyl, quinolinyl, nolinyl, indol-Z—yl, indol~3—yl, isoindol-l-yl, isoindol—3—yl, indol-Z—yljndchS—yl, purin-Z-yl. In particular embodiments, the aryl group is selected from the group comprising furan—Z— yl, thiophen-S—yl, pyrimidin—Z—yl, or pyrimidin~6myl, and pyridine—4-yl, In other particular embodiments, the heteroaryl group is selected from the group comprising furan-2—yl, thiophen—3—yl, pyrimidin—Z—yl, pyrimidine—371, pyridine-4—yl, lH—imidazol-Z—yl, lH-l,2,4— triazol—S—yl, lH-benzo[d]imidazol-2—yl, pyridin~2—y1, lH—imidazol—2-yl, l,3,4—thiadiazol-2~yl, lH-pyrazoln3—yl, 1,3—thiazol—2—yl, 1,2,4-thiadiazoi~3~yl, 1,3,4—thiadiazol—2—yl, 1,2,4— thiadiazol—Swyl, l,3~oxazol-2~y1 and oxadiazol—3~yl.
The heteroaryl groups as defined above, including the groups enumerated as examples and ular or ise further defined embodiments f, are optionally substituted by one or more substituents R.” ’.
As used herein, the term “cycloalkyl” ularly denotes a non-aromatic, mono— or polycyclic completely saturated or lly unsaturated hydrocarbon ring system. Said lkyl is ularly mono- or bicyclic, more particularly monocyclic. Said cycloalkyl is particularly completely saturated. Said cycloalkyl particularly comprises 3 to 10 carbon atoms, more particularly 3 to 7, even more particularly 3 to 6 carbon atoms. Even more particularly, said cycloalkyl is selected from the group comprising ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, l-norbornyl, 2—norbonryl, 7~norbornyl, l-adamantyl, and Z—adamautyl, yet even more particularly said cycloalkyl is cyclohexyl. The cycloalkyl groups as defined above, including the groups enumerated as examples and particular or otherwise further defined embodiments thereof, are optionally substituted by one or more substituents R’, and O, 1 or 2, particularly 0 or 1, more particularly 0 of the ring carbon atoms are attached to an oxygen atom via a double bond to form a carbonyl group.
As used herein, the term “heterocycloalkyl” particularly denotes a non—aromatic mono— or polycyclic tely saturated or partially unsaturated hydrocarbon ring system, wherein one or more, particularly 1 to 3, more particularly 1 or 2 of the ring carbon atoms are replaced by a heteroatom independently selected from N, O, or S- Said cycloalkyl is particularly mono— or bicyclic, more particularly monocyclic Said heterocycloalkyl is particularly tely saturated. Said heterocycloalkyl particularly is a 5— to lO—membered mono— or polycyclic ring system, more particularly 5— to 7»membered monocyclic ring system, even more particularly 5» or 6-membered monocyclic ring system. Even more particularly said heterocycloalkyl is selected from the group sing morpholinyl, dinyl, pyrrolidinyl, M41- and piperazinyl. The heterocycloalkyl group as defined above, ing the groups enumerated as examples and particular or otherwise further defined embodiments thereof, are optionally substituted by one or more substituents R’ as described herein, and 0, 1 or 2, particularly 0 or 1, more particularly 0 of the ring carbon atoms are attached to an oxygen atom via a double bond to form a carbonyl group.
As used , the term “halo” or “halogen” particularly independently denotes fluorine, chlorine, bromine or iodine, more particularly bromine, chlorine or fluorine, even more particularly chlorine or fluorine.
As used herein, the term “haloalkyl” s an alkyl group wherein one or more, particularly at least half, more particularly all of the hydrogen atoms on the hydrocarbon chain are replaced by n atoms. The haloalkyl group is particularly selected from the group comprising -C(R10)3, nag-cramp, chimp—CH3, camp—camp, camp—analog, - CHz—Cinnmp, -CH(R‘°)—C(R1°),, "CH(Rm)—CH3, and —C2H4—C(R10)3, more particularly — C(R10)3, wherein R10 represents halogen, ularly F. More particular haloalkyl groups are — CFg, —CH2CF3, and CF1Cl.
As used , the term “alkoxy” denotes an Osalkyl group, the alkyl group being defined as defined above. The alkoxy group is particularly selected from the group comprising xy and ethoxy.
As used herein, the term “alkylthio” s an —S—alkyl group, the alkyl group being as defined above.
As used herein, the term “haloalkoxy” denotes an O—haloalkyl group, kyl group being defined as defined above. The haloalkoxy group is particularly selected from the group comprising -OC(R10)3, —OCR1°(R‘°’)2, cmlhg, and -oczi—n—cmmp, wherein 1210,11” represent F, Cl, Br or I, particularly F.
As used herein, the term “alkylamino” denotes a NH—alkyl or diialkyl group, the alkyl group being as defined above, As used herein, the term lkyl” or “aralky ” particularly denotes a linear or branched C1" Cg—alkyl, more particularly CM-alkyl, even more particularly C1_2-alky1, yet even more particularly methyl, wherein “alkyl” is as defined herein, substituted with at least one, ularly exactly one, aryl group as defined herein. Exemplary arylalkyl groups include styryl, benzyl, phenylethyl, ularly the arylalkyl group is styryl or benzyl, ularly optionally substituted at its phenyl part as defined above for the aryl group.
Where chemically feasible from the viewpoint of molecule stability and/or chemical valence rules, a nitrogen heteroatom as defined herein, egg. in the context of “heteroaryl” and “heterocycle”, may e the N—oxide.
Where ally feasible from the viewpoint of molecule stability under physiological conditions and/or chemical e rules, the definition of a sulfur heteroatoni as defined herein, cg. in the context of “heteroaryl” and “heterocycle”, may include the sulfur oxide and/or the sulfur dioxide, tively.
For sake of completeness, it is mentioned that “morpholine—4—carbony ”’ is a group —CO- morpholine-4uyl.
As used herein the term “substituted with" or ,,substituted by” means that one or more hydrogen atoms connected to a carbon atom or heteroatorn of a chemical group or entity are exchanged with a substituent group, respectively; eg. substituted aryl comprises 4— yphenyl, n the H—atom in the 4-position of the phenyl group is exchanged with a hydroxyl group. Said hydrogen atom(s) to be replaced may be attached to a carbon atom or heteroatom, and may be expressly shown in a specific formula, such as for example in an -NH— group, or may not expressly be shown but intrinsically be present, such as for example in the typical “chain” notation which is commonly used to symbolize egi hydrocarbons. The skilled person will readily understand that particularly such substituents or substituent patterns are excluded, which lead to compounds witch are not stable and/or not accessible via the synthesis methods known in the art.
Unless specified otherwise, references to the nds ing to the present invention include the pharmaceutically acceptable derivatives, solvates or salts thereof as described , as well as to salts or solvates of said pharmaceutically acceptable derivatives and es of said salts.
As used herein, the term aceuticaliy able derivative” of a compound according to the present invention is for instance a prodrug of said compound, wherein at least one of the following groups are derivatized as specified in the following: A carboxylic acid group is derivatized into an ester, a hydroxyl group is derivatized into an ester, a carboxylic acid is derivatized into an amide, an amine is derivatized into an amide, a hydroxyl group is derivatized into a phosphate ester.
As used herein, the term “tautomer” used in reference to the compounds ing to the present invention, in particular includes tautomers that typically form with respect to substituted benzimidazole groups. As an illustration two tautomeric forms of an exemplary substituted beuzimidazole moiety, as is present in the nds according to the present invention, are shown: ’6 ANi—flkm The compounds according to the present invention are to be understood to comprise all tautomeric forms thereof, even if not sly shown in the formulae described herein, including formula (1). Throughout this specification, whenever a chemical formula, generic or otherwise, discloses a compound having a lH~benzimidazole moiety that is tituted at the 1 position, as shown on the left-hand side of the above ary illustration, said al formula it is to be understood to implicitly also relate to compounds wherein the benzimidazole moiety is erized to form the structure as shown on the right-hand side of the above exemplary illustration.
The compounds of formula (I) as defined herein are to be understood to encompass, where applicable, all stereoisomers of said compounds, unless specified otherwise. The term “stereoisomer” as used herein refers to a compound with at least one stereogenic , which may be R— or S~configurcd, as defined by the according iUPAC rules, and encompasses enantiomers and diastereorners as commonly understood by the skilled person. It has to be understood, that in compounds with more than one stereogenic centre, each of the individual genic centres may independently from each other be R— or S~conf1gured The term “stereoisomer” as used herein also refers to salts of the compounds herein described with optically active acids or bases.
In the present invention, the salts of the nds according to the present invention are in particular embodiments pharmaceutically acceptable saits of the compounds according to the present ion. Pharmaceutically acceptable salts are such salts which are usually considered by the skilled person to be suitable for medical applications, e. g. because they are not l to subjects which may be treated with said salts, or which give rise to side effects which are tolerable within the tive treatment. Usually, said phannaceutically acceptable salts are such salts which are considered as acceptable by the regulatory authorities, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Japanese Ministry of Health, Labor and Welfare Pharmaceuticals and Medical Devices Agency (PMDA). r, the present ion in principle also encompasses salts of the compounds according to the present invention which are as such not pharmaceutically acceptable, eg. as intermediates in the production of the compounds according to the t invention or physiologically functional derivatives f, or as intermediates in the production phannacologically acceptable salts of the compounds according to the present invention or physiologically functional derivatives f.
In each case, the skilled person can readily determine whether a certain nd according to the present invention or phannaceutically acceptable derivative thereof can form a suit, i.e. whether said compound according to the present invention or pharmaceutically able derivative or solvate thereof has a group which may carry a positive or negative charge, such as eg. an amino group, a carboxylic acid group, etc..
As used herein, a “solvate” is a complex formed in the crystalline state between one or more compounds according to the present invention (or phannaceutically able derivative or salt thereof) and one or more solvent les. In certain embodiments, such solvates are 1:2, 2:1 or 1:1, more particularly 1:1 stoichiometric complexes. Furthermore, in certain ,45- embodiments, complexes, such solvates are formed with a solvent selected from the group comprising water, methanol, ethanol or propanol, particularly water, methanol or ethanol, more particularly water (the latter is typically also known under the term “‘hydrate”).
As used , the term “room temperature”, “rt” or “rt.” relates to a temperature of about °C, unless specified otherwise.
As used herein, the term “stable” particularly relates to a nd in which the chemical structure is not altered when the compound is stored at a temperature from about -80 °C to about +40 0C, more particularly from about —80 CC to +25 DC in the absence of light, re or other chemically reactive conditions for at least one week, more ularly at least one month, even more particularly at least six months, yet even more particularly, at least one year, and/or a nd which under IUPAC standard conditions and in the absence of light, moisture or other chemically reactive ions maintains its structural integrity long enough to be useful for therapeutic or prophylactic administration to a patient, i.e. at least one week.
Stable in this context mean that under the aforementioned conditions and time periods and compared with the the timepoint 0, Le. when it was produced, the amount of impurities has increased by less than 2%, particularly less than 1% more particularly less thatn 0.5%, which can eg. be determined by analytic HPLC or LC-MS, or the like. Compounds which are not stable as described above are y to be considered not encompassed by the present invention, In ular, such compounds which at lUPAC standard conditions spontaneously decompose within a period of less than one day are regarded as not being stable compounds.
The skilled person will readily recognize, based on his general knowledge in his field of expertise, which compounds and which substitution patterns result in stable compounds.
As used herein, the term ment” includes complete or partial healing of a disease, prevention of a disease, alleviation of a disease or stop ofprogression of a given disease.
As used herein, the term amen ” includes the compounds of formula (I) as bed herein, phannacologically acceptable salts or physiologically functional derivatives thereof, which are to be administered to a subject in pure form, as well as compositions compiising at least one compound ing to the present invention, a pharmacologically acceptable salt or physiologically functional derivative thereof, which is suitable for administration to a subject. 2014/062774 The nds according to the present invention and their pharmacologically acceptable salts and physiologically functional derivatives can be administered to animals, ularly to mammals, and in particular to humans as therapeutics per so, as mixtures with one another or particularly in the form of pharmaceutical preparations or compositions which allow enteral (cg. oral) or parenteral administration and which comprise as active constituent a therapeutically effective amount of at least One compound according to the present invention, or a salt or physiologically functional derivative thereof, in addition to e.g. one or more components selected from the group comprising customary adjuvants, pharmaceutically innocuous excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
The ceutical compositions, medical uses and methods of treatment ing to the present invention may comprise the application or inclusion of more than one compound according to the present invention.
Pharmaceutical compositions comprising a compound according to the present invention, or a pharmaceutically acceptable salt or physiologically functional derivative may optionally comprise one or more r eutically active substances which are not compounds of formula (I) according to the present invention. As used herein, the term “therapeutically active nce” specifies a substance which upon administration can induce a medical effect in a subject. Said l effect may include the medical effect described herein for the compounds of formula (I) of the present ion, but may also, in the case of therapeutically active substances which are to be co—administered with the compounds according to the present invention, include other medical s, such as e.g. analgesic, antiinflammatory, antiemetic.
The term “pharmaceutically acceptable” is well known to the skilled person and usually means that the respective entity is not harmful to the subject to which the entity or the composition comprising the entity is administered, that said entity is stable and that said entity is chemically compatible (ie. non—reactive) with other ingredients of the respective pharmaceutical ition.
Medicaments and pharmaceutical compositions according to the t invention, comprising at least one compound according to the present invention or a pharmacologically "47- 2014/062774 acceptable salt or a physiologically functional derivative thereof include those suitable for oral, rectal, bronchial, nasal, topical, , ngual, vaginal or parenteral (including transdermal, subcutaneous, intramuscular, intrapulmonary, intravascular, intracranial, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form le for administration by inhalation or insufflation, including s and liquid aerosol administration, or by controlled release (eg. sustained release, pH—controlled release, delayed, release, repeat action e, prolonged release, extended release) systems. le examples of controlled release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules or colloidal drug carriers, e. g. polymeric nanoparticlcs, or controlled release solid dosage forms, e.g. core tablets or multi—layer tablets.
The production of medicaments or pharmaceutical itions comprising the compounds according to the present invention and their application can be performed according to methods which are well-known to the l practitioner.
Pharmaceutically acceptable carriers used in the preparation of a pharmaceutical composition or medicament comprising a compound according to the present invention, a pharmacologically acceptable salt or physiologically functional derivative thereof, can be either solid or liquid, Solid form pharmaceutical compositions comprising a nd according to the present invention, a pharrnacologically acceptable salt or physiologically fimctional derivative thereof, include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier may comprise one or more components, which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable tions and compacted in the shape and size desired. The tableting mixture can be ated, sieved and compressed or direct compressed. Suitable rs are ium carbonate, magnesium stearate, talc, sugar, e, pectin, dextrin, starch, ne, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low g wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, sachets and es are included. Tablets, powders, capsules, pills, sachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby to solidify. Compositions suitable for vaginal administration may be presented as peccaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ient such carriers as are known in the art to be appropriate. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water- propylene glycol solutions. For example, parenteral ion liquid preparations can be formulated as ons in aqueous polyethylene glycol solution.
The compounds according to the present ion may be ated for parenteral administration (eg. by injection, for example bolus ion or continuous infusion) and may be presented in unit dose form in ampoules, pre—filled syringes, small volume infusion or in multi-dose containers with an added vative. The compositions may take such forms as suspensions, ons, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, izing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lization from on, for re-constitution with a suitable vehicle, eg. sterile, pyrogen— free water, before use.
Aqueous solutions suitable for oral administration can be prepared by dissolving the active compenent in water and adding for example suitable colorants, flavours, stabilizing and thickening , as d. s suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well— known suspending agents.
Also included are solid form preparations, which are intended to be converted, shortly before administration, to liquid form preparations for oral administration Such liquid forms e ons, suspensions, and emulsions. These preparations may contain, in addition to the active component, for example nts, s, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing , and the like.
In an particular embodiment of the present invention the medicament is applied lly, eg. in the form of transdermal therapeutic systems (eg. patches) or topical formulations (eg. liposomes, cremes, ointment, lotion, gels, dispersion, suspension, spray, solution, foam, powder). This may be suitable to reduce possible side effects and, where appropriate, limit the necessary treatment to those areas affected.
Particularly the medicament may comprise carrier materials or excipients, ing but not limited to a lipophilic phase (as for example Vaseline, paraffines, triglycerides, waxes, polyalcylsiloxanes), oils (olive oil, peanut oil, castor oil, triglyceride oil), fier (as for example lecithin, phOSphatidylglyceroles, alkyl alcohols, sodium lauryl sulphate, polysorbates, Cholesterol, sorbitan fatty acid ester, polyoxyethylene fatty acid glycerol and — ester, poloxamers), preservatives (for instance benzalkonium chloride, chlorobutanol, parabene or thiomersal), flavouring agents, buffer substances (for example salts of acetic acid, citric acid, boric acid, phosphoric acid, c acid, trometamole or trolamine), ts (for instance polyethylenglycols, glycerol, l, isopropanol or propylene glycol) or solubilizers, agents for achieving a depot effect, salts for modifying the osmotic pressure, carrier materials for patches (for instance polypropylene, ethylone-vinylacetate—copolymer, polyacrylates, silicone) or antioxidants (for example ascorbate, tocopherol, butylhydroxyanisole, gallic acid esters or butylhydroxytoluol).
Ointinents and creams may, for e, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or 0in base and Will in l also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents. itions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, y sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes sing the active ingredient in a suitable liquid carrier.
Solutions or suspensions may be applied ly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi—dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the on or suspension. In the case of a spray, this may be achieved for example by means of a ng atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a rized pack with a suitable lant such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluorornethane, or rotetrafluoroethane, carbon dioxide, or other suitable gas.
The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the medicament may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrroliclone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges of, e.g., gelatine, or blister packs from which the powder may be stered by means of an inhaler.
In compositions for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
When desired, itions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations in certain embodiments are in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active ent. The unit dosage form can be a packaged ation, the package -51.. containing discrete ties of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, , sachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are particular compositions. r details on techniques for formulation and administration may be found in the 21S1 edition of Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa).
The compounds of the present invention may be used in combination with radiation therapy, or in combination with radiation therapy and other active compounds, already known for the treatment of the medical conditions disclosed herein, whereby a favourable additive or amplifying effect is noticed.
To prepare the pharmaceutical ations, pharmaceutically inert inorganic or organic excipients can be used. To prepare pills, tablets, coated tablets and hard gelatine capsules, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc. can he used. Excipients for soft gelatine capsules and suppositories are, for e, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable excipients for the production of solutions and syrups are, for example, water, e, invert sugar, glucose, s etc. Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or ble oils.
The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. For the above uses the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory s are achieved at dosage rates of about 1 to 100 mg/kg animal body weight particularly 1 to 50 rug/kg. Suitable dosage rates for larger mammals, for example humans, are of the order of from about 10 mg to 3 g/day, conveniently administered once, in divided doses 2 to 4 times a day, or in sustained release form.
The compounds ing to the present invention can be used for modulating cell proliferation. Accordingly, diseases that may be treated using the nds according to the -52, present invention include hyperproliferative diseases, such diseases related to benign cell growth or malignant cell growth.
Furthermore, the present invention relates to a method of treatment or prevention of the medical conditions specified herein, which comprises the administration of an effective amount of a compound according to the present invention, or a physiologically functional derivative, solvate or salt thereof to a subject in need thereof.
Furthermore, the present invention relates to the use of a compound according to the present invention, or a physiologically fimctional derivative, solvate or salt thereof in the treatment or prevention of the medical conditions specified herein.
More particularly, the compounds according to the present invention, solvates salts or physiologically onal tives f can be used for ng cancer.
In certain embodiments of the present ion, said cancer is selected from the group comprising cancer of the breast, esophagus, gastrointestinal tract, gastro~intestinal stromal tumors, pancreas, prostate, biliary tract, r, basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, glioma, small-cell lung cancer, oral squamous cell carcinoma, melanoma, colorectal cancer, non—small cell lung , osteosarcoma, glioblastoma, chronic lymphacytic leukemia, chronic myeloid ia, multiple myeloma, acute myeloid leukemia, n , meningioma, and liver cancer, more particularly pancreas cancer. In said cancer types, activation of the og pathway and/or GLll sion may be independent of the G protein-coupled receptor Smoothened. For further reference, see the introductory section of this cation and the reference documents cited herein.
In particular embodiments of the present invention, in said cancer, the hedgehog ing pathway is activated.
In particular embodiments of the present invention, in cells of said cancer, the hedgehog signaling pathway is activated.
In further particular embodiments of the present invention, said cancer does not respond to Smoothened inhibitor therapy.
WO 02638 In further particular embodiments of the present invention, cells of said cancer do not respond to Smoothened inhibitor therapy.
In further particular embodiments of the present invention, in said cancer the activation of the hedgehog signaling pathway is independent of signaling by the G n—coupled receptor Smoothened.
In further ular embodiments of the present invention, in cells of said cancer the activation of the hedgehog signaling pathway is independent of signaling by the G protein- conpied receptor Smoothened.
In further ular embodiments of the present invention, in said cancer the G protein— coupted receptor Sinoothened is not reaponsive to inhibition by Sinoothened inhibitors.
In further particular embodiments of the present ion, in cells of said cancer the G protein—coupled receptor Smoothened is not responsive to inhibition by Smoothened inhibitors.
In the context of the present invention, said cancer or cells of said cancer being not responsive to Smoothened inhibitor therapy includes both the case that the activation of the hedgehog signaling pathway is independent of signaling by the G n—coupled receptor Smoothened, and that the G protein—coupled receptor Smoothened is not responsive to inhibition by Smoothened inhibitors.
In the present invention ts wherein in said cancer, or in cells of said cancer, the hedgehog ing pathway is activated are in short referred to as "Hedgehog dependent patients", and patients wherein in said cancer, or in the cells of said , the hedgehog signaling pathway is not activated are in short referred to as "Hedgehog ndent patients". In the present invention, patients e.g. can be stratified into Hedgehog ent patients and Hedgehog independent patients by a procedure comprising the steps of 1) providing a sample from said t, wherein said sample comprises cancer cells from said patient, 2) optionally subjecting said sampte to a work—up step, 3) adding a Iabeied antibody which specifically binds to at least one protein playing a role in the hedgehog signaling pathway, adding a first antibody which cally binds to at least one protein playing a role in the hedgehog signaling pathway, and subsequently adding a second antibody which specifically binds to said first antibody, and wherein said second antibody is a labeled 4) washing said sample after step 3, ) determining whether said labeled antibody is detectable in said sample after step 4), 6) if in step 5) said marker moiety is detectable, classifying said patient as Hedgehog dependent patient, and if in step 5) said marker moiety is not detectable, classifying said patient as Hedgehog independent patient.
Antibodies used in the present invention are typically monoclonal antibodies.
The label in said labeled antibody can be selected from any label typically used as antibody label in the field of biochemistry, ar biology, immunochemistry, etc, for a label selected from the group comprising a fluorescence label, a dye, a FRET label, a radioactive label. moiety, or an enzymatically active moiety. Said enZymatically active moiety can process a reaction which in turn s in the release of a detectable substance, e. g. a dye.
In the above method of stratifying patients into Hedgehog dependent patients and Hedgehog independent patients, the work—up step is eg. in particular embodiments selected from the group comprising preservation, embedding, g and staining. Preservation can be performed by cryopreservation or fixation by eg. formaldehyde or ethanol. Embedding the tumor material prepares it for slicing. Staining can be performed with direct or indirect s. For further information and examples see DOI: 10.1354/Vp.42—4»405 J. A. Ramos— Vara, Technical Aspects of histochemistry, (2005) 42: 405 Vet .
In the context of the present ion, the sion ”said labeled antibody is detectable” means that by the state of the art measurement methods used for detecting Said label, no signal relating to said label is detectable, and/or said signal is not significant in relation to the background noise generated by said measurement method. -55, 2014/062774 In the above method to stratify patients into Hedgehog dependent patients and Hedgehog independent patients, washing step 4 is to remove unbound and/or unspecifically bound antibodies from step 3. In particular embodiments, said washing step comprises g with a buffer, e.g. a PBS , and optionally a serum protein, e. g. BSA. g step 4 can be ed as necessary to obtain a suitable signal/noise ratio, e.g. 2 or more, 3 or more, 4 or more times.
In certain embodiments of the above method to stratify patients into Hedgehog dependent cancer patients and Hedgehog ndent cancer patients, background signal by unspecific binding of antibodies is excluded by an isotype control. This control can be utilized when working with monoclonal primary antibodies. A ative sample treated as above is incubated with antibody diluent, supplemented with a non-immune immunoglobulin of the same isotype (for example, IgGl, lgGZA, lgGZB, IgM) and concentration as the aforementioned antibody. The sample is then incubated with the d antibody and detection reagents. These steps will help ensure that what appears to be specific staining was not caused by non—Specific interactions of immunoglobulin molecules with the sample.
Examples and a further ption of this method can be found in "Tissue Microarrays — Methods in Molecular Biology Volume 664, 2010, pp 113—126 linrnunohistochemical Analysis of Tissue Micro ; Ronald Simon, Martina Mirlacher, and Guido Sauter”.
In the context of the present invention the G protein-coupled or Sinoothened is interchangeably abbreviated as '"Smoothened" and "Smo".
In the context of the present invention the expression “the activation of the hedgehog signaling pathway” in particular refers to the activation of expression of primary target genes of the Hedgehog signaling pathway, including GL1, HHIP, Ptch, more particularly of GL1 expression via the hedgehog pathway. Typically, GL1 expression is triggered via binding of hedgehog to the Smo/Ptch (Smoothened/Patched) complex and pon GL1 expression via signalling by Smo.
In the context of the present invention, the “activation of the hedgehog signaling pathway is independent of signaling by the G n~coupled receptor ened“ as used in the present invention refers to the ability of certain cancers to activate the expression of primary target proteins of the Hedgehog signaling pathway, more particularly of GL1 expression n56_ independent of signaling via Smo. Instead, in these cases GL1 expression is activated by ate routes, which are ndent of the hedgehog signaling pathway as described above.
Known Smoothened tors are for example LDE225 (by Novartis), LEQ506 (by Novartis), Visrnodegib (GDC—0449), IPl—926 (by Infinity Pharmaceuticals), EMS—833923 (XL139) (by l Myers ; Exelixis), or PF—04449913 (by Pfizer), N—{3—(lH— Benziinidazol—Z—yl)—4—chloropl1enyl] —3 ,4,5~triethoxybenzarnide (SANT—Z), SANTl 9, SANTM, aSANT75, (3 B23 B} l 7,23 —Epoxy-3 -hydroxyveratrainan-l 1-one (l 1~ clopamine / e), Cur6l4l4 (by Curis), iPI—269609 (by Infinity), MRT 10, and for example cycloparnine (for further information and further Smoothened inhibitors, see eg.
Peukert S., Miller-Moslin K, ChemMedChern Volume 5, lssue 4, pages 500412, April 6, 2010).
