Ligands for aggregated molecules of tau-protein

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

 

A related application

The present application claims priority from patent application U.S. No. 61/099,376, filed September 23, 2008, the contents of which are incorporated into the present application in its entirety by reference.

The technical field

The present invention relates in General to materials, methods and models relating to the labeling and detection of neurofibrillary tangles. In addition, the present invention relates to ligands suitable for determining the stage diseases neurotic diseases, and their use in diagnosis, prognosis or treatment of diseases, such as Alzheimer's disease (ad).

The level of technology

In this patent application presents numerous patents and publications for a more complete definition and description of the invention and level of engineering that applies the present invention. The content of each of these references is incorporated into the present patent application in its entirety by reference in the description of the present invention to the same extent as in the case where it is specified that each of the individual links included in the present patent application by reference.

In the present description, including the following claims, if in the context specifies otherwise, it should be understood that the term "soda is to press" and its variations, such as "contains" and "contain", imply the inclusion of a specified number or step or group of integers or steps, but not the exclusion of any other numbers or stages or group of integers or steps.

It should be noted that in the description and appended claims, the singular number also include the plural forms unless the context clearly indicated otherwise. Thus, for example, reference to "a pharmaceutical carrier" can also refer to a mixture of two or more specified media, etc.

Ranges are often presented in this patent application as from "about" one particular value and/or to "about" another particular value. In another embodiment, the implementation of the description of the specified range includes the range from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximate values with the application of the definition of "about" is to be understood that the particular value forms another embodiment.

The present description includes data that can be useful for understanding the present invention. If this is the wrong assumption that any information given here refers to the state of the art or is directly related to the stated n the present invention, or that specifically or indirectly referenced publications to the level of technology.

State of dementia, such as Alzheimer's disease (ad) is often described as progressive accumulation of intracellular and/or extracellular deposits of protein structures, such as β-amyloid plaques and neurofibrillary tangles (NFC) in the brain of affected patients. The manifestation of these lesions is significantly associated with pathological neurofibrillary degeneration and atrophy of the brain, as well as with impaired cognitive functions (see, for example, work Ebookyou-Ladin with co-authors (Mukaetova-Ladinska EB, et al.), 2000).

When BA naliticheskie plaques and NFC contain paired helical filaments (PHF), the main component of which is a Tau proteins associated with microtubules (see, for example, the work of vesica with co-authors (Wischik et al.), 1988). Plaques also contain extracellular β-amyloid fibers, the resulting abnormal conversion of the precursor of beta-amyloid (PBA) (see, e.g., Kang and co-authors (Kang et al.), 1987). The article of vesica with co-authors (Wischik et al.) (in "Neurobiology of Alzheimer's Disease") discuss in detail the expected impact of the Tau protein in the pathogenesis of neurodegenerative dementia. The loss of normal forms of Tau proteins, the accumulation of pathological PHF and loss of synapse sredneobsky region of the cortex St. who are associated with impaired cognitive functions. In addition, synapse loss and loss of pyramidal cells are consistent with morphometric measurements of the Tau-jet neurofibrillary pathology, which corresponds, at the molecular level, almost complete redistribution of existing in the body of the Tau protein from the soluble polymerized form (for example, PHF) in Alzheimer's disease.

Tau protein exists in an alternate planned isoforms that contain three or four copies of a repetitive sequence corresponding to the binding domain with microtubules (see, for example, work Hadera with co-authors (Goedert M, et al.), 1989 and work Hadera with co-authors (Goedert, M., et al.), 1989). Tau-protein in PHF is protestirovanny cleave a protein associated with the nuclear domain (see, for example, work Kmicic with co-authors (C.M. Wischik, et al.), 1988; the work of vesica with co-authors (Wischik et al.), 1988; M. Nowak work with co-authors (M. Novak, et al.), 1993), which consists of a shifted phase version repetitive domain; in stable Tau-Tau interaction are only three repetitions (see, for example, work Rjaksa with co-authors (Jakes R., et al.), 1991). Transforming once, PHF-like Tau-protein act as a centre for further capture and provide a matrix for proteolytic processing of full-Tau protein (see, for example, the work of vesica with SOA is tori (Wischik et al.), 1996).

Phase shift, which is observed in the repetitive domain of Tau protein included in PHF, suggests that repetitive domain is subjected to induced conformational changes for inclusion in the filament. During the debut BA believe that this conformational change may be caused by the binding of Tau protein with the substrate pathology, such as damaged or mutated membrane proteins (see, for example, work Kmicic with co-authors (C.M. Wischik, et al.), 1997, "Microtubule-associated proteins: modifications in disease").

During the formation and accumulation of PHF first accumulate with the formation of amorphous aggregates in the cytoplasm, possibly of early oligomers of Tau proteins, which are shortened before or during the accumulation of PHF (see, e.g., R. MENA with co-authors (Mena R., et al.), 1995; work Rmina with co-authors (Mena R., et al.), 1996). These filaments then form a classical intracellular NF. In the specified state PHF consist of kernel truncated Tau protein and a porous outer shell, consisting of a full length Tau protein (see, for example, the work of vesica with co-authors (Wischik et al.), 1996). The accumulation process is exponential, consuming a pool of normal functioning of the Tau protein in the cell and causing a new synthesis of the Tau protein to compensate for the deficiency of the Tau protein (see, for example, work Rigli with co-authors (Lai R.YK., et al.), 1995). As a result, functional impairment of neurons leads to cell death with obtaining extracellular NFC. Mortality of cells closely associated with the amount of extracellular NF (see, for example, the work of vesica with co-authors (Wischik et al.) in "Neurobiology of Alzheimer's Disease"). As the balls squeezed in the extracellular space, there is a progressive loss of the porous outer shell of a neuron with a corresponding loss of immunoreactivity of the N-terminal Tau protein, but with preservation of immunoreactivity of the Tau protein associated with the PHF core (see, for example, work Rondareva with co-authors (BondareffW., et al.), 1994).

The results of studies of Tau protein and β-amyloid proteins in CSF samples taken using a lumbar puncture, have combined to increase the efficiency of diagnosis of ad (see, for example, the work of galasko with co-authors (Galasko et al.), 1998; the work of Hulstaert with co-authors (Hulstaert et al.), 1999; the work of Andreasen with co-authors (from et al.), 2001) and to identify differences between the BA and the control test and between ad and other degenerative dementia (the work of Gampela with co-authors (Hampel et al.), 2004). Compliance with these tests neuropathologically confirmed cases and cases at various stages of development, however, is currently limited (the work of Clark and co-authors (dark et al.), 2003; the work of Grossmann and co-authors (Grosmann et al.), 2005; work Engelborghs with co-authors (Engelborghs et al.), 2008). Although these and other (work vesica with co-authors (Wischik et al.), 2001; work Which, with co-authors (Carretero et al.), 1995) testing can provide additional data in support of diagnostic lumbar puncture is more invasive compared to the approaches of radiation medicine and has a higher risk (see, for example, work Dtelevel with co-authors (Villareal D.T. et al.), 1998; work Dubmarine with co-authors (Marin D.B. et al.), 1998; and work Lghqwli with co-authors (L.H. Kuller et al). 1998). Also developed EEG neurological diagnosis (see, for example, work Farga-Khadem with co-authors (Vargha-Khadem F. et al.), 1997; work Dboulanger with co-authors (Willmgham D.B. et al.), 1997; work Ilakaka with co-authors (Lakmache Y. et al.), 1995; and work Crhodes with co-authors (Hodges J.R. et al.), 1999), but in this case there is a need for inexpensive equipment that can be used in place of medical exposure.

When developing a treatment aimed in particular at preventing neurofibrillary degeneration of the Alzheimer's type there is an urgent need for simultaneous development of non-invasive methods of selection of patients for treatment and study their reaction to the treatment in accordance with defined and reproducible determination of the progression of the disease.

In WO 02/075318 described ligands for Agra the new paired helical filaments (PHF). The ligands can be used for marking of aggregated Tau proteins and in particular the extracellular aggregated Tau proteins present in neurofibrillary tangles.

Presents patterns include from sulphonated benzothiazoline connection below:

In SN 542266 described benzothiazoline compounds used in the textile industry. The described connection is represented by the following benzothiazoline structure (defined as the connection 73):

In WO 01/10845 described benzothiazoline compounds useful as optical brighteners. The described connection is represented by the following benzothiazoline structure (defined as compound 10):

In WO 2006/014382 described benzothiazoline compounds used in the methods of display sections deposits of amyloid protein in patients with dementia in a pre-diagnosed condition. The described connection is represented by the following benzothiazoline structure (defined as compound 43);

No.Structure
R-001

In the work of Lee and co-authors (Lee et al.) Bioorg. Med. Chem. Lett. 2008, 18, 1534 described benzothiazoline connection used for the detection of β-amyloid fibers. Various compounds are described as intermediates for obtaining benzothiazoline imaging agents, two examples of intermediate compounds which are mentioned below:

No.Structure
R-002
P-003

In WO 2007/020400 described benzothiazoline compounds used as imaging agents for the detection of amyloid proteins in vivo. The described connection is represented by the following benzothiazoline structure (defined as compound 8):

Also described intermediate obtain benzothiazoline imaging agents. Intermediate compounds have the General formula below (defined as compounds of formula (IIa)):

where:

-R1selected from C1-6of alkyl, C2-6alkenyl and C2-6the quinil;

-R2 selected from hydrogen, C1-10of alkyl, C1-10haloalkyl,6-14aryl, C6-14arylalkyl, -(CH2CH2O)q-CH3where q is an integer from 1 to 10;

-R3represents a leaving group; and

-R7, -R8, -R9and R10selected from a list of alternates.

Despite these descriptions, it should be understood that the addition of one or more compounds that were not previously identified as effective labels PHF, will contribute to this area of technology.

Disclosure of inventions

The authors of the present invention has identified specific compounds that, for example, are associated with paired helical filaments and/or are applicable for the detection of diseases such as Alzheimer's disease (ad). In the present invention proposed new and alternative ligands for the detection of these structures.

Therefore, the present invention relates to a method, use, composition, and other substances, which use these compounds as ligands PHF. The invention also suggested methods for obtaining such compounds.

These and other aspects of the present invention are discussed more fully below.

Short circuit drawings

The Figure 1 presents an example of the cell sample to study the aggregation of Tau proteins the century Low-level constitutional expression of truncated Tau protein is increased when the full expression of the Tau protein called IPTG. Truncated Tau protein derived from the full size of the Tau protein, which captures the truncated Tau protein and undergoes proteolysis and the re-capture of Tau-protein.

Figure 2A presents the binding primulina (a), SK2033-30 (VEMA-08) (b) and mAb 7/51 (C) filled with paraffin frontal lobe of the brain in mice line 66.

Figure 2B presents the binding SK2033-30 (VEMA-08) and mAb 7/51 filled with paraffin frontal lobe of the brain in mice line 66. CO-1 and CO-2 represent slices of the cerebral cortex, filled with mAb 7/51 and SK2033-30, respectively, and NS-1 and NS-2 are sections of hippocampal formation, filled with mAb 7/51 and SK2033-30, respectively.

The Figure 3 presents the binding LST-213 (BDF-04) with frozen sections of brain in mice. In the tissues of wild mice (A, bark; In the amygdala) see minimum fluorescence compared with tissues of transgenic mice lines 66 (C and E, bark; D and F, the amygdala), in which the fluorescent ligand was used in excess. The bottom pair (e, F) is a partition provided in the upper pair (C and D), on a larger scale. Marked structures exhibit a pattern of distribution similar to the distribution of Tau-positive neurons (which represent the go to Figure 1).

The Figure 4 presents the inclusion of LST-213 (BDF-04) in the cell structure. Cells were incubated in the presence of LST-213 for 18 hours. A significant amount of undissolved substances, as well as the inclusion in the structure of cells, can be seen in the background (upper image). Inclusion can clearly see after PBS washing, which removes most of nerastvorimogo substances from the outer membrane of the cells (bottom image).

The Figure 5 presents the selective binding of two different ligands of the present invention (LS-T213 [BDF-04] and SK2033-30 [VEMA-08]) with aggregated Tau protein inside cells. The ligands observed using fluorescence microscopy. On the top left image shows the binding of LS-T213 with aggregated Tau protein inside of induced cells. On the bottom left image shows the binding SK2033-30 with aggregated Tau protein inside of induced cells. The upper right image is a reference image, which presents neindutsirovannom cells, which were subjected to LS-T213.

Connection

According to one aspect, the present invention relates to a specific 1,4-disubstituted benzene compounds (for convenience, referred to in this patent application the General collective term "JB connections"), which are structurally related the Ana with N-(4-benzothiazol-2-ylphenyl)benzamido.

In one embodiment, the implementation of compounds selected from compounds of the following formula and their pharmaceutically and physiologically acceptable salt, hydrate and solvate:

where

R is independently selected from:

where (T) represents the place of joining-T;

and (Q) is a place of connection-Q-;

-Q - is independently chosen from:

-NHC(O)-; -NR1C(O)-;

-C(O)NH-; -C(O)NR1-;

-N=N-;

-CH=CH-;

-CR1=CH-; -CH=CR1-;

-CR1=CR1-;

-N=CH-; -CH=N-;

each of R1represents independently unsubstituted saturated alifaticheskii1-4alkyl;

-R is independently selected from:

where * indicates the place of attachment;

T is independently selected from:

where * indicates the place of attachment;

and X represents independently N or CH;

-W1is an independently-H or-WA;

-W2is an independently-H or-WA;

-W3is an independently-H or-WA;

-W4p is ecstasy an independently-H or-W A;

-W5is an independently-H or-WA;

-W6is an independently-H or-WA;

where-WAindependently chosen from:

-F, -Cl, -Br, -I,

-IT, -WA1-O-WA1,

-NH2, -NHWA1and-N(WA1)2;

and-WA1independently chosen from:

unsubstituted saturated aliphatic C1-4of alkyl,

-CF3,

-CH2CH2OH and

-CH2CH2N(Me)2;

-G1independently represents-H or-GA;

-G2independently represents-H or-GA;

where-GAindependently chosen from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6;

-G3independently represents-H or-GB;

-G4independently represents-H or-GB,

where-GBindependently chosen from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6;

where:

-R1independently represents-H or-PA;

-R2independently represents-H or-PB;

-R3independently represents-H or-PC;

-R4independently represents-H or-PB;

-R5independently made the focus of an-N or-P A;

and where:

each of PAeach of PBand each of PCindependently represents:

-F, -Cl, -Br, -I,

-R2,

-CF3, -OCF3,

-OH, -L1-OH,

-OR2, -L1-OR2, -O-L1-OR2,

-SH, -SR2,

-CN

-NO2,

-NH2-The other2, -NR22, -NR3R4,

-NHOH,

-L1-NH2, -L1-Other2, -L1-NR22, -L1-NR3R4,

-O-L1-NH2, -O-L1-Other2, -O-L1-NR22, -O-L1-NR3R4,

-C(=O)OH, -C(=O)OR2,

-OC(=O)R2,

-C(=O)NH2, -C(=O)other2, -C(=O)NR22, -C(=O)NR3R4,

-NHC(=O)R2, -NR2C(=O)R2,

-C(=O)NHOR2, -C(=O)NR2OR2,

-NHC(=O)OR2, -NR2C(=O)OR2,

-OC(=O)NH2, -OC(=O)other2, -OC(=O)NR22, -OC(=O)NR3R4,

-C(=O)R2,

-NHC(=O)NH2, -NHC(=O)other2,

-NHC(=O)NR22, -NHC(=O)NR3R4,

-NR2C(=O)NH2, -NR2C(=O)other2,

-NR2C(=O)NR22, -NR2C(=O)NR3R4,

-NHS(=O)2R2, -NR2S(=O)2R2,

-S(=O)2NH2, -S(=O)2Other2, -S(=O)2NR22, -S(=O)2NR3R4,

-S(=O)R2, -S(=O)2R2, -OS(=O)2R2or-S(=O)2 2

where:

each of L1- independently represents a saturated aliphatic C1-5alkylen;

in each of the groups-NR3R4, -R3and R4taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6 - or 7-membered nonaromatic ring containing exactly 1 heteroatom in the ring, exactly 2 heteroatom in the ring, where one of the 2 ring heteroatoms represents N and the other of these 2 ring heteroatoms independently represents N, O or S;

each of R2independently represents:

-RA1, -RA2, -RA3, -RA4, -RA5, -RA6, -RA7, -RA8,

-LA-RA4, -LA-RA5, -LA-RA6, -LA-RA7or-LA-RA8;

where:

each of RA1independently represents a saturated aliphatic C1-6alkyl;

each of RA2independently represents an aliphatic C2-6alkenyl;

each of RA3independently represents an aliphatic C2-6quinil;

each of RA4independently represents a saturated3-6cycloalkyl;

each of RA5independently represents a C3-6cycloalkenyl;

each of RA6independently represents a non-aromatic C3-7heterocyclyl;

cardys-R A7independently represents a C6-10carbaryl;

each of RA8independently represents a C5-10heteroaryl;

each of LA- independently represents a saturated aliphatic C1-3alkylen;

and where:

each of RA4, -RA5, -RA6, -RA7and RA8possibly substituted, for example, one or more Deputy-RB1and/or one or more Deputy-RB2and

each of RA1, -RA2, -RA3and-LA- may be substituted, for example, one or more Deputy-RB2,

where:

each of RB1independently represents a saturated aliphatic C1-4alkyl, phenyl or benzyl;

each of RB2independently represents:

-F, -Cl, -Br, -I,

-CF3, -OCF3.

-OH, -LC-OH, -O-LC-OH,

-ORC1, -LC-ORC1, -O-LC-ORC1,

-SH, -SRC1,

-CN

-NO2,

-NH2-The otherC1, -NRC12, -NRC2RC3,

-LC-NH2, -LC-OtherC1, -LC-NRC12, or-LC-NRC2RC3,

-O-LC-NH2, -O-LC-OtherC1, -O-LC-NRC12, -O-LC-NRC2RC3,

-C(=O)OH, -C(=O)ORC1,

-OC(=O)RC1,

-C(=O)RC1,

-C(=O)NH2, -C(=O)otherC1, -C(=O)NRC12, -C(=O)NRC2RC3,

-NHC(=O)RC1, -NRC1C(=O)RC1,

-NHS(=O)2RC1, -NRC1S(=O)2RC1,

-S(=O)2NH2, -S(=O)2OtherC1, -S(=O)2NRC12, -S(=O)2NRC2RC3or

-S(=O)2RC1;

where:

each of RC1independently represents an unsubstituted saturated aliphatic C1-4alkyl, phenyl or benzyl;

each of LC- independently represents an unsubstituted saturated aliphatic C1-5alkylen; and

in each of the groups-NRC2RC3, -RC2and RC3taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6 - or 7-membered nonaromatic ring containing exactly 1 heteroatom in the ring or exactly 2 heteroatom in the ring, where one of the 2 ring heteroatoms represents N and the other of these 2 ring heteroatoms independently represents N, O or S.

Possible limitations

In one or more aspects of the present invention (for example, the compounds, compositions, compounds used for treatment, the use of compounds to obtain medicines, methods, treatments, etc.) connections are perhaps similar to those shown in the present patent application, but with one or more possible limitation described in this patent application.

According to one implementation variant, the connection represents a connection, defined in the present patent application, with the limitation that the compound is not a compound selected from compounds of the P-001 to P-015.

No.LinkStructure
R-001Klunk et al. WO 2006/014382

No.LinkStructure
R-002Lee et al. Bioorg. Med. Chem. Lett. 2008,18,1534
P-003Lee et al. Bioorg. Med. Chem. Lett. 2008,18, 1534
P-004Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-005Lee et al. Bioorg. Med. Chem. Lett. 2008,18, 1534
P-006Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-007Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-008Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-009Lee et al. Bioorg. Med. Chem. Lett. 2008,18,1534

No.LinkStructure
P-010Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-011Lee et al. Bioorg. Med. Chem. Lett. 2008, 18,1534
P-012Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-013Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-014Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-015Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534

According to one implementation variant, the connection is a connection that is defined in the present patent application, with the limitation that the compound is not a compound selected from compounds of the P-001 to P-015.

According to one implementation variant, the connection is a connection that is defined in the present patent application, with the limitation that the compound is not a compound selected from compounds of the P-001 to P-015 and their salts, hydrate and solvate.

In one or more aspects of the present invention (e.g., associated with specific applications and methods, such as connections, used for marking aggregates of the Tau protein, the use of compounds for the diagnosis, methods of predicting or diagnosing or determining the stage of the disease, etc.) compounds may be compounds defined in the present patent application, but without any constraints, which are constraints on the connections from the P-001 to P-015.

For example, a link to a specific group of compounds without limitation, related to the connections from the P-001 to P-015" (for example, p is imeneniya in diagnostics) is used as reference compounds defined in this patent application, but in which the definition does not contain the specified limits. In these cases, as in the case if this limitation is removed from the connection definitions, the definition covers those compounds that are otherwise excluded by the specified constraint.

According to one implementation variant, the connection is a connection that is defined in the present patent application, with the limitation that the compound is not a compound, where T represents:

-R represents a

and - R represents:

and-W4represents-H, -Q - represents-CH=CH-, -G1, -G2and-G3represent-N and

(i) -P1, -P2, -P4and-R5represent-H, and-R3is a-RA1; or

(ii) one of R1, -R2, -R3, -R4and R5is a-RA7and the rest of R1, -R2, -R3, -R4and-R5represent-N.

The preferred connection

According to one implementation variant, the connection independently chosen from:

where-Q-, -R, -T, -G1, -G2, -G3and-G4ODA is defined above.

According to one implementation variant, the connection independently chosen from:

where-Q-, -R, X-W1, -W2, -W3, -W4, -G2and-G3defined above.

Benzothiazoline connection

According to one implementation variant, the connection independently represents:

where-Q-, -R, -W4, -G2and-G3defined above.

According to one implementation variant, the connection independently chosen from:

According to one implementation variant, the connection independently represents:

According to one implementation variant, the connection independently represents:

where-R1, -R2, -R3, -R4and-R5defined above.

According to one implementation variant, the connection independently represents:

According to one implementation variant, the connection independently represents:

where-R1, -R2, -R3, -R4and-R5defined above.

According to one implementation variant sedimentation represents:

According to one implementation variant, the connection independently represents:

where-R1, -R2, -R3, -R4and-R5defined above. According to one implementation variant, the connection independently represents:

where-R1, -R2, -R3, -R4and-R5defined above.

Imidazo[2,1-b][1,3]thiazole compounds

According to one implementation variant, the connection independently represents:

where-R, -W2, -W3, -G2and-G3defined above.

According to one implementation variant, the connection independently represents:

where W2, -W3, -G2, -G3, -P1, -P2, -P3, -P4and-R5defined above.

Imidazo[2,1-b][1,3]thiazole, imidazo[1,2-a]pyridine compounds

According to one implementation variant, the connection independently represents:

where-Q-, -R, -W1, X, -G2and-G3defined above.

According to one implementation variant, the connection independently represents:

where-Q, -P, -W1, -G2and-G3defined above.

According to the final implementation variant, the connection independently represents:

where-Q, -P, -W, -G2and-G3defined above.

According to one implementation variant, the connection independently chosen from:

where-P, -W1, X, -G2and-G3defined above.

According to one implementation variant, the connection independently represents:

where-P, -W1, X, -G2and-G3defined above.

According to one implementation variant, the connection independently represents:

where-P1, -P2, -P3, -P4and-P5defined above.

According to one implementation variant, the connection independently represents:

where-P, -W1, X, -G2and-G3defined above.

According to one implementation variant, the connection independently represents:

where-P, -W1, X, -G2and-G3defined above.

Halogenated compounds

According to one implementation variant DSB compound is a compound of formula (I), with the limitation that the compound contains-F, -Cl, -Br or-I group.

According to one implementation variant JB connection is a is connected to the e of the formula (I), with the limitation, what compound contains-F group.

According to one implementation variant DSB compound is a compound of formula (I), with the limitation that the compound contains -19F group.

According to one implementation variant DSB compound is a compound of formula (I), with the limitation that the compound contains-Cl, -Br or-I group.

According to one implementation variant, the group R is substituted by-F group or a substituted group containing a-F group. Thus one of R1, -R2, -R3, -R4or-R5, if present, may represent a-F or one of the-PA, -PBor-PCcontains-F group.

According to one implementation variant, the group T is replaced by-F group or a substituted group containing a-F group. Thus WArepresents-F or-WA1contains-F group.

According to one implementation variant, the group R is substituted by-F group or a substituted group containing a-F group. Thus GArepresents-F, or-GAcontains-F group.

The group-R-

According to one implementation variant-R is independently selected from:

According to one implementation variant-R is independently selected from

According to one implementation variant-R is independently selected from:

The group-Q-

According to one implementation variant-Q - is independently chosen from:

-NHC(O)-; -NR1C(O)-;

-C(O)NH-; -C(O)NR1-;

-N=N-;

-CH=CH-;

-CR1=CH-; -CH=CR1-;

-CR1=CR1-;

-N=C-; -C=N-.

According to one implementation variant-Q - is independently chosen from:

-NHC(O)-; -NR1C(O)-;

-N=N-;

-CH=CH-;

-N=C-; -C=N-.

According to one implementation variant-Q - is independently chosen from:

-NHC(O)-;

-N=N-;

-CH=CH-;

-N=C-.

According to one implementation variant-Q - is independently chosen from:

-NHC(O)-;

-N=N-;

-CH=CH-.

According to one implementation variant-Q - is independently selected from-NHC(O) -, and-NR1C(O)-.

According to one implementation variant-Q - is independently represents-NHC(O)-.

According to one implementation variant-Q - is independently selected from-N=N-, -CH=CH - and-N=C-.

According to one implementation variant-Q - is independently represents-N=N-.

According to one implementation variant-Q - is independently represents:

where * indicates the place of attachment.

According to one implementation variant-Q - is independently represents-CH=CH-.

According to one implementation variant-Q - is independently represents:

where * indicates the place of attachment.

According to one implementation variant-Q - is independently represents-N=C-.

According to one implementation variant-Q - is independently represents:

where * indicates the place of attachment.

The group-R1

According to one implementation variant, each of R1if present, independently represents an unsubstituted saturated aliphatic C1-4alkyl.

According to one implementation variant, each of R1if present, independently represents-Me.

According to one implementation variant, each of R1if present, independently represents-Et.

Group-P

According to one implementation variant, the R is independently selected from:

where * indicates the place of attachment.

According to one implementation variant, -R independently represents:

According to one implementation variant, the R is independently selected from:

According to one implementation variant, -R independently represents the Wallpaper:

According to one implementation variant, -R independently represents:

According to one implementation variant, -R independently represents:

Group-T

According to one implementation variant-T is independently selected from:

where X independently represents N or CH.

According to one implementation variant-T independently represents:

where X independently represents N or CH.

According to one implementation variant-T independently represents:

According to one implementation variant-T independently represents:

According to one implementation variant-T independently represents:

According to one implementation variant-T independently represents:

Group-W1

According to one implementation variant-W1independently represents-H or-WA.

According to one implementation variant-W1independently represents-N.

According to one implementation variant-W1independently researched the mo represents a-W A.

Group-W2

According to one implementation variant-W2independently represents-H or-WA.

According to one implementation variant-W2independently represents-N.

According to one implementation variant-W2independently represents-WA.

Group-W3

According to one implementation variant-W3independently represents-H or-WA.

According to one implementation variant-W3independently represents-N.

According to one implementation variant-W3independently represents-WA.

Group-W4

According to one implementation variant-W4independently represents-H or-WA.

According to one implementation variant-W4independently represents-N.

According to one implementation variant-W4independently represents-WA.

Group-W5

According to one implementation variant-W5independently represents-H or-WA.

According to one implementation variant-W5independently represents-N.

According to one implementation variant-W5independently represents-WA.

Group-W6

According to one implementation variant-W6independently represents-H or-WA.

With the according to one implementation variant-W 6independently represents-N.

According to one implementation variant-W6independently represents-WA.

Group-W2and-W3

According to one implementation variant, at least one of-W2and-W3represents-WA.

According to one implementation variant, one of the-W2and-W3represents-WA.

According to one implementation variant-W2represents-WA.

According to one implementation variant-W3represents-WA.

Group-W4, -W5and-W6

According to one implementation variant, at least one of-W4, -W5and-W6represents-WA.

According to one implementation variant, one of the-W4, -W5and-W6represents-WA.

According to one implementation variant-W4represents-WA.

According to one implementation variant-W5represents-WA.

According to one implementation variant-W6represents-WA.

Group-WA

According to one implementation variant-WAif present, independently selected from:

-F, -Cl, -Br, -I,

-IT, -WA1-O-WA1,

-NH2, -NHWA1and-N(WA1)2.

According to one implementation variant-WA/sup> if present, independently selected from:

-OH, -WA1-O-WA1,

-NH2, -NHWA1and-N(WA1)2.

According to one implementation variant-WAif present, independently selected from-OH, -WA1and-O-WA1.

According to one implementation variant-WAif present, independently selected from WA1and-O-WA1.

According to one implementation variant-WAif present, independently selected from-HE-O-WA1.

According to one implementation variant-WAif present, independently represents-WA1.

According to one implementation variant-WAif present, independently represents-O-WA1.

According to one implementation variant-WAif present, independently represents-HE.

According to one implementation variant-WAif present, independently selected from-NH2, -NHWA1and-N(WA1)2.

According to one implementation variant-WAif present, independently represents-NH2.

According to one implementation variant-WAif present, independently represents-NHWA1.

According to one implementation variant-WAif presets is there, independently represents-N(WA1)2.

According to one implementation variant-WAif present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant-WAif present, independently represents a-F or a-I.

According to one implementation variant-WAif present, independently represents-F.

Group-WA1

According to one implementation variant-WA1if present, independently selected from:

unsubstituted saturated aliphatic C1-4of alkyl,

-CF3,

-CH2CH2OH and

-CH2CH2N(Me)2.

According to one implementation variant-WA1if present, independently selected from unsubstituted saturated aliphatic C1-4the alkyl and-CF3.

According to one implementation variant-WA1if present, independently represents an unsubstituted saturated aliphatic C1-4alkyl.

According to one implementation variant-WA1if present, independently represents-Me.

According to one implementation variant-WA1if present, independently represents-Et.

According to one implementation variant-WA1if present, represent the screens a-CF 3.

According to one implementation variant-WA1if present, represents-CH2CH2OH.

According to one implementation variant-WA1if present, represents-CH2CH2N(Me)2.

Group-G1, -G2, -G3and-G4

According to one implementation variant, at least one in-G1, -G4and-G2and G3if there is not-H.

According to one implementation variant one-G1, -G4and-G2and G3if there is not -- N.

According to one implementation variant, each of the-G1, -G4and-G2and G3if present, independently represents-N.

Group-G1

According to one implementation variant-G1independently represents-H or-GA.

According to one implementation variant-G1independently represents-N.

According to one implementation variant-G1independently represents-GA.

Group-G2

According to one implementation variant-G2independently represents-H or-GA.

According to one implementation variant-G independently represents-N.

According to one implementation variant-G2independently represents Soboh the-G A.

Group-G3

According to one implementation variant-G3independently represents-H or-GB.

According to one implementation variant-G3independently represents-N.

According to one implementation variant-G3independently represents-GB.

Group-G4

According to one implementation variant-G4independently represents-H or-GB.

According to one implementation variant-G4independently represents-N.

According to one implementation variant-G4independently represents-GB.

Group-GA

According to one implementation variant-GAif present, independently selected from

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6.

According to one implementation variant-GAif present, independently selected from

-F

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6.

According to one implementation variant-GAif present, independently selected from

-F

-CF3, -OCF3,

-OH, -OR2.

According to one implementation variant-GAif present, it is not avisio selected from the

-F, -Cl, -Br, -I,

-OH, -OR2.

According to one implementation variant-GAif present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant-GAif present, independently represents-F.

According to one implementation variant-GAif present, independently selected from-HE-OR2.

According to one implementation variant-GAif present, independently represents-HE.

According to one implementation variant-GAif present, independently represents-OR2.

According to one implementation variant-GAif present, independently represents -[O-CH2CH2]n-RB2where n takes values from 2 to 6.

Group-GB

According to one implementation variant-GBif present, independently selected from

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6.

According to one implementation variant-GBif present, independently selected from

-F

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6.

According to one implementation variant - Bif present, independently selected from

-CF3, -OCF3,

-OH, -OR2;

-[O-CH2CH2]n-RB2where n takes values from 2 to 6.

According to one implementation variant-GBif present, independently selected from

-CF3, -OCF3,

-OH, -OR2.

According to one implementation variant-GBif present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant-GBif present, independently represents-F.

According to one implementation variant-GB, if present, is independently chosen from-CF3and-OCF3.

According to one implementation variant-GBif present, independently represents-CF3and-OCF3.

According to one implementation variant-GBif present, independently represents-OCF3.

According to one implementation variant-GBif present, independently selected from-HE-OR2.

According to one implementation variant-GBif present, independently represents-HE.

According to one implementation variant-GBif present, independently represents-OR2.

According to one version of the " the-G Bif present, independently represents-OCH2CH2N(Me)2.

According to one implementation variant-GBif present, independently represents -[O-CH2CH2]n-RB2where n takes values from 2 to 6.

According to one implementation variant-GBif present, independently represents -[O-CH2CH2]3-OMe.

Group n

According to one implementation variant n, when applied, independently denotes a number from 2 to 6.

According to one implementation variant n, when applied, independently denotes a number from 2 to 4.

According to one implementation variant n, in the case of application, regardless of means 2.

According to one implementation variant n, in the case of application, regardless of means 3.

Group-P1, -R2, -R3, -R4and-R5

According to one implementation variant, at least one of R1, -R2, -R3, -R4and-R5if there is a-PA, -PBor-PCin appropriate cases.

According to one implementation variant, one of R1, -R2, -R3, -R4and-R5if there is a-PA, -PBor-PCin appropriate cases.

who according to one implementation variant, at least one of R 1, -R2, -R3, -R4and-R5if there is not -- N.

According to one implementation variant, one of R1, -R2, -R3, -R4and-R5if there is not -- N.

According to one implementation variant, each of R1, -R2, -R3, -R4and-R5if present, independently represents-N.

According to one implementation variant, one of R1, -R2, -R3, -R4and-R5if present, independently represents-F.

Group-P1

According to one implementation variant-R1independently represents-H or-PA.

According to one implementation variant-R1independently represents-N.

According to one implementation variant-R1independently represents-PA.

According to one implementation variant-R1coincides with the-R5, if present.

Group-P2

According to one implementation variant-R2independently represents-H or-PB.

According to one implementation variant-R2independently represents-N.

According to one implementation variant-R2independently represents-PB.

According to one implementation variant-R2 coincides with the-R 4, if present.

Group-P3

According to one implementation variant-R3independently represents-H or-PC.

According to one implementation variant-R3independently represents-N.

According to one implementation variant-R independently represents-PC.

Group-P4

According to one implementation variant-R4independently represents-H or-PB.

According to one implementation variant-R4independently represents-N.

According to one implementation variant-R4independently represents-PB.

Group-P5

According to one implementation variant-R5if present, independently represents-H or-PA.

According to one implementation variant-R5if present, independently represents-N.

According to one implementation variant-R5if present, independently represents-PA.

Group-PA, -PBand-PC

According to one implementation variant, each of PAeach of PBand each of PCif present, independently selected from:

-F, -Cl, -Br, -I,

-R2,

-CF3, -OCF3,

-OH, -L1HE

-OR2, -L1-OR2, -O-L1 -OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4,

-NHOH,

-C(=O)OH, -C(=O)OR2,

-OC(=O)R2,

-C(=O)NH2, -C(=O)other2, -C(=O)NR22, -C(=O)NR3R4,

-NHC(=O)R2, -NR2C(=O)R2,

-C(=O)NHOR2, -C(=O)NR2OR2,

-NHC(=O)OR2, -NR2C(=O)OR2,

-OC(=O)NH2, -OC(=O)other2, -OC(=O)NR22, -OC(=O)NR3R4,

-C(=O)R2,

-S(=O)R2, -S(=O)2R2, -OS(=O)2R2or-S(=O)2OR2.

According to one implementation variant, each of PAeach of PBand each of PCif present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -L1-OH,

-OR2, -L1-OR2, -O-L1-OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4,

-NHOH,

-C(=O)OH, -C(=O)OR2,

-OC(=O)R2,

-NHC(=O)R2, -NR2C(=O)R2.

Group-PA

According to one implementation variant, each of PAif present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -L1-OH,

-OR2, -L1-OR2, -O-L1-OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, the distance between the th of P Aif present, independently selected from:

-F

-CF3, -OCF3,

HE

-OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, each of PAif present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant, each of PAif present, independently selected from-f

According to one implementation variant, each of PA, if present, is independently chosen from-CF3and-OCF3.

According to one implementation variant, each of PAif present, independently represents-CF3.

According to one implementation variant, each of PAif present, independently represents-OCF3.

According to one implementation variant, each of PAif present, independently selected from-HE-L1-OH.

According to one implementation variant, each of PAif present, independently represents-HE.

According to one implementation variant, each of PAif present, independently represents-L1HE.

According to one implementation variant, each of PAif present, independently select the n-OR 2, -L1-OR2and-O-L1-OR2.

According to one implementation variant, each of PAif present, independently represents-OR2.

According to one implementation variant, each of PAif present, independently represents-OMe.

According to one implementation variant, each of PAif present, independently represents-O(CH2)3-CF3.

According to one implementation variant, each of PAif present, independently represents-O(CH2)n-F, where n takes values from 2 to 6.

