# Patent

## Title
Thiazole and thiophene analogues, and their use in treating autoimmune diseases and cancers

## Abstract

Thiazole and thiophene compounds are disclosed having utility in treating inflammatory conditions, immunoinflammatory conditions, autoimmune diseases, and cancers. Methods for the synthesis of these compounds are also disclosed.

## Background
This application is a divisional of application Ser. No. 12/296,173, filing date Mar. 23, 2009; which was the national stage of international application PCT/US2007/066068, international filing date Apr. 5, 2007; which claimed the benefit both of the Apr. 7, 2006 filing date of United States provisional patent application 60/790,105, and of the Apr. 26, 2006 filing date of United States provisional patent application 60/795,430 under 35 U.S.C. §119(e); the complete disclosures of all of which are hereby incorporated by reference in their entirety.


TECHNICAL FIELD
This invention pertains to compounds and methods that are useful in blocking intracellular signal transduction factors, and in preventing or treating inflammation, autoimmune diseases, and cancer.
BACKGROUND ART
Thiazole and thiophene derivatives have been used as therapeutic agents for such things as to treat neurological disorders, migraine, pain, cancer, inflammation, and autoimmune disease. Aminothiazole compounds substituted at 5th position with substituents such as acyl, aroyl, nitro etc. have also been used for these purposes.
There is abundant evidence that T-lymphocytes orchestrate both the initiation and the propagation of the immune response through the secretion of protein mediators known as cytokines and chemokines. Cytokines and chemokines have been implicated in a number of inflammatory diseases. Inappropriate responses of T-lymphocytes have been associated with a range of immune-related diseases, including allergies, autoimmune diseases, asthma, psoriasis, rheumatoid arthritis, and transplant rejections.
Major functions of T lymphocytes include assisting B cells in the production of antibodies, cooperating with macrophages and related cell types to enhance their capacity to destroy microorganisms, acting as antigen-specific cytotoxic cells, and producing a family of cytokines and chemokines that have profound effects on the function of other cell types. The T cell has a highly-evolved specific antigen recognition system. T cells are activated following engagement of the T cell receptor (TCR), and the receipt of additional co-stimulatory signals. There are specific cytokines and growth factors that stimulate T cells to proliferate and differentiate.
Transcription factors regulate inducible gene expression. In activated T cells, transcription factors such as activator protein-1 (AP-1) regulate interleukin-2 (IL-2), IL-3, GM-CSF, and matrix metalloproteinases, while nuclear factor-κB (NF-κB) regulates transcription of the proinflammatory cytokines IL-1, IL-6, IL-8 and tumor necrosis factor α (TNFα). The ability of transcription factors to bind DNA and modulate gene transcription is tightly regulated in normal cells. Signal transduction pathways regulate cellular responses to stress and play a critical role in inflammation.
The AP-1 transcription factor comprises homo- or heterodimer proteins of the leucine zipper family. The leucine zipper family includes Fos (Fra-1, Fra-2, Fos-B, Fos-B2 and c-Fos), and Jun (c-Jun, JunB and JunD). The Jun family of proteins is widely known, and forms both homo- (Jun-Jun) and hetero- (Jun-Fos) dimers. Three mitogen activated kinase pathways (MAP) (ERKs, JNKs and p38) directly up regulate Fos family genes by phosphorylation. It appears that JNK pathways indirectly up regulate c-Jun expression.
The activated AP-1 complex translocates into the nucleus, where it initiates cytokine production. A variety of extracellular signals stimulate AP-1 activity, including tumor promoters, UV irradiation, growth factors, cytokines, neurotransmitters, and Ras oncoprotein.
The NF-κB transcription factor belongs to Rcl family of proteins, which primarily comprises homo- and heterodimeric proteins. The most commonly found combinations are p50/p65 heterodimers and p50/p50 homodimers. NF-κB is normally present in the cytoplasm in an inactive form, bound to inhibitory kappa B (IκB) protein. Several extracellular stimuli such as TNFα, IL-1, certain mitogens and stress factors activate the signaling pathway leading to IκB kinase (IKK), which phosphorylates IκB. Phosphorylated IκB undergoes degradation by 26S proteosome, releasing NF-κB, which translocates to the nucleus and initiates transcription.
Nuclear factor of activated T cells (NFAT) transcription factors play a critical role in transcriptional regulation of IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, TNFα, and GM-CSF. NFAT proteins are expressed in T cells, B cells, NK cells, mast cells, macrophages, and endothelial cells. NFAT's nuclear functions are regulated by cooperative interactions with AP-1. When certain ligands bind to receptors such as Fcg receptors on macrophages and NK cells, the histamine and thrombin G protein coupled receptors on endothelial cells, and Fce receptors on mast cells and basophils, phospholipase C is activated and inositol triphosphate (IP3) is generated. Calcium is then mobilized, and calcium- and calmodulin-dependent phosphatase calcineurin are activated. Calcineurin regulates the localization and transcriptional function of NFAT via dephosphorylation. Several kinases, including JNK, ERK, and p38, inhibit NFAT activation via phosphorylation at the NFAT regulatory domain where calcineurin binds.
Since many diseases are caused by the inappropriate production of proteins, many prior therapies have focused on inhibiting the function or activity of individual effector proteins. These treatments have not always proved effective, and have sometimes been associated with undesirable side effects.
There is an unfilled need for new compounds to treat inflammation, autoimmune diseases, and cancers. There is an unfilled need for compounds that will inhibit the transcription of one or more of AP-1, NF-κB, and NFAT transcriptional activation in T cells. Each of these transcription factors is regulated by a distinct signaling pathway involving several proteins including different kinases. There is an unfilled need for compounds that also inhibit the kinase(S) that regulates the activation of the transcription factors AP-1, NF-κB, and NFAT.
Transcriptional Inhibitors, Post-Transcriptional Inhibitors, and Multi-Pathway Inhibitors for Cancer Treatment
Most current anticancer treatments and drug discovery programs focus on targeting a single gene (for example, her2/neu or VEGF) or a single pathway (for example, kinase activation). However, cancer is a multifactor process involving the expression of many different proteins. This is reflected in the observation that many current clinical trials involve combinations of different drugs. A significant drawback to combined therapies is that each drug typically has its own associated side effects, and the combination of multiple drugs can lead to an increase in the number or intensity of side effects. There is an unfilled need for single compounds that can act upon multiple pathways and targets involved in cancers, for example, single compounds that can act against angiogenesis, growth, and metastasis, processes which involve diverse proteins (for example, VEGF, her2/neu receptor, and matrix metalloproteases, respectively). Classical drug discovery approaches, targeting each protein separately, are unlikely to find single compounds that serendipitously act upon other targets and pathways. There is an unfilled need for single compounds to inhibit the production of different proteins involved in different pathways.
U.S. Pat. No. 6,630,589 discloses screens for identifying small molecules capable of preventing the production of proteins at the post-transcriptional level, and discloses a small molecule that blocked her2/neu protein synthesis. Although the precise mechanism of action of this molecule was not elucidated, it may involve translational regulation. The regulation of other poorly translated proteins in cancer may be due to increased levels of the cap binding protein, eIF4E, which is often found in cancer cells, and the levels of which have been correlated with clinical recurrence. There is an unfilled need for compounds to target highly cap-dependent translation pathways, as such compounds could affect many genes involved in cancer growth and progression with reduced effects on normal cells.
Transcriptional regulation also plays an important role in the production of proteins involved in cancers; for example, NF-κB- and AP-1-inducible genes are targets for the development of anticancer agents. There is an unfilled need for single compounds that selectively inhibit the expression of multiple genes involved in cancers. There is an unfilled need for small molecules for treating cancers. Many current clinical trials involve relatively large molecules, such as monoclonal antibodies, recombinant proteins, peptide vaccines, siRNAs, and antisense RNA. While many of these approaches have shown promise, particularly monoclonal antibodies and recombinant proteins, they typically require injection and are usually expensive. Peptide vaccines and siRNAs are still in early stages of development, but would presumably also require injections and be expensive. Gene therapy and antisense strategies have had more failures than successes.
The usual approach in mechanism-based drug discovery is first, to optimize molecular properties against a single target, and then, to modify the molecule to have better “drug-like” properties. However, cancer is a complex disease that results from perturbations in as many as six different intracellular regulatory systems. A drug that affects a single target or pathway may therefore not be very effective against the heterogeneous distribution of cellular phenotypes that is typical of most cancers. The individual compounds of this invention affect multiple targets and pathways. Given the diversity of the proteins involved in different pathways, the conventional drug discovery approach, targeting a particular protein, is unlikely to develop single compounds to affect multiple pathways. The novel compounds instead prevent the production of critical proteins in multiple pathways by targeting transcriptional or post-transcriptional regulatory processes.
General transcriptional inhibitors, those affecting transcription of all mRNA, would be too toxic. Inhibition of specific transcriptional factors is desirable. NF-κB and AP-1 are the targets for the novel anti-cancer therapeutics. NF-κB and AP-1 pathways play an important role in promoting metastases, tumor progression, angiogenesis, and chemoresistance. Many genes involved in cancer (e.g., IL-6, IL-8, MMP-9, COX-2, and MCP-1) are regulated by the combined action of NF-κB and AP-1. Activated AP-1 and NF-κB are found in transformed keratinocytes, pancreatic cancers, and head and neck squamous cell carcinoma cell lines.
Inhibition of NF-κB and AP-1 by various natural products, including macrolides, endovanilloids, and EGCG has been demonstrated to have anti-inflammatory effects. EGCG has been studied for anticancer activities. Curcumin, derived from the plant Curcuma longa, has been demonstrated to down-regulate NF-κB and AP-1, and is also being studied as an anticancer agent. While existing work with these compounds demonstrates that inhibitors of NF-κB and AP-1 can be useful as anti-cancer agents, natural products can be costly to purify and usually are not very potent, requiring high dosages to elicit substantial anti-cancer activity. Structural modification and formulation of these natural products is a possibility in principle, but has proven to be challenging in practice. Other genes that are involved in angiogenesis and tumor growth are constitutively transcribed and regulated at the translational level in cancer cells. Thus targeting NF-κB and AP-1 alone may not inhibit many of the critical targets in cancer growth and metastasis.
The translation initiation factors eIF4E, eIF4F, and eIF4G, and mTOR have been shown to play a significant role in tumor progression. The factor eIF4E is elevated in most human breast and head and neck cancers, and its overexpression has been correlated with elevated angiogenic growth factors and by hypoxia. In head and neck tumors, elevated eIF4E levels have been associated with increased levels of VEGF, FGF-2, microvessel density, and poor outcome. In breast cancer, high eIF4E levels have also been associated with poor clinical outcome.
DISCLOSURE OF THE INVENTION
We have discovered new compounds that block the activation of one or more transcription factors (TFs), particularly NF-κB, AP-1, and NFAT. Without wishing to be bound by this hypothesis, we believe that the compounds act by inhibiting a family of specific kinases. Administering the novel compounds causes a decrease in one or more specific proinflammatory proteins, including I1-1, IL-2, I1-8, and TNF-α, which have been associated with tissue and organ damage in diseases such as rheumatoid arthritis, osteoarthritis, other autoimmune disorders, transplant rejection, and cancers. The compounds of the present invention are useful in treating these conditions, and more generally are useful as anti-inflammatory agents. The novel compounds may be administered by injection, and in many cases may be administered orally, a distinct advantage over most existing treatments, which usually require injection.
While it would seem extremely unlikely that a single agent could inhibit all three of these important, yet diverse, pathways leading to protein production, we have, in two different cell lines, identified at least four compounds (designated PMCR112 (example 225), PMCR 147 (example 244), PMCH24 (example 116), and PMCH16 (example 134)) that are capable of inhibiting both NF-κB and also highly cap-dependent translation. These four compounds and their analogs offer the potential for potent, safe, small molecule inhibitors of several proteins that are critical to the progression, growth and metastasis of breast cancer, other cancers, and inflammation.
The novel small molecule, multipathway inhibitors target many of the same genes that are targeted by other therapies that are currently in clinical trials, while having better bioavailability and being less expensive to produce.
The novel compounds are thiazole or thiophene derivatives. Methods for the synthesis of these compounds are also considered to be within the scope of this invention. The compounds have the following general structure I, as described more specifically below.




We have developed a NF-κB/AP-1 translation screen in HEK293 cells. We have also developed a highly cap-dependent translation screen in FaDu cells. Both screening systems can, for example, use a luciferin-luciferase system as an indicator. In addition, we have used a previously-developed screen involving the post-transcriptional regulatory element ARE of TNF-α to screen for anti-inflammatory and anti-cancer activity.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a generic scheme for the synthesis of a group of compounds within the scope of this invention.
FIG. 2 depicts a generic scheme for the synthesis of a group of compounds within the scope of this invention.
FIG. 3 depicts a generic scheme for the synthesis of a group of compounds within the scope of this invention.
FIG. 4 depicts a generic scheme for the synthesis of a group of compounds within the scope of this invention.
FIG. 5 depicts a generic scheme for the synthesis of a group of compounds within the scope of this invention.
FIG. 6 illustrates the percent of individual clones of FaDu cells stably transfected with the FGF 5′UTR or without the UTR that express luciferase activity in one of four groups (<100 units, 100-1000 units, 1100-5000 units, and >5000 units).
FIG. 7 illustrates the effect of 10 nM rapamycin on luciferase expression as measured from FaDu cells stably transfected with the FGF 5′UTR (FaDu UTR) or without the UTR (FaDu FF).
FIG. 8 illustrates the effect of 1 μM of each of 39 compounds dissolved in DMSO (0.3%) on luciferase expression as measured from FaDu cells stably transfected with the FGF 5′UTR (FaDu UTR) with values normalized to that of a DMSO control. Each bar represents the average and standard deviation of two experiments, each experiment testing each compound in triplicate.
FIG. 9 illustrates the effect of 14 selected compounds tested at each of six concentrations dissolved in DMSO (0.3%) on FaDu cell viability using an MTT assay with values normalized to that of a DMSO control. Each bar represents the result of one experiment.
FIG. 10 illustrates the effect of 1 μM of each of 14 selected compounds tested at each of six concentrations dissolved in DMSO (0.3%) on luciferase expression as measured from RAW 264.7 cells stably transfected with a vector expressing luciferase under the post-transcriptional control of the ARE from TNF-α with values normalized to that of the average expression level at the lowest tested concentration. Each bar represents the average and standard deviation of testing each compound in triplicate.
FIG. 11 illustrates the effect of 1 μM of each of 39 compounds dissolved in DMSO (0.3%) on luciferase expression as measured from HEK cells stably transfected with a plasmid expressing luciferase under the control of the NF-κB promoter with values normalized to that of a DMSO control. Each bar represents the average and standard deviation of two experiments, each experiment testing each compound in triplicate.
FIG. 12 illustrates the effect of 14 selected compounds tested at six concentrations dissolved in DMSO (0.3%) on luciferase expression as measured from HEK cells stably transfected with a plasmid expressing luciferase under the control of the NF-κB promoter with values normalized to that of the average expression level at the lowest tested concentration. Each bar represents the average and standard deviation of testing each compound in triplicate.
FIG. 13 illustrates the effect of 1 μM of each of 39 compounds dissolved in DMSO (0.3%) on luciferase expression as measured from HEK cells stably transfected with a plasmid expressing luciferase under the control of the AP-1 promoter with values normalized to that of a DMSO control. Each bar represents the average and standard deviation of two experiments, each experiment testing each compound in triplicate.
FIG. 14 illustrates the effect of 14 selected compounds tested at six concentrations dissolved in DMSO (0.3%) on luciferase expression as measured from HEK cells stably transfected with a plasmid expressing luciferase under the control of the AP-1 promoter with values normalized to that of the average expression level at the lowest tested concentration. Each bar represents the average and standard deviation of testing each compound in triplicate.
FIG. 15 illustrates the effect of 4 selected compounds tested at six concentrations dissolved in DMSO (0.3%) on TNF-α-induced luciferase expression as measured from HEK cells stably transfected with a plasmid expressing luciferase under the control of the NF-κB promoter with values normalized to that of the average expression level at the lowest tested concentration. Each bar represents the average and standard deviation of two experiments, each experiment testing each compound in triplicate.



MODES FOR CARRYING OUT THE INVENTION
Without wishing to be bound by this hypothesis, it is believed that the novel compounds function by inhibiting the kinase(s) that regulate the activation of TFs, such as NF-κB or AP-1. By disrupting the production of the activated TFs, the synthesis of pathological proteins is blocked at the transcription level, including proinflammatory cytokines associated with inflammation, autoimmune diseases and cancers. The compounds of this invention have activity in both preventing and treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis and transplant rejection (tissue and organ), autoimmune diseases (e.g., multiple sclerosis and asthma), and cancers.
Compounds that may be used in this invention include those having one of the following general structures:




wherein:

    A=C(R2) or N
    B═CH or N
    D(R)═CH2 or O or N(R)
    R═H, or substituted or unsubstituted C1-4 alkyl, aryl, aroyl, heteroaryl, or heteroaroyl
    R1=substituted or unsubstituted aryl, aroyl, heteroaryl, heteroaroyl, C1-4 alkoximino, or C1-8 esters
    X=chloro or bromo
    R2═—H, or -chloro, -fluoro, -bromo, —CH3, —OCH3, —NHCOCH3, —SCH3, SO2CH3, —SOCH3, CF3, or NH2 
    n=1 or 2
    R3═—CH3, —C2H5, —NH2, or substituted or unsubstituted aryl or heteroaryl, or —NMe2 
    R4═—NEt2, —NMe2, or —NH2 
    R5=substituted or unsubstituted aryl, heteroaryl, aroyl, heteroaroyl, —COOCH3, —COOC2H5, —COOaryl, or —COOheteroaryl
    R6=substituted or unsubstituted aryl or heteroaryl
    E=O or S


These expressions should be given their common meaning as understood by those in the art. For example, “C1-4 alkyl” should be interpreted to include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, and isobutyl.
As another example, “heteroaryl” means an aryl group with one or more heteroatom substitutions, such as mono or disubstitutions with halogen atoms such as chlorine, fluorine, and bromine; or methoxy; or methyl, or trifluoromethyl; or amino.
As another example, “aroyl” refers to the radical of an aromatic acid, e.g., benzoyl.
As another example, “substituted” refers to common substituents including mono- or di- or tri-substitutions with moieties such as trifluoromethoxy, methoxy, chlorine, bromine, fluorine, methyl, methoxy, pyridyl, furyl, triazyl, piperazinyl, pyrazoyl, imidazoyl, and the like. There may be further substitutions, such as piperazines having alkyl or aryl substitution, or thiazole and thiophene derivatives with heteroaryl, wherein R1 has one of the structures as those shown below:
wherein:




    R7═—H or —Br
    R8=Aryl or heteroaryl


Thiophene derivatives were prepared by the following procedure: The first step was the Willgerodt-Kindller reaction. In the second step, the reaction mixture was treated with triethylorthoformate and morpholine to produce an enamine, which on further treatment with an activated chloromethanone or activated chloromethane compound gave the desired thiophene derivative.
Thiazole derivatives were prepared by the following procedure: Nitriles were converted into amidines or guanidine and then treated with isothiocynates to obtain thiourea derivatives, followed by treatment with an activated chloromethanone or activated chloromethane to obtain the desired thiazole derivative.
EXAMPLES
The initial examples below describe the syntheses of representative compounds of this invention, and their intermediates. Those examples are followed by examples of in vivo assays, and experimental data showing the activity of various compounds.
Abbreviations: “M.P.”=melting point. “LC MS”=liquid chromatography/mass spectrometry. “Rf”=retention factor
Example 1
1-Morpholin-4-yl-2-phenyl-ethanethione
A solution of acetophenone (10.0 gm; 0.083 mol); sulphur (2.65 gm; 0.083 mol); and Morpholine (7.22 gm; 0.083 mol) with a catalytic amount of p-toluenesulphonic acid monohydrate refluxed 6 hour at 120° C. Then the mixture was poured into methanol (75 ml) and cooled at −20° C. for 6 hr. Precipitates were filtered out and washed with cold methanol (50 ml). Yield 7.5 gm (40.7%) M.P. 115-116° C. LC MS: 221 (M+1), Rf: 0.49, Mobile phase: acetonitrile:toluene 3:7.
Example 2
2-(4-Methanesulfonyl-phenyl)-1-morpholin-4-yl-ethanethione
The title compound was prepared from 1-(4-methanesulfonyl-phenyl)-ethanone (10.0 gm; 0.051 mol) as otherwise described in Example 1. Yield 9.0 gm (60%) M.P. 198-199° C., Rf: 0.56, LC MS: 300 (M+1).
Example 3
N-[4-(2-morpholin-4-yl-2-thioxo-ethyl)-phenyl]-acetamide
The title compound was prepared from N-(4-acetyl-phenyl)-acetamide (10.0 gm; 0.056 mol) as otherwise described in example 1. Yield 8.0 gm (50.72%) M.P. 210-212° C., Rf: 0.46, LC MS: 279 (M+1).
Example 4
2-(4-Chloro-phenyl)-1-morpholin-4-yl-ethanethione
The title compound was prepared from 1-(4-chloro-phenyl)-ethanone (10.0 gm; 0.065 mol) as otherwise described in Example 1. Yield 10.0 gm (60.15%) M.P. 175-177° C., Rf: 0.68, LC MS: 254.5 and 256.5 (M+2).
Example 5
1-Morpholin-4-yl-2-pyridine-3-yl-ethanethione
The title compound was prepared from 1-pyridine-3yl-ethanone (10.0 gm; 0.082 mol) as otherwise described in Example 1. Yield 8.0 gm (48.39%) M.P. 158-160° C., Rf: 0.58 LC MS: 223 (M+1).
Example 6
1-Morpholin-4-yl-2-pyridine-4-yl-ethanethione
The title compound was prepared from 1-pyridine-4-yl-ethanone (10.0 gm; 0.082 mol) as otherwise described in Example 1. Yield 7.68 gm (47.39%) M.P. 162-163° C., Rf: 0.41, LC MS: 223 (M+1).
Example 7
2-(4-Methanesulfanyl-phenyl)-1-morpholin-4-yl-ethanethione
The title compound was prepared from 1-(4-methylsulfanyl-phenyl)-ethanone (10.0 gm; 0.082 mol) as otherwise described in Example 1. Yield 9.0 gm (60%) M.P. 225-227° C., Rf: 0.48, LC MS: 268 (M+1).
Example 8
2-(4-Methanesulfonyl-phenyl)-1-(4-methyl-piperazine-1-yl)-ethanethione
The title compound was prepared from 1-(4-methylsulfonyl-phenyl)-ethanone (10.0 gm; 0.051 mol) and 1-Methyl-piperazine (5.0 gm; 0.051 mol) as otherwise described in Example 1. Yield 9.0 gm (56.70%) M.P. 172-177° C., Rf: 0.59, LC MS: 313 (M+1).
Example 9
1-Morpholin-4-yl-2-p-tolyl-ethanethione
The title compound was prepared from 1-p-tolyl-ethanone (10.0 gm; 0.075 mol) as otherwise described in Example 1. Yield 10.0 gm (56.91%) M.P. 182-185° C., Rf: 0.64, LC MS: 236 (M+1).
Example 10
2-(4-Methoxy-phenyl)-1-morpholin-4-yl-ethanethione
The title compound was prepared from 1-(4-methoxy-phenyl)-ethanone (10.0 gm; 0.067 mol) as otherwise described in Example 1. Yield 10.0 gm (56.91%) M.P. 145-147° C., Rf: 0.65, LC MS: 252 (M+1).
Example 11
(Z)-1,3-Di-morpholin-4-yl-2-phenyl-propenethione
A mixture of 1-morpholin-4-yl-2-phenyl-ethanethione (5.0 gm; 0.023 mol) and morpholine (1.92 gm; 0.023 mol) and triethyl orthoformate (25 ml) was refluxed for 18 hr. The reaction mixture was then evaporated under reduced pressure and poured into methanol (25 ml) and cooled at −20° C. for 6 hr. The precipitate was filtered out and dried. Yield 3.6 gm (50%). M.P. 152-154° C., Rf: 0.62, LC MS: 319 (M+1).
Example 12
(Z)-2-(4-Methanesulfonyl-phenyl)-1,3-dimorpholine-4-yl-propenethione
The title compound was prepared from 2-(4-methanesulfonyl-phenyl)-1-morpholin-4-yl-ethanethione (5.0 gm; 0.013 mol) as otherwise described in Example 11. Yield 5.0 gm (75.51%) M.P. 167-169° C. Rf: 0.25, LC MS: 397 (M+1).
Example 13
N-{4-[(Z)-1-(Morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide
The title compound was prepared from N-[4-(2-morpholin-4-yl-2-thioxo-ethyl)-phenyl]-acetamide (5.0 gm; 0.018 mol) as otherwise described in Example 11. Yield 4.0 gm (59.26%) M.P. 145-147° C. Rf: 0.36, LC MS: 376 (M+1).
Example 14
(Z)-2-(4-Chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione
The title compound was prepared from 2-(4-chloro-phenyl)-1-morpholin-4-yl-ethanethione (5.0 gm; 0.020 mol) as otherwise described in Example 11. Yield 5.40 gm (72.00%) M.P. 134-135° C. Rf: 0.54, LC MS: 352.5 (M+2).
Example 15
(Z)-1,3-Dimorpholin-4-yl-2-pyridin-3-yl-propenthione
The title compound was prepared from 1-morpholin-4-yl-2-pyridine-3-yl-ethanethione (5.0 gm; 0.023 mol) as otherwise described in Example 11. Yield 3.6 gm (46.23%) M.P. 133-135° C., Rf: 0.65, LC MS: 320 (M+1).
Example 16
(Z)-1,3-Dimorpholin-4-yl-2-pyridin-4-yl-propenthione
The title compound was prepared from 1-morpholin-4-yl-2-pyridine-4-yl-ethanethione (5.0 gm; 0.023 mol) as otherwise described in Example 11. Yield 3.0 gm (39.68%) M.P. 122-125° C., Rf: 0.49, LC MS: 320 (M+1).
Example 17
(Z)-2-(4-Methanesulfanyl-phenyl)-1,3-dimorpholine-4-yl-propenethione
The title compound was prepared from 2-(4-methanesulfanyl-phenyl)-1-morpholin-4-yl-ethanethione (5.0 gm; 0.013 mol) as otherwise described in Example 11. Yield 5.0 gm (75.51%) M.P. 189-190° C., Rf: 0.38, LC MS: 366 (M+1).
Example 18
(E)-2-(4-Methanesulfonyl-phenyl)-1,3-bis-(4-methyl-piperazin-1-yl)-propenethione
The title compound was prepared from 2-(4-methanesulfonyl-phenyl)-1-(4-methyl-piperazine-1-yl)-ethanethione (5.0 gm; 0.016 mol) as otherwise described in Example 11. Yield 3.4 gm (59.51%) M.P. 202-203° C., Rf: 0.58, LC MS: 423 (M+1).
Example 19
(Z)-1,3-Dimorpholin-4-yl-2-p-tolyl-propenethione
The title compound was prepared from 1-morpholin-4-yl-2-p-tolyl-ethanethione (5.0 gm; 0.015 mol) as otherwise described in Example 11. Yield 3.6 gm (53.82%) M.P. 212-213° C., Rf: 0.72, LC MS: 334 (M+1).
Example 20
(Z)-2-(4-Methoxy-phenyl)-1,3-dimorpholin-4-yl-propenethione
The title compound was prepared from 2-(4-methoxy-phenyl)-1-morpholin-4-yl-ethanethione (5.0 gm; 0.020 mol) as otherwise described in Example 11. Yield 3.8 gm (54.83%) M.P. 112-113° C., Rf: 0.32, LC MS: 350 (M+1).
The above intermediates may be used in the preparation of thiophene analogs. Intermediates for preparing thiazole analogs may be made as described below, as in Example 21.
Example 21
General Procedure
To a solution of isothiocyanate (0.0368 moles) in toluene was added N,N-diethyl acetamidine (0.0368 moles) in toluene at 0° C. in 10 min. The reaction mixture was stirred for 2 hours at 25°. The precipitate was filtered and washed with hexane to give the desired adduct.
Example 22
({[(1E)-1-(Diethylamino)methylidene]amino}carbonothioyl)carbamate
The title compound was made as otherwise described in Example 21 as a white solid. (91% yield) M.P. 119° C. Rf: 0.58 (Dichloromethane:Ethyl acetate: 1:0.3), IR (KBr, cm−1): 3170, 3080, 2970, 2930, 1736, 1656, 1568, 1544, 1476, 1464, 1448, 1348, 1296, 1276, 1192, 1140, 1096, 1072, 1028, 952, 780, 744, 712, 616, Mass (LC-MS, M+1): 246
Example 23
({[(1E)-1-(Diethylamino)ethylidene]amino}carbonothioyl)carbamate
The title compound was made as otherwise described in Example 21 as a white solid. (85% yield) M.P. 109° C., Rf: 0.55 (Dichloromethane:Ethyl acetate: 1:0.3) IR (KBr, cm−1): 3120, 3095, 2980, 2920, 1741, 1654, 1558, 1540, 1480, 1448, 1333, 1290, 1276, 1096, 1072, 952, 786, 750. Mass (LC-MS, M+1): 232.
Example 24
1-[1-Diethylamino-eth-(E)-ylidene]-3-methyl-thiourea
The title compound was made as otherwise described in Example 21 as white crystals (56% yield) M.P. 133-134° C., Rf: 0.58 (Dichloromethane:Ethyl acetate 1:0.3), IR (KBr, cm−1): 3180, 3110, 3000, 2950, 1590, 1520, 1500, 1476, 1428, 1372, 1352, 1316, 1280, 1244, 1220, 1175, 1148, 1100, 1084, 1048, 1024, 1004, 960, 896, 848, 832, 795, 756, 716, 700, 608, Mass (LC-MS, M+1): 250
Example 25
1-Benzoyl-3-[1-diethylamino-eth-(E)-yliden]-thiourea
The title compound was made as otherwise described in Example 21 as yellow crystals, (58% Yield) M.P. 111-112° C. Rf: 0.75 Dichloromethane:Ethyl acetate (1:0.3) IR (KBr, cm−1): 3190 (br), 2970, 2940, 1688, 1576, 1548, 1492, 1480, 1452, 1376, 13604, 1336, 1284, 1264, 1208, 1144, 1076, 1016, 880, 800, 712, 688, 660, Mass (LC-MS, M+1): 278.
Example 26
1-(4-Chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea
The title compound was made as otherwise described in Example 21 as white crystals (86.8% yield). M.P. 149-150° C. Rf: 0.63 (Dichloromethane:Ethyl acetate: 1:0.3), IR (KBr, cm−1): 3170 (br), 3090, 3000, 2940, 1596, 1584, 1524, 1492, 1424, 1372, 1352, 1312, 1280, 1240, 1176, 1148, 1088, 1008, 844, 816, 788, 724. Mass (LC-MS, M+, M+2): 284, 286.
Example 27
({[(1E)-(Diethylamino)(phenyl)ethylene]amino}carbonothioyl)carbamate
The title compound was made as otherwise described in Example 21 as a light yellow solid Yield: 80%, Melting point: 114-116° C., Rf: 0.32 (Toluene:acetonitrile 0.8:0.2), IR (KBr, cm−1): 3178, 2978, 1745, 1577, 1515, 1335, 1287, 1207, 1153, 1095, 1032, 787, 769, 689, 1HNMR (400 MHz, CDCl3) δ [ppm]=1.2 (t, 3H, OCH2—CH3); 1.3 (t, 3H, —N—CH2—CH3; 1.5 (t, 3H, —N—CH2—CH3); 3.2-3.4 (q, 2H, —N—CH2—CH3); 3.6-3.7(q, 2H, —N—CH2—CH3); 4.1-4.3 (q, 2H, OCH2—CH3); 7.2-7.4 (m, 5H, C6H5); 8.1 (S, 1H, NH), LCMS (M+1): 308.
Example 28
({[(1E)-(Diethylamino)(phenyl)methylene]amino}carbonothioyl)carbamate
The title compound was made as otherwise described in Example 21. as light yellow solid % Yield: 85, Melting point: 118-119° C., Rf: 0.32 (Toluene:Acetonitrile 0.7:0.3) IR (KBr, cm−1): 3178, 2983, 1745, 1571, 1529, 1339, 1288, 1208, 1096, 1153, 1042, 1041, 770, 716, 682, 1HNMR (400 MHz, CDCl3) δ [ppm]=1.3-1.4 (t, 3H, —N—CH2—CH2); 1.5-1.6 (t, 3H, —N—CH2—CH3); 3.2-3.4 (q, 2H, —N—CH2—CH3); 3.6-3.7 (q, 2H, —N—CH2—CH3); 3.8 (S, 3H, OCH3); 7.2-7.4 (m, 5H, C6H5); 8.1 (S, 1H, NH), LCMS (M+1): 294
Example 29
1-[1-Diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea
The title compound was made as otherwise described in Example 21, as a white solid Yield: 45%, Melting point: 54-56° C., Rf: 0.37 (Toluene:Acetonitrile 0.7:0.3), LCMS (M+1): 242
Example 30
1-Benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea
The title compound was made as otherwise described in Example 21 as a white solid Yield: 59%, M.P. 135-137° C., Melting point: 138-140° C., Rf: 0.3 l(Dichloromethane), IR (KBr, cm−1): 3180, 2990, 2930, 1584, 1536, 1508, 1428, 1336, 1308, 1276, 1236, 1208, 1188, 1144, 1088, 1064, 1020, 996, 948, 912, 884, 836, 780, 764, 744, 688, 640, 1HNMR (400 MHz, CDCl3) δ [ppm]=1.1-1.3 (t, 3H, —N—CH2—CH3); 1.4-1.6 (t, 3H, —N—CH2—CH3); 3.2-3.4 (q, 2H, —N—CH2—CH3); 3.6-3.8 (q, 2H, —N—CH2—CH3); 7.2-7.4 (m, 10H, C6H5, C6H5)); 8.2 (S, 1H, NH), LC-MS, M+1: 312.
Example 31
1-[1-Diethylamino-1-phenyl-meth-(E)-ylidene]-3-phenyl-thiourea
The title compound was made as otherwise described in Example 21. Yield: 56%, M.P. 110-112° C. Rf: 0.35 (Dichloromethane), 1H-NMR (400 MHz, CDCl3) δ [ppm]=1.1-1.3 (t, 3H, —N—CH2—CH3); 1.4-1.6 (t, 3H, —N—CH2—CH3); 3.2-3.4 (q, 2H, —N—CH2—CH3); 3.6-3.8 (q, 2H, —N—CH2—CH3); 7.2-7.4 (m, 10H, C6H5, CO—C6H5)); 9 (S, 1H, NH), LCMS (M+1): 340.
Example 32
1-(4-Chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea
The title compound was made as otherwise described in Example 21. Yield: 74%, Melting point: 138-140° C., Rf: 0.41(Toluene: Acetonitrile0.7:0.3), IR (KBr, cm−1: 3222, 2983, 1564, 1518, 1489, 1343, 1314, 1301, 1286, 1236, 1147, 1090, 1072, 823, 697, 1H-NMR (400 MHz, CDCl3) δ [ppm]=1.1-1.3 (t, 3H, —N—CH2—CH3); 1.4-1.6 (t, 3H, —N—CH2—CH3); 3.2-3.4 (q, 2H, —N—CH2—CH3); 3.6-3.8 (q, 2H, —N—CH2—CH3); 7.2-7.8 (m, 10H, C6H5, C6H5)); 8.2 (S, 1H, NH), LCMS (M+1): 346, 348
Example 33
1-[1-Diethylamino-1-phenyl-eth-(E)-ylidene]-3-methyl-thiourea
The title compound was made as otherwise described in Example 21. M.P: 141-143° C., Rf: 0.76, IR (KBr cm−1): 3207, 1596, 1559, 1375, 1360, 1314, 1284, 1233, 1145, 1080, 1020, 760, 715, 666. LCMS (M+1): 264
Example 34
1-[1-Diethylamino-1-phenyl-eth-(E)-ylidene]-3-phenyl-thiourea
The title compound was made as otherwise described in Example 21. M.P: 133-135° C., Rf: 0.54 IR (KBr cm−1): 3226, 2973, 1589, 1569, 1582, 1469, 1454, 1432, 1340, 1280, 1240, 1193, 1145, 1119, 1074, 1016, 699. LCMS (M+1): 326
Example 35
1-(4-Chloro-phenyl)-3-[1-diethylamino-1-phenyl-eth-(E)-ylidene]-thiourea
The title compound was made as otherwise described in Example 21. M.P:142-145° C., Rf: 0.42 IR (KBr cm−1): 3207, 2934, 1592, 1559, 1489, 1361, 1308, 1279, 1234, 1144, 1088, 1012, 844, 813, 770, 710. LCMS (M+1): 298
Example 36
({[(1E)-(Diethylamino)(benzyl)methylene]amino}carbonothioyl)carbamate
The title compound was made as otherwise described in Example 21. M.P: 165-167° C., Rf: 0.39 IR (KBr cm−1): 2994, 1757, 1589, 1562, 1359, 1260, 1226, 1129, 1032, 905, 763, 717. LCMS (M+1): 308
Example 37
({[(1E)-(Diethylamino)(benzoyl)ethylene]amino}carbonothioyl)carbamate
The title compound was made as otherwise described in Example 21. M.P: 120-122° C., Rf: 0.62 IR (KBr cm−1): 3192, 2983, 1757, 1591, 1574, 1351, 1275, 1206, 1162, 1135, 1032, 908, 768, 727. LCMS (M+1): 322
Example 38
1-Benzoyl-3-[1-diethylamino-1-phenyl-eth-(E)-ylidene]-thiourea
The title compound was made as otherwise described in Example 21. M.P: 160-163° C., Rf: 0.68, IR (KBr cm−1): 3241, 2983, 16891504, 1306, 1281, 1246, 1169, 1142, 1126, 787, 686. LCMS (M+1): 354
Example 39
4-[3-Phenyl-5-(4,5,6-trimethoxy-pyridine-2-yl)-thiophen-2-yl]-morpholine
(Z)-1,3-Di-Morpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 2-chloroethyl-3,4,5-trimethoxy-pyridine (0.604 gm, 0.0016 moles) were added to acetonitrile (10 ml). The reaction mixture was stirred at room temperature for 24 hour, and then cooled to −20° C. for 6 hr. The precipitate was separated and washed with cold acetonitrile (5 ml). Yield 57%. LC MS (M+1) 441. Rf: 0.65, M.P: 124° C.
Example 40
4-[5-(Methoxy-4,6-dimethyl-pyridine-2-yl)-3-phenyl-thiophene-2-yl]-morpholine
The title compound was made from (Z)-1,3-di-morpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 2-Chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.293 gm, 0.0016 moles) as otherwise described in Example 39. Yield 47%. LC MS (M+1) 381, Rf; 0.36 M.P: 136-8° C.
Example 41
4-{5-[5-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-yl]-3-phenyl-thiophene-2-yl}-morpholine
The title compound was made from (Z)-1,3-di-morpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 2-chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0016 moles) as otherwise described in Example 39. Yield 32%. LC MS (M+1) 435, Rf; 0.45 M.P: 145-7° C.
Example 42
(5-Morpholin-4-yl-4-phenyl-thiophen-2-yl)-phenyl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and phenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 68%. LC MS (M+1) 350, Rf: 0.54 M.P: 184-6° C.
Example 43
(5-Morpholin-4-yl-4-phenyl-thiophen-2-yl)-p-tolyl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.016 moles) and p-methylphenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 70%. LC MS (M+1) 364. Rf: 0.67, M.P: 198° C.
Example 44
(4-Methoxy-phenyl)-(5-morpholin-4-yl-4-phenyl-thiophene-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.016 moles) and p-methoxyphenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 380, Rf: 0.61 M.P: 158-9° C.
Example 45
(4-Chloro-phenyl)-(5-morpholin-4-yl-4-phenyl-thiophene-2-yl)-methanone
The title compound was made from (Z)-1,3-di-morpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and p-chlorophenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 58%. LC MS (M+2) 385, Rf; 0.58, M.P: 187-8° C.
Example 46
(2,4-Dichloro-phenyl)-(5-morpholin-4-yl-4-phenyl-thiophene-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 2,4-dichlorophenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+2) 419, Rf: 0.54, M.P: 198-9° C.
Example 47
(4-Methylsulfanyl-phenyl)-(5-morpholin-4-yl-4-phenyl-thiophene-2-yl)-methanone
The title compound was made from (Z)-1,3-di-morpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 4-methanesulfanylphenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 396. Rf: 0.62, M.P: 165° C.
Example 48
(4-Methylsulfonyl-phenyl)-(5-morpholin-4-yl-4-phenyl-thiophene-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 4-methanesulfonylphenacyl bromide (0.0016 moles) as otherwise described in Example 39. Yield 42%. LC MS (M+1) 426. Rf: 0.63, M.P: 175° C.
Example 49
N-[4-(5-Morpholin-4-yl-4-thiophene-2-carbonyl)-phenyl]-acetamide
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 1-[4-(2-Bromo-acetyl)-phenyl]-propan-2-one (0.0016 moles) as otherwise described in Example 39. Yield 36%. LC MS (M+1) 394, Rf; 0.52, M.P: 202-3° C.
Example 50
(5-Morpholin-4-yl-4-phenyl-thiophene-2-yl)-pyridine-3-yl-methanone
The title compound was made from (Z)-1,3-di-morpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 2-bromo-1-pyridin-3yl-ethanone (0.0016 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 351. Rf: 0.69, M.P: 180° C.
Example 51
(5-Morpholin-4-yl-4-phenyl-thiophene-2-yl)-pyridine-4-yl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenethione (0.500 gm, 0.0016 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0016 moles) as otherwise described in Example 39. Yield 38%. LC MS (M+1) 351. Rf: 0.60, M.P: 149° C.
Example 52
4-[3-(4-Methanesulfonyl-phenyl)-5-(5-methoxy-4,6-dimethyl-pyridine-2-yl)-thiophene-2-yl]-morpholine
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0013 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 459. Rf: 0.61, M.P: 152° C.
Example 53
4-{3-(4-Methanesulfonyl-phenyl)-5-[5-methyl-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-yl]-thiophene-2-yl}-morpholine
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 2-chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0013 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 513. Rf: 0.59, M.P: 156° C.
Example 54
[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-phenyl-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and phenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 68%. LC MS (M+1) 428. Rf: 0.67, M.P: 173° C.
Example 55
[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-p-tolyl-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and p-methylphenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 70%. LC MS (M+1) 364. Rf: 0.70, M.P: 189° C.
Example 56
[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-(4-methoxy-phenyl)-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and p-methoxyphenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 442. Rf: 0.72, M.P: 154° C.
Example 57
(4-Chloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and p-chlorophenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 58%. LC MS (M+2) 462. Rf: 0.73, M.P: 169° C.
Example 58
(2,4-Dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 2,4-dichlorophenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+2) 497. Rf: 0.62, M.P: 170° C.
Example 59
[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-(4-methylsulfanyl-phenyl)-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 4-methanesulfanylphenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 474. Rf: 0.42, M.P: 160° C.
Example 60
(4-Methanesulfonyl-phenyl)-[4-(4-methansulfonyl-phenyl)5-morpholin-4-yl-thiophene-2-yl]-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 4-methanesulfonylphenacyl bromide (0.0013 moles) as otherwise described in Example 39. Yield 42%. LC MS (M+1) 506. Rf: 0.47, M.P: 190° C.
Example 61
N-{4-[4-(4-Methansulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2carbonyl]-phenyl}-acetamide
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 1-[4-(2-bromo-acetyl)-phenyl]-propan-2-one (0.0013 moles) as otherwise described in Example 39. Yield 36%. LC MS (M+1) 485. Rf: 0.49, M.P: 129° C.
Example 62
[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-pyridin-3-yl-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0013 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 429. Rf: 0.24, M.P: 122° C.
Example 63
[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-pyridin-4-yl-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (0.500 gm, 0.0013 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0013 moles) as otherwise described in Example 39. Yield 38%. LC MS (M+1) 429. Rf: 0.39, M.P: 128° C.
Example 64
N-{4-[5-(5-Methoxy-4,6-dimethyl-pyridine-2-carbonyl)2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 466. Rf: 0.65, M.P: 145° C.
Example 65
N(4-{5-[5-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-2-morpholin-4-yl-thiophen-3-yl}-phenyl)-acetamide
The title compound was made from (N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 2-chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 454. Rf: 0.75, M.P: 155° C.
Example 66
N-[4-(5-Benzoyl-2-morpholin-4yl-thiophene-3-yl)-phenyl]-acetamide
The title compound was made from (N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and phenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 68%. LC MS (M+1) 437. Rf: 0.89, M.P: 165° C.
Example 67
N-{4-[5-(4-Methyl-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from (N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and p-methylphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 70%. LC MS (M+1) 421. Rf: 0.69, M.P: 168° C.
Example 68
N-{4-[5-(4-Methoxy-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and p-methoxyphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 437. Rf: 0.62, M.P: 198° C.
Example 69
N-{4-[5-(4-Chloro-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and p-chlorophenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 58%. LC MS (M+2) 442. Rf: 0.54, M.P: 120° C.
Example 70
N-{4-[5-(2,4-Dichloro-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 2,4-dichlorophenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+2) 476. Rf: 0.56, M.P: 145° C.
Example 71
N-{4-[5-(4-Methansulfanyl-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 4-methanesulfanylphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 453. Rf: 0.67, M.P: 167° C.
Example 72
N-{4-[5-(4-Methansulfonyl-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 4-methanesulfonylphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 42%. LC MS (M+1) 485. Rf: 0.52, M.P: 177° C.
Example 73
N-{4-[5-(4-acetylamino-benzoyl)-2-morpholin-4-yl-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 1-[4-(2-Bromo-acetyl)-phenyl]-propan-2-one (0.0014 moles) as otherwise described in Example 39. Yield 36%. LC MS (M+1) 464. Rf: 0.54, M.P: 152° C.
Example 74
N-{4-[2-Morpholin-4-yl-5-(pyridine-3-carbonyl)-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 2-bromo-1-pyridin-3yl-ethanone (0.0014 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 408. Rf: 0.69, M.P: 144° C.
Example 75
N-{4-[2-Morpholin-4-yl-5-(pyridine-4-carbonyl)-thiophene-3-yl]-phenyl}-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (0.500 gm, 0.0014 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0014 moles) as otherwise described in Example 39. Yield 38%. LC MS (M+1) 408. Rf: 0.82, M.P: 149° C.
Example 76
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-(5-methoxy-4,6-dimethyl-pyridin-2-yl)-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 466. Rf: 0.28, M.P: 160° C.
Example 77
4-{3-(4-Chloro-phenyl)-5-[5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiophen-2-yl}-morpholine
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 2-chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 454, Rf; 0.39, M.P: 177-8° C.
Example 78
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-phenyl-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and phenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 68%. LC MS (M+1) 437. Rf: 0.49, M.P: 180° C.
Example 79
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-p-tolyl-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and p-methylphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 70%. LC MS (M+1) 421. Rf: 0.52, M.P: 190° C.
Example 80
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-(4-methoxy-phenyl)-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and p-methoxyphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 437. Rf: 0.56, M.P: 120° C.
Example 81
(4-Chloro-phenyl)-[4-(4-chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and p-chlorophenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 58%. LC MS (M+2) 442, Rf; 0.52, M.P. 145-149° C.
Example 82
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-(2,4-dichloro-phenyl)-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 2,4-dichlorophenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+2) 476. Rf: 0.60, M.P: 110° C.
Example 83
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-(4-methansulfanyl-phenyl)-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 4-methanesulfanylphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 453, Rf; 0.39, M.P: 198-9° C.
Example 84
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-(4-methansulfonyl-phenyl)-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 4-methanesulfonylphenacyl bromide (0.0014 moles) as otherwise described in Example 39. Yield 42%. LC MS (M+1) 485, Rf; 0.58, M.P: 242-3° C.
Example 85
N-{4-[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-carbonyl]-phenyl}acetamide
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 1-[4-(2-bromo-acetyl)-phenyl]-propan-2-one (0.0014 moles) as otherwise described in Example 39. Yield 36%. LC MS (M+1) 464, Rf; 0.66, M.P: 125-7° C.
Example 86
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-pyridin-3-yl-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 2-bromo-1-pyridin-3yl-ethanone (0.0014 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 408. Rf: 0.63, M.P: 114° C.
Example 87
[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-pyridin-4-yl-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione (0.500 gm, 0.0014 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0014 moles) as otherwise described in Example 39. Yield 38%. LC MS (M+1) 408. Rf: 0.57, M.P: 117° C.
Example 88
4-[5-(5-Methoxy-4,6-dimethyl-pyridin-2-yl)-3-pyridin-3-yl-thiophen-2-yl]-morpholine
The title compound was made from (Z)-1,3-di-morpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 382, Rf; 0.42, M.P: 139-40° C.
Example 89
4-{5-[5-Methyl-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-3-pyridin-3-yl-thiphen-2-yl}-morpholine
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 2-chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 398. Rf: 0.58, M.P: 129° C.
Example 90
(5-Morpholin-4-yl-4-pyridin-3-yl-thiophene-2-yl)-phenyl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and phenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 68%. LC MS (M+1) 437, Rf; 0.53 M.P: 168-9° C.
Example 91
(5-Morpholin-4-yl-4-pyridin-3-yl-thiophene-2-yl)-p-tolyl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and p-methylphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 70%. LC MS (M+1) 351. Rf: 0.51, M.P: 134° C.