In the present invention, patients eg. can be stratified into patients wherein said cancer, or cells of said cancer, do not respond to Smoothened inhibitor therapy, and patients wherein in said cancer, or in the cells of said cancer, respond to ened inhibitor therapy, based on their medical history, i.e. if at a previous point said cancer did not respond or ceased to respond to (wherein said response encompasses the amelioration or stabilization of one or more of the following: Disease state, symptom severity, tumor volume, tumor aggressiveness, propensity to form metastases, tumor malignancy, tumor invasiveness and t’s overall physical state), to Smoothened inhibitor therapy. Alternatively, said fication can be done by a procedure comprising the steps of '25 1) providing a sample from said patient, wherein said sample comprises cancer cells from said patient, 2) preparing two or more cell cultures from said sample, 3) incubating said cell cultures to increase the number of cells in order to obtain in each cell culture a cell number which is sufficient to provide at least lug total RNA, 4) adding a Sine—inhibitor to all but one of said cell Cultures, ) adding a Smoothened t to said cell cultures, 6) ting said cell cultures, 7) determining the level of GL1 expression in said cell cultures, 8) comparing the level of GL1 expression in said cell cultures to which a Smoothencd inhibitor has been added to said sample which no Smoothened inhibitor has been added, 9) if the expression of GL1 in at least one of said cell cultures to which a Smoothened inhibitor has been added is lower than the expression of GLI in said sample which no Smoothened inhibitor has been added, fying said t as patient wherein said cancer, or the cells of said cancer, respond to Smoothened inhibitor therapy, and otherwise classifying said patient as patient wherein said cancer, or cells of said cancer, do not respond to Smoothened tor therapy.
In the above method, in step 2, cell cultures usually comprise at least a growth medium typically used in the field of cell biology; in step 3 in particular embodiments, said cell number is at least 500.000, more particularly at least 000, even more particularly at least 1,500.000 cells; in step 4 a Smoothened inhibitor is in particular embodiments added in an amount known to y at least partially inhibit cellular Smo activity; in the particular embodiments where a Smoothened inhibitor is added to more than one cell culture, a concentration gradient can be prepared by adding different amounts of Smoothened inhibitor to each cell culture; in step 4 the ened inhibitor is in ular embodiments a small molecule, more particularly a Smoothened inhibitor as bed herein, even more particularly a compound of the present invention, in step 5 in particular embodiments the Smoothened agonist is added to each cell culture in the same amount with respect to the ceil number (i.e. more agonist for a higher cell number) in said cell culture, and in an amount known to usually at least partially activate GLI sion; said amount can for instance be determined in one or more ative cell cultures comprising cancer cells of the same or similar tissue from a subject which is known to be a as patient wherein said cancer, or the cells of said cancer, d to Smoothened inhibitor therapy; in step 6 in particular embodiments said cell cultures are ted for at least 24h, 36h, or 48h, in this way the cells can express GL1 upon the addition of the Smocthened agonist (and in the case that said cancer cells respond to Smoothened inhibitor therapy, allows said cancer cells to degrade GL1); in steps 7 the level of GM expression can e.g. be determined with the qPCR and/or Western blot methods described herein; i58_ in step 9, in particular embodiments, to classify said patient as patient wherein said cancer, or the cells of said cancer, respond to Smoothened inhibitor y, the difference in the level of GL1 sion between said at least one of said cell cultures to which a Smoothened inhibitor has been added and said sample which no Smoothened inhibitor has been added is statistically significantly, eg. at least 20%, particularly at least 40%, more particularly at least 60%, even more particularly at least 75%, yet even more particularly at least 90%. ts can be stratified into patients having cancer wherein in said cancer or in cells of said cancer the activation of the hedgehog signaling pathway is independent of signaling by the G protein~coupled receptor Sinootliened and patients having cancer n in said cancer or in cells of said cancer the activation of the hedgehog signaling pathway is dependent of ing by the G proteinmcoupled receptor ened with common methods. For example, the specific genetic subtype of cancer can be determined and compared with a database. If in said specific genetic subtype of cancer activation of the hedgehog signaling pathway is known to be ndent of signaling by the G protein—coupled receptor Smoothened, eg. in the scientific ture, and in a particular example in the ific literature cited herein, said patient is classified as 81110 independent cancer patient. If in said specific genetic e of cancer activation of the hedgehog signaling pathway is known to be dependent of signaling by the G protein—coupled receptor Smoothened, eg, in the scientific ture, and in a particular example in the said patient is classified , as Srno dependent cancer patient.
Patients can further be stratified into patients having cancer n in said cancer or in cells of said cancer the activation of the hedgehog ing pathway is independent of signaling by the G protein—coupled receptor Smoothened and patients having cancer wherein in said cancer or in cells of said cancer the activation of the hedgehog signaling y is dependent of signaling by the G protein—coupled receptor Smoothened by a method comprising the steps of 1) providing a sample from said patient, wherein said sample comprises cancer cells from said patient, 2) preparing a cell culture from said sample, 3) incubating said cell culture to increase the number of cells in order to obtain a cell number which is sufficient to provide at least lug total RNA, 4) adding a Sino-inhibitor to said cell culture, -59, ) incubating said cell cultures, 6) determining the level of GL1 expression in said cell cultures, 7) if GL1 expression is detectable in said cell culture, classifying said t as patient having cancer wherein in said cancer or in cells of said cancer the activation of the hedgehog signaling pathway is independent of signaling by the G protein-coupled receptor ened, and if GL1 expression is not detectable in said cell culture, if GL1 expression is detectable in said cell culture, classifying said patient as patient having cancer wherein in said cancer or in cells of said cancer the activation of the og signaling pathway is dependent of signaling by the G protein—coupled receptor Smoothened. 1n the above method, in step 2, cell cultures usually comprise at least a growth medium typically used in the field of cell biology; in step 3 in particular embodiments, said cell number is at least 500.000, more particularly at least 1.000.000, even more particularly at least l.500.000 cells; in step 4 a Smoothened inhibitor is in particular embodiments added in an amount known to usually at least partially inhibit cellular Smo activity; in the particular ments where a Sinoothened tor is added to more than one cell culture, a concentration gradient can be prepared by adding different amounts of Smoothened inhibitor to each cell culture; in this case, the Smoothened inhibitor can also be and RNA molecule inhibiting the sion of Smo, e.g. siRNA or shRNA, particularly an RNA molecule which specifically and/or selectively binds to the gene encoding for Smo and prevents transcription of said gene (this is typically also known as a Smo knockdown); in step 4 the Smoothened inhibitor is in particular embodiments a small molecule, more particularly a Smoothened inhibitor as bed herein, even more particularly a compound of the present invention, in step 5 in particular embodiments in particular ments said cell cultures are ted for at least 12h, 2411, or 36 h, in this way the cells can express GL1; in step 6 the level of GL1 expression can e.g. be determined with the qPCR and/or Western blot methods described herein; in step 7 in particular embodiments, able means that by the state of the art measurement methods used for ing said label, no signal relating to GL1 expression is detectable; and/or said signal is not significant in relation to the background noise generated by said ement method, —60- 2014/062774 In the t of the present invention "the G protein—coupled receptor Smoothened is not responsive to inhibition by Smoothened inhibitors" means that Smoothened activity is not ted by Smoothened inhibitors. y, in these cases cancer cells show at least one mutation in a gene encoding for Smoothened, particularly The D473H mutation which results in an amino acid substitution at position 473 in Smoothened, from an ic acid (D) to a histidine (H). Said mutation typically leads to an alteration of the Sinoothened or which prevents binding of Smoothened inhibitors, in particular of known Sinoothened inhibitors which target wild type Smoothened. Said mutation may originate from the patient‘s innate chromosomal setup, i.e. a hereditary trait, or may be acquired at a later point, e.g. by a neous mutation of cancer cell DNA, which is then selected and passed on to further cancer cell generations as a response to therapy with Smoothened inhibitors. Patients can accordingly be classified as patients having cancer wherein in said cancer or in cells of said cancer the activation of the hedgehog signaling pathway is ndent of signaling by the G protein-coupled receptor Smoothened by analyzing the genes encoding for 81110 in cells from said patient’s cancer for the presence of a mutation as described above, which can eg. be done by the qPCR methods as described herein.
Patients having cancer wherein in said cancer or in cells of said cancer the'activation of the hedgehog signaling y is dependent of signaling by the G protein-coupled receptor Smoothened can further be stratified into patients having cancer wherein the G protein- coupled receptor Smoothened is not responsive to inhibition by 81110 inhibitors and patients having cancer n the G protein—coupled receptor Smoothened is not responsive to inhibition by Shin inhibitors by the method described above for stratifying into patients wherein said cancer, or cells of said cancer, do not respond to Smoothened inhibitor therapy, and patients wherein in said , or in the cells of said cancer, respond to Smoothened inhibitor therapy.
In the context of the present invention, said sample from said t comprising cancer cells from said patient is for instance a biopsy of said patient’s cancer.
As used herein, the term “DYRKIB” means an enzyme from the family of serinelthreonine s, more particularly a member of the Minibrain/DYRK family of kinases which is specified by the UniProt/Swiss—Prot 1D Q9Y463; or as Refseq proteins: NP_004705.1, NP_006474.1 and NPWOO6475J, and/or an sion product of a gene encoding for ‘6}.
WO 02638 DYRKlB as defined herein below. As used herein, the term “DYRKIB” in certain embodiments also includes variants of DYRKlB, such as isoforms, homologs and mutants of DYRKIB, which share at least 95% sequence homology, more particularly at least 97% sequence homology, even more particularly at least 99% sequence homology with DYRKIB as defined above, and in the case of proteins and/or gene expression products in certain embodiments have essentially the same enzymatic ty profile, i.e. process essentially the same substrates as DYRKIB as defined above, wherein however the enzymatic activity of said variants of DYRKlB may differ (i.e. be higher or lower than) fiom DYRKIB as d above by up to two orders of magnitude, ularly up to one order of magnitude, more particularly up to a factor of 2. A particular t of DYRKIB which is comprised by the present invention is Mirk, which typically is located in skeletal muscle tissue, whereas DYRKEB typically is located in brain tissue.
In the context of the present invention said at least one n playing a role in the hedgehog signaling pathway can e.g. be selected from the group comprising Patched, GL1, Smoothened, HHIP, Hedgehog and SUFU.
In the context of the present invention, the term “GL1” refers to members of the GL1 protein family, such as GLll, GLIZ, GLl3 in particular ments and, unless specified otherwise particularly to GL1].
In l, and unless specified otherwise, the proteins, genes and/or gene sion products as defined herein in certain embodiments also include variants of said proteins, genes and gene expression products, such as isoforrns, homologs and s thereof, which share at least 95% sequence homology, more particularly at least 97% sequence homology, even more particularly at least 99% sequence homology with the proteins, genes and/or gene sion products as defined herein, and in the case of proteins and/or gene expression products in certain ments have essentially the same enzymatic activity as , the proteins and/or gene expression products as defined herein, wherein however the enzymatic activity of said variants may differ (i.e. be higher or lower than) from the proteins, and/or gene expression products as defined herein by up to two orders of magnitude, particularly up to one order of magnitude, more particularly up to a factor of 2. —62— As used herein, the term “DYRKlB inhibitor” or “compound which inhibits the activity of DYRKlB” means a compound which is capable of inhibiting the enzymatic ty of DYRKlB in vitro and/or in vivo, eg. in a patient in need thereof, particularly with an inhibitory concentration ICSQ of 50 inM or lower, more particularly with an inhibitory tration IC50 of 20 mM or lower, even more particularly with an inhibitory concentration ICSG of 5 mM or lower, yet even more particularly with an inhibitory concentration leU of 1 mM or lower, e. g. in the kinase assay described herein. The chemical nature of the DYRKIB inhibitor is not particularly limited and can for example be selected from the group comprising synthetic compounds, naturally occurring compounds, peptides, proteins, antibodies, and small molecules.
In certain embodiments of the present invention, said DYRKlB inhibitor is selective and/or specific for DYRKlB, In certain embodiments of the present invention, said DYRKlB tor is non—selective and/or ecific for DYRKIB. It is apparent that non-selectivity and/or nomspecificity is able, as long as no intolerable side—effect occurs due to the non—selectivity and/or non—specificity of the DYRKIB inhibitor. In this t, “intolerable side—effect” means an effect of the addition or administration of the DYRKiB inhibitor which is ent from the inhibition of DYRKlB, eg, the inhibition of one or more further enzymes, and which conflicts with the objective to be achieved by the addition or administration of the DYRKIB inhibitor to such a degree that no acceptable results may be achieved. Examples are for instance a ceutical side effect which would t the use of the DYRKIB inhibitor for therapeutic purposes, such as high toxicity, cancerogenity or the like. As one example of tolerable non—selectivity and/or non-specificity, the DYRKlB inhibitor may inhibit DYRKlA in addition to DYRKlB. DYRKIA function is largely dispensable in GLI—driven cancer cells. Off—target effects of DYRKlB inhibitors will not be critical as inhibition of DYRKlA — if at all — will enhance the (ELI—antagonizing effect of DYRKlB inhibition in cancer cells. This effect is for instance credible in view of the results shown in Mac et al., .1. Biol. Chem.2002, 277, 38, 5161, in particular Figures 4 and 6.
As used herein, the expression that in a cancer or cells in a cancer the “hedgehog signaling pathway is ndent of signaling by the G protein—coupled receptor Smoothened” means that the eration of a certain cancer entity is independent of the G proteinmcoupled receptor Smoothened and thus not affected, or at least not substantially ed, by inhibition of the G protein—coupled or Smoothened. Accordingly, patients suffering from such cancer cannot be treated and do not benefit by eutic approaches which are directed to tion of the G protein~coupled or Smoothened.
As used herein, the term “hedgehog signaling y” means a cellular ing pathway comprising an ction with a protein of the family known as hedgehog proteins, Such as eg. the proteins commonly known as “sonic hedgehog” (UniProtKB/Swiss—Prot: Q15465), “indian hedgehog” (UniProtKB/Swisswl’rot: Q14623) and “descrt hedgehog” (UniProtKB/SwissaProt: 043323) (lngham and McMahon, 2001).
As used herein, the term “treating” or “treatment” encompasses the amelioration or stabilization of one or more of the following: Disease state, symptom severity, tumor volume, tumor aggressiveness, propensity to form metastases, tumor malignancy, tumor invasiveness and patient’s overall al state.
As used herein, the term “therapeutically effective amount” means an amount, eg. of a compound, which upon administration to a patient in need thereof results in a therapeutic effect on the disease to be treated. Such therapeutic effects, eg. in cancer therapy, may comprise an effect on diseased tissue or cells including changes in tumor size, metabolic activity, cell viability, blood supply of the tumor, i.e. angiogenesis, composition of the tumor, e.g. relationship of cells comprising the tumor e.g. tumor cells, immune cells, fibroblasts and endothelial cells; and an effect on the patient’s medical state including improvements in clinical status, health status, progression or stabilization of disease, increased time of progression free survival, cure of disease, ed overall al, delay of disease progression and ation of symptoms. Such effects usually do not occur immediately after administration of a compound and may be delayed, eg. by hours, days, weeks or months, ing cg. on the specific patient, type of disease and overall situation under which the therapy is administered.
As used herein, the term “sample” in principle comprises samples from natural sources, such as a sample obtainable from a mammal, and artificial samples, which are obtainable by admixing several ingredients, wherein said ingredients may or may not be d from natural sources, and may e. g. comprise ingredients selected from the group comprising tic and/or natural proteins, peptides, oligo— or cleic acids, etc. In certain embodiments, samples are from l sources, which include bodily fluids and/or tissue —64— samples, such as bodily fluid and/or a tissue sample obtainable from mammals. Said samples from natural sources can be used in the present invention with or without further processing after being obtained from their source, eg. a mammal. Such processing can for instance comprise separation, fractionation, on, sion, mechanical treatment such as sonification, or grinding, concentratiOn, removal of certain components of said sample, or addition of nds, such as salts, buffers, detergents, etc.
As used herein, the term ly fluid” or “body fluid” specifies a fluid or part of a fluid originating from the body of a patient, including fluids that are ed or secreted from the body of the patient, including but not limited to blood, including peripheral blood, serum, plasma, urine, interstitial fluid, liquor, aqueous humour and vitreous humour, bile, breast milk, cerebrospinal fluid, endolymph, perilymph, ejaculate, gastric juice, mucus, peritoneal fluid, pleural fluid, saliva, sweat, tears and vaginal secretion, particularly peripheral blood, serum, plasma and urine. Said bodily fluid itself may or may not comprise diseased and/or non—diseased cells.
As used herein, the term “tissue sample” es a nonwfluid al or solid originating from the body of a patient. Tissue samples include, but are not limited to samples of bone material, bone marrow, skin, hair le, mucosa, brain, cartilage, muscles, lung, kidney, stomach, intestines, bladder and liver. Said tissue sample itself may or may not comprise ed cells, and may for ce be a sample taken from a diseased region of a patient’s body, such as a biopsy of a tumor. In certain ments the tissue sample is selected from skin, hair follicle or oral mucosa.
In the embodiments of the present invention, the sample is obtained from the patient by any method and/or means commonly known to the skilled person in the field of medicine, eg. in certain embodiments blood sample taking by V'enipuncture.
As used herein, the term ”peripheral blood” specifies blood obtained from the circulation remote from the heart,- i.e. the blood in the systemic circulation, as for example blood from acral areas.
As used herein, the term ,,Whole blood” specifies unmodified blood comprising cells and fluid, as ed from the donor of said blood, such as a patient. -65— As used herein, the term ,,patien ” specifies a subject which is suspected of having a disease or disorder, in certain embodiments having a medical condition, which may require treatment.
In certain ments of the t invention, the patient is a cancer patient, i.e. a subject suffering from cancer. The patient may have received prior treatment for the disease in question, eg. in the case of a cancer patient by radiation or chemotherapy, or the t’s disease may be untreated prior to the application of the embodiments of the present invention to said patient.
As used herein, the term “gene encoding for DYRKlB” means a gene identified by the NCBI nce sequence (Refseq mRNAs NM_004714.1, NM_006483.1, 484.1, or the Ensemble transcripts 000323039(u0002omj.2) ENST00000348817(u00020mi2) ENST00000430012(uc0020mk.2 u000201nl.2)) As used herein, the term ited on the DNA level and/or on the RNA level” means that the intraceilular level of the protein of interest, in the case of the present invention DYRKlB, is diminished by ting the expression of the gene encoding for the protein of interest.
This can be achieved either by an inhibition on the DNA level, i.e. by inhibiting transcription of the gene encoding for the protein of interest, or by an inhibition on the RNA level, i.e. by inhibiting translation of an RNA ribed from the gene encoding for the protein of interest. The methods by which inhibition on the DNA level and/or on the RNA level can be achieved are well known to the skilled person and any such well known method which is le for the purposes of the present invention, eg. for therapeutic use in a patient suffering from , or for in vitro use such as in an assay, can be applied in the embodiments of the present invention.
In the context of the present invention, a mammal is in certain embodiments a human.
As used herein, the terms “inhibit DYRKEB”, “inhibition of DYRKIB” and “DYRKlB inhibition” are used interchangeably and mean that the enzymatic activity ofDYRKIB is diminished, which results in a diminished turnover rate with t to the conversion of DYRKlB substrates by DYRKlB, which can particularly be determined by measuring a reduction in the level of GL1 expression by the methods described herein, e.g. the qPCR or Western Blot methods described herein. Said reduction in the level of GL1 expression is in 2014/062774 ular embodiments at least 50%, more particularly at least 70%, even more particularly at least 80%, yet even more particularly at least 90%.
As used herein, the term “formation of resistance of cancer cells against chemotherapeutic agents” means that over the course of a treatment with a chemotherapeutic agent, the treated cancer cells develop a resistance against said chemotherapeutic agent, i.e. become non— responsive to said chemotherapeutic agent. The result of resistance against said chemotherapeutic agent is that the cancer cells will erate, irrespective of continued therapy with said chemotherapeutic agent. Usually, such resistance against a chemotherapeutic agent is not reversible, and usually, in such cases of resistance against a chemotherapeutic agent, therapy has to be changed to a different treatment regimen, e.g. assing the administration of a different chemotherapeutic agent, radiotherapy, or the like.
In the embodiments of the present invention, in particular wherein a DYRKIB inhibitor is administered in an amount which is effective to inhibit DYRKIB said DYRKIB inhibitor is administered in an amount which is effective to inhibit DYRKlB by for example by at least 50%, more particularly at least 75%, even more particularly at least 90%, inhibition of DYRKlB can be ined in vitro by a DYRKIB kinase assay and ex vivo by measuring the expression level of a y target gene of the hedgehog signaling pathway, eg. GL1, particuiarly in a sample obtained from a t; this can be done by the methods described herein, In further particular embodiments of the t invention, the compounds inhibit the hedgehog signaling pathway, which can be determined by measuring the expression level of a primary target gene of the hedgehog signaling y, eg. GL1, particularly in a sample obtained from a patient; this can be done by the methods described , e.g. qPCR or Western Blot.
In r particular embodiments of the present invention, the compounds inhibit the celluiar expression of GLI, particulariy GLII.
In further particular embodiments of the present invention, the. compounds t the hedgehog signaling pathway—mediated cellular expression of GLI, particularly GL1}. -67— WO 02638 Furthermore, particular cancer types of certain embodiments of the present invention are listed in the ing; reference documents with further information are indicated in parentheses: esophagus / G1 (Wang, Y., et a1. (2012). Cane. cell 21(3) 7. doi:10.1016/j.ccr.2011.12.028); gastrointestinal (Berman, D. M., et a1. (2003). Nature, 425(6960), 846—851. doizl0.1038/nature01972); gastrointestinal stromal tumors (Pelczar, P. et a1. (2013). Gastroenterology, 144(1), 134m 144.66. doi:IO.l053/j.gastro.2012.09.061); as (Nolan—Stevaux, O. et al. (2009). Genes & Development, 23(1), 24—36. doi:10.1101/gad.1753809; Feldmann, G., et a1. (2007). Cancer Research, 67(5), 2187w2196. doi:10.1158/0008-5472CAN—06—3281; Karhu, R. et al. (2006) Genes, chromosomes & cancer 45, 7215730; Merchant, A.A., and Matsui, W. (2010) Clin. Cane. Res. 16, 3130—3140); prostate (Karhadkar, SS et a1. (2004). Nature, 431(7009), 707—712. doi:10.1038/natnre02962; Sanchez, P., et a1. (2004). PNAS, 101(34), 12561—12566. doi:10.1073/pnas.0404956101); biliary tract n, DM et a1. (2003). Nature, 425(6960), 8464851. doi:10.103 8/nature01972); bladder / urogenital (Fei, DL et al. Cancer Res. 2012 Sep l;72(17):4449—58); basal cell carcinoma / skin (Hahn, 1-1., et a1. (1996). Cell, 85(6), 841~851); medulloblastoma / brain (Goodrich, L. V., et a1. (1997). Science, 277(5329), 1109—1113); rhabdornyosarcorna (Ecke, I. et a1. (2008). lar carcinogenesis, 47(5), 2. doi:10.1002/mc20394; Deng, X. et a1. (2006) Cancer research 66, 4149—4158; Friedman, E. (2011) Sarcoma 2011, , doi:10.1155/2011/260757; Jin, K. et a1. (2007) Cancer research 67, 7247-7255; Mercer, S.E. et a1. (2006) Cancer research 66, 51436150; Yang et a1., Carcinogenesis. 2010 Apr;31(4):552—558); glioma / brain (Clement, V., et a1. (2007). Current biology: CB, 17(2), 1654172. doi:10.1016/j.cub.2006.11.033); smallucell lung cancer / lung (Watkins, D. N. et a1. . Nature, 422(6929), 313—317. doi:10.1038/nature01493; Park KS, et al. Nat Med. 2011 Oct 1):1504—8. doi: .1038/nm.2473.); oral squamous cell carcinoma (Yan M, et a1. Oral Oncol. 2011 (6):504-«9. doi: .1016/j.oraloncology.201 1.03 .027. Epub 2011 May 4); ~68— melanoma / skin (Stecca B et al. (2007) PNAS ) 5895—5900 doi:10.1073/pnas.0700776l04); colorectal cancer/ G1 (Varnat, F., et al. . EMBO molecular medicine, 1(6w7), 338w351. doizl0.1002/e1n1nrn.200900039; Deng, X. et al. (2006) Cancer research 66, 4149—4158; Friedman, E. (2011) Sarcoma 2011, 260757, doi:10.1155/2011/260757; Jin, K. et a1. (2007) Cancer research 67, 7247—7255; , 8.13. et a1. (2006) Cancer research 66, 5143—5150; Yang et al., Carcinogenesis. 2010 Apr;31(4):552-558); non—small cell lung cancer / lung (Yuan, 2., et al. (2007). Oncogene, 26(7), 1046—1055. doi:10.1038/sjonc.1209860); arcoma / bone (Bovee, J. V. M. (3., et al. (2010). Nature Reviews Cancer, 10(7), 481m 488. doi:10.1038/nrc2869; Ho, L., et al. (2009). Cancer cell, 16(2), 126—136. doi:10.1016/j.ccr.2009.05.013; Friedman, E. (2011) Sarcoma 2011, 260757, doi:10.1155/2011/260757; Iin, K. et al. (2007) Cancer research 67, 7247-7255; Mercer, SE. et a1. (2006) Cancer research 66, 51436150; Yang et al., Carcinogenesis. 2010 (4):552—558); glioblastoma / brain (Clement, V., et a1. (2007). Current biology : CB, 17(2), . doi:10.1016/j.cub.2006.11.033); chronic cytic leukemia / blood (Desch, P., et a1. (2010). Oncogene, 1*11. doi:10.1038/onc.2010.243); chronic myeloid leukemia / blood (Dierks, C., et a1. (2008). Cancer cell, 14(3), 238M249. doi:10.1016/j.ccr.2008.08.003); multiple myeloma / blood (Peacock CD, et al. PNAS 2007 Mar 6;104(10):4048-53); ovarian cancer / urogenital (McCann CK, et al. PLoS One. 20ll;6(11):e28077. doi: .l371/journal.pone.0028077. Epub 2011 Nov 29.; Friedman, E. (2007) Journal of cellular biochemistry 102, 274—279, 2007; Karhu et al., Genes Chromosomes Cancer. 2006 Aug;45(8):721—730); meningioma / brain (Clark, V.E. et al., Science, 2013 Jan 24., Epub ahead of print, PMID (PubMed—ID) 23348505 — as supplied by publisher; Aavikko M. et al., Am J Hum Genet, 2012 Sep 7, 91(3), 520626); liver/ GI (Arzumanyan A. et al. Cancer Res. 2012 Nov 15;72(22):5912-20); liver (Huang, 8., et al. (2006). Carcinogenesis, 27(7), 1334—1340. doi:10.1093/carcin/bgi378).