According to one implementation variant, each of PAif present, independently represents-O(CH2)2-F.

According to one implementation variant, each of PAif present, independently selected from-L1-OR2and-O-L1-OR2.

According to one implementation variant, each of PAif present, independently selected from:

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, each of PAif present, independently represents-NO2.

According to one implementation variant, each of PAin case the e if present, independently selected from-NH2-The other2, -NR22and-NR3R4.

According to one implementation variant, each of PAif present, independently selected from-NH2-The other2and-NR22.

According to one implementation variant, each of PAif present, independently represents-NR3R4.

According to one implementation variant, each of PAif present, independently selected from-NH2-The other2and-NR22.

According to one implementation variant, each of PAif present, independently represents-NH2.

According to one implementation variant, each of PAif present, independently represents-other2.

According to one implementation variant, each of PAif present, independently represents-NHMe.

According to one implementation variant, each of PAif present, independently represents - NH-(CH2)n-F, where n takes values from 2 to 6.

According to one implementation variant, each of PAif present, independently represents - NH-(CH2)n-F, where n takes on the values 2, 3, or 4.

According to one implementation variant, the AC is ery of P Aif present, independently represents-NR22.

According to one implementation variant, each of PAif present, independently represents-NMe2.

According to one implementation variant, each of PAif present, independently represents-R2.

Group-PB

According to one implementation variant, each of PBif present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -L1-OH,

-OR2, -L1-OR2, -O-L1-OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, each of PBif present, independently selected from:

-F

-CF3, -OCF3,

HE

-OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, each of PBif present, independently selected from:

-F

-CF3, -OCF3,

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, each of PBif present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant, each and the-P Bif present, independently represents-F.

According to one implementation variant, each of PB, if present, is independently chosen from-CF3and-OCF3.

According to one implementation variant, each of PBif present, independently represents-CF3.

According to one implementation variant, each of PBif present, independently represents-OCF3.

According to one implementation variant, each of PBif present, independently selected from-HE-L1-OH.

According to one implementation variant, each of PBif present, independently represents-HE.

According to one implementation variant, each of PBif present, independently represents-L1HE.

According to one implementation variant, each of PBif present, independently selected from-OR2, -L1-OR2and-O-L1-OR2.

According to one implementation variant, each of PBif present, independently represents-OR2.

According to one implementation variant, each of PBif present, independently selected from-L1-OR2and-O-L1-OR2.

According to one the implementation variant, each of PBif present, independently represents - O-(CH2)n-F, where n takes values from 2 to 6.

According to one implementation variant, each of PBif present, independently represents - O-(CH2)2-F.

According to one implementation variant, each of PBif present, independently selected from

-NO2,

-NH2-The other2, -NR22, -NR3R4.

According to one implementation variant, each of PBif present, independently represents-NO2.

According to one implementation variant, each of PBif present, independently selected from-NH2-The other2, -NR22and-NR3R4.

According to one implementation variant, each of PBif present, independently selected from-NH2-The other2and-NR22.

According to one implementation variant, each of PBif present, independently represents-NR3R4.

According to one implementation variant, each of PBif present, independently selected from-NH2-The other2and-NR22.

According to one implementation variant, each of PB, if present, is independently researched the mo represents-NH 2.

According to one implementation variant, each of PBif present, independently represents-other2.

According to one implementation variant, each of PBif present, independently represents-NHMe.

According to one implementation variant, each of PBif present, independently represents - NH-(CH2)n-F, where n takes values from 2 to 6.

According to one implementation variant, each of PBif present, independently represents - NH-(CH2)n-F, where n takes on the values 2, 3, or 4.

According to one implementation variant, each of PBif present, independently represents-NR22.

According to one implementation variant, each of PBif present, independently represents-NMe2.

According to one implementation variant, each of PBif present, independently represents-R2.

Group-PC

According to one implementation variant, each of PCif present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -L1-OH,

-OR2, -L1-OR2, -O-L1-OR2,

-NO2,

-NH2-The other2, -NR2 2, -NR3R4,

-NHOH,

-C(=O)OH, -C(=O)OR2,

-OC(=O)R2,

-NHC(=O)R2, -NR2C(=O)R2.

According to one implementation variant, each of PCif present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

HE

-OR2,

-NO2,

-NH2-The other2, -NR22, -NR3R4,

-NHOH,

-OC(=O)R2,

-NHC(=O)R2.

According to one implementation variant, each of PCif present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant, each of PCif present, independently selected from-F, -Cl and-Br.

According to one implementation variant, each of PCif present, independently represents-F.

According to one implementation variant, each of PC, if present, is independently chosen from-CF3and-OCF3.

According to one implementation variant, each of PCif present, independently represents-CF3.

According to one implementation variant, each of PCif present, independently represents-OCF3.

According to one implementation variant, each of PCif present, independently selected from-HE-L1HE.

According to gnome implementation variant, each of PCif present, independently represents-HE.

According to one implementation variant, each of PCif present, independently represents-L1HE.

According to one implementation variant, each of PCif present, independently selected from-OR2, -L1-OR2and-O-L1-OR2.

According to one implementation variant, each of PCif present, independently represents-OR2.

According to one implementation variant, each of PCif present, independently represents-OMe.

According to one implementation variant, each of PCif present, independently represents-O(CH2)2HE.

According to one implementation variant, each of PCif present, independently represents - O-(CH2)n-F, where n takes values from 2 to 6.

According to one implementation variant, each of PCif present, independently represents - O-(CH2)2-F.

According to one implementation variant, each of PCif present, independently represents - O-(CH2)n-CF3where n takes values from 1 to 6.

According to one variant is realizatsii, each of PCif present, independently represents - O-(CH2)n-CF3where n takes values from 1, 2 or 3.

According to one implementation variant, each of PCif present, independently selected from-L1-OR2and-O-L1-OR2.

According to one implementation variant, each of PCif present, independently selected from:

-NO2,

-NH2-The other2, -NR22, -NR3R4,

-NHOH.

According to one implementation variant, each of PCif present, independently represents-NO2.

According to one implementation variant, each of PCif present, independently represents-NHOH.

According to one implementation variant, each of PCif present, independently selected from-NH2-The other2, -NR22, -NR3R4and-NHOH.

According to one implementation variant, each of PCif present, independently selected from-NH2-The other2, -NR22and-NR3R4.

According to one implementation variant, each of PCif present, independently selected from-NH2-The other2and-NR22.

According to one implementation variant, each of PCif present, independently represents-NR3R4.

According to one implementation variant, each of PCif present, independently selected from-NH2-The other2and-NR22.

According to one implementation variant, each of PCif present, independently represents-NH2.

According to one implementation variant, each of PCif present, independently represents-other2.

According to one implementation variant, each of PCif present, independently represents-NHMe.

According to one implementation variant, each of PCif present, independently represents - NH-(CH2)n-CF3where n takes values from 1 to 6.

According to one implementation variant, each of PCif present, independently represents - NH-(CH2)n-CF3where n takes on the values 2, 3, or 4.

According to one implementation variant, each of PCif present, independently represents - NH-(CH2)n-F, where n takes values from 2 to 6.

According to one implementation variant, each of PCif present, independently represents - NH-(CH2)n-F, where n takes on the values 2, 3, or 4.

According to one implementation variant, each of PCif present, independently represents-NR22.

According to one implementation variant, each of PCif present, independently represents-NMe2.

According to one implementation variant, each of PCif present, independently selected from-C(=O)HE-C(=O)OR.

According to one implementation variant, each of PCif present, independently represents-C(=O)HE.

According to one implementation variant, each of PCif present, independently represents-C(=O)OR2.

According to one implementation variant, each of PCif present, independently represents-C(=O)OMe.

According to one implementation variant, each of PCif present, independently selected from-NHC(=O)R2and-NR2C(=O)R2.

According to one implementation variant, each of PCif present, independently represents-NHC(=O)R2.

According to one implementation variant, each of PCif present, independently represents-NHC(=O)CF3.

According to one implementation variant, each of PCif there is, regardless, not only is no a-NR 2C(=O)R2.

According to one implementation variant, each of PCif present, independently represents-R2.

Group-L1-

According to one implementation variant, each of the-L1-, if present, independently represents an unsubstituted saturated aliphatic C1-5alkylen.

According to one implementation variant, each of the-L1-, if present, independently represents-CH2-.

According to one implementation variant, each of the-L1-, if present, independently represents-CH2CH2-.

The group-R2

According to one implementation variant, each of R2if present, independently represents:

-RA1, -RA2, -RA3, -RA4, -RA5, -RA6, -RA7, -RA8,

-LA-RA4, -LA-RA5, -LA-RA6, -LA-RA7or-LA-RA8;

and each of RA4, -RA5, -RA6, -RA7and RA8is a possibly substituted, for example, one or more Deputy-RB1and/or one or more Deputy-RB2and

each of RA1, -RA2, -RA3and-LA- is a possibly substituted, for example, one or more Deputy-RB2.

According to one variant the NTU implementation, each of R2if present, independently represents-RA1.

The group-RA1

According to one implementation variant, each of RA1if present, independently represents a possibly substituted saturated aliphatic C1-6alkyl.

According to one implementation variant, each of RA1if present, independently represents a possibly substituted saturated aliphatic C1-4alkyl.

According to one implementation variant, each of RA1if present, independently represents an unsubstituted saturated aliphatic C1-6alkyl.

According to one implementation variant, each of RA1if present, independently represents an unsubstituted saturated aliphatic C1-4alkyl.

According to one implementation variant, each of RA1if present, independently represents an unsubstituted-Me.

According to one implementation variant, each of RA1if present, independently represents an unsubstituted-Et.

According to one implementation variant, each of RA1if present, independently represents an unsubstituted-Pr.

According to one implementation variant, each of RA1that is the case, if present, independently represents a possibly substituted-Me.

According to one implementation variant, each of RA1if present, independently represents a possibly substituted-Et.

According to one implementation variant, each of RA1if present, independently represents a possibly substituted-Pr.

According to one implementation variant, each of RA1if present, independently represents a possibly substituted-Bu.

According to one implementation variant, each of RA1if present, independently represents-CF3.

According to one implementation variant, each of RA1if present, independently represents-CH2CF3.

According to one implementation variant, each of RA1if present, independently represents-CH2CH2CF3.

According to one implementation variant, each of RA1if present, independently represents-CH2CH2CH2CF3.

According to one implementation variant, each of RA1if present, independently represents-CH2F.

According to one implementation variant, each of RA1if present, independently presented yet a-CH 2CH2F.

According to one implementation variant, each of RA1if present, independently represents-CH2CH2CH2F.

According to one implementation variant, each of RA1if present, independently represents-CH2CH2N(Me)2.

The group-RB2

According to one implementation variant, each of RB2if present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -LC-OH, -O-LC-OH,

-ORC1, -LC-ORC1, -O-LC-ORC1,

-NHS(=O)2RC1, -NR2S(=O)2RC1.

According to one implementation variant, each of RB2if present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -LC-OH, -O-LC-OH,

-ORC1, -LC-ORC1, -O-LC-ORC1.

According to one implementation variant, each of RB2if present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3,

-OH, -O-LC-OH,

-ORC1, -LC-ORC1, -O-LC-ORC1.

According to one implementation variant, each of RB2if present, independently selected from:

-F, -Cl, -Br, -I,

-CF3, -OCF3.

According to one implementation variant, each of RB2 if present, independently selected from-F, -Cl, -Br, and-I.

According to one implementation variant, each of RB2, if present, is independently chosen from-CF3and-OCF3.

According to one implementation variant, each of RB2if present, independently selected from-F and-CF3.

According to one implementation variant, each of RB2if present, independently represents-F.

According to one implementation variant, each of RB2if present, independently represents-CF3.

According to one implementation variant, each of RB2if present, independently selected from:

-OH, -LC-OH, -O-LC-OH,

-ORC1, -LC-ORC1, -O-LC-ORC1.

According to one implementation variant, each of RB2if present, independently selected from:

-OH, -O-LC-OH,

-ORC1, -O-LC1-ORC1.

According to one implementation variant, each of RB2if present, independently selected from-HE-ORC1.

According to one implementation variant, each of RB2if present, independently selected from-O-LC-OH and-O-LC-ORC1.

According to one implementation variant, each of RB2if present, it is not avisio represents-O-L CHE.

According to one implementation variant, each of RB2if present, independently represents-O-LC-ORC1.

Group-LC-

According to one implementation variant, each of LC-, if present, independently represents an unsubstituted saturated aliphatic C1-5alkylen.

According to one implementation variant, each of LC-, if present, independently represents-CH2CH2-.

The group-RC1

According to one implementation variant, each of RC1if present, independently represents an unsubstituted saturated aliphatic C1-4alkyl, phenyl or benzyl.

According to one implementation variant, each of RC1if present, independently represents an unsubstituted saturated aliphatic C1-4alkyl.

According to one implementation variant, each of RC1if present, independently represents-Me.

According to one implementation variant, each of RC1if present, independently represents an unsubstituted phenyl.

According to one implementation variant, each of RC1if present, independently represents an unsubstituted benzyl.

Combination of the Sabbath.

All compatible combinations of variants of the implementation described above, explicitly disclosed in the present description, as if every combination was individually and explicitly described.

Physico-chemical properties

Preferred ranges of physico-chemical properties to increase the penetration through the blood-brain barrier discuss in more detail next. However, on the basis of existing CNS active agents described below, the following preferred criteria for JB connections:

Molecular mass

According to one implementation variant DSB compound has a molecular weight equal to from 330 to 600.

According to one implementation variant, the lower limit of the range is from 350, 375, 400 or 425.

According to one implementation variant, the upper limit of the range is 600, 575, 550, 525, 500 or 450.

According to one implementation variant, the range is from 375 to 575.

According to one implementation variant DSB compound has a molecular weight of 500 or less.

According to one implementation variant DSB compound has a molecular weight equal to 450 or less.

miLog P

According to one implementation variant JB connection has value miLog P equal to from 2.0 to 5.3.

According to one implementation variant, the lower limit of the range of the composition is yet from 2.8, to 2.9, and 3.0 or 3.1.

According to one implementation variant, the upper limit of the range is 5.0, 5,1, 5,2, 5,3, a 4.5 or 4.0.

According to one implementation variant, the range is from 3.0 to 5.1.

According to one implementation variant JB connection has value miLog P equal to from 2.0 to 5.0.

According to one implementation variant JB connection has value miLog P equal to from 2.0 to 4.0.

Log D

According to one implementation variant JB connection has a value of Log D, is equal to from 2.0 to 5.0.

According to one implementation variant JB connection has a value of Log D, is equal to from 2.0 to 4.0.

Log D is the ratio of the equilibrium concentrations of all fragments (UN-ionized and ionized) molecules in octanol to the content of these molecules in the aqueous phase at 25°C.

According to one implementation variant Log D represents the ratio of the equilibrium concentrations of all fragments (UN-ionized and ionized) molecules in octanol to the content of these molecules in the aqueous phase at 25°C and pH 7.4.

The surface area of topological polar region

According to one implementation variant DSB compound has a surface area of topological polar region, is from 45 to 95 Å2.

According to one implementation variant, the lower limit of the range is from 50, 55 or 60.

Coz the ACLs to one implementation variant, the upper limit of the range is 70, 75, 80, 85 or 90.

According to one implementation variant, the range is from 55 to 75.

According to one implementation variant DSB compound has a surface area of topological polar region, is equal to 90 Å2or less.

According to one implementation variant DSB compound has a surface area of topological polar region, is equal to 70 Å2or less.

The hydrogen bond donors

According to one implementation variant DSB compound contains 3 or less donor hydrogen bonds.

According to one implementation variant DSB compound contains 2 or less donor hydrogen bonds.

According to one implementation variant DSB compound contains 1 or does not contain a hydrogen bond donor.

Examples of specific implementation options

According to one implementation variant of compounds selected from compounds having the formula shown below, and their pharmaceutically acceptable salt, hydrate or of a solvate.

Compounds in which Q represents-NHC(O)-; -NR1C(O)-; -C(O)NH - or-C(O)NR1-

Benzothiazoline connection

The non-fluorinated methoxyamine

Abbreviated nameNo. of connectionsStructure
AVM is -01 SKT01-13
AVMA-02SKT01-23
AVMA-03SKT01-9
AVMA-04SKT01-99
AVMA-05SKT01-41
AVMA-06SKT01-21
AVMA-07SKT01-103

Abbreviated nameNo. of connectionsStructure
AVMA-08SKT01-63
AVMA-09SKT01-61
AVMA-1 SKT01-155
AVMA-11SKT01-161
AVMA-12SKT04-87
AVMA-13SKT04-89
AVMA-14SKT03-141
AVMA-15SKT03-137
AVMA-16SKT03-33

According to one implementation variant, the connection independently chosen from:

AVMA-04; AVMA-05; AVMA-06; AVMA-07; AVMA-08; AVMA-09; AVMA-10; AVMA-11; AVMA-13; AVMA-14; AVMA-15 and AVMA-16.

According to one implementation variant, the connection independently chosen from:

AVMA-04; AVMA-05; AVMA-06; AVMA-07; AVMA-08; AVMA-09; AVMA-10; AVMA-11 and AVMA-13.

Fluorinated methoxyamine

Abbreviated name No. of connectionsStructure
ABFMA-01SK2033-50
ABFMA-02SK2033-49
ABFMA-03SK2033-47
ABFMA-04SKT04-155
ABFMA-05SKT05-7
ABFMA-06SKT05-9
ABFMA-07SKT04-173

Abbreviated nameNo. of connectionsStructure
ABFMA-08SKT05-33
ABFMA-09SKT05-31
ABFMA-10SKT05-21
ABFMA-11SKT04-175
ABFMA-12SKT02-103
ABFMA-13SKT02-169
ABFMA-14SKT03-39
ABFMA-15SKT01-157
ABFMA-16SKT01-149

Abbreviated nameNo. of connectionsStructure
ABFMA-17SKT02-31
ABFMA-18SKT01-159
ABFMA-19SKT02-25
ABFMA-20SKT01-137

According to one implementation variant, the connection independently chosen from:

ABFMA-04; ABFMA-05; ABFMA-06; ABFMA-07; ABFMA-08; ABFMA-09; ABFMA-11; ABFMA-12; ABFMA-14; ABFMA-15 and ABFMA-17.

According to one implementation variant, the connection independently selected from ABFMA-15 and ABFMA-12.

Monohalogenated methoxyamine

Abbreviated nameNo. of connectionsStructure
ABMFMA-01SKT02-135
ABMFMA-02SKT04-137

Abbreviated nameNo. of connectionsStructure
ABMFMA-03SKT04-111
ABMFMA-04
ABMFMA-05SKT03-99
ABMFMA-06SKT03-75
ABMFMA-07SKT03-93
ABMFMA-08SKT04-33
ABMFMA-09SKT04-29
ABMFMA-10SKT05-37

According to one implementation variant, the connection independently chosen from:

ABMFMA-02; ABMFMA-03; ABMFMA-04; ABMFMA-05; ABMFMA-07; ABMFMA-08; ABMFMA-09 and ABMFMA-10.

According to one implementation variant, the connection independently chosen from:

ABMFMA-02; ABMFMA-03; ABMFMA-05; ABMFMA-08 and ABMFMA-09.

The non-fluorinated hydroxyamide

SKT01-101
Abbreviated nameNo. of connectionsStructure
AVNA-01
AVNA-02SKT01-77
AVNA-03SKT01-57
AVNA-04SKT01-111
AVNA-05SKT02-177

According to one implementation variant, the connection independently chosen from:

AVNA-01; AVN-02; AVN-03 and AVNA-05.

According to one implementation variant, the connection independently chosen from:

AVNA-01; AVN-02 and AVNA-03.

Fluorinated hydroxyamide

Abbreviated nameNo. of connectionsStructure
ABFHA-01SKT03-07
ABFHA-02SKT02-45
ABFHA-03SKT02-149/td>
ABFHA-04SKT03-41
ABFHA-05SKT02-171
ABFHA-06SKT05-39
ABFHA-07SKT02-163
ABFHA-08SKT05-17
ABFHA-09SKT05-13

Abbreviated nameNo. of connectionsStructure
ABFHA-10SKT04-179
ABFHA-11SKT03-129

According to one implementation variant, the connection independently chosen what about:

ABFHA-01; ABFHA-02; ABFHA-03; ABFHA-05; ABFHA-06; ABFHA-07; ABFHA-08; ABFHA-09; ABFHA-10 and ABFHA-11.

According to one implementation variant, the connection independently chosen from:

ABFHA-01; ABFHA-02; ABFHA-03; ABFHA-05; ABFHA-06; ABFHA-08; ABFHA-09; ABFHA-10 and ABFHA-11.

The non-fluorinated methylamide

Abbreviated nameNo. of connectionsStructure
AVA-01SK2033-51
AVA-02SK2033-46
AVA-03SK2033-67
AAA-04SK2033-55

Abbreviated nameNo. of connectionsStructure
AAA-05SK2033-72
AAA-06LS-T107
AVA-07SKT01-5
AVA-08SK2033-93
AAA-09SK2033-71
AAA-10SK696-32
AVA-11SK696-54
AVA-12SK2033-94

According to one implementation variant, the connection independently chosen from:

AVA-01; AVA-02; AVA-03; AVA-06; AVA-09; AVAA-10, AVAA-11.

According to one implementation variant, the connection independently chosen from:

AAA-06; AVAA-10, AVAA-11.

Dimethylamylamine

Abbreviated nameNo. of connectionsStructure
ABDMAA-01SKT03-171
ABDMAA-02SKT03-171.01

Unsubstituted amides

Abbreviated nameNo. of connectionsStructure
AUB-01SKT04-127
AUB-02SKT04-143

Abbreviated nameNo. of connectionsStructure
AUB-03SKT04-163

Imidazo[1,2-a] pyridine compounds

Abbreviated nameNo. of connectionsStructure
AIPN-01SKT05-123
AIPN-02SKT05-93
AIPN-03SKT05-107
AIPN-04SKT05-171
AIPN-05SKT06-5
AIPN-06SKT05-169
AIPN-07SKT06-53

Abbreviated nameNo. of connectionsStructure
AIPN-08SKT06-63
AIPN-09SKT05-165
AIPN-10SKT05-173
AIPN-11SKT06-71
AIPN-12SKT06-67
AIPN-13SKT06-7
AIPN-14SKT06-11
AIPN-15SKT06-25
AIPN-16SKT06-29

Abbreviated nameNo. of connectionsStructure
AIPN-17SKT06-15
AIPN-18SKT06-13
AIPN-19SKT06-35
AIPN-20SKT06-55
AIPN-21SKT06-59
AIPN-22SKT06-39
AIPN-23SKT06-49
AIPN-24SKT06-45
AIPN-25SKT06-79

Abbreviated nameNo. of connectionsStructure
AIPN-26SKT06-51
AIPN-27SKT06-57
AIPN-28SKT06-61
AIPN-29SKT06-103
AIPN-30 SKT06-99
AIPN-31SKT06-81

According to one implementation variant, the connection independently chosen from:

AIPN-01; AIPN-02; AIPN-05; AIPN-07; AIPN-08; AIPN-09; AIPN-10; AIPN-11; AIPN-12; AIPN-13; AIPN-14; AIPN-15; AIPN-16; AIPN-18; AIPN-19; AIPN-20; AIPN-21; AIPN-22; AIPN-23; AIPN-24; AIPN-25; AIPN-26; AIPN-27; AIPN-28; AIPN-29; AIPN-30 and AIPN-31.

According to one implementation variant, the connection independently chosen from:

AIPN-01; AIPN-02; AIPN-05; AIPN-07; AIPN-08; AIPN-09; AIPN-10; AIPN-11; AIPN-12; AIPN-13; AIPN-14; AIPN-16; AIPN-18; AIPN-20; AIPN-21; AIPN-22; AIPN-23; AIPN-24; AIPN-25; AIPN-26; AIPN-27; AIPN-28; AIPN-29; AIPN-30 and AIPN-31.

As an addition or alternatively, imidazo[1,2-a]pyridine compound is independently selected from:

Abbreviated nameNo. of connectionsStructure
AIPN-32SKT08-153
AIPN-33SKT08-165
AIPN-34SKT06-155
AIPN-35 SKT06-153
AIPN-36SKT06-141
AIPN-37SKT06-137
AIPN-38SKT06-131
AIPN-39SKT06-165

According to one implementation variant, the compound is independently optionally or alternatively, selected from AIPN-38 and AIPN-39.

Imidazo[1,2-a]pyrimidine compounds

Abbreviated nameNo. of connectionsStructure
AIPM-01SKT05-95

Imidazo[2,1-b][1,3]thiazole compounds

Abbreviated nameNo. of connectionsStructure
AIT-01 SKT05-149
AIT-02SKT05-143

Compounds in which Q represents-CH=CH-; -CR1=CH-; -CH=CR1or CR1=CR1

Benzothiazoline connection

Non-fluorinated methylalkanes

Abbreviated nameNo. of connectionsStructure
VEMA-01SK696-39
VEMA-02SKT01-15

Abbreviated nameNo. of connectionsStructure
VEMA-03SKT01-53
VEMA-04SKT01-3
VEMA-05SKT01-55
VEMA-06SKT01-69
VEMA-07SKT01-17
VEMA-08SK2033-30
VEMA-09SK696-62
VEMA-10SK696-57
VEMA-11SK696-43
VEMA-12SK2033-29

According to one implementation variant, the connection independently chosen from:

VEMA-02; VEMA-03; VEMA-04; VEMA-07 and VEMA-10.

According to one implementation variant, the connection independently represents VEMA-10.

Non-fluorinated metaxylene

Abbreviated nameNo. of connectionsUEMOA-01SKT01-71
UEMOA-02SKT01-73
UEMOA-03SKT02-67
UEMOA-04SKT01-109
UEMOA-05SKT01-107
UEMOA-06SKT01-189
UEMOA-07SKT03-57
UEMOA-08SKT03-91

Abbreviated nameNo. of connectionsStructure
UEMOA-09SKT03-107

According to one implementation variant, the connection independently chosen from:

UEMOA-01; UEMOA-02; UEMOA-03; UEMOA-04; UEMOA-05; UEMOA-07, UEMOA-08.

According to one implementation variant, the compound is independently selected from UEMOA-03, UEMOA-05.

As an addition or alternatively, the non-fluorinated metaxylene connection independently chosen from:

Abbreviated nameNo. of connectionsStructure
UEMOA-10SKT08-143

Fluorinated metaxylene

Abbreviated nameNo. of connectionsStructure
BEFA-01SK2033-44
BEFA-02SK2033-42

Abbreviated nameNo. of connectionsStructure
BEFA-03SK2033-40
BEFA-04SKT02-17
BEFA-05SKT02-11
BEFA-06SKT02-117
BEFA-07SKT02-153
BEFA-08SKT02-119
BEFA-09SKT02-81
BEFA-10SKT02-137
BEFA-11SKT03-167
BEFA-12SKT03-77

Abbreviated nameNo. of connectionsStructure
BEFA-13SKT04-187
BEFA-14SKT04-159

According to one implementation variant, the connection independently chosen from:

BEFA-05; BEFA-06; BEFA-07; BEFA-08; BEFA-10; BEFA-11; BEFA-13 and BEFA-14.

According to one implementation variant, the connection independently chosen from:

BEFA-06 and BEFA-10.

Monitor and fluorinated hydroxyalkoxy

Abbreviated nameNo. of connectionsStructure
BEHF-01SKT02-165
BEHF-02SKT02-155
BEHF-03SKT02-127
BEHF-04SKT02-111

Abbreviated nameNo. of connectionsStructure
BEHF-05SKT02-51
BEHF-06SKT05-05
BEHF-07SKT04-169

According to one implementation variant, the connection independently chosen from:

BEHF-01; BEHF-02; BEHF-03; BEHF-05; BEHF-06 and BEHF-07.

According to one implementation variant, the connection independently chosen from:

BEHF-01; BEHF-02; BEHF-06 and BEHF-07.

Imidazo[1,2-a]pyridine compounds

Abbreviated nameNo. of connectionsStructure
IEPN-01SKT06-117

As an addition or alternatively, imidazo[1,2-a]pyridine compound is selected from:

Abbreviated nameNo. of connectionsIEPN-02SKT06-161
IEPN-03SKT07-81
IEPN-04SKT07-115
IEPN-05SKT07-131
IEPN-06SKT07-113
IEPN-07SKT08-137

Compounds in which Q represents-N=N-

Benzothiazoline connection

Abbreviated nameNo. of connectionsStructure
BDF-09LS-T229
BDF-10LS-T235A
BDF-11LS-T235B
BDF-12LS-T236A
BDF-13LS-T236B
BDF-14LS-T274
BDF-15LS-T272

Abbreviated nameNo. of connectionsStructure
BDF-16LS-T288
BDF-17LS-T289

According to one implementation variant, the connection independently chosen from:

BDF-01; BDF-02; BDF-03; BDF-04; BDF-05; BDF-06; BDF-07; BDF-10; BDF-11; BDF-12; BDF-13; BDF-14; BDF-15; BDF-16 and BDF-17.

As an addition or as an alternative benzothiazoline connection independently chosen from:

Abbreviated nameNo. of connectionsStructure
BDF-18SC598
BDF-19SC588

Imidazo[1,2-a]pyridine compounds

Abbreviated nameNo. of connectionsStructure
DPN-001SKT05-163

Essentially purified form.

According to one aspect of the present invention relates to JB compounds described in this patent application, in a substantially purified form and/or in the form of essentially not containing impurities.

According to one implementation variant essentially purified form is equal to at least 50% by weight, for example at least 60% by weight, for example at least 70% by weight, for example at least 80% by weight, for example at least 90% by weight, for example at least 95% by weight, for example at least 97% by weight, for example, m is Nisha least 98% by weight, for example, at least 99% by mass.

If not given specification, essentially purified form refers to the connection in any stereoisomeric or enantiomeric forms. For example, according to one implementation variant, essentially purified form refers to a mixture of stereoisomers, i.e. purified from other compounds. According to one implementation variant, essentially purified form refers to a single stereoisomer, e.g., optically pure stereoisomer. According to one implementation variant, essentially purified form refers to the mixture of enantiomers. According to one implementation variant essentially purified form refers to an equimolar mixture of enantiomers (i.e. racemic mixture, a racemate). According to one implementation variant essentially purified form refers to one of the enantiomers, for example, optically pure enantiomer.

According to one implementation variant impurities are not more than 50% by weight, for example, not more than 40 mass%, for example, not more than 30 mass%, for example not more than 20 mass%, for example, not more than 10% by weight, for example, not more than 5 mass%, for example, not more than 3 mass%, for example, not more than 2% by weight, for example, not more than 1 mass%.

If not given specification, impurities are other compounds that are different from stereozoom the ditch or enantiomers. According to one implementation variant impurities include other compounds and other stereoisomers. According to one implementation variant impurity belong to other compounds or other enantiomer.

According to one implementation variant essentially purified form is at least 60% optically pure (i.e. 60% of the compound, in a molar content, represent a target stereoisomer or enantiomer, and 40% is the unwanted stereoisomer or enantiomer), for example, at least 70% optically pure, for example at least 80% optically pure, for example at least 90% optically pure, for example at least 95% optically pure, for example at least 97% optically pure, for example, at least 98% optically pure, for example at least 99% optically pure.

Isomers

Specific compounds may exist with one or more particular geometric, optical, enantiomeric, diastereomeric, epimeres, athropology, stereoisomeric, tautomerism, conformational, or anomeric form, including, but not limited to, CIS - and TRANS-forms; E - and Z-forms; C-, t - and r-forms; endo - and Exo-forms; R-, S -, and meso-forms; D - and L-forms; d - and l-forms; (+) and (-) forms; keto-, enol -, and enolate forms; SYN - and anti-forms; synclinal-and anticlinal shape; α is β-forms; axial and Equatorial forms; conformation bath, chair, twist -, envelope and armchair; and combinations thereof, hereinafter generally called "isomers" (or "isomeric forms").

Note that, with the exception discussed below specific tautomeric forms, are excluded from the term "isomers", the term "isomers"as used in this patent application, is a structural (or isomers composition) isomers (i.e. isomers, which differ in the order of relations between the atoms, and not the position of atoms in space). For example, a reference to the methoxy group, -och3that should not be construed as a reference to its structural isomer, hydroxymethylene group, -CH2HE. Similarly, a reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, the reference to the class of structures can be successfully include structural isomeric form, falling within the class (for example, C1-7alkyl includes n-propyl and ISO-propyl; butyl includes n-, ISO-, sec - and tert-butyl; methoxyphenyl includes ortho-, meta -, and para-methoxyphenyl).

The above exclusion does not apply to tautomeric forms, for example, keto-, enol -, and enolate forms, as, for example, the following tautomeric pairs: keto/enol (below), Imin/enamine, amide/iminspect, amicin/amidin, nitroso/oxime, thioketone/e is thiol, N-nitroso/hydroxilase and nitro/ACI-nitro.

Note that the term "isomer" specifically includes compounds with one or more isotropic replacements. For example, H may be in any isotopic form, including1H,2H (D) and3H (T); C may be in any isotopic form, including12C,13C and14With; may be in any isotopic form, including16O and18About; and so Also F may be in any isotopic form, including18F and19F.

Unless otherwise specified a reference to a particular connection includes all of these isomeric forms, including mixtures thereof (e.g. racemic mixtures). Methods of obtaining (e.g., asymmetric synthesis) and separation (for example, by means of fractional crystallization and chromatography) of these isomeric forms are also known in the art or easily obtained by adapting investigated in the present patent application of known methods or methods known manner.

Unless otherwise noted, group-N=N-, -CH=CH-; -CR1=CH-; -CH=CR1- and-CR1=CR1- can be in CIS - or TRANS-forms.

According to one implementation variant, the group-N=N-, if present, may be in CIS - or TRANS-form.

According to one implementation variant, the group-N=N-, CL is tea if present, located in the CIS-form.

According to one implementation variant, the group-N=N-, if present, is in the TRANS form.

For example:

where * indicates the point of attachment.

According to one implementation variant of the group-CH=CH-; -CR1=CH-; -CH=CR1- and-CR1=CR1-, if present, may be in CIS - or TRANS - forms.

According to one implementation variant of the group-CH=CH-; -CR1=CH-; -CH=CR1and CR=CR1-, if present, are in the CIS-form.

According to one implementation variant of the group-CH=CH-; -CR1=CH-; -CH=CR1and CR=CR1-, if present, are in the TRANS form.

For example,

where * indicates the point of attachment.

Salt

It may be convenient or necessary for the receiving, cleaning and/or storage of the corresponding salt of the compound, for example, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge with co-authors (Berge et al.), 1977, "Pharmaceutically Acceptable Salts", J. Pharm. Sci., Vol.66, pp 1-19.

For example, if soy is inania is anionic or contains a functional group, which may be anionic (e.g.,- COOH may be in the form-soo-), salt can be obtained with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions, such as Na+and+the cations of alkaline earth metals such as CA2+and Mg2+other cations, such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4+) and substituted ammonium ions (e.g., NH3R+, NH2R2+, Other3+, NR4+). Examples of some suitable substituted ammonium ions are ammonium ions derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylendiamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a typical Quaternary ammonium ion is a N(CH3)4+.

If the connection is cationic or contains a functional group which can be cationic (e.g., NH2may be in the form of NH3+can be obtained salt with a suitable anion. Examples of the approach is the yaschih inorganic anions include, but not limited to, anions derived from the following inorganic acids: chloroethanol, Hydrobromic, iodomethane, sulfuric, sulfurous, nitric, nitrous, phosphoric and phosphorous.

Examples of suitable organic anions include, but are not limited to, anions which are derived from the following organic acids: 2-acetyloxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamon, lemon, ethylenediaminetetraacetic, etandisulfonata, econsultancy, fumaric, glucoheptonate, gluconic, glutamic, glycolic, hydroxymaleimide, hydroxymatairesinol, isetionate, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucinosa, oleic, oxalic, palmitic, pambou, Pantothenic, phenylacetic, vinylsulfonate, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic wine, toluensulfonate and valerianic. Examples of suitable polymeric organic anions include, but are not limited to, anions derived from the following polymeric acid, tannic acid, carboxymethyl cellulose.

According to one implementation variant Sol independently selected from salts of the following acids: chloroethanol and meta the sulfonic.

Unless otherwise specified, reference to a particular compound also includes the connection specified in the form of a salt.

The solvate and hydrate

It may be convenient or necessary for the receiving, cleaning and/or storage of the corresponding MES connection. The term "MES" used in this patent application in the conventional value to refer to the complex solute (for example, the compounds, salts of compounds) and solvent. If the solvent is a water, the MES can be called a hydrate, for example, monohydrate, dihydrate, trihydrate, etc.

Unless otherwise specified, reference to a particular compound also includes its solvate and hydrate form.

Chemically protected form

It may be convenient or necessary for the receiving, cleaning and/or storage of compounds in chemically protected form. The term "chemically protected form" used in this patent application in the ordinary way, and the term refers to the connection in which one or more reactive group protects from unwanted chemical reactions under specific conditions (e.g. pH, temperature, radiation level, a solvent and so on). In practice, well-known methods, which are used for the reversible deactivation of the functional group, which in FR the main case is reactive under certain conditions. In a chemically protected form one or more functional group are in the form of protected or protecting group (also known as hidden or hiding groups or blocked or blocking group). Due to the protection of the reactive functional groups can be reactions with other unprotected reactive functional groups without impacts on protected groups; the protecting group can be removed, usually at the next stage, without a significant impact on the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (.Green and P.Wuts; 3rd Edition; John Wiley and Sons, 1999).