Example 92
(4-Methoxy-phenyl)-(5-morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and p-methoxyphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 365. Rf: 0.54, M.P: 149° C.
Example 93
(4-Chloro-phenyl)-(5-morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-methanone
The title compound was made from ((Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and p-chlorophenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 58%. LC MS (M+2) 386. Rf: 0.58, M.P: 196° C.
Example 94
(2,4-Dichloro-phenyl)-(5-morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 2,4-dichlorophenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+2) 420. Rf: 0.69, M.P: 176° C.
Example 95
(4-Methylsulfanyl-phenyl)-(5-morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-methanone
Article I. The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 4-methanesulfanylphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 397. Rf: 0.29, M.P: 182° C.
Example 96
(4-Methylsulfonyl-phenyl)-(5-morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 4-methanesulfonylphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 42%. LC MS (M+1) 429. Rf: 0.49, M.P: 147° C.
Example 97
N-[4-(5-Morpholin-4-yl-4-pyridin-3-yl-thiophen-2-carbonyl)-phenyl]-acetamide
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 1-[4-(2-bromo-acetyl)-phenyl]-propan-2-one (0.0015 moles) as otherwise described in Example 39. Yield 36%. LC MS (M+1) 408. Rf: 0.62, M.P: 120° C.
Example 98
(5-Morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-pyridin-3-yl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 2-bromo-1-pyridin-3yl-ethanone (0.0015 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 352. Rf: 0.63, M.P: 145° C.
Example 99
(5-Morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-pyridin-4-yl-methanone
The title compound was made (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0015 moles) as otherwise described in Example 39. Yield 38%. LC MS (M+1) 352. Rf: 0.64, M.P: 128° C.
Example 100
4-[5-(5-Methoxy-4,6-dimethyl-pyridin-2-yl)-3-pyridin-4-yl-thiophen-2-yl]-morpholine
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 382. Rf: 0.58, M.P: 129° C.
Example 101
4-{5-[5-Methyl5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-3-pyridin-4-yl-thiphen-2-yl}-morpholine
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 2-chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 398. Rf: 0.59, M.P: 149° C.
Example 102
(5-Morpholin-4-yl-4-pyridin-4-yl-thiophene-2-yl)-phenyl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and phenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 68%. LC MS (M+1) 351. Rf: 0.63, M.P: 122° C.
Example 103
(5-Morpholin-4-yl-4-pyridin-4-yl-thiophene-2-yl)-p-tolyl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and p-methylphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 70%. LC MS (M+1) 365, M.P: 144-5° C., Rf; 0.56.
Example 104
(4-Methoxy-phenyl)-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and p-methoxyphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 381. Rf: 0.60, M.P: 193° C.
Example 105
(4-Chloro-phenyl)-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-methanone
The title compound was made from ((Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and p-chlorophenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 58%. LC MS (M+2) 386. Rf: 0.67, M.P: 176° C.
Example 106
(2,4-Dichloro-phenyl)-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 2,4-dichlorophenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+2) 420. Rf: 0.70, M.P: 180° C.
Example 107
(4-Methylsulfanyl-phenyl)-(5-morpholin-4-yl-4-pyridin-3-yl-thiophen-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 4-methanesulfanylphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 48%. LC MS (M+1) 397. Rf: 0.59, M.P: 127° C.
Example 108
(4-Methylsulfonyl-phenyl)-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 4-methanesulfonylphenacyl bromide (0.0015 moles) as otherwise described in Example 39. Yield 42%. LC MS (M+1) 429. Rf: 0.54, M.P: 128° C.
Example 109
N-[4-(5-Morpholin-4-yl-4-pyridin-4-yl-thiophen-2-carbonyl)-phenyl]-acetamide
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 1-[4-(2-Bromo-acetyl)-phenyl]-propan-2-one (0.0015 moles) as otherwise described in Example 39. Yield 36%. LC MS (M+1) 408. Rf: 0.64, M.P: 139° C.
Example 110
(5-Morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-pyridin-3-yl-methanone
The title compound was made from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenthione (0.500 gm, 0.0015 moles) and 2-bromo-1-pyridin-3yl-ethanone (0.0015 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 352. Rf: 0.74, M.P: 124° C.
Example 111
(5-Morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-pyridin-4-yl-methanone
The title compound was made (Z)-1,3-dimorpholin-4-yl-2-pyridin-3-yl-propenthione (0.500 gm, 0.0015 moles) and 2-bromo-1-pyridin-4yl-ethanone (0.0015 moles) as otherwise described in Example 39. Yield 38%. LC MS (M+1) 352. Rf: 0.74, M.P: 124° C.
Example 112
Bis-[4-(4-methansulfonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-methanone
The title compound was made from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholine (1.0 gm, 0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 39. Yield 69%. LC MS (M+1) 672. Rf: 0.62, M.P: 235-236° C.
Example 113
N-{4-{5-[4-(4-acetylamino-phenyl)-5-morpholin-4-yl-thiophene-2-carbonyl]-2-morpholin-4-yl-thiophene-3-yl}-phenyl)-acetamide
The title compound was made from N-{4-[(Z)-1-(morpholine-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide (1.0 gm, 0.0028 moles) and 1,3-Dichloroacetone (0.0014 moles) as otherwise described in Example 39. Yield 69%. LC MS (M+1) 630. Rf: 0.52, M.P: 140-142° C.
Example 114
Bis-[4-(4-chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-methanone
The title compound was made from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholine (1.0 gm, 0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 39. Yield 69%. LC MS (M+1) 584. Rf: 0.58, M.P: 135-136° C.
Example 115
(4-Amino-2-phenylamino-thiazole-5-yl)-4-(methoxy-phenyl)-methanone
The title compound was made from 1-diaminomethyline-3-phenyl-thiourea (0.0026 moles) and p-methoxyphenacyl bromide (0.0026 moles) as otherwise described in Example 39. Yield 39%. LC MS (M+1) 325. Rf: 0.52, M.P: 222-225° C.
Example 116
[2-(4-Chloro-phenylamino)-4-pyridin-4-yl-thiazole-5-yl]-4-methoxy-phenyl)-methanone
The title compound was made from 1-[1-Amino-1-pyridin-4-yl-meth-(Z)-ylidene]3-(4-chloro-phenyl)-thiourea (0.0026 moles) and p-methoxyphenacyl bromide (0.0026 moles) as otherwise described in Example 39. Yield 50%. LC MS (M+1) 422. Rf: 0.52, M.P: 201-202° C.
Example 117
1-(4-Fluoro-phenyl)-3-[5-(4-methoxy-benzoyl)-2-phenylamino-thiazol-4-yl]-urea
(4-Amino-2-phenylamino-thiazole-5-yl)-4-(methoxy-phenyl)-methanone (0.0003 mole) in dry THF (10 ml) and p-fluorophenyl isocyanate (0.0003) were added to 5 ml THF. The reaction mixture was stirred for 2 hours. The title compound separated as a white precipitate. Yield 80%. LC MS (M+1) 463, M.P: 177-8° C., Rf; 0.39.
Example 118
Bis-(4-methyl-2-methylamino-thiazole-5-yl)-methanone
The title compound was made from 1-[1-diethylamino-eth-(z)-ylidene]-3-methyl-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 70%. LC MS (M+1) 283, M.P: 184-5° C., Rf; 0.32.
Example 119
Bis-(4-methyl-2-phenylamino-thiazole-5-yl)-methanone
The title compound was made from 1-[1-diethylamino-eth-(z)-ylidene]-3-phenyl-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 50%. LC MS (M+1) 407, M.P: 194-6° C., Rf; 0.82.
Example 120
Bis-[2-(4-Chloro-phenylamino)-4-methyl-thiazole-5-yl]-methanone
The title compound was made from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+ and M+2) 474 & 476, M.P: 184-6° C., Rf; 0.49.
Example 121
Bis-[2-(2-Benzoyl-amino)-4-methyl-thiazole-5-yl]-methanone
The title compound was made from 1-benzoyl-3-[1-diethylamino-eth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 463, M.P: 232-3° C., Rf; 0.58.
Example 122
Bis-[2-(2-Furoyl-amino)-4-methyl-thiazole-5-yl]-methanone
The title compound was made from 1-furoyl-3-[1-diethylamino-eth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 443, M.P: 198-9° C., Rf; 0.55.
Example 123
Dimethyl[carbonyl-bis(4-methyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from methyl ({[(1E)-1-(diethylamino)methylidene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 371, M.P: 188-9° C., Rf; 0.63.
Example 124
Diethyl[carbonyl-bis(4-methyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from ethyl ({[(1E)-1-(diethylamino)ethylidene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 399, M.P: Char at 284° C., Rf; 0.29.
Example 125
Bis-(2-methylamino-4-Phenyl-thiazole-5-yl)-methanone
The title compound was made from [1-diethylamino-1-phenyl-meth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-Dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 70%. LC MS (M+1) 407, M.P: Char at 280° C., Rf; 0.43.
Example 126
Bis-(2-phenylamino-4-phenyl-thiazole-5-yl)-methanone
The title compound was made from 1-[1-diethylamino-1-phenyl-meth-(Z)-ylidene]-3-phenyl-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 50%. LC MS (M+1) 531, M.P: Char at 290° C., Rf; 0.78.
Example 127
Bis-[2-(4-Chloro-phenylamino)-4-phenyl-thiazole-5-yl]-methanone
The title compound was made from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+2) 602, M.P: Char at 290° C., Rf; 0.56.
Example 128
Bis-[2-(2-Benzoyl-amino)-4-methyl-thiazole-5-yl]-methanone
The title compound was made from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 587, M.P: Char at 290° C., Rf; 0.36.
Example 129
Bis-[2-(2-Furoyl-amino)-4-phenyl-thiazole-5-yl]-methanone
The title compound was made from 1-furoyl-3-[1-diethylamino-1-phenyl-meth-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 566, M.P: Char at 260° C., Rf; 0.58.
Example 130
Dimethyl[carbonyl-bis(4-phenyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from methyl ({[(1E)-(diethylamino) (phenyl) methylene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 522, M.P: Char at 250° C., Rf; 0.63.
Example 131
Diethyl[carbonyl-bis(4-phenyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from ethyl ({[(1E)-(diethylamino) (phenyl) ethylene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 523, M.P: Char at 245° C., Rf; 0.46.
Example 132
Bis-(2-methylamino-4-benzayl-thiazole-5-yl)-methanone
The title compound was made from [1-diethylamino-1-benzyl-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 70%. LC MS (M+1) 407, M.P: Char at 268° C., Rf; 0.67.
Example 133
Bis-(2-phenylamino-4-benzayl-thiazole-5-yl)-methanone
The title compound was made from 1-[1-diethylamino-1-benzyl-(Z)-ylidene]-3-phenyl-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 50%. LC MS (M+1) 531, M.P: Char at 285° C., Rf; 0.53.
Example 134
Bis-[2-(4-Chloro-phenylamino)-4-benzayl-thiazole-5-yl]-methanone
The title compound was made from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-benzyl-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-Dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+2) 602, M.P: 265-6° C., Rf; 0.28.
Example 135
Bis-[2-(2-benzoyl-amino)-4-benzayl-thiazole-5-yl]-methanone
The title compound was made from 1-benzoyl-3-[1-diethylamino-1-benzyl-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 587, M.P: 294° C., Rf; 0.47.
Example 136
Bis-[2-(2-furoyl-amino)-4-benzayl-thiazole-5-yl]-methanone
The title compound was made from 1-furoyl-3-[1-diethylamino-1-benzyl-(Z)-ylidene]-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 566, M.P: Char at 265° C., Rf; 0.58.
Example 137
Dimethyl[carbonyl-bis(4-benzyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from methyl ({[(1E)-(diethylamino) (benzyl)methylene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 522, M.P: 189-90° C., Rf; 0.69.
Example 138
Diethyl[carbonyl-bis(4-benzyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from ethyl ({[(1E)-(diethylamino) (benzyl)methylene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as otherwise described in Example 112. Yield 60%. LC MS (M+1) 523, M.P: 145-6° C., Rf; 0.67.
Example 139
2-(2-Chloroacetyl amino) benzoic acid
Anthranilic acid (50 g, 0.365 mole) was dissolved in dichloromethane. An equimolar amount of triethylamine (TEA) was added, and the reaction mass was cooled to 0° C. Chloroacetyl chloride (41.12 g, 0.365 mol) was added over a period of 15 minutes, while maintaining the temperature at 0° C. The reaction mass was then stirred at room temperature (rt) for 4 hr. A white solid precipitated, which was filtered and washed with ample water, and then dried and recrystallized to obtain 55 g of the title compound. Yield: 64.5%, M.P. 183-5° C., LC-MS: 214(M+1), Rf: 0.47
Example 140
2-Chloromethyl-3-(4-chlorophenyl)-3H-quinazolin-4-one
2-(2-Chloroacetyl amino) benzoic acid 20 g (0.094 mole) and an equimolar amount of p-chloro aniline were dissolved in toluene and stirred at rt for 30 minutes. An equimolar amount of phosphorus trichloride was then added with continued stirring. The temperature was raised, and the reaction mixture was refluxed until thin-layer chromatography (TLC) indicated completion of the reaction. The reaction mixture was then cooled to rt, and the solvent was evaporated under vacuum. To the residue was added water, and the mixture was neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulphate. The solvent was removed under vacuum, and the residue was recrystallized from methanol to produce 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one. Yield: 26.5%, M.P. 234-5° C., LC-MS: 305(M+1), Rf: 0.62
Example 141
2-Chloromethyl-3-(2-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and o-chloroaniline as otherwise described in Example 140. Yield 25.6%, M.P. 195-6° C., LC-MS: 305(M+1), Rf: 0.61.
Example 142
2-Chloromethyl-3-(3-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and m-chloroaniline as otherwise described in Example 140. Yield: 27.5%, M.P. 202-5° C., LC-MS: 305(M+1), Rf: 0.59.
Example 143
2-Chloromethyl-3-(4-methyl-phenyl)-3H-quinazolin-4-one
2-(2-Chloroacetyl amino) benzoic acid 20 g (0.094 mole) and an equimolar amount of p-methylaniline were dissolved in toluene and stirred at rt for 30 minutes. An equimolar amount of phosphorus trichloride was added with continued stirring. The temperature was raised, and the reaction mixture was refluxed until thin-layer chromatography (TLC) indicated completion of the reaction. To the residue was added water, and the mixture was neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulphate. The solvent was removed under vacuum, and the residue was recrystallized from methanol to produce 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one. Yield: 36%, M.P. 265-6° C., LC-MS: 285(M+1), Rf: 0.64
Example 144
2-Chloromethyl-3-(2-methyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and o-methylaniline as otherwise described in Example 143. Yield: 29%, M.P. 205-6° C., LC-MS: 285(M+1), Rf: 0.54.
Example 145
2-Chloromethyl-3-(3-methyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and m-methylaniline as otherwise described in Example 143. Yield: 32.5%, M.P. 183-5° C., LC-MS: 285(M+1), Rf: 0.58.
Example 146
2-Chloromethyl-3-(4-methoxy-phenyl)-3H-quinazolin-4-one
2-(2-Chloroacetyl amino) benzoic acid 20 g (0.094 mole) and an equimolar amount of p-methoxyaniline were mixed in toluene and stirred at rt for 30 minutes. An equimolar amount of phosphorus trichloride was added with continued stirring, and the temperature was raised and the reaction mixture was refluxed until TLC indicated completion of reaction. The reaction mixture was then cooled to rt, and the solvent was evaporated under vacuum. To the residue was added water, and the reaction mixture was neutralized with sodium bicarbonate and extracted with chloroform. The solvent was removed under vacuum, and the residue was recrystallized from methanol to produce 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one. Yield: 34%, M.P. 154-5° C., LC-MS: 301(M+1), Rf: 0.57.
Example 147
2-Chloromethyl-3-(2-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and o-methoxyaniline as otherwise described in Example 146. Yield: 31.4%, M.P. 193-4° C., LC-MS: 301(M+1), Rf: 0.62.
Example 148
2-Chloromethyl-3-(3-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and m-methoxy aniline as otherwise described in Example 146. Yield: 32.2%:, M.P. 180-2° C., LC-MS: 301(M+1), Rf: 0.62.
Example 149
2-Chloromethyl-3-(phenyl)-3H-quinazolin-4-one
2-(2-Chloroacetyl amino) benzoic acid 20 g (0.094 mole) and an equimolar amount of aniline were dissolved in toluene and stirred at rt for 30 minutes. An equimolar amount of phosphorus trichloride was added with continued stirring, and the temperature was raised and the reaction mixture was refluxed until TLC indicated completion of reaction. The reaction mixture was then cooled to rt, and the solvent was evaporated under vacuum. To the residue was added water, and the reaction mixture was neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulphate. The solvent was removed under vacuum, and the residue was recrystallized from methanol to produce2-Chloromethyl-3-(phenyl)-3H-quinazoline-4-one. Yield: 28.3%, M.P. 152-3° C. LC-MS: 271(M+1), Rf: 0.48.
Example 150
2-Chloromethyl-3-(p-acetyl phenyl)-3H-quinazolin-4-one
The title compound was prepared from 2-(2-chloroacetyl amino) benzoic acid and acetophenone as otherwise described in Example 146. Yield: 36%, M.P. 180-1° C. LC-MS: 313(M+1), Rf: 0.54.
Example 151
2-Acetylamino-benzoic acid
The title compound was prepared from anthranilic acid and acetyl chloride as otherwise described in Example 139. Yield: 65.3%, M.P. 157-8° C., LC-MS: 170(M+1), Rf: 0.51.
Example 152
3-(4-Chlorophenyl)-2-methyl-3H-quinazolin-4-one
The title compound was prepared from 2-acetylamino-benzoic acid and p-chloroaniline as otherwise described in Example 140. Yield: 37.5%, M.P. 141-2° C., LC-MS: 271(M+1), Rf: 0.61.
Example 153
2-(3-Chloro-2-oxo-propyl)-3-(4-chlorophenyl)-3H-quinazolin-4-one
3-(4-Chloro-phenyl)-2-methyl-3H-quinazolin-4-one 40 g (0.15 moles) was dissolved in dry tetrahydrofuran (THF), cooled to 0° C., and then maintained between 0° C. to 5° C. An equimolar amount of chloroacetyl chloride in dry THF was added. The reaction mixture was stirred between 0° C. to 5° C. for 2 hrs, and then at rt for 3 hrs. The reaction mixture was then poured over crushed ice, stirred well, filtered, and recrystallized from methanol to produce 2-(3-Chloro-2-oxo-propyl)-3-(4-chloro-phenyl)-3H-quinazolin-4-one. Yield: 26.4%, M.P.>275° C. LC-MS: 347(M+1), Rf: 0.52.
Example 154
(4-Methyl-5-(4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
A solution of carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester (1 gm, 0.001 mole) and an equimolar amount of 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one in acetonitrile was heated to 80° C. for 4 hrs and then cooled to rt. The title compound precipitated was filtered and recrystallized in methanol. Yield: 48%, M.P. 248-251° C., LC-MS: 407(M+1), Rf: 0.52.
Example 155
(4-Methyl-5-(4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid methyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-methyl ester and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 41.4%, M.P.>275° C., LC-MS: 393(M+1).
Example 156
2-(4-Methyl-2-methylamino-thiazol-5-yl)-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-methyl-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 32.6%, M.P. 209-10° C., LC-MS: 348(M+1), Rf: 0.5.
Example 157
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 72.36%, M.P. 260-2° C., LC-MS: 411(M+1), Rf: 0.51.
Example 158
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.46%, M.P. 230-232° C., LC-MS: 445(M+1), Rf: 0.32.
Example 159
[5-(4-Oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzenecarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 78.94%, M.P. 245-7° C., LC-MS: 469(M+1), Rf: 0.41.
Example 160
[5-(4-Oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzenecarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.96%, M.P.>275° C., LC-MS: 454(M+1), Rf: 0.48.
Example 161
3-Phenyl-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 78.8%, M.P. 181-2° C., LC-MS: 473(M+1), Rf: 0.67.
Example 162
N-[5-(4-Oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-Benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 74.6%, M.P.>275, LC-MS: 491(M+1), Rf: 0.70.
Example 163
4-Methyl-N-[5-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 69%, M.P.>275° C., LC-MS: 515(M+1), Rf: 0.73
Example 164
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 52.77%, M.P. 271-2° C., LC-MS: 491(M+1), Rf: 0.67.
Example 165
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 60.9%, M.P.>275° C., LC-MS: 507(M+1), Rf: 0.68.
Example 166
[4-Methyl-5-(4-oxo-3-o-tolyl-3,4-dihidro-quinazolin-2-yl)-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(Diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-Chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 42.35%, M.P.>275° C., LC-MS: 421(M+1), Rf: 0.61.
Example 167
[4-Methyl-5-(4-oxo-3-o-tolyl-3,4-dihidro-quinazolin-2-yl)-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from carbamic acid,[{(1-(Diethyl amino)ethylidene)amino}thiaoxomethyl]-methyl ester and 2-Chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.8%, M.P.>275° C., LC-MS: 407(M+1), Rf: 0.70.
Example 168
2-(4-Methyl-2-methylamino-thiazol-5-yl-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-methyl-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 30%, M.P. 218-220° C., LC-MS: 363(M+1), Rf: 0.63.
Example 169
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.7%, M.P. 227-228° C., LC-MS: 425(M+1), Rf: 0.64.
Example170
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 53.9%, M.P.>275° C., LC-MS: 459(M+1), Rf: 0.63.
Example 171
[5-(4-Oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-Chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 70.5%, M.P.>275, LC-MS: 483(M+1), Rf: 0.68.
Example 172
[5-(4-Oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 60%, M.P.>275° C., LC-MS: 469(M+1), Rf: 0.70.
Example 173
2-(2-methylamino-4-phenyl-thiazol-5-yl)-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 24.7%, M.P. 220-5° C., LC-MS: 425(M+1), Rf: 0.62.
Example 174
3-o-Tolyl-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 65.7%, M.P. 141-3° C., LC-MS: 487(M+1), Rf: 0.48.
Example 175
N-[5-(4-Oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.14%, M.P.>275° C., LC-MS: 515(M+1), Rf: 0.70.
Example176
4-Methyl-N-[5-(4-oxo-3-o-tolyl-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 59.3%, M.P.>275° C., LC-MS: 528(M+1), Rf: 0.73.
Example 177
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 55.7%, M.P. 262-3° C., LC-MS: 477(M+1), Rf: 0.52.
Example 178
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-o-tolyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 57.33%, M.P.>275° C., LC-MS: 521(M+1), Rf: 0.70.
Example 179
(4-Methyl-5-(4-oxo-3-m-tolyl-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-Chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.24%, M.P. 210-1° C., LC-MS: 421(M+1), Rf: 0.57.
Example180
[4-Methyl-5-(4-oxo-3-m-tolyl-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from carbamic acid,[{(1-(Diethyl amino)ethylidene)amino}thiaoxomethyl]-methyl ester and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 232-3° C., LC-MS: 407(M+1), Rf: 0.48.
Example 181
2-(4-methyl-2-methylamino-thiazol-5-yl)-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-methyl-thiourea and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 30.20%, M.P.>275° C., LC-MS: 363(M+1), Rf: 0.49.
Example182
2-(4-Methyl-2-phenylamino-thiazol-5-yl-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.85, M.P. 198-201° C., LC-MS: 425(M+1), Rf: 0.62
Example 183
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 51%, M.P. 236-8° C., LC-MS: 459(M+1), Rf: 0.65.
Example 184
[5-(4-Oxo-3-m-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-Chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 53.2%, M.P. 261-3° C., LC-MS: 483(M+1), Rf: 0.68.
Example 185
[5-(4-Oxo-3-m-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-Chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 51%, M.P.268-9° C. LC-MS: 469(M+1), Rf: 0.39.
Example 186
2-(2-methylamino-4-phenyl-thiazol-5-yl)-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 46.5%, M.P. 186-7° C. LC-MS: 425(M+1), Rf: 0.40.
Example 187
3-m-Tolyl-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-Diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-Chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 59.6%, M.P. 105-7° C. LC-MS: 487(M+1), Rf: 0.42.
Example 188
N-[5-(4-Oxo-3-m-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. M.P.>275° C., LC-MS: 515(M+1), Rf: 0.53.
Example189
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-m-tolyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 42.7%, M.P. 233-5° C. LC-MS: 521(M+1), Rf: 0.61.
Example 190
(4-Methyl-5-(4-oxo-3-p-tolyl-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(Diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-Chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 54.11%, M.P. 220-2° C. LC-MS: 421(M+1), Rf: 0.61.
Example 191
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 58.6%, M.P. 256-7° C. LC-MS: 425(M+1), Rf: 0.53
Example 192
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 40%, M.P.>275° C. LC-MS: 459(M+1), Rf: 0.61.
Example 193
[5-(4-Oxo-3-p-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 55.12%, M.P.>275° C., LC-MS: 483(M+1), Rf: 0.46.
Example 194
[5-(4-Oxo-3-p-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 55.35%, M.P.>275° C., LC-MS: 469(M+1), Rf: 0.61.
Example 195
2-(2-Methylamino-4-phenyl-thiazol-5-yl)-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 40.6%, M.P: 192-3° C., LC-MS: 425(M+1), Rf: 0.49.
Example 196
3-p-Tolyl-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 53.72%, M.P. 225-8° C., LC-MS: 487(M+1), Rf: 0.51.
Example 197
N-[5-(4-Oxo-3-p-tolyl-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. M.P.>275° C., LC-MS: 515(M+1), Rf: 0.42.
Example198
4-Methyl-N-[5-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-Diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-Chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 217-8° C., LC-MS: 528(M+1), Rf: 0.49.
Example 199
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 41.43%, M.P. 231-2° C., LC-MS: 477(M+1), Rf: 0.53
Example 200
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-p-tolyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.33%, M.P.>275° C., LC-MS: 521(M+1), Rf: 0.58
Example 201
{5-[3-(2-Methoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-yl]-thiazol-2-yl}-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 37.29%, M.P. 263-4° C., LC-MS: 437(M+1), Rf: 0.35
Example 202
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-(2-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 36.58%, M.P. 169-70° C., LC-MS: 441(M+1), Rf: 0.56
Example 203
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(2-methoxyphenyl)-3H-quinazoline-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example154. Yield: 40.72%, M.P. 225-6° C., LC-MS: 475(M+1), Rf: 0.61
Example 204
[5-(4-Oxo-3-(2-methoxyphenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 228-30° C., LC-MS: 485(M+1), Rf: 0.50
Example 205
2-(2-Methylamino-4-phenyl-thiazol-5-yl)-3-(2-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-(2-methoxyphenyl)1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 35.6%, M.P. 241-3° C., LC-MS: 441(M+1), Rf: 0.70
Example 206
3-(2-Methoxyphenyl)-2-(4-phenyl-2-phenylamino-thiazol-5yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 52.66%, M.P. 224-5° C., LC-MS: 563(M+1), Rf: 0.62
Example 207