It is apparent that the embodiments of the t ion as described herein may be combined to form firrther particular embodiments of the t invention. ~69— Examples Synthesis Examples Synthesis of final comgounds Unless otherwise specified, starting materials, reagents and solvents were commercially available and were used without further purification.
N—(5~Cyano-lH—benzo[d]imidazol—Z-yl)—2-(2,3-dihydrobenzofuran~5~yl)thiazole—4~ carboxamide (1) sMWfiIUN CN To a solution of 2—(2,3—dihydro-l—benzofuran—S—yl)—l,3—thiazole-4—carboxylic acid (123 mg, 0.50 mmol) in 2 ml MN—dimethylformamide, were added o-lH—benzo[d]imidazole—5- carbonitrile (130 mg, 0.54 mmol), 2-(lH—benzotriazole—l—yl)—l,1,3,3—tetramethyluronium hexafluorophosphate (HBTU) (188 mg, 0.5 mmol), 4~dimethylaminopyridine (6 mg, 0.05 mmol) and N,N—diisopropylethylamine (0.22 ml, 1.24 mmol). The reaction e was stirred overnight at room temperature. It was poured into ice water. The formed itate was filtered off and dried. The product was ed as a light yellow solid (154 mg, 0.40 mmol, 79 % yield). 1H NMR (400 MHZ, DMSO‘dfi) 8 ppm 3.29 (t, J=8.75 HZ, 2 H), 4.65 (t, J=8.75 Hz, 2 H), 6.91 (d, J=8.34 Hz, 1 H), 7.54 (dd, J=8.25 Hz, J=1.32 Hz, 1 H), 7.67 (d, Jm8.28 Hz, 1 H), 7.92 (d, J=1.92 Hz, 1 H), 7.95 (bs, l H), 8.13 (135, 1 H), 8.58 (s, l H), 11.84 (bs, 1 H), 12.69 (b3, 1 H). LC/Ms [M+H]+: 387.8 N—(S-Chlorofluoro-lH-benzo[d]imidazol-Z-yi)—2-(2,3-dihydr0benzofuran—5- yl)thiazolew4wcarboxamide (2) N Cl HN / SM%N]©:F To a solution of 2-(2,3-dihydro—1vbenzofilrai1~5-yl)—l,3-thiazole—4—carboxylic acid (150 mg, 0.61 n11n01) in 4 ml MN-dimethylfonnamide was added 5~chlor0~6~fluoro—1H- benzo[aflimidazol—2—amine (124 mg, 0.67 mmol). Then 2-(1H—benzotriazole—1—yl)u1,1,3,3— tetramethyluronium hexafluorophosphate (HBTU) (230 mg, 0.61 11111101), 4— dimethylaminopyridine (7 mg, 0.06 11111101) and sopropyiethyiamine (0.26 mi, 1.52 mmol) were added. The reaction mixture was stirred overnight at room temperature. It was poured into ice water. The formed precipitate was filtered off and dried to obtain a white solid. The crude product was purified by preparative TLC (PLC silica gel 60 F254, 1 mm, DCM:MeOH 9:1). The product was ed as a white solid (4 mg, 0.01 mmol, 2 % yield). 1H NMR (400 MHz, DMSO—dfi) 8 ppm 3.22-3.36 (m, 2 H), 4.64 (t, J=8.75 Hz, 2 H), 6.91 (d, J=8.34 Hz, 1 H), 7.49 (d, #975 Hz, 1 H), 7.65 ((1, .12687 Hz, 1 H), 7.92 (dd, 0738.37 Hz, JIL83 Hz, 1 H), 8.11 (13s, 1 H), 8.56 (s, 1 H), 11.71 (113, 1 H), 12.49 (bs, 1 H). LCMS [M+H]+: 414.7 2-(2,3-Dihydrobenzofuran-S-yi)—N—(5—(methylsulfonyl)—lH—benzo[dlimidazol-Z— yl)thiazole—4-carboxamide (3) To a solution of 2—(2,3—dihydro—1-benzofuran—5—yl)—1,3-thiazole—4—carboxy1ic acid (142 mg, 0.58 mmol) in 3 ml MN—dimethylfonnamide, were added 5—(1nethylsu1fony1)-1H— d]imidazolw2—amine (134 mg, 0.63 inmol), 2-(1H—benzotfiazoie—l-y1)—1,1,3,3a tetramethyluronium hexafluorophosphate (HBTU) (218 mg, 0.58 11111101), 4 dimethylaininopyridine (7 mg, 0.06 11111101) and NN—diisopropylethylamine (0.25 ml, 1.44 mmol). The reaction mixture was stirred overnight at room temperature. It was poured into ice water and extracted with EtOAc and DCM. The organic extracts were combined, dried over MgSO4, filtered and concentrated under d re. The e was washed with MeOH and diisopropylether. The product was ed as a pale yellow solid (142 mg, 0.32 11111101, 51 % yield). IH NMR (400 MHZ, DMSO—dfi) 5 ppm 3.19 (s, 1 H), 3.24-3.41 (in, 2 H), 7.49 (d, Jm9.75 Hz, 1 H), 7.65 (d, J=6.87 Hz, 1 H), 4.65 (t, J=8.67 Hz, 2 H), 6.91 (d, J=8.31 112,1 H), 7.71 (bs, 2 H), 7.93 (d, #819 Hz, 1 H), 8.05 (135, 1 H),'8.13 (bs, 1 H), 8.58 (s, 1 H), 11.98 (b3, 1 H), 12.64 (05, 1 H). LC/MS [M+H)+: 440.7 2w(2,3-Dihydrobenzofuran-S-yl)‘N-(5—methoxy—1H—benzo[d]infidazol—Z-yl}thiazole~4~ carboxamide (4) N 0\ HN / 3M —<N:©/ To a solution of 2—(2,3—dihydro—1—benzofuran—5-yl)-1,3—thiazo1e~4—carboxylic acid (200 mg, 0.81 n111101) in 5 1111 MN—dimethylformamide was added 5—methoxy—1H—benzo[d]imidazol—2— amine hydrobromide (310 mg, 0.8911111101). Then 2—(1H—benzotriazole—1—y1)—1,1,3,3* tetramethyluronium hexafluorophosphate (HBTU) (307 mg, 0.81 11111101), 4 dimethylarninopyridine (10 mg, 0.08 11111101) and MN—diisopropy1ethy1a1nine (0.35 1111, 2.0 11111101) were added. The reaction mixture was stirred overnight at 100111 temperature. It was poured into ice water, a precipitate was obtained. The crude product was d by preparative TLC (PLC silica gel 60 F254, 1 111111, OH 9:1). The crude product was purified by preparative HPLC. The product was obtained as a rose soiid (8 mg, 0.02 11111101, 3 % yieid). 1H NMR (400 MHZ, DMSO'dfi) 5 ppm 3.29 (t, J=8.66 Hz, 2 H), 3.78 (s, 3 H), 4.64 (t, J=8.75 Hz, 2 H), 6.79 (dd, 0128.70 112, Jm2.43 1-12, 1 H), 6.91 (d, J=8.34 Hz, 1 H), 7.07 (d, J=2.31 Hz, 1 H), 7.40 (d, J=8.67 Hz, 1 1-1), 7.90 (dd, J=8.34 Hz, J=1.95 Hz, 1 H), 8.08 (bs, 1 H), 8.51 (s, 1 H), 11.94 (ha, 2 H). LC/MS [NIH-11+: 392.8 2—(2,3—Dihydrobenzofuran—S—y1)—N—(5—(trifiuoromethyl)-lH—benzo[a’]imidazoI-Z- yl)thiazole—4-carboxamide (S) N 01:3 HM / SM«ND 0 To a solution of 2—(2,3-dihydro—1-benzofuran—5—y1)—1,3-thiazoie—4-carboxylic acid (1.00 g. 4.04 11111101) in 20 1111 MN-dimethylfonnamide, were added 5—(trifluoromethyl)-1H— benzo[d]imidazol-2—amine (895 mg, 4.45 mmol), 2-(1H—benzotriazole—1-y1)—1,1,3,3- ethyluronium hexafluorophosphate (HBTU) (1.53 g, 4.04 ), 4- dimethylaininopyridine (49 mg, 0.40 n111101) and MN—diisopropylethylamine (1.76 1111, 10.11 11111101). The on mixture was stirred over weekend at room ature. It was poured into ice water. The formed precipitate was dried and purified by flash column chromatography (DCM/MeOH 95:5 to . The crude product was suspended in Etzo, filtered and dried. The product was obtained as a white solid (1.07 g, 2.49 mmol, 62 % yield). 1H NMR (400 MHZ, DMSO'dfi) 5 ppm 3.16—3.30 (m, 2 H), 4.57 (t, 75 Hz, 2 H), 7.40 (dd, J28.46 Hz, J31.44 Hz, 1 H), 7.62 (d, J28.34 Hz, 1 H), 7.77 (bs, 1 H), 7.85 (dd, 1:833 Hz, J=1.91 Hz, 1 H), 8.04 (‘03, 1 H), 8.50 (s, 1 H), 11.81 (bs, 1 H), 12.51 (bs, 1 H). LC/MS [Mi—H11: 431.0 N—(S—Chloro-lH—benzo[d]imidazol-Z-yl)-2~(2,3—dihydrobenzofuranyl)thiazoIe carboxamide (6) s/WN_</N:©/N CI 0 To a solution of 2-(2,3—dihydrobenzofuran—5—y1)~1,3-thiazoleoarboxylie acid (100 mg, 0.40 mmol) in 4 1111 MN—dimethylfonnamide, was added 5~chloro~lH-benzofflimidazolw 2-arnine hydrobromide (75 mg, 0.44 mmol). Then 2—(lH—benzotriazoleyl)—1,1,3,3— tetramethyluronium hexafluorophosphate (HBTU) (153 mg, 0.40 mmol), 4— dimethylarninopyridine (5 mg, 0.04 minol) and MN—diisopropylethylamine (0.18 ml, 1.01 mmol) were added. The reaction mixture was stirred overnight at room temperature. It was poured into ice water. The formed precipitate was filtered off and dried to obtain a yeliow solid. The crude product was washed with acetone, ol and EtOAe. The solid was filtered off and dried. The product was obtained as a beige solid (55 mg, 0.14 mmol, 34 "/0 yield). 1H NMR (400 MHz, DMSO~d6) 5 ppm 3,133.47 (111,2 H), 4.64 (t, Jams HZ, 2 H), 6.90 (d, J=8.34 Hz, 1 H), 7.16 (dd, J38.46 HZ, J=1.92 Hz, 1 H), 7.50 (d, J=8.58 Hz, 1 H), 7.53 (bs, 1 11),, 7.91 (d, J=8.31 Hz, 1 H), 8.10 (bs, 1 H), 8.54 (s, 1 H), 11.66 (193, 1 H), 12.41 (b5, 1 H). LC/MS [M+H]": 396.8 -Dihydrobenzofuran—S-yl)~N-(S-(dimethylcarbamoyl)—1H—benzo[flimidazol-Z- yl)thiazole—4-carboxamide (7) S _</NJ©/KN/| \ N 2014/062774 To a solution of 24(2,3—dihydro~1~henzofuran-5—yl)—1,3—thiazole—4—carboxylic acid (319 mg, 1.29 11111101) in 6 1111 ethylforrnarnide, were added 2—aIniiio—MNndimethy1»1H~ benzo[d]irnidazole—5—carboxamide (290 mg, 1.42 11111101), 2—(lH—benzotriazole—1-yl)—1,1,3,3— tetrarnethyluroniurn hexafluorophosphate (HBTU) (490 mg, 1.29 mmol), 4- dimethylaminopyridine (16 mg, 0.13 mmol) and MN—diisopropylethylamine (0.56 ml, 3.23 mmol). The reaction mixture was stirred overnight at room temperature. It was poured into ice water. The formed precipitate was filtered off, washed with MeOH and diisopropylether and dried. The product was obtained as a white solid (170 mg, 0.39 mmol, 30 % yield) and was sent for biological evaluation. 1H NMR (400 MHZ, DMSO-dfi) 5 ppm 2.98 (s, 6 H), 3.11—3.53 (in, 2 H), 4.64 (t, J28 .61 Hz, 2 H), 6.90 (d, Jm8.31 Hz, 1 H), 7.20 (d, Jfi7.62 Hz, 1 H), 7.52 (d, J=8.43 Hz, 1 H), 7.55 (bs, 1 H), 7.91 (d, J27.98 Hz, 1 H), 8.10 003, 1 H), 8.54 (s, 1 H), 11.984 (13$, 2 11). LC/MS [Mi-113*“: 433.8 2-(2,3-Dihydrobenzofuran-S-yI)—N-(5-(4-((tetrahydrofuran—Z-yl)methyl)piperazine—1~ carbonyl}IH-benzo[d]imidazol—Z—yi)thiazole—4—carb0xamide (8) To a solution of 2—(2,3-dihydro—1—benzofuran—5—y1)-1,3-thiazole—4—carboxylic acid (135 mg, 0.55 11111101) in 3 ml MN—dimethylformamide, were added (2-a1ninom1H—benzo[d]in1idazol—5— y1)(4-((tetrahydrofirran—Z»y1)1nethy1)piperazin—1-y1)rnethanone hydrobromide (1-50) (198 111g, 0.60 11111101), 2-(1H—benzotriazole—1«y1)-1,1,3,3~tetramethyluroniun1 hexafluorophosphate (HBTU) (207 mg, 0.55 01), 4—dimethylaniinopyridine (7 mg, 0.05 11111101) and MN- diisopropylethylarnine (0.24 1111, 1.37 11111101). The on mixture was stirred overnight at room temperature. It was poured into ice water and extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and trated under reduced pressure. The residue was washed with MeOH and diisopropylether and dried. The crude product was purified by preparative TLC (DCM/MeOH 90:10). The crude product was suspended in Bt20, filtered and dried. The product was obtained as a light yellow solid (65 mg, 0.12 inmoi, 21 % yield). 1H NMR (400 MHZ, é) 5 ppm 3.28-3.40 (1n, 3 H),1.37—1.57 (n1, 1 H), 1.67- 186 (111,2 H), 0 (m, 1 H), 2.31247 (1n, 3 H), 3.40—3.66 (111, 8 H), 3.68—3.79 (111,2 H), 3.88—4.00 (111, 1 H), 4.65 (t, J=8.76 Hz, 2 H), 6.91 (d, J=8.34 Hz, 1 H), 7.18 (dd, J=8.19 Hz, JELSO Hz, 1 H), .60 (m 2 H), 7.92 (dd, J=8.34 Hz, Jml.95 Hz, , 1 H), 8.11 (bs, 1 H), 8.54 (s, 1 H), 11.67 (135, 1 H), 12.43 (bs, 1 H). LC/MS [Mai-HT: 558.8 Ethyl 2-(2-(2,3~dihydrobenzofuran—S-yl)thiazole—4—carboxamide)-IH—benzo[d}imidazole- Smearboxylate (9) S HN—</ \ N:I::j/fl\ 2—(2,3—Dihydrobenzofirran—5-y1)thiazole—4—earboxylic acid (80 mg, 0.32 mmcl), ethyl 2- aminc-lH—benzo[aflimidazole—Scarboxylate (66 mg, 0.32 mmol), 2-(lH-benzo[1,2,3]triazol— 1—y1)—1,1,3,3—tetramethyluronium orophosphate (HBTU) (123 mg, 03211111101) and N,N—dimethylpyridin—4—amine (4 mg, 0.03 mmol) were suspended in 1 1111 MN- dimethylformamide. MN'diisopi-opylemylamine (0.13 ml, 0.81 11111101) was added and the reaction mixture was stirred at 60 °C for 18 h. It was poured into ice water and extracted with EtOAc. The organic extracts were dried over MgSO4, d and trated under reduced pressure. The residue was purified by preparative HPLC. The product was obtained as a light yellow solid (6 mg, 0.01 mol, 4 % yield). EH NMR (400 MHZ, DMSO—ds) 8 ppm 1.35 (t, J=7.11 Hz, 3 H), 3.20-3.36 (111,2 H), 4.33 (q, J=7.11 112,2 H), 4.65 (t, J=8.76 Hz, 2 1-1), 6.91 (d, J=8.34 Hz, 1 H), 7.51—7.63 (m, 1 H), 7.81 (dd, J=8.40 Hz, #162 Hz, 1 H), 7.93 (dd, J=8.34 Hz, Jm1.98 Hz, 1 H), 8.04823 (1n, 2 H), 8.57 (s, 1 H), 11.74 (115, 1 H), 12.58 (133, 1 H). LC/MS [M+H]+: 434.9 2-(2,3-Dihydrobenzofuran-S—yl)—N—(5-(morpholinecarbonyl)—1H-benzoMimidazul-Z- yl)thiazolecarboxamide (10) To a solution of 2—(2,3—dihydr0-1—benzofi1ran~5-yl)—1,3—thiazolecarboxylic acid (142 mg, 0.58 mmol) in 3 m1 MN—dimethylformamide, were added (2—amino-1H—benzo[d]imidazol—5- y1)(morpholino)methanone (156 mg, 0.63 mmol), 2~(1H—benzotriazcle—l-yl)—l,l,3,3- tetramethyluronium hexafluorophosphate (HBTU) (218 mg, 0.58 mmol), 4» dimethyiaminopjmdine (7 mg, 0.06 11111101) and N,N«diisopropylethylamine (0.25 ml, 1.44 mmol). The reaction mixture was stirred overnight at room temperature. It was poured into ice water and extracted with EtOAc and DCM. The organic ts were combined, dried over MgSO4, d and concentrated under reduced pressure. The residue was washed with MeOH and diisoprOpylether. The product was obtained as a pale yellow solid (108 mg, 0.23 mmol, 36 % yield). 1H NMR (400 MHZ, DMSO—dg) 5 ppm 3.15—3 .44 (m, 2 H), 3.53 (bs, 4 H), 3.61 (bs, 4 H), 4.64 (t, J=8.58 Hz, 2 H), 6.91 (d, #828 Hz, 1 H), 7.21 (d, J=7.71 Hz, 1 H), 7.45—7.64 (m, 2 H), 7.92 (d, #852 Hz, 1 H), 8.11 (bs, 1 H), 8.54 (s, 1 H), 11.66 (bs, 1 H), 12.44 (bs, 1 H). LC/MS [M+H]+: 475.3 2-(2,3-Dihydrobenzofuran—5-yl)-N-(IH-imidazol—2-yl)thiazole-4—carboxamide (1 1) HN~<’N] To a solution of —dihydro—1—benzofi1rar1—5—y1)—1,3-thiazole—4-carboxylic acid (150 mg, 0.61 11111101) in 2 ml MN—dimethylformamide, were added lHnlmidazoi—Z-yiamine (88 mg, 0.67 mmol), 2—(1H—benzotriazole—1—y1)—1,1,3,3—tetramethy1uronium hexafluorophosphate (HBTU) (230 mg, 0.61 mmol), 4—dimethyiarninopyridine (7 mg, 0.06 mmol) and MN— diisopropyiethylamine (0.26 ml, 1.52 mmol). The reaction mixture was stirred overnight at room temperature. It was poured into ice water. The precipitate was d off, washed with M6011 and diisopmpylether. The crude product was purified by preparative TLC (DCM/MeOH 90:10). The product was obtained as a light yellow solid (40 mg, 0.13 mmol, 21 % yield). 1H NMR (400 MHz, fi) 5 ppm 3.22—3.36 (m, 2 H), 4.63 (t, J38.76 Hz, 2 H), 6.84 (bs, 2 H), 6.89 (d, J=8.37 Hz, 1 1-1), 7.88 (dd, J=8.34 Hz, $41.53 Hz, 1 H), 8.06 (bs, 1 H), 8.40 (s, 1 H), 11.48 (bs, 2 H). LC/MS [M+H]_+: 312.8 2-(2,3—Dihydrobenzofuran—S—yl)—N~(4-(triflu0romethyl)~1H—benzo[d]imidazol—Z— yl)thiazole—4—carboxamide (12) SMN—(NbN —76— To a solution of —dihydro-lfibenzofuran—S—yl)—l,3—thiazole—4—Carboxylic acid (104 0.42 mmol) in 2,5 m] MN—dimethylformamide was added 7-(trifluoromethyl)—1H~ benzo[d]imidazol—2—amine (130 mg, 0.46 minol). Then 2—(1H—benzotiiazole~lmyl)—1,1,3,3~ tetramethyluronimn hexafluorophosphate (HBTU) (159 mg, 0.42 mmol), 4— dimethylaminopydidine (5 mg, 0.04 mmol) and MN~diisopropy1ethylamine (0.17 ml, 1.00 mmol) were added. The reaction mixture was d over weekend at room ature. It was poured into ice water. The precipitate was filtered off, washed with MeOH and diisopropylether. The product was obtained as a white solid (135 mg, 0.31 mmol, 75 % yield). 1H NMR (400 MHZ, DMSO—dfi) 5 ppm 3.21-3.39 (m, 2 H), 4.65 (t, J=8.73 Hz, 2 H), 6.91 (d, J=8.34 Hz, 1 H), 7.28 (t, J=7.85 Hz, 2 H), 7,48 (d, J=7.62 Hz, 1 H), 7.84 (d, 4737.95 Hz, 1 H), 7.94 (dd, J3829 1-12,.12190 Hz, 1 H), 8.15 (bs, 1 H), 8.59 (s, 1 1-1), 11.89 (bs, ] H), 12.70 (135, 1 H). LC/MS {M+H]*: 430.7 2-(2,3-Dihydrobenzofuran—S—yl)—N—(4-(3-methoxyphenyl)—1H-imidazol-2~yl)thiazole-4~ carboxamide (13) N o HN—<” l S\ N A mixture of (2—amino—4—(3-methoxypheny1)-lH—imidazol-1—yl)(2—(2,3~dihydrobenzofuran—5— azol—4—yl)methanone (1-48) (206 mg, 0.49 mmol), 10 ml Xylene and 1 1111 MN- dimethylfonnamide was refluxed for 4 11. All volatiles were removed under reduced pressure.
The residual Solid was washed with diisopropylether. The product was ed as a light yellow solid (144 mg, 0.34 mmol, 70 % yield). 1H NMR (400 MHZ, DMSO-dfi) 8 ppm 3.18- 3.44 (m, 2 H), 3.79 (s, 3 H), 4.64 (t, #8370 Hz, 2 H), 6.76 (d, J=6.30 Hz, 1 H), 6.90 (d, J=8.16 Hz, 1 H), 7.15—7.49 (m, 4 H), 7.91 (d, J=7.95 Hz, 1 H), 8.11 (bs, 1 H), 8.44 (s, 1 H), 11.20 (bs, 1 H), 11.95 (133, 1 H). LC/MS [M+H]‘*‘: 418.8 2-(2,3-Dihydrobenzofuran-S-yl)~N—(6~(trifluoromethoxy)—1H~benzo[d]imidazol yl)thiazole—4—carboxamide (14) N O HN-</Q \i/ F to”{QB—<0 a To a solution of —dihydro~1—benzofi1ran—5-yl)—l,3—thiazole—4—carboxylic acid (122 mg, 0.50 mmol) in 2 ml MN—dimethylformamide, were added 6—(t1ifluoromethoxy)—1H— benzo[d]imidazol—2—amine (162 mg, 0.54 mmol), 2—(1H—benzotriazole—l—yl)—1,1,3,3m tetramethyluronium hexafluorophosphate (HBTU) (188 mg, 0.50 mmol), 4~ dimethylaminopyridine (6 mg, 0.05 mmol) and MN—diisopropylethylamine (0.22 ml, 1.24 mmol). The reaction mixture was stirred ght at room temperature. It was poured into ice water. The formed precipitate was filtered off, washed with Etgo and dried. The product was ed as a light yellow solid (86 mg, 0.19 mmol, 39 % yield). 1H NMR (400 MHz, DMSO— d6) 5 ppm 3.15—3.51 (m, 2 H), 4.65 (t, Jm8.34 Hz, 2 H), 6.91 (d, J=7.80 Hz, 1 H), 7.13 (d, J27.32 Hz, 1 H), 7.48 (s, 1 H), 7.59 (d, J=7.32 Hz, 1 H), 7.93 (d, J=7.53 Hz, 1 H), 8.11 (bs, l H), 8.56 (s, 1 H), 11.70 (bs, 1 H), 12.50 (bs, l H). LC/MS [Ml-HT: 446.8 Methyl 5—(2—(2,3—di11ydrobenzofuran—S—y1)thiazole—4—carboxamido)—1H—1,2,4-triazole-3— carboxylate (15) To a solution of 2—(2,3—dihydro—1—benzofuran—5—yl)—1,3—thiazole-4ncarb0xylic acid (100 mg, 0.40 mmol) in 5 ml ethylfomnamide was added S—Amino—lH-[l,2,4}—triazoie—3— carboxylic acid methyl ester (58 mg, 0.40 mmol). Then 2—(1H—benzotriazole—1-y1)-1,1,3,3- tetramethyluronium orophosphate (HBTU) (153 mg, 0.40 mmol), 4— dimethyiaminopyridine (5 mg, 0.04 mmol) and isopropylethylamine (0.18 ml, 2.02 mmol) were added. The reaction mixture was stirred at 65 °C for 18 h. Additional N,N- diisopropylethylamine (0.18 ml, 1.01 mmol) and 2—(1H—benzotriazole-1—y1)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU) (153 mg, 0.40 mmol) were added and the reaction mixture was stirred at 65 °C for further 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with an aqueous 5% citric acid solution and an aqueous 5% NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained as a white solid (1.5 mg, 0.004 mmol, 1 % yield). IH NMR (400 MHz, DMSO—d6) 5 ppm 3.20-3.36 (m, 2 H), 3.89 (s, 3 H), 4.64 (1, J=8.75 112,2 H), 6.90 (d, #834 Hz, 1 H), 7.92 (dd, #334 Hz, J=1.74 Hz, 1 H), 3.12 (be, 1 H), 8.53 (s, 1 H), 11.98 (135, 1 H), 14.26 (bs, 1 H). LC/MS [M+H]+: 372.0 2-.(2,3nDihydrobenzofuran—S—yl)—N-(3-hydroxypyridin-Z—yl)thiazolecarboxamide (16) SMNQN \ {gm/EN O OH To a solution of 242,3—dihydro—1—benzofi.rran—5—y1)-1,3-thiazoler4~earboxylic acid (100 mg, 0.4 mmol) in 3 ml MN—dimethylfonnamide, was added 2-mnino—3—hydroxypy1idine (49 mg, 0.44 mmol). Then 2~(1H—benzotriazole—1—y1)—1,1,3,3—tetramethyluronium hexafluorophosphate (HBTU) (153 mg, 0.4 mmol), 4—dimethy1aminopyridine (5 mg, 0.04 mmol) and MN—diisopropylethylamine (0.17 ml, 1.00 mmol) were added. The on e was stirred over weekend at room temperature. It was poured into ice water. The precipitate was washed with diisopropylether and dried. The product was obtained as a yellow solid (57 mg, 0.17 inmol, 42 % yield). 1H NMR (400 MHZ, DMSO—dg) 5 ppm 3.19—3.43 (m, 2 H), 4.64 (t, J=8.73 Hz, 2 H), 6.92 (d, J=8.31 Hz, 1 H), 7.17 (dd, J=4.63 Hz, J=7.96 Hz, 1 H), 7.33 (d, J37.95 Hz, 1 H), 7.85 (d, J=8.31 Hz, 1 H), 7.95 (d, J=444 Hz, 1 H), 7.99 (be, 1 H), 8.41 (s, l H), 10.20 (bs, 1 H), 10.31 (b5, 1 H). LC/MS [M+H]+: 340.0 2—(2,3—Dihydrobenzofuran—S-y1)~N—(pyridin—Z-yl)thiazoIecarhoxamide (17) HN / \ 0 To a solution of 2—(2,3-dihydro—l—benzofuran—5—y1)—1,3wthiazolecarboxylic acid (100 mg, 0.40 mmol) in 5 ml MN—dimethylfonnamide was added 2—aminopyiidine (42 mg, 0.44 11111101).