A large number of these methods of "protection", "blocking", "masking" is widely used and well known in organic synthesis. For example, a compound that contains two nonequivalent reactive group, each of which is reactive under specific conditions, may be subjected to transformation with a translation of one of the functional groups in protected form, respectively, in the inactive state, under specific conditions; thus, a secure connection can be used as a reagent, which has only one effective reactive group. After completion of the targeted response (involving other functional group) with the protection of the military group you can "unprotect" with the return of the original functionality of the specified group.

For example, the hydroxyl group can be protected in the form of simple ether (-OR) or of ester (-OC(=O)R), such as t-butyl ether; a benzyl, benzhydryl (diphenylmethylene) or tretilova (triphenylmethyl) ether; trimethylsilyloxy or t-butyldimethylsilyl ether; or acetylator ester (-OC(=O)CH3-SLA).

For example, aldehyde or ketone group may be protected as acetal (R-CH(OR)2or Catala (R2C(OR)2), respectively, in which the carbonyl group (>C=O) turn in devernay (>C(OR)2using interaction with, for example, a primary alcohol. Aldehyde or ketone group easily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, the amino group may be protected, for example, in the form of an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, in the form: methylamide (-NHCO-CH3); benzylcyanide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxyimino (-NHCO-OC(CH3)2With6H4With6H5, -NH-Bpoc), 9-fluorenylacetamide (-NH-Fmoc), as a 6-nitroferricyanide (-NH-Nvoc), 2-trimethylsilylacetamide (-NH-Teoc), as a 2,2,2-trichloroacetamide (-NH-Troc), as alkoxyamine (-NH-Alloc), 2-(phenylsulfonyl)ataxia the IDA (-NH-Psec) or in appropriate cases (for example, for cyclic amines) in the form of radical nitroxide (>N-O·).

For example, the carboxyl group can be protected in the form of ester, for example, in the form:1-7alkyl ether complex (for example, methyl ether complex; t-butyl ether complex); C1-7haloalkaline of ester (for example, C1-7trihalogenmethanes of ester); Tris1-7alkylsilane-C1-7alkyl ether complex; or (C5-20aryl-C1-7alkyl ether complex (for example, benzyl ether complex, nitrobenzylamine of ester); or in the form of an amide, for example, in the form of metiamide.

For example, Tolna group can be protected in the form of tiefer (-SR), for example, in the form:

benzyl tiefer; acetamidomethyl ether (-S-CH2NHC(=O)CH3).

The prodrug

It may be convenient or necessary for the receiving, cleaning and/or storage of the compound in the form of prodrugs. The term "Prodrug"as used in this patent application refers to a connection that as a result of metabolism (e.g., in vivo) leads to obtain the desired active compound. Typically, the Prodrug is inactive or less active compared to the target of an active compound, but may provide advantages in storage, the introduction or metabolic properties.

For example, some prolec is rstv are esters of active compounds (for example, physiologically acceptable and metabolically labile ester). In the metabolism of ester group (-C(=O)OR) is destroyed with receiving active drug. These esters can be obtained by using the esterification, for example, any carboxylic acid group (-C(=O)OH) parent compound, with prior protection of any other reactive groups present in the initial compound, with subsequent removal of the protection if necessary.

Some prodrugs are activated by enzymes with the active compound or compounds, which result in additional chemical reaction leads to the production of active compounds (for example, as in the cases ADEPT, GDEPT, LIDEPT etc). For example, the Prodrug may be a derivative of sugar or other glycoside conjugate or may be an ester derived amino acids.

Composition

One aspect of the present invention relates to compositions (e.g., diagnostic compositions containing ZB connection described in this patent application, and a physiologically acceptable carrier, diluent or excipient.

Another aspect of the present invention relates to a method for obtaining the composition (e.g., diagnostic compositions), including AC is shivanie ZB compounds described in this patent application, and physiologically acceptable carrier, diluent or excipient.

Pharmaceutical and diagnostic compositions

Another aspect of the present invention relates to a pharmaceutical or diagnostic composition containing ZB connection described in this patent application.

Another aspect of the present invention relates to a pharmaceutical or diagnostic composition containing ZB connection described in this patent application, and a physiologically acceptable carrier, diluent or excipient.

Another aspect of the present invention relates to a method for producing a pharmaceutical or diagnostic composition comprising mixing ZB compounds described in this patent application, and a physiologically acceptable carrier, diluent or excipient.

Examples of suitable physiologically acceptable carriers, diluents and excipients are pharmaceutically acceptable carriers, diluents and excipients are described below.

The application

Compounds described in this patent application (for example, without limitation, are suitable, for example, in methods and models relating to the labeling and detection of neurofibrillary tangles and in particular of paired helical filaments.

Methods of marking PHF and aggregirovany the x Tau-proteins

According to one aspect of the present invention, a method for marking PHF, comprising bringing into contact with PHF JB connection and detecting the presence of the specified connection. Applications can be conducted, for example, analogous to the use of ligands described previously (see, for example, the work of men with co-authors (Mena et al.), 1995; the work of men with co-authors (Mena et al.), 1996; Work Rly with co-authors (R. Lai et al.); work Rondareva with co-authors (Bondareff W. et al.); work Difresh with co-authors (Resch J.F. et al.); work with co-authors M. Nowak (M. Novak et al.); Work Civista with co-authors (Wischik C.W. et al.), 1996; and work Civista with co-authors (Wischik C.W. et al.), 1989).

Thus, according to one aspect of the present invention, a method of labelling aggregated Tau proteins or molecules, such Tau-proteins, comprising bringing into contact of the aggregated molecules of the Tau protein with JB connection and detecting the presence of the specified connection. Applications can be conducted, for example, analogous to the use of ligands described previously (see, for example, the work of men with co-authors (Mena et al.), 1995; the work of men with co-authors (Mena et al.), 1996; Work Rly with co-authors (R. Lai et al.); work Rondareva with co-authors (Bondareff W. et al.); work Difresh with co-authors (Resch J.F. et al.); work with co-authors M. Nowak (M. Novak et al.); Work Civista with co-authors (Wischik C.W. et a.), 1996; and work Civista with co-authors (Wischik C.W. et al.), 1989).

In the case of use in the present patent application the term "Tau protein" refers generally to any protein family of Tau-protein. Tau proteins are characterized as one of the most numerous families who soogisooda with microtubules during repeated cycles of accumulation and destruction (work Shelanski with co-authors (Shelanski et al.), 1973 Proc. Natil. Acad. Sci. USA, 70., 765-768) and is known as proteins associated with microtubules (MAP). The members of the family of Tau proteins share common properties, consisting in the content characteristic N-terminal segment, a sequence of about 50 amino acids contained in the N-terminal segment, which is widely regulated by the brain, a characteristic region of tandem repeats containing 3 or 4 tandem repeat 31-32 amino acids and the C-terminal tail. See, for example, the work of vesica with co-authors (Wischik et al.), 2001 and loc. cit.

Molecules, "such Tau-proteins"include, for example, MAR, which is the predominant protein associated with microtubules in somatodendritic Department (work Amatus (Matus A.) in "Microtubules" [Hyams and Lloyd, eds.] pp 155-166, John Wiley and Sons, NY). Isoforms MAR are almost identical to Tau protein in the field of tandem repeat, but differ essentially from the sequence and size of the N-terminal to the s (the work of Kindler and garner (Kindler and Garner), 1994, Mol. Brain Res. 26. 218-224). However, aggregation in the field of tandem repeat is not selective for domain repeat Tau protein. Thus, it should be understood that any discussion in the present patent application is related to Tau protein or Tau-Tau aggregation should be considered as related to Tau-MAR aggregation, MAR-MAR aggregation etc.

JB the connection can be paired to form a complex or otherwise associated with an additional group or a particle, which has diagnostic, prognostic or therapeutic purpose or effect, for example, with a fluorescent group, which, thus, provides visualization of neurofibrillary tangles, which binds the ligand.

Diagnostic ligands

ZB compounds capable of acting as ligands or labels Tau protein (or aggregated Tau protein). In particular, ZB compounds applicable in the methods of medical imaging.

There are various ways in which aggregated Tau protein can be visualized in vivo, which include the use of ligands, which JB compound contains19F (MRI-scan),18F (scan positron emission tomography (PET)or a stable nitroxyl free radical (contrast agent for MRI and proton-e the Tronic double resonance imaging (PEDRI)). Also included is the use of ligands containing a radioactive isotope I (single photon emission computed tomography, mect).

The use of the agents described in this patent application, in any of these ways included in the scope of the present invention.

Thus, according to one implementation variant, JB compound is a ligand of the Tau protein (or aggregated Tau protein).

These DSB compounds (ligands) may include, be coupled to form a complex or otherwise be associated with other chemical groups, such as stable and unstable detected isotopes, radioactive isotopes, a positron-emitting atoms, labels, magnetic resonance, dyes, fluorescent markers, antigenic groups, therapeutic groups or any other groups that may contribute to prognostic, diagnostic or therapeutic application.

For example, as described above. According to one implementation variant, ZB connection is defined above, but with the additional constraint that the compound includes, carries or forms a complex or otherwise associated with one or more (e.g. 1, 2, 3, 4, etc.) isotope, radioactive isotope, a positron-active atom, tagged magnetic resonance, dye, fluorescent mA is-ker, antigenic group or therapeutic group.

According to one implementation variant JB connection represents a ligand, and a label, for example, the label of the Tau protein (or aggregated Tau protein), and includes, involves, forms a complex or otherwise associated with one or more (e.g. 1, 2, 3, 4, etc.) detectable label.

For example, According to one implementation variant JB connection is defined above, but with the additional constraint that the compound includes, involves, forms a complex or otherwise associated with one or more (e.g. 1, 2, 3, 4, etc.) detectable label.

Labeled JB connection (e.g., associated with Tau protein or aggregated Tau protein) can be visualized or detected by any appropriate means, and specialist in the art will understand that you can use any suitable method of detection known in the art.

For example, DSB compound (ligand-label) can be appropriately detected by using the activation of the positron-active atom (for example,11C) (for example, in the form of a carbon atom by one or more substituent alkyl groups, for example, the substituent methyl group) and detection connection with the use of positron emission tomography (PET) in accordance with the method, and is known in this technical field.

Typically, RFID tags used in PET imaging can be obtained and visualized over a time interval comparable with the half-life of the isotope, usually within two half-lives after receiving radioactive isotope.

18F has a half-life of 110 minutes, which provides enough time for relatively complex synthesis and biological research. An additional advantage is the fact that18F has low energy positron and its maximum value (2.4 mm) provides the most clear image with high resolution PET. For these reasons, the F-containing ZB compounds described in this patent application include compounds in which one or more F atoms, if present, is an atom18F.

18F can be included in the ligand using, for example, fluoride ion or [18F]F2. The fluoride ion is the more desirable of the two ions, as can be obtained without additional media. Essentially, 100% of the isotope can be included in the label. On the contrary, the maximum radiochemical yield in the case of the use of [18F]F2as the precursor is about 50%, as only one of the fluorine atoms in the molecule fluorine is IU the Yong and usually included only one of the fluorine atoms.

A key requirement for successful radiotolerance is to maintain the solubility of [18F]fluoride. [18F]fluoride first get in an aqueous solution of potassium carbonate. Then water is removed as the azeotrope, usually with acetonitrile. However, the potassium ion leads to limited solubility in some solvents of the reaction mixture. Adding aminopolyamide Kryptofix 2.2.2 (K222) improves the solubility of potassium ion and hence greatly facilitates the nucleophilic radiotolerance [18F]fluoride in aliphatic and aromatic substrates.

As of the end of the study labeled product may be separated from any unreacted substances using HPLC that, as a rule, is required to obtain a substance with high specific activity.

In one aspect of the present invention proposed the use of DSB compounds as imaging in vivo PHF and PHF Tau-protein agents.

ZB compounds can be used in the method of determining the stage of neurofibrillary degeneration associated with taupata, the subject has significantly suffering from the specified disease, which involves the following stages:

(i) introduction to the subject ZB compounds capable of labeling of paired helical filaments (PHF)Tau protein,

(ii) detecting the presence and/or quantity ZB connection associated with extracellular aggregated PHF Tau protein in the medial temporal lobe of the brain of a subject

(iii) correlating the result of the determination made at stage (ii) with the stage of neurofibrillary degeneration of the subject.

The definition of stage (ii) can be used to determine the density of ligand binding.

The correlation stage (iii) can be carried out by reference to known data.

Tapatia can be an Alzheimer's disease (ad).

ZB compounds may be able to cross the blood-brain barrier.

Determining at the above stage (ii) is carried out based on extracellular aggregated Tau protein. In General, the objectives of the present invention, the determination can be also performed for extracellular tangles.

In histological studies have previously shown that during the aggregation of the Tau protein is binding compounds, such as thiazin red and tioflavin-S (see the work of men with co-authors (Mena et al.), 1995; the work of men with co-authors (Mena et al.), 1996). It is possible to show that the link is inside the ball and not in the external proteins (work Civista with co-authors (Wischik C.W. et al.), 1989). Thus intracellular and extracellular tangles marked to some extent these ligands, campocatino using histological studies.

However, for greater accuracy, the ligands can be visualized or detected by any suitable means, and the specialist will be clear that in these examples can be any suitable detection methods known in the art.

These methods can be based on the methods described in WO 02/075318. Examples of diagnostic ligands

According to one implementation variant diagnostic ligands selected from compounds of the following formula and their pharmaceutically acceptable salt, hydrate and solvate.

Abbr.Applies toStructure
DL-001ABMFMA-05
DL-002ABMFMA-02
DL-003AIPN-33

Abbr.Applies toStructure
DL-004 AIPN-06
DL-005IEPN-04
DL-006BEFA-12
DL-007BDF-18

Additional ways of marking PHF and Tau-proteins

In the present invention, a method for marking of paired helical filaments (PHF), which includes bringing into contact with PHF JB connection described in this patent application, and the detection of the presence of the specified connection.

The method can be carried out in vivo. If the method is a method carried out in vivo, the compound is administered to the subject. The subject may be a mammal. According to one implementation variant, the subject is a rodent. In another variant implementation, the subject is a human.

As an alternative method may be performed in vitro.

PHF can be isolated from the subject described in this patent application. According to one implementation variant PHF isolated from the brain of the subject. PHF can be taken from IFII fraction of the sample of the brain, for example, in accordance with op is a description, data in the work Kmicic (..Wischik, Thesis "The structure and biochemistry of paired helical filaments in Alzheimer's disease" Part I and II; Cambridge University, 1989).

According to one implementation variant, the sample of the brain contains a sample of the medial temporal lobe, i.e. E2/Trans (layer entorhinal crust 2/transit antoinella bark) and E4/NA (layer entorhinal crust 4 and the hippocampus), and neocortical structures (F/T/P area - anterior, temporal, parietal) brain.

According to one implementation variant PHF isolated from the brain of a subject suffering from Alzheimer's, or entity, who is suspected Alzheimer's disease. The subject may be a human.

JB connection can be applied individually or included in a composition with suitable carriers, diluents, fillers, etc. described in this patent application.

The presence ZB compounds can be detected using methods that are appropriate for your connection type.

JB connection can be detected using fluorescence spectroscopy. Such methods are suitable for use in determining ZB compounds capable of fluorescence.

JB connection can be detected by means of a counter radiation. Such methods are suitable for use in determining ZB compounds containing radioactive tag.

P is OUTSTA ZB compounds can be detected by a competitive research in which track the substitution of a known ligand PHF on JB connection, including quantities, by identifying changes in the designated data. Known ligand may be a fluorescent ligand. Substitution of the known ligand PHF can be tracked, it is possible to assess in quantitative terms, using fluorescence spectroscopy. These methods suitable for use in determining ZB compounds that are not capable of fluorescence, or compounds that fluoresce in the conditions or wavelength that does not overlap with the fluorescence signal determined for a known ligand.

According to one implementation variant, the presence ZB compounds determined using replacement program known ligand PHF. Known ligand may be a fluorescent ligand.

Substitution of the known ligand PHF on JB connection can be detected by decreasing the activity of fluorescence. According to one implementation variant known ligand capable of increased fluorescence upon binding with PHF.

According to one implementation variant, the known ligand is primulin.

According to one implementation variant DSB compound has a greater affinity for PHF compared with primulinum.

According to one implementation variant is connected to the e, contains18F radioactive label can be detected using counter radiation, for example, counter gamma particles.

Other detection methods ZB compounds of the present invention include the methods described in section Diagnostic ligands of the present patent application.

In the present invention is also a method of labelling aggregated Tau proteins or molecules, similar to Tau-protein, comprising the bringing into contact of the aggregated molecules of the Tau protein with JB connection and detecting the presence of the specified connection.

The method can be carried out in vivo or in vitro. If the method is a method carried out in the body, the compound is administered to the subject. The subject may be a mammal. According to one implementation variant, the subject is a rodent. In another variant implementation, the subject is a human.

According to one implementation variant JB connection is brought into contact with aggregated Tau protein or molecules, similar to the Tau protein, in a sample of a brain of the subject. According to one implementation variant, the subject is an entity, not being a person capable of full expression of human Tau protein. The subject may be a transgenic rodents expressing full-sized human Tau protein, about adeusi double P301S mutation/G335D.

According to one implementation variant, aggregated Tau protein or molecule, similar to Tau-protein produced in cell lines expressing full-Tau-protein ("t") and/or a fragment of Tau protein with PHF-core (fragment with a weight of 12 KD). Cell line may be a cell line fibroblast. According to one implementation variant cell line is a cell line ST.

According to one implementation variant JB connection receive, and then brought into contact with or aggregated PHF Tau protein or molecules, similar to Tau-protein, or administered to a subject within 14 days after receipt.

JB the connection can be subject to interference or entered within 7 days 2 days 24 hours 12 hours 6 hours or 3 hours after receipt.

DSB compound can be administered to the subject, and the distribution ZB connections in one or more of the body of the subject can be examined.

According to one implementation variant examine the distribution ZB connections in the brain.

JB connection can reach a maximum concentration in the brain at least 10 minutes, 5 minutes or 2 minutes after administration to a subject.

Content ZB compounds remaining in the brain, can reach a level equal to 50% of the maximum concentration in the brain, not more than 120 minutes, no more than 6 minutes or not more than 30 minutes after injection.

The total content of JB connections in the brain, in the percentage of the initial dose administered to the subject is at least 1%, at least 2%, at least 3% or at least 4% of the total content entered ZB connection. The time interval for measuring the total content can be a time interval in which the content in the brain reaches its maximum concentration. Alternatively, the time interval may be 1, 2, 5 or 10 minutes after injection.

According to one implementation variant JB connection is at least essentially dissolved in the solution containing aprotic solvent. Aprotic solvent may constitute DMSO. JB the connection can be at least essentially dissolved in the solution containing at least 1% DMSO, at least 5% DMSO or at least 10% DMSO. The solution can be an aqueous solution.

According to one implementation variant JB connection is at least essentially dissolved in the solution containing the proton solvent. Proton solvent can be methanol or ethanol. JB the connection can be at least essentially dissolved in the solution containing at least 10% of the proton solvent, at least 25% vs. the ton of the solvent or at least 50% of the proton solvent. According to one implementation variant, the solution is a solution containing a proton solvent and an aprotic solvent.

Sets

According to one aspect, the present invention relates to a kit containing (a) ZB connection described in this patent application, or a composition comprising JB connection described in this patent application, for example, preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on the method of administration of the compound or composition.

Applications for diagnostics

JB compound, or composition containing the specified connection, can be used in the method for diagnosis, prognosis, or treatment of human or animal with the help of therapy, especially in relation to the state, such as BA, described in the present patent application.

According to another aspect of the present invention provides a method of diagnosis or prognosis, including an introduction to the mammal one or more DSB compounds described in this patent application, diagnostically or prognostically effective amount. This aspect covers these compounds used in the method for the diagnosis or prediction. In a specific aspect described Ave the changes in vivo and in vitro. The methods carried out in vitro, administered by (i) obtaining a sample of the corresponding tissue of the subject; (ii) bringing into contact of the sample and ZB connection; (iii) detecting the amount and/or localization JB connection associated with the sample; (iv) correlating the result of stage (iii) with the stage or degree of disease of the subject.

The method can be carried out under clinical trials to determine the effectiveness of the inhibitor of the aggregation of Tau proteins.

According to another aspect of the present invention provides the use of DSB connection to obtain compositions for the diagnosis, prognosis, or treatment of the diseases described above.

The disease or condition may represent, for example, BA or condition associated with BA, or other condition, which is caused by the aggregation of protein molecules.

It should be noted that Tau-protein (and its aberrant function or education) is not only in the case of Alzheimer's disease. It is shown that the pathogenesis of neurodegenerative disorders, such as disease Peak and progressive supranuclear palsy (PNP) is associated with the accumulation of pathological shortened aggregates of the Tau protein in the dentate gyrus and star pyramidal cells of the neocortex, respectively. Other dementia include dementia of the frontal lobe (DLD); parkinsonism associated with x is omosomes 17 (FTDP-17); complex disinhibition-dementia-parkinsonism-amyotrophy (DDPAC); pallido-Ponto-nigaloo degeneration (PPND); Gramsci syndrome ALS; pallido-nigro-Lukianova degeneration (PNLD); corticobasal degeneration (CBD) and others (see the work of vesica with co-authors (Wischik et al.), 2001, loc.cit, for a detailed discussion specifically in Table 5.1). In all these diseases, which are mainly or partially abnormal aggregation of Tau protein, referred to in the present patent application as "topatoi".

Methods introduction

DSB compound or pharmaceutical composition comprising JB compound, can be administered to the subject by any suitable route of administration, systemic/peripheral or local (i.e. in place the necessary actions).

Methods of introduction include, but are not limited to, oral (e.g. by ingestion); transbukkalno; sublingual, subcutaneous (including, for example, the introduction by means of adhesive or adhesive tape, etc.); transmucosal (including, for example, the introduction by means of adhesive or adhesive tape, etc.); intranasal (e.g., using a spray in the nose); eye (for example, using eye drops); pulmonary (e.g. by inhalation or insufflation therapy using, for example, aerosol, e.g. through mouth or nose); re is quarterly (for example, using a suppository or enema); vaginally (for example, using the pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, podkapsuliarnaya, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and epigastric; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

The subject/Patient

The subject/patient may be an animal, a mammal, a placental animal, rodent (e.g. a Guinea pig, hamster, rat, mouse), murine (e.g., mice), lagomorphs (e.g., a rabbit), avian (e.g., bird), canids (e.g., a dog), feline (e.g. a cat), equine (e.g. a horse), porcine (e.g., a pig), Ovine (e.g., a sheep), bovine (e.g., a cow), a Primate, a monkey (e.g., martiskainen monkey or apes the monkey), martiskainen monkey (for example, igranka or baboon), anthropoid APE (e.g., gorilla, chimpanzee, orangutan, Gibbon), or a person.

Additionally, the subject/patient may be one of the forms of development, for example, the embryo.

In one preferred options implementing the tion of the subject/patient is a human. In other embodiments of the subject/patient is not a person.

Suitable subjects can be selected on the basis of common factors. Thus, the initial choice of the patient may include any one or more factor: expert evaluation by an experienced physician; the maximum possible exception of a diagnosis other than BA, with additional laboratory and other studies; objective assessment of cognitive function using neuropathologically approved tests.

Structures

If perhaps an individual introduction ZB connection, preferably introduced in the form of a physiologically acceptable composition.

The following comments relate to pharmaceutical compositions, but with appropriate modifications can be applied to diagnostic compositions.

Thus the proposed pharmaceutical composition (e.g., composition, preparation, medication)containing at least one DSB connection described in this patent application, together with one or more other pharmaceutically acceptable ingredients well known to experts in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, substances, fillers, buffers, preservatives, and the t-oxidants, lubricants, stabilizers, soljubilizatory, surfactants (e.g., humidifiers), masking agents, colorants, flavors and sweeteners. The composition may optionally contain other active substances, for example, other therapeutic or prophylactic agent.

Thus, in the present invention is additionally proposed pharmaceutical compositions, as defined above, and methods for producing pharmaceutical compositions, comprising mixing at least one DSB compounds described in this patent application, together with one or more other pharmaceutically available ingredient, well known to experts in the art, for example, a carrier, diluent, filler, etc. In case of inclusion compounds in the composition of individual particles (e.g., tablets, etc.) each particle contains a predetermined amount (dosage) of the specified connection.

The term "pharmaceutically acceptable"as used in this patent application relates to compounds, ingredients, substances, compositions, dosage forms, etc. that are part of a thorough medical examination are appropriate for application to interact with the tissues of the examined subject (e.g. human), do not show izbytochnovo, irritation, allergic reactions or other problems or complications, and comparable with the maximum allowable ratio of benefit/risk. Each of the carriers, diluents, fillers, etc. must also be "reasonable" in relation to compatibility with other ingredients of the composition.

Suitable carriers, diluents, fillers, etc. can be found in the usual pharmaceutical reference books, for example, Remington''s Pharmaceutical Sciences, 18thedition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5thedition, 2005.

The compounds may be obtained by any of the means well known in the pharmaceutical industry. These methods include the stage of bringing in the interaction of the compound with a carrier that contains one or more additional ingredient. Typically, the compositions are produced by continuous and careful interaction of compounds with the media (for example, liquid carriers, finely dispersed solid media etc) and then cut to shape if necessary.

The composition can be obtained to provide a fast or slow release; immediate, delayed, delayed or sustained release; or combinations thereof.

The compositions may suitably be a liquid solution (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, in the Yes in oil), elixirs, syrups, electuaries, liquid for mouth rinses, drops, tablets (including, for example, tablets, coated tablets, granules, powders, lozenges, tablets, capsules (including, for example, hard and soft gelatine capsules, starch capsules, pills, capsules, tablets large size, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, suspensions, or aerosols.

The compositions can be appropriately set in the form of plaster, adhesive plaster, bandage or dressing or other form, which is saturated by one or more connection and possibly one or more other pharmaceutically acceptable ingredients, including, for example, power penetration, permeability or absorption. The compositions can also be appropriately delivered in the form of a depot or reservoir.

The connection can be dissolved, suspended or mixed with one or more pharmaceutically acceptable ingredient. The connection may be present in a liposome or other microparticle, which is designed to deliver the connection, for example, to blood components or one or more of the body.

Formulations suitable for oral administration (e.g., through ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (n is an example, oil-in-water, water in oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, starch capsules, pills, capsules, tablets large size.

Formulations suitable for transbukkalno include the introduction of liquid for mouth rinses, lozenges, lozenges, as well as plasters, adhesive tapes, depots and tanks. Lozenges, as a rule, contains a join in a flavored basis, usually sucrose and gum or tragacanth gums. Tablets usually contain the compound in an inert matrix, such as gelatin and glycerol or sucrose and gum. Liquid for rinsing the mouth, as a rule, contain the compound in a suitable liquid carrier.

Formulations suitable for sublingual administration, include tablets, lozenges, tablets, capsules and pills.

Formulations suitable for not oral transmucosal introduction, include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil in water, water in oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as plasters, adhesive tapes, depots and tanks.

Chemical synthesis

Some methods of chemical synthesis ZB compounds of the present invention described in this patent application. These and/or D. the other well known methods can be modified and/or adapted in known ways to simplify the synthesis of additional compounds within the present invention.

Standard procedures

In one of the approaches ZB compounds can be obtained according to the method, including the connection of connection And connectivity:

where-PAand-PBrepresents a reactive functional group, and-T, -P and group-G1to-G4are defined in accordance with ZB compounds of the present invention and their protected form.

According to one implementation variant-PAand-PBrepresent an amide linking group. The reaction product binding is an amide bond, i.e. Q-represents-NHC(O)-; -NR1C(O)-; -C(O)NH - or-C(O)NR1-. Thus, one of the-PAand-PBcan represent-C(O)IT or its activated form, and the other may represent-NH2or other1.

According to one implementation variant-PArepresents-NH2or other1. According to one implementation variant, -PArepresents-NH2.

According to one implementation variant-PBrepresents-C(O)HE or-C(O)Cl.

According to one implementation variant-PAand-PBare alkenone linking group. The reaction product link is alanovoy communication, i.e. Q-represents-CH=CH-; -CR1=CH-; -CH=CR 1or CR1=CR1-.

According to one implementation variant alkenone linking group-PAand-PBmay represent a linking group by Wittig or group, the same groups Wittig, for example, linking groups Horner-Watford-Emmons. Thus, one of the-PAand PBcan represent-C(O)H or-C(O)R1and the other may be a phosphonate.

According to one implementation variant, one of the-PAand-PBrepresents-C(O)N.

According to one implementation variant of the other-PAand-PBrepresents-P(O)(OEt)2.

According to one implementation variant-PBrepresents-C(O)N.

According to one implementation variant of the other-PArepresents-P(O)(OEt)2.

According to one implementation variant alkenone linking group-PAand-PBmay represent a linking group Hake or group, the same groups Hake.

Thus, one of the-PAand-PBmay represent alkenyl, for example, N2C=CH-and the other may represent-Cl, -Br, -I, -N2+X-(where X represents Cl or BF4or-OTf.

And In contact with a catalyst, typically palladium catalyst, such as Pd or Pd(OAc)2. You can also paragraph is to change any base.

According to one implementation variant-PAand-PBare diazo-binding group. The reaction product link is a diazo-communication, i.e. Q-represents-N=N-.

According to one implementation variant-PAand-PBare minovia linking group. The reaction product link is kinoway communication, i.e. Q-represents-N-CH - or-CH=N-. Thus, one of the-PAand-PBcan represent-NH2and the other may represent-C(=O)N.

Obtaining fluorinated compounds

Specific implementations of the present compounds are JB compounds containing-F group, in other embodiments of the proposed DSB compounds containing -18F group.

In one of the common ways ZB compounds containing-F group, can be obtained from JB compounds containing-Oh group. -Oh group can be converted into an activated leaving group. The activated leaving group activate to replace F by a nucleophile. The interaction of compounds containing activated group, with a source of fluoride nucleophile results in DSB compounds containing-F group. If fluoride nucleophile is a -18F nucleophile, the product of the interaction is JB Obedinenie, containing -18F group.

An activated leaving group include groups similar to the groups such as mesilate (-OS(O)2CH3and toilet (-OS(O)2PhCH3). DSB compound containing-Oh group can interact with mesolthelioma or totalfreedom education ZB compounds containing

According to one implementation variant-IT group is a Deputy saturated aliphatic alkyl groups, for example, saturated aliphatic C1-6alkyl groups, substituted-HE, or group linking-Oh group, such as saturated aliphatic C1-5alkylenes group, associate IT with the group.

Examples of groups suitable for use include groups in which-WA1represents-CH2CH2OH, one of the-PA, -PBor-PCrepresents-L1-OH, -GAor-GBis a -[O-CH2CH2]n-RB2and RB2represents-LC-OH, -O-LC-OH, or-IT, or in which RB2represents-LC-OH, or-O-LC-OH, if these groups are present.

In the present invention the methods of obtaining JB connections where the connection And associated with the connection, in accordance with the above description, with the formation of the final joint is, containing the group-Q-. Connection a or connection b can contain a-F group. Specified-F group can participate in all the remaining stages of the synthesis and remain in the final JB product. Examples of compounds of formulas a and b, containing-F group, are presented in this description.

Examples

The following examples are presented solely to illustrate the present invention and which should not be construed as limiting the scope of the invention described in this patent application.

General methods

Amide linking

In this reaction, the amine and the acid chloride contacted to obtain the corresponding amide, as shown in the following scheme

where T-, -R - and-R as previously defined.

In the standard reaction of the amine (1 EQ.) interacts with the acid chloride (X equiv.) in the presence of excess base, as a rule, organic bases such as pyridine or diisopropylethylamine, to obtain the corresponding amide product, which can be allocated as a result of processing, including, for example, extraction, filtration, column chromatography, crystallization and/or drying. The reaction can be conducted at elevated temperature, for example at the boiling point, and perhaps in an inert atmosphere, for example, in an argon atmosphere. The reaction can be carried out in organic is kOhm solvent, for example, THF, or can be done in pure organic base.

The acid chloride can be obtained from the carboxylic acid and, for example, thionyl chloride. In the reaction of amide linkage is possible to apply the crude acid chloride.

In a typical example, 2-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide was obtained in accordance with the following description.

2-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-13

To a stirred solution of 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0,30 g at 1.17 mmol) in dry pyridine (15 ml) at room temperature was added in one portion to 2-nitrobenzaldehyde (0.24 g, 1,29 mmol) in argon atmosphere. The reaction mixture was heated at 90°C for 7 h and cooled to room temperature, the mixture was added to water (150 ml). The precipitate was collected by filtration and dried in vacuum at 50°C overnight to obtain the title compound (0,42 g, 88%) as a colourless solid.

Recovery nitro

In this reaction the functional nitro-group is converted into the corresponding amino group. As a rule, nitrosoaniline (1 EQ.) interacts with chloride dihydrate tin (II) (8 EQ.) in a solvent, for example ethanol, obtaining after appropriate processing, the corresponding amino compounds. Treatment which may include the stage of obtaining the free base, separation, extraction, filtration, column chromatography, crystallization and/or drying. The reaction can be conducted at elevated temperature, for example at the boiling point, and perhaps in an inert atmosphere, for example, in an argon atmosphere.

In a typical example, 2-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide was obtained in accordance with the following description.

2-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-99

A mixture of 2-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (1.0 g, 2,47 mmol) and chloride dihydrate tin (II) (4,45 g to 19.74 mmol) in EtOH (20 ml) was boiled under reflux for 6 hours. Upon cooling to room temperature the reaction mixture, uselocale by adding a saturated solution of NaHCO3and then was extracted with EtOAc (4×50 ml). The combined organic extracts were washed brine (80 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain the title compound (0,79 g, 85%) as pale yellow needle-like particles as a result of recrystallization from EtOH.

Demethylation

In this reaction the functional methoxy group aryl ring is transformed into the corresponding hydroxyl group of the aryl rings. As a rule, methoxyaniline compound (1 EQ.) maintains deistvuet with BBr 3in a solvent, for example, in DHM, obtaining after processing, the corresponding hidroxiaril connection. The processing may include the stage of obtaining the free base, separation, acidification, extraction, filtration, column chromatograph AI, crystallization and/or drying. The reaction can be conducted at low temperature, for example at a temperature from 0°C to -78°C.

In a typical example, 2-amino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide receive in accordance with the following description.

4-amino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-57

To a stirred suspension of 4-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (50 mg, 0.13 mmol) in dry DHM (3 ml) at room temperature dropwise added BBr3(1.0 M solution in DHM, of 0.67 ml, 0.67 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction repaid by adding the Meon dropwise, and the reaction mixture was placed in a solution of ammonia (25 ml), the aqueous phase was separated, neutralized by adding 1M HCl and was extracted with EtOAc (4×60 ml). The combined organic extracts were dried (Na2SO4) and solvent removed under reduced pressure to obtain solid, which was purified using flash chromatography (1:1 hexane/EtAc, then EtOAc) to give the title compound (27 mg, 56%) as a brown solid.

Getting alkene

In this reaction phosphonate and aldehyde interact in the presence of a base to obtain alkinoos product, for example, as shown in the following diagram

where T-, -R - and-R described earlier.

In a typical reaction of the phosphonate (1 equiv.) interacts with the aldehyde (1 EQ.) in the presence of a base (2 equiv.) for example, sodium methoxide, sodium hydride or t butoxide potassium, in an organic solvent, for example, the Meon or THF, to obtain the corresponding alkinoos product, which can be selected after processing, including, for example, acidification, extraction, filtration, column chromatography, crystallization and/or drying. The reaction can be conducted at low temperature, for example at a temperature from 0°C to -78°C or at higher temperatures, for example at the boiling point.

In a typical example, 2-{4-[2-(nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole received in accordance with the following description.

2-{4-[2-(nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT01-71

To a stirred solution of diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.10 g, 0.25 mmol) and 2-nitrobenzaldehyde (0.39 g, 0.25 mm is l) in the dry Meon (10 ml) at 0°C dropwise added a solution of 0.5 m of sodium methoxide (of 1.02 ml, 0.51 mmol). Then the reaction mixture was left to warm to room temperature and boiled under reflux for 18 hours. The reaction mixture was cooled to room temperature and added water (30 ml) followed by addition of 1M HCl to achieve pH of the reaction mixture. Then the reaction mixture was extracted with DHM (3×80 ml) and the combined organic extracts were washed brine (50 ml), and dried (Na2SO4). Removed solvent under reduced pressure to obtain solid, which was purified using flash chromatography (DHM) to obtain the title compound (0,043 g, 43%) as a yellow solid.

Amination

In this reaction, the primary amine is transformed into tertiary amine. In a typical reaction of the primary amine (1 EQ.) interacts with the aldehyde (10 equiv.) for example, paraformaldehyde, in the presence of a reducing agent, for example, cyanoborohydride sodium (5 EQ.) to obtain the corresponding product of tertiary amine, which can be selected after processing, including, for example, obtain the free base, extraction, filtration, column chromatography, crystallization and/or drying. The reaction can be carried out in an organic solvent, such as Asón.

In a typical example, 2-dimethylamino-N-(6-methoxybenzothiazole-2-yl)phenyl]benzamide on what was taught in accordance with the following description.