{5-[3-(4-Methoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-yl]-thiazol-2-yl}-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 201. Yield: 44.1%, M.P. 222-4° C., LC-MS: 437(M+1), Rf: 0.66
Example 208
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-(2-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.32%, M.P. 230-2° C., LC-MS: 537(M+1), Rf: 0.62
Example 209
{5-[3-(3-Methoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-yl]-thiazol-2-yl}-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-chloromethyl-3-(3-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 46.89%, M.P. 235-6° C., LC-MS: 438(M+1), Rf: 0.34
Example 210
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-(3-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(3-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 46.34%, M.P.>275° C., LC-MS: 441(M+1), Rf: 0.38
Example 211
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(3-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(3-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 243-4° C., LC-MS: 475(M+1), Rf: 0.42
Example 212
[5-(4-Oxo-3-(3-methoxyphenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(3-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example154. Yield: 49.1%, M.P. 204-5° C., LC-MS: 499(M+1), Rf: 0.50
Example 213
3-(3-methoxyphenyl)-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-3-(3-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.52%, M.P. 250-52° C., LC-MS: 503(M+1), Rf: 0.47
Example 214
N-[5-(4-Oxo-3-(3-methoxyphenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(3-methoxyphenyl)1-3H-quinazoline-4-one as otherwise described in Example 154. M.P.195-6° C., LC-MS: 531(M+1), Rf: 0.45
Example 215
{5-[3-(4-Methoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-yl]-thiazol-2-yl}-carbamic acid ethyl ester
The title compound was prepared from Carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester and 2-Chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 44.1%, M.P.>275° C., LC-MS: 437(M+1), Rf: 0.30
Example 216
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.12%, M.P. 265-6° C., LC-MS: 441(M+1), Rf: 0.45
Example217
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(4-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.32%, M.P.>275, LC-MS: 475(M+1), Rf: 0.70
Example 218
[5-(4-Oxo-3-(4-methoxyphenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.96%, M.P. 256-7° C., LC-MS: 499(M+1), Rf: 0.65
Example 219
[5-(4-Oxo-3-(4-methoxyphenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 43.63%, M.P. 272-4° C., LC-MS: 485(M+1), Rf: 0.71
Example 220
2-(2-Methylamino-4-phenyl-thiazol-5-yl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.98%, M.P. 235-6° C., LC-MS: 441(M+1), Rf: 0.62
Example 221
3-(4-Methoxyphenyl)-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.52%, M.P. 135-7° C., LC-MS: 503(M+1), Rf: 0.58
Example 222
N-[5-(4-Oxo-3-(4-methoxyphenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 56.76%, M.P.>275° C., LC-MS: 531(M+1), Rf: 0.61
Example 223
4-Methyl-N-[5-(4-oxo-3-(4-methoxyphenyl)-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 52.66%, M.P.>/275° C., LC-MS: 544(M+1), Rf: 0.68
Example 224
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-(4-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 46.21%, M.P. 262-4° C., LC-MS: 493(M+1), Rf: 0.63
Example 225
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-(4-methoxyphenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-methoxyphenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.32%, M.P. 220-1° C., LC-MS: 537(M+1), Rf: 0.58
Example 226
(4-Methyl-5-(4-oxo-3-(2-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester (1 gm, 0.001 mole) and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 43.57%, M.P. 246-7° C., LC-MS: 442(M+1), Rf: 0.50
Example 227
(4-Methyl-5-(4-oxo-3-(2-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid methyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-methyl ester and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 41.30%, M.P. 243-5° C., LC-MS: 428(M+1), Rf: 0.40
Example 228
2-(4-Methyl-2-methylamino-thiazol-5-yl-3-(2-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-methyl-thiourea and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 34%, M.P. 214-5° C., LC-MS: 384(M+1), Rf: 0.30
Example 229
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-(2-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 228-9° C., LC-MS: 446(M+1), Rf 0.40
Example 230
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(2-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 237-8° C., LC-MS: 480(M+1), Rf: 0.51
Example 231
[5-(4-Oxo-3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.30%, M.P. 236-8° C., LC-MS: 504(M+1), Rf: 0.66
Example 232
[5-(4-Oxo-3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 46.98%, M.P.>275° C., LC-MS: 490(M+1), Rf: 0.60
Example 233
2-(2-Methylamino-4-phenyl-thiazol-5-yl)-3-(2-Chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-(2-chloro-phenyl) l-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 41.34%, M.P. 215-7° C., LC-MS: 446(M+1), Rf: 0.60
Example 234
3-(2-Chloro-phenyl)-2-(4-phenyl-2-phenylamino-thiazol-5yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 54.25%, M.P. 210-12° C., LC-MS: 508(M+1), Rf: 0.65
Example 235
N-[5-(4-Oxo-3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-2-yl-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 56%, M.P. 212-4° C., LC-MS: 536(M+1), Rf: 0.74
Example 236
4-Methyl-N-[5-(4-oxo-3-(2-chloro-phenyl)-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-chloromethyl-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 52.31%, M.P.>275° C., LC-MS: 549(M+1), Rf: 0.77
Example 237
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-(2-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-(2-chloro-phenyl)1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 53.1%, M.P.>275° C., LC-MS: 498(M+1), Rf: 0.72
Example 238
2-[2-(4-Chlorophenylamino)-4-phenyl-thiazol-5-yl]-3-(2-Chloro-phenyl)1-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 51.28%, M.P. 242-3° C., LC-MS: 542(M+1), Rf: 0.77
Example 239
(4-Methyl-5-(4-oxo-3-(3-chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester (1 g, 1 mmol) and 2-chloromethyl-3-(3-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 262-3° C., LC-MS: 442(M+1), Rf: 0.48
Example 240
[5-(4-Oxo-3-(3-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(3-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 47.85%, M.P. 235-6° C., LC-MS: 504(M+1), Rf: 0.52
Example 241
[5-(4-Oxo-3-(3-chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(3-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. M.P. 230-1° C., LC-MS: 490(M+1), Rf: 0.61
Example 242
(4-Methyl-5-(4-oxo-3-(4-chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester (1 g, 1 mmol) and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.81%, M.P.>275° C., LC-MS: 442(M+1), Rf: 0.56
Example 243
(4-Methyl-5-(4-oxo-3-(4-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid methyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-methyl ester and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 42.93%, M.P. >275° C., LC-MS: 428(M+1), Rf: 0.58
Example 244
2-(4-Methyl-2-methylamino-thiazol-5-yl)-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-methyl-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 41%, M.P. 195-7° C., LC-MS: 484(M+1), Rf: 0.61
Example 245
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.64%, M.P.>275, LC-MS: 446(M+1), Rf: 0.54
Example 246
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example154. Yield: 43.79%, M.P. 267-8° C., LC-MS: 480(M+1), Rf: 0.52
Example 247
2-[2-(4-Methylphenylamino)-4-methyl-thiazol-5-yl]-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-methyl-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.34%, M.P.>275° C., LC-MS: 498.5(M+1), Rf: 0.48
Example 248
2-[2-(4-Methoxy-lphenylamino)-4-methyl-thiazol-5-yl]-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-methoxyl-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.46%, M.P.>275° C., LC-MS: 542(M+1), Rf: 0.56
Example 249
[5-(4-Oxo-3-(4-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.31%, M.P.>275° C., LC-MS: 504(M+1), Rf: 0.62
Example 250
[5-(4-Oxo-3-(4-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example154. Yield: 48.8%, M.P.>275° C., LC-MS: 490(M+1), Rf: 0.57
Example 251
2-(2-Methylamino-4-phenyl-thiazol-5-yl)-3-(4-Chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-(4-chloro-phenyl) 1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 44.7%, M.P.>275° C., LC-MS: 446(M+1), Rf: 0.61
Example 252
3-(4-Chloro-phenyl)-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 52.94%, M.P. 218-22° C., LC-MS: 508(M+1), Rf: 0.64
Example 253
N-[5-(4-Oxo-3-(4-Chloro-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-Benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 53.33%, M.P.>275° C., LC-MS: 536(M+1), Rf: 0.54
Example 254
4-Methyl-N-[5-(4-oxo-3-(4-Chloro-phenyl)-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-chloromethyl-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.33%, M.P.>275° C., LC-MS: 549(M+1), Rf: 0.59
Example 255
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-(4-Chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 53.34%, M.P. 270-4° C., LC-MS: 498(M+1), Rf: 0.62
Example 256
2-[2-(4-Chloro-phenylamino)-4-phenyl-thiazol-5-yl]-3-(4-Chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 38.46%, M.P. 271-2° C., LC-MS: 542(M+1), Rf: 0.64
Example 257
2-[2-(4-Methyl-phenylamino)-4-phenyl-thiazol-5-yl]-3-(4-Chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-methyl-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.52%, M.P. 225-7° C., LC-MS: 497(M+1), Rf: 0.61
Example 258
2-[2-(4-Methoxyl-phenylamino)-4-phenyl-thiazol-5-yl]-3-(4-Chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-methoxyl-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 43.96%, M.P. 262-3° C., LC-MS: 453(M+1), Rf: 0.59
Example 259
(4-Methyl-5-(4-oxo-3-(4-acetyl-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid ethyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-ethyl ester (1 g, 1 mmol) and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 47.25%, M.P.>275° C., LC-MS: 449(M+1), Rf: 0.61
Example 260
(4-Methyl-5-(4-oxo-3-(4-acetyl-phenyl)-3,4-dihydro-quinazolin-2-yl)-thiazol-2-yl)-carbamic acid methyl ester
The title compound was prepared from carbamic acid,[{(1-(diethyl amino)ethylidene)amino}thiaoxomethyl]-methyl ester and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 44.9%, M.P. 232-4° C., LC-MS: 435(M+1), Rf: 0.47
Example 261
2-(4-Methyl-2-methylamino-thiazol-5-yl)-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-methyl-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 29.52%, M.P. 245-6° C., LC-MS: 391(M+1), Rf: 0.46.
Example 262
2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(1-diethylamino-eth-(E)-ylidene)-3-phenyl-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.21%, M.P. 271-3° C., LC-MS: 453(M+1), Rf: 0.51.
Example 263
2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-eth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 43.27%, M.P. 209-10° C., LC-MS: 487(M+1), Rf: 0.52
Example 264
[5-(4-Oxo-3-(4-acetyl-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid ethyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(ethoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.60%, M.P. 245-7° C., LC-MS: 511(M+1), Rf: 0.58.
Example 265
[5-(4-Oxo-3-(4-acetyl-phenyl)-3,4-dihidro-quinazolin-2-yl)-4-phenyl-thiazol-2-yl]-carbamic acid methyl ester
The title compound was prepared from benzencarboximidamide, N,N-diethyl-N′-[(methoxycarbonylamino)thioxomethyl] and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.52%, M.P. 203-4° C., LC-MS: 497(M+1), Rf: 0.56
Example 266
2-(2-Methylamino-4-phenyl-thiazol-5-yl)-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl) 1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 43.96%, M.P. 239-40° C., LC-MS: 453(M+1), Rf: 0.53
Example 267
3-(4-acetyl-phenyl)-2-(4-phenyl-2-phenylamino-thiazol-5-yl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-[(E)-((Z)-1-propenyl)-buta-1,3-dienyl]-thiourea and 2-chloromethyl-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.32%, M.P. 223-5° C., LC-MS: 515(M+1), Rf: 0.61.
Example 268
N-[5-(4-Oxo-3-(4-acetyl-phenyl)-3,4-dihydro-quinazolin-2-yl)-4-phenyl-thiazole-2-yl]benzamide
The title compound was prepared from 1-benzoyl-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 50.33%, M.P. 250-2° C., LC-MS: 543(M+1), Rf: 0.70
Example 269
4-Methyl-N-[5-(4-oxo-3-(4-acetyl-phenyl)-3,4-dihydroquinazolin-2-yl)-4-phenyl-thiazol-2-yl]-benzamide
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(4-methyl-benzoyl)-thiourea and 2-chloromethyl-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 48.37%, M.P. 266-7° C., LC-MS: 556(M+1), Rf: 0.62.
Example 270
2-[2-(1-Furan-2-yl-vinylamino)-4-phenyl-thiazol-5-yl]-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl)1-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 45.64%, M.P. 232-3° C., LC-MS: 505(M+1), Rf: 0.40.
Example 271
2-[2-(4-Chlorophenylamino)-4-phenyl-thiazol-5-yl]-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from 1-(4-chloro-phenyl)-3-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-thiourea and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 44.30%, M.P. 218-20° C., LC-MS: 548.5(M+1), Rf: 0.49.
Example 272
2-(5-Morpholin-4-yl-4-phenyl-thiophene-2-yl)-3-phenyl-3H-quinazolin-4-one
(Z)-1,3-Di-morpholin-4-yl-2-phenyl-propenthione was dissolved in acetonitrile and heated to 78° C. At this temperature 2-chloromethyl-3-phenyl-3H-quinazolin-4-one in acetonitrile was added, and the reaction mixture was held at 78° C. for 6-8 hrs. Then it was cooled to room temperature, and solvent was removed under vacuum. The solid residue was recrystallized to obtain 2-(5-morpholin-4-yl-4-phenyl-thiophene-2-yl)-3-phenyl-3H-quinazolin-4-one. Yield: 57.82%, M.P. 218-20° C., LC-MS: 466(M+1), Rf: 0.53.
Example 273
2-[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-phenyl-3H-quinazoline-4-one as otherwise described in Example 272. Yield: 51.41%, M.P. 229-30° C., LC-MS: 500(M+1), Rf: 0.53
Example 274
N-{4-[2-Morpholin-4-yl-5-(4-oxo-3-phenyl-3-,4-dihydro-quinazolin-2-yl)-thiophene-3-yl]-phenyl}-acetamide
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-phenyl-3H-quinazoline-4-one as otherwise described in Example 272. Yield: 56.83%, M.P.>275° C., LC-MS: 523(M+1), Rf: 0.34
Example 275
2-[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-di-morpholin-4-yl-propenethione and 2-chloromethyl-3-phenyl-3H-quinazoline-4-one as otherwise described in Example 272. Yield: 58.39%, M.P.>275° C., LC-MS: 544(M+1), Rf: 0.53
Example 276
2-[4-(4-Methylsulfanyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methylsulfanyl-phenyl)-1,3-di-morpholin-4-yl-propenethione and 2-chloromethyl-3-phenyl-3H-quinazoline-4-one as otherwise described in Example 272. Yield: 46.15%, M.P. 218-20° C., LC-MS: 480(M+1), Rf: 0.53
Example 277
2-(5-Morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl-3-phenyl-3H-quinazolin-4-one
(Z)-1,3-Di-morpholin-4-yl-2-pyridin-4-yl-propenethione was dissolved in dimethyl formamide. At room temperature, 2-chloromethyl-3-phenyl-3H-quinazoline-4-one in dimethyl formamide was added. The reaction mixture was stirred at room temperature for 24 hrs, after which it was poured into ice water, stirred well for 10 minutes, and filtered. The residue was dried and recrystallized from methanol to obtain pure 2-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3-phenyl-3H-quinazolin-4-one. Yield: 37.67%, M.P. 230-1° C., LC-MS: 467(M+1), Rf: 0.34
Example 278
2-(5-Morpholin-4-yl-4-phenyl-thiophene-2-yl)-3-0-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-0-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 54.30%, M.P. 187-8° C., LC-MS: 480(M+1), Rf: 0.60.
Example 279
2-[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 53.42%, M.P. 186-9° C., LC-MS: 514(M+1), Rf: 0.0.62
Example 280
N-{4-[2-Morpholin-4-yl-5-(4-oxo-3-0-tolyl-3-,4-dihydro-quinazolin-2-yl)-thiophene-3-yl]-phenyl}-acetamide
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-0-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 51.74%, M.P. 242-3° C., LC-MS: 537(M+1), Rf: 0.30.
Example 281
2-[4-(4-Methanesulfonylphenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-o-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 55.71%, M.P. 255-8° C., LC-MS: 557(M+1), Rf: 0.42
Example 282
2-[4-(4-Methylsulfanylphenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-0-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methylsulfanyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-0-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 43.75%, M.P.>275° C., LC-MS: 525(M+1), Rf: 0.59
Example 283
2-(5-Morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3-o-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-mimorpholin-4-yl-2-pyridin-4-yl-propenethione and 2-chloromethyl-3-0-tolyl-3H-quinazoline-4-one as otherwise described in Example 285. Yield: 38.66%, M.P. 208-10° C., LC-MS: 481(M+1), Rf: 0.38.
Example 284
2-(5-Morpholin-4-yl-4-phenyl-thiophene-2-yl)-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 53.64%, M.P. 194-6° C., LC-MS: 480(M+1), Rf: 0.50.
Example 285
2-[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 49.32%, M.P. 228-30° C., LC-MS: 514(M+1), Rf: 0.57.
Example 286
N-{4-[2-Morpholin-4-yl-5-(4-oxo-3-m-tolyl-3-,4-dihydro-quinazolin-2-yl)-thiophene-3-yl]-phenyl}-acetamide
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 52.44%, M.P.>275° C., LC-MS: 537(M+1), Rf: 0.61
Example 287
2-[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 54.54%, M.P. 208-10° C., LC-MS: 558(M+1), Rf: 0.62
Example 288
2-[4-(4-Methylsulfanyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methylsulfanyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 43.05%, M.P. 220-1° C., LC-MS: 525(M+1), Rf: 0.59
Example 289
2-(5-Morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3-m-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenethione and 2-chloromethyl-3-m-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 36%%, M.P. 230-2° C., LC-MS: 481(M+1), Rf: 0.57.
Example 290
2-(5-Morpholin-4-yl-4-phenyl-thiophene-2-yl)-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-di-morpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 54.30%, M.P. 207-9° C., LC-MS: 480(M+1), Rf: 0.63.
Example 291
2-[4-(4-Chlorophenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 51.36%, M.P. 224-6° C., LC-MS: 514(M+1), Rf: 0.63.
Example 292
2-[4-(4-Methanesulfonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 57.86%, M.P. 265-8° C., LC-MS: 558(M+1), Rf: 0.57.
Example 293
2-[4-(4-Methylsulfanyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-p-tolyl-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methylsulfanyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-Chloromethyl-3-p-tolyl-3H-quinazoline-4-one as otherwise described in Example 277. M.P. 238-40° C., Rf: 0.59.
Example 294
3-(2-Methoxy-phenyl)-2-(5-morpholin-4-yl-4-phenyl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-(2-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 52.20%, M.P. 152-4° C., LC-MS: 496(M+1), Rf: 0.56.
Example 295
2-[4-(4-Chlorophenyl)-5-morpholin-4-yl-thiophene-2-yl]-3-(2-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(2-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 47.68%, M.P. 216-7° C., LC-MS: 530(M+1), Rf: 0.65.
Example 296
N-(4-{5-[3-(2-methoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-2-morpholin-4-yl-thiophene-3-yl}-acetamide
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-(2-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 53.74%, M.P. 163-4° C., LC-MS: 553(M+1), Rf: 0.64
Example 297
2-[4-(4-Methanesulphonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-(2-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-di-morpholin-4-yl-propenethione and 2-chloromethyl-3-(2-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 55.17%, M.P. 222-3° C., LC-MS: 574(M+1), Rf: 0.62
Example 298
3-(2-Methoxy-phenyl)-2-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenethione and 2-chloromethyl-3-(2-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 41.29%, M.P. 204-5° C., LC-MS: 497(M+1), Rf: 0.58.
Example 299
3-(3-Methoxy-phenyl)-2-(5-morpholin-4-yl-4-phenyl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-(3-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 50.95%, MP: 269-72° C., LC-MS: 496(M+1), Rf: 0.63.
Example 300
2-[4-(4-Methanesulphonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-(3-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-di-morpholin-4-yl-propenethione and 2-chloromethyl-3-(3-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 56.55%, M.P. 203-5° C., LC-MS: 574(M+1), Rf: 0.58.
Example 301
3-(4-Methoxy-phenyl)-2-(5-morpholin-4-yl-4-phenyl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-(4-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 52.23%, M.P. 164-5° C., LC-MS: 496(M+1), Rf: 0.67.
Example 302
2-[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-3-(4-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(4-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 49%, M.P. 217-8° C., LC-MS: 530(M+1), Rf: 0.69.
Example 303
2-[4-(4-Methanesulphonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-(4-methoxy-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(4-methoxy-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 55.86%, M.P. 240-3° C., LC-MS: 574(M+1), Rf: 0.49.
Example 304
3-(2-Chlorophenyl)-2-(5-morpholin-4-yl-4-phenyl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 50.63%, M.P. 160-1° C., LC-MS: 500(M+1), Rf: 0.65.
Example 305
2-[4-(4-Chlorophenyl)-5-morpholin-4-yl-thiophene-2-yl]-3-(2-chlorophenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 51.97%, M.P. 215-7° C., LC-MS: 534(M+1), Rf: 0.68.
Example 306
3-(2-Methoxy-phenyl)-2-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 48.65%, M.P. 210-2° C., LC-MS: 557(M+1), Rf: 0.59.
Example 307
2-[4-(4-Methanesulphonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-(2-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 58.62%, M.P.>275° C., LC-MS: 577, Rf: 0.56.
Example 308
3-(2-Chloro-phenyl)-2-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenethione and 2-chloromethyl-3-(2-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 39.49%, M.P. 179-80° C., LC-MS: 501(M+1), Rf: 0.58.
Example 309
3-(4-Chloro-phenyl)-2-(5-morpholin-4-yl-4-phenyl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 54.43%, M.P. 223-4° C., LC-MS: 500(M+1), Rf: 0.68.
Example 310
2-[4-(4-Chloro-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 55.26%, MP: 240-3° C., LC-MS: 534(M+1), Rf: 0.68
Example 311
N-(4-{5-[3-(4-Chloro-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-2-morpholin-4-yl-thiophene-3-yl}-acetamide
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 54.05%, M.P.>275° C., LC-MS: 557(M+1), Rf: 0.29.
Example 312
2-[4-(4-Methanesulphonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-dimorpholin-4-yl-propenethione and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 56.55%, M.P.>275° C., LC-MS: 577(M+1), Rf: 0.54
Example 313
3-(4-Chloro-phenyl)-2-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-pyridin-4-yl-propenethione and 2-chloro-methyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 285. Yield: 39.74%, MP: 195-7° C., LC-MS: 501(M+1), Rf: 0.57.
Example 314
3-(4-Acetyl-phenyl)-2-(5-morpholin-4-yl-4-phenyl-thiophen-2-yl-3H-quinazolin-4-one
The title compound was prepared from (Z)-1,3-dimorpholin-4-yl-2-phenyl-propenthione and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield 51.88%, M.P.>275° C., LC-MS: 508(M+1), Rf: 0.47.
Example 315
2-[4-(4-Acetyl-phenyl)-5-morpholin-4-yl-thiophene-2-yl]-3-(4-chloro-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-di-morpholin-4-yl-propenethione and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 50.32%, M.P. 222-6° C., LC-MS: 542(M+1), Rf: 0.45.
Example 316
N-(4-{5-[3-(4-Acetyl-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-2-morpholin-4-yl-thiophene-3-yl}-acetamide
The title compound was prepared from N-{4-[(Z)-1-(morpholin-4-carbothioyl)-2-morpholin-4-yl-vinyl]-phenyl}-acetamide and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 55.33%, M.P. 259-61° C., LC-MS: 565(M+1), Rf: 0.49.
Example 317
2-[4-(4-Methanesulphonyl-phenyl)-5-morpholin-4-yl-thiophen-2-yl]-3-(4-acetyl-phenyl)-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-methanesulfonyl-phenyl)-1,3-di-morpholin-4-yl-propenethione and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 54.05%, M.P. 239-42° C., LC-MS: 586(M+1), Rf: 0.51.
Example 318
3-(4-Chlorophenyl)-2-[4-(4-methanesulfonyl-phenyl)-5-(4-methyl-piperazine-1-yl)-thiophen-2-yl]-3H-quinazolin-4-one
The title compound was prepared from (Z)-2-(4-chloro-phenyl)-1,3-bis-(4-methyl-piperazin-1-yl)-propenethione and 2-chloromethyl-3-(4-chloro-phenyl)-3H-quinazoline-4-one as otherwise described in Example 277. Yield: 52.6%, M.P.232-3° C., LC-MS: 590(M+1) Rf: 0.63
Example 319
3-(4-acetyl-phenyl)-2-(5-morpholin-4-yl-4-pyridin-4-yl-thiophen-2-yl)-3Hquinazolin-4-one
The title compound was prepared from (Z)-1,3-di-morpholin-4-yl-2-pyridin-4-yl-propenethione and 2-chloromethyl-3-(4-acetyl-phenyl)-3H-quinazoline-4-one as otherwise describe in example 277. Yield: 42.0%, M.P.: 241-2° C., Rf: 0.53, LC-MS (m/e): 509 (M+1), 1H-NMR (300 MHz, CDCl3) δ□[ppm]: 2.69 (s,3H,—COCH3), 2.92-2.95 (m,4H,proton at C3 and C5 position of morpholine), 2.71-2.75(m,4H), 6.12 (s,1H), 7.19-8.16 (m,9H), 8.28-8.48 (m,1H), 8.43-8.45 (m,2H), Elemental analysis: Calculated : C, 68.49; H, 4.76; N, 11.02 Obtained: C, 68.44; H, 4.64; N, 11.54.
Example 320
2-(2-Methylamino-4-phenyl-thiazole-5-yl)-3-phenyl-3H-quinazolin-4-one
The title compound was prepared from 1-[1-diethylamino-1-phenyl-meth-(E)-ylidene]-3-methyl-thiourea and 2-chloromethyl-3-(phenyl)-3H-quinazoline-4-one as otherwise described in Example 154. Yield: 23.8%, M.P. 224-5° C., LC-MS: 411(M+1), Rf: 0.52.
Example 321
4-Amino-(2-phenylamino-thiazol-5-yl)-(4-methoxy-phenyl)-methanone
T o a solution of 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol was added p-methoxyphenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole). The solution was refluxed for 3 hours, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under vacuum. Crushed ice was added to the residue, and the separated solid was filtered and washed with water to give yellow crystals (41% yield). M.P. 222° C. Recrystallization Solvent: methanol. TLC: Mobile Phase: Ethyl acetate, Rf: 0.68. IR (KBr, cm-1) showed 3489 (NH), 3319, 3265 (NH2), 3084, 1885, 1622, 1562, 1499. Mass, (LC-MS, M+1): 326. 1H-NMR (CDCl3, δ, ppm): 3.8 (m, 3H, OCH3), 6.9 (d, 2H, phenyl), 7.2-7.4 (m, 2H of NH2 and 5H of phenyl), 7.43 (s, 1H, of NH), 7.74-7.76 (d, 2H, phenyl), and Molecular formula as C17H15N3O2S.
Example 322
4-Amino-(2-phenylamino-thiazol-5-yl)-p-tolyl-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, p-methylphenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 50.72%. M.P. 211-212° C., LC MS: 310 (M+1). C17H15N3OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.78. IR (KBr, cm-1): 3480, 3250, 3200, 1610, 1590, 1520
Example 323
(4-Amino-2-phenylamino-thiazol-5-yl)-(4-chloro-phenyl)-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 4-chlorophenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 67.72%. M.P. 221-222° C., LC MS: 331 (M+2). C16H12ClN3OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.57. IR (KBr, cm-1): 3460, 3250, 3080, 1720, 1580, 1515
Example 324
(4-Amino-2-phenylamino-thiazol-5-yl)-(2,4-dichloro-phenyl)-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 2,4-dichlorophenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 47.34%. M.P. 234-235° C., LC MS: 366 (M+2). C16H11Cl2N3OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.48. IR (KBr, cm-1): 3456, 3290, 3050, 1690, 1570, 1520