Then 2~(lH—benzotriazole-1—yl)-l,1,3,3—tetramethy1uronium orophosphate (HBTU) (153 mg, 0.40 mmol), 4—dimethylaminopyridine (5 mg, 0.04. mmol) and MN— diisopropylethylamine (0.18 ml, 1.01 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was poured into ice water and the ing precipitate was filtered off. The crude product was purified by ative TLC (PLC silica gel 60 F254, 1 mm, eluent DCMzMeOH 98:2). The product was obtained as a white solid (24 mg, 0.07 mmol, 18 % yield). 1H NMR (400 MHz, DMSO—de) 8 ppm 3.24—3.34 (m, 2 H), 4.64 (t, J=8.76 112,2 H), 6.91 (d, J=8.34 Hz, 1 H), 7.21 (ddd, #759 Hz, .72487 Hz, J=1.02 Hz, 1 H), 7.82-7.93 (m, 2 H), 8.01 (d, #153 Hz, 1 H), 8.23 (dt, J=8.31 Hz, J=0.90 Hz, 1 H), 8.40 (ddd, J=4.96 Hz, J=1.89 Hz, J=0.90 Hz, 1 H), 8.47 (s, 1 H), 10.04 (bs, 1 H). LC/MS {M+H}+: 324.0 N—(4—Cyanopyridin—Z-yl)—2-(2,3-dil1ydrobe112;ofuran—S-yl)thiazole—4-carboxamide (18) To a solution of 2-(2,3—dihydrobenzofi1ran-5—yl)—1,3—thiazole—4-earboxy1ie acid (100 mg, 0.40 mmol) in 4 m1 NN-dimethylformamide was added o—4—cyanopyridine (53 mg, 0.44 mmol). Then 2~(1H—benzotiiazole-l—y1)—l,1,3,3—tetramethylumnium hexafluoro— phosphate (HBTU) (153 mg, 0.40 11111101), 4-dimethyiamin0pyridine (5 mg, 0.04 mmol) and N,Nvdiisopropylethylamine (0.18 1111, 1.01 mmol) were added. The reaction mixture was stirred ght at room temperature. Additional 4—dimethy1aminopyridine (5 mg, 0.04 11111101) was added and the mixture was stirred at room temperature for 5 days. Additional N,N—diisopropylethylaniine (0.18 1111, 1.01 mmol) and 2—(1H—benzotriazoley1)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU) (77 mg, 0.20 lnmol) Were added and the mixture was d at room temperature for 18 h. The mixture was d with EtOAc and the biphasie mixture was separated. The organic layer was washed three times with an aqueous 5% NaHC03 solution. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (PLC silica gel 60 F254, 2 mm, eluent: DCMzMeOI-I 95:5). The product was ed as a white solid (1 mg, 0.003 11111101, 1 % yield). iH NMR (400 MHz, DMsouds) 8 ppm 3.25—3.34 (111, 2 H), 4.64 (t, Jm8.78 Hz, 2 H), 6.91 (d, J=8.28 Hz, 1 H), 7.66 (dd, $15.04 Hz, J=1.41 Hz, 1 H), 7.87 (dd, #834 Hz, #201 Hz, 1 H), 8.04 .53 Hz, 1 H), 8.51 (dd, J=1,35 Hz, J:0.93 Hz, 1 H), 8.53 (s, 1 H), 8.67 (dd, 4125.06 Hz, J=0.90 Hz, 1 H), 10.49 (bs, 1 H). LC/MS [NIH-11+: 349.0 2—(2,3-Dihydrobenzofuran—5~yl)-N-(3-(methylcarhamoyl)-1H—1,2,4-triazol—S—yl)thiazole— 4-carboxamide (19) ~80- Na)“ Her—(Ll H <0)?kaS\ N, To a solution of 2—(2,3-dihydro~l—benzofuran—5—y1)—1,3-thiazole-4—carboxylic acid (100 mg, 0.40 mmol) in 5 ml NN—dimethyiformamide was added 3,5~diamino—1,2,4~triazole (40 mg, 0.40 mmol). Then 2—(lH-benzotriazole—l—yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (153 mg, 0.40 mmol), 4-dimethylarninopyaidine (5 mg, 0.04 mmol) and NN—diisopropylethylamine (0.18 ml, 1.01 ininol) were added. The reaction e was stirred at 65 °C for 6 h. The mixture was poured into ice water, no precipitate was obtained. The mixture was diluted with EtOAc and the organic layer was washed three times with an aqueous 5% NaHCO3 solution, an s 5% citric acid solution and water.
The c layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (PLC silica gel 60 F254, 1 min, DCMzMeOH 9:1). The product was obtained as a light yellow solid (4 mg, 0.01 mmol, 3 % yield). 3H NMR (400 MHZ, DMSO—dé) 8 ppm 2.78 (d, J=4.74 Hz, 3 H), 3.09—3.45 (m, 2 H), 4.64 (t, J=8.76 Hz, 2 H), 6.90 (d, J=8.34 Hz, 1 H), 7.90 (dd, J=8.34 Hz, J21.83 Hz, 1 H), 8.07 (s, 1 H), 8.35 (bs, 1 H), 8.47 (s, 1 H). LC/MS [M+H]*: 371.1 Ethyl 5-(2—(2,3udi11ydrobenzofuran—S-yl)thiazole-4—carboxamido)-4H—1,2,4-triazoIe-3— carboxylate (20) /\(new WO f\N%NH \ 5 Method A. To a suspension of 2—(2,3—dihydro~1abenzofuran-S—ylyl,3-thiazole-4—carboxylic acid (381 mg, 1.54 mmol) and ethyl S—amino-l,2,4-triazole—3—carboxylate (219 mg, 1.54 mmol) in 5.4 ml dry pyridine at boiling 2-(1H—benzotriazoleu1—y1)-1,1,3,3—tetramethyluronium hexafluorophosphate (HBTU) (643 mg, 1.70 mmol) was added in portions while solid dissolves lly; clear solution forms 5 minutes after all 2—(1H—benzotriazole—l~yl)—1,1,3,3- tetramethyluroniuin orophosphate (HBTU) was added. The solution war kept at stirring at 80 ‘1C during 15 h. Pyridine was evaporated to dryness, residue was washed with water, an aqueous NaHC03 solution, water, diluted aqueous AcOi-I and again water. The residue was dissolved in hot thylfonnainide, filtered, filtrate was evaporated to dryness, the residue was treated with boiling ethanol, cooled and filtered off. The procedure was repeated twice afier which the residue was washed with ether and dried to give (339 mg, 0.88 mmol, 57 0A.) pure product. EH NMR (400 MHZ, fi) 5 ppm 14.16 (s, 1H, NH), 11.95 (s, 1H, NH), 8.46 (s, 1H, CH—thiazole), 8.08 (s, 1H, , 7.88 (d, J: 8.2 Hz, 1H, CH—Ar), 6.84 (d, J: 8.3 Hz, 1H, (EH-Ar), 4.65 (t, J: 8.7 Hz, 21-1, OCH2CH2), 4.34 (q, J: 7.0 Hz, 2H, OCHgCHg), 3.30 (t, J= 8.7 Hz, 1H, 2), 1.37 (t, J: 7.1 Hz, 3H, OCHQCHg).
LC/MS [Mid—11+: 386.0 Method B. Solution of2—(2,3-dihydro—1~benzofi1ran—5-yl)4,3—thiazole—4—carboxylic acid (174 mg, 0.70 tunnel) in 10 ml SOCl2 was refluxed for 2 h and evaporated to dryness. To the residue (yellow powder), ethyl 5-amino—4H—1,2,4~triazole—3-carboxylate was added (100 0.64 mmol). To a mixture, 4 ml pyridine was added at cooling with ice water bath. New precipitate formed gradually. The suspension was refluxed for 10 min while precipitate dissolved completely. The solution was refluxed for further 1 h. The reaction mixture was evaporated to dryness, the residue was washed with water, an aqueous NaHC03 solution, water, diluted aqueous AcOH and again water. The residue was dissolved in hot MN— dimethylformamide, filtered, the filtrate was evaporated to dryness, the residue was treated with boiling l, cooled, filtered off, washed with some ether and dried to give (168 0.44 mmol, 68 % yield) as a grey powder. 1H NMR (400 MHZ, DMSO—dé) 5 ppm 14.16 (s, 1H, NH), 11.95 (s, 1H, NH), 8.46 (s, 1H, azole), 8.08 (s, 1H, (EH—Ar), 7.88 (d, J= 8.2 Hz, 1H, CH—Ar), 6.84 (d, J= 8.3 Hz, 1H, CH—Ar), 4.65 (t, J: 8.7 Hz, 2H, OCHQCHQ), 4.34 (q, J= 7.0 Hz, 2H, OCHgCllg), 3.30 (t, J: 8.7 Hz, 1H, OCHzCHZ), 1.37 (t, J: 7.1 Hz, 3H, OCH2CH3). LC/MS [M+H]+: 386.0 2-(2,3-Dihydrobenzofuran—S—yl)—N-(S-(methylthio)-4H—1,2,4-triazoI—3—yl)thiazole carboxamide (21) whrrx8\ HRN S Suspension of 2-(2,3—dihydr0~l—henzofuran—5-yl)-l,3—thiazole—4—carboxy1ic acid (247 mg, 1.00 mmol) in 10 ml thionyl chloride was refluxed 1 h during which the acid dissolved lly followed by formation of new precipitate. Excess thionyi chloride was evaporated to s, to a residue 3—(n1ethylthio)—1,2,4—triazol-5—amine (130 mg, 1.00 mmol) was added.
To a mixture, 4 ml dry ne was added. The reaction e was refluxed for 1 h. The reaction mixture was evaporated to s, the residue was washed with water, an aqueous NaHCO3 on, water, diluted s AcOH and again water. The residue was dissolved in hot MN-dirnethylformamide, filtered, the filtrate was evaporated to dryness, the residue was treated with boiling ethanol, cooled and filtered off, washed with ether and dried to give (131 mg, 0.36 mmol, 36 % yield) pure product. 111 NMR (400 MHz, p) 5 ppm 13.34 (s, 1H, NH), 11.33 (s, 1H, NH), 8.38 (s, 1H, CH—arom), 8.04 (s, 1H, CH-arom), 7.85 (d, J: 8.2 Hz, 1H, CH-arorn), 6.81 (d, J: 8.3 Hz, 1H, CH-arom), 4.65 (t, J: 8.7 Hz, 2H, CH2CH2), 3.31 (t, J: 8.7 Hz, 2H, CHgCHg), 2.55 (s, 3H, SMe). LC/MS [M+H]+: 360.0 2—(2,3—Dihydr0benzofuranyl)—N—(5—(pyrrolidine—l—carbonyl)—1H—be11zo[djimidazol-Z- y1)thiazoleearboxamide (22) SM“ dbIZ/LZ gm .
A e of (3,4-dinitr0pheny1)(pyrrolidin—1-y1)rnetha110ne (120 mg, 0.45 11111101), 10 ml ethanol and Pd/C catalyst (0.05 g, 10% Pd) was stirred in an autoclave under hydrogen pressure 10 l<rglem2 and room temperature for 3 11. The catalyst was filtered off and cyanogen bromide (80 mg, 0.75 11111101) was added to the e. After stirring at room temperatrne for 1 day the solvent was ated in vacuo and t0 the residue were added 10 1111 diehlorornetliane and 2—(2,3—dihydro—1~benzofi1ran-S—y1)~1,3-thiazole—4~carbox_ylic acid (106 mg, 0.4 11111101), 2—(1H-benzotriazole-1—y1)-1,1,3,3—tetramethyluronium hexafluorophosrihate (HBTU) (208 mg, 0.55 mmol) and ropylether (0.2 1111, 1.15 nunol). The mixture was stirred at room temperature for 1 day, the solvent was evaporated to dryness in vacuo and an aqueous 5% Na2C03 solution (10 ml) was added to the residue. 111 1 h the residue solidified, the precipitate was filtered off and crystallized from ethanol to give the product as white crystals (65 mg, 0.14 11111101, 35 “/0 yield). Mp. : 245—250 0C. 1H NMR (400 MHZ, DMSO—d6) 8 ppm 1.85 (d, J=19.56 Hz, 4 H) 3.18 m 3.32 (111,3 H) 3.40 — 3.60 (m, 5 11) 4.64 (t, .12851 Hz, 2 H) 6.90 (d, #841 Hz, 1 H) 7.33 (d, J:8.22 Hz, 1 H) 7.51 (d, J=7.83 Hz, 1 H) 7.67 (115, 1 H) 7.91 (d, J28.22 Hz, 1 H) 8.10 (bs, 1 H) 8.55 (s, 1 H) 12.36 (bs, 1 H). LC/MS (M+H]+: 460.0 2—(2,3—1)ihydrebenzofuran-S-yl)—N—(5-((2-meth0xyethy£)carbamoyl)—lH—benzo[d] imidazoI-Z-yl)thiazole—4—carboxamide (23) _33- WO 02638 A mixture of N—(2-methoxyethyl)-3,4—dinitrobenzamide (I-52) (121 mg, 0.45 mmol), 10 ml ethanol and Pd/C catalyst (0.05 g, 10% Pd) was stirred in an ave under hydrogen pressure 10 leg/cm2 and room temperature for 3 h. The catalyst was filtered off and cyanogen bromide (80 mg, 0.75 mmol) was added to the e. After stirring at room temperature for 1 day the solvent was ated in vacuum and to the residue were added 10 ml dichloromethane and 2—(2,3—dihydro—1—benzofuran-5~yl)—l,3-thiazolecarboxylic acid (106 mg, 0.4 mmol), 2-(1Hmbenzotiiazole-l-yl)-1,l,3,3—tetramethyluronium hexafluorophosphate (HBTU) (208 mg, 0.55 mmol) and diisopropylether (0.2 ml, 1.15 mmol). The mixture was stirred for 1 day at room temperature, the solvent was evaporated to dryness in vacuum and an aqueous 5% Na2C03 solution (10 ml) was added to the residue. In 1 h the residue solidified, the itate was d off and llized from ethanol to give the product as White crystals (75 mg, 0.16 mmol, 40 % yield). Mp. 2 185-190 0C. 1H NMR (400 MHz, DMSO"d6) 8 ppm 3.13 (bs, 4 H) 3.32 (hs, 4 H) 3.48 (bs, 4 H) 4.64 (t, £7.40 Hz, 2 H) 6.82 (d, J=7.53 Hz, 1 H) 7.49 (ha, 1 H) 7.65 (d, J=753 Hz, 1 H) 7.76 - 7.93 (m, 1 H) 7.93 - 8.14 (m, 2 H) 8.25 Cos, l H) 8.42 (bs, l H) 11.40 (bs, 1 H) 12.38 (be, 1 H). LC/MS [M+H]+: 463.9 2-(2,3-Dihydrobenzofuran-S—yi)—N-(3—(isopropylthio)—lH—1,2,4—triazolns-yl)thiazole carboxamide (24) To a mixture of 2—(2,3—dihydro-l-benzofuran-5~yl)—l,3-thiazole—4—carbonyl chloride (202 mg, 0.76 mmol) and 3—(isopropylthio)-lH—l,2,4—triazol—5~amine (120 mg, 0.76 mol) 3 m1 of dry hot pyridine was added. The solution was heated at reflux for 3 h, pyridine was evaporated and the residue was diluted with an aqueous Na2C03 solution. The resulting precipitate was filtered off and purified by flash chromatography (EtOAc) to give the product as a light yellow solid (80 mg, 0.21 mmol, 27 % yield). 1H NMR (400 MHZ, Dix/18046) 5 ppm 1.35 (6H, d, 2CH3), 3.29 (2H, t, $201120), 3.69 (1H, m, SCH), 4.64 (2H, t, OCT-12), 6.90 (1H, d, —84— CH-arom.), 7.91 (1H, d, (EH—atom), 8.10 (1H, s, CH—arom.), 8.49 (1H, s, CH-thiazol), 11.70 (1H, 193, NH), 13.70 (1H, bs, NH). LC/MS [M+H]+: 388.0 N-(3—(Cyclopr0pylcarbamoyl)—1H-l,2,4-triazol—5—yl)-2n(2,3-dihydr0benzofuran-5— yl)thiazole—4~carboxamide (25) s aN—Q’INNjLNAH To a mixture of 2~(2,3~dihydro-l-benzofuran-5—yl)—1,3-thiazole—4-carboxylic acid (74 mg, 0.30 mmol), lH—l,2,4—triazol«5—amine (50 mg, 0.30 mmol) and 2—(1H—benzotriazole-1—y1)~ 1,1 ,3,3—tetramethyluronium hexafluorophosphate (HBTU) (120 mg, 0.32 mmol) under stirring and heating at 110 °C 2 ml of dry pyridine were added. The mixture was heated at 110 CC for h, pyridine was evaporated, and the residue was diluted with an aqueous N32CO3 solution.
The ing precipitate was filtered off, dried and washed with EtOAc and hexane. The product was obtained as a light yellow solid (80 mg, 0.20 mmol, 67 % . [H NMR (400 MHZ, DMSO—dfi) 6 ppm 0.64—0.69 (4H, m, ZCHg), 2.85 (1H, m, CH), 3.28 (2H, t, @CHgO), 4.64 (2H, t, OCHz), 6.90 (1H, d, (EH—mom), 7.90 (1H, d, CH~arom.), 8.08 (1H, s, CH-arom.), 8.46 (1H, 5, NH), 8.48 (11-1, 5, CH—thiazol), 11.70 (1H, 3, NH), 13.70 (1H, s, NH). LC/MS [M+H]*: 397.0 2-(2,3-Bihydrobenzofuran—S-yD-N—(S—(morpholine—4-carbonyl}-4H-1,2,4~triazol~3m yl)thiazole-4—carboxamide (26) VOO H A solution of ethyl —(2,3—dihydro-l“benzofuran—S—ylyl,3—thiazol—4—yl]carbonyl}amino)- 1,2,4-triazoleearboxylate (35 mg, 0.10 mmol) in 2 ml morpholine was refluxed for l h.
Excess morpholine was evaporated, the residue was llized from l to give pure product as a light yellow powder (23 mg, 0.05 mmol, 54 % yield). IH NMR (400 MHz, DMSO+D3CC(WO)OD) 8 ppm 8.52 (s, 1H, CH-arom.), 8.10 (s, 1H, CI-I—arom.), 7.92 (d, J= 7.8 Hz, 1H, Cid—atom), 6.90 (d, J= 8.3 Hz, 1H, CH-het.), 4.64 (t, J= 8.6 Hz, 1H, CH2CH2), 3.87 (s, 2H, CHZ—morph.), 3.65 (m, 6H, GHQ—morph), 3.28 (t, J = 8.6 Hz, 1H, CHgCl-Ig).