2-dimethylamino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-103

One portion of cyanoborohydride sodium (84 mg, of 1.33 mmol) was added to a stirred mixture of 2-amino-N-[4-(b-methoxybenzothiazole-2-yl)phenyl]benzamide (100 mg, 0,266 mmol) and paraformaldehyde (80 mg, of 2.66 mmol) in Asón (2 ml). The reaction mixture was stirred at room temperature for 18 hours and then added to water (30 ml) and brought to an alkaline environment (pH 8-9) by adding sodium bicarbonate. The mixture was extracted with DHM (3×30 ml) and the combined organic extracts were washed brine (25 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a yellow residue, which was purified using flash chromatography (2:1 hexane/EtOAc) to give the title compound (63 mg, 59%) as a colourless solid.

Getting thioamide

In this reaction, amide turn in thioamide. In a typical reaction of the amide (1 EQ.) dissolved in hot toluene (dry, about 40.) and add the reagent Losson (1.5 EQ.). The reaction mixture is heated to 80°C. in a nitrogen atmosphere for 2 hours. The reaction mixture is then cooled to room temperature and filtered. The precipitate was washed with EtOAc, then dried under reduced pressure to obtain the corresponding untreated thioamide the th product. To obtain pure target substance conducting column chromatography.

Getting benzothiazole using potassium ferricyanide

In this reaction thiobenzamide make benzothiazole in the presence of potassium ferricyanide. In a typical reaction thiobenzamide (1 EQ.) dissolved in NaOH (1,5M, 39 equiv.) and the solution is cooled to 5°C. with ice. Add ferricyanic potassium in water (20%, 15 vol.) and the reaction mixture was stirred at room temperature for 18 hours. The mixture is filtered, and the solid is washed with H2O - a Solid substance dissolved in DHM (20 vol.), dried (Na2SO4) and remove the solvent under reduced pressure to get crude product of benzothiazole. To obtain pure target substance can be applied column chromatography.

Diazomethylene

In this reaction arylamine and arenas, for example, phenol, are connected through the education of diasease. In a typical reaction arylamine (1 EQ.) dissolved in the Meon (10 vol.) and the solution is cooled to 5°C. with ice. Then to the solution was added HCl (3 EQ., 2M). Added dropwise NaNO2in H2O (10 vol.). The reaction mixture was stirred at 5°C for 10 minutes. In a separate flask arenas (1 EQ.) add to H2O (20 vol.). Add Na2CO3(2 equiv.) and then NaOH (1 EQ.) and the resulting suspension is added dropwise to the salt Diaz is tion. The reaction mixture is stirred for 30 minutes before extraction with EtOAc (3×20 vol). The combined organic layers washed with H2O (10 vol.), saline solution (10 vol.) and dried (Na2SO4). Remove the solvent under reduced pressure to get crude target substance, which can be purified by using column chromatography.

Compounds in which Q represents-NHC(O)-; -NR1C(O)-; -C(O)NH; or-C(O)NR1-

The intermediate 5-methoxy-2-aminobenzoyl

A mixture of 2-amino-6-methoxybenzothiazole (15 g, or 83.2 mmol), ethylene glycol (on 20, 23 g, 0.33 mol) and 50 wt%./about. KOH (100 ml) was boiled under reflux for 24 hours. Upon cooling to room temperature was added toluene (60 ml) and the reaction mixture is cooled in an ice bath and was acidified with acetic acid (final pH 5-6). The reaction mixture was extracted with toluene (5×300 ml) and the combined organic layers were washed brine (2×200 ml), dried (MgSO4) and solvent removed under reduced pressure to obtain the title compound (11.1 g, 86%) as a yellow solid, which was used without further purification.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ is 3.21 (s, 3H), 6,13 (d, J=8,8 Hz, 1H), 6,30 (d, J=8,8 Hz, 1H), to 6.39 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 55,87, 113,61, 115,41, 116,47, 119,00, 140,58, 152,52.

<> The experimental data are consistent with data obtained previously Mathis with co-authors (Mathis et al.) and Hoquiam with co-authors (Haugwitz et al.).

2-(4-nitrophenyl)-6-methoxybenzothiazole

A mixture of 2-amino-5-methoxybenzamide (5.0 g, to 32.2 mmol) and 4-nitrobenzylamine (6.0 g, to 32.2 mmol) in toluene (250 ml) was boiled under reflux with a catalytic amount of 4-toluensulfonate acid in the nozzle Dean-stark for 6 hours. After cooling to room temperature the precipitate was collected by filtration, washed with toluene and recrystallize from Asón to obtain the title compound (7.0 g, 76%) as a pale yellow solid.

1H NMR (400MHz, CDCl3) δ 3.88 (s, 3H), 7.11 (dd, J=8.9, 2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.16 (d, J=G Hz, 2H), 8.29 (d, J=8.9 Hz, 2H);13With NMR (100 MHz, CDCl3) δ 55.88, 104.00, 116.64, 124.32, 124.51, 127.83, 137.09, 139.39, 148.69, 148.73, 158.58, 162.19.

The experimental data are consistent with data obtained previously Casemay with co-authors (Kashiyama et al.) and Shi and co-authors (Shi et al.).

2-(4-nitrophenyl-2-trifluoromethyl)-6-methoxybenzothiazole

Thoroughly mixed paste of 2-amino-5-methoxybenzamide (1.0 g, 6,44 mmol) and 4-nitro-2-triftorperasin acid (1.51 g, 6,44 mmol) in trimethylsilyltriflate (PPSE) (5 ml) was heated with stirring at 150°C in argon atmosphere is 3 hours. After cooling to room temperature the reaction mixture was a solid mass, which was dissolved in DHM and adsorbing onto silica and purified in a small column filled with silica (1:1 hexane/EtOAc). First eluruume fraction was collected and solvent removed under reduced pressure to obtain an orange solid (1.5 g), which was additionally purified using flash chromatography (3:1 hexane/EtOAc) to give the title compound (0,85 g, 37%) as a yellow solid.

PPSE was obtained from commercial sources. As an alternative, PPSE can be obtained in accordance with methods described in the work of Imamoto with co-authors (Imamoto et al.).

1H NMR (400 MHz, CDCl3) 5 3.88 (s, 3H), 7.14 (dd, J=8.9, 2.4 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 8.46 (dd, J=8.5, 2.0 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.93, 103.50, 116.75, 122.41 (q, JCF=274 Hz), 122.63 (q, JCF=5.9 Hz), 124.81, 126.39, 130.61 (q, JCF=33 Hz), 133.98, 137.85, 138.95, 148.06, 158.59, 158.87.

2-(4-nitrophenyl-3-trifluoromethyl)-6-methoxybenzothiazole

Thoroughly stirred slurry of 2-amino-5-methoxybenzamide (2.0 g, 12,88 mmol) and 4-nitro-3-triftorperasin acid (3.03 g, 12,88 mmol) in trimethylsilyltriflate (10 ml) was heated with stirring at 150°C in argon atmosphere for 2 hours. After cooling the Oia to room temperature, the reaction mixture was dissolved in DHM (100 ml) and washed 1M HCl (2×50 ml), saturated NaHCO3(2×50 ml), brine (80 ml) and dried (Na2SO4). Removed solvent under reduced pressure to obtain a brown solid, which was purified using flash chromatography (2:1 hexane/EtOAc) to give the title compound (2,36 g, 52%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 3.90 (s, 3H), 7.14 (dd, J=9.1, 2.4 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.24 (d. J=8.5 Hz, 1H), 8.47 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.88, 103.95, 116.95, 121.75 (q, JCF=274 Hz), 124.68, 124.75 (q, JCF=35 Hz), at 126.00, 126.30, 130.83, 137.10, 137.97, 148.17, 148.55, 158.84, 160.38.

2-(2-methoxy-4-nitrophenyl)-6-methoxybenzothiazole

Thoroughly mixed paste of 2-amino-5-methoxybenzamide (2.0 g, 12,88 mmol) and 2-methoxy-4-nitrobenzoic acid (2,54 g, 12,88 mmol) in trimethylsilyltriflate (10 ml) was heated with stirring at 150°C in argon atmosphere for 30 minutes. After cooling to room temperature the reaction mixture is suspended in DHM/Meon and using filtering gathered orange solid. The filtrate is washed 1M HCl (2×50 ml), saturated NaHCO3(2×50 ml), brine (70 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to obtain solid, which was combined with the previously collected solid and paracrystals the Wali of the Asón to obtain the title compound (3,43 g, 83%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 3.90 (s, 3H), 4.15 (s, 3H), 7.13 (dd, J=9.1, 2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.89 (s, 1H), 7.97 (m, 2H), 8.66 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.84, 56.38, 103.24, 106.87, 116.22, 116.45, 124.09, 128.27, 129.79, 138.00, 146.84, 149.09, 156.71, 157.97, 158.13.

2-(3-methoxy-4-nitrophenyl)-6-methoxybenzothiazole

Thoroughly mixed paste of 2-amino-5-methoxybenzamide (2.0 g, 12,88 mmol) and 3-methoxy-4-nitrobenzoic acid (2,54 g, 12,88 mmol) in trimethylsilyltriflate (10 ml) was heated with stirring at 150°C in argon atmosphere for 2 hours. After cooling to room temperature the reaction mixture is suspended in DHM (300 ml) and adsorbing the silicon oxide for flash chromatography and were initially purified using a column of silica flash chromatography with elution DHM, and then DHM/EtOAc (6:1). Additional cleaning of the collected fractions using flash chromatography (20:1 DHM/hexane) yielded the title compound (1,32 g, 32%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 4.07 (s, 3H), 7.10 (dd, J=8.9, 2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.5, 1.7 Hz, 1H), 7.84 (d, 1H, J=1.7 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.88, 56.86, at 104.02, 111.50, 116.56, 119.08, 124.37, 126.56, 137.01. 139.15, 140.24, 148.58, 153.50, 158.51, 162.44.

2-(2-methoxy-4-nitrophenyl)benzothiazole

Thoroughly stirred slurry of 2-aminobenzoyl (0,63 g 5,07 mmol) and 2-methoxy-4-nitrobenzoic acid (1.0 g, 5,07 mmol) in trimethylsilyltriflate (5 ml) was heated with stirring at 150°C in argon atmosphere for 1.5 hours. After cooling to room temperature the reaction mixture was a solid mass, to which was added DHM (35 ml) and Et2O (50 ml). Solid to grind and was collected by filtration, then recrystallize from Asón and was dried in high vacuum for 18 hours to obtain the title compound (0,90 g, 62%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 4.16 (s, 3H), 7.40-7.46 (m, 1H), 7.51-7.56 (m, 1H), 7.91 (s, 1H), 7.93-8.05 (m, 2H), 8.12 (d, J=7.9 Hz, 1H), 8.72 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 56.39, 106.84, 116.11, 121.42, 123.42, 125.61, 126.49, 127.93, 130.21, 136.37, 149.40, 152.05, 157.04, 160.45.

2-(4-amino-2-methoxyphenyl)benzothiazole

Received in accordance with section description restoration of the nitro group using 2-(2-methoxy-4-nitrophenyl)benzothiazole (0.1 g, 0.35 mmol) and chloride dihydrate tin (II) (0,63 g, 2.8 mmol) in EtOH (12 ml) to give the title compound (0,086 g, 96%) as a pale orange solid after processing and flash chromatography (2:1 hexane/THF).

1H NMR (250 MHz, CDCl3) δ 3.99 (br s, 5H), 6.30 (d, J=1.5 Hz, 1H), 6.41 (dd, J=8.5, 1.5 Hz, 1H), 7.25-7.32 (m, 1H), 7.39-7.46 (m, 1H),7.85 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.9 Hz, 1H), 8.31 (d,J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.51, 97.48, 107.97, 113.01, 121.06, 121.98, 123.83, 125.69, 130.95, 135.49, 150.42, 152.21, 158.90, 163.89

2-(2-hydroxy-4-nitrophenyl)benzothiazole

Obtained in accordance with the description above section Dimitrievna using 2-(2-methoxy-4-nitrophenyl)benzothiazole (0.5 g, about 1.75 mmol) in dry DHM (30 ml) added dropwise Vugs (1.0m solution in DHM, and 8.8 ml of 8.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was repaid by adding the Meon (5 ml) and was extracted with 8% wt./about. NaOH (5×35 ml). The combined aqueous extracts were acidified using 6M HCl and was extracted with EtOAc (3×70 ml). The combined organic extracts were washed brine (40 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain solid, which was purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0,47 g, 99%) as a pale yellow solid after processing and flash chromatography (1:1 hexane/EtOAc).

1H NMR (250 MHz, CDCl3) δ 7.49-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.78-7.95 (m, 2H), 7.95-7.98 (m, 2H), 8.06 (d, J=7.9 Hz, 1H), 12.95 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 113.24, 114.14, 121.78, 122.79, 126.65, 127.34, 129.03, 132.99, 149.79, 151.40, 158.28, 166.88 (1 missing).

2-[2-(1,3-benzothiazol-2-yl)-5-nitrophenoxy]-N,N-dime elatonin

N,N-dimethylethanolamine To stir a mixture of 2-(2-hydroxy-4-nitrophenyl)benzothiazole (0.15 g, 0.55 mmol), triphenylphosphine (0,216 g, 0,825 mmol) and N,N-dimethylethanolamine (0,059 g, 0.66 mmol) in dry THF (10 ml) at 0°C dropwise added DIAD (0.167 g, 0,825 mmol). The reaction mixture was stirred at 0°C for 0.5 hours, then left to warm to room temperature over night. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (20:1 DHM/Meon) to obtain the title compound (0,089 g, 47%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 2.41 (s, 6H), 2.98-3.03 (m, 2H), 4.36-4.40 (m, 2H), 7.39-7.45 (m, 1H), 7.49-7.55 (m, 1H), 7.89-7.96 (m, 3H), 8.10 (d, J=7.6 Hz, 1H), 8.71 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 46.18, 57.93, 68.47, 107.63, 116.11, 121.42, 123.42, 125.60, at 126.48, 128.05, 130.30, 136.36, 149.34, 151.99, 156.37, 160.47.

Applicable conditions of the reaction based on the methods described in the works of Malamas with co-authors (Malamas et al.) and Mann and co-authors (Mann et al.) for the reaction of 4-hydroxybenzaldehyde with aliphatic alcohols.

2-[2-{2-(2-(2-methoxyethoxy)ethoxy)ethoxy}-4-nitrophenyl]-1,3-benzothiazol

To a stirred mixture of 2-(2-hydroxy-4-nitrophenyl)benzothiazole (0.15 g, 0.55 mmol), triphenylphosphine (0,216 g, 0,825 mmol) and nanometrology ether of triethylene glycol (to 0.108 g, 0.66 mmol) in dry THF (10 m is) at 0°C was added dropwise DIAD (0.167 g, 0,825 mmol). The reaction mixture was stirred at 0°C for 0.5 hours, then left to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0,176 g, 76%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 3.32 (s, 3H), 3.47-3.52 (m, 2H), 3.61-3.67 (m, 2H), 3.68-3.75 (m, 2H), 3.76-3.84 (m, 2H), 4.06-4.10 (m, 2H), 4.44-4.48 (m, 2H), 7.39-7.45 (m, 1H), 7.49-7.55 (m, 1H), 7.92-7.96 (m, 3H), 8.10 (d, J=7.9 Hz, 1H), 8.71 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 59.05, 69.34 (2×C), 70.68, 70.79, 70.99, 71.94, 107.91, 116.19, 121.44, 123.41, 125.58, 126.45, 128.11, 130.22, 136.48, 149.31, 152.02, 156.39, 160.56.

Applicable conditions of the reaction based on the methods described by Zhang and co-authors (Zhang et al.) for the reaction of glycols with phenolic compounds.

2-(4-AMINOPHENYL)-6-methoxybenzothiazole

Received in accordance with section description restoration of the Nitro group using 2-(4-nitrophenyl)-6-methoxybenzothiazole (5.0 g, 17.5 mmol) and chloride dihydrate tin (II) (31.5 g, 0.14 mol) in EtOH (150 ml) to give the title compound (4,2 g, 93%) as a colourless solid after treatment and recrystallization from EtOH.

1H NMR (250 MHz, CDCl3) δ 3.86 (s, 3H), 3.96 (s, 2H), 6.71 (d, J=8.5 Hz, 2H), 7.04 (dd, J=8.5, 2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.87 (d, J=8.5 Hz, 2H);13C NMR (62.5 M is C, CDCl3) δ 55.82, 104.34, 114.84, 115.10, 123.00, at 124.20, 128.81, 135.92, 148.84, 148.87, 157.29, 166.15. The experimental data is consistent with data obtained previously Mathis with co-authors (Mathis et al.) and Shi and co-authors (Shi et al.).

2-(4-amino-2-triptoreline)-6-methoxybenzothiazole

Received in accordance with section description restoration of the Nitro group using 2-(4-nitro-2-triptoreline)-6-methoxybenzothiazole (0.6 g, was 1.69 mmol) and chloride dihydrate tin (II) (a 3.06 g, 13.56 mmol) in EUN (35 ml) to give the title compound (0.51 g, 93%) as a colourless solid after processing and flash chromatography (30:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 3.88 (s, 3H), 4.08 (br s,2H), 6.83 (d, J=8.2 Hz, 1H), 7.04 (s, 1H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.85, 103.69, 112.69 (q, JCF=4.9 Hz), 115.61, 116.78, 122.01, 123.59 (q, JCF=274 Hz), 124.00, 130.00 (q, JCF=31 Hz), 133.73, 137.55, 147.89, 148.02, 157.75, 162.86.

2-(4-amino-3-triptoreline)-6-methoxybenzothiazole

Received in accordance with section description restoration of the Nitro group using 2-(4-nitro-3-triptoreline)-6-methoxybenzothiazole (1.0 g, 2.82 mmol) and chloride dihydrate tin (II) (5,1 g, and 22.6 mmol) in EtOH (50 ml) to give the title compound (0.84 g, 91%) as a pale orange solid after processing iFlash-chromatography (2:1 hexane/EtOAc).

1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H), 4.44 (br s, 2H), 6.76 (d, J=8.4 Hz, 1H), 7.03 (dd, J=8.8, 2.4 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.91 (dd, J=8.4, 2.0 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H);13With YAIR (62.5 MHz, CDCl3) δ 55.84, 104.26, 113.70 (q, JCF=30.3 Hz), 115.54, 117.26, 123.22, 123.41, 124.55 (q, JCF=272 Hz), 125.99 (q, JCF=3.9 Hz), 131.71, 135.88, 146.33, at 148.44, 157.60, 164.59.

2-(4-amino-2-methoxyphenyl)-6-methoxybenzothiazole

Received in accordance with section description restoration of the Nitro group using 2-(2-methoxy-4-nitrophenyl)-6-methoxybenzothiazole (1.0 g, of 3.13 mmol) and chloride dihydrate tin (II) (5,66 g, 25,08 mmol) in EtOH (50 ml) to give the title compound (0,79 g, 89%) as a pale yellow solid after purification and recrystallization from EtOH.

1H NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H), 3.87 (s, 3H), 5.82, (br s, 2H), 6.27 (dd, J=8.5, 1.7 Hz, 1H), 6.29 (d, J=1.7 Hz, 1H), 6.98 (dd, J=8.9, 2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 56.01, 56.24, 96.71, 104.78, 107.72, 110.09, 115.43, 122.43, 130.18, 136.59, 147.01, 153.53, 156.85, 158.99, 161.62.

2-(4-amino-3-methoxyphenyl)-6-methoxybenzothiazole

Received in accordance with section description restoration of the Nitro group using 2-(3-methoxy-4-nitrophenyl)-6-methoxybenzothiazole (0.5 g, 1.56 mmol) and chloride dihydrate tin (II) (2,61 g, 11,58 mmol) in EtOH (35 ml) to give the title compound (0,41 g, 91%) in VI is e light orange solid after processing and flash chromatography (2:1 hexane/THF).

1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 3.97 (s, 3H), 4.12 (br s, 2H), 6.72 (d, J=7.9 Hz, 1H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.40 (dd, J=7.9, 1.2 Hz 1H), 7.56 (d, J=1.2 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.74, 55.81, 104.33, 108.55, 114.06, 115.09, 121.48, 122.93, 124.12, 135.95, 139.17, 147.12, 148.76, 157.27, 166.46.

4-(1,3-benzothiazol-2-yl)-3-[2-(dimethylamino)ethoxy]aniline

Received in accordance with section description restoration of the Nitro group using 2-[2-(1,3-benzothiazol-2-yl)-5-nitrophenoxy]-N,N-dimethylethanamine (0,073 g, 0.21 mmol) and chloride dihydrate tin (II) (0,38 g, 1.7 mmol) in EtOH (7 ml) to give the title compound (0.05 g, 75%) as a cream solid color after processing and flash chromatography (Meon).

1H NMR (400 MHz, CDCl3) δ 2.36 (s, 6N), 2.94 (t, J=6.5 Hz, 2H), 3.98 (br s, 2H), 4.21 (t, J=6.5 Hz, 2H), 6.25 (d, J=2.4 Hz, 1H), 6.37 (dd, J=8.5, 2.4 Hz, 1H), 7.24-7.28 (m, 1H), 7.37-7.41 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.95 (d,, J=8.2 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 46.15, 58.05, 67.52, 98.25, 108.03, 113.26, 120.95, 121.93, 123.72, 125.59, 130.97, 135.46, 150.21, 152.18, 158.04, 163.74.

4-(1,3-benzothiazol-2-yl)-3-[2-{2-(2-methoxyethoxy)ethoxy}ethoxy]aniline

Received in accordance with section description restoration of the Nitro group using 2-[2-{2-(2-(2-methoxyethoxy)ethoxy)ethoxy}-4-nitrophenyl]-1,3-benzothiazole (0.15 g, 0.36 mmol) and chloride dihydrate tin (II) (0.65 g, 2,87 mmol) in EtOH (12 ml) to obtain t is olnogo connection (0,13 g, 92%) as a viscous yellow oily liquid after processing and flash chromatography (EtOAc).

1H NMR (250 MHz, CDCl3) δ 3.30 (s, 3H), 3.47-3.49 (m, 2H), 3.59-3.62 (m, 2H), 3.62-3.65 (m, 2H), 3.73-3.75 (m, 2H), 3.95-3.97 (m, 2H), 4.10-4.28 (m, 4H), 6.19 (s, 1H), 6.33 (d, J=8.5 Hz, 1H), 7.23-7.29 (m, 1H), 7.37-7.43 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H);13With NMR (62.5 MHz, CDCb) δ 58.99, 68.23, 69.55, 70.54, 70.69, 70.80, 71.89, 98.26, 108.15, 112.79, 121.05, 121.89, 123.73, 125.66, 130.81, 135.55, 150.75, 152.11, 158.09, 164.03.

2-methoxy-5-(triptoreline)benzoic acid

To a stirred solution of 2-methoxy-5-triphtalocyaninine (2.0 g, 9.09 mmol) and 50% KOH (4,1 ml) in the Meon (15 ml) at 65°C dropwise added hydrogen peroxide (30%, 7,4 ml) for 20 minutes. The reaction mixture was stirred at 65°C for 10 minutes, cooled to room temperature, was acidified using 1M HCl and was extracted with Et2O (3×40 ml). The combined organic extracts were washed brine (35 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain light yellow viscous oily liquid, which was left to cure at room temperature overnight to obtain the title compound (1,95 g, 91%) as a pale yellow solid.

1H NMR (250 MHz, CDCl3) δ 4.07 (s, 3H), 7.07 (d, J=9.2 Hz, 1H), 7.41 (dd, J=9.2, 2.1 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 8.80-11.0 (vbr s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 57.22, 113.13, 118.95, 120.1 (q, the jcf=258 Hz), 126.20, 127.83, 143.22, 156.68, 164.82.

The oxidation of aromatic aldehydes to aromatic acids described by Kong and co-authors (Cong et al.).

4-(2,2,2-triptoreline)benzaldehyde

To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.87 g, and 21.8 mmol) in DMSO (20 ml) at 10-15°C in argon atmosphere was added triptoreline (of 3.97 g, and 39.7 mmol). The reaction mixture was stirred at the same temperature for 20 minutes, then added in one portion to 4-nitrobenzaldehyde (3.0 g, 19,85 mmol). The reaction mixture was stirred at 10-15°C for 3 hours and then at room temperature for 60 hours. Carefully added to a mixture of saline solution (100 ml)and then was extracted with Et2O (3×70 ml). The combined organic extracts were washed with water, dried (MgSO4) and solvent removed under reduced pressure to obtain oily liquid, which was purified using flash chromatography (3:1 hexane/EtOAc) to obtain yellow oily liquid, which was left to cure at room temperature to obtain the title compound (1,76 g, 43%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 4.42 (q, J=7.9 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 65.5 (q, JCF=36 Hz), 115.02, 123.02 (q, JCF=277 Hz), 131.34, 132.01, 161.82, 190.62.

The experience is imentally data matched data, obtained previously Go with co-authors (Idaux et al.) (1983) and Go with co-authors (Idaux et al.) (1985).

4-(2,2,2-triptoreline)benzoic acid

To a mixed solution of 50 wt%./about. KOH (1.2 ml) and 4-(2,2,2-triptoreline)benzaldehyde (0.6 g, to 2.94 mmol) in Meon (5 ml) at 65°C dropwise added an aqueous solution of hydrogen peroxide (30% wt. in water, 2.4 ml) for 20 minutes. After complete addition, the reaction mixture was additionally heated to 65°C for 10 minutes. After cooling to room temperature the reaction mixture was acidified using 1M HCl and was extracted with Et2O (3×30 ml). The combined organic extracts were washed with saline (20 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain the title compound (0,59 g, 91%) as a pale yellow solid that was used without further purification.

1H NMR (250 MHz, acetone-d6) δ 4.80 (q, J=7.9 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 8.05 (d, J=8.5 Hz, 2H);13With NMR (62.5 MHz, acetone-d6) δ 66.34 (q, JCF=35 Hz), 115.36, 124.72 (q, JCF=277 Hz), 125.31, 132.78, 161.79, 167.00.

Applicable conditions of the reaction based on the methods described by Kong and co-authors (Cong et al.).

4-(3,3,3-cryptocracy)benzaldehyde

To a stirred solution of 4-hydroxybenzaldehyde (0.36 g, with 2.93 mmol), 3,3,3-three is forproposal (0.5 g, 4,39 mmol) and triphenylphosphine (1,15 g, 4,39 mmol) in dry THF at 0°C in an atmosphere of argon dropwise added diisopropylcarbodiimide (0,89 g, 4,39 mmol). After complete addition, the reaction mixture was stirred at room temperature for 60 hours. Removed solvent under reduced pressure and the residue was purified using flash chromatography (4:1 hexane/EtOAc) to give the title compound (0.25 g, 46%) as a colourless solid.

1H NMR (250 MHz, CDCl3) δ 2.57-2.75 (m, 2H), 4.27 (t, J=6.4 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 2H), 9.89 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 33.82 (q, JCF=28.3 Hz), 60.87, 113.87, 123.91, 125.79 (q, JCF=276 Hz), 131.78, 161.50, 168.12.

Applicable conditions of the reaction based on the methods described in the works of Malamas with co-authors (Malamas et al.) and Mann and co-authors (Mann et al.).

4-(3,3,3-cryptocracy)benzoic acid

To a mixed solution of 50 wt%./about. KOH (0.8 ml) and 4-(3,3,3-triptoreline)benzaldehyde (0.4 g, to 1.83 mmol) in Meon (4 ml) at 65°C dropwise added an aqueous solution of hydrogen peroxide (30% wt. in water, 1.5 ml) for 20 minutes. After complete addition, the reaction mixture was additionally heated to 65°C for 10 minutes. After cooling to room temperature the reaction mixture was acidified using 1M HCl and was extracted with Et2O (3×25 ml). About yedinenye organic extracts were washed brine (25 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain the title compound (0.36 g, 83%) as a colourless solid, which was used without further purification.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 2.42-2.60 (m, 2H), 4.10 (t, J=6.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 33.71 (q, JCF=29.3 Hz), 60.80, 113.83, 123.84, 125.78 (q, JCF=276 Hz), 131.67, 161.42, 167.92.

Ethyl 4-(4,4,4-triptoreline)benzoate

A mixture of 4-hydroxybenzaldehyde (0,46 g, 2,80 mmol), 1-iodine-4,4,4-triptorelin (0,67 g, 2,80 mmol) and anhydrous K2CO3(of 1.16 g of 8.40 mmol) in methyl ethyl ketone (5 ml) was boiled under reflux for 4 hours in argon atmosphere. After cooling to room temperature the solvent was removed under reduced pressure and the residue was separated by water (15 ml) and Et2O (30 ml). The organic layer was separated, and the aqueous phase was extracted with Et2O (2×20 ml), the combined organic extracts were washed brine (15 ml) and dried (Na2SO4). Removed solvent under reduced pressure to obtain solid, which was purified using flash chromatography (3:1 hexane/EtOAc) to give the title compound (0,67 g, 87%) as a colourless solid.

1H NMR (250 MHz, CDCl3) δ 1.36 (t, J=7.0 Hz, 3H), 2.00-2.11 (m, 2H), 2.21-2.40 (m, 2H), 4.05 (t, J=5.8 Hz, 2H), 4.33 (q, J=7.0 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 14.36, 22.09 (q, JCF=2.9 Hz), at 30.67 (q, JCF=29 Hz), 60.70, at 66.15, 113.95, 123.30, 127.06 (q, JCF=276 Hz), 131.61, 162.22, 166.31.

Applicable conditions of the reaction based on the methods described in the work of Pesa with co-authors (Fez et al.), alkylation of 4-hydroxybenzaldehyde yozilganmi.

4-(4,4,4-triptoreline)benzoic acid

To a stirred solution of ethyl-4-(4,4,4-triptoreline)benzoate (0,60 g, 2,17 mmol) in a mixture of THF/water (3:1 vol./about., 15 ml) at room temperature was added in one portion LiOH (0.11 g, 4,34 mmol). The reaction mixture was stirred at room temperature for 18 hours, then was added (15 ml) to give a clear solution and kept stirring for 48 hours. Removed the solvents under reduced pressure and to the residue was added water (30 ml). The resulting mixture was extracted with DHM (30 ml) and the aqueous phase was acidified using 1M HCl and was extracted with EtOAc (3×30 ml). The combined organic extracts were washed brine (30 ml) and dried (Na2SO4). Removed solvent under reduced pressure to obtain the title compound (0.51 g, 95%) as a colourless solid, which was used without further purification.

1H NMR (250 MHz, acetone-d6) δ 2.03-2.14 (m, 2 is), 2.37-2.56 (m, 2H), 4.21 (t, J=5.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 7.99 (d, J=8.8 Hz, 2H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 21.88 (q, JCF=1.9 Hz), 30.41 (q, JCF=29 Hz), 65.93, 113.77, 123.39, 127.00 (q, JCF=276 Hz), 131.65, 161.98, 168.03.

4-(2-floratone)benzaldehyde

To a mixture of 4-hydroxybenzaldehyde (1.45 g, to 11.9 mmol), triphenylphosphine (6,87 g, 26,2 mmol) and 2-ftramadol (1.68 g, to 26.2 mmol) in dry THF (70 ml) at 0°C dropwise added DIAD (5.29 g, to 26.2 mmol). The reaction mixture was stirred at 0°C for 1 hour, then left to warm to room temperature and was stirred for 48 hours. Removed solvent under reduced pressure and the residue was purified using flash chromatography (5:1 DHM/hexane) to give the title compound (0,807 g, 40%) as a colourless solid connection.

1H NMR (250 MHz, CDCl3) δ 4.28 (dist d oft, JHF=28 Hz, JHH=4.0 Hz, 2H), 4.77 (dist d oft, JHF=47 Hz, JHH=4.0 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 9.87 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 67.33 (d, JCF=19.5 Hz), 81.59 (d, JCF=172 Hz), 114.85, 130.38, 132.06, 163.36, 190.86.

Applicable conditions of the reaction based on the methods described in the works of Malamas with co-authors (Malamas et al.) and Mann and co-authors (Mann et al.).

4-(2-floratone)benzoic acid

To a mixed solution of 50 wt%./about. KOH (1.3 ml) and 4-(2-floratone)is benzaldehyde (0.5 g, 2,98 mmol) in Meon (6 ml) at 65°C dropwise added an aqueous solution of hydrogen peroxide (30% mass water at 2.45 ml) for 20 minutes. After complete addition, the reaction mixture was additionally heated to 65°C for 10 minutes. After cooling to room temperature the reaction mixture was acidified using 1M HCl and was extracted with Et2O (3×30 ml). The combined organic extracts were washed brine (30 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain solid, which was purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0,278 g, 63%) as a colourless solid.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 4.09 (dist d of t, JHF=28 Hz, JHH=3.0 Hz, 2H), 4.59 (dist d of t, JHF=47 Hz, JHH=3.0 Hz, 2H), 6.76 (d, J=8.2 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 67.06 (d, JCF=19.5 Hz), 81.64 (d, JCF=170 Hz), 113.94, 123.73, 131.73, 161.82, 168.08.

Applicable conditions of the reaction based on the methods described by Kong and co-authors (Cong et al.), oxidation of aromatic aldehydes to aromatic acids.

Benzothiazoline non-fluorinated compounds of methoxyamine 2-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-13

Obtained in accordance with the description of the m section above Amide binding.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 3.15 (s, 3H), 6.34 (dd, J=8.8, 1.8 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 6.96-7.02 (m, 2H), 7.07-7.15 (m, 4H), 7.27 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 1H), 10.08 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.26, 103.91, 115.21, 119.54, 122.79, 123.72, 127.17, 128.52, 128.87, 130.26, 132.52, 133.38 is awaited, 135.61, 140.78, 146.08, 147.91, 157.09, 163.98, 164.10 (splitting of the carbonyl).

3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-23

Obtained in accordance with the description above section Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.25 g, 0.98 mmol) and 3-nitrobenzotrifluoride (0.20 g, 1.07 mmol) in dry pyridine (15 ml) to give the title compound (0,38 g, 96%) as a colourless solid after processing.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 3.22 (s, 3H), 6.41 (dd, J=8.8, 1.8 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 7.10 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.34 (m, 4H), 7.74 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 8.29 (br s, 1H), 10.01 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.31, 103.89, 115.24, 120.38, 122.37, 122.82, 125.69, 127.07, 128.70, 129.31, 133.92, 135.69, 135.92, 140.74, 147.52, 147.97, 157.15, 163.19, 164.13.

4-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-9

Obtained in accordance with the description above section Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0,30 g at 1.17 mmol) and 4-nitrobenzoic the chloride (0.24 g, 1,29 mmol) in dry pyridine (15 ml) to give the title compound (0,369 g, 78%) as a fine yellow needle-like particles after treatment and recrystallization from 1,2-dichloroethane.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 3.15 (s, 3H), 6.34 (dd, J=8.8, 1.8 Hz, 1H), 6.73 (d, J=1.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.26 (m, 4H), 7.51 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 9.92, (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.25. 103.89, 115.23, 120.26. 122.79, 122.90, 127.01, 128.64, 128.87, 135.63, 140.02, 140.69, 147.91, 148.90, 157.09, 163.59, 163.99.

2-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-99

Obtained in accordance with the description above partition Recovery nitro-group.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 3.31 (s, 3H), 6.08 (t, J=7.6 Hz, 1H), 6.21 (d, J=8.2 Hz, 1H), 6.50 (dd, J=8.8, 2.1 Hz, 1H), 6.64 (t, J=7.6 Hz, 1H), 6.84 (d, J=2.1 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 9.51 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.39, 103.92, 115.149, 115.211, 115.47, 116.55, 120.23, 122.85, 127.10, 128.07, 128.58, 132.07, 135.74, 141.50, 148.13, 149.21, 157.15, 164.57, 168.03.

3-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-41

Received in accordance with section description restoration of the nitro group using 3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.33 g, 0.81 mmol) and chloride dihydrate tin (II) (1.47 g, 6,51 mmol) at EtH (20 ml) to give the title compound (0.24 g, 79%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 5.30 (s, 2H), 6.71 (dd, J=7.9, 2.1 Hz, 1H), 7.02-7.08 (m, 3H), 7.09-7.13 (m, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 10.31 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.32, 103.89, 113.42, 115.19, 115.85, 117.31, 119.95, 122.79, 127.06, 128.00, 128.56, 135.64, 141.51, 147.33, 147.46, 148.02, 157.09, 164.41, 166.56.

4-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-21

Received in accordance with section description restoration of the nitro group using 4-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.31 g, 0,765 mmol) and chloride dihydrate tin (II) (1,38 g, 6.12 mmol) in EtOH (5 ml) to give the title compound (0,212 g, 74%) as a pale yellow solid after processing.

1H NMR (250 MHz, DMSO-d6) δ 3.84 (s, 3H), 5.84 (s, 2H), 6.61 (d, J=8.5 Hz, 2H), 7.11 (dd, J=8.8, 2.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.8 Hz, 1H), 7.96 (dist (d, J=8.8 Hz, 2H), 7.99 (dist (d, J=8.8 Hz, 2H), 10.06 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 55.18, 103.94, 112.45, 115.07, 119.65, 120.99, 122.59, 126.84, 127.26, 129.14, 135.44, 141.93, 147.85, 151.57, 156.90, 164.23, 165.36.

2-dimethylamino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-103

Received in accordance with section description Amination.

1H NMR (250 MHz, CDCl3) δ 2.84 (s, 6H), 3.87 (s, 3H), 7.08 (dd, J=8.9, 2.4 is C, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.32 (m, 2H), 7.50 (dt, J=8.5, 1.5 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.92 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.5 Hz, 2H), 8.28 (dd, J=7.6, 1.5 Hz, 1H), 12.57 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 45.60, 55.84, 104.20, 115.54, 120.00, 120.55, 123.47, 125.32, 127.40, 128.17, 129.12, is 131.75, 132.74, 135.31, 141.11, 148.78, 152.21, 157.63, 164.27, 165.28.