Example 325
(4-Amino-2-phenylamino-thiazol-5-yl)-(4-methanesulfonyl-phenyl)-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml p-methylsulfonyl phenacylbromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 39.4%. M.P. 257-258° C., LC MS: 374 (M+1). C17H15N3O3S2. TLC: Mobile Phase: Ethyl acetate, Rf: 0.37.
Example 326
N-[4-(4-Amino-2-phenylamino-thiazole-5-carbonyl)-phenyl]-acetamide
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, N-[4-(2-Bromo-acetyl)-phenyl]-acetamide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 39.4%. M.P. 257-258° C., LC MS: 353 (M+1). C18H16N4O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.37.
Example 327
(4-Amino-2-phenylamino-thiazol-5-yl)-pyridin-3-yl-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-3yl-ethanone (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 62.27%. M.P. 263-264° C., LC MS: 297 (M+1). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.42.
Example 328
(4-Amino-2-phenylamino-thiazol-5-yl)-pyridin-4-yl-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-4yl-ethanone (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example to provide desired compound. Yield 77.32%. M.P. 257-258° C., LC MS: 297 (M+1). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.44.
Example 329
(4-Amino-2-phenylamino-thiazol-5-yl)-pyridin-2-yl-methanone
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-2yl-ethanone (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 24.22. 2%. M.P. 214-215° C., LC MS: 297 (M+1). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.37.
Example 330
5-(4-Methoxy-3,5-dimethyl-pyridin-2-yl)-N2-phenyl-thiazole-2,4-diamine
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Cholromethyl-4-methoxy-3,5-dimeth-yl-pyridine (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 26.32%. M.P. 251-253° C., LC MS: 327 (M+1). C17H18N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.52.
Example 331
5-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-N2-phenyl-thiazole-2,4-diamine
The title compound was prepared from 1-amidino-3-phenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Chloromethyl-4-methyl-3-(2,2,2-trifluoro-ethoxy)-pyridine (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 42.00%. M.P. 199-201° C., LC MS: 381 (M+1). C17H15F3N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.53.
Example 332
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-methoxy-phenyl)-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, p-methoxyphenacyl bromide (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 51.79%. M.P.>280° C., LC MS: 361 (M+2). C17H14ClN3O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.67.
Example 333
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-p-tolyl-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, p-methylphenacyl bromide (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 40.47%. M.P. 195-196° C., LC MS: 345 (M+2). C17H14ClN3OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.54.
Example 334
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 4-chlorophenacyl bromide (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 67.72%. M.P. 224-225° C., LC MS: 366 (M+2). C16H11Cl2N3OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.53.
Example 335
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(2,4-dichloro-phenyl)-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 2,4-dichlorophenacyl bromide (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 27.34%. M.P. 254-235° C., LC MS: 398 (M+2). C16H10Cl3N3OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.78.
Example 336
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-methanesulfonyl-phenyl)-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, p-methylsulfonyl phenacyl bromide (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 64.42%. M.P.>285° C., LC MS: 409 (M+2). C17H14ClN3O3S2. TLC: Mobile Phase: Ethyl acetate, Rf: 0.53.
Example 337
N-{4-[4-Amino-2-(4-chloro-phenylamino)-thiazole-5-carbonyl]-phenyl}-acetamide
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, N-[4-(2-Bromo-acetyl)-phenyl]-acetamide (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 39.4%. M.P.>285° C., LC MS: 388 (M+2). C18H15ClN4O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.42.
Example 338
(4-Amino-2-(4-chlorophenylamino)-thiazol-5-yl)-pyridin-3-yl-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-3yl-ethanone (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 62.27%. M.P. 223-224° C., LC MS: 332 (M+2). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.42.
Example 339
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-pyridin-4-yl-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-4yl-ethanone (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 77.32%. M.P. 227-228° C., LC MS: 332 (M+2). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.24.
Example 340
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-pyridin-2-yl-methanone
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-2yl-ethanone (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 24.22. 2%. M.P. 224-225° C., LC MS: 332 (M+2). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.42.
Example 341
N2-(4-Chloro-phenyl)-5-(4-Methoxy-3,5-dimethyl-pyridin-2-yl)-thiazole-2,4-diamine)
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 2-Cholromethyl-4-methoxy-3,5-dimeth-yl-pyridine (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 26.32%. M.P. 255-256° C., LC MS: 362 (M+2). C17H18N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.47.
Example 342
(N2-(4-Chloro-phenyl)-5-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazole-2,4-diamine)
The title compound was prepared from 1-amidino-3-p-chlorophenylthiourea (0.0057 mole) in 10 ml ethanol, 2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0057 mole) and tri-ethylamine (0.0057 mole) as per described in the example 39 to provide desired compound. Yield 42.00%. M.P. 199-201° C., LC MS: 416 (M+2). C17H14F3N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.43. IR (KBr, cm-1): 3390, 3260, 3050, 1615, 1550, 1490. 1HNMR(CDCl3, δ, ppm): 2.21 (m, 3H, CH3), 4.8 (m, 2H, OCH2CF3), 6.8-7.7 (m, 4H, phenyl), 8.2-8.3 (m, 2H of NH2 and 2H of pyridine), 10.4 (s, 1H, of NH).
Example 343
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-methoxy-phenyl)-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0057 mole) in 10 ml ethanol, p-methoxyphenacyl bromide (0.0057 mole) and tri-ethylamine (0.0057 mole) as described in the example 39 to provide desired compound. Yield 51.79%. M.P.>280° C., LC MS: 356 (M+1). C18H17N3O3S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.76.
Example 344
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-p-tolyl-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, p-methylphenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as described in the example 39 to provide desired compound. Yield 50.72%. M.P.>280° C., LC MS: 340 (M+1). C18H17N3O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.67.
Example 345
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 4-chlorophenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 67.72%. M.P.>280° C., LC MS: 361 (M+2). C17H14ClN3O2S. TLC : Mobile Phase: Ethyl acetate, Rf: 0.53.
Example 346
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(2,4-dichloro-phenyl)-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 2,4-dichlorophenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 47.34%. M.P.>280° C., LC MS: 396 (M+2). C17H13Cl2N3O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.43.
Example 347
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-methanesulfonyl-phenyl)-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, p-sulfonylphenacyl bromide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 37.2%. M.P.>280° C., LC MS: 404 (M+1). C18H17N3O4S2. TLC: Mobile Phase: Ethyl acetate, Rf: 0.47.
Example 348
(N-{4-[4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-phenyl}-acetamide)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, N-[4-(2-Bromo-acetyl)-phenyl]-acetamide (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 39.4%. M.P.>280° C., LC MS: 383 (M+1). C19H18N4O3S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.49.
Example 349
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-3-yl-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-3yl-ethanone (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 62.27%. M.P.>280° C., LC MS: 327 (M+1). C15H12N4OS. TLC: Mobile Phase: Ethyl acetate, Rf: 0.34.
Example 350
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-4-yl-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-4yl-ethanone (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 77.32%. M.P.>280° C., LC MS: 327 (M+1). C16H14N4O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.32.
Example 351
([4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-2-yl-methanone)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Boromo-1-pyridin-2yl-ethanone (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 24.22. 2%. M.P.>280° C., LC MS: 327 (M+1). C16H14N4O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.27.
Example 352
(5-(4-Methoxy-3,5-dimethyl-pyridin-2-yl)-N2-(4-methoxy-phenyl)-thiazole-2,4-diamine)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Cholromethyl-4-methoxy-3,5-dimeth-yl-pyridine (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 26.32%. M.P.>280° C., LC MS: 357 (M+1). C18H20N4O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.39. 1HNMR(CDCl3, δ, ppm): 2.21 (s, 6H, CH3), 3.7 (s, 6H, OCH3), 6.49-7.7 (m, 4H of phenyl and 1H of pyridine), 7.0-7.7 (m, 4H, phenyl), 8.2 (s, 2H of NH2), 10.5 (s, 1H, of NH). IR (KBr, cm-1): 3350, 3260, 3180, 1650, 1585, 1545.
Example 353
(N2-(4-Methoxy-phenyl)-5-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazole-2,4-diamine)
The title compound was prepared from 1-amidino-3-p-methoxyphenylthiourea (0.0077 mole) in 10 ml ethanol, 2-Chloromethyl-5-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0077 mole) and tri-ethylamine (0.0077 mole) as per described in the example 39 to provide desired compound. Yield 42.00%. M.P.>280° C., LC MS: 411 (M+1). C18H17F3N4O2S. TLC: Mobile Phase: Ethyl acetate, Rf: 0.41.
Example 354
1-(4-Fluoro-phenyl)-3-[5-(4-methoxy-benzoyl)-2-phenylamino-thiazol-4-yl]-urea
The (4-amino-2-phenylamino-thiazol-5-yl)-(4-methoxy-phenyl)-methanone (0.0016 mole) was taken in 5 ml of THF and cooled to 0-5° C. and then slowly p-fluorophenyl isocyanate (0.0015) was added dropwise to it. The reaction mixture was stirred for 30 minutes at RT, the white precipitate was filtered, and then washed with cool THF. Rf: 0.64. Yield 67.98%. LC MS 463 (M+1). M.P.>280° C. M.F.=C24H19FN4O3S. Elemental Analysis: Calculated; C, 62.33; H, 4.14; N, 12.11. Observed; C, 62.35; H, 4.44; N, 12.45. 1H NMR (DMSO-d6, δ, ppm): 3.81 (s, 3H, —OCH3), 6.5-7.0 (m, 7H, aromatic), 7.08-7.69 (m, 6H, aromatic), 8.68 (s, 1H, —NH), 10.87 (s, 2H, —NH urea).
Example 355
1-[2-(4-Chloro-phenylamino)-5-(4-methoxy-benzoyl)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from ([4-amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-methoxy-phenyl)-methanone) (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 70.79%. M.P.>280° C., LC MS: 498 (M+2). C24H18ClFN4O3S. TLC: M.P.: Ethyl acetate, Rf: 0.67. 1H NMR (DMSO-d6, δ, ppm): 3.67 (s, 3H, —OCH3), 6.9-7.1 (m, 6H, aromatic), 7.3-7.7 (m, 6H, aromatic), 8.87 (s, 1H, —NH), 10.91 (s, 2H, —NH urea).
Example 356
1-[2-(4-Chloro-phenylamino)-5-(4-methyl-benzoyl)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from (([4-amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-p-tolyl-methanone) (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 75.79%. M.P.>280° C., LC MS: 482 (M+2). C24H18ClFN4O2S. TLC: M.P.: Ethyl acetate, Rf: 0.62. Elemental Analysis: Calculated; C, 55.10; H, 3.02; N, 11.17; Observed; C, 55.64; H, 3.52; N, 11.88. 1H NMR (DMSO-d6, δ, ppm): 2.39 (s, 3H, —CH3), 6.9 (m, 6H, aromatic), 7.2-7.7 (m, 6H, aromatic), 8.36 (s, 1H, —NH), 9.61 (s, 2H, —NH urea).
Example 357
1-[5-(4-Chloro-benzoyl)-2-(4-chloro-phenylamino)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from ([4-amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 69.29%. M.P.>280° C., LC MS: 482 (M+2). C23H15Cl2FN4O2S. TLC: M.P.: Ethyl acetate, Rf: 0.72.
Example 358
1-[2-(4-Chloro-phenylamino)-5-(2,4-dichloro-benzoyl)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from [4-amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(2,4-dichloro-phenyl)-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to give the compound whose M.P.>280° C., yield 62.42%. IR (KBr, Cm-1); 3299, 3085, 1885, 1635, 1510, 1405, 1209, 1012. LC MS shows the 496 (M+), 497 (M+1) and 498 (M+2) peaks. TLC: M.P.: Ethyl acetate, Rf: 0.69., 1H-NMR (DMSO-d6, δ, ppm): 6.98-6.98 (m, 4H, aromatic), 7.2-7.4 (m, 8H, aromatic), 8.32 (s, 1H, —NH), 8.65 (s, 2H, —NH urea), and molecular formula as C23H14Cl3FN4O2S, Elemental Analysis is shown as Calculated; C, 51.56; H, 2.63; N, 10.46; Observed; C, 51.24; H, 2.52; N, 10.54.
Example 359
1-[2-(4-Chloro-phenylamino)-5-(pyridine-3-carbonyl)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from (4-amino-2-phenylamino-thiazol-5-yl)-pyridin-3-yl-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 35.34%. M.P.>280° C., LC MS: 469 (M+2). C22H15ClFN5O2S. TLC: M.P.: Ethyl acetate, Rf: 0.42.
Example 360
1-[2-(4-Chloro-phenylamino)-5-(pyridine-4-carbonyl)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from (4-amino-2-phenylamino-thiazol-5-yl)-pyridin-4-yl-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 47.23%. M.P.>280° C., LC MS: 469 (M+2). C22H15ClFN5O2S. TLC: M.P.: Ethyl acetate, Rf: 0.47.
Example 361
1-{2-(4-Chloro-phenylamino)-5-[4-methyl-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazol-4-yl}-3-(4-fluoro-phenyl)-urea
The title compound was prepared from N2-(4-chloro-phenyl)-5-[4-methyl-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazole-2,4-diamine (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 62.43%. M.P.>280° C., LC MS: 553 (M+2). C24H18ClF4N5O2S. TLC: M.P.: Ethyl acetate, Rf: 0.47.
Example 362
1-[2-(4-Methoxy-phenylamino)-5-(4-methyl-benzoyl)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from ([4-amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-methoxy-phenyl)-methanone) (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 75.79%. M.P.>280° C., LC MS: 477 (M+1). C25H21FN4O3S. TLC: M.P.: Ethyl acetate, Rf: 0.59.
Example 363
1-[5-(4-Chloro-benzoyl)-2-(4-methoxy-phenylamino)-thiazol-4-yl]-3-(4-fluoro-phenyl)-urea
The title compound was prepared from [4-amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 56.34%. M.P.>280° C., LC MS: 498 (M+2). C24H18ClFN4O3S. TLC: M.P.: Ethyl acetate, Rf: 0.62.
Example 364
1-(4-Fluoro-phenyl)-3-[5-(4-methanesulfonyl-benzoyl)-2-(4-methoxy-phenyl amino)-thiazol-4-yl]-urea
The title compound was prepared from [4-amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-methansulfonyl-phenyl)-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 56.34%. M.P.>280° C., LC MS: 541 (M+1). C25H21FN4O5S2. TLC: M.P.: Ethyl acetate, Rf: 0.62.
Example 365
1-(4-Fluoro-phenyl)-3-[2-(4-methoxy-phenylamino)-5-(pyridine-4-carbonyl)-thiazol-4-yl]-urea
The title compound was prepared from [4-amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-4-yl-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 37.39%. M.P.>280° C., LC MS: 541 (M+1). C23H18FN5O3S. TLC: M.P.: Ethyl acetate, Rf: 0.32.
Example 366
1-(4-Fluoro-phenyl)-3-[5-(5-methoxy-4,6-dimethyl-pyridin-2-yl)-2-(4-methoxy-phenylamino)-thiazol-4-yl]-urea
The title compound was prepared from 5-(5-methoxy-4,6-dimethyl-pyridin-2-yl)-N2-(4-methoxy-phenyl)-thiazole-2,4-diamine (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 39.67%. M.P.>280° C., LC MS: 494 (M+1). C25H24FN5O3S. TLC: M. P.: Ethyl acetate, Rf: 0.32.
Example 367
1-(4-Fluoro-phenyl)-3-{2-(4-methoxy-phenylamino)-5-[4-methyl-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazol-4-yl}-urea
The title compound was prepared from N2-(4-methoxy-phenyl)-5-[4-methyl-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazole-2,4-diamine (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 62.43%. M.P.>280° C., LC MS: 548(M+1). C25H21F4N5O3S. TLC: M.P.: Ethyl acetate, Rf: 0.47.
Example 368
1-(4-Fluoro-phenyl)-3-[2-(4-methoxy-phenylamino)-5-(pyridine-2-carbonyl)-thiazol-4-yl]-urea
The title compound was prepared from [4-amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-2-yl-methanone (0.0018 mole) in 10 ml THF and p-fluorophenyl isocyanate (0.0018) as per described in the example 353 to provide desired compound. Yield 27.39%. M.P.>280° C., LC MS: 541 (M+1). C23H18FN5O3S. TLC: M.P.: Ethyl acetate, Rf: 0.29.
Example 369
N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide
A 250 ml, 2-necked round bottom flask was charged with furan-2-yl-piperazin-1-yl-methanone (0.056 mole) and 200 ml toluene and cooled to 0-5° C. Then benzoyl isothiocyanate was added drop wise at 5° C. The reaction mixture was stirred for 24 hr. at room temperature. The white precipitate was filtered out and washed with cold toluene. The precipitate was again re-crystallized with ethyl acetate. Mobile phase: Toluene:Acetonitrile 7:3, Rf: 0.73. LC MS (M+1): 344. C17H17N3O3S. Yield: 78.57%. 1H NMR (DMSO-d6, δ, ppm): 3.26-4.25 (m, 8H of piperazine and 1H of NH), 6.49-6.51 (m, 1H of furan), 7.04-7.08 (m, 1H of furan), 7.29-7.61 (m, 3H of phenyl and 1H of furan), 7.86-7.88 (m, 2H of phenyl). Elemental Analysis: Observed; C, 59.46; H, 4.99; N, 12.24. Calculated; C, 59.76; H, 5.17; N, 12.70.
Example 370
Furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide
A 250 ml, 2-necked round bottom flask was charged with furan-2-yl-piperazin-1-yl-methanone (0.056 mole) and 200 ml toluene and cooled to 0-5° C., Then furoyl isothiocyanate was added drop wise at 5° C. The reaction mixture was stirred for 24 hr. at room temperature. The white precipitate was filtered out and washed with cold toluene. The precipitate was re-crystallized with ethyl acetate. Mobile phase: Toluene:Acetonitrile 7:3, Rf: 0.69. LC MS (M+1): 334. C15H15N3O4S. Yield: 67.34%.
Example 371
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-p-tolyl-methanone
A 25 ml 2-necked round bottom flask was charged with furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and 10 ml ethanol, followed by p-methylphenacyl bromide (0.0015 mole). The reaction mixture was stirred for 24 hr. This reaction mixture was cooled to −20° C. for 24 hr. The yellow precipitate was filtered and washed with cold methanol. Yield: 56.34%. LC MS (M+1): 448. C24H21N3O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.59.
Example 372
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-(4-methoxy-phenyl)-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and p-methoxyphenacyl bromide (0.0015 mole) as per example 39. Yield: 56.34%. LC MS (M+1): 464. C24H21N3O5S. M.P.: >280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.54.
Example 373
(4-Chloro-phenyl)-{2-[4-(furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and p-chlorophenacyl bromide (0.0015 mole) as per example 39. Yield: 56.34%. LC MS (M+2): 469. C24H18ClN3O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.62.
Example 374
(2,4-Dichloro-phenyl)-{2-[4-(furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and 2,4-dichlorophenacyl bromide (0.0015 mole) as per example 39. Yield: 37.34%. LC MS (M+2): 503. C24H17Cl2N3O4S. M.P.:>280 C; Mobile phase: ethyl acetate: hexane (9:1) Rf: 0.69.
Example 375
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-(4-methanesulfonyl-phenyl)-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and p-methylsulfonylphenacyl bromide (0.0015 mole) as per example 39. Yield: 42.34%. LC MS (M+1): 512. C24H21N3O6S2. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.71.
Example 376
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-pyridin-3-yl-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and 2-bromo-1-pyridin-3-yl-ethanone (0.0015 mole) as per example 39. Yield: 48.34%. LC MS (M+1): 435. C22H18N4O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.37.
Example 377
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-pyridin-4-yl-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and 2-bromo-1-pyridin-4-yl-ethanone (0.0015 mole) as per example 39. Yield: 37.34%. LC MS (M+1): 435. C22H18N4O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.42.
Example 378
Furan-2-yl-{4-[4-furan-2-yl-5-(4-methoxy-3,5-dimethyl-pyridin-2-yl)-thiazol-2-yl]-piperazin-1-yl}-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0015 mole) as per Example 39. Yield: 54.34%. LC MS (M+1): 465. C24H24N4O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.52.
Example 379
Furan-2-yl-(4-{4-furan-2-yl-5-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-thiazol-2-yl}-piperazin-1-yl)-methanone
The title compound was made from USA-2 (0.0015 mole) and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0015 mole) as per example 39. Yield: 23.47%. LC MS (M+1): 519. C24H21F3N4O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.52.
Example 380
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-furan-2-yl-thiazol-5-yl}-pyridin-2-yl-methanone
The title compound was made from furan-2-carboxylic acid [4-(furan-2-carbonyl)-piperazine-1-carbothioyl]-amide (0.0015 mole) and 2-bromo-1-pyridin-2-yl-ethanone (0.0015 mole) as per example 39. Yield: 37.34%. LC MS (M+1): 435. C22H18N4O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.32.
Example 381
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-tolyl-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and p-methylphenacyl bromide (0.0015 mole) as per example 39. Yield: 66.34%. LC MS (M+1): 458. C26H23N3O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.67.
Example 382
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-(4-methoxy-phenyl)-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and p-methoxyphenacyl bromide (0.0015 mole) as per example 39. Yield: 47.44%. LC MS (M+1): 474. C26H23N3O4S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.62. Elemental Analysis: Observed; C, 65.94; H, 4.90; N, 8.87. Calculated; C, 65.67; H, 4.77; N, 8.97. 1H NMR (DMSO-d6, δ, ppm): 3.7-3.8 (m, 8H of piperazine and 3H of OCH3), 6.6-6.7 (m, 2H of furan and 1H of phenyl), 7.05-7.4 (m, 1H of furan and 6H phenyl), 7.8-8.0 (m, 2H of phenyl).
Example 383
(4-Chloro-phenyl)-{2-[4-(furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and p-chlorolphenacyl bromide (0.0015 mole) as per example 39. Yield: 56.34%. LC MS (M+2): 479. C25H20ClN3O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.59.
Example 384
(2,4-Dichloro-phenyl)-{2-[4-(furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and 2,4-dichlorolphenacyl bromide (0.0015 mole) as per example 39. Yield: 37.45%. LC MS (M+2): 513. C25H19C12N3O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.57.
Example 385
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-(4-methanesulfonyl-phenyl)-methanone
The title compound was made from USA-2 (0.0015 mole) and p-sulfonylphenacyl bromide (0.0015 mole) as per US-1. Yield: 42.34%. LC MS (M+1): 522. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.71, IR (KBr, Cm-1); 3333, 3114, 2930, 2866, 1757, 1681, 1616, 1291, 1091, 1H NMR (DMSO-d6, δ, ppm): 3.1-3.8 (m, 8H of piperazine and 3H of SO2CH3), 6.6 (s, 1H of furan), 7.0-8.3 (series of peaks like m, 2H of furan and 9H phenyl), Elemental Analysis: Observed; C, 59.87; H, 4.44; N, 8.06. Calculated; C, 59.62; H, 4.89; N, 8.32., and molecular formula as C26H23N3O5S2.
Example 386
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-pyridin-3-yl-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and 2-bromo-1-pyridin-3-yl-ethanone (0.0015 mole) as per example 39. Yield: 48.34%. LC MS (M+1): 445. C24H20N4O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.33.
Example 387
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-pyridin-4-yl-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and 2-bromo-1-pyridin-4-yl-ethanone (0.0015 mole) as per example 39. Yield: 37.34%. LC MS (M+1): 445. C24H20N4O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.42.
Example 388
Furan-2-yl-{4-[5-(4-methoxy-3,5-dimethyl-pyridin-2-yl)-4-phenyl-thiazol-2-yl]-piperazin-1-yl}-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (0.0015 mole) as per example 39. Yield: 54.34%. LC MS (M+1): 475. C26H26N4O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.27.
Example 389
Furan-2-yl-(4-{5-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4-phenyl-thiazol-2-yl}-piperazin-1-yl)-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine (0.0015 mole) as per example 39. Yield: 23.47%. LC MS (M+1): 529. C26H23F3N4O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.52.
Example 390
{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-4-phenyl-thiazol-5-yl}-pyridin-2-yl-methanone
The title compound was made from N-[4-(Furan-2-carbonyl)-piperazine-1-carbothioyl]-benzamide (0.0015 mole) and the 2-bromo-1-pyridin-2-yl-ethanone (0.0015 mole) as per example 39. Yield: 37.34%. LC MS (M+1): 445. C24H20N4O3S. M.P.:>280 C; Mobile phase: ethyl acetate:hexane (9:1) Rf: 0.32.
Example 391
Bis-[2-(2-methoxy-phenylamino)-4-phenyl-thiazol-5-yl]-methanone
The title compound was made from ethyl 1-(diethylamino-phenyl-methylene)-3-(2-methoxy-phenyl)-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as described in example 39. Yield 43%. LC MS (M+1) 591, M.P:>285° C., Rf; 0.46. C33H26N4O3S2
Example 392
Bis-[2-(3-methoxy-phenylamino)-4-phenyl-thiazol-5-yl]-methanone
The title compound was made from ethyl 1-(diethylamino-phenyl-methylene)-3-(3-methoxy-phenyl)-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as described in example 39. Yield 54%. LC MS (M+1) 591, M.P:>285° C., Rf; 0.39. C33H26N4O3S2
Example 393
Bis-[2-(4-methoxy-phenylamino)-4-phenyl-thiazol-5-yl]-methanone
The title compound was made from ethyl 1-(diethylamino-phenyl-methylene)-3-(4-methoxy-phenyl)-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as described in example 39. Yield 62%. LC MS (M+1) 591, M.P:>285° C., Rf; 0.37. C33H26N4O3S2
Example 394
Bis-[2-(4-methyl-phenylamino)-4-phenyl-thiazol-5-yl]-methanone
The title compound was made from ethyl 1-(diethylamino-phenyl-methylene)-3-(4-methyl-phenyl)-thiourea (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as described in example 39. Yield 49%. LC MS (M+1) 559, M.P:>285° C., Rf; 0.42. C32H26N4O2S2
Example 395
Diphenyl[carbonylbis(4-Benzyl-1,3-thiazole-5,2-diyl)]biscarbamate
The title compound was made from ethyl ({[1-(diphenylamino) (phenyl)methylene]amino}carbonothioyl)carbamate (0.0026 moles) and 1,3-dichloroacetone (0.0013 moles) as described in example 39. Yield 49%. LC MS (M+1) 559, M.P:>285° C., Rf; 0.42. C33H22N4O5S2
Example 396
N-(4-methyl-5-(4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)thiazol-2-yl)furan-2-carboxamide
The title compound was prepared from 1-[1-Diethylamino-1-phenyl-meth-(E)-ylidene]-3-(furan-2-carbonyl)-thiourea and 2-Chloro methyl-3-(4-phenyl)-3H-quinazoline-4-one as described in example 201. Yield:52.77%, M.P.>275:, LC-MS (m/e):443; (M+1); Rf;0.59.
Examples of Compounds
Examples of Compounds that may be used in practicing this invention include but are not limited to the various general structures depicted below, as well as the specific exemplary compounds with specific substituents listed in the following tables. The tables give cross-references to the above “Example” numbers. The “% Protection” is defined in Example 397. The “NF-κB Inhibition@1 μM” and “AP-1 Inhibition@1 μM”were determined as described in Example 398.:







TABLE 1













 















NFkB
AP-1






inhibition
inhibition
Example


R
R′
% Protection P
@ 1 uM
@ 1 uM
No.















H
CO-Phenyl
53.46
NR
NR
Example 42


H
CO-p-methyl phenyl
5.33
−15.26
27.3
Example 43


H
CO-p-methoxy phenyl
66.67
14.88
55.37
Example 44


H
CO-p-Chloro phenyl
53.46
NT
NT
Example 45


H
CO-2,4-Dichloro phenyl
68.31
NT
NT
Example 46


H
CO-p-sulfanyl phenyl
5
−1.5
21.23
Example 47


H
CO-p-sulfonyl phenyl
30
NT
NT
Example 48


H
CO-p-acetyl amino phinyl
68.31
NT
NT
Example 49


H
CO-3-pyridin
6.9
NT
NT
Example 50


H
CO-4-pyridine
39.65
8.36
16.77
Example 51


H
4-methoxy-3,5-dimethyl pyridine
38
7.26
30.77
Example 37


H
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
10.89
NT
NT
Example 38


H
3,4,5-trimethoxypyridine
19.65
NT
NT
Example 39


SO2CH3
CO-Phenyl
17.82
NT
NT
Example 54


SO2CH3
CO-p-methyl phenyl
−13.54
NT
NT
Example 55


SO2CH3
CO-p-methoxy phenyl
77.78
18.07
76.09
Example 56


SO2CH3
CO-p-Chloro phenyl
26.88
NT
NT
Example 57


SO2CH3
CO-2,4-Dichloro phenyl
50
NT
NT
Example 58


SO2CH3
CO-p-sulfanyl phenyl
45.83
NT
NT
Example 59


SO2CH3
CO-p-sulfonyl phenyl
59.88
NT
NT
Example 60


SO2CH3
CO-p-acetyl amino phinyl
25
NT
NT
Example 61


SO2CH3
CO-3-pyridin
0
NT
NT
Example 62


SO2CH3
CO-4-pyridine
50
10.47
5.71
Example 63


SO2CH3
4-methoxy-3,5-dimethyl pyridine
61.11
5.81
−7.93
Example 52


SO2CH3
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
2.08
−2.17
25.04
Example 53


NHCOCH3
CO-Phenyl
40
24.23
−2.98
Example 66


NHCOCH3
CO-p-methyl phenyl
7.67
NT
NT
Example 67


NHCOCH3
CO-p-methoxy phenyl
40
NT
NT
Example 68


NHCOCH3
CO-p-Chloro phenyl
−21.78
NT
NT
Example 69


NHCOCH3
CO-2,4-Dichloro phenyl
39.16
18.58
54.04
Example 70


NHCOCH3
CO-p-sulfanyl phenyl
2.5
7.6
27.75
Example 71


NHCOCH3
CO-p-sulfonyl phenyl
50
NT
NT
Example 72


NHCOCH3
CO-p-acetyl amino phinyl
−23.49
−28.62
19.87
Example 73


NHCOCH3
CO-3-pyridin
34
NT
NT
Example 74


NHCOCH3
CO-4-pyridine
45.69
17.44
45.5
Example 75


NHCOCH3
4-methoxy-3,5-dimethyl pyridine
49.05
−4.95
26.2
Example 64


NHCOCH3
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
30
NT
NT
Example 65


Cl
CO-Phenyl
−48.27
NT
NT
Example 78


Cl
CO-p-methyl phenyl
−31.03
NT
NT
Example 79


Cl
CO-p-methoxy phenyl
18.85
−2.91
30.55
Example 80


Cl
CO-p-Chloro phenyl
20
NT
NT
Example 81


Cl
CO-2,4-Dichloro phenyl
22.75
0.6
34.27
Example 82


Cl
CO-p-sulfanyl phenyl
27
NT
NT
Example 83


Cl
CO-p-sulfonyl phenyl
23
−11.66
30.88
Example 84


Cl
CO-p-acetyl amino phinyl
20
−17.34
22.58
Example 85


Cl
CO-3-pyridin
28.09
3.6
15.17
Example 86


Cl
CO-4-pyridine
35
NT
NT
Example 87


Cl
4-methoxy-3,5-dimethyl pyridine
17
NT
NT
Example 76


Cl
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
23
NT
NT
Example 77


3-pyridine
CO-Phenyl
6.09
7.91
59.49
Example 90


3-pyridine
CO-p-methyl phenyl
25.33
1.28
48.98
Example 91


3-pyridine
CO-p-methoxy phenyl
68.98
NT
NT
Example 92


3-pyridine
CO-p-Chloro phenyl
0
NT
NT
Example 93


3-pyriidne
CO-2,4-Dichloro phenyl
−51.4
NT
NT
Example 94


3-pyridine
CO-p-sulfanyl phenyl
42.44
11.24
64.02
Example 95


3-pyridine
CO-p-sulfonyl phenyl
46.75
−12.88
37.72
Example 96


3-pyridine
CO-p-acetyl amino phinyl
46.75
NT
NT
Example 97


3-pyridine
CO-3-pyridin
42
NT
NT
Example 98


3-pyridine
CO-4-pyridine
26.04
NT
NT
Example 99


3-pyridine
4-methoxy-3,5-dimethyl pyridine
−18.05
NT
NT
Example 88


3-pyridine
3-methyl-4-(2,2,2-trifluoromethoxy)
−18.05
NT
NT
Example 89



pyridine






4-Pyridine
CO-Phenyl
52
NT
NT
Example 102


4-pyridine
CO-p-methyl phenyl
−30.79
10.32
4.35
Example 103


4-Pyridine
CO-p-methoxy phenyl
43.47
NT
NT
Example 104


4-Pyridine
CO-p-Chloro phenyl
47.22
NT
NT
Example 105


4-Pyridine
CO-2,4-Dichloro phenyl
−75.24
NT
NT
Example 106


4-Pyridine
CO-p-sulfanyl phenyl
−42.44
1.69
19.05
Example 107


4-Pyridine
CO-p-sulfonyl phenyl
54.24
−8.31
46.59
Example 108


4-Pyridine
CO-p-acetyl amino phinyl
−75.24
NT
NT
Example 109


4-Pyridine
CO-3-pyridin
−6.93
NT
NT
Example 110


4-Pyridine
CO-4-pyridine
59.08
NT
NT
Example 111


4-Pyridine
4-methoxy-3,5-dimethyl pyridine
54.24
5.21
47.43
Example 100


4-Pyridine
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
47
NT
NT
Example 101
















TABLE 2













 















NFkB
AP-1






inhi-
inhi-





% 
bition
bition
Example


R
R′
Protection P
@ 1 uM
@ 1 uM
No.















CH3
CH3
58.62
22.14
51.05
Example 







117


CH3
Ph
40.89
8.84
33.36
Example 







118


CH3
p-ClPh
45.46
8.39
26.01
Example 







119


CH3
COPh
64.62
20.3
76.25
Example 







120


CH3
CO-Furan
62
NT
NT
Example 







121


CH3
NHCOOCH3
23.89
NT
NT
Example 







123


CH3
NHCOOC2H5
65.66
20.06
71.56
Example 







124


Ph
CH3
23.24
27.08
23.8
Example 







125


Ph
Ph
64.54
22.19
27.11
Example 







126


Ph
p-ClPh
43.49
NT
NT
Example 







127


Ph
COPh
34
NT
NT
Example 







128


Ph
CO-Furan
55
NT
NT
Example 







129


Ph
NHCOOCH3
40.78
12.78
9.2
Example 







130


Ph
NHCOOC2H5
69.77
NT
NT
Example 







131


Ph
(C2H5)2
47
NT
NT
Example 







132


Ph
CO-p-
59
NT
NT
Example 



MethoxyPh



391


Ph
p-MethylPh
62
NT
NT
Example 







392


Ph
p-MethoxyPh
32
NT
NT
Example 







393



m-MethoxyPh
56
18.74
41.92
Example 







394


Ph
p-MethoxyPh
66
NT
NT
Example 







395


Benzyl
CH3
19.09
17.74
24.53
Example 







133


Benzyl
Ph
75.69
67.87
72.77
Example 







134


Benzyl
p-ClPh
34.72
39.98
41.43
Example 







135


Benzyl
COPh
45.13
44.46
32.23
Example 







136


Benzyl
CO-Furan
47.22
7.69
51.3
Example 







137


Benzyl
NHCOOCH3
88.89
55.56
83.62
Example 







138


Benzyl
NHCOOC2H5
69.61
62.63
74.4
Example 







139
















TABLE 3













 















NFkB
AP-1






inhibition
inhibition



R
R′
% Protection P
@ 1 uM
@ 1 uM
Example No















H
p-methoxy benzoyl
30.55
−39.23
−70.59
Example 114


H
p-methyl benzoyl
12.25
NT
NT
Example 321


H
p-chloro benzoyl
23.98
NT
NT
Example 322


H
2,4-dichloro benzoyl
43
NT
NT
Example 323


H
p-methylsulfonyl benzoyl
55
NT
NT
Example 324


H
p-acetyl amino benzoyl
12
NT
NT
Example 325


H
3-pyridinoyl
34
NT
NT
Example 326


H
4-pyridinoyl
32
NT
NT
Example 327


H
4-methoxy-3,5-dimethyl pyridinyl
76
NT
NT
Example 328


H
3-methyl-4-(2,2,2-tirfluoroethoxy)
54
NT
NT
Example 329



pyridinyl






H
2-pyridinoyl
24
NT
NT
Example 330


Cl
p-methoxy benzoyl
62.26
−10.62
27.39
Example 331


Cl
p-methyl benzoyl
36
0.13
−32.18
Example 332


Cl
p-chloro benzoyl
34.59
8.19
14.23
Example 333


Cl
2,4-dichloro benzoyl
28.3
−38.54
37.62
Example 334


Cl
p-methylsulfonyl benzoyl
30.32
NT
NT
Example 335


Cl
p-acetyl amino benzoyl
28.3
NT
NT
Example 336


Cl
3-pyridinoyl
18.23
−93.38
−37.01
Example 337


Cl
4-pyridinoyl
25.78
−84.08
−89.08
Example 338


Cl
4-methoxy-3,5-dimethyl pyridinyl
12
NT
NT
Example 339


Cl
3-methyl-4-(2,2,2-trifluoroethoxy)pyridinyl
34
−18.22
57.3
Example 340


Cl
2-pyridinoyl
32
NT
NT
Example 341


OCH3
p-methoxy benzoyl
76
NT
NT
Example 342


OCH3
p-methyl benzoyl
54
NT
NT
Example 343


OCH3
p-chloro benzoyl
79.8
49.01
70.28
Example 344


OCH3
2,4-dichloro benzoyl
34.59
NT
NT
Example 345


OCH3
p-methylsulfonyl benzoyl
28.3
−4.13
64.63
Example 346


OCH3
p-acetyl amino benzoyl
30.32
NT
NT
Example 347


OCH3
3-pyridinoyl
28.3
NT
NT
Example 348


OCH3
4-pyridinoyl
18.23
−35.86
51.52
Example 349


OCH3
4-methoxy-3,5-dimethyl pyridinyl
25.78
NT
NT
Example 350


OCH3
3-methyl-4-(2,2,2-trifluoroethoxy)pyridinyl
27
−35.86
51.52
Example 351


OCH3
2-pyridinoyl
23
NT
NT
Example 352
















TABLE 4













 















NFkB inhibition
AP-1 inhibition



R
R′
% Protection P
@ 1 uM
@ 1 uM
Example No.