LC/MS [Mt-HT: 427.0 2—(2,3—Dihydrobenzofuran-S-yI)—N-(5-(4wmethylpiperazine—l-carbonyl)—4H-1,2,4~triazol— 3-y1)thiazole—4~carboxamide (27) S \ HN\_<\ TI/lLN/fi Method A. A solution of ethyl 5-({[2—(2,3—dihydro-l—benzofiiranyl)ml,3-thiazol-4— yl]carhonyl}amino)~l,2,4—triazole—3~carboxylate (56 mg, 0.l6 mmol) in 3.4 ml l~ methylpiperazine was refluxed for 85 min. Solution attained reddish color. All volatiles were evaporated, the e was treated subsequently with boiling hexane and water. The e was collected with ethanol, solvent was ated, the residue was crystallized from EtOAc A hexane to give the product as light yellow needles (17 mg, 0.04 mmol, 24 “/0 yield). 1H NMR (400 MHz, DMSO—db) 5 ppm 8.50 (s, 1H, CPI-atom), 8.10 (s, 1H, CH-arom.), 7.95 — 7.87 (m, 1H, CH—arom.), 6.90 (d, J = 8.4 Hz, 1H, CH—het.), 4.64 (t, J ..—. 8.7 Hz, 2H, CHZCHz), 3.79 (s, 2H, CHZ-piperaz.), 3.65 (s, 2H, peraZJ, 3.28 (t, J m 8.8 Hz, 2H, CH2CH2), 2.35 (d, J r 13.7 Hz, 4H, CH2~piperaz.), 2.21 (s, 3H, CH3). LC/MS [M+H]+: 440.0 Method B. To a suspension of -(2,3-dihydro—1-benzofi1ran—5~yl)-1,3-thiazol—4- yl]carbonyl}amino)—l,2,4-triazole-3—carboxylic acid (51 mg, 0.14 mmol) in 2.7 ml absolute dioxane 2—(lH—benzotriazole—1—yl)—1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (126 mg, 0,33 mmol) was added. After that N—methylpiperazine (182 mg, 1.82 mmol) were added. The precipitate dissolved partially at warming and stirring. The reaction e was warmed to boiling until the precipitate dissolved completely. After that the solution was left stirring at room temperature for 2 days. Dioxane was evaporated, the residue was dissolved in water and filtered off. The filtrate was neutralized with AcOH which lead to a precipitate formation. The precipitate was filtered off and dried. The precipitate was then collected with hot MN—dimethylformamide, MN—dimethylformamide was evaporated to s, the residue was crystallized from EtOI—I to give the product as a light brown powder (37 mg, 0.08 mmol, 60 % . IH NMR. (400 MHZ, DMSO'dfi) 5 ppm 8.50 (s, 1H, (EH-atom), 8.10 (s, 1H, CH— arom.), 7.95 — 7.87 (m, 1H, m.), 6.90 (d, J: 8.4 Hz, 1H, CPI-hot), 4.64 (t, J: 8.7 Hz, 2H, CHZCHZ), 3.79 (s, 2H, CHz—piperaz.), 3.65 (s, 2H, CHg—piperaz-), 3.28 (t, J= 8.8 Hz, 2H, CH2CH2), 2.35 (d, J: 13.7 Hz, 4H, CHg—piperaz.), 2.21 (s, 3H, CH3). LC/MS [ix/Imp: 440.0 2-(2,3—Dihydrobenzofuran—S—yl)~N—(5-(pyrroiidine—l~carbony1)—4H—1,2,4-triazol—3— yl)thiazole—4~carboxamide (28) commWAD solution of ethyl ethyl 5-({[2—(2,3—dihydro—1—benzofiiran«5—yl)~1,3—thiazol~4-— y1]carbonyl}amino)—1,2,4-triazole—3 ~0arboxy1ate (22 mg, 0.06 mmol) in 2.3 ml piperidine was refluxed for 70 min. All volatiles were evaporated in vacate, the residue was treated subsequently with boiling hexane and water. The residue was llized from EtOH to give of pure product as light yellow powder (10 mg, 0.02 mmol, 41 0/0 . 1H NMR (400 MHZ, DMSO'dfi) 8 ppm 12.28 (bs, 1H, NH), 1039 (bs, 1H, NH), 8.23 (s, 1H, m.), 7.86 (s, 1H, CIT—morn), 7.71 (d, Jz 7.9 Hz, 1H, CH-arom.), 6.86 (d, J: 8.2 Hz, 1H, CH—het.), 4.68 (t, J = 8.6 Hz, 1H, CHZCHZ), 3.72 (t, J 2 6.6 Hz, 1H, CHZCHZ), 3.97 (bs, 2H, CH2-piperid.), 3.32 (t, J x 8.6 Hz, 2H, CHypiperid.), 2.05 — 1.87 (m, 4H, CH2~piperid.). LC/MS [Marl-IT: 411.0 2-(2,3—Dihydr0benzofuran~5—y1)—N-(S—(dimethylcarbamoyl)-4H-1,2,4-triazol yl)thiazole—4-carboxamide (29) HN_</NTHKN/l S \ N’N To a suspension of S—amino—MN—dimethyl-l,2,4~triazoleearboxamide hydrochloride (77 mg, 0.40 mmol) and 2—(2,3—dihydro—1~benzofurana5—yl)—1,3nthiazole—4—carboxylic acid (99 mg, 0.40 mmol) in 2.6 ml dry pyridine (166 mg, 0.44 mmol) 2—(1H—benzotriazole-1—y1)— 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) was added. The suspension was refluxed for 5 h. Pyridine was evaporated and the residue was treated subsequently with water, a saturated aqueous NaHC03 solution, water, aqueous AcOH and water again. The e was dissolved in hot MN-dimethylformamide and d. The filtrate was trated under reduced pressure. The residue was llized from ethanol to give the product as grayish powder (52 mg, 0.14 mmoi, 34 % yield). E11 NMR (400 MHz, DMSO~d5) 8 ppm 13.99 (s, 1H, NH), 11.89 (s, 1H, NH), 8.50 (s, 1H), 8.10 (s, 1H, CH-arom.), 7.91 (d, J = 8.3 Hz, 1H, CH-arom.), 6.90 (d, J = 8.3 Hz, 1H, CH—arom.), 4.64 (t, J = 8.7 Hz, 2H, CHZCHZ), 3.34 (s, 3H, NCH}), 3.28 (t, J = 8.7 Hz, 2H, ), 3.02 (s, 3H, NCH3). LC/MS [Mi-Hr: 385.0 2-(2,3nDihydrobenzofuran-S—yl)»N-(3-(propylthio)-1H-1,2,4~triazol~5—yl)thiazoIe—4- amide (30) C©0SHNfi 0 S” To a mixture ,3—dihydro—1-benzofuran—5—y1)—l,3—thiazole—4—carbony1 chloride (125 mg, 0.47 mmol) and 3-(propylthio)—1H~1,2,4—t1iazol—5—amine (70 mg, 0.44 mmol) 3 1111 of dry pyridine was added. The solution was heated at reflux for 2 h, pyridine was evaporated and the residue was diluted with aqueous . The resulting precipitate was filtered off and washed with ethanol to give the product as a light yellow solid (35 mg, 0.09 mmol, 21 % yield). I1-1 NMR (400 MHZ, DMSO-dfi) 8 ppm 0.98 (3H, t, C113), 1.69 (2H, m, CH2), 3.06 (2H, m, SCHQ), 3.29 (2H, t, @CHQO), 4.64 (2H, t, OCHz), 6.90 (1H, d, Cit-mom), 7.90 (1H, d, (DH-atom), 8.10 (1H, s, CH—arom.), 8.49 (111, S, CH—thiazol), 11.70 (1H, 135, NH), 13.60 (1H, bs, NH). LC/MS [Mad-1r: 388.0 5-(2-(2,B-Dihydrobenzofuranyl)thiazole—4-carboxamido)-4H-1,2,4-triazole-3u carboxylie acid (31) To suspension of ethyl 5 -({[2—(2,3—dihydro—1—benzofiira11— 5 -yl)n1,3—thiazol yl]earbonyl}amino)-1,2,4—triazole-3—earboxylate (20) (99 mg, 0.26 mmol) in 3.48 ml water NaOH was added (53 mg, 1.33 mmol). The reaction mixture was stirred at room temperature while the solid dissolved almost immediately. After several minutes, new white amorphous precipitate formed. The suspension was stirred at room temperature for 1 day after which 6 drops cone. HCl were added, to give pH~2. Bulky white precipitate . The precipitate was centrifuged with water twice, than with ethanol and ether to give the product as white powder. (76 mg, 0.21 mmol, 82 % yield). 1H NMR (400 MHZ, DMSO'dfi) 6 ppm 14.17 003, _ 88 _ 1H), 13.22 (65, 1H, OH), 11.99 (ha, 111, NH).8.52 (s, 111, 011—611—6111.), 8.12 (s, 1H, cumin), 7.92 (d, J m 8.3 Hz, 1H, CPI—2110111.), 6.90 (d, J: 8.3 Hz, 1H, err—616111.), 4.64 (t, J: 8.7 Hz, 2H, CHZCHZ), 3.28 (1,61: 8.7 Hz, 2H, (31120112). LC/MS [11/114110 358.0 N—(3-(Benzylthi0)-1H-1,2,4—triazol-S-yl)—2-(2,3-dihyd10benzofuran-S-yl)thiazole~4- carboxamide (32) To a mixture of 2—(2,3—dihydro—1rbenzofilran-S-yl)—l,3—thiazole—4—carboxy1ic acid (60 mg, 0.24 11111101), 3~(benzylthio)—1H—l,2,4-triazol—5—a111ine (50 mg, 0.24 11111101) and 2~(1H~ benzotriazole—l~yl)-1,l,3,3—tetra111ethyluronium orophosphate (HBTU) (120 mg, 0.32 11111101) under stirring and heating at 110 °C 2 ml of dry pyridine were added. The mixture was heated at 110 0C for 5 11, pyridine was ated, and the residue was diluted with a saturated s Na2C03 solution. The ing precipitate was filtered off, dried and washed with EtOAc and hexane. The product was obtained as a light yellow solid (72 mg, 0.17 11111101, 69 % yield). 1H NMR (400 MHz, DMSO—dfi) 0 ppm 3.28 (2H, t, O), 4.36 (2H, s, CH2), 4.64 (2H, t, OCHZ), 6.90 (1H, d, CPI-310111.), 7.23—7.42 (5H, m, CH—arom.), 7.91 (1H, d, (EH—810111.), 8.11 (1H, s, CH—arom.), 8.50 (1H, s, CH~thiazol), 11.70 (111, 135, NH), 13.70 (1H, bs, NH). LC/MS [M+H]+: 436.0 N-(S-((4—Ch10robenzy1)thio)—1H—1,2,4-triazolyl)(2,3~dihydrobenzofuran-5— y1)thiazole—4—carboxamide (33) SM“45")?I2 To a mixture of 2—(2,3—dihydro-1—benzofilran—5—yl)—1,3—thiazole—4—carboxylic acid (51 mg, 0.21 11111101), 3w((4—chlorobenzyl)thio)~1H~l,2,4—triazol-5—amine (50 mg, 0.21 11111101) and 2- (EH-benzotriazole—l—y1)—1,1,3,3—tetra1nethyluroniurn hexafluorophosphate (HBTU) (120 mg, 0.32 11111101) under stirring and g at 110 °C 2 1111 of dry pyxidine were added. The 139- mixture was heated at 110 °C for 5 h, pyridine was evaporated, and the e was diluted with a saturated s N32C03 solution. The resulting precipitate was filtered off, dried and washed with EtOAc and hexane. The product was obtained as a light yellow solid (62 mg, 0.13 mmol, 63 % yield). 1H NMR (400 MHZ, DMSO‘dfi) 5 ppm 3.28 (2H, t, ), 3.35 (2H, s, CH2), 4.64 (2H, t, OCHZ), 6.90 (1H, d, CH-arom.), 7.37+7.43 (4H, AB—Syst,, CH- arom.), 7.91 (1H, d, m.), 8.11 (1H, s, CPI-atom), 8.49 (1H, s, CH—thiazol), 11.70 (1H, 133, NH), 13.70 (1H, bs, NH). LC/MS [M+H]+: 469.9 2-(2,3-Dihydrobenzofuran-S-yl)—N—(3-(isobutylthio)—III—1,2,4-triazol—S-y1)thiazole-4~ carboxamide (34) N ax MW/1 To a mixture of 2-(2,3-dihydro—1—benzofuran—5-yl)—1,3—thiazolecarboxylic acid (72 mg, 0.29 mmol), 3~(isohuty1thio)—1H—l,2,4~triazola1nine (50 mg, 0.29 mmol) and 2—(1H— benzotriazole—l—yl)—l,1,3,3—tetramethyluronium hexafluorophosiihate (HBTU) (120 mg, 0.32 mmol) under stirring and heating at 1 10 EC 2 ml of dry pyridine were added. The mixture was heated at 110 °C for 5 h, pyridine was evaporated, and the residue was diluted with a saturated s N32C03 solution. The resulting precipitate was filtered off, dried and crystallized from BtOAo : hexane. The product was obtained as a light yellow solid (65 mg, 0.16 mmol, 56 % yield). ;H NMR (400 MHZ, DMSO-dé) 5 ppm 0.99 (6 H, d, 2CH3), 1.91 (l H, m, CH), 2.99 (2 H, (1, CH2), 3.28 (2 H, t, QfigCHZO), 4.64 (2 H, t, OCHg), 6.90 (1 H, d, (SH—arena), 7.91 (1 H, d, CH—arom.), 8.10 (1 H, s, CH—arom.), 8.48 (1 H, s, CH-thiazol), 11.70 (1 H, be, NH), 13.70 (1 H, bs, NH). LC/MS [M+H]+: 402.0 2-(2,3—Dihydrobenzofuran—S-y1)-N-(5—(((tetrahydrofuramz—y1)methyl)carbamoy1}—IH~ benzo[dlimidazol—Z-yl)thiazole—4-carboxamide (35) HNsMUi’UH S \ A mixture of 3,4-dinitro—N—((tetrahydrofiiran—Z-yl)methyl)benzamide (1-51) (132 mg, 0.45 mmol), 10 ml ethanol and Pd/C catalyst (0.05 g, 10% It’d) was stirred in an ave under en pressure 10 kg/crn2 and room temperature for 3 h. The catalyst was filtered off and cyanogen bromide (80 mg, 0.75 mmol) was added to the filtrate. After stirring at room temperature for 1 day the solvent was evaporated in vacuo and to the residue were added 10 ml dichloromethane and 2—(2,3—dihydro-1~benzofuran—5—yl)—1,3—thiazolecarboxylic acid (1 06 mg, 0.43 mmol), 2—(1H—benzotriazole—1 ~yl)-1 1 ,3,3 ~tetramethyluronium hexafluorophosphate HBTU (208 mg, 0.55 mmol) and diis0propylether (0.2 ml, 1.15 mmol).
The on mixture was stirred for 1 day at room temperature, the t was evaporated in vacuo and and 10 ml of an aqueous 5% Na2C03 on were added to the residue. In 1 h the residue solidified, the precipitate was filtered off and crystallized from ethanol to give the product as white ls (88 mg, 0.18 mmol, 45 0/0 yield). Mp. = 185-190 0C. 1H NMR (400 MHz, DMSO-dfi) 8 ppm 1.57 — 1.74 (m, l H) 1.75 — 2.05 (m, 3 H) 3.21 - 3.41 (m, 4 H) 3.66 (q, J=7.11 Hz, 1 H) 3.83 (q, J17.03 Hz, 1 H) 3.93 — 4.06 (m, I H) 4.64 (t, J=8.66 Hz, 2 H) 6.82 (d, #828 Hz, 1 H) 7.48 (d, J27.53 Hz, 1 H) 7.57 — 7.72 (m, 1 H) 7.84 ((1, 5127.78 Hz, 1 H) 8.01 (d, J:6.52 Hz, 2 H) 8.11 ~ 8.28 (m, 1 H) 8.42 (s, 1 H) 11.38 (133, 1 H) 12.35 (bs, 1 H).
LC/MS (ramp: 490.0 2-(2,3~Dihydrobenzofuran—S-yl)~N—(3~phenethyI-1H—1,2,4—triazol~5-yl)thiazole-4— carboxamide (36) To a mixture of 2—(2,3—dihydro—1—benzofi1ran—5—yl)—l,3-thiazole-4—carboxylic acid (66 mg, 0.26 , lH—l,2,4-triazol—5—amine (50 mg, 0.26 mmol) and benzotriazole—l-yl)— 1,1 ,3,3—tetra1nethy1uronium hexafluorophosphate (HBTU) (120 mg, 0.32 mmol) under stirring and heating at 110 °C 2 ml of dry pyridine were added. The mixture was heated at 110 °C for h, pyridine was evaporated, and the residue was diluted with a saturated aqueous NagCOg solution. The resulting precipitate was filtered off, dried and crystallized from EtOAc : hexane. The product was obtained as alight yellow solid (49 mg, 0.12 mmol, 44 “/0 yield). 11-1 NMR (400 MHZ, DMSO—dé, CC14) 5 ppm 2.92 (2 H, m, CH2), 3.03 (2 H, t, CH2), 3.30 (2 H, t, QIQCHZO), 4.64 (2 H, t, OCHz), 6.81 (1 H, d, CH—arom.), 7.14726 (5 H, m, CH~arom.), 7.83 (1 H, d, CI-I—arorn.), 8.02 (1 H, s, CH—arom.), 8.34 (1 H, s, CI-I—thiazol), 11.30 (1 H, bs, NH), 13.10 (1 H, bs, NH). LCMS [M+H]+: 418.0 2-(2,3-})ihydrobenzofuran—S-yl)—N—(3-(phenethylthio)—1H-1,2,4-triazol-S-yl)thiazole~4~ carboxamide (37) N 8 8 HM T VT) \ (N To a e of 2—(2,3~dihydro-l—benzofuran~5-yl)-1,3—thiazole—4-earbexylic acid (56 mg, 0.23 mmol), 3{phenethylthio}1H—1,2,4—triazol—5namine (50 mg, 0.23 rmnol) and 2—(1H— benzotriazole—l-yl)—1,1,3,3—tetramethyluronium hexafluorophosphate (HBTU) (120 mg, 0.32 rnrnol) under stirring and heating at 110 °C 2 ml of dry pyridine were added. The mixture was heated at 110 °C for 5 h, ne was evaporated, and the residue was diluted with a saturated aqueous N32C03 solution. The resulting precipitate was filtered off, dried and washed with EtOAe and hexane. The product was obtained as a light yellow solid (70 mg, 0.16 mmol, 69 % yield). EH NMR (400 MHZ, DMSO—ds) 5 ppm 2.99 (2 H, t, CH2), 3.28 (2 H, t, QHQMCHQO), 3.32 (2 H, ’5, CH2), 4.64 (2 H, t, OCHg), 6.90 (1 H, d, Gil—atom), 7.21...7.33 (S H, m, rn.), 7.91 (1 H, d, CH—arom.), 8.11 (1 H, s, CH—arom.), 8.51 (1 H, s, CH— thiazol), 11.74 (1 H, s, NH), 13.67 (1 H, s, NH). LC/MS [MM-1T: 449.9 N—(3—((Cyanomethyl)thio)—1H-1,2,4~tri.azol—S—yl)—2—(2,3-dihydr0henzofuran-S—yl)thiazole— 4-carboxamide (38) N 8/ HN~</ 8\ l To a mixture of 2‘(2,3-dihydrobenzofuran—5—yl)-1,3—thiazole—4—carboxylic acid (80 mg, 0.32 mmol), 1H-l,2,4vtriazol-S-amine (50 mg, 0.32 mmol) and 2-(1H—benzot1iazole—l—yl)- 3—tetramethyluronium hexafluorophosphate (HBTU) (120 mg, 0.32 mmol) under stirring and heating at 110 DC 2 ml of dry pyridine were added. The e was heated at 110 (3C for h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution.
The resulting precipitate was filtered off, dried and washed with EtOAe and hexane. The product was obtained as light yellow solid (42 mg, 0.11 mmol, 34 % yield). 1H NMR (400 MHz, DMSO'dé) 5 ppm 3.28 (2 H, t, QQCHQO), 4.23 (2 H, s, CH2), 4.64 (2 H, t, OCHz), 6.90 (1 H, d, CH—arom.), 7.91 (1 H, d, CH—arom.), 8.11 (1 H, s, CPI-310111.), 8.53 (1 H, s, CH- thiazol), 11.80 (I H, bs, NH), 13.90 (1 H, bs, NH). LC/MS [M+H]+: 384.9 N—(3-(Allylthio)—1H—1,2,4-triazol—5-yl)u2—(2,3-dihydrobenzofuran—Synthiazole—4— carboxamide (39) N S\/\\\ / \l/I To a mixture of 2—(2,3-dihyd1‘0—1—benz0furan—5—yl)—1,3-tl1iazolen4—carboxylic acid (80 mg, 0.32 11111101), 1H—1,2,4—triazolamine (50 mg, 0.32 11111101) and 2-(1H—benzotria201e-1—y1)~ 1,1,3,3 utetramethyluroniuln hexafluorophosphate (HBTU) (120 mg, 0.32 11111101) under stirring and heating at 110 0C 2 ml of dry pyridine were added. The mixture was heated at 110 0C for 11, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution.
The resulting precipitate was filtered off, dried and washed with EtOAc and hexane. The product was obtained as a light yellow solid (65 mg, 0.17 11111101, yield 53 % yield). 1H NMR (400 MHZ, DMSO'dfi) 5 ppm 3.28 (2 H, t, QflgCH20), 3.76 (2 H, d, CH2), 4.64 (2 H, t, OCHZ), 5.09 (1 H, d, CH), 5.26 (1 H, (:1, CH), 5.96 (1 H, 111, CH), 6.90 (1 H, d, CH—arom.), 7.91 (1 H, d, (EH—arena), 8.11 (1 H, s, CH—arom.), 8.49 (1 H, s, azol), 11.70 (1 H, bs, NH), 13.70 (1 H, bs, NH). LC/MS [M+H]+: 385.9 2-(2,3-Dihyd1‘obenzofu1°air-5~yl)—N-(6-(morpholinomethy1)benzo[d]thiazol-Z-yl)thiazole- 4—carb0xamide (40) 92221000N To a solution of —dihydro-l«benzofinan-S—yl)—1,3’~thiazole—4—carboxy1io acid (100 mg, 0.40 01) in 5 1111 ethylformamide, was added 6-(1norpholin0methy1) benzo[d]thiaz01—2—amine (101 mg, 0.40 11111101). Then benzotriazole—1—y1)—1,1,3,3~ tetramethyluronium hexafiuorophosphate (HBTU) (153 mg, 0.40 11111101), 4— dimethylaminopyridine (4.9 mg, 0.04 11111101) and NN-diisopropylethylamine (0.18 1111, 1.01 mmol) were added. The reaction e was stirred overnight at room temperature. The mixture was poured into ice water. The resulting precipitate was d off, dried and purified by preparative TLC (PLC silica gel 60 F254, 1 mm, PE:EtOAc:MeOH 426:1). The main spot was isolated, concentrated in vacuo and dried. The product was obtained as a baige solid (12 mg, 0.03 mmol, 6 % yield). 1H NMR (400 MHZ, DMSO~d6) 5 ppm 2.39 (bs, 4 H), 3.22-3.35 (m, 2 H), 3.59 (bs, 6 H), 4.65 (t, J=8.76 Hz, 2 H), 6.91 (d, J=8.34 Hz, 1 H), 7.43 (dd, J=8.28 Hz, J=1.47 Hz, 1 H), 7.75 (d, Jm8.28 Hz, 1 H), 7.90—7.99 (m, 2 H), 8.14 (bs, 1 H), 8.59 (s, 1 H), 12.48 (bs, 1 H). LC/MS [M+H]+: 479.0 -Dihydrobenzofuran-S-yl)—N~(6—(4—methylpiperazin—1—yl)benzo[d] thiazol—Z— yl)thiazole—4-carboxamide (41) SMN—QSDN’fiN fl” 0 W To a solution of 2—(2,3—dihydro—1-benzofuranm5—yl)—1,3—thiazole-4—carboxylic acid (100 mg, 0.40 mmol) in 5 ml MN—dimethylformamide, was added 6—(4—Methylmpiperazin—l—yl)— benzothiazol—2-y1a1nine (100 mg, 0.40 mmol). Then 2-(1H-benzot1iazole-lnyl)—1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU) (153 mg, 0.40 11111101), 4— dimethylaminopyridine (4.9 mg, 0.04 mmol) and N,N—diiSOproperthylamine (0.18 ml, 1.01 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was poured into ice water. The mixture was diluted with EtOAc and the biphasic mixture was ted. The organic layer was washed with an s 5% NaHC03 on, an aqueous 5% citric acid solution and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude yellow oil was purified by preparative TLC (PLC silica gel 60 F254, 2 mm, eiuent: DCM:MeOH 9:1). The crude yellow solid was d again by preparative TLC (PLC silica gel 60 F254, 1 mm, DCM:MeOH 9:1). The product was obtained as a yellow soiid (14 mg, 0.03 mmol, 7 % yield). gH NMR (400 MHZ, g) 5 ppm 2.24 (s, 3 H), 2.43—2.55 (m, 4 H), 3.08—3.23 (m, 4 H), 3.23—3.45 (m, 2 H), 4.65 (t, J=8.76 Hz, 2 H), 6.90 (d, J=8.34 Hz, 1 H), 7.15 (dd, J=8.98 Hz, J=2.44 Hz, 1 H), 7.51 (d, Jt2.37 Hz, 1 H), 7.63 ((1,.12891 Hz, 1 H), 7.92 (dd, J=8.34 Hz, J=1.95 Hz, 1 H), 8.12 (be, 1 H), 8.55 (s, l H), 12.26 (‘08, 1 H). LC/MS [M+H]*: 477.9 2—(2,3-Dihydrobenzofuran—S-yl)—N—(3—(pyridinyl)—1H—1,2,4-triazoly1)thiazole carboxamide (42) _94_ To a mixture of 2—(2,3-dihydro—1—benzofurann5—yl}1,3-thiazole—4—carboxylie acid (77 mg, 0.31 mmol), 1H—1,2,4—triazol—5~amine (50 mg, 0.31 mmol) and 2»(lH—benzohiazole-1—yl)— 1,1,3,3-tetra1nethy1uroniu1n hexafluorophosphate (HBTU) (120 mg, 0.32 11111101) under stirring and heating at 110 °C 2 m1 of dry pyridine were added. The mixture was heated at 110 DC for h, pyridine was evaporated, and the residue was diluted with an aqueous N32C03 solution.
The resulting precipitate was filtered off, ved in hot MN—dimethylformarnide, settled by addition of EtOAe and hexane, filtered off and dried. The product was obtained as a light yellow solid (75 mg, 0.19 11111101, 62 % yield). 1H NMR (400 MHZ, DMSOndg, CCl4) 8 ppm 3.31 (2 H, t, figCHgO), 4.65 (2 H, t, OCHZ), 6.83 (l H, d, ms), 7.87 (l H, (1, CH— arom.), 7.90 (2 H, m, CH—pyr.), 8.07 (l H, s, CH—arom.), 8.44 (1 H, s, CH-thiazol), 8.62 (2 H, m, CH—pyr.), 11.68 (1 H, bs, NH), 13.87 (1 H, bs, NH). LC/MS [Ma—HT: 391.0 -Dihydrobenzofuran—S-yl)—N-(3—(methylsulfonyl)-1H—1,2,4-triazol~5—yl)thiazoIe amide (43) \ ,o HN—<“z1 \o s\ ,N To a mixture of 2-(2,3~dihydro-1—beuzofuran—5—yl)—1,3—thiazole-4—earboxylic acid (76 mg, 0.31 1nn101), 1H—l,2,4—triazol—5~a1nine (50 mg, 0.31 11111101) and 2~(1H—benzotriazole—l'yl)— 1,1,3,3—tetra1nethyluronium hexafluorophosphate (HBTU) (120 mg, 0.32 mmol) under stirring and heating at l 10 ”C 2 m1 of dry pyridine were added. The mixture was heated at 110 0C for h, pyridine was evaporated, and the e was diluted with an aqueous Na2C03 solution.
The resulting itate was filtered off, ved in hot NN—dirnethylformamide, settled by addition of EtOAc and hexane, filtered off and dried. The product was obtained as a light yellow solid (60 mg, 0.15 11111101, 49 % yield). 1H NMR (400 MHZ, DMSO'dfi, CC14) 5 ppm 3.28 (3 H, s, CH3), 3.30 (2 H, t, figCHgO), 4.64 (2 H, t, OCHg), 6.82 (1 H, d, CH—arom.), 7.87 (1 H, d, CH—arom.), 8.07 (1 H, s, m.), 8.44 (1 H, bs, CH—thiazol), 12.03 (1 H, bs, NH), 14.45 (1 H, bs, NH). LC/MS [M‘i‘Hrl 391.9 2-(2,3-Dihydrobenzofuran-S-yl)—N—(3-methyl-1H-1,2,4-triazol-S—yl)thiazole—4- carboxamide (44) S HN—</ \ N’N To a mixture of 2-(2,3-dihydro~1—benzofuran~5—yl)—1,3-thiazole~4«carboxy1ic acid (126 mg, 0.51 1n1nol), 1H—1,2,4-triazol-5—amine (50 mg, 0.5] mmol) and 2—(1H—benzotriazole-1—yl} 1,1 ,3,3—tetramethyluronium hexafluorophosphate (HBTU) (120 mg, 0.32 inmol) under ng and heating at 110 °C 2 1111 of dry pyridine were added. The e was heated at 110 DC for h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 on.
The ing precipitate was filtered off, dissolved in hot NN-diinethylformainide, settled by addition of EtOAc and hexane, filtered off and dried. The product was obtained as a light yellow solid (82 mg, 0.25 01, 49 % yield). 1H NMR (400 MHZ, DMSO-dfi, CC14) 8 ppm 2.29 (3 H, 135, CH3), 3.30 (2 H, t, QflCHZO), 4.64 (2 H, t, OCHg), 6.80 (1 H, d, CH—arom.), 7.82 (l H, d, CH~arom.), 8.00 (1 H, s, CH—arom.), 8.31 (1 H, be, CH—thiazol), 11.20 (1 H, bs, NH), 12.95 (i H, bs, NH). LC/MS {M+H]+: 328.0 2-(2,3—Dihydrobenzofuran-S-yl)~N—(3-(pyridin—3~yl)—1H~1,2,4-triazol—S—yl)thiazole carboxamide (45) 2O To a mixture of 2~(2,3—dihydro-1~benzofi11an~5~yl)—l,3-thiazole—4—earboxylic acid (77 mg, 0.31 11111101), 1H—l,2,4-triazo1—5—ainine (50 mg, 0.31 minol) and 2—(lH—benzotriazole-1—yl)- 1,1,3,3—tetran1ethyluronium hexafluorophosphate (HBTU) (120 mg, 0.32 inmol) under stirring and heating at 110 DC 2 1111 of dry pyridine were added. The e was heated at 110 °C for h, pyridine was evaporated, and the residue was diluted with an aqueous , solution.
The resulting precipitate was filtered off, diss01Ved in hot MN—diinethylforinamide, settled by addition of EtOAe and hexane, filtered off and dried. The product was obtained as a light yellow solid (78 mg, 0.20 mmol, 64 % yield). 1H" NMR (400 MHZ, DMSO—dfi, (301415 ppm -96— 3.31 (2 H, t, $151120), 4.65 (2 H, t, OCHg), 6.84 (1 H, d, CH—arom.), 7.45 (1 H, m, CH— pyr.), 7.88 (1 H, d, CPI-atom), 8.08 (1 H, s, CH-arom.), 8.30 (1 H, d, CH~pyr.), 8.45 (1 H, s, CH-thiazol), 8.57 (1 H, m, CH—pyr.), 9.17 (1 H, s, CH~pyr.), 11.68 (1 H, 133, NH), 13.76 (1 H, bs, NH). LC/MS [M+H]+: 391.0 2-(2,3-Dihydrobenzofuran-S-yl)-N-(3-(furanyl)—1H-1,2,4-triazo1'5—y1)thiazole—4— carboxamide (46) To a mixture of 2—(2,3-dihydro—1—benzofi1ran-5—yl)-1,3—thiazole—4ncarboxy1ic acid (82 mg, 0.33 mmol), 1H~1,2,4-tria201amine (50 mg, 0.33 mmol) and benzotriazole-1—3/1)— 1,1,3,3—tetxamethy1uronium orophosphate (HBTU) (120 mg, 0.32 mmol) under stifling and heating at 110 DC 2 ml of dry pyridine were added. The mixture was heated at 110 DC for h, pyridine was evaporated, and the residue was dikuted with an aqueous Na2C03 solution.