Demethylation of aniline compounds described in the work It with co (Ono et al.).

3-dimethylamino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-63

Received in accordance with section description Amination using cyanoborohydride sodium (67 mg, 1.06 mmol), 3-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (80 mg, 0,213 mmol) and paraformaldehyde (64 mg, 2,13 mmol) in AcOH (2 ml) to give the title compound as colourless plates (53 mg, 62%) after recrystallization in EtOH.

1H NMR (250 MHz, CDCl3) δ 3.02 (s, 6H), 3.88 (s, 3H), 6.91 (dd, J=8.2, 2.1 Hz, 1H), 6.78 (d, J=8.8 Hz, 2H), 7.05-7.12 (m, 2H), 7.29-7.36 (m, 3H), 7.92 (d, J=8.8 Hz, 1H), 8.03 (dist (d, J=8.8 Hz, 3H);13C NMR (62.5 MHz, CDCl3) δ 40.68, 55.85, 104.20, 111.55, 114.14, 115.61, 115.96, 120.01, 123.53, 128.14, 129.46, 129.67, 135.61, 136.33, 140.25, 148.70, 150.61, 157.69, 166.48 (1 missing).

Demethylation of aniline compounds described in the work It with co (Ono et al.).

4-dimethylamino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-61

Received in accordance with section description Amination with prima is the group of cyanoborohydride sodium (67 mg, 1.06 mmol), 4-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (80 mg, 0,213 mmol) and paraformaldehyde (64 mg, 2,13 mmol) in Asón (2 ml) to give the title compound in the form of colorless needle-like particles (49 mg, 57%) after recrystallization in EtOH.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 2.19 (s, 6H), 3.02 (s, 3H), 5.88 (d, J=8.8 Hz, 2H), 6.22 (dd, J=8.8, 2.1 Hz, 1H), 6.66 (d, J=2.1 Hz, 1H),7.01 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 7.12 (m, 4H), 9.21 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 39.41, 55.17, 103.95, 110.16, 115.09, 119.68, 120.50, 122.57, 126.82, 127.27, 128.94, 135.41, 141.85, 147.82, 151.99, 156.88, 164.18, 165.22.

4-acetoxy-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-155

Obtained in accordance with the description above section Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.25 g, 0,976 mmol) and 4-acetoxybenzoic (0,22 g, 1.07 mmol) in dry pyridine (10 ml) to give the title compound (0,385 g, 94%) as a colourless solid after processing.

1H NMR (250 MHz, DMSO-d6) δ 1.55 (s, 3H), 3.10 (s, 3H), 6.30 (dd, J=9.1, 2.1 Hz, 1H), 6.46 (d, J=8.5 Hz, 2H), 6.71 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.21 (m, 4H), 7.27 (d, J=8.2 Hz, 2H), 9.66 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 20.56, 55.22, 103.91, 115.15, 119.96, 121.17, 122.69, 126.95, 128.10, 128.89, 132.01, 135.55, 141.20, 147.88, 152.66, 157.01, 164.07, 164.79, 168.19.

4-hydroxy-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-161

A mixture of 4-acetoxy-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.31 g, of 0.74 mmol) and NazCOs (0.24 g, 2.22 mmol) in the Meon (15 ml) and water was stirred at room temperature for 18 hours. To the reaction mixture were added water (25 ml), then the mixture was acidified using 1M HCl, the precipitate was collected by filtration. Purification using flash chromatography (3:1 DHM/EtOAc) yielded the title compound (0,22 g, 78%) as a colourless solid.

1H NMR (250 MHz, DMSO-d6) δ 3.84 (s, 3H), 6.87 (d, J=7.9 Hz, 2H), 7.10 (d, J=9.1 Hz, 1H), 7.68 (s, 1H), 7.86-7.94 (m, 3H), 7.94-8.01 (m, 4H), 10.16 (s, 1H), 10.27 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.18, 103.91, 114.53, 115.10, 119.82, 122.62, 124.88, 126.87, 127.62, 129.39, 135.49, 141.62, 147.85, 156.93, 160.44, 164.17, 165.21.

4-acetoxy-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT04-87

A mixture of 4-acetoxy-3-nitrobenzoic acid (0,44 g of 1.95 mmol) and thionyl chloride (5 ml) was boiled under reflux for 1.5 hours. The reaction mixture was cooled to room temperature and the excess reagent were removed under reduced pressure to obtain the crude acid chloride. Amide was obtained in accordance with the description above section Amide linking with the use of acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.50 g, of 1.95 mmol) in dry THF (25 ml)containing diisopropylethylamine (0,302 g, 2,34 IMO the b) obtaining the title compound (0,728 g, 86%) as a solid brown color after processing.

1H NMR (250 MHz, DMSO-d6) δ 2.38 (s, 3H), 3.85 (s, 3H), 7.12 (dd, J=8.8, 2.1 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 0.07 (d, J=8.8 Hz, 2H), 8.40 (dd, J=8.5, 1.8 Hz, 1H), 8.73 (d, J=1.8 Hz, 1H), 10.83 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 20.44, 55.39, 103.91, 115.32, 120.43, 122.91, 125.02, is the 127.20, 128.84, 133.17, 134.29, 135.78, 140.72, 140.95, 145.60, 148.03, 157.24, 162.66, 164.31, 167.69 (1 missing).

4-hydroxy-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT04-89

A mixture of 4-acetoxy-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.20 g, 0,464 mmol) and potassium hydroxide (of 0.081 g, 1,45 mmol) in MeOH (10 ml) was intensively stirred at room temperature for 1.5 hours. Then the reaction mixture was acidified using 1M HCl and was extracted with EtOAc (3×20 ml). The combined organic extracts were washed with water (20 ml), brine (20 ml) and dried Na2SO4. The solvent was removed under reduced pressure to obtain solid, which was purified using flash chromatography (3:2 hexane/THF) to give the title compound (0,052 g, 29%) as a yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.12 (dd, J=8.8, 1.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 8.17 (dd, =8.8, 1.8 Hz, 1H), 8.59 (d, J=1.8 Hz, 1H), 10.57 (s, 1H), 11.84 (br s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.28, 103.88, 115.21, 119.15, 120.23, at 122.77, 124.95, 125.49, 127.01, 128.33, 134.85, 134.94, 135.63, 141.03, 147.94, 155.36, 157.09, 163.06, 164.20.

Fluorinated methoxyamine

2-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT2033-50

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.06 g, 0.23 mmol) and 2-triftormetilfullerenov (0,054 g, 0.26 mmol) in dry pyridine (7.5 ml) to give the title compound (0,093 g, 93%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.12 (dd, J=9.0, 2.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.79-7.83 (m, 1H), 7.87-7.89 (m, 3H), 7.92 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H), 10.87 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 56.19, 105.32, 116.29, 120.33, 123.66, 124.23 (q, JCF=274 Hz), 126.30 (q, JCF=31.1 Hz), 126.86 (q, JCF=4.6 Hz), 128.12, 128.96, 129.02, 130.71, 133.15, 136.32, 141.68, 148.53, 157.85, 164.71, 166.29 (1 missing).

3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SK2033-49

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.06 g, 0.23 mmol) and 3-triftormetilfullerenov (0,054 g, 0.26 mmol) in dry pyridine (7.5 ml) to give the title compound (0085 g, 85%) as a colourless solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.11 (dd, J=9.0, 2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.97-7.99 (m, 3H), 8.05 (d, J=8.6 Hz, 2H), 8.29 (d, J=7.8 Hz, 1H), 8.32 (s, 1H), 10.73 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ 56.18, 105.32, 116.29, 121.09, 123.64, 124.42 (q, JCF=272.5 Hz), 124.81 (q, JCF=3.9 Hz), 127.99, 128.79, 128.99, 129.66 (q, JCF=32.7 Hz), 130.23, 132.42, 135.98, 136.32, 141.72, 148.53, 157.85, 164.73, 164.75.

4-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SK2033-47

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.06 g, 0.23 mmol) and 3-triftormetilfullerenov (38 μl, 0,054 g, 0.26 mmol) in dry pyridine (8 ml) to give the title compound (0,093 g, 93%) as a colourless solid after processing.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.12 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.85-7.97 (m, 3H), 7.97-8.07 (m, 4H), 8.18 (d, J=7.6 Hz, 2H), 10.75 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ 56.20, 105.33, 114.06, 116.31, 121.04, 123.65, at 124.35 (q, JCF=272.4 Hz), 125.91 (q, JCF=3.9 Hz), 127.98, 128.79, 129.01, 129.17, 131.99 (q, JCF=31.9 Hz), 136.32, 141.69, 148.51, 157.85, 164.75.

3-trifluoromethyl-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide

no connection SKT04-155

Received in accordance with section description Amide linking to what label 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.5 g, 1,95 mmol) and 4-methoxy-3-triftormetilfullerenov (0,47 g of 1.95 mmol) in dry pyridine (15 ml) to give the title compound (0,77 g, 93%) as a pale yellow feathery crystals after treatment and recrystallization from acetic acid.

1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 3.94 (s, 3H), 7.06 (dd, J=8.9, 2.4 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.92 (d, J=8.9 Hz, 2H), 7.98 (d, J=8.9 Hz. 2H), 8.23 (s, 1H), 8.25 (d, J=8.9 Hz, 1H), 10.5 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.46, 56.01, 103.94, 111.47, 115.33, 117.49 (q, JCF=31.2 Hz), 120.40, 122.93, 123.12 (q, JCF=273 Hz), 126.27, 126.87 (q, JCF=3.9 Hz), 127.23, 128.49, 133.62, 135.81, 141.25, 148.10, 157.27, 159.55, 164.24, 164.62.

2-trifluoromethyl-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide

no connection SKT05-7

Stir a mixture of 4-methoxy-2-triftorperasin acid (0.50 g, of 2.27 mmol) and thionyl chloride (9 ml) was boiled under reflux for 4 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using crude 4-methoxy-5-triftormetilfullerenov and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0,58 g of 2.27 mmol) in dry pyridine (15 ml) to give the title compound (0,478 g, 46%) as light yellow needle is ASTIC after treatment and recrystallization from acetic acid.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 3.89 (s, 3H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 7.30-7.38 (m, 2H), 7.64-7.77 (m, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.92 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 2H), 10.81 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.35, 55.45, 103.91, 112.08 (q, JCF=4.9 Hz), 115.26, 116.02, 119.65, 122.85, 122.99 (q, JCF=274 Hz), is the 127.20, 128.04, 128.40 (q, JCF=32 Hz), 128.45, 130.13, 135.71, 141.08, 148.02, 157.16, 159.91, 164.32, 165.64.

2-methoxy-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-5-(triptoreline)benzamid

no connection SKT05-9

Stir a mixture of 2-methoxy-5-cryptomaterial acid (0.50 g, 2,12 mmol) and thionyl chloride (9 ml) was boiled under reflux for 4 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.54 g, 2,12 mmol) in dry pyridine (15 ml) to give the title compound (0,607 g, 60%) as light yellow crystals after recrystallization from dioxane.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 3.91 (s, 3H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.53 (dd, J=8.8, 2.1 Hz, 1H), 7.59 (br s, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.8 Hz, 2H), 10.55 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.82, 56.91, 104.14, 112.80, 115.63, 120.40, 12052 (q, JCF=258 Hz), at 122.77, 123.52, 125.33, 126.14, 128.10, 129.73, 136.33, 140.11, 143.38, 148.69, 155.50, 157.69, 161.73, 165.00.

N-[3-trifluoromethyl-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide

no connection SKT04-173

Received in accordance with section description Amide linking using 2-(4-amino-2-triptoreline)-6-methoxybenzothiazole (0.10 g, 0.31 mmol) and 4-methoxybenzylamine (0,053 g, 0.31 mmol) in dry pyridine (5 ml) to give the title compound (0.12 g, 85%) as a cream solid color after processing on recrystallization from acetic acid.

1H NMR (250 MHz, CDCl3) δ 3.86 (s, 3H), 3.89 (s, 3H), 6.95 (d, J=8.8 Hz, 2H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 8.21 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 55.56, 55.88, 103.61, 114.15, 116.00, 118.11 (q, JCF=4.9 Hz), 122.45, 123.32 (q, JCF=274 Hz), 124.22, 126.14, 127.94, 129.15, 129.69 (q, JCF=31 Hz), 133.36, 137.63, 139.84, 147.92, 157.99, 161.81, 162.95, 165.49.

2-methoxy-N-(3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-5-(triptoreline)benzamid

no connection SKT05-33

Stir a mixture of 2-methoxy-5-cryptomaterial acid (0,248 g, 1.05 mmol) and thionyl chloride (4 ml) was boiled under reflux for 4 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure is to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)aniline (0,30 g, 1.05 mmol) in dry pyridine (8 ml) to give the title compound (0,389 g, 73%) as an almost colorless solid after treatment and recrystallization from acetic acid.

1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 3.88 (s, 3H), 3.98 (s, 3H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.4 Hz, 1H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 10.48 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.79 (2×C), 56.89, 103.46, 103.63, 112.26, 112.80, 115.41, 118.37, 120.51 (q, JCF=258 Hz), 122.68, 123.00, 125.21, 126.20, 129.23, at 137.29, 141.02, 143.34, 146.78, 155.52, 157.21, 157.72, 160.59, 161.85.

2-trifluoromethyl-N-[3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide

no connection SKT05-31

Stir a mixture of 4-methoxy-2-triftorperasin acid (0,23 g, 1.05 mmol) and thionyl chloride (4 ml) was boiled under reflux for 3 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)Ani is in (0,30 g, 1.05 mmol) in dry pyridine (8 ml) to give the title compound (0,398 g, 78%) as a pale yellow feathery crystals after treatment and recrystallization from acetic acid.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 3.49 (s, 3H), 3.51 (s, 3H), 3.67 (s, 3H), 6.67 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 6.86 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.99 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 9.98 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.49 (2×C), 55.57, 102.90, 103.22, 112.10, 112.28 (q, JCF=5 Hz), 115.19, 116.06, 117.32, 122.55, 123.14 (q, JCF=274 Hz), 128.19, 128.76 (q, JCF=32 Hz), 128.84, 130.29, 136.76, 142.15, 146.17, 156.90, 157.13, 160.13, 160.25, 166.00.

2-trifluoromethyl-N-[2-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide

no connection SKT05-21

Stir a mixture of 4-methoxy-2-triftorperasin acid (0.15 g, 0.69 mmol) and thionyl chloride (4 ml) was boiled under reflux for 3.5 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)aniline (0.20 g, 0.69 mmol) in dry pyridine (5 ml) to give the title compound (0,13 g, 38%) as a pale yellow solid after processing and flash games the-chromatography (2:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 7.25-7.27 (m, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 9.73 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.40, 55.46, 55.74, 103.92, 108.01, 112.32 (q, JCF=3.9 Hz), 115.23, 116.33, 119.81, 120.16, 122.88, 122.97 (q, JCF=273 Hz), 127.40, 128.14 (q, JCF=32 Hz), 129.23, 129.37, 130.21, 135.75, 147.79, 148.81, 157.24, 160.13, 164.34, 165.31.

3-trifluoromethyl-N-[2-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide

no connection SKT04-175

Received in accordance with section description Amide linking using 2-(4-amino-3-methoxyphenyl)-6-methoxybenzothiazole made (0.13 g, 0.45 mmol), 4-methoxy-3-triftormetilfullerenov (0.11 g, 0.45 mmol) in dry pyridine (5 ml) to give the title compound (0.18 g, 79%) as a colourless solid after treatment and recrystallization from acetic acid.

1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 3.98 (s, 3H), 4.07 (s, 3H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.5, 1.2 Hz, 1H), 7.73 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 8.05 (dd, J=8.8, 2.1 Hz, 1H), 8.12 (s, 1H), 8.58 (s, 1H), 8.59 (d, J=8.2 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 55.83, 56.32 (2×C), 104.17, 107.96, 111.98, 115.69, 119.05 (q, JCF=32 Hz), 119.56, 121.16, 123.12 (q, JCF=273 Hz), 123.44, 126.55 (q, JCF=4.9 Hz), 126.68, 129.37, 129.88, 132.55, 136.33, 148.30, 148.45, 157.75, 160.25, 163.62, 165.30.

4-nitro-3-trifluoromethyl-N-[4-(6-meth is cybersociety-2-yl)phenyl]benzamide

no connection SKT02-103

A mixture of 4-nitro-3-triftorperasin acid and 0.46 g of 1.95 mmol) and thionyl chloride (0,47 g, 4.0 mmol) in chloroform (5 ml) was boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with the description above section Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.50 g, of 1.95 mmol) in dry pyridine (25 ml) to give the title compound (0.84 g, 91%) as an orange solid after processing.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.13 (dd, J=2.1, 8.8 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 2H), 8.35 (d, J=8.5 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.54 (s, 1H), 10.94 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 56.23, 105.42, 116.26, 121.24, 121.88 (q, JCF=33.5 Hz), 122.37 (q, JCF=274 Hz), 123.67, 126.13, 127.86 (q, JCF=5.4 Hz), 127.99, 129.45. 134.37, 136.39, 139.16, 141.28, 148.60, 149.24, 157.95, 163.12, 164.64.

4-nitro-3-trifluoromethyl-N-[4-(6-(2-dimethylaminoethoxy)benzothiazol-2-yl)phenyl]benzamide

no connection SKT03-171

To a stirred mixture of 4-nitro-3-vermeil-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide (0.05 g, 0,109 mmol), triphenylphosphine (0,043 g, 0,163 the mol) and N,N-dimethylethanolamine (0.015 g, 0,163 mmol) in dry THF (5 ml) at 0°C dropwise added DIAD (0,033 g, 0,163 mmol) the Reaction mixture was stirred at 0°C for 1 hour, then left to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (1:1 hexane/EtOAc, 3:1 EtOAc/MeOH) to give the title compound (0,029 g, 50%) as a yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 2.50 (s, 6N), 2.70 (t, J=5.8 Hz, 2H), 4.15 (t, J=5.8 Hz, 2H), 7.14 (dd, J=8.5, 2.7 Hz, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 8.09 (d, J=8.5 Hz, 2H), 8.36 (d, J=8.5 Hz, 1H), 8.51 (d, J=8.5 Hz, 1H), 8.54 (s, 1H), 10.96 (s, 1H).

N-[4-(1,3-benzothiazol-2-yl)-3-(2-(dimethylamino)ethoxy)phenyl]-4-fluoro-3-nitrobenzamide

no connection SKT04-163

A mixture of 4-nitro-2-fermenting acid (0,030 g, 0,128 mmol) and thionyl chloride (1.5 ml) was boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature and the excess reagent were removed under reduced pressure to obtain the crude acid chloride. Amide was obtained in accordance with section description Amide linking using the acid chloride and 4-(1,3-benzothiazol-2-yl)-3-[2-(dimethylamino)ethoxy]aniline (0,040 g, 0,128 mmol) in dry pyridine (5 ml) to give the title compound (0,045 g, 66%) as a yellow solid after processing and flash chromatography the raffia (12:1 DHM/Meon).

X 3437,3058, 2951,2831,2784,1681, 1602, 1540, 1460, 1429, 1359, 1320, 1253, 1184, 1145, 1047, 967, 923, 856, 760, 731 cm-1;1H NMR (400 MHz, CDCl3) δ 2.39 (s, 6N), 2.97 (t, J=6.0 Hz, 2H), 4.33 (t, J=6.0 Hz, 2H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.43 (t, J=7.2 Hz, 1H), 7.81-7.87 (m, 3H), 7.97 (d, J=8.2 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 8.29 (s, 1H), 8.44 (d, J=8.5 Hz, 2H).

4-nitro-2-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-137

A mixture of 4-nitro-2-triftorperasin acid (0.50 g, 2,13 mmol) and thionyl chloride (0,46 g, a 3.83 mmol) in chloroform (5 ml) was boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.54 g, 2,13 mmol) in dry pyridine (20 ml) to give the title compound (0.84 g, 83%) as a yellow solid after processing.

1H NMR (250 MHz, CDCl3) δ 3.90 (s, 3H), 7.09 (dd, J=2.4, 8.8 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 8.51 (dd, J=8.5, 2.1 Hz, 1H), 8.63 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.54, 103.97, 115.46, 120.13, 121.58, 122.23 (q, JCF=274 Hz), 123.11, 126.62, 127.52, 128.71 (q, JCF=33 Hz), 129.42, 130.24, 135.97, 140.32, 41.31, 147.61, 148.20, 157.43, 163.86, 164.40.

4-amino-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-157

Received in accordance with section description restoration of the nitro group using 4-nitro-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.35 g, of 0.74 mmol) and chloride dihydrate tin (II) (1,33 g, 5,91 mmol) in EtOH (7 ml) to give the title compound (0.24 g, 73%) as a pale yellow solid after processing and flash chromatography (3:2 hexane/EtOAc).

X 3385, 3328, 3069, 2939, 2837, 1661, 1607, 1523, 1488, 1463, 1437, 1407, 1314, 1264, 1225, 1173, 1137, 1056, 1027, 968, 829 cm-1.1H NMR (250 MHz, acetone-d6) δ 3.94 (s, 3H), 5.88 (br s, 2H), 7.01 (d, J=8.2 Hz, 1H), 7.15 (dd, J=8.2, 1.6 Hz, 1H), 7.60 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 8.03-8.11 (m, 5H), 8.16 (s, 1H), 9.72 (s, 1H).

4-amino-2-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-149

Received in accordance with section description restoration of the nitro group using 4-nitro-2-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.50 g, 1.05 mmol) and chloride dihydrate tin (II) (1.90 g, of 8.40 mmol) in EtOH (8 ml) to give the title compound (0.32 g, 69%) as a pale yellow solid after processing and flash chromatography (1:1 hexane/EUAs).

X 3365-3050 (br), 3446, 3261, 3007, 2966, 2936, 2831, 1660, 1631, 1607, 1530, 1490, 1464, 1406, 1325, 1266, 1225, 1168, 1122, 1045, 1024, 969, 831 with the -1.1H NMR (250 MHz, DMSO-d6) δ 3.83 (s, 3H), 5.62 (br s, 2H), 6.78 (d, J=8.5 Hz, 1H), 6.95 (s, 1H), 7.02 (dd, J=8.8, 2.1 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.79-7.92 (m, 4H), 7.96 (s, 1H), 10.36 (s, 1H).

4-dimethylamino-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-31

Received in accordance with section description Amination using cyanoborohydride sodium (71 mg, 1.13 mmol), 4-amino-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (100 mg, 0,226 mmol) and paraformaldehyde (68 mg, of 2.26 mmol) in Asón (3 ml) to give the title compound (54 mg, 51%) as a colourless solid after processing and flash chromatography (20:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.91 (s, 6H), 3.89 (s, 3H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.91-7.96 (m, 3H), 8.04 (d, J=8.8 Hz, 2H), 8.10 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 44.44, 55.84, 104.20, 115.66, 120.26, 120.41, 121.51 (q, JCF=30.3 Hz), 123.50, 124.08 (q, JCF=273.4 Hz), 126.37, 127.74 (q, JCF=5.9 Hz), 128.11, 129.77, 131.22, 136.33, 140.05, 148.61, 155.33, 157.72, 164.40, 164.97.

4-dimethylamino-2-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-159

Received in accordance with section description Amination using cyanoborohydride sodium (66 mg, 1.05 mmol), 4-amino-2-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (100 mg, 0,226 the mol) and paraformaldehyde (63 mg, 2,11 mmol) in Asón (3 ml) to give the title compound (39 mg, 37%) as a colourless solid after processing and flash chromatography (20:1 DHM/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.97 (s, 6N), 3.80 (s, 3H), 6.93-6.95 (m, 2H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H), 10.57 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 40.24, 56.25, 105.49, 109.20 (q, JCF=5.4 Hz), 114.41, 116.18, 120.25, 122.91, 123.60, 124.45 (q, JCF=274 Hz), 127.99, 128.07 (q, JCF=30.4 Hz), 128.58, 130.59, 136.32, 142.29, 148.63, 151.35, 157.89, 164.87, 166.74.

4-(2,2,2-triptoreline)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-25

A mixture of 4-(2,2,2-triptoreline)benzoic acid (0,30 g, 1.35 mmol) and thionyl chloride (0.32 g, of 2.72 mmol) in chloroform (5 ml) was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.34 g, 1.35 mmol) in dry pyridine (15 ml) to give the title compound (0.56 g, 91%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.82 (q, J=9.0 Hz, 2H), 7.06 (dd, J=9.0, 2.7 is C, 1H), 7.16 (d, J=9.0 Hz, 2H), 7.63 (d, J=2.7 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.91 (dist (d, J=9.0 Hz, 2H), 7.94-7.98 (m, 4H), 10.38 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 56.38 (q, JCF=8 Hz), 65.21 (q, JCF=34 Hz), 105.50 (q, JCF=6 Hz), 115.19, 116.45, 121.12, 123.82, 124.55 (q, JCF=278 Hz), 128.09, 128.74, 128.81, 130.50 (q, JCF=6 Hz), 136.46, 142.32, 148.69, 158.00, 160.19, 165.10, 165.63.

4-(3,3,3-cryptocracy)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-39

A mixture of 4-(3,3,3-cryptocracy)benzoic acid (0.32 g, of 1.39 mmol) and thionyl chloride (0.33 g, 2,78 mmol) in chloroform (5 ml) was boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.36 g, of 1.39 mmol) in dry pyridine (10 ml) to give the title compound (0,59 g, 90%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 2.74-2.83 (m, 2H), 3.80 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 7.07 (dd, J=9.0, 2.7 Hz, 1H), 7.65 (d, J=2.7 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.92-7.99 (m, 6H), 10.33 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 33.40 (q, JCF=27 Hz), 56.40, 61.85, 105.56, 114.85, 116.44, 121.85, 123.79, 127.34 (q, JCF=277 Hz), 127.78, 128.09, 128.65, 130.47, 136.48,142.48, 148.75, 158.01, 161.34, 165.07, 165.70.

4-(4,4,4-triptoreline)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-169

A mixture of 4-(4,4,4-triptoreline)benzoic acid (0.20 g, 0,806 mmol) and thionyl chloride (0,42 g, 3.54 mmol) in chloroform (5 ml) was boiled under reflux for 8 hours. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0,206 g, 0,806 mmol) in dry pyridine (10 ml) to give the title compound (0,343 g, 87%) as a colourless solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 1.89-1.96 (m, 2H), 2.33-2.45 (m, 2H), 3.80 (s, 3H), 4.09 (t, J=6.1 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 7.07 (dd, J=9.1, 2.4 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.94 (d, J=9.1 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 10.30 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 22.03 (q, JCF=6.3 Hz), 29.97 (q, JCF=28.05 Hz), 56.24, 66.60, 105.46, 114.66, 116.16, 120.86, 123.58, 127.38, 127.85, 128.05 (q, JCF=276.4 Hz), 128.51, 130.21. 136.32, 142.32, 148.63, 157.86, 161.63, 164.89, 165.54.

Monoglucuronide methoxyamine

4-fluoro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-135

A mixture of 4-torbe what sainoi acid (0.20 g, of 1.43 mmol) and thionyl chloride (0,93 g, 7,81 mmol) in chloroform (5 ml) was boiled under reflux for 3.5 hours. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.36 g, 1,43 mmol) in dry pyridine (15 ml) to give the title compound (0.26 g, 48%) as colorless needle-like particles after recrystallization from EtOAc.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.12 (dd, J=2.1, 8.8 Hz, 1H), 7.40 (t, JCF=8.8 Hz, 2H), 7.70 (d, J=2.1 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 8.00-8.10 (m, 2H), 10.55 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.22, 103.89, 114.73 (d, JCF=21.5 Hz), 115.16, 120.01, 122.68, 126.93, 128.10, 130.03 (d, JCF=8.8 Hz), 130.67 (d, JCF=2.9 Hz), 135.53, 141.16, 147.86, 156.99, 163.97 (d, JCF=251 Hz), 164.06, 164.38.

6-fluoro-N-(4-[6-methoxy-1,3-benzothiazol-2-yl]phenyl)pyridine-3-carboxamide

no connection SKT04-137

A mixture of 6-fornicating acid (0.125 g, 0,647 mmol) and thionyl chloride (3 ml) was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature and the excess reagent were removed under reduced pressure to get neocide the aqueous acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0,166 g, 0,647 mmol) in dry THF (5 ml)containing diisopropylethylamine (0.10 g, 0,776 mmol), to obtain the title compound (of € 0.195 g, 79%) as colorless crystals after treatment and recrystallization from dioxane.

1H NMR (400 MHz, DMSO-d6) δ 3.80, s, 3H), 7.07 (dd, J=8.9, 2.7 Hz, 1H), 7.34 (dd, J=8.5, 2.0 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.91 (dd, J=8.9, 2.0 Hz, 2H), 8.01 (dd, J=8.9, 2.0 Hz, 2H), 8.47 (dt, J=8.5, 2.7 Hz, 1H), 8.79 (d, J=2.7 Hz, 1H), 10.67 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 56.40, 105.52, 110.22 (d, JCF=37 Hz), 116.51, 121.14, 123.85, 128.20, 129.20, 129.77 (d, JCF=3.8 Hz), 136.51, 141.79, 142.72 (d, JCF=9.2 Hz), 148.58 (d, JCF=16.8 Hz), 148.69, 158.04, 163.79, 164.90, 165.04 (d, JCF=241 Hz).

6-chloro-N-(4-[6-methoxy-1,3-benzothiazol-2-yl]phenyl)pyridine-3-carboxamide

no connection SKT04-111

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.75 g, with 2.93 mmol) and 6-chloronicotinamide (0,515 g of 2.93 mmol) in dry THF (20 ml)containing diisopropylethylamine (0.45 g, to 3.52 mmol) to give the title compound (0,784 g, 68%) in the form of small colorless crystals after treatment and recrystallization from dioxane.

1H NMR (250 MHz, DMSO-d6) δ 3.73 (s, 3H), 6.93 (dd, J=8.8, 2.4 is C, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.25 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 2H), 8.13 (dd, J=8.2, 2.4 Hz, 1H), 8.77, (d, J=1.8 Hz, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) 55.22 5, 103.86, 115.21, 120.16, 122.76, 123.53, 127.00, 128.55, 129.14, 135.58, 138.39, 140.63, 147.86, 148.97, 153.08, 157.05, 162.68, 163.95.

6-bromo-N-(4-[6-methoxy-1,3-benzothiazol-2-yl]phenyl)pyridine-3-carboxamide

no connection SKT05-63

To a solution of 6-bromonicotinic acid (0.16 g, 0.78 mmol) in dry THF (5 ml) in an argon atmosphere was added 1,1'-carbonyldiimidazole made (0.13 g, 0.78 mmol) and the reaction mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.2 g, 0.78 mmol) for 2 minutes, stirring continued at room temperature for 1 hour, then boiled under reflux for 18 hours. After cooling to room temperature the reaction mixture was diluted with Et2O (30 ml) and the precipitate was collected by filtration, washed Et2O (50 ml) and dried in high vacuum to obtain the title compound (0,101 g, 29%) as an orange solid.

1H NMR (250 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.14 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 8.28 (d, J=8.2 Hz, 1H), 8.96 (s, 1H), 10.78 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.17, 103.91, 115.18, 120.07, 122.69, 126.95, 127.2, 128.44, 129.42, 135.50, 138.02, 140.60, 144.14, 147.79, 149.31, 156.98, 162.71, 163.81.

Applicable conditions of the reaction based on the methods described in the work of Bocelli with co-authors (Boschelli et al.), link 6-bromonicotinic acid N-methylpiperazine using the OED.

4-fluoro-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-99

A mixture of 4-fluoro-3-nitrobenzoic acid (0.36 g, of 1.95 mmol) and thionyl chloride (0,93 g, 7,81 mmol) in chloroform (5 ml) was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature and remove excess reagents and solvent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride, 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.50 g, of 1.95 mmol) in base Hunya (0.28 g, of 2.15 mmol) in dry THF (20 ml) to give the title compound (0,49 g, 59%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 7.06 (dd, J=8.9, 2.7 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.73 (dd, J=11.3, 8.9 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.91 (d, J=8.9 Hz, 2H), 7.99 (d, J=8.9 Hz, 2H), 8.36 (m, 1H), 8.72 (dd, J=7.5, 2.4 Hz, 1H), 10.72 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 56.38, 105.52, 116.48, 119.54 (d, JCF=21 Hz), at 121.30, 123.84, 126.53, 128.16, 129.33, 132.02 (d, JCF=3.8 Hz), 136.42, 136.53, 137.31 (d, JCF =8 Hz), 141.69, 148.72, 157.13 (d, JCF=267 Hz), 158.06, 163.27, 164.87.

N-[4-(1,3-benzothiazol-2-yl)-3-methoxyphenyl]-4-fluoro-3-nitrobenzamide

no connection SKT04-127

A mixture of 4-fluoro-3-nitrobenzoic acid (0,062 g, 0,336 mmol) and thionyl chloride (5 ml) was boiled under reflux for 2 hours. The reaction mixture was cooled to room temperature and removed the excess reagent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride, 2-(4-amino-2-methoxyphenyl)benzothiazole (0,086 g, 0,336 mmol) and substrate Hunya (0,052 g, 0,403 mmol) in dry THF (5 ml) to give the title compound (0,105 g, 74%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 4.02 (s, 3H), 7.34-7.38 (m, 1H), 7.45-7.49 (m, 1H), 7.58 (dd, J=8.8, 1.9 Hz, 1H), 7.73-7.78 (m, 2H), 9.97 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 8.36-8.39 (m, 1H), 8.89 (d, J=8.8 Hz, 1H), 8.74 (dd, J=7.1, 2.2 Hz, 1H), 10.77 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 61.14, 108.85, 117.97. 122.11, 124.08 (d, JCF=19.4 Hz), 126.89 (d, JCF=10.9 Hz), 127.32 (d, JCF=8.5 Hz), 129.80 is awaited, 131.03, 131.35, 134.28, 136.44 (d, JCF=3.9 Hz), 140.29, 141.05, 141.82 (d, JCF=7.8 Hz), 147.69, 156.79, 161.72 (d, JCF=267 Hz), 162.43, 167.07, 167.86.

N-[4-(1,3-benzothiazol-2-yl)-3-[2-{2-(2-methoxyethoxy)ethoxy}ethoxy]phenyl]-4-fluoro-3-nitrobenzamide

no connection SKT04-143

A mixture of 4-fluoro-3-nitrobenzoic acid (0,048 g, 0,257 mmol) and thionyl chloride (2 ml) was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature and removed the excess reagent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with the description above section Amide linking using the crude acid chloride, 4-(1,3-benzothiazol-2-yl)-3-[2- {2-(2-methoxyethoxy)ethoxy} ethoxy] aniline (0.10 g, 0,257 mmol) and substrate Hunya (0,040 g, 0,308 mmol) in dry THF (5 ml) to give the title compound (0,140 g, 98%) as a yellow solid after processing and flash chromatography (EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 3.22 (s, 3H), 3.41-3.43 (m, 2H), 3.54-3.57 (m, 2H), 3.62-3.64 (m, 2H), 3.73-3.76 (m, 2H), 4.04-4.06 (m, 2H), 4.42-4.44 (m, 2H), 7.45 (dt, J=7.0, 1.2 Hz, 1H), 7.55 (dt, J=7.0, 1.2 Hz, 1H), 7.64 (dd, J=8.6, 1.9 Hz, 1H), 7.82 (dd, J=10.9, 9.0 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.44-8.48 (m, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.82 (dd, J=7.0, 2.3 Hz, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 58.44, 68.87, 69.15, 70.07, 70.35, 70.48, 71.69, 104.85, 113.38, 117.62, 119.39 (d, JCF=21 Hz), 122.05, 122.59, 125.07, 126.28, 126.58, 129.63, 131.72 (d, JCF=3.9 Hz), 135.76, 136.26 (d, JCF=10 Hz), 137.10 (d, JCF=7.7 Hz), 142.82, 152.02, 156.93, 156.98 (d, JCF=267 Hz), 162.49, 163.14.

4-chloro-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-93

Obtained in compliance and with the description section Amide linking using 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.50 g, 1,95 mmol), 4-chloro-3-nitrobenzotrifluoride (0,43 g of 1.95 mmol) and substrate Hunya (0.28 g, of 2.15 mmol) in dry THF (20 ml) to give the title compound (0,83 g, 97%) as a yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 7.07 (dd, J=8.8, 2.7 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 2H), 8.00, dd, J=8.8, 1.9 Hz, 2H), 8.25 (dd, J=8.5, 1.9 Hz, 1H), at 8.62 (d, J=1.9 Hz, 1H), 10.81 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.14, 103.92, 115.21, 120.13, 122.57, 124.50, 126.90, 128.28, 131.34, 132.44, 133.98, 135.38, 140.57, 146.87, 147.47, 156.96, 161.95, 163.84 (1 missing).