Furan
p-methyl benzoyl
34
10.37
25.65
Example 371


Furan
p-methoxy benzoyl
52.21
NT
NT
Example 372


Furan
p-Chloro benzoyl
42
−6.07
26.93
Example 373


Furan
2,4-Dichloro benzoyl
62.63
6.25
46.22
Example 374


Furan
p-methylsulfonyl benzoyl
49
−13.24
22.11
Example 375


Furan
3-pyridinoyl
33
−14.11
45.91
Example 376


Furan
4-pyridinoyl
32
−7.88
4.84
Example 377


Furan
4-methoxy-3,5-dimethyl pyridin-2-yl
84.21
22.05
43.26
Example 378


Furan
3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl
62.42
51.11
3.23
Example 379


Furan
2-pyridinyl
42
NT
NT
Example 380


Ph
p-methyl benzoyl
53
−1.91
10.42
Example 381


Ph
p-methoxy benzoyl
45.96
NT
NT
Example 382


Ph
p-Chloro benzoyl
62
−0.23
13.28
Example 383


Ph
2,4-Dichloro benzoyl
71.61
−1.4
42.53
Example 384


Ph
p-methylsulfonyl benzoyl
67
−15.1
6.44
Example 385


Ph
3-pyridinoyl
23
52.83
22.49
Example 386


Ph
4-pyridinoyl
32
NT
NT
Example 387


Ph
4-methoxy-3,5-dimethyl pyridin-2-yl
73.4
7.64
52.06
Example 388


Ph
3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl
61.61
30.74
42.45
Example 389


Ph
2-pyridinoyl
17
0.47
40.89
Example 390
















TABLE 5













 















NFkB
AP-1






inhibition
inhibition



R
n
% Protection P
@ 1 uM
@ 1 uM
Example No.





SO2CH3
1
55.65


Example 112


NHCOCH3
1
45.54


Example 113


Cl
1
56.57


Example 114
















TABLE 6













 















NFkB
AP-1






inhibition
inhibition



R
R′
% Protection P
@ 1 uM
@ 1 uM
Example No.





CH3
COPhenyl
90.92


Example 115
















TABLE 7













 















NFkB
AP-1






inhibition
inhibition



R
R′
% Protection P
@ 1 uM
@ 1 uM
Example No.





H
p-methoxy benzoyl
45.49
34.2
 2.59
Example 116


Cl
p-methoxy benzoyl
82.49
59.1
62.02
Example 353


Cl
p-methyl benzoyl
26.27
NT
NT
Example 354


Cl
p-Chloro benzoyl
62.57
NT
NT
Example 355


Cl
2,4-Dichloro benzoyl
69.54
 54.62
48.44
Example 356


Cl
3-pyridinyl
24.27
NT
NT
Example 357


Cl
4-pyridinyl
72.54
NT
NT
Example 358


Cl
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
64.23
NT
NT
Example 359


OCH3
p-methyl benzoyl
69.84
NT
NT
Example 360


OCH3
p-Chloro benzoyl
77.89
NT
NT
Example 361


OCH3
p-sulfonyl benzoyl
61.34
NT
NT
Example 362


OCH3
4-pyridinyl
54.54
NT
NT
Example 363


OCH3
4-methoxy-3,5-dimethyl pyridine
66.78
NT
NT
Example 364


OCH3
3-methyl-4-(2,2,2-trifluoroethoxy)pyridine
69.56
NT
NT
Example 365


OCH3
2-pyridinyl
19.14
NT
NT
Example 366
















TABLE 8













 

















NFkB
AP-1






%
inhibition
inhibition
Example


R1
R2
R3
Protection
@ 1 uM
@ 1 uM
No
















COOC2H5
CH3
H
12.00%
19
−13
154


COOCH3
CH3
H
0
24
−1
155


CH3
CH3
H
NT


156


Ph
CH3
H
12
25
16
157


p-Cl Ph
CH3
H
4
−9
−20
158


COOC2H5
Ph
H
75%
80
7
159


COOCH3
Ph
H
NT


160


Ph
Ph
H
60
80
7
161


Benzoyl
Ph
H
87%
58
17
162


p-CH3 
Ph
H
77
88
68
163


Benzoyl








Furoyl
Ph
H
66
2
53
164


p-Cl Ph
Ph
H
87%
−47
27
165


COOC2H5
CH3
2-CH3
NT
21
14
166


COOCH3
CH3
2-CH3
NT


167


CH3
CH3
2-CH3
35
16
67
168


Ph
CH3
2-CH3
42
21
60
169


p-Cl Ph
CH3
2-CH3
45


170


COOC2H5
Ph
2-CH3
52
23
52
171


COOCH3
Ph
2-CH3
NT
0
25
172


CH3
Ph
2-CH3
NT


173


Ph
Ph
2-CH3
NT


174


Benzoyl
Ph
2-CH3
NT


175


p-CH3 
Ph
2-CH3
NT
−8
29
176


Benzoyl








Furoyl
Ph
2-CH3
NT


177


p-Cl Ph
Ph
2-CH3
51
nt
nt
178


COOC2H5
CH3
3-CH3
NT


179


COOCH3
CH3
3-CH3
NT


180


CH3
CH3
3-CH3
nt
10
20
181


Ph
CH3
3-CH3
NT


182


p-Cl Ph
CH3
3-CH3
NT
2
39
183


COOC2H5
Ph
3-CH3
NT


184


COOCH3
Ph
3-CH3
NT


185


CH3
Ph
3-CH3
nt
23
10
186


Ph
Ph
3-CH3
NT


187


Benzoyl
Ph
3-CH3
NT
42
63
188


p-Cl Ph
Ph
3-CH3
38
−4
83
189


COOC2H5
CH3
4-CH3
23.97


190


Ph
CH3
4-CH3
NT


191


p-Cl Ph
CH3
4-CH3
37
12
2
192


COOC2H5
Ph
4-CH3
31
2
11
193


COOCH3
Ph
4-CH3
NT


194


CH3
Ph
4-CH3
NT


195


Ph
Ph
4-CH3
NT
38
10
196


Benzoyl
Ph
4-CH3
NT


197


p-CH3 
Ph
4-CH3
NT


198


Benzoyl








Furoyl
Ph
4-CH3
NT


199


p-Cl Ph
Ph
4-CH3
56
−16
2
200


COOC2H5
CH3
2-OCH3
NT


201


Ph
CH3
2-OCH3
NT


202


p-Cl Ph
CH3
2-OCH3
27
NT
NT
203


COOCH3
Ph
2-OCH3
NT


204


CH3
Ph
2-OCH3
56
61
90
205


Ph
Ph
2-OCH3
NT


206


Furoyl
Ph
2-OCH3
NT


207


p-Cl Ph
Ph
2-OCH3
31
NT
NT
208


COOC2H5
CH3
3-OCH3
NT
29
5
209


Ph
CH3
3-OCH3



210


p-Cl Ph
CH3
3-OCH3
NT


211


COOC2H5
Ph
3-OCH3
NT


212


Ph
Ph
3-OCH3
38
35
33
213


Benzoyl
Ph
3-OCH3
NT
34
30
214


COOC2H5
CH3
4-OCH3
25
34
−6
215


Ph
CH3
4-OCH3
NT


216


p-Cl Ph
CH3
4-OCH3
50
−38
−43
217


COOC2H5
Ph
4-OCH3
20
22
24
218


COOCH3
Ph
4-OCH3
NT


219


CH3
Ph
4-OCH3
NT


220


Ph
Ph
4-OCH3
85.00%
79
18
221


Benzoyl
Ph
4-OCH3
24%
15
0
222


p-CH3 
Ph
4-OCH3
NT
−24
−28
223


Benzoyl








Furoyl
Ph
4-OCH3
79%
−24
2
224


p-Cl Ph
Ph
4-OCH3
80.00%
47
58
225


COOC2H5
CH3
2-Cl
NT


226


COOCH3
CH3
2-Cl
NT


227


CH3
CH3
2-Cl
NT


228


Ph
CH3
2-Cl
NT
6
21
229


p-Cl Ph
CH3
2-Cl
58
60
21
230


COOC2H5
Ph
2-Cl
NT


231


COOCH3
Ph
2-Cl
NT
55
67
232


CH3
Ph
2-Cl
NT


233


Ph
Ph
2-Cl
NT


234


Benzoyl
Ph
2-Cl
NT


235


p-CH3 
Ph
2-Cl
NT


236


Benzoyl








Furoyl
Ph
2-Cl
NT


237


p-Cl Ph
Ph
2-Cl
61


238


COOC2H5
CH3
3-Cl
NT


239


COOC2H5
Ph
3-Cl
NT


240


COOCH3
Ph
3-Cl
NT


241


COOC2H5
CH3
4-Cl
65%
53
12
242


COOCH3
CH3
4-Cl
NT


243


CH3
CH3
4-Cl
71%
93
82
244


Ph
CH3
4-Cl
72
79
82
245


p-Cl Ph
CH3
4-Cl
38%
96
74
246


p-CH3 Ph
CH3
4-Cl
71.90%


247


p-OCH3Ph
CH3
4-Cl
NT


248


COOC2H5
Ph
4-Cl
81%
16
0
249


COOCH3
Ph
4-Cl
83
17
5
250


CH3
Ph
4-Cl
92.00%
85
69
251


Ph
Ph
4-Cl
81%
80
21
252


Benzoyl
Ph
4-Cl
83
87
28
253


p-CH3 
Ph
4-Cl
NT
0
2
254


Benzoyl








Furoyl
Ph
4-Cl
NT
0
7
255


p-Cl Ph
Ph
4-Cl
84%
99
61
256


p-CH3 Ph
Ph
4-Cl
NT
−10
−51
257


p-OCH3Ph
Ph
4-Cl
NT


258


COOC2H5
CH3
4-COCH3
69.7%


259


COOCH3
CH3
4-COCH3
NT


260


CH3
CH3
4-COCH3
42
71
−33
261


Ph
CH3
4-COCH3
NT
15
7
262


p-Cl Ph
CH3
4-COCH3
13
0
2
263


COOC2H5
Ph
4-COCH3
40
25
25
264


COOCH3
Ph
4-COCH3
NT
0
16
265


CH3
Ph
4-COCH3
NT
4
15
266


Ph
Ph
4-COCH3
NT
43
19
267


Benzoyl
Ph
4-COCH3
NT
18
44
268


p-CH3 
Ph
4-COCH3
NT
27
1
269


Benzoyl








Furoyl
Ph
4-COCH3
20
11
18
270


p-Cl Ph
Ph
4-COCH3
23
−12
31
271
















TABLE 9













 















NFkB
AP-1






inhibition
inhibition
Example


R1
R2
% Protection
@ 1 uM
@ 1 uM
No















H
H
30
−2
11
272


Cl
H
0
−35
−17
273


NHCOCH3
H
28
29
NT
274


SO2CH3
H
25
9
28
275


SCH3
H
49
−10
−17
276


4-Pyridyl
H
65
30
38
277


H
2-CH3
37
NT
NT
278


Cl
2-CH3
0
NT
NT
279


NHCOCH3
2-CH3
NT


280


SO2CH3
2-CH3
50
NT
NT
281


SCH3
2-CH3
NT


282


4-Pyridyl
2-CH3
51
53
−18
282


H
3-CH3
NT


284


Cl
3-CH3
NT


285


NHCOCH3
3-CH3
52
35
13
286


SO2CH3
3-CH3
51
NT
NT
287


SCH3
3-CH3
31
NT
NT
288


4-Pyridyl
3-CH3
30
42
35
289


H
4-CH3
48
NT
NT
290


Cl
4-CH3
53
NT
NT
291


SO2CH3
4-CH3
31
NT
NT
292


4-Pyridyl
4-CH3



293


H
2-OCH3
34
NT
NT
294


Cl
2-OCH3
52
NT
NT
294


NHCOCH3
2-OCH3
NT


296


SO2CH3
2-OCH3
63
55
33
297


4-Pyridyl
2-OCH3
42
55
33
298


H
3-OCH3
NT


299


SO2CH3
3-OCH3
48
20
−4
300


H
4-OCH3
NT


301


Cl
4-OCH3
NT


302


SO2CH3
4-OCH3
53
60
10
303


H
2-Cl
37
NT
NT
304


Cl
2-Cl
40
NT
NT
305


NHCOCH3
2-Cl
NT


306


SO2CH3
2-Cl
31
NT
NT
307


4-Pyridyl
2-Cl
43
80
35
308


H
4-Cl
66
0
2
309


Cl
4-Cl
60
0
14
310


NHCOCH3
4-Cl
28
0
17
311


SO2CH3
4-Cl
57
0
7
312


4-Pyridyl
4-Cl
52
68
32
313


H
4-
36
0
25
314



COCH3






Cl
4-
51
0
7
315



COCH3






NHCOCH3
4-
NT


316



COCH3






SO2CH3
4-
73
46
31
317



COCH3






4-Pyridyl
4-
81
66
84
319



COCH3




















TABLE 10













 















NFkB
AP-1






inhibition
inhibition
Example


R1
R2
% Protection
@ 1 uM
@ 1 uM
No.





SO2CH3
4-Cl
21
NT
NT
318









Example 397
Anti-Inflammatory Activity
Sprague-Dawley rats, male and female, 150-250 g will be used in an edema test. Rats will be deprived of food but not water for 18 hours prior to the experiment. The test compounds will be administered with a blunt-tipped needle orally, 50 mg/kg, as a suspension in 0.1% sodium CMC (carboxymethylcellulose) vehicle. Alternatively, the test compounds will be injected intravenously, subcutaneously, or intraperitoneally. One hour later, 0.1 ml of a 1% carrageenan solution in saline will be injected in the sub-plantar region of the right hind paw of each rat. Five minutes after the administration of carrageenan, displacement in a mercury-filled plethysmometer will be observed by dipping the treated paw up to a pre-marked line on ankle. The reading will be repeated 3 hours later. The displacement readings give a measure of carageenan-induced edema. Any reduction in carageenan-induced edema with a test compound, as compared to saline control, is a measure of the anti-inflammatory activity of the test compound. The percentage protection at 50-mg/kg doses was calculated according to the following formula: % Protection=[(Control−Test)/Control]×100%.
Example 398
Development and Results of Screening Assays (eIF4E, ARE, NF-κB and AP-1)
Development of eIF4E Screen: The focus of this assay is to identify compounds capable of inhibiting highly cap-dependent translation, without affecting normal cap-dependent translation. Since highly cap-dependent translation is associated with synthesis of proteins involved in cancer, a compound that inhibits this pathway may be used as an anti-cancer agent. The assay was developed by cloning the highly structured 5′ UTR of FGF, which requires high levels of eIF4E before protein synthesis can initiate, into the proper orientation of the reporter gene luciferase, and then stably transfecting the modified luciferase gene into the cell line FaDu that is known to have high levels of eIF4E. The activity of luciferase is then monitored in the presence and absence of the tested compound.
Generation of Stable Cell Lines: The pMS110 plasmid (pGL3-control plasmid from Promega which contains a neo selectable marker) was used to generate pMS110-5′UTR by cloning the 5′ UTR of FGF just upstream of the luciferase AUG start codon. FaDu cells, a head and neck cancer cell line, were transfected using Lipofectamine2000 (Invitrogen). Twenty-four hours after transfection G418 was added at 500 μg/ml. Cells were maintained in G418 for 14 days, and then individual colonies were transferred to a 96-well plate for propagation. Individual clones were analyzed for luciferase expression by plating 104 cells per well in a 96-well plate for 24 hours before lysing the cells and analyzing for luciferase activity in a Victor III (Perkin Elmer) or Lucy2 (Rosys Anthos). FaDu9000 and FaDuUTR were the clones that expressed the highest level of active luciferase following transfection of pMS110 and pMS110-5′UTR, respectively.
Analysis of Rapamycin Responsiveness: Cells of FaDu9000 and FaDuUTR were plated at 1×104 cells/well in a 96-well dish. Twenty-four hours after plating, 0.1% DMSO (vehicle control) or 10 nM rapamycin were added to each well, and the cells were maintained for an additional 24 or 48 hours. The cells were then lysed and luciferase activity was determined using BriteGlo (Promega) as per manufacturer's instruction and recorded using the Victor III. Following subtraction of background activity, the mean value of quadruplicate samples for a given experiment was determined, and the treated cells were normalized to the control. At least four separate experiments were conducted, and the mean and standard error were calculated. To determine if rapamycin affected cell viability, an MTS assay (Cell Proliferation One Solution, Promega) was carried out on each population at 48 hours in two separate experiments.
Development of ARE Screen: The regulation of TNF-α and other cytokines that are involved in inflammation and cancer progression occurs, in part, at the post-transcriptional level through an AU-rich element in the 3′ UTR called ARE. The ARE regulates both the stability and the translational efficiency of the mRNA and thus represents a potential target for novel anti-inflammatory molecules. The 3′ UTR from TNF-α, which contains the ARE, was cloned in the proper orientation and used to screen a compound library as reported in reference 55. Briefly, the 3′ UTR was cloned into pMS 110, and both the UTR and parental plasmids were stably transfected into RAW264.7 cells, a macrophage cell line. Individual clones were propagated and tested for luciferase activity. Clones with and without the UTR that demonstrated similar levels of luciferase activity were recovered and used for compound screening. The UTR-containing clones responded to LPS by inducing luciferase expression similar to the endogenous increase in TNF-α following LPS stimulation. Compounds that decreased luciferase expression in the UTR-containing construct but did not affect luciferase expression of the control construct are useful as anti-inflammatory agents. Thus, molecules identified with this screening assay are also useful as anti-cancer agents. By analogy, thalidomide, which has been reported to work in part through posttranscriptional regulation of TNF-α, has been approved for the treatment of multiple myeloma and is now in development for the treatment of cancers.
Development of NF-κB and AP-1 Screens: Two HEK293 cell lines were purchased from Panomics. One cell line was stably transfected with a plasmid in which luciferase expression is regulated by six copies of the NF-κB transcriptional element (5′-AGTTGAGGGGACTTTCCCAGGC-3′); and the other cell line was stably transfected with a plasmid in which luciferase expression is regulated by three copies of the AP-1 transcriptional element (TGACTAA). To test the biological activity of the promoters, the HEK/NF-κB cell line was stimulated with TNF-α (20 ng/ml) for 24 hours, and the HEK/AP-1 cell line was stimulated with PMA (10 ng/ml) for 24 hours. Both cell lines increased luciferase activity after stimulation: stimulation with NF-κB increased luciferase expression by 100-fold, and stimulation with AP-1 increase luciferase expression by 30-fold. In addition, a pyrimidine carboxyimide that had previously been shown (ref. 58) to be an inhibitor of transcription mediated by NF-κB and AP-1 reduced luciferase activity by approximately 40% in each of the NF-κB and AP-1 cell lines.
Thirty-nine representative compounds have been screened through the four screens (eIF4E, ARE, NF-κB and AP-1) to identify multi-pathway inhibitors. These 39 compounds were:














Example # of



Compound
Compound


Compound #
Designation
Description

















1
PMCR111
Example 224


2
PMCR112
Example 225


3
PMCR145
Example 242


4
PMCR147
Example 244


5
PMCR148
Example 245


6
PMCR152
Example 246


7
PMCR153
Example 249


8
PMCR155
Example 251


9
PMCR156
Example 252


10
PMCR157
Example 253


11
PMCR9
Example 159


12
PMCR11
Example 320


13
PMCR12
Example 161


14
PMCR13
Example 162


15
PMCR16
Example 165


16
PMCR105
Example 218


17
PMCR108
Example 221


18
PMCR109
Example 222


19
PMCH18
Example 135


20
PMCH19
Example 136


21
PMCH20
Example 113


22
PMCH21
Example 112


23
PMCH22
Example 114


24
PMCH23
Example 115


25
PMCH24
Example 116


26
PMCH25
Example 46


27
PMCH26
Example 105


28
PMCH27
Example 116


29
PMCH4
Example 123


30
PMCH8
Example 126


31
PMCH9
Example 127


32
PMCH13
Example 132


33
PMCH14
Example 139


34
PMCH15
Example 138


35
PMCH16
Example 134


36
PMCH17
Example 133


37
PMCR14
Example 163


38
PMCR159
Example 255


39
PMCR160
Example 256









eIF4E Assay Development
Following transfection and selection with G418, individual clones were transferred to 96-well plates and propagated, before testing for luciferase activity. A total of 118 individual clones were analyzed for luciferase activity, 87 with a pMS110 plasmid lacking a structured FGF 5′UTR, and 31 with a plasmid containing the 5′ UTR of FGF. For both clone types, almost 50% of the clones did not demonstrate any luciferase activity. Of those clones that did express luciferase, the clones without the FGF 5′ UTR had higher luciferase activity than did the clones containing the FGF 5′UTR (FIG. 6). In FIG. 6, luciferase activity was tested using a Victor II luminometer. Expression levels of luciferase were placed into four groups: no expression (<100 units), low expression (100-1000 units), mid expression (1100-5000 units), and high expression (>5000 units). The percentages of clones from each transfection (with and without UTR) that fell into each of the four groups is shown in FIG. 6. A similar depression of luciferase activity was noted when two sets of independently transfected populations were analyzed (data not shown). These results demonstrated that while the 5′ UTR of FGF somewhat inhibited luciferase expression, FaDu cells transfected with the FGF 5′UTR were capable of translating the luciferase RNA, consistent with high levels of intracellular eIF4E.
Rapamycin, a well-established inhibitor of eIF4E, was tested for its ability to inhibit luciferase expression in the transfected FaDu cells. Rapamycin would be expected to preferentially inhibit the FaDu cells expressing luciferase under the control of the FGF 5′ UTR, since lowering levels of eIF4E would affect those transcripts containing highly structured UTRs, thus affecting highly cap-dependent translation. Although 24 hr treatment did not decrease expression in either cell line, after 48 hr luciferase expression decreased significantly (p<0.001) in the FaDu cells containing the plasmid with the FGF UTR (FIG. 7). In FIG. 7, FaDu cells transfected with the luciferase reporter gene with the 5′UTR of FGF (FaDu UTR) or without this UTR (FaDu FF) were plated at 50% confluence. After 24 hr, the cells were treated with either 10 nM rapamycin or vehicle (DMSO). Luciferase activity was then measured as above, and the activity was normalized versus the vehicle-treated cells.
eIF4E Inhibitor Screen
The FaDu cell line stably transfected with FGF 5′UTR was used to screen thirty-nine representative compounds, each at a concentration of 1.0 μM. Additional cells were treated with vehicle, 0.3% DMSO. Cells were plated for twenty-four hours in a 96-well plate. Each compound was then added to triplicate wells, and the cells were incubated for forty-eight hours before measuring luciferase activity as above. The mean luciferase activity was measured using Promega's Brite-Glo kit, and the mean for each sample was normalized to DMSO. The experiment was then repeated, and the average and standard deviation of the two experiments were determined (FIG. 8).
A number of the compounds inhibited luciferase expression under the control of the FGF 5′UTR (notably, compounds numbered 4, 5, 23, 25, 35, and 36), and a few compounds actually increased luciferase expression (Compounds numbered 11, 21, 24, 30, and 39) (Compound numbers as indicated in table 11, column 1. Values greater than 1.0 indicate activation, and values less than 1.0 indicate inhibition.) The compounds that inhibited luciferase translation might, potentially, act by generally inhibiting translation, by reducing cell numbers through inhibition of growth or by cell toxicity, or specifically by inhibiting highly cap-dependent translation. To analyze any general effects on cell viability, fourteen compounds were selected that altered luciferase activity (including a few that increased activity) to test for any effects on cell number. An MTT assay was used to monitor compounds for inhibition of cell growth and cell toxicity. The compounds were tested once in a six-point dose-response assay starting at 10 nM and increasing to 3.3 μM. FaDu cells were plated in a 96-well plate for 24 hr before addition of the compounds. Each compound was added in each of six concentrations (10 nM, 30 nM, 100 nM, 330 nM, 1000 nM, and 3300 nM), and each concentration was tested in triplicate. In addition, DMSO was used as a control. After incubating for 24 hr, the cell number was measured using the MTT assay. FIG. 9 shows the results of the 14 compounds at each of the indicated concentrations after normalizing the results to the DMSO control.
Compound 35 strongly inhibited luciferase activity (>60% inhibition) without affecting cell viability ( ̃20% inhibition) at the highest concentration tested. Compound 25 was also interesting. Although it inhibited cell numbers at each concentration tested, it had the most pronounced effect on luciferase activity, inhibiting it by greater than 90% at the highest concentration tested, 10 μM. Other compounds, such as Compound 3, inhibited luciferase activity at 1 μM and cell growth at nearly the same concentration (3.3 μM). While this inhibition of eIF4E-induced luciferase expression may simply be due to fewer cells, it is also possible that the inhibition leads to reduced cell number. It seems more likely that the remaining cells would also have lower levels of expression, suggesting that compounds 35 and 27 would be of greater interest for identification of specific eIF4E inhibitors.
ARE Screen
The same fourteen compounds (those numbered 2, 3, 4, 6, 8, 11, 15, 20, 21, 24, 25, 32, 33, and 35) were tested for dose-response in an assay that measured inhibition of luciferase expression under control of an ARE. As in the eIF4E assay, AREs are responsible for post-transcriptional regulation of gene expression, influencing both translation and mRNA stability. Raw 254.7 cells stably transfected with a vector expressing luciferase under the post-transcriptional control of the ARE from TNF-α were plated in a 96-well plate. After 24 hr, each compound was added in triplicate for each of six concentrations (10 nM, 33 nM, 100 nM, 330 nM, 1000 nM, and 3300 nM). After 24 hr incubation, the cells were lysed and a luciferase assay was conducted. The results were normalized to DMSO by the average expression level at the lowest concentration tested. (On the first run, 3% DMSO instead of 0.3% was used as a control, and the cells died. The average luciferase units from all the compounds tested at 10 nM in experiment 1 was 0.568, and in experiment 2 was 0.561. Thus, since we did not have a true DMSO control for experiment 1, we normalized to the average value of the lowest concentration for each experiment. The actual luciferase level in experiment 2 was 1.897. Because the two averages at 10 nM were essentially identical, the actual inhibition was greater than what it may appear.) The results are shown in FIG. 10.
Almost all of the fourteen compounds inhibited luciferase expression in the presence of ARE. Compounds 2 and 3 were the only two that indicated a substantial dose response. The strength of the inhibition, in many cases ≧80% at 3.3 μM, was impressive, and indicated that these compounds are potent anti-inflammatory agents.
NF-κB Inhibitor Screen
The above two assays analyzed the effects of the compounds on post-transcriptional gene regulation, which is known to play a key role in cancer and inflammation. By contrast, the NF-κB assay and the following assay (AP-1) test whether the compounds act at the transcriptional level. Thirty-nine representative compounds were screened in an HEK/NF-κB cell line. HEK cells were stably transfected with a plasmid expressing luciferase under the control of the NF-κB promoter. These transfected cells were plated on a 96-well plate. As above, initial screening was carried out at 1.0 μM by adding compound in DMSO (0.3%) twenty-four hours after plating. Each compound was added to each of triplicate wells. DMSO (0.3%) was added to one set of wells as a control. Luciferase activity was determined using Promega's Brite-Glo kit, and the mean for each sample was normalized to that for DMSO. The experiment was repeated, and the average and standard deviation of the two experiments are shown in FIG. 11.
Most of the compounds inhibited NF-κB-dependent luciferase expression, indicating anti-inflammatory activity. One compound (compound 24) actually potentiated expression in one of the two experiments.
The fourteen representative compounds identified in the eIF4E screen as interesting (Numbered 2, 3, 4, 6, 8, 11, 15, 20, 21, 24, 25, 32, 33, and 35) were then tested for luciferase activity in a six-point dose response (10 nM, 33 nM, 100 nM, 330 nM, 1000 nM, and 3300 nM). Screening was carried out as described above by monitoring the effects of the compounds on basal NF-κB-dependent luciferase expression. Each dose was used out in triplicate, and repeated between two and four times. Results were normalized by the average expression level at the lowest concentration level, as described above. The mean and standard deviation of the averages from each replicate are presented in FIG. 12.
As shown in FIG. 12, five compounds (numbered 3, 4, 6, 25 and 35) inhibited NF-κB-dependent luciferase expression by about 50% at 3.3 μM. As shown above, at this concentration, all but Compound 35 inhibited the growth/viability of the FaDu cancer cell line. Each of the five compounds also demonstrated a substantial dose-response over the concentrations tested. Four of the five compounds (3, 4, 6 and 35) had substantial activity at submicromolar concentrations. As NF-κB activation has been demonstrated to play a role in cancer, in addition to its well understood role in inflammation, these inhibitors will be useful as anti-cancer agents.
AP-1 Inhibitor Screen
Since inflammation and cancer have also been linked to AP-1 promoter activation, the thirty nine representative compounds were also screened for inhibition in an HEK/AP-1 cell line. HEK cells were stably transfected with a plasmid expressing luciferase under the control of the AP-1 promoter. The transfected cells were plated on a 96-well plate for 24 hr. Then 1.0 μM of each compound in DMSO (0.3%) was added to triplicate wells and incubated for 48 hr. DMSO (0.3%) was added to one set of triplicate wells as a control. Luciferase activity was determined using Promega's Brite-Glo kit, and the mean for each sample was normalized to that for DMSO. The experiment was repeated, and the average and standard deviation of the two experiments are shown in FIG. 13.
As seen above using the NF-κB screen, many of these compounds inhibited AP-1-dependent luciferase expression, although fewer demonstrated the robust inhibition observed in the NF-κB screen. In the AP-1 screen, about 50% of the compounds inhibited activity by about 50%, compared with about 75% of the compounds in the NF-κB screen. Interestingly, Compound 25 showed almost complete inhibition of activity in both AP-1 replicates.
The fourteen representative compounds identified in the eIF4E screen as interesting (Numbered 2, 3, 4, 6, 8, 11, 15, 20, 21, 24, 25, 32, 33, and 35) were then tested for luciferase activity in a six-point dose response (10 nM, 33 nM, 100 nM, 330 nM, 1000 nM, and 3300 nM). Screening was carried out as described above, monitoring the compounds' effects on basal AP-1-dependent luciferase expression. Each dose-response experiment was carried out in triplicate and repeated between two and four times. The mean and standard deviation of the averages from each replicate are presented in FIG. 9.
As shown in FIG. 14, compounds 2, 3, 4, 6, 15, 25 and 35 all inhibited AP-1-dependent luciferase expression by about 50% or greater at 3.3 μM. As with the NF-κB inhibitors, at this concentration, all but Compound 35 inhibited the growth/viability of the FaDu cancer cell line. Each of the five compounds also demonstrated a substantial dose-response over the concentrations tested. Five of the seven compounds (3, 4, 6, 15 and 35) had substantial activity at submicromolar concentrations. As AP-1 activation has been demonstrated to play a role in cancer, in addition to its well understood role in inflammation, these inhibitors will have activity as anti-cancer agents.
Selected Compound Effects on NF-κB Induction
The above screening for transcriptional inhibition of luciferase expression was carried out in non-induced cell lines to determine the effects of compound on basal gene expression. However, in some cancer cases, these transcriptional factors may induce transcription. To analyze the effects of selected compounds on TNF-α induced NF-κB dependent luciferase expression, HEK cells were stably transfected with a plasmid expressing luciferase under the control of NF-κB, and were plated in a 96-well plate for 24 hr. Four of the compounds (numbered 3, 4, 25, and 35) that demonstrated robust inhibition in the dose-response assay above were added at six different concentrations (10 nM, 33 nM, 100 nM, 330 nM, 1000 nM, and 3300 nM). After 2 hr incubation, 20 ng/ml TNF-α was added to each well to induce NF-κB dependent gene transcription. After 24 hr, the cells were lysed and the luciferase assay was conducted as described above. The experiment was repeated. The results were normalized by the average expression level at the lowest concentration tested, and are shown in FIG. 15.
As seen in FIG. 15, all four of the compounds strongly inhibited (>70%) TNF-α induced NF-κB gene expression at 3.3 μM concentration. One of the compounds, Compound 35 had an IC50 of less than 100 nM, with each of the other three at sub-μM activities. These compounds have activity as anti-cancer and anti-inflammatory agents.
All four of the compounds shown in FIG. 15 showed inhibitory effects in all the screens—indicating an ability to inhibit multiple pathways involved in cancer and inflammation. All compounds tested (39 total) showed some inhibition in at least one of the assays, indicating inhibition of at least one pathway involved in cancer and inflammation.
Additional compounds have also been tested for their ability to inhibit both TNF-α-induced NF-κB—expression and PMA-induced AP-1 expression. In both tests, the compound was added for 1 h, then the appropriate inducer was added, and luciferase activity was monitored 24 h later. Values were then normalized to the vehicle control, DMSO. Following the initial luciferase screens, studies were conducted to assess the cytotoxicity of the compounds in normal cells such as VSMC, HUVEC, or HPT cells. Human umbilical vein endothelial cells (HUVEC) represent the normal endothelium, vascular smooth muscle cells (VSMC) were represented by cells from the adult rat aorta, and human proximal tubule (HPT) cells represent the normal proximal tubule in vivo. These cells were grown to near confluency in multi-well plates, and were then treated for 48 h with either vehicle (0.1% DMSO) or 10 μM of each drug candidate. Following treatment, the media from the VSMC and HUVEC incubations were removed, and the amount of lactate dehydrogenase (LDH) released into the medium was determined with a commercial kit. LDH is normally confined to the cytosol, and its release represents “leakiness” of the plasma membrane. LDH activity was expressed as % increase over vehicle-treated cells. In another assay of viability, the treated VSMC and HUVEC were removed by trypsinization and treated with trypan blue, a dye that is taken up only by dead cells. The number of both live and dead cells was counted using an automated cell viability analyzer. The % decrease in numbers of viable cells was determined. Toxicity in the treated HPT cells was determined by the ethidium homodimer (EthHD) uptake assay. EthHD is a fluorescent dye that is excluded from live cells, but is taken up by cells that have lost permeability barriers. Inside the cell, EthHD produces a strong fluorescent signal, which is proportional to the number of dead cells. Results were expressed as a % increase in cell death over vehicle-treated cells. The lead compounds were also tested in two pairs of cell lines from either the skin or prostate, one tumorigenic and one non-tumorigenic, to test for any differences in toxicity or heightened sensitivity in the tumorigenic lines. The cells were treated for 48 h with vehicle (0.1% DMSO) or 10 μM of each drug candidate. Following treatment, the viability of the cells was determined by the MTT assay. In this assay, the MTT dye is converted only in viable cells by intracellular enzymes to a colorimetric product that is quantitated by a microplate reader. Results are presented in the Table 12.







TABLE 12





Compound Charcterization Data






















Functional Assays
Toxicity Assays (Normal Cell Lines)

Cell Death
Viability
Viability



















NF-κB
AP-1
Viable Cells
Viable Cells
LDH release
LDH release
(EthHD)
(MTT)
(MTT)



Com-
%
%
% Decrease
% Decrease
% Increase
% Increase
% Increase
% Decrease
% Decrease


Example No.
pound
inhibition
inhibition
VSMC
HUVEC
VSMC
HUVEC
HPT
HaCaT
SRB12-p9






Vehicle
100  
100  
0
0
0
0
−10 
0
 0


Example 164
PMCR15
2 
53**
4
7
2
4
101#
7
18


Example 168
PMCR19
18 
67**
29#
20 
4
14 
 63#
6
21


Example 169
PMCR20
21 
73**
34#
28#
9
17 
109#
6
14


Example 171
PMCR25
23 
52**
56#
40#
78#
59#
 34#
−5 
 28#


Example 188
PMCR45
42 
63**
67#
41#
116# 
123# 
 49#
19 
20


Example 397
PMCR55
68**
83**
90#
72#
137# 
199# 
 1
59#
 40#


Example 205
PMCR75
61**
90**
70#
41#
31#
15 
 4
46#
 61#


Example 230
PMCR120
60**
27 
13 
16 
11 
6
17
−4 
 85#


Example 232
PMCR122
55**
66**
45#
32#
20 
37#
210#
6
11


Example 244
PMCR147
0 
87**
70#
63#
68#
124# 
180#
25#
 28#


Example 283
PMCR188
53 
0 
92#
60#
148# 
160# 
250#
0
 0


Example 297
PMCR204
55**
33 
70#
65#
164# 
214# 
207#
−8 
12


Example 298
PMCR206
31 
33 
0
12 
0
−1 
147#
11
 30#


Example 303
PMCR216
60**
10 
6
−1 
−10 
0
152#
−21 
16


Example 308
PMCR224
80**
45 
63#
43#
18 
28#
266#
−4 
13


Example 313
PMCR236
68**
32 
94#
60#
91#
39#
172#
6
19


Example 319
PMCR242
66**
84**
90#
60#
68#
61#
 50#
−28 
14



PMCR302
27 
67**
81#
77#
68#
125# 
 4
16 
 48#










IC50 concentrations












NF-κB
AP-1







PMCR 20
—
10 μM*



PMCR 75
500 nM* 
200 nM* 



PMCR 120
10 μM*
—



PMCR 242
10 μM*
 5 μM*










As shown in Table 12, functional assays identified 18 compounds with greater than 50% inhibition of either AP-1 or NF-κB activity (Values marked with **). From the toxicology assays, the percent (over 25%) viable endothelial or epithelial cells, percent increase in LDH release, or ethidium homodimer fluorescence, relative to vehicle control cells for each compound are marked as #. The IC50 concentration, designated by * for the four lead compounds, was determined for AP-1 or NF-κB activity from 6 point dose-response curves.
From these results, four lead compounds were chosen from the 18 compounds that had been screened (Table 13). All four compounds were inhibitors of AP-1, NF-κB, or both. Three compounds showed a lack of toxicity in one or more of the normal cells, or were selectively toxic to cancer cells in culture. PCMR242 was selected differently in that it was a dual inhibitor and also strongly inhibited inflammation in the in vivo assay. In contrast to the other three compounds, it showed significant toxicity in normal cells, but it was included as a lead compound to check the validity of the battery of safety assays.
For the results in Table 13, cells were grown to near confluency in multi-well plates, then treated for 48 h with either vehicle (0.1% DMSO) or 10 μM of each drug candidate. Following treatment, the media from the VSMC and HUVEC incubations were removed, and the amount of lactate dehydrogenase (LDH) released into the medium was determined with a commercial kit and expressed as a % increase over vehicle-treated cells. HPT toxicity was determined by the ethidium homodimer (EthHD) uptake assay. Inside the cell, EthHD produces a strong fluorescent signal, which is proportional to the amount of cell death, expressed as a % increase in cell death over vehicle-treated cells. The lead compounds were also tested in two pairs of cell lines from the skin or prostate, one tumorigenic and one non-tumorigenic, to test for differing toxicity or heightened sensitivity in the tumorigenic lines. The cells were treated for 48 h with vehicle (0.1% DMSO) or 10 μM of each drug candidate, and the viability of the cells was determined by the MTT assay, expressed as a % decrease in viability compared to vehicle-treated cells. The in vivo inflammation model measured the % inhibition of rat paw edema induced by carageenan injection.







TABLE 13







Summary of Properties of Four Lead Compounds




















Differential




NF-κB
AP-1
VSMC
HUVEC
HPT
Toxicity*
In vivo inflammation















Compound
% inhibition
% inhibition
Toxicity
Toxicity
Toxicity
Skin
Prostate
% inhibition





PMCR 20
21
73
−
−
+
Neither
Cancer
42


PMCR 75
61
90
+
−
−
Both
Normal
56


PMCR 120
60
27
−
−
−
Cancer
Both
58


PMCR 242
66
84
+
+
+
Neither
Cancer
80









Miscellaneous
Anticancer Activities of Compounds
The compounds identified in this invention may be used for the treatment of cancer or other proliferative disorders. A compound's activity may be measured against a known cancer cell line or against primary cancer cells for its ability to inhibit cancer cell growth, cancer cell migration, invasion or metastasis, or for the ability to cause death of the cancer cell. Some of the cell lines which can be used in such testing include, without limitation, MCF-7, MDA-MB-231, FaDu, DU145, PC3, and SKBR3. A compound's activity to inhibit growth/viability may be tested, for example, in the NIH cell screening assay, which provides access to over 60 different cancer cell lines representing a large number of different cancer types. For each compound that inhibits cancer cell growth or cause cancer cell death in vitro, further tests will confirm that the compound has low toxicity to normal, non-cancerous cells, such as WI-38 cells. The compound is then tested in standard animal models for its ability to kill tumors, prevent/inhibit tumor growth, or prevent/inhibit tumor metastasis. Additionally, a compound may be tested for its ability to prevent/inhibit tumor recurrence. A number of animal models are available for these tests and are well known to those skilled in the art. A compound can be administered to an animal either alone or in combination, including combinations with other known or suspected anticancer agents. Compounds demonstrating efficacy in an animal model will then be tested for human efficacy through an FDA approved protocol in clinical trials generally similar to those used to test other anticancer agents.
Compound Administration
Compounds of the present invention may be administered in pharmaceutical compositions to treat patients (humans and other mammals) with auto-immune disorders, inflammation, or cancer. Thus, the invention includes pharmaceutical compositions containing at least one compound from the present invention and a pharmaceutically acceptable carrier. A composition of the invention may further include at least one other therapeutic agent, for example, a combination formulation or combination of differently formulated active agents for use in a combination therapy method.
The present invention also features methods of using or preparing or formulating such pharmaceutical compositions. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques known to those skilled in the art of preparing dosage forms. It is anticipated that the compounds of the invention can be administered by oral, parenteral, rectal, topical, or ocular routes, or by inhalation. Preparations may also be designed to give slow release of the active ingredient. The preparation may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, compounds may be administered by intravenous infusion or topical administration, but more preferably by oral administration.
For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like; typical liquid oral excipients include ethanol, glycerol, water and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid, semi-solid, or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
Liquids for oral administration may be suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Compositions of such liquid may contain pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if needed, flavoring or coloring agents.
The compounds of this invention may also be administered by non-oral routes. The compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Singer's solution and isotonic sodium chloride. Such forms will be presented in unit dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Another mode of administration of the compounds of the invention may utilize a patch formulation to affect transdermal delivery. The compounds of this invention may also be administered by inhalation, via the nasal or oral routes using a spray formulation consisting of the compound of the invention and a suitable carrier.
Methods are known in the art for determining effective doses for therapeutic (treatment) and prophylactic (preventative) purposes for the pharmaceutical compositions or the drug combinations of the present invention, whether or not formulated in the same composition. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration, and the weight of the patient. For therapeutic purposes, “effective dose” or “effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., preventing or inhibiting the onset or progression of a disorder), the term “effective dose” or “effective amount” or “therapeutically effective dose” or “therapeutically effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor, or other clinician, the delaying of which disorder is mediated, at least in part, by the NF-κB and/or AP-1 mediated transcription factors and/or the post-transcriptional regulation through eIF4E and/or AREs. Methods of combination therapy include co-administration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation; and administration of two or more active agents separately formulated.
It is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.01 to 1000 mg per day, more usually from 1 to 500 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg. Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, taken in 1 to 4 separate doses. Some compounds of the invention may be orally dosed in the range of about 0.05 to about 50 mg/kg daily, others may be dosed at 0.05 to about 20 mg/kg daily, while still others may be dosed at 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to 1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical administration compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
It will be appreciated that, although specific embodiments of this invention have been described herein for purpose of illustration, various modification may be made without departing from the spirit and scope of the invention.
The complete disclosures of all references cited in this specification are hereby incorporated by reference, as is the complete disclosures of priority U.S. provisional patent applications 60/790,105 and 60/795,430. In the event of an otherwise irreconcilable difference, however, the present specification shall govern.
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## Claims

1. A compound having the structure




wherein:
R1 has one of the structures shown below:




R3═—CH3, —C2H5, —NH2, or substituted or unsubstituted aryl or heteroaryl, or —NMe2 
R5=substituted aryl, substituted heteroaryl, substituted or unsubstituted aroyl, substituted or unsubstituted heteroaroyl, —COOCH3, —COOC2H5, —COOaryl, or —COOheteroaryl
R7═—H or —Br
R8=aryl or heteroaryl.

2. A compound having the structure




wherein
n=1 or 2
R3═—CH3, —C2H5, —NH2, or substituted or unsubstituted aryl or heteroaryl, or —NMe2 
R5=substituted aryl, substituted heteroaryl, substituted or unsubstituted aroyl, substituted or unsubstituted heteroaroyl, —COOCH3, —COOC2H5, —COOaryl or —COOheteroaryl.

3. The compound of claim 1, wherein said compound is 2-(4-Methyl-2-phenylamino-thiazol-5-yl)-3-o-tolyl-3H-quinazolin-4-one.

4. The compound of claim 1, wherein said compound is 2-[2-(4-Chlorophenylamino)-4-methyl-thiazol-5-yl]-3-(2-chloro-phenyl)-3H-quinazolin-4-one.

5. A composition comprising the compound of claim 1 and a pharmaceutical acceptable carrier or a pharmaceutically acceptable diluent.