The resulting itate was filtered off, dissolved in hot MN-dimethylformamide, settled by addition of EtOAC and hexane, filtered off and dried. The t was obtained as a light ye11ow solid (85 mg, 0.22 mmol, 70 % yield). 1H NMR (400 MHZ, DMSO—de, CC14) 8 ppm 3.31 (2 H, t, QHéCHgO), 4.64 (2 H, t, OCHZ), 6.53 (1 H, s, CH—fury1), 6.80 (1 H, d, CH— arom.), 6.83 (1 H, s, CH—furyl), 7.63 (1 H, s, CH-furyI), 7.85 (1. H, d, CH—arom.), 8.05 (1 H, s, (SH-aroma), 8.38 (1 H, s, CH—thiazol), 11.51 (1 H, bs, NH), 13.52 (1 H, bs, NH); MSHR: LC/MS : 380.0 2-(2,3—Dihydrobenzofuran—S-yI)-N~(5-(4-ethylpiperazine-1—carbonyl)—1H- benzo[d]inn'dazol—Z—yDthiazolew4-carb0xamide (47) “H“,flfi013,N N A mixture of 2-(2,3—dihydro-1—benzofuran—5—yl)—1,3—thiazole—4—earboxy1ie acid (160 mg, 0.6 mmol), (2—mino—1H—benzimidazol—5~y1)(4—ethy1piperazin—1-y1).methanone hydrobromide (I— 54) (248 mg, 0.7 mmol), 2—(1H—ben20triazoIe—1—y1)~1,1,3,3-tetramethyluronium hexafluorOphosphate (HBTU) (312 mg, 0.82 mmol), diisopropylether (0.3 ml, 1.82 mmol) and 10 m1 DCM was stirred at room temperature for 1 day. The solvent was evaporated in vacuum and 20 ml of an aqueous 10 % Na2C03 soiution were added to the residue. The resin formed. The supernatant was poured out; the resin was washed with water, dissolved in 5 ml chloroform and ted on the column with silica gel (0.0400100 mm). Eiuent: chloroform : l = 5:1. The fraction with Rf = 0.55 was collected, the solvent evaporated and the residue crystallized from minimal amount of ethanol to give the product as a yellowish solid (87 mg, 0.17 mmoi, 29 % . Mp. : 238—240 °C. EH NMR (400 MHZ, DMSO‘dfi) 6 ppm 1.05 (t, J£6.53 Hz, 4 H) 2.39 (bs, 7 H) 3.09 (bs, 2 H) 3.29 (t, J=8.16 Hz, 3 H) 3.37 ~ 3.67 (m, 5 H) 4.63 (t, J=8.41 112,3 H) 6.81 (d, Jx8.28 Hz, 1 H) 7.11 (d, J37.78 H2, 1 H) 7.50 (bs, 2 H) 7.83 (d, J37.78 Hz,1I-1)8.01 (bs, 1 H) 8.43 (s, 1 H) 11.97 (’03, 1 H). LC/MS ; 503.0 2~(2,3—Dihydrobenzofuran—S—yl)—N—[5n(thiophene-Z—carbonyl)—IH~1,3-benzodiazol—2- yl}-1,3-thiazole—4-carboxamide (48) To a solution of 2—(2,3—d111ydro-1—benzofurany1)—1,3—thiazole—4-carboxylic acid (111 mg, 0.45 mmol) in 5 ml MN—dimethylformamide were added (2—Amino-lH-benzoimidazol—S—yl)- thiophen—3~y1~methanonehydrobromide (160 mg, 0.49 mmol), 2—(1H—benzotriazoled—y1)— 1,1,3,3~tetra1nethyluroniumhexafluorophospha’te (HBTU) (170 mg, 0.45 11111101), 4- (dimethylamino)-pyridine (5.5 mg, 0.04 11111101) and MN—diisopropylethyi amine (0.2 ml, 1.12 11111101). The reaction mixture was stirred at room temperature for 18 h, and then poured into ice water. The formed precipitate was fiitered off and dried. The crude product was washed with diisopropyl ether and MeOH. The t was obtained as a yellow solid (102 mg, 0.22 mmol, 48 % yield). 1H NMR (400 MHz, DMSO~d6) 5 ppm 320—3 .40 (m, 2 H), 4.65 (t, J 2 8.2 Hz, 2 H), 6.91 (d, J 2 8.3 Hz, 1 H), 7.24—7.39 (m, 1 H), 7.59-7.87 (m, 3 H), 7.93 (d, J 2 8.5 Hz, 1 H), .21 (m, 3 H), 8.58 (s, 1 H), 11.86 (bs, 1 H), 12.55 (bs, 1 H). LC/MS [Ma—HT: 472.8. 2-(2,3—Dihydro—1-benzoiuran—5—yl)—N-[541H—pyrrole—2~carbonyi)-—1H—1,3-benzodiazol~2~ y11~1,3—thiazole—4-carboxamide (49) M1HN /N HN / To a solution of 2—(2,3-dihydro—1-henzofuran-5~yl)—l,3—thiazole—4—carboxylic acid (171 mg, 0.69 11111101) in 5 1111 NZN-dimethylfonnamide, were added no—lH—benzo[d]imidazol—5- yl) (1 H-pyrrol-Q—yl)111ethanone hydrobromide (234 mg, 0.76 11111101), 2—(1H—benzotriazole—1— yl)-1,1,3,3—tetramethyluroniumhexafluorophosphate (HBTU) (262 mg, 0.69 01), 4— (dimethylamino)-pyridine (8.5 mg, 0.07 11111101) and MN~diisopropy1ethylamine (0.3 1111, 1.73 11111101). The reaction mixture was stirred at room temperatme for 18 h, and then poured into ice water. The formed white precipitate was filtered off and dried. The crude product was washed with diisopropyl ether and MeOH. The product was obtained as a light brown solid (236 mg, 0.52 name], 75 % yield). 1H NMR (400 MHz, fi) 5 ppm 3.10—3.50 (m, 2 H), 4.64 (bt, 2 H), 6.29 (s, 1 H), 6.71—7.07 (m, 2 H), 7.19 (s, 1 H), 7.46—7.82 (m, 2 H), 7.82—8.27 (m, 3 H), 8.56 (s, 1 H), 11.81 (bs, l H), 11.95 (s, 1 H), 12.49 (13$, 1 H). LC/MS {M+H].+: 455.8.
N-(IH—1,3—Benzodiazol—2—yl)—2-(2,3-dihydro—1-benzofuran—S-yl)—1,3—thiazole—4~ amide (50) SMHN—< \N O To a solution of 2—(2,3~dihydro-l-benzofuran—5—y1)~l,3-thiazole—4-carboxylic acid (179 mg, 0.72 11111101) in 4 ml MN~dimethylformamide, were added Z-aminobenzimidazole (106 mg, 0.8 mmol), 2~(1H—benzotriazole—l—yl)—1,l,3,3-tetramethyluroniumhexafluorophosphate (HBTU) (275 mg, 0.72 11111101), 4—dimethylaminopyridine 8.8 mg, 0.07 11111101) and MN- ropylethylamine (0.32 1111, 1.81 11111101). The reaction mixture was stirred at room temperature for 18 h, and then poured into ice water. The formed white precipitate was filtered off and dried. The crude product was washed with MeOH and diisopropyl ether and dried. The t was obtained as a white solid (183 mg, 0.5 mmoi, 7o % yield). 11-1 NMR (400 MHZ, DMSO'dfi) 8 ppm 3.15-3.50 (m, 2 H), 4.64 (t, J x 8.3 Hz, 2 H), 6.91 (d, J z 8.0 Hz,11-1), 7.14 (bs, 2 H), 7.50 (19$, 2 H), 7.91 (d, J: 7.68 Hz, 1 H), 8.10 (s, 1 H), 8.51 (s,1 H), 11.92 (bs, 2 H). LC/MS : 362.9. 2-(2,3—Dihydro-1—beuzofuran-5~y1)~N-{ti-(morpholinecarbonyl)—l,3-benzothiazol—2—yl]— I,3—thiazole—4—carboxamide (51) 14ng N 0 To a stirred suspension of 2~({[2—(2,3—dihydro~1—benzofiiran-5—yl)~1,3-thiazol—4— y1]carboriyl}amino)-1,3-benzothiazole-G—carboxylic acid (230 mg, 0.54 mmol) and HBTU (309 mg, 0.82 mmol) in 3.6 mi absolute dioxane, line (238 mg, 3.26 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, the precipitate was filtered off and washed with dioxane. Filtrate was evaporated to dryness, residue was treated with water which led to an oily residue which solidified on treating with diluted HCl. The product was 'filtered off, washed with water and crystallized from EtOH. The precipitate was dissolved in chloroform and ted to flash column chromatography on silica gel, eluent chloroform followed by EtOAc. Fractions containing the product were ed, the solvent was evaporated to dryness and the residue was crystallized from a mixture of chloroform and EtOH to give pure product as light beige powder (60 mg, 0.12 mmoi, 23 % yield). 1H NMR (400 MHz, CDC13) 8 ppm 3.33 (t, J: 8.7 Hz, 3 H), 3.75 (bs, 8 H), 4.70 (t, J: 8.8 Hz, 2 H), 6.87 (d, J2 8.3 Hz, 1 H), 7.51 (dd, J: 8.3, 1.6 112,1 H), 7.74 (dd,J: 8.3, 1.9 Hz, 1 H), 7.85 (d, J: 8.3 Hz, 1 H), 7.88 (d, J= 1.3 Hz, 1 H), 7.98 (d, J2 1.3 Hz, 1 H), 8.25 (s, 1 H), 10.78 (s, 1 H). Mp: 258—260 BC (decomposition). LC/MS [M+H]+: 492.8. 2—(2,3—Dihydrobenzofuranyl)—N-[5-(piperidin—i-yl)—l,3,4—thiadiazol—2—yl]-1,3- thiazole—4—carboxamide (52) —100— H44)1 "“‘N . 0 To a stirred suspension of 2-(2,3—dihydro-1~benzofuran—5—yi)—1,3-thiazoIe—4~carboxylic acid (235 mg, 0.95 mmol), 5-piperidin—1—yl—1,3,4~thiadiazol~2-arnine (88 mg 1.05 mmol) and HBTU (541 mg, 1.43 mmol) in 2.2 ml absolute dioxane DIPEA (346 mg, 2.68 mmol) was added. The sion was stirred at room temperature for 20 h, d, washed with some dioxane and EtZO. The residue was crystallized from a e of DMF and EtOH, and washed with some cold EtOH, EtZO and dried. The product was obtained as a pale pink powder (69 mg, 0.17 mmol, 18 % yield). 1H NMR (400 MHZ, DMSO-dfi) 5 ppm 12.20 (s, 1 H), 8.47 (s, 1 H), 8.09 (d, J= 1.4 Hz, 1 H), 7.89 (dd,J= 8.3, 2.0 Hz, 1 H), 6.88 (d, J: 8.3 Hz, 1 H), 4.63 (t, J= 8.8 Hz, 2 H), 3.42 (d, J: 5.1 Hz, 4 H), 3.27 (t, J: 8.8 Hz, 2 H), 1.60 (s, 6 H). Mp: 208—210 5C (decomposition). LC/MS [M+H]+: 413.9.
Ethyl 1—{5—[2—(2,3-dihydro—1~benzofuran~5~yl)—1,3nthiazoleamido]-1,3,4-thiadiazol eridinecarboxylate (53) Q 1);}:H o m To a mixture of 2—(2,3—dihydro-1~benzofurany1)—1,3—thiazole—4—carboxylic acid (80 mg, 0.32 mmol), ethyl 1—(5—amino-1,3,4—thiadiazol—Z—y1)piperidine—4~carboxylate ' (83 mg, 0.32 mmol) and HBTU (120 mg, 0.32 mmol) under stirring and heating at 100 OC 1 ml of dry pyridine was added. The mixture was stirred at 100 DC for 5 h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution. The resulting itate was filtered off and purified by flash column chromatography on silica gel (EtOAc as eluent). The product was obtained as a light yellow solid (112 mg, 0.23 mmol, yield 72 % yield). 1H NMR (DMSO—dfi, CC14) 5 ppm 1.24 (t, J = 7.2 Hz, 3 H), 1.73 (in, 2 H), 1.98 (m, 2 H), 2.59 (in, 1 H), 3.18 (111,2 H), 3.30 (t, J = 8.6 Hz, 2 H), 3.85011, 2 H), 4.10 (q, J 2 7.2 Hz, 2 H), 4.64 (t, J E 8.6 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 1 H), 7.85 (dd, J 2 8.4, 2.0 212,] H), 8.05 (d, J = 2.0 Hz, 1 H.), 8.17 (s, 1 H), 11.94 (‘65, 1 H). Mp: 186—188 °C. LC/MS [Mei-HT: 485.9. ~101~ 2-(2,3-Dihydro-I-benzofuran—S-yl)—N—(1-methyI-1H-1,3—benzodiazofyl)—1,3-thiazoEe—4~ carboxamide (54) :H'QD To a solution of 2-(2,3—dihydro-1—benzofiiran—5—yl)—1,3—thiazole—4~earb0xylic acid (171 mg, 0.69 11111101) in 4 1111 MN—dimethyiformamide, were added 2—amino-1~111ethylbenzimidazole (112 mg, 0.76 11111101), 2~(lH—benzotriazole—1—y1)—l,1,3,3—tetramethyluroniumhexafluoro— phosphate (HBTU) 262 mg, 0.69 minol), 4—(dimethylamino)pyridine (8.5 mg, 0.07 11111101) and NN—diisopropylethylamine (0.3 1111, 1.73 mmol). The on mixture was stirred at room ature for 18 11, and then poured into ice water. The formed white precipitate was filtered off and dried. The crude product was washed with MeOH and diisopropyl ether and dried. The product was obtained as a white solid (212 mg, 0.56 11111101, 82 ”/0 yield). tH NMR (400 MHz, DMSO'dfi) 6 ppm 3.13—3.49 (111, 2 H), 3.71 (s, 3 H), 4.63 (t, J m 8.3 Hz, 2 H), 6.90 (d,J 2 8.0 Hz, 1 H), 7.080.316 (111, 2 H), 7.36—7.68 (111, 2 1-1), 7.68—8.04 (111, 2 H), 8.39 (s, 1 H), 12.56 (bs, 1 H). LC/MS [M+H]+: 376.9.
Ethyl 3—[2—(2,3—-dihydro—1-benzofuran-5—yl)—1,3—thiazoleamid0}~1H-pyrazole—4- carboxylate (55) s /\>_<< \N/NH "‘1.
N ‘0 The mixture of ethyl 3—a111in0—lH—pyrazole—4-carboxylate (62 mg, 0.40 01), 2-(2,3— dihydro-l—benzofuran—5—yl)-1,3-thiazole—4—carboxylic acid (106 mg, 0.43 mmol), HBTU (205 mg, 0.54 11111101) and l 1111 dry pyridine was stirred at 100 °C for 2 h. After cooling, 5 ml l was added to the on mixture and the suspension was stirred for 0.5 h. The precipitate was filtered off, suspended in 20 m1 ethanol and refluxed for 10 min. After —102— 2014/062774 cooling, the precipitate was filtered off, washed with ethanol and dried on air. The product was obtained as a white solid (85 mg, 0.22 11111101, 55 % yield). 1H NMR (400 MHZ, DMSO— d6+CD3COOD) 5 ppm 1.38 (t, J = 7.0 Hz, 3 H) 3.31 (t, J = 8.7 Hz, 2 H) 4.35 (q, J = 7.2 Hz, 2 H) 4.65 (t, J": 8.7 H2, 2 1-1) 6.86 (d, J = 8.3 Hz, 1 H) 7.75 — 7.84 (111,2 H) 7.87 (s, 1 H) 8.39 (d, J = 1.3 Hz, 1 H) 10.96 (s, 1 H). M.p.2 3 0C. LC/MS T: 384.8. 2—(2,3—Dihydro~1~benzofuran-S-yi)—N-[S—(morpholin—4—yl)—1,3,4-thiadiazolyl]-1,3- thiazole—4-carb0xamide (56) To a mixture of 2~(2,3-dihydro—1—benzofuran—5-yl)~l,3—thiazole—4—carboxylic acid (80 mg, 0.32 11111101), 5-1110rpholin~4~yl-1,3,4—thiadiazol-2—amine (62 mg, 0.32 11111101) and HBTU (120 mg, 0.32 111mol) under stirring and heating at 100 0C, 11111 of dry ne was added. The mixture was heated at 100 0C for 4 h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution. The resulting precipitate was filtered off, washed with hot EtOAc and hexane, filtered off and dried. The product was obtained as a light yellow solid (115 mg, 0.28 11111101, 86 % yield). l1-1 NMR (DMSO—a’é, CClg) 5 ppm 3.30 (t, J = 8.6 Hz, 2 H), 3.43 (111, 4H), 3.76 (m, 4H), 4.64 (t, J z 8.6 Hz, 2 H), 6.81 (d, J 2 8.4 Hz, 1 H), 7.86 (dd, J m 8.2, 1.8 H2, 1 H), 8.05 (s, 1 H), 8.38 (S, 1 H), 12.02 (bs, l H). Mp: 213—215 0C. LC/MS [M+H]+: 415.9.
-Dihydro—I—benzofuran-S-yl)—N—[5-(4-methylpiperazin—1—yl)~1,3,4-thiadiazol—2-yl]- 1,3-thiazole—4—carboxamide (57) To a mixture of 2—(2,3—dihydro—l—benzofuran—S-yl)-l,3—thiazole—4—carboxylie acid (80 mg, 0.32 11111101), 5~(4~methylpiperazin-1—yl)—1,3,4mthiadiazol—2~arnine (64 mg, 0.32 11111101) and HBTU (120 mg, 0.32 11111101) under stirring and heating at 100 °C, 1 1111 of dry pyridine was ~103— added. The mixture was heated at 100 0C for 5 h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution. The resulting precipitate was filtered off, washed with hot EtOAe and hexane, filtered off and dried. The product was obtained as a pale yellow solid (97 mg, 0.23 mmol, 71 0/0 yield). 1H NMR (DMSO-ds, CCla) 8 ppm 2.26 (s, 3 H), 2.49011, 4 H), 3.30 (t, J = 8.6 Hz, 2 H), 3.43 (in, 4 H), 4.64 (t, J = 8.6 Hz, 2 H), 6.81 (d, J 2.8.4 Hz, 1 H), 7.83 (d, J m 8.2 Hz, 1 H), 8.02 (s, 1 H), 8.31 (s, 1 H), 12.00 (bs, 1 H). M.p.: 230—232 00. LC/MS {M+H]+: 428.8. 2-(2,3-Dihydro-l-benzofuran-S-yl)~N—(5—methyl-1,3-thiazolyl)-1,3-thiazole—4— carboxamide (58) HN / 3M_<81 \N O To a mixture of 2-(2,3—dihydro—l—benzofuran—5—y1)-1,3—thiazolen4—carboxylic acid (80 mg, 0.32 mmol), 5—1nethy1thiazol—2—amine (37 mg, 0.32 nnnol) and HBTU (120 mg, 0.32 rnmol) under ng and g at 90 °C, 1 ml of dry pyridine was added. The mixture was heated at 90 °C for 4.5 h, pyridine was evaporated, and the e was diluted with an aqueous Na2C03 solution. The resulting precipitate was filtered off and purified by flash column chromatography on silica gel (CHClg as eluent). The product was obtained as a white solid (94 mg, 0.27 mmol, 86 0/0 yield). 1H NMR (DMSO-dfi, CCla) 5 ppm 2.42 (s, 3 H), 3.30 (t, J m 8.6 Hz, 2 H), 4.64 (t, J 2 8.6 Hz, 2 H), 6.81 (d, J = 8.4 112,1 H), 7.14 (s, 1 H), 7.83 (dd, J = 8.4, 2.0 Hz, 1 H), 8.01 (d, J2 1.2 Hz, 1 H), 8.38 (s, 1 H), 11.61 (bs, 1 H). M.p.: 2 °C.
LC/MS [mars 3438. 2-(2,3-Dihydro~I-benzofnran-S-yl)-N—[S-(pyridin-4~yl)—1,3,4wthiadiazolyl}-1,3-thiazole~ 4~carboxamide (59) / \N "-._ N O -104— To a stirred suspension of 2—(2,3—dihydro—1—benzofi1ran—5-y1)—1,3—thiazole—4-carboxylic acid (77 mg, 0.31 mmol), 5-pyridinw4—ylml,3,4~thiadiazol—2—amine (61 mg 0.34 mmol) and HBTU (177 mg, 0.47 mmol) in 2.3 ml dry CHZCEZ, DIPEA (128 mg, 0.99 rnmol) was added. The suspension was stirred at room temperature for 24 h, the precipitate was filtered off, washed with some CHZClg, Eth, diluted ACOH, then with water and dried. The precipitate was crystallized from a e of DMF and EtOH to give the product as a pale yellow powder (118 mg, 0.29 mmol, 93 % yield). 1H NMR (400 MHz, DMSO'dfi) 5 ppm 12.93 (s, 1 H), 8.71 (d, J: 6.0 Hz, 2 H), 8.52 (s, 1 H), 8.08 (s, 1 H), 7.91 (d, J= 1.6 Hz, 1 H), 7.88 (s, 1 H), 6.84 (d, J = 8.3 Hz, 2 H), 4.65 (t, J= 8.8 Hz, 2 H), 3.32 (t, J: 8.7 Hz, 2 H). M.p.2 177—180 cC.
LC/MS {M+H]+: 407.3.
N—(S-Benzoyl-1H-1,3-benzodiazolyl)-2—(2,3-dihydro—1-benzofuran~5-yl}-1,3—thiazole-4— carboxamide (60) “H —<,,, O O\N To a solution of 2~(2,3—dihydrobonzofi1ran—5-yl)~l,3~thiazole—4-carboxy1ic acid (104 mg, 0.42 mmol) in 5 ml MN—dimethylformamide, were added (Z-amino-1H—benzo[d]imidazol—5— yl)(phenyl)methaiione hydrobromide (147 mg, 0.46 mmol), benzotriazole-1—yl)« 1,1,3,3—tetramethyluroniumhexafluorophosphate (HBTU) (160 mg, 0.42 mmol), 4- (dimethylamino)—pyridir1e (5.1 mg, 0.04 mmol) and MN—diiSOpropylethyl amine (0.18 ml, 1.05 mmol). The reaction mixture was stirred at room temperature for 18 h, and then poured into ice water. The formed precipitate was filtered off and dried. The crude product was washed with diisopropyl ether and MeOH. The product was obtained as a white solid (119 mg, 0.26 mmol, 61 % yield). 1H NMR (400 MHZ, g) 8 ppm 3.15-3.51 (m, 2 H), 4.65 (bs, 2 H), 6.92 (bs, 1 H), 7.44—8.25 (m, 10 H), 8.57 (s, l H), 11.87 (bs, 1 H), 12.57 (bs, 1 H).
LC/MS [M+Hl+: 466.8.
Ethyl [2—(2,3—dihydro—1-benzofuran—5-yl)~I,3~thiazoleamido]-1H—1,2,4—triazol yl}sulfanyl)acetate (61) -105, 2014/062774 HM”N Wftfihfl To a mixture of 2-(2,3-dihydrobenzofuran—5—yl)—l,3—thiazole—4—carbonyl chloride (144 mg, 0.54 mmol) and ,4—triazol—5-amine (100 mg, 0.49 mmol) 2 ml of dry hot pyridine was added. The solution was heated at reflux for 3 h, ne was evaporated and the residue was diluted with an aqueous Na2C03 solution. The resulting precipitate was filtered off and dried.
The crude product was purified by flash column tography on silica gel (EloACZCHgClz 1:1). The product was obtained as a light yellow solid (40 mg, 0.09 mmol, 19 “/0 yield). 1H NMR (DMSO-ds) 6 ppm 1.19 (t, J: 7.2 Hz, 3 H), 3.28 (t, J= 8.8 Hz, 2 H), 4.01 (s, 2 H), 4.11 (q, J m 7.2 Hz, 2 H), 4.64 (t, J: 8.8 112,2 H), 6.90 (d, J: 8.4 Hz, 1 H), 7.91 ((1.1: 8.4 Hz, 1 H), 8.10 (s, 1 H), 8.50 (s, 1 H), 11.70 (bs, 1 H), 13.70 (bs, 1 H). LC/MS [M+H]+: 431.8. 2-(2,3-Dihydrobenzofuran—S-yl)—N—(lH—pyrazol—3-yl)—1,3—t11iazole-4—carboxamide (62) “HQHN )L‘WH - The mixture of 1H~pyrazol—3—amine (50 mg, 0.61 mmol), 2—(2,3—dihydro—1—benzofi1ran—5—yl)— 1,3—thiazoIe—4—earboxylic acid (106 mg, 0.40 mmol), HBTU (205 mg, 0.54 mmol) and 1 ml dry pyridine was stirred at 100 0C for 2 11. Afier cooling 10 ml water was added to the reaction mixture and the suspension was stirred for 0.5 h. The precipitate was filtered off and crystallized from a minimal amount of ethanol (1 ml). The product was obtained as a light yellow solid (54 mg, 0.17 mmol, 43 % yield). 1H NMR (400 MHz, é) 5 ppm 3.30 (t, J = 8.7 112,2 H) 4.64 (t, J = 8.8 Hz, 2 H) 6.64 (bs, 1 H) 6.82 (d, J: 8.3 Hz, 1 H) 7.52 (bs, 1 H) 7.80 (dd, J = 8.3, 1.51 Hz, 1 H) 7.94 (s, 1 H) 8.21 (s, 1 H) 9.91 (bs, 1 H) 12.37 (bs, 1 H).
M.p.: 200—203 0C. LC/MS [M~+H]+: 312.9. 2-(2,3-Dihydro—1-henzofuran—S-yl)—N—(lH-1,2,4-triazolyl)-I,3—thiazolecarboxamide (63) ~106~ To a stirred suspension of 2—(2,3-dihydro—1—13enzofuranu5-y1)—1,3-thiazole-4—carboxylic acid (100 mg, 0.40 mmol), 1H~1,2,4—triazol—3—arnine (34 mg 0.41 1n1n01) and HBTU (230 mg, 0.61 11111101) in 1.8 1111 dry pyridine, DIPEA (131 mg, 1.01 11111101) was added. The suspension was refluxed under stirring for 2 h and all volatiles were evaporated to s at reduced pressure. The residue was washed subsequendy with water, an aqueous NaZCO3 solution, water, diluted H01, water again, and then dried. The crude product was crystallized from DMF. The product was obtained as a light yellow solid (71 mg, 0.23 111m01, 57 % yield). 1H NMR (400 MHZ, acetic acid) 8 ppm 9.07 (s, 1 H), 9.01 (s, 1 H), 8.06 (s, 1 H), 8.00 (d, J = 8.5 Hz, 1 H), 7.10 (d, J: 8.6 Hz, 1 H), 4.87 (t, J: 8.7 Hz, 2 H), 3.42 (t, J: 8.7 112,2 H). M.p.: >307 °c. LC/MS [M+H]+: 313.9. 2—(2,3-Dihydr0—l-benzofuran—5—yl)—N—(5-methoxy-1,2,4—thiadiaz0]y1)—1,3—thiazole—4- carboxamide (64) The mixture of 5—1nethoxy—1,2,4-thiadiazol~3-amine (59 mg, 0.45 11111101), 2-(2,3—dihydro-1— benzofuran~5-y1)~1,3~thiazole—4—carboxylic acid (106 mg, 0.43 11111101), HBTU (205 mg, 0.54 11111101), DIPEA (0.15 1111, 0.87 11111101) and 5 1111 dry DCM was stirred at room temperature for 18 11. Subsequently, the t was evaporated to dryness, 5 1111 of an 5% aqueous Na2CO3 solution were added to the residue and the suspension was d for 1 h. The atant was poured off from the ing resin. The resin was dissolved in 3 ml chloroform and subjected to flash column chromatography on silica gel (0040-0100 111111) using chloroform as eluent.