4-bromo-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT04-33

A mixture of 4-bromo-3-nitrobenzoic acid (0.24 g, 0,976 mmol) and thionyl chloride (5 ml) was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature and remove excess reagents and solvent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride, 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.25 g, 0,976 mmol) and substrate Hunya (0,151 g at 1.17 mmol) in dry THF (10 ml) to give the title compound (0,368 g, 78%) as small yellow crystals after treatment and recrystallization from DMF.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.1 (dd, J=8.8, 2.4 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 8.18 (dd, J=8.5, 1.8 Hz, 1H), 8.61 (d, J=1.5 Hz, 1H), 10.80 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.39, 103.89, 115.32, 117.01, 120.44, 122.91, 124.53, 127.18, 128.92, 132.46, 134.71, 134.85, 135.77, 140.58, 148.03, 149.15, 157.24, 162.35, 164.24.

4-iodine-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT04-29

A mixture of 4-iodine-3-nitrobenzoic acid (0,286 g, 0,976 mmol) and thionyl chloride (5 ml) was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature and remove excess reagents and solvent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride, 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.25 g, 0,976 mmol) and substrate Hunya (0,151 g at 1.17 mmol) in dry THF (10 ml) to give the title compound (0,403 g, 78%) as a yellow solid after processing.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.94-7.99 (m, 3H), 8.05 (d, J=8.8 Hz, 2H), 8.32 (d, J=8.2 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 10.78 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ at 55.29, 91.17, 103.88, 115.26, 120.33, 122.82, 123.86, 127.06, 128.73, at 132.15, 135.35, 135.67, 140.58, 141.37, 147.94, 152.64, 157.13, 162.50, 164.06.

4-dimethylamino-3-nitro-N-[4-(6-methoxybenzoate the evils-2-yl)phenyl]benzamide

no connection SKT03-141

A mixture of 4-fluoro-3-nitro^-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.10 g, 0,237 mmol), dimethylamine hydrochloride (0,039 g, 0,474 mmol) and potassium carbonate (of 0.085 g, 0,616 mmol) in DMSO (4 ml) and water (1 ml) was stirred and boiled under reflux for 3 days. The reaction mixture was cooled to room temperature and added water (10 ml), the precipitate was collected by filtration. Purification using flash chromatography (2:1 EtOAc/hexane) yielded the title compound (0,029 g, 27%) as an orange solid.

1H NMR (400 MHz, DMSO-d6) δ 2.94 (s, 6N), 3.85 (s, 3H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 7.27 (d, 7=9.1 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H),.7.96 (d, J=8.2 Hz, 2H), 8.04 (d, J=8.2 Hz, 2H), 8.10 (dd, J=9.1, 2.1 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H), 10.46 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 41.68, 55.31, 103.86, 115.19, 116.56, 120.12, 121.93, at 122.77, 126.50, 127.03, 128.13, 132.44, 135.66, 136.31, 141.29, 147.15, 148.00, 157.09, 163.47, 164.34.

Applicable conditions of the reaction based on the methods described in the work Ermert with co-authors (Ermert et al.), enable dimethylaminopropyl the result of nucleophilic substitution in DMSO.

3,4-dinitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-137

A mixture of 3,4-dinitrobenzoic acid (0.21 g, 0,976 mmol) and thionyl chloride (1 ml) in chloroform (5 ml) was boiled with bratim refrigerator for 4 hours. The reaction mixture was cooled to room temperature and remove excess reagents and solvent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride, 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.25 g, 0,976 mmol) in dry THF (20 ml)containing diisopropylethylamine (0.14 g, 1.07 mmol), to obtain the title compound (0,334 g, 76%) as an orange solid after processing and flash chromatography (EtOAc, then 1:1 EtOAc/MeOH).

1H NMR (250 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.13 (dd, J=8.8, 2.1 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 2H), 8.09 (d. J=8.5 Hz, 2H), 8.43 (d, J=8.5 Hz, 1H), 8.54 (d, J=7.9 Hz, 1H), 8.79 (s, 1H), 11.08 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.18, 103.88, 115.21, 120.32, 122.74, 124.45, 125.21, 126.96. 128.83, 133.42, 135.55, 139.06, 140.25, 141.50, 143.19, 147.79, 157.02, 161.18, 163.75.

4-(2-floratone)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-75

A mixture of 4-(2-floratone)benzoic acid (0.20 g, 1.11 mmol) and thionyl chloride (0,53 g of 4.44 mmol) in chloroform (5 ml) was boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature and remove excess reagents and solvent under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with OPI what W section Amide linking using the crude acid chloride, 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.28 g, 1.11 mmol) in dry pyridine (10 ml) to give the title compound (0.34 g, 72%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 4.29 (dist d of t, JHF=30 Hz, JHH=3.7 Hz, 2H), 4.73 (dist d of t, JHF=48 Hz, JHH=3.7 Hz, 2H), 7.06 (m, 3H), 7.65 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.91-7.98 (m, 6H), 10.33 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 56.40, 67.97 (d, JCF=19 Hz), 82.70 (d, JCF=167 Hz), 105.56, 114.86, 116.44, 121.04, 123.79, 127.63, 128.09, 128.64, 130.47, 136.47, 142.48, 148.73, 158.01, 161.65, 165.08, 165.75; MCHP (ESI-) 421 (M+-H, 100%).

4-(2-hydroxyethoxy)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-33

A mixture of 4-hydroxy-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.20 g, of 0.53 mmol), chloroethanol (0,064 g, 0.80 mmol) and potassium carbonate (0.26 g, of 1.86 mmol) was heated at 100°C in dry DMF (10 ml) for 18 hours. After cooling to room temperature, added water (30 ml) and the reaction mixture was extracted with EtOAc (7×40 ml). The combined organic extracts were washed brine (80 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to obtain the title compound (0.17 g, 76%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ 3.70 (q, J=4.8 Hz, 2H), 3.80 (s, 3H), 4.03 (t, J=4.8 Hz, 2H), 4.87 (t, J=5.1 Hz, 1H), 7.03 (d, J=8.9 Hz, 2H), 7.07 (dd, J=2., 8.9 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.93-7.98 (m, 6H), 10.33 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 56.40. 60.11, 70.48, 105.56, 114.78, 116.42, 121.00, 123.78, 127.18, 128.06. 128.59, 130.43, 136.47, 142.56, 148.75, 158.00, 162.25, 165.09, 165.79.

Applicable conditions of the reaction based on the methods described by Zhang and co-authors (Zhang et al.), the reaction of phenolic compounds with chlorinated alcohols.

4-dimethylamino-N-[4-(6-(2-hydroxyethoxy)benzothiazol-2-yl)phenyl]benzamide

no connection SKT03-19

A mixture of 4-dimethylamino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide (0.20 g, 0.51 mmol), chloroethanol (0.05 g, of 0.62 mmol) and potassium carbonate (0,23 g, and 1.63 mmol) was heated at 100°C in dry DMF (10 ml) for 18 hours. After cooling to room temperature, added water (30 ml) and the reaction mixture was extracted with EtOAc (7×40 ml). The combined organic extracts were washed brine (80 ml) and dried (Na2SO4). Removed solvent under reduced pressure to obtain the title compound (0,117 g, 53%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 2.96 (s, 6N), 3.71 (m, 2H), 4.03 (m, 2H), 4.86 (br s, 1H), 6.72 (d, J=9.2 Hz, 2H), 7.07 (dd, J=8.9, 2.4 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.85 (d, J=9.2 Hz, 3H), 7.93 (m, 4H), 10.08 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 39.50, 59.55, 69.79, 104.70, 110.21, 115.58, 119.77, 120.55, 122.60, 126.89, 127.40, 128.98, 135.44, 141.85, 147.88, 152.04, 156.39, 164.32, 165.39.

Primenews the growing conditions of the reaction-based methods, described by Zhang and co-authors (Zhang et al.), the reaction of phenolic compounds with chlorinated alcohols.

4-fluoro-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT05-37

A mixture of 4-fluoro-6-triftorperasin acid (0.32 g, 1.56 mmol) and thionyl chloride (5 ml) was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature and the excess reagent were removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 2-(4-AMINOPHENYL)-6-methoxybenzothiazole (0.40 g, 1.56 mmol) in dry pyridine (12 ml) to give the title compound (0,502 g, 72%) as a colorless solid after recrystallization of the Asón.

1H NMR (250 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (s, 1H), 7.72 (m, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 8.03 (d, J=8.5 Hz, 2H), 8.38 (d, J=6.1 Hz, 1H), 8.30-8.43 (m, 1H), 10.71 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ at 56.22, 105.42, 116.21, 117.13 (d of q, JCF=32.7, 13.3 Hz), 117.99 (d, JCF=21.0 Hz), 121.14, 122.84 (q, JCF=272.5 Hz), 123.63, 127.54 (d of q, JCF=4.6, 1.5 Hz), 127.92, 129.14, 131.97 (d, JCF=3.8 Hz), 135.58 (d, JCF=10.1 Hz), 136.37, 141.60, 148.61, 157.92, 161.19 (d of q, JCF=258.5, 1.6 Hz), 163.74, 164.71.

The non-fluorinated hydroxyamide

2-amino-N-[4-(6-hydro is dibenzothiazyl-2-yl)phenyl]benzamide

no connection SKT01-101

Obtained in accordance with the description section Demeterova using 2-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (50 mg, 0.13 mmol) in dry DHM (3 ml) and BBr3(1.0m solution in DHM, of 0.67 ml, 0.67 mmol) to give the title compound (31 mg, 64%) as a colourless solid after processing and flash chromatography (6:1 Et2O/hexane).

1H NMR (400 MHz, DMSO-d6) δ 6.42 (br s, 2H), 6.65 (t, J=7.5 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 7.03 (dd, J=8.6, 1.2 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H), 8.03 (d, J=8.6 Hz, 2H), 9.89 (s, 1H), 10.30 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 107.25, 115.16, 115.31, 116.46, 116.91, 120.96, 123.65, 127.69, 128.50, 129.29, 132.85, 136.26, 142.13, 147.69, 150.38, 156.04. 163.75, 168.48.

3-amino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-77

Received in accordance with section description Demethylation using 3-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (50 mg, 0.13 mmol) in dry DHM (3 ml) and BBr3(1.0m solution in DHM, of 0.67 ml, 0.67 mmol) to give the title compound (29 mg, 60%) as light brown solid after processing and flash chromatography (1:1 hexane/EtOAc, then EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 5.37 (s, 2H), 6.77 (d, J=7.3 Hz, 1H), 6.98 (dd, J=8.5, 2.1 Hz, 1H), 7.07-7.20 (m, 3H), 7.40 (d, J=2.1 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.93-8.0 (m, 4H), 9.92 (s, 1H), 10.37 (s, 1H);13With NMR (62.5 MHz, DMSO-d6) δ 106.80, 112.92, 114.87, 116.04, 117.19, 135.65, 123.21, 147.20, 155.60, 128.88, 163.35, 166.72, 141.71, 147.20, 148.85, 155.60, 163.35, 166.72

4-amino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-57

Received in accordance with section description Demethylation using 4-amino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (50 mg, 0.13 mmol) in dry DHM (3 ml) and BBr3(1.0m solution in DHM, of 0.67 ml, 0.67 mmol) to give the title compound (27 mg, 56%) as a brown solid after processing and flash chromatography (1:1 hexane/EtOAc, then EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 5.84 (s, 2H), 6.62 (d, J=8.5 Hz, 2H), 6.98 (dd, J=1.5, 8.8 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.8 Hz, 1H), 7.95 (br s, 4H), 9,90 (vbr s, 1H), 10.05 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 106.17, 112.65, 115.54, 119.82, 121.00, 122.60, 126.79, 127.48, 129.15, 135.38, 141.64, 146.88, 151.51, 155.11, 163.30, 165.56.

2-dimethylamino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT01-111

Received in accordance with section description Demethylation using 2-dimethylamino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (40 mg, 0.09 mmol) in dry DHM (3 ml) and BBr3(1.0m solution in DHM, 0.5 ml, 0.5 mmol) to obtain the title compound (23 mg, 59%) as a colourless solid after processing and flash chrome is adopted (4:1 DHM/EtOAc, then EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 2.82 (s, 6N), 6.93 (d, J=8.5 Hz, 1H), 7.11 (m, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.28 (s, 1H), 7.44 (m, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.78-7.85 (m, 3H), 7.85-7.95 (m, 2H), 9.69 (s, 1H), 11.81 (s, 1H);13With NMR (100.5 MHz, CDCl3/DMSO-d6) δ 44.88, 107.08, 116.46, 119.91, 120.32, 123.21, 123.58, 127.73, 127.98, 129.00, 130.88, 132.48, 136.35, 141.74, 147.85, 152.12, 156.14, 163.74, 165.87.

4-dimethylamino-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-177

Received in accordance with section description Demethylation using 4-dimethylamino-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.50 g, 1,24 mmol) in dry DHM (50 ml) and BBr3(1.0m solution in DHM, 6.2 ml, 6.2 mmol) to give the title compound (0.45 g, 93%) as a yellow solid after processing and flash chromatography (4:1 DHM/EtOAc, then EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 3.00 (s, 6N). 6.75 (d, J=8.5 Hz, 2H), 7.00 (d, J=9.1 Hz, 1H), 7.43 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.92-8.02 (m, 5H), 10.07 (s, 1H), 10.24 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 40.59, 107.23, 111.20, 116.50, 120.68, 121.07, 123.51, 127.61, 128.10, 129.87, 136.11, 142.63, 147.57, 152.98, 156.21, 163.68, 165.85

Fluorinated hydroxyamide

4-nitro-3-trifluoromethyl-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-7

Received in accordance with section description Demethylation using 4-nitro-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.10 g, 0.2 mmol) in dry DHM (10 ml) and BBr 3(1.0m solution in DHM, 1.1 ml, 1.1 mmol) to give the title compound (0.07 g, 71%) as a yellow solid after processing and flash chromatography (3:1 EtOAc/hexane).

1H NMR (400 MHz, DMSO-d6) δ 6.93 (dd, J=8.5, 2.4 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.91 (dd, J=8.9, 2.0 Hz, 2H), 8.00 (dd, J=8.9, 2.0 Hz, 2H), 8.30 (d, J=8.2 Hz, 1H), 8.44 (dd, J=8.2, 1.7 Hz, 1H), 8.48 (s, 1H), 9.82 (s, 1H), 10.86 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 107.46, 116.74, 121.20, 121.35, 122.01 (q, J=33 Hz), 123.92, 126.44, 128.09, 129.69, 134.65, 136.52, 139.39, 141.32, 147.82, 149.38, 156.33, 163.41, 163.66 (1 missing).

4-amino-3-trifluoromethyl-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-45

Received in accordance with section description Demethylation using 4-amino-3-trifluoromethyl-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0,30 g of 0.68 mmol) in dry DHM (10 ml) and BBr3(1.0m solution in DHM, 5,42 ml, 5,42 mmol) to give the title compound (0,064 g, 22%) as an orange solid after processing and flash chromatography (3:1 DHM/EtOAc).

X 3610-2880 (br), 3378. 3259, 1650, 1611, 1525, 1502, 1486, 1456, 1439, 1406, 1318, 1277, 1243, 1181, 1144, 1110, 1051, 974, 907, 832 cm-1;1H NMR (250 MHz, acetone-d6) δ 5.85 (s, 2H), 7.02 (d, J=8.8 Hz, 1H), 7.07 (dd, J=8.8, 2.1 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.98-8.08 (m, 5H), 8.16 (s, 1H), 8.81 (br s, 1H). 9.71 (s, 1H).

4-(2,2,2-triptoreline)-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-149

Received in accordance with section description Demethylation using 4-(2,2,2-triptoreline)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.20 g, 0,437 mmol) in dry DHM (15 ml) and BBr3(1.0m solution in DHM, 2,18 ml of 2.18 mmol) to give the title compound (0,174 g, 89%) as a colourless solid after processing and flash chromatography (3:1 EtOAc/hexane).

1H NMR (250 MHz, DMSO-d6) δ 4.90 (q, J=8.8 Hz, 2H), 6.98 (dd, J=8.8, 2.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.40 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.95-8.04 (m, 6H), 9.86 (s, 1H), 10.42 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 64.81 (q, JCF=35 Hz), 106.24, 113.94, 115.63, 120.10, 122.74, 123.07 (q, JCF=278 Hz), 126.95, 128.30, 128.36, 129.62, 135.63, 141.19, 147.12, 155.28, 159.27, 163.28, 164.90.

4-(3,3,3-cryptocracy)-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-41

Received in accordance with section description Demethylation using 4-(3,3,3-cryptocracy)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0,30 g to 0.63 mmol) in dry DHM (30 ml) and BBr3(1.0m solution in DHM, 3.2 ml, 3.2 mmol) to give the title compound (0,103 g, 35%) as a pale orange solid after processing and flash chromatography (20:1 DHM/Meon).

1H NMR (400 MHz, DMSO-d6) δ 2.74-2.83 (m, 2H), 4.26 (t, J=5.8 Hz, 2H), 6.93 (dd, J=8.8, 2.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 7.35 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.91-7.97 (m, 6H), 9.81 (s, 1H), 10.33 (s, 1H);13The NMR (62.5 MHz, CDCl3/DMSO-d6) δ 33.22 (q, JCF=28 Hz), 60.67 (q, JCF=3.9 Hz), 106.27, 113.61, 115.63, 120.10, 122.76, 125.73 (q, JCF=276 Hz), 126.96, 127.31, 128.27, 129.54, 135.64, 141.26, 147.16, 155.28, 160.36, 163.34, 165.14.

4-(4,4,4-triptoreline)-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-171

Received in accordance with section description Demethylation using 4-(4,4,4-triptoreline)-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.10 g, 0,206 mmol) in dry DHM (10 ml) and BBr3(1.0m solution in DHM, 1.0 ml, 1.0 mmol) to obtain the title compound (17 mg, 17%) as a yellow solid after processing, flash chromatography (3:1 EtOAc/hexane) and recrystallization from EtOAc.

1H NMR (250 MHz, DMSO-d6) δ 1.94-2.01 (m, 2H), 2.40-2.55 (m, 2H), 4.13 (t, J=5.5 Hz, 2H), 6.97 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.91-8.05 (m, 6N), 9.84 (s, 1H), 10.35 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 22.01 (q, JCF=3.1 Hz), 29.95 (q, JCF=28.0 Hz), 66.60, 107.24, 114.69 last, 116.53, 120.94, 123.64, 127.34, 127.73, 128.04 (q, JCF=276 Hz), 128.68, 130.20, 136.27, 142.06, 147.70, 156.03, 161.63, 163.79, 165.63.

2-hydroxy-N-[3-hydroxy-4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]-5-(triptoreline)benzamid

no connection SKT05-39

Received in accordance with section description Demethylation using 2-methoxy-N-[3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-5-(triptoreline)benzamide (0,30 g, 0.59 mmol) in dry DHM (12 ml) and BBr 3(1.0m solution in DHM, 1.9 ml, 1.9 mmol) at -78°C in argon atmosphere. Dropwise addition was added BBr3(1.0m solution in DHM, 1.9 ml, 1.9 mmol) and the reaction mixture was stirred at room temperature for 4 days to obtain the title compound (88 mg, 32%) as a pale yellow solid connection after processing and flash chromatography (4,2:0,3 hexane/EtOAc/MeOH).

1H NMR (400 MHz, DMSO-d6) δ 6.98 (dd, J=9.0, 2.3 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 7.26 (dd, J=8.6, 0.9 Hz, 1H), 7.39 (d, J=2.3 Hz, 1H), 7.43 (dd, J=9.0, 2.3 Hz, 1H), 7.62 (d, J=0.9 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 9.74 (s, 1H), 10.54 (s, 1H), 11.68 (s, 1H), 11.2-12.2 (br s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 106.96, 108.30, 112.56, 114.88, 116.55, 119.08, 120.39, 120.70 (q, JCF=255 Hz). 122.50, 122.91, 126.76, 129.05, 135.54, 140.87, 141.67, 145.45, 155.96, 156.69, 157.00, 162.73, 164.92.

4-fluoro-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT02-163

Received in accordance with section description Demethylation using 4-fluoro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (100 mg, 0.26 mmol) in dry DHM (10 ml) and BBr3(1.0m solution in DHM, 1.3 ml, 1.3 mmol) to give the title compound (96 mg, 99%) as a pale yellow solid after processing and flash chromatography (1:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 6.93 (dd, J=8.5, 2.4 Hz, 1H), 7.34 (t, J=8.8 Hz, 2H), 7.35 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H) 8.01 (dd, J=8.8, 5.5 Hz, 2H), 9.82 (s, 1H), 10.48 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 106.30, 114.86 (d, JCF=22.5 Hz). 115.69, 120.23, 122.80, 127.04, 128.56, 130.12 (d, JCF=8.8 Hz), 130.84 (d, JCF=1.9rn), 135.71, 141.03, 147.18, 155.33, 163.34, 164.21 (d, JCF=252 Hz), 164.74.

The title compound is presented in WO 2006/014382.

2-trifluoromethyl-N-[4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]-4-(hydroxy)benzamid

no connection SKT05-17

Received in accordance with section description Demethylation using 2-trifluoromethyl-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide (0,30 g, 0,655 mmol) in dry DHM (15 ml) and BBr3(1.0m solution in DHM, and 1.4 ml, 1.4 mmol) at -78°C in argon atmosphere. Stirring was continued at -78°C for 1 hour, then the reaction mixture was left to warm to room temperature overnight. Additionally added BBr3(1.0m in DHM, and 1.4 ml, 1.4 mmol) and the reaction mixture was stirred at room temperature for 24 hours to obtain the title compound (0,175 g, 62%) as a colourless solid after processing and flash chromatography (15:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 6.99 (dd, J=8.5, 2.1 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.17 (s, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 7.99 (d, J=8.5 Hz, 2H), 9.60-10.64 (vbr s, 2H), 10.70 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 106.16, 112.96 (q, JCF=3.9 Hz), 115.55, 117.77, 119.43, 122.1, 123.04 (q, JCF=274 Hz), 126.37, 126.93, 128.04 (q, JCF=32 Hz), 128.31, 129.99, 135.52, 140.98, 147.01, at 155.25, 158.48, 162.94, 165.78.

Synthesis of 2-hydroxy-N-[4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]-5-(triptoreline)benzamide

no connection SKT05-13

Received in accordance with section description Demethylation using 2-methoxy-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-5-(triptoreline)benzamide (0,30 g, 0,633 mmol) in dry DHM (15 ml) and BBr3(1.0m solution in DHM, and 1.4 ml, 1.4 mmol) at -78°C in argon atmosphere. Additionally added Vugs (1,Ω DHM, and 1.4 ml, 1.4 mmol) and the reaction mixture was stirred at room temperature for 24 hours to obtain the title compound (0,255 g, 90%) as a colourless solid after processing and flash chromatography (10:1 DHM/Meon).

1H NMR (400 MHz, DMSO-d6) δ 6.93 (dd, J=8.9, 2.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.39-7.42 (m, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.80 (m, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.97 (d, J=8.5 Hz, 2H), 9.83 (s, 1H), 10.58 (s, 1H), 11.35-12.08 (vbr s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 107.44, 116.73, 119.21, 120.65, 120.85 (q, JCF=256 Hz), 121.39, 122.79, 123.94, 127.10, 128.10, 129.50, 136.50, 140.92, 140.99, 147.82, 156.31, 156.87, 163.69, 165.09.

4-hydroxy-N-[4-(6-hydroxy-1,3-benzothiazol-2-yl)-3-(trifluoromethyl)phenyl]benzamide

no connection SKT04-179

Received in accordance with section description Demetriadou using N-[3-trifluoromethyl-4-(6-m is oxybisethanol-2-yl)phenyl]-4-(methoxy)benzamide (90 mg, 0,196 mmol) in dry DHM (5 ml) and BBr3(1.0m solution in DHM, 0,413 ml, 0,413 mmol) at -78°C To produce the title compound (68 mg, 81%) as a colourless solid after processing and flash chromatography (1:1 hexane/EtOAc).

1H NMR (250 MHz, CD3OD) δ 6.90 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.2 Hz, 2H), 8.11 (d, 7=8.2 Hz, 1H), 8.36 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 106.20, 115.32, 116.22, 118.31 (q, JCF=2.9 Hz), 122.54, 123.54 (q, JCF=274 Hz), 123.83. 125.41, 126.98, 128.87 (q, JCF=31 Hz), 129.87, 132.86, 137.44, 141.06, 147.06, 155.69, 161.01, 161.17, 166.43.

4-fluoro-3-nitro-N-[4-(6-hydroxybenzothiazole-2-yl)phenyl]benzamide

no connection SKT03-129

Received in accordance with section description Demethylation using 4-fluoro-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (0.10 g, 0.24 mmol) in dry DHM (10 ml) and BBr3(1.0m solution in DHM, 1.2 ml, 1.2 mmol) to obtain the title compound (0,062 g, 63%) as a colourless solid after processing and flash chromatography (2:1 hexane/EtOAc, then 2:1:0,1 EtOAc/hexane/Meon and final elution with 4:1 EtOAc/MeOH).

1H NMR (250 MHz, DMSO-d6) δ 6.99 (dd, J=8.8, 2.1 Hz, 1H), 7.42 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 8.04 (d, J=8.5 Hz, 2H), 8.40-8.45 (m, 1H), 8.79 (dd, JHH=1.2, JHF=7.0 Hz, 1H), 9.91 (s, 1H), 10.83 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 106.24, 115.68, 118.18 (d, JCFCF=3.9 Hz), 135.52 (d, JCF=11.7 Hz), 135.61, 136.36 (d, JCF=7.8 Hz), 140.43, 147.09, 155.33, 156.41 (JCF=269 Hz), 162.18, 162.97.

Nptribune of methylamide

N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide

no connection SK696-32

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methylbenzothiazole (1.0 g, 4,16 mmol) and benzoyl chloride (0,58 g of 4.16 mmol) in dry THF (10 ml)containing triethylamine (0,46 g, 4,58 mmol), to obtain the title compound (1.23 g, 86%) as a colourless solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.34 (dd, J=8.2, 1.2 Hz, 1H), 7.53-7.56 (m, 2H), 7.59-7.63 (m, 1H), 7.89-7.91 (m, 2H), 7.96-7.99 (m, 4H), 8.06 (d, J=9.0 Hz, 2H), 10.55 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 21.47, 120.95, 122.19, 122.65, 128.12, 128.21, 128.45, 128.64, 128.87, 132.21, 135.00, 135.19, 135.48, 142.38, 152.32, 166.29, 166.32.

2-nitro-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-51

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methylbenzothiazole (0,59 g, 2.45 mmol) and 2-nitrobenzotrifluoride (0.50 g, 2,69 mmol) in dry pyridine (10 ml) to give the title compound (0,94 g, 98%) as brown crystals after recrystallization from 1,2-dichloroethane.

1H NMR (250 MHz, DMSO-d6) δ 2.45 (s, MN), 7.34 (d, J=8.2 Hz, 1H, 7.75-7.93 (m, 7H), 8.08 (d, J=8.2 Hz, 2H), 8.18 (d, J=7.9 Hz, 1H), 10.99 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 21.15, 119.73, 121.11, 121.949, 123.83, 127.55, 128.98, 130.29, 132.76, 133.47, 134.48, 134.80, 141.08, 146.17, 151.68, 164.38, 165.80.

3-nitro-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-46

Received in accordance with section description Amide linking using 2-(4-AMINOPHENYL)-6-methylbenzothiazole (0.5 g, of 2.08 mmol) and 3-nitrobenzotrifluoride (0,77 g 4,06 mmol) in dry pyridine (10 ml) to give the title compound (0.75 g, 93%) after treatment and flash chromatography (2:1 hexane/EtOAc, then 1:1 hexane/EtOAc, then EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 2.43 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.80-7.84 (m, 2H), 7.88 (d, J=8.5 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 8.41-8.43 (m, 2H), 8.80 (s, 1H), at 10.82 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 21.1, 120.46, 121.09, 121.95, 122.46, 125.77, 127.38, 127.57, 128.73, 129.32, 134.49, 134.79, 136.00, 141.02, 147.60, 151.68, 163.31, 165.78.

4-nitro-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-67

Received in accordance with section description Amide linking with the use of 1,2-dichloroethane 2-(4-AMINOPHENYL)-6-methylbenzothiazole (2.5 g, 10.4 mmol) and 4-nitrobenzylamine (2,12 g of 11.4 mmol) in dry pyridine (30 ml) to give the title compound (4.0 g, 99%) as a small brown acicular particles after recrystallization from a mixture of DMF/in the A.

1H NMR (250 MHz, CDCl3/DMSO-d6) δ 1.79 (s, 3H), 6.59 (d, J=8.5 Hz, 1H), 7.04 (s, 1H), 7.15 (d,J=8.2 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 9.96 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 20.98, 120.27, 121.05, 121.86, 122.91, 127.27, 127.48, 128.59, 128.89, 134.35, 134.65, 140.04, 140.94, 148.92, 151.60, 163.65, 165.53.

For reference, see the work of Weisswange with co-authors (Weisswange et al.).

2-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-55

Received in accordance with section description restoration of the nitro group using 2-nitro-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.5 g, 1.28 mmol) and chloride dihydrate tin (II) (1.45 g, 6.42 per mmol) in EtOH (50 ml) to give the title compound (0,063 g, 14%) as a brown needle-like particles after recrystallization from EtOH.

1H NMR (250 MHz, DMSO-d6) δ 2.44 (s, 3H), 6.40 (s, 2H), 6.57-6.63 (m, 1H), 6.77 (d, J=8.2 Hz, 1H), 7.19-7.25 (m, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.89-7.92 (m, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.5 Hz, 2H), 10.30 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 21.40, 116.00, 116.22, 116.99, 120.46, 121.25, 122.17, 127.71 (×2), 128.55, 128.70, 132.40, 134.82, 134.94, 141.64, 148.98, 152.05, 166.49, 168.25.

3-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-72

Received in accordance with section description restoration of the nitro group using 3-nitro-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.3 g, 0.77 mmol) and chloride dihydrate tin (II) (1.39 g, 6,16 mmol) in EtOH (25 ml) to give the title compound (0,131 g, 47%) as a pale yellow solid after flash chromatography (1:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.39 (s, MN), 5.31 (s, 2H), 6.72 (dd, J=7.9, 2.1 Hz, 1H), 7.03-7.07 (m, 2H), 7.08-7.12 (m, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.83-7.86 (m, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 10.37 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 20.96, 113.13, 115.38, 117.03, 119.85, 121.02, 121.76, 127.17, 127.41, 127.79, 128.42, 134.29, 134.51, 135.49, 141.78, 147.83, 151.62, 165.76, 166.53.

4-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection LS-T107

Received in accordance with section description restoration of the nitro group using 4-nitro-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.39 g, 1.0 mmol) and chloride dihydrate tin (II) (1.13 g, 5.00 mmol) in EtOH (20 ml) to give the title compound (0,30 g, 83%) as a pale yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 2.44 (s, 3H), 5.85 (s, 2H), 6.61 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.80-7.92 (m, 2H), 7.97 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.5 Hz, 2H), 10.07 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 20.98, 112.73, 119.73, 121.02, 121.48, 121.73, 127.17, 127.38, 129.23, 134.29, 134.45, 142.18, 151.33, 151.65, 165.58, 165.87 (1 missing).

2-dimethylamino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SKT01-5

Obtained in accordance with the description once who ate Amination using cyanoborohydride sodium (0.35 g, 5,55 mmol), 2-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.40 g, 1.11 mmol) and paraformaldehyde (0.34 g, 11,13 mmol) in Asón (10 ml) to give the title compound (0.312 g, 73%) as pale yellow crystals after recrystallization from EUN.

1H NMR (250 MHz, CDCl3) δ 2.49 (s, 3H), 2.86 (s, 6H), 7.25-7.35 (m, 3H), 7.48-7.55 (m, 1H), 7.67 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.2 Hz, 1H), 8.08 (d, J=8.5 Hz, 2H), 8.28 (dd, J=7.6, 1.5 Hz 1H), 12.58 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 21.60, 45.60, 120.01, 120.57, 121.39, 122.43, 125.35, 127.40, 127.93, 128.41, 129.01, 131.76, 132.76, 135.04, 135.19, 141.34, 152.18, 164.31, 166.74 (1 missing).

Applicable conditions of the reaction based on the methods described in the work It with co (Ono et al.), demetilirovania aniline compounds.

3-dimethylamino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-93

Received in accordance with section description Amination using cyanoborohydride sodium (0,44 g, 6.95 mmol), 3-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.50 g, of 1.39 mmol) and paraformaldehyde (0,42 g, a 13.9 mmol) in AcOH (8 ml) to give the title compound (0.15 g, 28%) as colorless solids processing and flash chromatography (2:1 hexane/EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.48 (s, 3H), 2.99 (s, 6H), 6.88 (dd, J=8.2, 2.1 Hz, 1H), 7.09 (d, J=7.3 Hz, 1H), 7.26 (m, 2H), 7.32 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H), 8.08 (s, 1H);13SAMR (62.5 MHz, CDCl3) δ 21.60, 40.54, 111.38, at 113.91, 115.82, 120.02, 121.41, 122.52, 127.94, 128.33, 129.45, 129.60, 135.13, 135.26, 135.55, 140.50, 150.75, 152.29, 166.45, 166.63.

Applicable conditions of the reaction based on the methods described in the work It with co (Ono et al.), demetilirovania aniline compounds.

4-dimethylamino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide

no connection SK2033-71

Received in accordance with section description Amination using cyanoborohydride sodium (0,44 g, 6.95 mmol), 3-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.50 g, of 1.39 mmol) and paraformaldehyde (0,42 g, a 13.9 mmol) in AcOH (8 ml) to give the title compound (0.04 g, 7%) as colorless solids processing and flash chromatography (3:1 hexane/EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 2.44 (s, 3H), 3.00 (s, 6H), 6.77 (d, J=7.9 Hz, 2H), 7.33 (d, J=8.2 Hz, 1H), 7.84-7.92 (m, 4H), 7.98 (dist (d, J=8.5 Hz, 2H), 8.03 (dist (d, J=8.5 Hz, 2H), 10.17 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 39.42, 110.04, 110.15, 119.64, 120.49, 120.99, 121.61, 127.03, 127.17, 127.31, 128.92, 129.06, 134.11, 134.31, 142.10, 151.50, 151.96, 165.22, 165.64.

Applicable conditions of the reaction based on the methods described in the work It with co (Ono et al.), demetilirovania aniline compounds. 3-hydroxy-N-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]benzamide

no connection SK696-54

To a stirred solution of 3-hydroxybenzoic acid 0,69 g, 5.0 mmol) in 1:1 THF/DHM (20 ml) was added thionyl chloride (0.65 g, 5.5 mmol) and a drop of DMF. The reaction mixture is boiled under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and the mixture is moved through the catheter in the mixed solution dihydrothiazine (1.20 g, 5.0 mmol) in THF (20 ml) at 0°C. the Mixture was stirred at 0°C for 2 hours, then left to warm to room temperature overnight. The yellow precipitate was collected by filtration under vacuum and washed THF and water (600 ml). The solid is dried at 80°C in an oven for 5 hours to obtain the title compound (0,59 g, 33%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.02 (dd, J=7.8, 1.6 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.35-7.37 (m, 2H), 7.42 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.6 Hz, 2H), 9.69 (br s, 1H), 10.38 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 21.47, 115.14, 118.77, 119.23, 120.90, 122.16, 122.64, 128.09, 128.43, 128.57, 129.89, 134.99, 135.46, 136.61, 142.42, 152.33, 157.89, 166.33 (1 missing).

3-(methylamino)-N-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]benzamide

no connection SK2033-94

To a stirred mixture of 3-amino-N-[4-(6-methylbenzothiazol-2-yl)phenyl]benzamide (0.50 g, of 1.39 mmol) and paraformaldehyde (0,059 g of 1.95 mmol) in Meon (15 ml) at 0°C dropwise added a solution of sodium methoxide in Meon (0,5M, 3,9 ml of 1.95 mmol). The reactions is nnow the mixture is then boiled under reflux for 1 hour. The reaction mixture was cooled to room temperature, was added sodium borohydride (of 0.081 g of 2.09 mmol) and kept boiling under reflux for 1 hour. The reaction mixture was cooled to 0°C and added 1M NaOH solution, then extracted DHM (3×70 ml). The combined organic extracts were dried (Na2SO4) and solvent removed under reduced pressure to obtain an almost colorless solid, which was purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0,096 g, 18%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 2.75 (d, J=5.2 Hz, 3H), 5.82 (q, J=5.1 Hz, 1H), 6.75 (dd, J=8.2, 2.0 Hz, 1H), 7.08 (m, 1H), 7.14 (d, J=7.4 Hz, 1H), 7.21-7.25 (m, 1H), 7.33 (dd, J=8.6, 1.6 Hz, 1H), 7.88 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.6 Hz, 2H), 10.31 (s, 1H);13C NMR (100 MHz, DMSO-d6) 21.47, 30.20, 111.07, 115.16, 115.47, 120.87, 122.19, 122.63, 128.09, 128.44, 129.27, 134.98, 135.46, 136.08, 142.56, 150.45, 152.33, 166.36, 167.100.

Imidazo[2,1-b][1,3]thiazole intermediate connection

2-methyl-6-(4-nitrophenyl)imidazo[2,1-b][1,3]thiazole

A mixture of 2-amino-5-methylthiazole (0.24 g, 2,11 mmol) and 2-bromo-4'-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (20 ml) was boiled under reflux for 16 hours. The reaction mixture is cooled and added sodium bicarbonate (200 mg, of 2.38 mmol) and heating was continued for 1 hour. After cooling the to room temperature the solvent was removed under reduced pressure and the residue was dissolved in DHM (75 ml) and washed with water (30 ml), saline solution (30 ml) and dried (Na2SO4). Removed solvent under reduced pressure and the residue was purified using flash chromatography (50:1 DHM/Meon) to obtain the title compound (0,143 g, 26%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 2.45 (s, 3H), 6.49 (s, 1H), 7.76 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 8.25 (d, J=8.5 Hz, 2H);13C NMR (100.5 MHz, DMSO-d6) δ 13.20, 108.67, 111.25, 124.54, 125.67, 128.65, 141.43, 144.53, 146.37, 150.06.