The fractions containing t were collected. The product was obtained as a light yellow solid (54 mg, 0.15 11111101, 38 % yield). 1H NMR (400 MHz, é) 5 ppm 3.29 (t, J z 8.8 Hz, 2 H) 4.20 (s, 3 H) 4.63 (t, J = 8.8 Hz, 2 H) 6.85 (d, J = 8.3 Hz, 1 H) 7.83 (dd, J 2 8.3, 1.76 Hz, 1 H) 7.98 (s, 1 H) 8.37 (s, 1 H) 10.60 (s, 1 H). Mp: 133-136 °C. LC/MS [M+H]+: 360.8. ~107— 2014/062774 2—(2,3—Dihydro—1—benzofuran—5-yl)~N—(1,3-thiazol—2-yi)—1,3-thiazolecarboxamide (65) 3MN\</j \N S To a on of 2~(2,3~dihydro—l—benzofi1ran—5-y1)-l,3-thiazole—4—carboxylic acid (110 mg, 0.44 mmol) in 2 m1 MN—dimethyifonnamide, were added 2—aminothiazole (49 mg, 0.49 mmol), 2—(1H—benzotriazole— l —y1)—] ,1,3 ,3—tetramethyluroniumhexafluorophosphate (HBTU) (169 mg, 0.44 mmol), 4-(dimethyiamino)pyridine (5.4 mg, 0.04 mmol) and MN— diisopropylethyl amine (0.19 ml, 1.11 mmol). The reaction mixture was stirred at room temperature for 18 h, and then poured into ice water. The formed precipitate was filtered off.
The crude product was purified by flash column chromatography on silica gel (eluent: DCM 100 %). The crude product was suspended in diisopmpyl ether, filtered off and dried. The t was obtained as a white solid (67 mg, 0.2 mmol, 46 % yield). 1H NMR (400 MHZ, é) 8 ppm 3.20—3.36 (m, 2 H), 4.63 (t, J = 8.8 Hz, 2 H), 6.90 (d, J m 8.3 Hz, 1 H), 7.32 (d, J: 3.5 Hz, 1 H), 7.58 (d,J“—" 3.5 Hz, 1 H), 7.91 (dd,J= 8.3, 1.9 Hz, 1 H), 8.10 (bs, 1 H), 8.51 (s, l H), 12.21 (bs, 1 H). LC/MS : 329.8. 2-(2,3—Dihydrow}vbenzofuran-S-yl)~N—(5-methyl-1H-pyrazol—3-yl)—1,3—thiazole carboxamide (66) To a mixture of 2—(2,3—dihydro-1~benzofiiranyl)-1,3—thiazole-4—carboxy1ic acid (80 mg, 0.32 mmol), 5-methy1-lH—pyrazol—Smarnine (31 mg, 0.32 mmol) and HBTU (120 mg, 0.32 mmol) under stirring and heating at 90 0C, 1 m1 of dry pyridine was added. The mixture was heated at 90 CC for 5 h, pyridine was evaporated, and the residue was diluted with an aqueous Na2CO3 on. The resulting precipitate was filtered off and purified by flash column chromatography on silica gel (EtOAc:CHC13 1:1). The product was obtained as a white solid (56 mg, 0.17 mmol, 54 % yield). 1H NMR (DMSO-dg, C014) 6 ppm 2.27 (s, 3 H), 3.30 (t, J = 8.8 Hz, 2 H), 4.63 (t,J m 8.6 Hz, 2 H), 6.39 (s, 1 H), 6.81 (d, J z 8.4 Hz, 1 H), 7.79 (dd, J 2 8.6 1.2 Hz, 1 H), 7.94 (s, 1 H), 8.19 (s, 1 H), 9.76 (bs, 1 H), 12.03 (bs, 1 H). M.p.: 210—212 0c. LC/MS {M+H]*: 326.9. —108— N—(S—Bromo-1,3,4-thiadiazoi—2—yl)—2-(2,3-dihydro—1—benzofuran-Swyl)-1,3-thiazole carboxamide (67) 8MN86”’1, \ s N I To a d suspension of 2—(2,3—dihydro-1~benzofuran—5—yl)—1,3uthiazole—4—carboxylic acid (116 mg, 0.47 11111101), 110~1,3,4-thiadiazol—2—amine (92 mg 0.52 11111101) and HBTU (266 mg, 0.70 11111101) in 1.9 1111 absolute dioxane, DIPEA (151 mg, 1.17 m11101) was added. The suspension was stirred at room temperature for 20 h, filtered, washed with some EtOH and E120, dried, washed with water and dried again. The product was obtained as a pale yellow powder (70 mg, 0.17 11111101, 36 % yield). 1H NMR (400 MHZ, DMSO'dfi.) 8 ppm 3.31 (t, J 2 8.7 Hz, 2 H), 4.65 (t, J: 8.8 Hz, 2 H), 6.83 (d, J: 8.3 Hz, 1 H), 7.88 (dd, J3 8.3,1.9 Hz, 1 H), 8.07 (d,J= 1.3 Hz, 1 H), 8.51 (s, 1 11), 13.06 (s, 1 H). Mp: 142—144 °C. LC/MS [M+H]+: 408.9. 2—(2,3-Dihydro~1—benzofuran-S-yl)—N-[3—(3-fluorophenyi)- lH-l,2,4-triazol~5-yI]—1,3- thiazole—4mcarboxanfide (68) HN\<I F s \ 1 \ HN"N To a mixture of 2—(2,3—dihydro-l-benzofu1a11—5—y1)-1,3~thiazole—4—carboxylie acid (70 mg, 0.28 inmol), lH—l,2,4—t11azol—5—amine (50 mg, 0.28 1n1n01) and HBTU (120mg, 0.32 01) under stifling and heating at 110 OC, 2 1111 of dry pyridine was added. The mixture was heated at 110 °C for 5 h, pyridine was evaporated, and the residue was d with an aqueous Na2C03 solution. The resulting precipitate was filtered off, dissolved in hot DMF, settled by on of EtOAc and hexane, filtered off and dried. The product was obtained as a light yellow solid (67 mg, 0.16 mmol, 59 % yield). 1H NMR (DMSO‘dfi, CCl4) 5 ppm 3.31 (t, J *—" 8.8 Hz, 2 H), 4.65 (t, J = 8.8 112,2 H), 6.83 (d, J= 8.0 Hz, 1 H), 7.14 (111, 1 H), 7.46 (111, 1 H), 7.71 (d, J: 10.4 Hz, 1 H), 7.84—7.90 (111, 2 H), 8.06 (s, 1 H), 8.42 (s, 1 H), 11.55 (bs, 1 H), 13.66 (bs, 1 11). LC/MS [NH-HT: 407.8. ~109- 2—(2,3~Dihydro-1—benzofuran-5—yl)-N-(3-methyl—l,2,4—thiadiazol—5—y[)~1,3—thiazole—4— carboxamide (69) MW2% The mixture of 3-methyl-1,2,4—thiadiazol~5—amine (50 mg, 0.43 mmol), 2—(2,3-dihydro—l— benzofuran—S—yl)—l,3uthiazole—4—oarboxylic acid (106 mg, 0.40 11111101), HBTU (205 mg, 0.54 mmol), DIPEA (0.15 ml, 0.87 mmol) and 5 ml dry DCM was stirred at room ature for 18 h. Subsequently, the solvent was ated to dryness, 5 m1 l was added to the residue and the suspension was refluxed for 15 min. After cooling, the precipitate was filtered off, washed with ethanol and dried on air. The product was obtained as a pale yellow solid (99 mg, 0.29 mmol, 72 % yield). 1H NMR (400 MHZ, DMSO'dfi) 5 ppm 2.52 (s, 3 H) 3.30 (t, J = 8.66 Hz, 2 H) 4.64 (t, J z 8.7 112,2 H) 6.81 (d, J = 8.3 Hz, 1 H) 7.86 (dd, J m 83,176 Hz,1 H) 8.05 (s, 1 H) 8.50 (s, l H) 12.92 (s, 1 H). Mp: 208—210 0C. LC/MS [M+H]+: 344.8.
N-(S-Amino-1,2,4-thiadiazolyl)—2—(2,3-dihydro-1—benzefuran-5~yE)-1,3-thiazole-4~ carhoxanflde (70) The mixture of 1,2,4~thiadiazole~3,5—diamine (96 mg, 0.80 mmol), 2-(2,3—dihydro—l— benzofiiran-S~yl)-1,3-thiazole—4-carboxylic acid (106 mg, 0.40 mmol), HBTU (205 mg, 0.54 mmol), DIPEA (0.15 ml, 0.87 mmol) and 5 m1 dry DCM was stirred at room temperature for 18 h. The precipitate was filtered off, washed by DCM and suspended in ethanol (20 ml). The suspension was refluxed for 15 min. After cooiing the precipitate was filtered off and the filtrate was evaporated in vacuum to 5 ml volume. After staying for 2 hours in the erator (approx. 4 0C) the residue of pure product was d off, washed with ethanol and dried on air. The product was obtained as a white solid (60 mg, 0.17 mmol, 43 % yield). 1H NMR (400 MHZ, DMSO'dfi) 8 ppm 3.30 (t, J m 8.8 Hz, 2 H) 4.64 (t, J x 8.8 112,2 H) 6.82 (d, J z 8.3 Hz, — 110 — 1 H) 7.77 (dd, J = 8.3, 1.76 Hz, 1 H) 7.85 — 7.98 (m,~3 H) 8.27 (s, 1 H) 9.97 (s, 1 H). 171.16.: 245-248 °C. LC/MS [M+H1*: 345.8. 2—(2,3—Dihydro—I—benzofuran—S~yl)—N—(1,3,4-thiadiazol—2-yl)—1,3-thiazole—4-carb0xamide (71) o 5/\ N NJ\\N>N To a mixture of 2—(2,3—dihydro-1—benzofuran-5—yl)—l,3—thiazole—4—carboxylic acid (80 mg, 0.32 rnrnol), 1,3,4-thiadiazolamine (33 mg, 0.32 mmol) and HBTU (120 mg, 0.32 rnmol) under stirring and heating at 100 °C, 1 ml of dry pyridine was added. The mixture was heated at 100 DC for 5 h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution. The resulting precipitate was d off, washed with hot EtOAe and hexane, d off and dried. The product was obtained as a pale yellow solid (87 mg, 0.26 11111101, 82 % yield). 1H NMR dfi, C014) 5 ppm 3.31 (t, J "—" 8.6 Hz, 2 H), 4.64 (t, J m 8.6 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 8.07 (s, 1 H), 8.47 (s, 1 H), 9.11 (s, 1 11), 12.57 (‘08, 1 H). M.p.; 214 0C. LC/MS [M+H]+: 330.8. 2-(2,3-Dihydro—l—benzofuranw5—yi)-N-(4-methyl-1,3-thiazol—2—yl)—1,3-tl1iazole~4~ carboxamide (72) fifLNilH N O ‘ To a mixture of 2—(2,3-dihydro—l—benzofiiranm5~yi)—l,3-thiazole-4—earb0xylic acid (80 mg, 0.32 mrnol), 4—1nethylthiazolamine hloride (49 mg, 0.32 11111101) and HBTU (120 mg, 0.32 mmol) under ng and heating at 100 0C, I ml of dry pyridine was added. The mixture was heated at 100 0C for 5 h, pyridine was evaporated, and the residue was diluted with an aqueous N82C03 solution. The resulting precipitate was filtered off and purified by flash column tography on silica gel (EtOAc as eluent). The product was obtained as a pale yellow solid (60 mg, 0.17 mmol, 55 % yield). 1H NMR (DMSO—dg, CCl4) 5 ppm 2.34 (s, 3 H), 3.30 (t, J = 8.6 Hz, :2 H), 4.64 (t, J z 8.6 Hz, 2 H), 6.70 (s, 1 H), 6.81 (d,J = 8.6 Hz, 1 H), ~111- 7.31m, J = 8.6, 2.0 Hz, 1 1—1), 8.03 (d, J = 1.2 Hz, 1 H), 8.38 (s, 1 H), 11.74 (bs, 1 11). M.p.: 8 00. LC/MS [M+H]+: 343.8. 2-(2,3-Dihydro—1-benzofuran—S—yl)—N—(1,2,4-thiadiazol—5—y1)—1,3-thiazolecarboxamide (73) To a stirred suspension of 2-(2,3—dihydro-1—benzofuran—5—yl)—l,3mthiazole—4wcarboxylic acid (100 mg, 0.41 01), 1,2,4—thiadiazol-5—amine (41 mg 0.41 11111101) and HBTU (230 mg, 0.61 11111101) in 2.7 1111 dry CHgClg, DIPEA (131 mg, 1.01 11111101) was added. The suspension was stirred at room temperature for 2 days and filtered, washed with some CH2C12. The precipitate on the filter was washed subsequentiy with water, an aqueous Na2C03 solution, water, diluted HCl, water again and then dried. The omde product was crystallized from a mixture of DMF and EtOH to give the product as a pale yellow solid (102 mg, 0.31 mmol, 75 "/0 yield). 1H NMR (400 MHZ, DMSO'dfi) 5 ppm 13.31 (s, 1 H), 8.63 (s, l H), 8.52 (s, 1 H), 8.09 (s, 1 H), 7.91 (dd, J= 83,161 Hz, 1 H), 6.88 (d, J: 8.3 , 4.65 (t, J: 8.7 Hz, 2 H), 3.30 (t,J: 8.7 Hz, 2 H). Mp: 274-276 °C (without decomposition). LC/MS [M+H]+: 330.8. 2-(2,3-Dihydrobenzofuran-S—yl)—N~(dimethyi—I,3-thiazoly1)~1,3-thiazole—4- amide (74) 8M1: ‘ To a mixture of- 2—(2,3—dihydro—1—benzofura11y1)—1,3—thiazoIe—4—carboxylic acid (80 mg, 0.32 11111101), 4,5—dimethy1thiazoI—2—ami11e (41 mg, 0.32 11111101) and HBTU (120 mg, 0.32 11111101) under stirring and g at 90 °C 11111 of dry pyridine was added. The mixture was heated at 90 DC for 4.5 h, pyridine was evaporated, and the residue was diluted with an aqueous Nagcog solution. The resulting precipitate was filtered off and purified by flash ~112« WO 02638 column chromatography on silica gel (CHC13 as solvent). The product was obtained as a white solid (93 mg, 0.26 mmol, 81 % yield). 1H NMR (DMSO—ds, CC14) 5 ppm 2.22 (s, 3 H), 2.30 (s, 3 H), 3.29 (t, J x 8.6 Hz, 2 H), 4.64 (t, J z 8.6 Hz, 2 H), 6.80 (d, J = 8.4 Hz, 1 H), 7.82 (dd, J: 8.4, 1.6 Hz, 1 H), 8.01 (d, J= 1.2 Hz, 1 H), 8.35 (s, l H), 11.48 (bs, 1 H). M.p.: 194 0C. LC/MS {M+H}+: 357.8.
N-(1,3-Benzothiazol—Z-yl)—2-(2,3—dihydrobenzofuranyl)—1,3-thiazoIe-4»carboxamide (75) S/HN_<S/RN The mixture of 1,3-benzothiazolamine (60 mg, 0.40 mmol), 2-(2,3-dihydro-1—benzofuran— —y1)—1,3—thiazcle—4—carboxylic acid (106 mg, 0.40 mmol), HBTU' (205 mg, 0.54 mmol), DIPEA (0.15 ml, 0.87 mmol) and 5 ml dry DCM was stirred at room temperature for 18 11.
Subsequently, the solvent was ated to dryness. The residue was suspended in a mixture of 10 ml water and 0.2 ml triethylamine and d at room temperature for 1 day. The precipitate was filtered off, washed with water and crystallized (with filtration from insoluble part) from 20 ml ethanol. The t was obtained as a pale yellow solid (74 mg, 0.20 mmol, 50 0/0 yield). 1H NMR (400 MHZ, DMSO-dé) 8 ppm 3.31 (t, J = 8.7 Hz, 2 H) 4.64 (t, J z 8.7 Hz, 2 H) 6.82 (d, J m 8.3 Hz, 1 H) 7.25 — 7.35 (m, 1 H) 7.37 — 7.47 (m, 1 H) 7.76 (d, J 2 8.0 Hz, 1 H) 7.86 (dd, J m 8.4, 1.9 Hz, 1 H) 7.92 (d, J: 7.3 Hz, 1 H) 8.05 (s, 1 H) 8.48 (s, 1 H) 12.06 (bs, l H). Mp: 212—214 °C. LC/MS [M+H]+: 379.8.
N—(4—Acetyl~1,3—thiazol—2-yi)—2-(2,3—dihydro—1-benzofuran—5—yI)-l,3—thiazole-4— carboxamide (76) ~113- The mixture of mino-1,3—thiazol—4—yl)ethanone (57 mg, 0.40 01), 2—(2,3-dihydro—1— benzofuran—S—yl)-l,3-thiazole—4—carboxylic acid (106 mg, 0.40 mmol), HBTU (205 mg, 0.54 11111101), DIPEA (0.15 1111, 0.87 11111101) and 5 ml dry DCM was stirred at room temperature for 18 h. Subsequently, the solvent was evaporated to dryness, 5 ml ethanol was added to the residue and the sion was stirred at room temperature for 1 day. The precipitate was filtered off, washed with ethanol and dried on air. The product was obtained as a pale yellow solid (102 mg, 0.27 mmol, 69 % yield). 1H NMR (400 MHz, DMSO'dfi) 5 ppm 2.56 (s, 3 H) 3.30 (t, J = 8.7 112,2 H) 4.64 (t, J = 8.7 Hz, 2 H) 6.84 (d, J = 8.0 Hz, 1 H) 7.88 (d, J r 8.3 Hz, 1 H) 7.99 — 8.18 (In, 2 H) 8.49 (bs, 1 H) 12.38 ((1, J = 14.6 Hz, 1 H). Mp: 223—227 0C.
LC/MS {M+H]+: 371.8. 2-(2,3-Dihydro—I-benzofuran—5—yl)-Ne[S-(methylsulfanyl)—1,2,4-thiadiazol—3-yl]—1,3— thiazole—4ncarb0xamjde (77) SH\</ \Sx. wk / N S The mixture of 5—(methylsulfanyl)~1,2,4-thiadiazol—3~amine (49 mg, 0.40 mmol), — dihydro—1—henzofuran~5—yl)—1,3—thiazole—4mca1hoxylic acid (106 mg, 0.40 mmol), HBTU (205 mg, 0.54 mmol) and 1 ml dry pyridine was stirred at 100 °C for 2 h. After cooling 10 ml water were added to the on mixture and a resin formed. The supernatant was poured off; the resin was dissolved in 3 1111 chloroform and purified by flash column chromatography on silica gel (0040—0100 min) using chloroform as eluent. The fractions containing compound were ted. Subsequently, the solvent was evaporated in vacuum and the residue was crystallized from 3 m1 ethanol. The product was obtained as a white solid (75 mg, 0.20 mmol, 50 % yield). EH NMR (400 MHZ, DMSO-dg) 5 ppm 2.79 (s, 3 H) 3.30 (t, J = 8.7 Hz, 2 H) 4.64 (t, J = 8.7 Hz, 2 H) 6.82 (d, J 2 8.3 Hz,1 H) 7.81 (dd, J: 8.3, 2.0 Hz, 1 H) 7.92 — 8.01 (111, l H) 8.34 (s, 1 H) 10.67 (s, 1 H). Mp: 105—107 °C. LC/MS {M+H]+: 376.7.
Ethyl 2-[2—(2,3-dihydro-l—benzofnran-S-yl)-1,3-thiazole~4—amjd0]—1,3-thiazo]e—4- carboxylate (78) —114— SHN\<:N o/\ The mixture of ethyl 2—a1nino—1,3vthiazolem4—earboxy1ate (344 mg, 2.0 mmol), 2—(2,3-dihydrom ofilran—5-yl)~l,3—thiazole—4—carboxylic acid (530 mg, 2.0 01), HBTU (1.03 g, 2.7 mrnol), 0.75 in} DIPEA and 25 ml dry DCM was stirred at room ature for 18 h.
Subsequently, the solvent was evaporated to dryness, 50 ml of an 10% aqueous Na2C03 solution was added to the residue and the mixture was stirred for 2-3 h until the resinous residue solidified. The precipitate was filtered off and refluxed in 30 m1 ethanol for 30 min.
After cooling the precipitate was filtered off, washed with ethanol and dried on air. The product was obtained as a pale yellow solid (450 mg, 1.12 11111101, 56 % yield). 1H NMR (400 MHZ, DMSO'dfi) 5 ppm 1.37 (t, J = 7.0 Hz, 3 H), 3.30 (t, J = 8.7 Hz, 2 H), 4.31 (q, J m 7.2 Hz, 2 H), 4.64 (t, J = 8.8 112,2 H), 6.80 (d, J = 8.3 Hz, 1 H), 7.85 (dd, J m 8.3, 1.5 112,111), 7.94 (s, 1 H), 8.05 (s, 1 H), 8.42 (s, 1 H), 12.46 (s, 1 H). Mp: 183-18500. LC/MS {M+H]-+: 401.8. 2-(2,3-Dihydro-I~henzofuran-5—yl)-N-(l,3—oxazol—2—yl)-1,3—thiazole—4—carboxamide (79) 8.3—1%] To a stirred sion of —dihydro~1~benzofuran—5—yl)-1,3—thiazole—4—earboxylic acid (100 mg, 0.41 mmol), 1,3—oxazol—2—a1nine (34 mg, 0.41 mmol) and HBTU (230 mg, 0.61 mmol) in 4.1 ml dry CH2C12, DIPEA (131 mg, 1.01 mmol) was added. The suspension was stirred at room temperature for 24 h and filtered, washed with hot CH2C12. The filtrate was evaporated to dryness. The e was treated subsequently with water, an aqueous N32C03 solution, water, diluted HCl and water again. The crude product was crystallized iron} EtOH to give the product as a white powder (67 mg, 0.21 mmol, 52 % yield). 1H NMR (400 MHZ, DMSO~d6) 6 ppm 11.18 (S, 1 H), 8.39 (s, 1 H), 8.02 (s, 1 H), 7.92 (s, 1 H), 7.85 (d, J: 8.3 Hz, ~115~ 1 H), 7.15 (S, 1 H), 6.85 (d, J: 8.3 Hz, 1 H), 4.63 (t, Jr» 8.7 Hz, 2 H), 3.28 (t, J= 8.7 Hz, 2 H). M.p.: 192494 °C. LC/MS [M+H}+: 313.9. 2-(2,3—Dihydro—l-benzofuran~S—y1)—N—[5—(methoxymethyl)-1,2,4-oxadiazolyl]-1,3— thiazoEe—4-carboxamjde (80) \ HN\</ \O N Ng/IK/o o \ 2—(2,3—Dihydro—1—benzofiiran-5—y1)—l,3-thiazoie~4-carboxylic acid (100 mg, 0.40 mrnol) was refluxed in 4.0 m1 SOClz for 2 h. The excess of SOC12 was evaporated in vacuo and 3 ml pyridine was added to the residue. The mixture was stirred for 10 minutes, 5 (methoxy1nethy1)—1,2,4woxadiazol—3—amine (63 mg, 0.49 01) was added and stirring continued overnight. The mixture was poured into ice water, no precipitate was obtained. The solution was diluted with ethyl acetate. The biphasic mixture was ted and the organic layer was washed twice with an aqueous 5% NaHC03 solution and an s 5% citric acid solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by preparative TLC (PLC silica gel 60 F254, 2mm, DCMzMeOI-I 95:5). The product spot was isolated and concentrated in vacuo. The crude product was purified again by preparative TLC (PLC silica gel 60 F254, 0.5 mm, OH 95:5). The main spot was ed. The product was obtained as a pale yellow solid (5 mg, 0.01 mmol, 4 % yield). 1H NMR (400 MHZ, DMSO—dg) 8 ppm 3.22—3.34 (in, 2 H), 3.43 (s, 3 H), 4.64 (t, J: 8.8 Hz, 2 H), 4.77 (s, 2 H), 6.90 (d, J: 8.4 Hz, 1 H), 7.91 (dd, J z 8.4, 1.51 Hz, 1 H), 8.08 (d, J: 1.5 Hz, 1 H), 8.48 (s, 1 H), 11.28 (s, 1 H). LC/MS [Md—Hf: 359.0.
Ethyl 2-[2-(2,3wdihydrobenzofuranw5—y1)—1,3-thiazoie~4-amido]-1,3-oxazole—4- carboxylate (81) M4 o/\ I — 116— 2—(2,3—Dihydrobenzofi1ran~5—yl)-1,3-thiazole—4—carboxylic acid (100 mg, 0.40 mmol) was refluxed in 4 ml SOClz for 2 h. The excess of SOCIQ was evaporated in vacuo and 3 m1 pyridine was added to the e. The mixture was stirred for 10 minutes, 2-amiuo—oxazole— 4-carboxy1ic acid ethyl ester (156 mg, 0.40 mmol) was added and stirring continued for 18 h.
The mixture was poured into iced water, no precipitate was ed. The solution was diluted with ethyl acetate. The biphasic mixture was separated and the organic layer was washed twice with an aqueous 5% NaHC03 on and an aqueous 5% citric acid solution. The c layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by ative TLC (PLC silica gel 60 F254, 2mm, DCM:MeOH 95:5). The crude product was dissolved in a mixture of dichloromethane and methanol. The product was d off and dried. The product was obtained as a pale pink solid (2 mg, 0.005 mol, 1 % yield). 1H NMR (400 MHZ, DMSO-dg) 5 ppm 1.30 (t, J n 7.1 Hz, 3 H), 3.20-3.35 (1n, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 4.64 (t, J 2 8.8 Hz, 2 H), 6.90 (d, J = 8.3 Hz, 1 H), 7.90 (dd, J = 8.4, 2.0 Hz, 1 H), 8.07 (d, J =3 1.5 Hz, 1 H), 8.48 (s, l H), 8.71 (s, 1 H), 11.69 (bs, 1 H).
LC/Ms [M+H]*: 386.0.
Ethyl 2~{2-(2,3—dihydro-l—benzofuran—S—y1)-1,3-thiazoIeamidol-1,3-thiazole. carboxylate (82) HN —</ s l H\ s 0 N O To a mixture of 2w(2,3—dihydro—1—benzofuran—5-yl)—l,3~thiazole—4-carboxylic acid (80 mg, 0.32 mmol), ethyl 2—amino—l,3—thiazole-5—carboxylate (56 mg, 0.32 mmol) and HBTU (120 mg, 0.32 mmol) under stirring and heating at 90 °C 1 ml of dry pyridine was added. The mixture was heated at 90 °C for 3 h, pyridine was evaporated, and the residue was diluted with an aqueous Na2C03 solution. The ing precipitate was filtered off and purified by flash column chromatography on silica gel (CHClg, as eluent). The product was obtained as a white solid (68 mg, 0.17 mmol, 53 % yield). 1H NMR (Db/18046, CCl4) 6 ppm 1.37 (t, J 2 7.2 Hz, 3 H), 3.30 (t, J = 8.6 Hz, 2 H), 4.31 (q, J i 7.2 Hz, 2 H), 4.64 (t, J = 8.6 Hz, 2 H), 6-81 (d,J£ 8.4 Hz, 1 H), 7.86 (1dd, J = 84,18 Hz, 1 H), 8.03 (d,Jt 1.2 Hz, 1 H), 8.13 (5,1 H), 8.49 (s, 1 H), 12.45 (138, 1 H). Mp: 179—181 °C. LC/MS [M+H]+: 401.8. ~117~ sof Intermediates and startin materials (2-Amino(3-methoxyphenyl)—1H—imidazol—1—yl)(2—(2,3—dihydrobenzofuran—S— yl)thiazol~4~yl)methanone (1-48) HZNYr‘j/Q s N 0 To a solution of 2-(2,3—dihyd1‘0-1—benzofuran—5—yl)~l,3—thiazolen4—0arboxylic acid (150 mg, 0.61 11111101) in 2 ml MN—dimethylfonnamide, were added 5-(3—Methoxyphenyl)—lH—imidazol- e (126 mg, 0.67 mmol), 2—(1H—benzotriazole—l—yl)-1,1,3,3-tetramethyluronium hexafluoro— phosphate (HBTU) (230 mg, 0.61 mm01), 4-dimethylaminopyridine (7 mg, 0.06 inmol) and MN-diisopropylethylamiue (0.26 1111, 1.52 11111101). The reaction mixture was stirred overnight at 100m temperature. It was poured into ice water. The formed yellow precipitate was filtered off and washed with water and diisopropylether. The product was ed as a light yellow solid (206 mg, 0.49 11111101, 8] % yield). ’11 NMR (400 17111231130416) 8 ppm 3.17—3.44 (111, 2 11), 3.79 (s, 3 H), 4.64 (1, J=8.66 Hz, 2 H), 6.83 (br. 121,057.17 Hz, 1 11), 6.94 (131. d, J=8.13 Hz, 1 H), 7.06 (bs, 1 H), 7.18—7.42 (111,3 H), 7.82 (131. 11, 127.65 Hz, 1 H), 7.93 (bs, 1 H), 8.28 (be, 1 H), 8.70 (bs, 1 H). LC/MS [Mam 418.8 (3,4-dinitrophenyl) {4-(tetrahydrofuran-Z-ylmethpriperazinyl]methanone (1-49) 0 0 030000118: A mixture of 3.4wdinitrobenzoic acid (420 mg, 2.0 mmol) and PCls (400 mg, 1.9 11111101) was heated at 60—65°C for 1 h. After cooling 20 ml hexane was added and the mixture was stirred at room temperature until solidifying of the residue. Solids were filtered off, washed with 10 ml hexane and dissolved in 2.0 ml CHZCIZ. 2.5 ml Acetic acid and l—(tetrahydrofiiran—Z- ylmethyl)piperazine (0.34 g, 2.3 11111101) were added to this solution and the mixture was stirred at room ature for 1 day. The solvent was evaporated in vacuum, the residue was treated with 15 m1 of an s 10% NaZCO3 solution, the precipitate was filtered off, - 118 — washed with 3% ammonia and dried on air to give the t as pale yellow crystals (600 mg, 1.65 mmol, 82 %, yield).
(Z-amino—IH-benzimidazol—S-yl) trahydrofuran—Z—ylmethyl)piperazin-1~ yHmethanone hydrobromide (1-50) H H—Br aroma-H2 A mixture of (3,4-dinitropheny1)[4—(tetrahydrofiu'an—Z—ylmethyl)piperazin—1—yl]methanone (In 49) (60 mg, 1.65 mmol), 20 ml ethanol and Pd/C catalyst (0.08 g, 10% Pd) was stirred in an ave under hydrogen pressure 10 kg/cm2 and room temperature for 3 h. Catalyst was filtered off and cyanogen bromide (230 mg, 2.14 mmol) was added to the e. After ng at r00m temperature for 1 day the solvent was evaporated in vacuum, the residue suspended in 20 ml ethyl acetate and stirred for 30 min. ly rosy precipitate was filtered off, washed with ethyl acetate and dried on air to give the product (0.64 g, 1.55 mmol, 94 0/0, yield). 3,4-d'mitrc—N—(tetrahydrofuran-Z-ylmethyl)benzamide (1—51) k #4.
O O A mixture of 3.4—dinitrobenzoic acid (420 mg, 2.0 mmol) and PC15 (0.4 g, 1.9 mmol) was heated at (BO-65°C for 1 h. After cooling 20 ml hexane was added and the mixture was d at room temperature until solidifying of the residue. Solids were filtered off, washed with 10 ml hexane and dissolved in 20 ml CH2C12. 2.5 ml Acetic acid and 1-(tetrahydrofuran-2— yl)rnethanamine (250 mg, 2.5 mmol) were added to this solution and the mixture was stirred at room temperature for 1 day. The solvent was evaporated in vacuum, the residue was treated with 15 m1 of an aqueous 10% Na2C03 solution, the precipitate was filtered off, washed with 3% ammonia and dried on air to give the as pale yellow crystals (400 mg, 1.4 mmol, 68 %, yield).
N—(Z-methoxyethyl)-3,4-dinitrobenzamide (I—52) —119— 123+ -0 a O"?!1+ \/\O/ o o A mixture of 3.4—dinitrobenzoic acid (420 mg, 2.0 mmol) and PCl5 (400 mg, 1.9 mmol) was heated at 60*65°C for 1 h. After cooling 20 m] hexane was added and the mixture was stirred at room temperature until solidifying 0f the residue. Solids were filtered off, washed with 10 ml hexane and dissolved in 20 ml CHZClZ. 2.5 ml Acetic acid and 2—methcxyethanamine (0.20 g, 2.7 mmol) were added to this solution and the e was stirred at room ature for 1 day. The solvent was evaporated in , the residue was treated with 15 m1 of an aqueous 10% Na2C03 solution, the precipitate was filtered off, washed with 3% ammonia and dried on air to give the product as pale yellow crystals (390 mg, 1.5 mmol, 73 %, yield). (3,4-dinitrophenyl)(4-ethylpiperaz'm-l-yl)methanone (l—53) O O N _ VNJ finial)- A mixture of nitrcbenzoic acid (420 mg, 2.0 mmol) and PCls (400 mg, 1.9 mmol) was heated at 60—65°C for 1 h. After cooling 20 hexane was added and the mixture was stirred at room temperature until solidifying of the e. Solids were filtered off, washed with 10 ml hexane and dissolved in 20 ml CH2C12. 2.5 ml Acetic acid and lpiperazine (280 mg, 2.5 mmol) were added to this solution and the mixture was stirred at room temperature for 1 day.
The solvent was evaporated in vacuum, the residue was treated with 15 ml of an aqueous 10% Na2C03 solution, the precipitate was filtered off, washed with 3% ammonia and dried on air to give the product as pale yellow ls (340 mg, 1.1 mmol, 55%). 1H NMR (400 MHZ, DMSO“d6) 5 ppm 1.05 (t, J=7.15 Hz, 3 H), 2.26-2.49 (m, 6 H), 3.34 (bs, 2 H), 3.66 (bs, 2 H), 7.93 (dd, J28.28, J=l.51 Hz,1H),8.18 (d, J=1.51 Hz, 1 H), 8.23 (d, J=8.28 Hz, 1 H). (2-amino-1H—benzimidazol-S-yi)(4nethylpiperazinyl)methanone hydrobromide (I—54) H H—Br /\UflN%NH2N O A mixture of (3,4dinitrophenyl)(4-ethylpiperazinn1~yl)methanone (1-53) (330 mg, 1.07 mmol), 20 ml ethanol and Pd/C catalyst (0.05 g, 10% Pd) was stirred in an autoclave under —l20— hydrogen pressure 10 kg/crn2 and room temperature for 3 h. Catalyst was filtered off and cyanogen bromide (150 mg, 1.38 mmol) was added to the filtrate. After stirring at room temperature for 1 day the solvent was evaporated in vacuum, the residue suspended in 20 ml ethyl e and stirred for 30 min- Slightly rosy precipitate was filtered off, washed with ethyl acetate and dried on air to give the product (350 mg, 0.99 mmol, 92 %, .
DYRKIB kinase assay The assay was carried out by Reaction Biology Corp, Malverne, PA, USA according to specifications by Reaction Biology Corp, as detailed herein below and further described in Anastassiadis et al., Nature Biotechnology, 29 (2011) 10394045.
The substrate DYRKtide (synthetic peptide ASPLRGPPK) was dissolved in freshly prepared Base Reaction Buffer (20 mM Hepes (pH 7.5), 10 mM Mng, 1 111M EGTA, 0.02% Brij35, 0.02 myml BSA, 0.1 mM , 2 111M DTT, 1% DMSO) at a concentration of 20 nM. DYRKlB was added to the substrate solution in a concentration of 0.3 nM and gently mixed. Dilution series of the compounds according to the present ion in DMSO were prepared. Each dilution was added to a batch of the above reaction mix, followed 20 min later by addition of a mixture of ATP and ”P ATP (specific activity 0.01 uCi/nl final) to a final concentration of 10 pM. Reactions were carried out at 25°C for 120 min, followed by spotting the ons onto P81 ion exchange filter paper. Unbound phOSphate was removed by extensive washing of the ‘filters in 0.75% phosphoric acid. After subtraction of ound derived from control ons containing inactive enzyme, kinase activity data were expressed as the percent remaining kinase ty in test samples compared to vehicle (DMSO) reactions. 1C5u values and curve fits were obtained using Prism (Graph Pad Software).
DYRKlB used in the above assays are further described in the below table: Genbank Protein Clone Expression Tag Accession # Accession # N-terrninal DYRKIB NPM004705 Q9Y463 full~1ength Insect Exemplary compound dilution series, finai concentrations of compound in the assay vesscl; the individual trations and the range of concentrations covered by the on series may differ for each compound, as long as enough data points are obtained to determine the ~121— 2014/062774 compound’s IC50: DYRK 1B: 1,00E-05 M, 3,33E—O6 M, 1,1 113—06 M, 3,70E—07 M, 1,23E~07 M, 4,12E—08 M, 1,37E—08 M, 4,57E-09 M, 1,52E—09 M, 5,08E—10 M.
The followin tables show 5 ecific com ounds of the resent invention and their activit in the above kinase assay: —122~ WO 02638 ~123— 2014/062774 HN / 12 SM —<Nfi> 156 HN / 13 S/H_<Nl 111 WO 02638 29.4 18 19.5 19 M fl 9.68 N 0 HN / SMA<N, 109 “125- WO 02638 23 <fj]:::j/L:N H 0699 SHN—</’1§*"<S S/§>_fig N/N 351 -126m WO 02638 29 SM N/N 72 HN / fit“3M ~<N’NH 7.97 HN / 31 SM —<N/N 68.1 HN /; 32 —< SCHNk1 1350 33 sz“<NJN 337 _ H ~127- WO 02638 HN—< 34 SM fi’N 38.1 (ffm5} 36 SMN-<N,N 112 *~ H HN~</ f 38 SM H” 3.97 N O N SA HN / I 39 a. H 11.9 ~128~ WO 02638 42 206 43 535 44 601 45 281 —129— 2014/062774 HN / 46 SM _<N’N 15.3 R H 47 SMHN-{ND/lN/WN K/Nx/ 2.17 DYRKlB —130- WO 02638 55 20.6 —131- WO 02638 —132- WO 02638 ~133— WO 02638 “134— WO 02638 —</ 1 OE)/“ —<8i I ~135— SHN\.</ I 78 \N S 79 ]o\N s HN /N\0 \“HfixO 80 N 81 S/HN\</\N o HN41 82 SM 8 \/ Hedgehog reporter assay —136- In order to investigate the y of test compounds to inhibit the Hedgehog signaling pathway, a GlimReporter assay was performed. The "Gli Reporter — NIH3T3” cell line contains the firefly luciferase gene under the control of Gli responsive elements stably ated into murine NIHST3 cells (cells purchased from AMS Biotechnology ltd, 184 Milton Park, Abingdon 0X14 48E, UK.) The luciferase expression correlates with activation of the hedgehog signaling pathway. This cell line is validated for its se to stimulation with murine Sonic Hedgehog and to ent with inhibitors of the hedgehog signaling pathway.
A multiplexed Viability assay was used to discriminate inhibition on the pathway activity from cell ty.
Growth Medium: DMEM (Dulbecco's d Eagle Medium); 10% Fetal Calf Serum; 1% Penicillin/Streptomycin; 500ug/ml Geneticin (G418 Stock 50mg/ml).
Assay Medium: OptinEM® Reduced Serum Medium; 0,33% Calf Serum; 1% non—essential amino acids; lmM Nanpyruvate; lOmM HEPES; 1% llin/Streptomycin. .000 cells per well were seeded into a white 96 well plate in 100ul growth medium and incubated over night at 37°C and 5% C02. After removing the supernatant the test compounds and controls were added in different concentrations in a final volume of 45m and incubated for 111 at 37°C and 5% (302. For the stimulation of the Hedgehog y Sui of lOug/ml concentrated murine SHH (or mSHH; murine sonic hedgehog protein) was added to the cells.
A final concentration of lug/ml mSHH and 0.1% DMSO was reached per well. After incubation for 2411 at 37°C the cells were igated for viability and reporter activity.
Viability: For the determination of the viability of the treated cells the CellTiter—FluorTM Kit from Promega comprising the fluorogenic, cell—permeant peptide substrate (glycylphenyla1anyl—aminofluorocoumarin GF-AFC was used. Roughly, only proteases of viable cells are able to cleave the GFuAFC. By this cleavage the fluorescent AFC is set free and Can be detected in a fluorescence reader. For this assay lOul of GF—AFC substrate (CellTiter—Fluorm, Promega #66082) was d in End assay buffer from the ter~ FluorTM Kit and will of this dilution was added per well to the cells and incubated for 30 min at 37°C. The fluorescence was measured with an excitation of 380w400nm and an emission of 505nm. “137“ Reporter activity: The firefly luciferase reporter activity was detected with the ONE—GloTM Luciferase Assay System from Promega. For this assay 50u1 ONE—Glo luciferase reagent (Promega #E6120, contains cell lysis buffer and Iuciferin) was added to each well and incubated at room temperature for 5 min. Luminescence was detected in a plate reader and served as a measure for reporter activity.
In the above hedgehog assay, compounds 4, 12, 17, 26, 2’7, 28, 29, 32, 41, 44, and 46 show an K350 of3—10 uM, compounds 1, 2, 5, 6, ll, 13, 14, 19, 25 and 45 Show an 1050 of 1-3 uM and compounds 3, 7, 8, 9, 10, 22, 23, 35 and 47 show an K350 of less than I aM.
Xenograft assay A xenograft assay with L3 .6131 cancer cells was prepared as follows: 1 x 105 L3.6p1 (Bruns et al., 1999) human metastatic atic adenocarcinoma cells in 25% el (BI) Bioscieuces, NJ, USA) were injected aneously into the lower flanks of Foxnlnu/nu nude mice (Charles River Laboratories, USA). The compound of example 5 was stered p.o. daily with lOOmgfltg/day, dissolved in a e of 20% Glycofurol 75, 20% Oleic acid and 60% Olive oil; administration was started at the same day of injection of tumor cells. As a ve control, separate s were administered solvent vehicle without active compound. The tumor volume was measured with a caliper and calculated according to the formula [4/3 x a x (length/2) x (width/2) x (height/2). Results are showu in Fig. l, the p value was < 0.01. The animals’ weight was essentially unchanged over the course of the experiment. —138—

Claims (13)

What we claim is:
1. A compound of formula (I) or a solvate or salt thereof, wherein the X1-azol moiety is ed at the 5- or 6- on of the 2,3-dihydrobenzofuran moiety, n is an integer from 0 to 2; m is an integer from 0 to 3; p is an integer from 0 to 4; R1 is H; R2 is H; R3 is H; R4 is H; X1 is independently selected from the group comprising NRn, O and S; Rn is independently selected from the group comprising H, alkyl, aralkyl, haloalkyl, haloalkoxy, OH, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CONH2, -CONH(R’), -CO(R’), -COO(R’), and ’); A is a monocyclic heteroaromatic ring system consisting of 5 ring atoms, or a bicyclic heteroaromatic ring system ting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein optionally one to three further ring atoms are heteroatoms independently selected from the group comprising O, S and N and wherein the remaining ring atoms are carbon atoms; RA is independently selected from the group comprising H, halogen, CN, NO2, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -OR’, -CO-R’, -COO-R’, - ’, -NHCO-R’, -CON(R’)2, -NR’CO-R’, -NR’-CONR’, -NR’-COOR’, -S-R’, - SO-R’, -SO2-R’, -NHSO2-R’, -SO2NH-R’, NHR’, -O-CO-R’, -R’-O-R’, R ’, -R’-NH-R’, -R’-CONH-R’, -R’-NHCO-R’, -CONH-alkyl-O-R’, -CONH-alkyl-R’, - lkyl-O-R’, -NHCO-alkyl-R’, -alkyl-R’, -CO-R’-alkyl, , -NHR’, NH2, -S-R’, -S-alkyl-R’ and alkyl-R’; R’ is independently selected from the group comprising H, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; wherein any of the entioned alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may independently be substituted with one or more, particularly one to three, more particularly one or two substituents R’’, wherein R’’ independently selected from the group comprising C1alkyl n, C1haloalkyl, OH, C1alkoxy, C1haloalkoxy, nitro, -NH2, -N(C1alkyl)2, -NH(C1alkyl), -NHCO(C1alkyl), -CONH2, -CONH(C1 alkyl), -CO(C1alkyl), -COH, 1alkyl), -COOH and –CN; wherein each alkyl group is independently a linear or branched C1-C6 alkanyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the total number of ring atoms in each aryl group is independently 6 to 14; wherein the total number of ring atoms in each heteroaryl group is independently 5 to 14; n each lkyl group independently comprises 3 to 10 carbon atoms; wherein each heterocycloalkyl group is, independently, a 5- to 10-membered mono- or polycyclic ring system; wherein each kyl group independently denotes an alkyl group wherein one or more of the hydrogen atoms on the hydrocarbon chain are replaced by halogen atoms; wherein each alkoxy group independently denotes an O-alkyl group, the alkyl group being as defined above; wherein each alkylthio group independently denotes an -S-alkyl group, the alkyl group being as defined above; wherein each haloalkoxy group independently denotes an O-haloalkyl group, haloalkyl group being as defined above; and wherein each alkylamino group independently denotes an yl or N-dialkyI group, the alkyl group being as defined above.
2. A compound according to claim 1, wherein A is a monocyclic heteroaromatic ring system consisting of 5 ring atoms, or a bicyclic heteroaromatic ring system consisting of 9 ring atoms, wherein at least one of the ring atoms is an N atom, wherein ally one or two further ring atoms are N atoms or one further ring atom is an O or S atom, or one further ring atom is an N atom and one ring atom is an O or S atom, and wherein the remaining ring atoms are carbon atoms, n A is optionally substituted with one or two substituents RA ed from the group comprising H, CN, NO2, NH2, N(alkyl)2, halogen OH, alkoxy, kyl, alkyl, haloalkoxy, alkoxyalkyl, heterocycloalkyl, -heterocycloalkyl-alkyl, -heterocycloalkyl- COO-alkyl, heteroaryl, -COOH, -COO-alkyl, aralkyl, aryl, -aryl-halogen, -CO-N(alkyl)2, -CONH-(alkyl), -CONH-alkyl-alkoxy, -CONH- cycloalkyl, -CONH-alkyl-heterocycloalkyl, -CO-heterocycloalkyl-alkylheterocycloalkyl , -CO-heterocycloalkyl, -CO-heteroaryl, -CO-aryl, -CO-alkyl, -SO2- alkyl, -S-alkyl, -S-alkyl-COO-alkyl, and -S-aralkyl, or a e or salt thereof.
3. A compound according to one of claim 1 or 2, wherein A is a monocyclic or bicyclic heteroaromatic ring system selected from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazole, imidazole, triazole, thiadiazole, and oxadiazole, wherein A is optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, Br, OH, C1alkyl, C1alkoxy, CF3, OCF3, -COOH, -COO-(C1- 2-alkyl), benzyl, phenethyl, , fluorophenyl, C1alkyl)2, -CONH-(C1 alkyl), -CONH-(C1alkyl)-O(C1alkyl), -CONH-(C3cycloalkyl), -CONH-(C1alkyltetrahydrofuryl ), -CO-piperazinyl-(C1alkyl)-tetrahydrofuranyl, -CO-morholinyl, -CO- pyrrolidinyl, -CO-(methyl-piperazinyl)-, -SO2(C1alkyl), -S-(C1alkyl), -S-benzyl, -S- (chlorophenylmethyl), -S-phenethyl, -CO-thienyl, -CO-pyrrolyl, -CO-piperidinyl, -CO- piperidinyl-COO-(C1alkyl), morpholinyl, C1alkylpiperazinyl, C1alkylthiazolyl, pyridyl, -CO-phenyl, -S-(C1alkyl)-COO-(C1alkyl), NH2, N(C1alkyl)2, alkyl, and -alkyl)-O(C1alkyl), and wherein, when A is benzoxazole, benzothiazole or benzimidazole, A may optionally further be substituted with a halogen atom, and wherein, when A is le, A may ally r be substituted with a methyl group, or a solvate or salt thereof.
4. A compound according to any one of claims 1 to 3, wherein the X1-azol moiety is attached at the 5- position of the 2,3-dihydrobenzofuran mioety.
5. A compound according to claim 1, wherein the X1-azol moiety is attached at the 5- position of the 2,3-dihydrobenzofuran moiety; X1 is independently ed from the group sing NRn, O and S; Rn is independently selected from the group comprising H, methyl, ethyl, OH, -CONH2, -CONH-methyl, and ethyl; R1 is H; R2 is H; R3 is H; R4 is H; A is independently ed from the group comprising thiazole, oxazole, pyrazole, pyrrole, benzoxazole, benzothiazole, benzimidazole, imidazole, le, thiadiazole, and oxadiazole; wherein A is optionally substituted with a substituent RA selected from the group comprising H, CN, F, Cl, Br, OH, lkyl, C1alkoxy, CF3, OCF3, -COOH, -COO-(C1- 2-alkyl), benzyl, phenethyl, phenyl, fluorophenyl, -CO-N(C1alkyl)2, -CONH-(C1 alkyl), -CONH-(C1alkyl)-O(C1alkyl), -CONH-(C3cycloalkyl), -CONH-(C1 alkyl-tetrahydrofuryl), -CO-piperazinyl-(C1alkyl)-tetrahydrofuranyl, -CO- morholinyl, -CO-pyrrolidinyl, -CO-(methyl-piperazinyl)-, -SO2(C1alkyl), -S-(C1 alkyl), -S-benzyl, -S-(chlorophenylmethyl), -S-phenethyl, ienyl, -CO-pyrrolyl, - CO-piperidinyl, -CO-piperidinyl-COO-(C1alkyl), morpholinyl, C1alkylpiperazinyl, C1alkylthiazolyl, pyridyl, -CO-phenyl, -S-(C1alkyl)-COO-(C1alkyl), NH2, N(C1 alkyl)2, alkyl, and -(C1alkyl)-O(C1alkyl); and wherein, when A is benzoxazole, benzothiazole or benzimidazole, A may ally r be substituted with a halogen atom, and wherein, when A is thiazole, A may optionally further be substituted with a methyl group, or a solvate or salt thereof.
6. A compound according to claim 1, wherein the X1-azol moiety is attached at the 5- position of the 2,3-dihydrobenzofuran moiety, X1 is S; A is a monocyclic or bicyclic heteroaromatic ring system selected from the group comprising 1H-imidazolyl, 1H-1,2,4-triazolyl, 1H-benzo[d]imidazolyl, pyridin- 2-yl, 1,3,4-thiadiazolyl, 1H-pyrazolyl, 1,3-thiazolyl, and 1,2,4-thiadiazolyl; wherein A is optionally substituted with a tuent RA selected from the group comprising F, Cl, Br, CN, , -SO2-Me, OMe, CF3, -CO-N(Me)2, -CO-N(Me)2, 5-(4- ((tetrahydrofuranyl)methyl)piperazinecarbonyl, -COO-Et, morpholinecarbonyl, OCF3, -COO-Me, OH, -CO-NHMe, -S-Me, pyrrolidincarbonyl, -CO-NH-C2H4-OMe, - S-iPr, cyclopropylcarbamoyl, 4-methylpiperazinecarbonyl, -S-nPr, COOH, -S-benzyl, -S-(4-chlorobenzyl), -S-iBu, ((tetrahydrofuranyl)methyl)carbamoyl, phenethyl, -S- phenethyl, -CO-thienyl, -CO-pyrrolyl, -CO-piperidinyl, -CO-(4ethoxycarbonylpiperidinyl ), morpholinyl, 4-methyl-piperazinyl, 5-methyl-thiazolyl, n- 4-yl, -CO-phenyl, -S-(CH2)-COOMe, NH2, -CO-C1alkyl, 3-fluorophenyl, acetyl, - methylthio, and methoxymethyl; and wherein, when A is zo[d]imidazolyl, A may optionally further be substituted with a ne atom, and when A is 1,3-thiazolyl, A may optionally r be substituted with a methyl group, or a e or salt thereof.
7. A compound according to any one of claims 1 to 6, wherein said compound is selected from the group comprising No. Structure N N 47 S N N N O H S HN 52 S N N N O 76 S N O S HN 81 O or a solvate or salt thereof.
8. A compound according to any one of claims 1 to 7, or a solvate or salt thereof for use in the treatment of a medical condition selected from the group comprising cancer of the breast, esophagus, intestinal tract, gastro-intestinal stromal tumors, pancreas, prostate, biliary tract, bladder, basal cell carcinoma, oblastoma, rhabdomyosarcoma, glioma, small-cell lung cancer, oral squamous cell carcinoma, melanoma, colorectal cancer, non-small cell lung cancer, osteosarcoma, glioblastoma, chronic lymphacytic leukemia, c myeloid leukemia, multiple a, acute myeloid leukemia, ovarian cancer, meningioma, and liver cancer .
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a solvate or salt thereof and one or more pharmaceutically able excipients.
10. Use of a compound ing to any of claims 1 to 7, or a solvate or salt thereof in the manufacture of a medicament for the treatment of a medical ion selected from the group comprising cancer of the breast, esophagus, gastrointestinal tract, gastro-intestinal stromal tumors, pancreas, prostate, y tract, bladder, basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, glioma, small-cell lung cancer, oral us cell carcinoma, melanoma, colorectal cancer, non-small cell lung cancer, osteosarcoma, glioblastoma, chronic lymphacytic leukemia, chronic myeloid leukemia, multiple myeloma, acute myeloid leukemia, ovarian cancer, meningioma, and liver cancer.
11. A compound according to claim 1, substantially as herein described or exemplified.
12. A ceutical ition according to claim 9, substantially as herein described or exemplified.
13. A use according to claim 10, substantially as herein described or exemplified.
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