4-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)aniline

Received in accordance with section description restoration of the nitro group using 2-methyl-6-(4-nitrophenyl)imidazo[2.1-b][1,3]thiazole (0.10 g, 0,386 mmol) and chloride dihydrate tin (II) (0,69 g, to 3.09 mmol) in EUN (15 ml) to give a light orange solid (66 mg, 75%) after treatment and flash chromatography (1:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.39 (s, 3H), 3.44 (br s, 2H), 6.70 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 7.47 (s, 1H), 7.59 (d, J=8.5 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 14.09, 106.20, 115.15, 115.30, 125.04, 125.80, 126.25, 145.69, 146.98, 149.29.

3-methyl-6-(4-nitrophenyl)imidazo[2,1-b][1,3]thiazole

A mixture of 2-amino-4-methylthiazole (0.24 g, 2,11 mmol) and 2-bromo-4'-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (20 ml) was boiled under reflux for 16 hours. The reaction mixture is cooled and added sodium bicarbonate (200 mg, of 2.38 mmol) and heating was continued in accordance with the s 1 hour. After cooling to room temperature the solvent was removed under reduced pressure and to the residue was added DHM. The insoluble substance was collected by filtration and purified using flash chromatography (50:1 DHM/Meon) to obtain the title compound (0,266 g, 50%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 2.40 (s, 3H), 7.72 (s, 1H), 8.02 (d, J=8.5 Hz, 2H), 8.21 (d, J=8.5 Hz, 2H), 8.37 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 14.07, 112.53, 117.16, 124.54, 125.60, is the 127.20, 141.38, 143.56, 146.29, 149.82

4-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)aniline

Received in accordance with section description restoration of the nitro group using 3-methyl-6-(4-nitrophenyl)imidazo[2,1-b][1,3]thiazole (0.20 g, 0,772 mmol) and chloride dihydrate tin (II) (0.87 g, 3,86 mmol) in EUN (20 ml) to give the title compound (88 mg, 50%) as a pale orange solid after processing and flash chromatography (1:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.39 (s, 3H), 3.69 (s, 2H), 6.70 (d, J=8.5 Hz, 2H), 7.07 (s, 1H), 7.46 (s, 1H), 7.59 (d, J=8.5 Hz, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 13.97, 107.10, 114.38, 117.08, 122.91, 124.78, 126.07, 146.98, 148.04, 148.22.

Imidazo[2,1-b][1,3]thiazole compounds

4-(dimethylamino)-N-[4-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]benzamide

no connection SKT05-149

Received in accordance with section description Amide linking prima is the group of 4-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)aniline (53 mg, 0,231 mmol) and 4-dimethylaminobenzaldehyde (42 mg, 0,231 mmol) in dry pyridine (4 ml) to give the title compound (76 mg, 87%)as a colourless solid after processing and flash chromatography (25:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.01(s, 6H), 6.78 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 7.81 (s, 4H), 7.89 (d, J=8.5 Hz, 2H), 8.21 (s, 1H), 9.94 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 13.31, 40.16, 107.21, 107.64, 111.22, 120.68, 121.53, 125.27, 128.59, 129.56, 129.65, 139.10, 146.74, 148.81, 152.82, 165.55.

4-(dimethylamino)-N-[4-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]benzamide

no connection SKT05-143

Received in accordance with section description Amide linking using 4-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)aniline (68 mg, 0,297 mmol) and 4-dimethylaminobenzaldehyde (55 mg, 0,297 mmol) in dry pyridine (5 ml) to give the title compound (74 mg, 66%)as a colourless solid after processing and flash chromatography (25:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.41 (s, 3H), 3.00 (s, 6H), 6.76 (d, J=8.8 Hz, 2H), 7.70 (s, 1H), 7.77 (m, 4H), 7.88 (d, J=8.8 Hz, 2H), 8.08 (s, 1H), 9.92 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 14.06, 40.17, 109.00, 111.22, 117.15, 120.66, 121.54, 125.17, 125.63, 129.56, 129.60, 139.00, 145.72, 148.55, 152.81, 165.54.

Imidazo[1,2-a]pyrimidine intermediate connection

The hydrobromide of 2-(4-nitrophenyl)imidazo[1,2-a]pyrimidine

A mixture of 2-aminopyrimidine (0.40 g, 4,22 mmol) and 2-b is ω-4'-nitroacetophenone (1,03 g, 4,22 mmol) in DMF (8 ml) was stirred at room temperature for 16 hours. To the resulting yellow viscous mixture was added EtOAc (15 ml) and the precipitate was collected by filtration and washed EtOAc (50 ml). After drying in high vacuum received a yellow solid (0,67 g, 51%).

X 3107, 3073, 1601, 1522, 1508, 1345, 1313, 1241, 1209, 1110, 855, 799, 745 cm-1;1H NMR (400 MHz, DMSO-d6) δ 7.09 (dd, J=6.6, 3.9 Hz, 1H), 8.26 (d, J=9.0 Hz, 2H), 8.32 (d, J=9.0 Hz, 2H), 8.58 (s, 1H), 8.59 (dd,J=3.9, 1.9 Hz, 1H), 8.99 (dd,J=6.6, 1.9 Hz, 1H)

4-(imidazo[1,2-a]pyrimidine-2-yl)aniline

Received in accordance with section description restoration of the nitro group using the hydrobromide of 2-(4-nitrophenyl)imidazo[1,2-a]pyrimidine (0,673 g of 2.18 mmol) and chloride dihydrate tin (II) (2,46 g, 10,89 mmol) in EtOH (50 ml) to give the title compound (of 0.337 g, 74%) as a pale orange solid after processing and flash chromatography (4:1 EtOAc/Meon).

1H NMR (250 MHz, DMSO-d6) δ 5.35 (s, 2H), 6.64 (d, J=8.5 Hz, 2H), 6.95-7.00 (m, 1H), 7.67 (d, J=8.5 Hz, 2H), 8.10 (s, 1H), 8.41-8.44 (m, 1H), 8.86-8.89 (m, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 105.57, 108.98, 114.48, 121.50, 127.49, 134.86, 147.49, 148.58, 149.67, 149.83.

Imidazo[1,2-a]pyrimidine compounds

4-(dimethylamino)-N-(4-imidazo[1,2-a]pyrimidine-2-ylphenyl)benzamid

no connection SKT05-95

Received in accordance with section description Amide linking using 4-imidazo[1,2-a]pyrimidine-2-yl)aniline (80 mg, 0,381 mmol) and 4-dimethylaminobenzaldehyde (70 mg, 0,381 mmol) in dry pyridine (8 ml) to give the title compound (49 mg, 36%) as an almost colorless solid after processing and flash chromatography (15:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 3.00 (s, 6H), 6.77 (d, J=8.5 Hz, 2H), 7.01-7.06 (m, 1H), 7.87-7.98 (m, 6H), 8.31 (s, 1H), 8.49 (bs, 1H), 8.95 (d, J=6.4 Hz, 1H), 9.99 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 40.15, 107.22, 109.15, 111.28, 120.73, 121.59, 126.46, 128.59, 129.62, 135.18, 140.34, 145.99, 148.55, 150.37, 152.95, 165.68

Imidazo[1,2-a]pyridine intermediate connection

2-(4-nitrophenyl)imidazo[1,2-a]pyridine

A mixture of 2-aminopyridine (0.20 g, 2,11 mmol) and bromo-4'-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (25 ml) was boiled under reflux for 18 hours. The reaction mixture is left to cool and added sodium bicarbonate (88 mg, 1.05 mmol) and heating was continued for 2 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was dissolved in DHM (40 ml), washed with water (40 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to obtain a brown solid, which was purified using flash chromatography (15:1 DHM/Meon) to obtain the title compound (0.27 g, 54%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 6.82-6.87 (m, 1H), 7.21-7.25 (m, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 8.12-8.17 (m, 1H), 8.29 (d, J=8.8 Hz, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 112.07, 113.31, 117.46, 124.55, 126.28, 126.78, 127.67, 141.02, 142.53, 145.75, 147.02.

4-(imidazo[1,2-a]pyridine-2-yl)aniline

Received in accordance with section description restoration of the nitro group using 2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0,216 g, 0.90 mmol) and dihydrochloride tin (II) (1,02 g, to 4.52 mmol) in EtOH (25 ml) to give the title compound (0,144 g, 76%) as a pale yellow solid after processing and flash chromatography (9:1 EtOAc/DHM).

1H NMR (400 MHz, DMSO-d6) δ 5.21 (br s, 2H), 6.60 (d, J=7.9 Hz, 2H), 6.79 (m, 1H), 7.14 (m, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.61 (d, J=7.9 Hz, 2H), 8.08 (s, 1H), 8.42 (d, J=6.3 Hz, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 107.11, 112.06, 114.40, 116.52, 122.24, 124.46, 126.80, 127.07, 145.06, 146.26, 149.01

6-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine

A mixture of 2-amino-5-picoline (0.88 g, 8,19 mmol) and 2-bromo-4'-nitroacetophenone (2.0 g, 8,19 mmol) in ETOH (50 ml) was boiled under reflux for 17 hours. The reaction mixture is left to cool and added sodium bicarbonate (840 mg, of 9.99 mmol) and heating was continued for 18 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0.84 g, 40%) as yellow is on solid.

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 7.16 (d, J=9.1 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.28 (d, J=8.8 Hz, 2H), 8.34 (s, 1H), 8.54 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.94, 111.74, 116.85, 122.60, 124.50, 124.92, 126.61, 129.29, 141.19, 142.34, 144.84, 146.87.

4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline

Received in accordance with section description restoration of the nitro group using 6-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0,423 g, 1,67 mmol) and chloride dihydrate tin (II) (1.89 g, at 8.36 mmol) in ETOH (45 ml) to give the title compound (0,216 g, 58%) as a pale orange solid after processing and flash chromatography (EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.29 (s, 3H), 3.74 (s, 2H), 6.74 (d, J=8.5 Hz, 2H), 6.95 (d, J=9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.64 (s, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.85 (s, 1H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 17.47, 105.99, 113.97, 115.21, 120.74, 122.06, 123.24, 126.23, 126.79, 143.56, 145.25, 147.55.

6-fluoro-2-(4-nitrophenyl)imidazo[1,2-a]pyridine

To a stirred mixture of 2-amino-5-herperidin (0,80 g, 7,13 mmol) and sodium bicarbonate (0,60 g, 7,14 mmol) was added to a suspension of 2-bromo-4'-nitroacetophenone (1,74 g, 7,13 mmol) in chloroform (10 ml). Stir the reaction mixture is boiled under reflux for 20 hours. After cooling to room temperature the precipitate was collected by filtration under vacuum and washed with chloroform (2×40 ml)Tordue substance was then purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0,596 g, 32%) as a brown solid.

1H NMR (250 MHz, CDCl3) δ 7.13-7.21 (m, 1H), 7.59-7.66 (m, 1H), 7.99 (s, 1H), 8.07-8.10 (m, 3H), 8.30 (d, J=8.8 Hz, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 113.43 (d, JCF=Hz), 114.30 (d, JCF=42.0 Hz), 118.17 (d, JCF=26.4 Hz), 118.23 (d, JCF=10.2 Hz), 124.51, 126.77, 140.61, 143.66, 143.75 (d, JCF=Hz), 147.08, 153.26 (d, JCF=233.6 Hz).

4-(6-torymidae[1,2-a]pyridine-2-yl)aniline

Received in accordance with section description restoration of the nitro group using 6-fluoro-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.45 g, a 1.75 mmol) and chloride dihydrate tin (II) (1.97 g, is 8.75 mmol) in EtOH (25 ml) to give the title compound (0,325 g, 82%) as a pale yellow solid after processing and flash chromatography (4:1 EtOAc/DHM).

1H NMR (250 MHz, DMSO-d6) δ 5.26 (s, 2H), 6.61 (d, J=8.2 Hz, 2H), 7.21-7.28 (m, 1H), 7.51-7.60 (m, 1H), 7.62 (d, J=8.2 Hz, 2H), 8.12 (s, 1H), 8.68 (br s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 108.73 (d, JCF=1.5 Hz), 113.48 (d, JCF=41 Hz), 114.39, 115.90 (d, JCF=25.7 Hz), 117.00 (d, JCF=10.1 Hz), 121.90, 142.99, 147.63, 149.18, 152.80 (d, JCF=231 Hz).

6-iodine-2-(4-nitrophenyl)imidazo[1,2-a]pyridine

To a stirred mixture of 2-amino-5-iopidine (0,80 g of 3.64 mmol) and sodium bicarbonate (0.34 g, 3,99 mmol) was added to a suspension of 2-bromo-4'-bromoacetophenone(0,89 g of 3.64 mmol) in chloroform (15 ml). Stir the reaction mixture was heated to reverse the m refrigerator for 24 hours. After cooling to room temperature the precipitate was collected by filtration under vacuum and washed with chloroform (2×40 ml), water (40 ml) and then dried at 90°C for 24 hours to obtain the title compound (0,827 g, 62%) as a pale green solid.

1H NMR (250 MHz, DMSO-d6) δ 7.49 (s, 2H), 8.22 (d, J=8.8 Hz, 2H), 8.31 (d, J=8.2 Hz, 2H), 8.55 (s, 1H), 8.96 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 77.10, 111.73, 118.66, 124.53, 126.88, 132.22, 133.78, 140.43, 142.73, 144.27, 147.13.

4-(6-itemids[1,2-a]pyridine-2-yl)aniline

Received in accordance with section description restoration of the nitro group using 6-iodine-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.45 g, of 1.23 mmol) and chloride dihydrate tin (II) (1.39 g, 6,16 mmol) in EtOH (25 ml) to give the title compound (0,301 g, 73%) as a yellow solid after processing and flash chromatography (4:1 EtOAc/DHM).

1H NMR (250 MHz, DMSO-d6) δ 5.27 (s, 2H), 6.60 (d, J=7.6 Hz, 2H), 7.34 (s, 2H), 7.60 (d, J=7.6 Hz, 2H), 8.04 (s, 1H), 8.82 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 75.32, 107.03, 114.40, 117.79, 121.57, 127.19, 131.37, 131.93, 143.66, 146.62, 149.28.

6-methyl-2-phenylimidazo[1,2-a]pyridine

no connection SK2033-32

Stir a mixture of 2-amino-5-picoline (0.56 g, with 5.22 mmol) and 2-bromoacetophenone (1.0 g, 5,02 mmol) in EtOH (50 ml) was boiled under reflux for 2 hours. The reaction mixture is left of ohlord is the promise to room temperature and then added sodium bicarbonate (0,76 g, 9,04 mmol) and the reaction mixture is boiled under reflux for 15 hours. Then solvent removed under reduced pressure and the residue was dissolved in EtOAc (70 ml) and washed with water (40 ml). The organic phase was dried (Na2SO4) and solvent removed under reduced pressure to obtain an orange solid. Specified solid was purified using flash chromatography (1:1 hexane/EtOAc) to give the title compound (0,753 g, 70%) as a pale orange solid.

1H NMR (250 MHz, CDCl3) δ 2.30 (s, 3H), 7.01 (d, J=9.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.39-7.45 (m, 2H), 7.53 (d, J=9.5 Hz, 1H), 7.76 (s, 1H), 7.88 (s, 1H), 7.93 (d, J=7.5 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 18.09, 107.91, 116.75, 121.99, 123.36, 125.92, at 127.80, 127.85, 128.72, 133.95, 144.73, 145.39.

2-foradil-p-toluensulfonate

To a stirred solution of 2-ftramadol (1.92 g, 29,97 mmol) in dry pyridine (15 ml) in an argon atmosphere at 0°C was added p-toluensulfonate within 15 minutes, keeping the temperature not exceeding 5°C. Then the reaction mixture was stirred at 0°C for 4 hours, then at room temperature for 12 hours. The reaction mixture was cooled to 0°C and added ice (15 g)and then water (40 ml) and EtOAc (50 ml). The organic extract was washed with water (30 ml), 1M HCl (until the acidic aqueous extracts), 10% sodium carbonate (2×30 ml), with which the combat solution (40 ml) and dried (Na 2SO4). Removed solvent under reduced pressure to obtain the title compound (5.10 g, 78%) as a colorless oily liquid.

1H NMR (250 MHz, CDCl3) δ 2.44 (s, 3H), 4.25 (dist d of t, JHF=27 Hz, JHH=4.3 Hz, 2H), 4.56 (dist d of t, JHF=47 Hz, JHH=4.3 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 21.68, 68.52 (d, JCF=21.5 Hz), 80.57 (d, JCF=174 Hz), 127.99, 129.98, 132.65, 145.21.

Imidazo[1,2-a]pyridine compounds

4-(dimethylamino)-N-[4-(imidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT05-123

Received in accordance with section description Amide linking using 4-(imidazo[1,2-a]pyridine-2-yl)aniline (70 mg, 0,335 mmol) and 4-dimethylaminobenzaldehyde (62 mg, 0,335 mmol) in dry pyridine (5 ml) to give the title compound (70 mg, 59%) as a pale yellow solid connection after processing and flash chromatography (20:1 DHM/Meon).

1H NMR (400 MHz, DMSO-d6) δ 2.98 (s, 6H), 6.75 (d, J=9.0 Hz, 2H), 6.85 (dd, J=6.7, 0.7 Hz, 1H), 7.21 (dd, J=9.0, 0.7 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.88 (d, J=9.0 Hz, 2H), 7.91 (d, J=8.7 Hz, 2H), 8.31 (s, 1H), 8.49 (d, J=6.7 Hz, 1H), 9.93 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 40.16, 108.88, 111.23, 112.55, 116.91, 120.68, 121.49, 125.16, 126.22, is the 127.20, 129.10, 129.61, 139.81, 144.90, 145.23, 152.85, 165.62.

4-(dimethylamino)-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT05-93

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (70 mg, 0,314 mmol) and 4-dimethylaminobenzaldehyde (58 mg, 0,314 mmol) in dry pyridine (5 ml) to give the title compound (63 mg, 54%) as a pale yellow solid connection after processing and flash chromatography (20:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.00 (s, 6H), 6.76 (d, J=8.5 Hz, 2H), 7.08 (d, J=9.5 Hz, 1H), 7.46 (d, J=9.5 Hz, 1H), 7.82-7.92 (m, 6H), 8.23 (s, 1H), 8.30 (s, 1H), 9.95 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.97, 40.15, 108.62, 111.23, 116.26, 120.67, 121.44, 121.81, 124.60, 126.10, 128.23, 129.16, 129.60, 139.66, 144.24, 144.58, 152.85, 165.64.

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-4-carboxamide

no connection SKT05-107

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (70 mg, 0,314 mmol) and hydrochloride isonicotinohydrazide (56 mg, 0,314 mmol) in dry pyridine (5 ml) to give the title compound (92 mg, 89%) as a pale yellow solid connection after processing and flash chromatography (10:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 7.10 (d,.7=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.87-7.89 (m, 2H), 7.96 (d, J=8.2 Hz, 2H), 8.27 (s, 1H), 8.32 (s, 1H), 8.80 (d, J=0.6 Hz, 2H), 10.60 (s, 1H);13C NMR (62.5 MHz, CDCl3/DMSO-d6) δ 17.24, at 107.80, 115.41, 120.12, 120.89, 121.09, 123.58, 125.30, 127.26, 12.46, 137.62, 141.48, 143.48, 143.58, 149.62, 163.30.

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide

no connection SKT05-171

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (70 mg, 0,314 mmol) and hydrochloride nicotinanilide (56 mg, 0,314 mmol) in dry pyridine (5 ml) to give the title compound (62 mg, 60%) as a pale yellow solid connection after processing and flash chromatography (EtOAc, then 20:1 EtOAc/Meon).

1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 7.04 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.53 (dd, J=7.9, 4.9 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.20 (s, 1H), 8.25-8.27 (m, 2H), 8.72 (d, J=4.8 Hz, 1H), 9.07 (d, J=2.1 Hz. 1H), 10.48 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 18.17, 109.05, 116.59, 121.08, 122.02, 124.17, 124.83, 126.45, 128.45, 130.45, 131.27, 136.12, 138.93, 144.52, 144.63, 149.33, 152.76, 164.66.

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-2-carboxamide

no connection SKT06-5

To a stirred suspension pikolinos acid (56 mg, 0.45 mmol) in DHM (1 ml) was added thionyl chloride (2 ml), and then a drop of DMF. The mixture was stirred at room temperature for 4 hours, then the excess reagent and solvent was removed under reduced pressure to obtain a green solid. Amide obtained in accordance with section description Amide linking with application of n is purified solids and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (70 mg, 0,314 mmol) in dry pyridine (4.5 ml) to give the title compound (65 mg, 44%) as a pale yellow solid after processing and flash chromatography (20:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 7.10 (d, J=9.2 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 7.67-7.72 (m, 1H), 7.95 (d, J=8.8 Hz, 2H), 8.00 (d, J=8.8 Hz, 2H), 8.05-8.11 (m, 1H), 8.19 (d, J=7.3 Hz, 1H), 8.27 (s, 1H), 8.31 (s, 1H), 8.76 (d, J=4.6 Hz, 1H), 10.74 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.94, 108.81, 116.42, 120.80, 121.76, at 122.77, 124.61, 126.29, 127.31, 128.16, 130.34, 138.17, 138.55, 144.38, 144.58, 148.87, 150.41, 162.84.

6-fluoro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide

no connection SKT05-169

Stir a suspension of 6-fornicating acid (80 mg, 0,414 mmol) in thionyl chloride (2 ml) was boiled under reflux for 4 hours. Then removed the excess reagent under reduced pressure to get crude solid. Amide obtained in accordance with section description Amide linking with the use of untreated solids and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (92 mg, 0,414 mmol) in dry THF (13 ml) and diisopropylethylamine (106 μl, 0,608 mmol) to give the title compound (86 mg, 60%) as a colourless solid after processing and flash chromatography (EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 7.05 (dd, J=9.2, 1.2 Hz, 1H), 7.32 (dd, J=8.5, 2.4 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.9 (d, J=8.8 Hz, 2H), 8.20 (s, 1H), 8.26 (s, 1H), 8.46 (dt, J=8.5, 2.4 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 10.48 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 18.17, 109.06, 109.97, 110.34, 116.58, 121.11, 122.03, 124.84, 126.47, 128.47, 130.00 (d, JCF=3.8 Hz), 130.51, 138.80, 142.58 (d, JCF=9.1 Hz), 144.56 (d, JCF=7.6 Hz), 148.42 (d, JCF=16.0 Hz), 163.43, 164.95 (d, JCF=239 Hz).

6-fluoro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-2-carboxamide

no connection SKT06-53

Stir a suspension of 2-herperidin-6-carboxylic acid (86 mg, 0,448 mmol) in thionyl chloride (2 ml) was boiled under reflux for 5 hours. Then removed the excess reagent under reduced pressure to get crude solid. Amide obtained in accordance with section description Amide linking with the use of untreated solids and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (100 mg, 0,448 mmol) in dry THF (20 ml) and diisopropylethylamine (94 μl, 0,539 mmol) to give the title compound (85 mg, 55%) as a colourless solid after processing and flash chromatography (2:1 EtOAc/hexane).

1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 7.05 (dd, J=9.2, 1.7 Hz, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.45 (dd, J=8.3, 1.7 Hz, 1H), 7.87-7.92 (m, 4H), 8.04 (dd, J=7.3, 1.7 Hz, 1H), 8.18-8.24 (m, 1H), 8.22 (s, 1H), 8.27 (s, 1H), 10.48 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.94, 108.86, 113.54 (d, JCF=36.5 Hz), 116.43, 121.05 (d, JCF=3.9 Hz), 121.17, 121.76, 124.61, 126.23, 128.17, 130.58, 137.97, 144.30, 14.38, 144.53, 149.23 (d, JCF=11.7 Hz), 161.77, 162.12 (d, JCF=240.6 Hz).

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-4-nitrobenzamide

no connection SKT06-63

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.20 g, 0,897 mmol) and 4-nitrobenzylamine (0,166 g, 0,897 mmol) in dry pyridine (13 ml) to give the title compound (0,266 g, 80%) as a pale yellow solid after processing and flash chromatography (1:1 EtOAc/MeOH).

1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 7.04 (dd, J=9.3, 1.5 Hz, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.8 Hz, 2H), 8.15 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 8.26 (s, 1H), 8.33 (d, J=8.8 Hz, 2H), 10.62 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.95, 108.85, 116.42, 121.09, 121.78, 123.94, 124.63, 126.28, 128.20, 129.66, 130.56, 138.60, 141.12, 144.52, 149.66, 164.27.

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-4-nitro-3-(trifluoromethyl)benzamid

no connection SKT05-165

Stir a suspension of 4-nitro-3-triftorperasin acid (0,239 g, 0,986 mmol) in thionyl chloride (4 ml) was boiled under reflux for 5 hours. Then removed the excess reagent under reduced pressure to get crude solid. Amide obtained in accordance with section description Amide linking with the use of untreated solids and 4-(6-methylimidazo[1,2-a]pyrid the h-2-yl)aniline (0.20 g, 0,897 mmol) in dry pyridine (8 ml) to give the title compound (of 0.337 g, 85%) as a yellow solid after processing and flash chromatography (25:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 7.10 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 2H), 8.27 (s, 1H), 8.32 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.53 (s, 1H), 10.76 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.94, 108.91, 116.43, 121.19, 121.80, 121.86 (JCF=34 Hz), 122.72 (JCF=273 Hz), 124.63, 126.12, 126.33, 127.75 (JCF=5.5 Hz), 128.22, 130.80, 134.26, 138.31, 139.47, 144.40, 144.45, 149.14, 162.81; ICSD (ESI+) 486 (M++Na, 100%), 441 (M++H, 34).

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-4-hydroxylamino-3-(trifluoromethyl)benzamid

no connection SKT05-173

Received in accordance with section description restoration of the nitro group using N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-4-nitro-3-(trifluoromethyl)benzamide (0.25 g, 0,568 mmol) and chloride dihydrate tin (II) (0.64 g, 2,84 mmol) in ETOH (30 ml) to give the title compound (0.20 g, 87%) as a pale yellow solid after processing and flash chromatography (15:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 7.10 (d, J=9.2 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 8.13-8.18 (m, 2H), 8.25 (s, 1H), 8.32 (s, 1H), 9.04 (s, 1H), 9.08 (s, 1H), 10.23 (s, 1H);13C NMR (67.5 MHz, CDCl3/DMSO-d6) δ 17.67, 107.55, 111.42 (q, JCF=31.2 Hz), 112.94, 115.83, 120.49, 21.47, 123.42, 123.97 (q, JCF=272 Hz), 124.62, 125.63, 125.97 (q, JCF=5.9 Hz), 127.57, 129.08. 132.51, 138.55, 144.09, 144.40, 150.91, 164.29.

4-amino-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-71

Received in accordance with section description restoration of the nitro group using T-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-4-nitrobenzamide (0.10 g, 0,269 mmol) and chloride dihydrate tin (II) (0,30 g of 1.34 mmol) in EtOH (15 ml) to give the title codeinone (0,072 g, 78%) as a pale yellow solid after processing and flash chromatography (15:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.29 (s, 3H), 5.79 (s, 2H), 6.62 (d, J=8.2 Hz, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.8 Hz, 2H), 8.24 (s, 1H), 8.31 (s, 1H), 9.85 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.97, 108.54, 113.00, 116.33, 120.56, 121.53, 121.69, 124.58, 126.08, 128.08, 129.17, 129.82, 139.75, 144.27, 144.73, 152.61, 165.69.

4-(methylamino)-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-67

To a stirred solution of 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.10 g, 0,448 mmol), 1-hydroxybenzotriazole (0.06 g, 0,448 mmol), 4-methylaminoethanol acid (0,068 g, 0,448 mmol) and triethylamine (62 μl, of 0.045 g, 0,448 mmol) in dry DMF (5 ml) at 0°C was added the hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (0,086 g, 0,448 mmol) in argon atmosphere. After 10 min the t removed the cooling bath and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was then added to water (150 ml) under stirring and the precipitate collected by filtration. Purification using flash chromatography (25:1 DHM/Meon) led to the title compound (0,053 g, 33%) as an almost colorless solid.

1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.69 (d, J=4.9 Hz, 3H), 6.30 (q, J=4.9 Hz, 1H), 6.54 (d, J=8.8 Hz, 2H), 7.04 (dd, J=9.3, 1.5 Hz, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 8.18 (s, 1H), 8.25 (s, 1H), 9.82 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ at 17.93, 29.79, 108.51, 110.94, 116.34, 120.66, 121.48, 121.65, 124.56, 126.10, 128.03, 129.27, 129.73, 139.75, 144.33, 144.83, 153.10, 165.71.

4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-7

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (70 mg, 0,314 mmol) and 4-methoxybenzylamine (54 mg, 0,314 mmol) in dry pyridine (5 ml) to give the title compound (89 mg, 79%) as a pale yellow solid after processing and flash chromatography (15:DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.85 (s, 3H), 7.08 (d, J=8.5 Hz, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.25 (s, 1H), 8.32 (s, 1H), 10.19 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.94, 55.90, 108.65, 114.10, at 116.39, 120.89, 121.71, 124.59, 126.18, 127.54, 128.10, 129.81, 130.04, 139.30, 144.37, 144.72, 162.42, 165.32.

4-is hydroxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-11

Received in accordance with section description Demethylation using 4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.07 g, 0,196 mmol) in dry DHM (5 ml), tribromide boron in DHM (1.0m, of 0.24 ml, 0.24 mmol) at -78°C. the Reaction mixture was stirred at -78°C for 1 hour, then left to warm to room temperature. After 18 hours at room temperature was added an additional amount of tribromide boron in DHM (1.0m, 0.7 ml, 0.7 mmol) and stirring continued at room temperature to obtain the title compound (0,043 g, 64%) as a pale yellow solid after processing and flash chromatography (10:1 DHM/Meon).

1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 6.82 (d, J=8.5 Hz, 2H), 7.04 (dd, J=9.0, 1.5 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 8.18 (s, 1H), 8.25 (s, 1H), 10.02 (s, 1H) 9.80-10.81 (br s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 18.17, 108.86, 115.57, 116.53, 120.93, 121.96, 124.79, at 126.00, 126.32, 128.37, 129.72, 130.37, 139.60, 144.49, 144.80, 161.25, 165.72.

3,4,5-Cryptor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-25

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.50 g, 2,24 mmol) and 3,4,5-triterpenoid (0,436 g, 2,24 mmol) in dry pyridine (20 m is) to obtain the title compound (0,617 g, 72%) as a colourless solid after treatment and recrystallization of the Asón.

1H NMR (250 MHz, DMSO-d6) δ 2.32 (s, MN), 7.45 (d, J=9.2 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.90-7.96 (m, 2H), 7.93 (d, J=8.8 Hz, 2H), 8.43 (s, 1H), 8.48 (s, 1H), 10.51 (s, 1H).

4-(dimethylamino)for 3,5-debtor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl] benzamide

no connection SKT06-29

Stir a mixture of 3,4,5-Cryptor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.10 g, 0.26 mmol), dimethylamine hydrochloride (0,087 g, 1.07 mmol) and potassium carbonate (0,147 g, 1.07 mmol) in dry DMSO (3 ml) was heated at 120°C for 22.5 hours. After cooling to room temperature the reaction mixture was added to water (100 ml) and the collected precipitate by vacuum filtration and washed with water (40 ml). The precipitate was dried in an oven at 95°C, and then purified using flash chromatography (25:1 DHM/Meon) to obtain the title compound (0,084 g, 80%) as a colourless solid.

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.92 (s, 6H), 7.10 (d, J=8.9 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.68 (d, JH,F=10.1 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.26 (s, 1H), 8.32 (s, 1H), 10.22 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.53, 42.72 (t, JCF=3.9 Hz), 107.60, 111.59 (m), 115.67, 120.26, 121.22, 123.45, 125.46, 126.98 (t, JCF=7.8 Hz), 127.40, 129.22, 131.58 (t, JCF=12.7 Hz), 138.16, 143.89, 144.14, 155.84 (dd, JCF=246 Hz, JCF=7.8 Hz), 162.68.

4-f the PR-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-3-(trifluoromethyl)benzamid

no connection SKT06-15

To a stirred solution of 4-fluoro-3-triftorperasin acid (0,103 g, 0,493 mmol) in thionyl chloride (3 ml) was added a drop of DMF and the reaction mixture is boiled under reflux for 2 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to get the crude residue. Amide obtained in accordance with section description Amide linking with the use of the crude residue and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.10 g, 0,448 mmol) in dry mixture of pyridine/THF (1:1, 10 ml) to give the title compound (0,146 g, 78%) as a colourless solid after processing and flash chromatography (DHM/EtOAc 1:1).

1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 7.08 (dd, J=9.0, 1.2 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.68-7.76 (m, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.95 (d, J=9.0 Hz, 2H), 8.23 (s, 1H), 8.29 (br s, 1H), 8.33-8.37 (m, 2H), 10.52 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 17.96, 108.85, at 116.39, 117.02 (d of q, JCF=32.7, 12.5 Hz), 117.99 (d, JCF=21.0 Hz), 121.04, 121.80, 122.85 (q, JCF=272.4 Hz), 124.63, 126.25, 127.42 (d of q, JCF=4.6, 1.6 Hz), 128.23, 130.35, 132.19 (d, JCF=3.9 Hz), 135.53 (d, JCF=10.2 Hz), 138.62, 144.32, 144.43, 161.08 (d of q, JCF=258.4, 1.6 Hz), 163.44 17.96, 108.85, at 116.39.

6-chloro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide

no connection SKT06-13

Obtained in accordance with the description of the section Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.08 g, 0,359 mmol) and 6-chloronicotinamide (0,063 g, 0,359 mmol) in dry pyridine (5 ml) to give the title compound (0,087 g, 67%) as a colourless solid after processing and flash chromatography (20:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 7.10 (d, J=9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 8.26 (s, 1H), 8.32 (s, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.96 (s, 1H), 10.56 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.97, 108.86, 116.40, 120.92, 121.79, 124.59, 124.63, 126.27, 128.23, 130.42, 130.43, 138.51, 139.50, 144.32, 144.41, 149.77, 153.19, 163.27.

3,4-debtor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide

no connection SKT06-35

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.50 g, 2,24 mmol) and 3,4-differentiald (0,395 g, 2,24 mmol) in dry pyridine (20 ml) to give the title compound (0,556 g, 68%) as a colourless solid after treatment and recrystallization of the Asón.

1H NMR (250 MHz, DMSO-d6) 8 2.27 (s, 3H), 7.09 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.57-7.68 (m, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.83-7.92 (m, 1H), 7.93 (d, J=8.8 Hz, 2H), 8.00-8.08 (m, 1H), 8.24 (s, 1H), 8.30 (s, 1H), 10.38 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.94, 108.79, at 116.39, 117.57 (d, JCF=18.7 Hz), 118.04 (d, JCF=18.1 Hz), 121.04, 121.76, 124.62, 125.68 (dd, JCF=7.0 Hz, JCF=3.1 Hz), 126.24, 128.18, 130.34, 132.77 (m), 138.69, 144.37, 144.55, 149.57 (dd, JCF=237.4 Hz, Jsub> CF=12.5 Hz), 152.04 (dd, JCF=242.1 Hz, JCF=13.3 Hz), 163.60.

3-fluoro-4-(dimethylamino)-N-[4-(6-methylimidazo [1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-55

Stir a mixture of 3,4-debtor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.10 g, 0,275 mmol), methylamine hydrochloride (0,37 g of 5.50 mmol) and potassium carbonate (0,76 g of 5.50 mmol) in dry DMSO (2 ml) was heated at 120°C for 60 hours. After cooling to room temperature the reaction mixture was added to water (100 ml) and the collected precipitate by vacuum filtration and washed with water (40 ml). The precipitate was dried in an oven at 95°C, and then purified using flash chromatography (EtOAc) to give the title compound (0,077 g, 75%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.74 (d, J=4.9 Hz, 3H), 6.19-6.21 (m, 1H), 6.68 (t, J=8.8 Hz, 1H), 7.04 (dd, J=9.0, 1.5 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.65 (dd, J=13.2, 1.7 Hz, 1H), 7.71 (dd, J=8.5, 1.7 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 8.18 (s, 1H), 8.25 (s, 1H), 9.91 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.95, 29.72, 108.61, 110.39 (d, JCF=4.6 Hz), 113.89 (d, JCF=19.5 Hz), 116.38, 120.78, 121.21 (d, JCF=5.4 Hz), 121.70, 124.59, 125.86 (d, JCF=1.6 Hz), 126.15, 128.09, 129.58, 139.44, 141.41 (d, JCF=12.5 Hz), 144.36, 144.76, 150.29 (d, JCF=238 Hz), 164.68 (d, JCF=2.3 Hz).

3,5-debtor-4-(dimethylamino)-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl] benzamide

no connection SKT06-59

Stir a mixture of 3,4,5-Cryptor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.10 g, 0,275 mmol), methylamine hydrochloride (0,44 g of 6.50 mmol) and potassium carbonate (0,90 g of 6.50 mmol) in dry DMSO (2 ml) was heated at 120°C for 47 hours. After cooling to room temperature the reaction mixture was added to water (150 ml) and the collected precipitate by vacuum filtration and washed with water (40 ml). The precipitate was dried in an oven at 95°C, and then purified using flash chromatography (EtOAc/hexane 3:1) to give the title compound (0,046 g, 63%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.93-2.95 (m, 3H), 5.88-5.91 (m, 1H), 7.04 (dd, J=9.0, 1.5 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.56 (dist dd, J=9.0, 2.7 Hz, 1H), 7.61 (dist dd, J=9.0, 2.7 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 8.19 (s, 1H), 8.26 (d, J=0.49 Hz, 1H), 9.99 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.97, 32.31 (t, JCF=3.8 Hz), 108.71, 111.93 (m), 116.36, 120.55 (t, JCF=7.8 Hz), 120.78, 121.75, 124.62, 126.17, 128.16, 129.79, 130.91 (t, JCF=14 Hz), 139.03, 144.29, 144.55, 150.97 (dd, JCF=239 Hz, JCF=10.1 Hz), 163.40.

4-(dimethylamino)-3-fluoro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-39

Stir a mixture of 3,4-debtor-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.10 g, 0,275 mmol), methylamine hydrochloride (0,045 g, 0,551 mmol) and potassium carbonate (0,080 g, 0,577 mmol) in dry DMSO (3 ml) was heated Ave is 100°C for 18 hours. After cooling to room temperature the reaction mixture was added to water (100 ml) and the collected precipitate by vacuum filtration and washed with water (50 ml). Dried in air, the solid is then purified using flash chromatography (25:1 DHM/Meon) to obtain the title compound (of 0.066 g, 62%) as a colourless solid.

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.93 (s, 6H), 7.01 (t, J=9.2 Hz, 1H), 7.10 (d, J=9.2 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.73-7.79 (m, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 8.25 (s, 1H), 8.32 (s, 1H), 10.10 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.94, 42.36 (d, J=4.7 Hz), 108.65, 115.92 (d, JCF=23.3 Hz), 116.37, 117.20 (d, JCF=4.7 Hz), 120.86, 121.71, 124.59, 125.13, 125.15, 125.77 (d, JCF=6.2 Hz), 126.17, 128.10, 129.82, 139.19, 143.20 (d, JCF=7.7 Hz), 144.52 (d, JCF=34.3 Hz), 152.81 (d, JCF=243 Hz), 164.30.

3-fluoro-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-49

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0,30 g of 1.34 mmol) and 3-fluoro-4-methoxybenzonitrile (0.25 g, of 1.34 mmol) in dry pyridine (14 ml) to give the title compound (0,357 g, 71%) in the form of small colorless needle-like particles after processing, flash chromatography (DHM/Meon 18:1) and recrystallization from 1,4-dioxane.

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, MN), 3.93 (s, MN), 7.10 (d, J=Hz, 1H), 7.33 (m, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.85-7.91 (m, 2H), 7.93 (d, J=8.5 Hz, 2H), 8.26 (s, 1H), 8.32 (s, 1H), 10.23 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) 17.96 5, 56.70, 108.74, 113.71 (d, JCF=2.3 Hz), 115.66 (d, JCF=19.5 Hz), 116.37, 120.89, 121.75, 124.60, 125.40 (d, JCF=3.1 Hz), 126.17, 127.65 (d, JCF=5.4 Hz), 128.16, 129.94, 138.98, 144.31, 144.54, 150.39 (d, JCF=10.8 Hz), 151.28 (d, JCF=244.4 Hz), 164.13.

3,5-debtor-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-45

To a stirred solution of 3,5-debtor-4-methoxybenzoic acid (0.25 g, of 1.34 mmol) in thionyl chloride (4 ml) was added a drop of DMF and the reaction mixture is boiled under reflux for 5 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to get the crude residue. Amide obtained in accordance with section description Amide linking with the use of the crude residue and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0,30 g of 1.34 mmol) in dry pyridine (14 ml) to give the title compound (0.33 g, 62%) as a pale yellow solid after processing and flash chromatography (DHM/Meon 20:1).

1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 3.98 (s, 3H), 7.04 (dd, J=9.2, 1.5 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.78-7.85 (m, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 8.26 (s, 1H), 10.44 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 18.18, 62.42, 109.06, 113.04 (m), 116.58, 121.22, 121.7, 124.84, 126.35, 128.41, 129.87 (t, JCF=Hz), 130.42, 138.87, 139.09 (t, JCF=Hz), 144.50, 144.63, 154.86 (dd, JCF=246 Hz, JCF=6 Hz), 163.12.

2,6-debtor-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-79

To a stirred solution of 2,6-debtor-4-methoxybenzoic acid (0.25 g, of 1.34 mmol) in thionyl chloride (7 ml) was added a drop of DMF and the reaction mixture is boiled under reflux for 3 hours. After cooling to room temperature, the excess reagent was removed under reduced pressure to get the crude residue. Amide obtained in accordance with section description Amide linking with the use of the crude residue and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0,30 g of 1.34 mmol) in dry pyridine (15 ml) to give the title compound (0.24 g, 45%) as a pale yellow solid after processing and flash chromatography (2:1 EtOAc/hexane, then EtOAc, then the Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.84 (s, 3H), 6.90 (d, J=10.1 Hz, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 8.26 (s, 1H), 8.32 (d, J=0.6 Hz, 1H), 10.72 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.98, 56.88, 98.98 (d, JCF28.7), 108.58 (t, JCF22.6), 108.85, at 116.39, 119.98, 121.80, 124.63, 126.40, 128.23, 130.31, 138.55, 144.31, 144.38, 158.57, 160.34 (dd, JCF246 and 11.7), 162.21 (t, JCF14.8).

3,5-debtor-4-hydroxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]b is Samid

no connection SKT06-51

Obtained in accordance with the description of the Demethylation section above using 3,5-debtor-4-methoxy-M-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.20 g, 0,509 mmol) in dry DHM (10 ml) and tribromide boron in DHM (1,Ω, of 0.62 ml of 0.62 mmol) at -78°C To produce the title compound (0,057 g, 29%) as a colourless solid after processing and flash chromatography (12:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.27 (s, 3H), 7.09 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.73 (d, J=7.9 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 8.25 (s, 1H), 8.31 (s, 1H), 10.19 (s, 1H), 11.05 (brs, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.95, 108.76, 112.08 (m), at 116.39, 120.99, 121.77, 124.63, 125.10 (t, JCF=7.0 Hz), 126.23, 128.18, 130.16, 137.61 (t, JCF=16.3 Hz), 138.81, 144.37, 144.58, 152.20 (dd, JCF=242 Hz, JCF=7.0 Hz), 163.31.

3-fluoro-4-hydroxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-57

Obtained in accordance with the description of the Demethylation section above using 3-fluoro-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.20 g, of 0.53 mmol) in dry DHM (15 ml) and BBr3(1,Ω, 1.3 ml, 1.3 mmol) at -78°C To produce the title compound (0,070 g, 36%) as a colourless solid after processing and flash chromatography (10:1 DHM/Meon).

1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 7.01 (t, J=8.5 Hz, 1H), 7.05 (dd, J=9.3, 1.5 Hz, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.66 (dd, J=8.5, 1.5 Hz, 1H), 7.75-7.78 (m, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.86 (d. J=8.8 Hz, 2H), 8.20 (s, 1H), 8.27 (s, 1H), 10.08 (s, 1H), 10.57 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.97, 108.71, 116.17 (d, JCF=19.5 Hz), 116.36, 117.73 (d, JCF=3.1 Hz), 120.85, 121.77, 124.60, 125.38 (d, JCF=2.3 Hz), 126.17, 126.33 (d, JCF=4.6 Hz), 128.18, 129.81, 139.12, 144.31, 144.57, 148.76 (d, JCF=12.5 Hz), 150.83 (d, JCF=241.3 Hz), 164.38 (d, JCF=1.6 Hz).

4-methoxy-3-trifluoromethyl-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-61

Received in accordance with section description Amide linking using 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.20 g, 0,897 mmol) and 4-methoxy-3-triftormetilfullerenov (0.21 g, 0,897 mmol) in dry pyridine (15 ml) to give the title compound (0,147 g, 38%) as a colourless solid after processing and flash chromatography (15:1 EtOAc/hexane).

1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 3.94 (s, 3H), 7.04 (dd, J=9.0, 1.5 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.8 Hz, 2H), 8.20 (s, 1H), 8.22 (dd, J=10.7, 1.9 Hz, 2H), 8.26 (d,J=1.5 Hz, 1H), 10.33 (s, 1H);13With NMR (100.5 MHz, CDCl3/DMSO-d6) δ 17.80,56.05, 107.66, 111.53, 115.97, 117.63 (q, JCF=31 Hz), 120.77, 121.73, 123.20 (q, JCF=272 Hz), 123.45, 125.85, 126.58, 126.90 (q, JCF=3.9 Hz), 127.79, 129.37, 133.45, 138.38, 144.28, 144.43, 159.49, 164.26.

6-(dimethylamino)-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-Carbo who said

no connection SKT06-155

Stir a mixture of 6-chloro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide (0.15 g, 0,414 mmol), dimethylamine hydrochloride (0,845 g, 10,36 mmol) and K2CO3(1,43 g, 10,36 mmol) in dry DMSO (10 ml) was heated at 170°C for 16 hours in an argon atmosphere. The cooled reaction mixture was added to water (200 ml) and the collected precipitate by vacuum filtration and dried in air. The solid was purified using flash chromatography (12:1 DHM/Meon) to obtain the title compound (0,113 g, 73%) as a pale yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.11 (s, 6H), 6.71 (d, J=9.2 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.07 (dd, J=1.5, 8.5 Hz, 1H), 8.23 (s, 1H), 8.30 (s, 1H), 8.74 (s, 1H), 10.03 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.98, 38.04, 105.05, 108.64, 116.36, 117.89, 120.68, 121.72, 124.60, 126.14, 128.12, 129.53, 136.99, 139.35, 144.29, 144.63, 148.99, 160.48, 164.66.

6-(methylamino)-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide

no connection SKT06-153

Stir a mixture of 6-chloro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]pyridine-3-carboxamide (0.15 g, 0,414 mmol), methylamine hydrochloride (0,69 g, 10,36 mmol) and K2CO3(1,43 g, 10,36 mmol) in dry DMSO (10 ml) was heated at 170°C for 17.5 hours in argon atmosphere. Ohlazhdenku the reaction mixture was added to water (150 ml) and the collected precipitate by filtration and dried in air. The solid was purified using flash chromatography (10:1 DHM/Meon) to obtain the title compound (0,059 g, 40%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.82 (d, J=4.7 Hz, 3H), 6.49 (d, J=9.0 Hz, 1H), 7.08 (dd, J=9.0, 1.6 Hz, 1H), 7.13 (q, J=4.7 Hz, 1H), 7.45 (d, J=9.4 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.93 (dd, J=9.0, 2.4 Hz, 1H), 8.22 (s, 1H), 8.29 (s, 1H), 8.66 (d, J-2.4 Hz, 1H), 9.96 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.98, 28.30, 108.64, 116.36, 118.21, 120.66, 121.73, 124.60, 126.13, 128.12, 129.46, 136.41, 139.41, 144.29, 144.65, 149.38, 161.36, 164.80 (1 missing).

4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-2-(trifluoromethyl)benzamid

no connection SKT06-141

Stir a solution of 4-methoxy-2-triftorperasin acid (0,197 g, 0,897 mmol) in thionyl chloride (5 ml)containing a drop of DMF was heated under reflux for 3 hours. Excess reagents were removed under reduced pressure to get crude solid. Amide obtained in accordance with section description Amide linking with the use of untreated solids and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0.20 g, 0,897 mmol) in dry pyridine (15 ml) to give the title compound (0,087 g, 23%) as a colourless solid after processing and flash chromatography (1:1:0.1 to DHM/EtOAc/Meon).

1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.88 (s, 3H), 7.07 (dd, J=9.4, 1. Hz, 1H), 7.30-7.34 (m, 2H), 7.45 (d, J=9.4 Hz, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 8.22 (s, 1H), 8.28 (d, J=0.7 Hz, 1H), 10.51 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.97, 56.38, 108.77, 112.59 (q, JCF=5.4 Hz), 116.38, 117.65, 120.16, 121.77, 123.92 (q, JCF=274 Hz), 124.61, 126.29, 128.12 (q, JCF=32 Hz), 128.19, 129.05 (q, JCF=2.3 Hz), 130.05, 131.04, 138.98, 144.31, 144.48. 160.39, 165.82.

N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-2,6-debtor-4-hydroxybenzamide

no connection SKT06-137

Obtained in accordance with the description of the Demethylation section above using 2,6-debtor-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (0.10 g, 0,254 mmol) in dry DHM (9 ml) and BBr3in DHM (1,Ω, 1.3 ml, 1.3 mmol) at 0°C. to obtain the title compound (to 0.055 g, 57%) as a pale yellow solid after processing and flash chromatography (15:1 DHM/Meon, then 10:1 DHM/Meon and, finally, 5:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 6.53 (d, JHF=10.7 Hz, 2H), 7.09 (d, J=9.8 Hz, 1H), 7.47 (d, J=9.8 Hz, 1H), 7.73 (d, J=7.9 Hz, 2H), 7.91 (d, J=7.9 Hz, 2H), 8.24 (s, 1H), 8.31 (s, 1H), 10.60 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.97, 99.73 (d, JCF=25.7 Hz), 107.07 (t, JCF=22.6 Hz), 108.84, 116.36, 119.93, 121.81, 124.63, 126.38, 128.26, 130.18, 138.62, 144.29, 144.36, 158.85, 160.34 (dd, JCF=246 and 11.7 Hz), 160.91 (t, JCF=14.8 Hz).

2-fluoro-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-81

<> Mix a solution of 2-fluoro-4-methoxybenzoic acid (0,23 g of 1.34 mmol) in thionyl chloride (7 ml)containing a drop of DMF was heated under reflux for 4 hours. Excess reagents were removed under reduced pressure to get crude solid. Amide obtained in accordance with section description Amide linking with the use of untreated solids and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0,30 g of 1.34 mmol) in dry pyridine (15 ml) to give the title compound (0,323 g, 80%) as a colourless solid after processing and flash chromatography (EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.85 (s, 3H), 6.91 (d, J=9.0 Hz, 1H), 6.97 (d, J=13.1 Hz, 1H), 7.10 (d, J=9.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.66 (t, J=8.8 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.92 (d, J=7.9 Hz, 2H), 8.25 (s, 1H), 8.31 (s, 1H), 10.26 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.94, at 56.44, 102.34 (d, JCF=26.4 Hz), 108.71, 110.99 (d, JCF=2.3 Hz), at 116.39, 117.28 (d, JCF=14.1 Hz), 120.45, 121.73, 124.59, 126.28, 128.12, 130.06, 131.63 (d, JCF=4.7 Hz), 138.90, 144.48 (d, JCF=24.8 Hz), 160.82 (d, JCF=249 Hz), 162.79, 163.00, 163.10.

2-fluoro-4-hydroxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-103

Obtained in accordance with the description of the Demethylation section above using 2-fluoro-4-methoxy-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]benzamide (100 mg, 0,267 mmol) in dry DHM(10 ml) and BBr 3in DHM (1.0m, and 1.4 ml, 1.4 mmol) at -78°C To produce the title compound (30 mg, 31%) as a colourless solid after processing and flash chromatography (10:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 6.63-6.73 (m, 2H), 7.09 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.55 (t, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.23 (s, 1H), 8.31 (s, 1H), 10.13 (s, 1H), 10.47 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.95, 103.31 (d, JCF=24.9 Hz), 108.70, 112.15, 115.68 (d, JCF=13.2 Hz), at 116.39, 120.43, 121.73, 124.60, 126.27, 128.13, 129.94, 131.83 (d, JCF=4.6 Hz), 139.01, 144.50 (d, JCF=28.8 Hz), 160.92 (d, JCF=248 Hz), 161.73, 161.86, 163.01.

4-(methylamino)-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-3-(trifluoromethyl)benzamid

no connection SKT06-99

Stir a mixture of 4-fluoro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-3-(trifluoromethyl)benzamide (0.05 g, 0,121 mmol), methylamine hydrochloride (0.20 g, to 3.02 mmol) and K2CO3(0,42 g, to 3.02 mmol) in dry DMSO (5 ml) was heated at 160°C for 22 hours in an argon atmosphere. The cooled reaction mixture was added to water (100 ml) and the collected precipitate by vacuum filtration and dried in air. The solid was purified using flash chromatography (5:1 EtOAc/hexane) to give the title compound (0,032 g, 62%) as a pale yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.86 (d, J=4.3 Hz, 3H), 6.29-6.31 (q, J=3.9 Hz, 1H), 6.84 (d, =9.2 Hz, 1H), 7.09 (d, J=9.1 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 8.12 (br s, 2H), 8.24 (s, 1H), 8.31 (s, 1H), 10.13 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 17.96, 30.40, 108.74, 110.86 (q, JCF=29.6 Hz), 111.25, 116.20, 119.99, 120.58, 120.87, 121.94, 124.66, 125.21 (q, JCF=270 Hz), 126.16, 126.94 (q, JCF=6.1 Hz), 128.41, 129.36, 130.80, 133.71, 139.34, 144.17, 144.34, 149.07, 164.60.

4-(dimethylamino)-N-[4-(6-torymidae[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-131

Received in accordance with section description Amide linking using 4-(6-torymidae[1,2-a]pyridine-2-yl)aniline (100 mg, 0.44 mmol) and 4-dimethylaminobenzaldehyde (81 mg, 0.44 mmol) in dry pyridine (5 ml) to give the title compound (59 mg, 36%) as a pale yellow solid after processing and flash chromatography (1:1 DHM/EtOAc).

1H NMR (250 MHz, DMSO-d6) δ 3.01 (s, 6N), 6.77 (d, J=8.5 Hz, 2H), 7.31 (t, J=9.2 Hz, 1H), 7.63 (dd, J=9.2, 4.9 Hz, 1H), 7.82-7.93 (m, 6N), 8.33 (s, 1H), 8.75 (br s, 1H), 9.95 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 40.15, 110.42 (d, jcf=1.5 Hz), 111.28, 113.85 (d, JCF=41.2 Hz), 116.75 (d, JCF=25.6 Hz), 117.53 (d, JCF=9.3 Hz), 120.75, 121.62, 126.26, 128.87, 129.60, 139.99, 143.21, 146.30, 152.94, 152.98 (d, JCF=232.8 Hz), 165.66.

4-(dimethylamino)-N-[4-(6-itemids[1,2-a]pyridine-2-yl)phenyl]benzamide

no connection SKT06-165

Received in accordance with section description Amide linking using 4-(6-itemids[1,2-a]pyridine-2-yl)aniline is (100 mg, 0,298 mmol) and 4-dimethylaminobenzaldehyde (55 mg, 0,298 mmol) in dry pyridine (5 ml) to give the title compound (45 mg, 31%) as a pale yellow solid after flash chromatography (20:10:1 DHM/EtOAc/Meon).

1H NMR (250 MHz, DMSO-d6) δ 3.01 (s, 6N), 6.77 (d, J=8.5 Hz, 2H), 7.42 (s, 2H), 7.84-7.89 (m, 6N), 8.26 (s, 1H), 8.90 (s, 1H), 9.96 (s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 76.19, 108.72, 111.21, 118.13, 120.57, 121.44, 126.33, 128.46, 129.61, 131.76, 132.68, 140.06, 143.80, 145.13, 152.85, 165.64 (1 missing).

4-bromo-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-3-nitrobenzamide

no connection SKT08-153

To a stirred suspension of 4-bromo-3-nitrobenzoic acid (0,330 g, 1,344 mmol) in thionyl chloride (7 ml) was added a drop of DMF and the reaction mixture is boiled under reflux for 3 hours. The excess reagent was then removed under reduced pressure to get crude solid. Amide obtained in accordance with section description Amide linking with the use of untreated solids and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0,300 g, 1,344 mmol) in dry pyridine (16 ml) to give the title compound (0,448 g, 74%) as a yellow solid after treatment and recrystallization from a mixture of DMF/water (1:0.76 to about./vol.).

1H NMR (250 MHz, DMSO-d6) δ 2.27 (s, 3H), 7.10 (d, J=9.5 Hz, 1H), 7.47 (d, J=9.5 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.2 Hz, 2H), 8.09-8.18 (m, 2H) 8.26 (s, 1H), 8.31 (s, 1H), 8.59 (s, 1H), 10.60 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.95, 108.90, 116.33, 116.87, 121.10, 121.89, 124.67, 124.97, 126.32, 128.36, 130.46, 133.06, 135.49, 135.96, 138.48, 144.30, 144.34, 149.99, 162.93.

4-fluoro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-3-nitrobenzamide

no connection SKT08-165

To a stirred suspension of 4-fluoro-3-nitrobenzoic acid (0,254 g, 1,344 mmol) in thionyl chloride (7 ml) was added a drop of DMF and the reaction mixture is boiled under reflux for 3 hours. The excess reagent was then removed under reduced pressure to obtain the crude acid chloride. Amide obtained in accordance with section description Amide linking using the crude acid chloride and 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (0,300 g, 1,344 mmol) in dry pyridine (16 ml) to give the title compound (0,334 g, 64%) as a pale orange solid after treatment and recrystallization from a mixture of 1,4-dioxane/water (3,75:1 vol./vol.).

1H NMR (250 MHz, DMSO-d6) δ 2.27 (s, 3H), 7.09 (d, J=9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.78 (m, 1H), 7.84 (d, J=8.2 Hz, 2H). 7.96 (d, J=8.2 Hz, 2H), 8.25 (s, 1H), 8.30 (s, 1H), 8.35-8.47 (m, 1H), 8.77 (d, J=7.3 Hz, 1H), 10.61 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.94, 108.85, 116.42, 119.24 (d, JCF=21.8 Hz), 121.15, 121.78, 124.63, 126.16, 126.29, 128.19, 130.57, 132.23 (d, JCF=3.9 Hz), 136.08 (d, JCF=10.2 Hz), 137.18 (d, JCF=7.7 Hz), 138.49, 144.392, 144.51, 156.77 (d, JCF=266 Hz), 162.77.

Compounds in which Q represents-CH=CH-; -CR1=CH-; -CH=CR1-; or-CR1=CR1-

Benzothiazoline intermediate connection

5-methyl-2-aminobenzoyl

A mixture of 2-amino-6-methylbenzothiazole (15 g, of 91.3 mmol), ethylene glycol (22,26 g, 0.36 mol) and 50 wt%./about. KOHN (180 ml) was boiled under reflux for 62 hours. After cooling to room temperature was added toluene (60 ml) and the reaction mixture is cooled in an ice bath and was acidified with acetic acid (final pH 5-6). The reaction mixture was extracted with toluene (5×300 ml) and the combined organic extracts were washed brine (2×200 ml), dried (MgSO4) and solvent removed under reduced pressure to obtain the title compound (11.1 g, 86%) as a yellow solid, which was used without further purification.

1H NMR (250 MHz, CDCl3) δ 2.13 (s, 3H), 4.19 (br s, 2H), 6.64 (d, J=7.9 Hz, 1H), 6.95 (s, 1H), 6.97 (d, J=7.9 Hz, 1H);13With NMR (62.5 MHz, CDCl3) δ 20.09, 115.35, 118.92, 127.54, 132.37, 137.09, 146.22.

2-(4-(methyl bromide)phenyl-6-methylbenzothiazol

A mixture of 2-amino-5-methylbenzamide (0.518 g, 3.73 mmol), 4-bromomethylphenyl acid (0,80 g, 3.73 mmol) and trimethylsilyltriflate (11.2 ml) was boiled under reflux in toluene (20 ml) in an argon atmosphere for 15 hours. The reaction mixture was cooled to room temperature and added water (100 ml),then was extracted with chloroform (3×60 ml). The combined organic extracts were washed brine (60 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a light brown solid, which was washed Et2O (60 ml) to give the title compound (0,816 g, 69%) as a colourless solid.

1H NMR (250 MHz, CDCl3) δ 2.49 (s, 3H), 4.52 (s, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.67 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 21.62, 32.70, 121.42, 122.82, 127.85, 128.11, 129.71, 133.70, 135.22, 135.66, 140.39, 152.16, 166.17; MCHP (ESI) 319.9 (M+(81Br)+H, 100%), 317.9 (M+(79Br)+H, 93%).

2-(4-(methyl bromide)phenyl-6-methoxybenzothiazole

A mixture of 2-amino-5-methoxybenzamide (9,25 g, 59,7 mmol) and 4-bromomethylphenyl acid (12.8 g, 59,7 mmol) in trimethylsilyltriflate (70 ml) has been carefully mixed and heated at 110°C in argon atmosphere for 3 hours. The reaction mixture was cooled to 60°C. and added water (25 ml), then was extracted with chloroform (5×80 ml). The combined organic extracts were washed brine (150 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a brown solid, which was purified using flash chromatography (4:1 DHM/hexane) to give the title compound (10,9 g, 55%) as a colourless solid.

1 H NMR (250 MHz, CDCl3) δ 3.88 (s, 3H), 4.52 (s, 2H), 7.09 (dd, J=8.9, 2.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.9 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ at 32.75, 55.85, 104.16, 115.85, 123.84, 127.63, 129.70, 133.78, 136.50, 140.13, 148.69, 157.94, 164.66.

The synthesis described in the work of Yoshino with co-authors (Yoshino et al.).

Diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate

A mixture of 2-(4-(methyl bromide)phenyl-6-methylbenzothiazole (0,30 g of 0.94 mmol) and triethylphosphite (3.5 ml) was heated at 170°C for 15 minutes in an argon atmosphere. After cooling to room temperature the excess triethylphosphite removed by distillation to obtain a brown oily liquid, which solidified upon cooling. Specified solid was purified using flash chromatography (3:1 EtOAc/hexane) to give the title compound (0,319 g, 90%) as a colourless solid.

1H NMR (250 MHz, CDCl3) δ 1.22 (t, J=7.0 Hz, 6N), 2.45 (s, 3H), 3.18 (d, JHP=22 Hz, 2H), 4.01 (m, 4H), 7.25 (dd, J=8.2, 1.2 Hz, 1H), 7.39 (dd, J=8.2, 2.4 Hz, 2H), 7.64 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.99 (d, J=8.2 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 16.41 (d, JCP=5.8 Hz), 21.57, 33.86 (d, JCP=138 Hz), 62.29 (d, JCP=6.8 Hz), 121.37, 122.66, 127.54, 127.94, 130.40 (d, JCP=6.8 Hz), 132.44 (d, JCP=1.9 Hz), 134.74 (d, JCP=9.8 Hz), 135.28 (d, JCP=12.7 Hz), 135.38, 152.23, 166.60.

The synthesis described in the work of Yoshino with co-authors (Yoshino et al.).

Diethyl 4-(6-methoxybenzothiazole-2-yl)b is nilpotent

A mixture of 2-(4-(methyl bromide)phenyl-6-methoxybenzothiazole (10.0 g, 29,95 mmol) and triethylphosphite (20 ml) was heated at 130°C for 4 hours in argon atmosphere. After cooling to room temperature, the obtained solid substance was recrystallize from cyclohexane to obtain the title compound (11,25 g, 96%) as a colourless solid.

1H NMR (250 MHz, CDCl3) δ 1.23 (t, J=7.3 Hz, 6N), 3.18 (d, JHP=22 Hz, 2H), 3.86 (s, 3H), 4.01 (m, 4H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.39 (dd, J=8.2, 2.1 Hz, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.2 Hz, 2H);13C NMR (100.5 MHz, CDCl3) δ 16.39 (d, JCP=6.2 Hz), 33.83 (d, JCP=138 Hz), 55.79, 62.26 (d, JCP=7.0 Hz), 104.15, 115.65, 123.65, 127.35 (d, JCP=3.1 Hz), 130.38 (d, JCP=6.2 Hz), 132.43 (d, JCP=3.1 Hz), 134.48 (d, JCP=9.3 Hz), 136.37, 148.64, 157.78, 165.16 (d, JCP=2.3 Hz).

2-bromo-1-tert-butyldimethylsiloxy

To a stirred solution of bromoethanol (9,912 g, 79,32 mmol) in dry DHM (25 ml) was added in one portion tert-butyldimethylsilyloxy (13,212 g, 85,03 mmol) and the reaction mixture was stirred at room temperature. Then dropwise added a solution of triethylamine (8,865 g, 12.3 ml, 87,61 mmol) in dry DHM (40 ml) for 1 hour and 20 minutes. The reaction mixture was stirred at room temperature for 3 days, then added water (30 ml). The organic phase was separated, and the aqueous phase is ex who was regionali DHM (2×20 ml). The combined organic extracts were washed brine (30 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain pale yellow oily liquid. Distillation under reduced pressure led to the title compound (10,54 g, 55%) as a colorless oily liquid.

1H NMR (250 MHz, CDCl3) δ 0.08 (s, 6N), 0.90 (s, 9H), 3.34 (t, J=6.41 Hz, 2H), 3.88 (t, J=6.4 Hz);l3C NMR (62.5 MHz, CDCl3) δ 5.23, 18.35, 25.85, at 33.31, 63.54.

Received in accordance with a method adapted from the work of Kawabe with co-authors (Kuwabe et al.).

4-([2-tert-butyldimethylsiloxy]ethoxy)benzaldehyde

To a stirred suspension of 4-hydroxybenzaldehyde (0,500 g to 4.012 mmol) and anhydrous potassium carbonate (0,833 g 6,019 mmol) in dry MeCN (15 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxy (83%, 1,730 g 6,019 mmol) and the reaction mixture is boiled under reflux in the course of 20.5 hours. Added water (25 ml) and the reaction mixture was extracted with Et2O (4×25 ml). The combined organic extracts were washed brine (50 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a light yellow oily liquid, which was purified using flash chromatography (3:1 hexane/Et2O) to give the title compound (0,895 g of 7.5%) as a colorless oily liquid.

1H NMR (250 MHz, CDCl3) δ 0.08 (s, 6N), 0.89 (s, 9H), 3.98 (t, J=4.3 Hz, 2H), 4.11 (t, J=4.3 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 9.87 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 5.20, 18.42, 25.90, 61.81, 69.67, 114.88, 129.96, 131.99, 164.09, 190.78.

Received in accordance with a method adapted from the work of Kawabe with co-authors (Kuwabe et al.).

6-methoxy-2-(4-{(E)-2-[4-(2-tert-butyldimethylsilyloxy)phenyl]ethynyl}phenyl)-1,3-benzothiazol

no connection SKT08-101

In calcined round bottom flask in an argon atmosphere was added sodium hydride (68 mg, 60% dispersion in mineral oil, 1,71 mmol), which was washed with dry hexane (3x8 ml) and the flask was placed in a deep vacuum for 5 minutos premises flask in an atmosphere of argon was added dry THF (35 ml) and the suspension was stirred at room temperature for 5 minut.zatem added diethyl [4-(6-methoxy-1,3-benzothiazol-2-yl)benzyl]phosphonate (0,558 g of 1.43 mmol) as a solid in several portions in for 1 minute and the reaction mixture was stirred at room temperature for 30 minutes before adding dropwise during 1 minute 4-([2-tertBUTYLPEROXY]ethoxy)benzaldehyde (0.400 g, 1,43 mmol). The reaction mixture is then boiled under reflux for 16.5 hours. After cooling to room temperature, added water (1 ml) and solvent removed under reduced d is the pressure to obtain yellow solid, which recrystallize from a mixture of DMF/water (15:1) to give the title compound (0,549 g, 74%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 0.06 (s, 6N), 0.86 (s, 9H), 3.85 (s, 3H), 3.91 (t, J=4.7 Hz, 2H), 4.06 (t, J=4.7 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 7.15 (d, J=16.4 Hz, 1H), 7.32 (d, J=16.4 Hz, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.69 (m, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.91 (d, J=9.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H).

2-(4-{(E)-2-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]vinyl}phenoxy)ethyl ester methanesulfonic acid

no connection SKT08-179

To a stirred solution of 2-(4-{(E)-2-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]ethynyl}phenoxy)ethanol (55,2 mg, 0,137 mmol) in dry pyridine (10 ml) at room temperature was added methanesulfonamide (22,4 CL, 0,287 mmol). After maturation for 15 hours at room temperature the reaction mixture was cooled to 0-5°C. and added ice water (25 ml) to give a yellow precipitate, which was collected via vacuum filtration and washed with water (4×30 ml) and dried in an oven at 85°C for 1.5 hours. The yellow solid is washed Et2O and dried at 85°C for 2 hours to obtain the title compound (53,5 mg, 81%) as a yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 3.25 (s, 3H), 3.86 (s, 3H), 4.30 (m, 2H), 4.55 (m, 2H), 7.02 (d, J=8.5 Hz, 2H), 7.15 (m, 1H), 7.21 (d, J=16.5 Hz, 1H), 7.37 (d, J=16.5 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.72 (m, 1H), 7.74 (d,J=8.5 Hz, 2H), 7.94 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H).

Benzothiazoline connection

Non-fluorinated metaxylene

2-{4-[2-(2-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT01-71

Received in accordance with section description Receive alkene.

1H NMR (250 MHz, CDCl3) δ 3.89 (s, 3H), 7.07-7.13 (m. 2H), 7.35 (s, 1H), 7.39-7.45 (m, 1H), 7.59-7.64 (m, 4H), 7.72-7.79 (m, 1H), 7.93-8.00 (m, 2H), 8.04 (d, J=7.9 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 55.85, 104.14, 115.83, 123.81, 124.95, 127.65, 128.28, 128.33, 132.80, 132.89, 133.25, 133.72, 136.51, 138.61, 148.05, 148.79, 157.89, 164.88 (2 missing).

2-{4-[2-(3-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT01-73

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.10 g, 0.25 mmol) and 3-nitrobenzaldehyde (0.39 g, 0.25 mmol) in dry MeOH (10 ml) and 0.5 m of sodium methoxide (of 1.02 ml, 0.51 mmol) to give the title compound (0.079 in g, 80%) as a yellow feathery crystals after treatment and recrystallization from Snss.

X 3120, 1603, 1560, 1521, 1489, 1464, 1403, 1358, 1287, 1264, 1225, 1062, 1026. 967, 815 cm-1;1H NMR (250 MHz, CDCl3) δ 3.89 (s, 3H), 7.09 (dd, J=8.8, 2.1 Hz, 1H), 7.20 (dist (d, J=18 Hz, 1H), 2.27 (dist (d, J=18 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.50-7.57 (m, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.81 (d, J=7.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 8.11 (d, J=8.5 Hz, 1H), 8.39 (s, 1H).

2-{4-[2-(4-nitrophenyl)vinyl]phenyl}-6-methoxybenzo the azole

no connection SKT02-67

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (3.0 g, 7,66 mmol) in dry MeOH (60 ml) and 0.5 m of sodium methoxide (30,6 ml of 15.3 mmol) to give the title compound (2,189 g, 74%) as an orange solid after processing.

1H NMR (250 MHz, CDCl3) δ 3.89 (s, 3H), 7.10 (dd, J=9.2, 2.1 Hz, 1H), 7.21 (dist (d, J=17.7 Hz, 1H), 7.30 (dist (d, J=17.7 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.95 (d, J=9.1 Hz, 1H), 8.06 (d,, J=8.2 Hz, 2H), 8.23 (d, J=8.5 Hz, 2H);13With NMR (62.5 MHz, CDCl3/DMSO-d6) δ 55.79, 104.09, 115.83, 123.66, 124.12, 127.09, 127.55, 127.71, 132.21, 133.73, 136.40, 138.24, 143.45, 146.84, 148.61, 157.86, 164.58 (1 missing).

2-{4-[2-(2-AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT01-109

Received in accordance with section description restoration of the nitro group using 2-{4-[2-(2-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole (0.03 g, 0,077 mmol) and chloride dihydrate tin (II) (0,139 g, 0,618 mmol) in EtOH (3 ml) to give the title compound as a colourless solid (0,019 g, 68%) after treatment and flash chromatography (DHM, then 6:3:1 DHM/hexane/EtOAc).

13With NMR (100 MHz, DMSO-d6) δ 56.23, 97.72, 105.34, 109.42, 116.51, 120.44, 120.96, 122.85, 123.39, 123.89, 127.52, 128.53, 132.37, 133.57, 136.18, 136.30, 136.53, 148.56, 158.03, 164.61.

2-{4-[2-(3-AMINOPHENYL)vinyl]phenyl}-6-meth is cybersociety

no connection SKT01-107

Received in accordance with section description restoration of the nitro group using 2-{4-[2-(3-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole (0,046 g, amount of 0.118 mmol) and chloride dihydrate tin (II) (0,214 g, 0,947 mmol) in EUN (3 ml) to give a colorless solid (0,023 g, 54%) after treatment and flash chromatography (3:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 3.71 (br s, 2H), 3.91 (s, 3H), 6.71 (dd, J=8.8, 2.1 Hz, 1H), 6.85 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 7.06-7.20 (m, 4H), 7.34 (d, J=2.1 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.5 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 55.84, 104.16, 113.02, 115.10, 115.71, 117.52, 123.67, 126.98, 127.58, 129.71, 130.36, 132.68, 136.42, 138.05, 139.68, 146.73, 148.79, 157.77, 165.24 (1 missing).

2-{4-[2-(4-AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT01-189

Received in accordance with section description restoration of the nitro group using 2-{4-[2-(4-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole (0.10 g, 0.28 mmol) and chloride dihydrate tin (II) (0.5 g, of 2.23 mmol) in EUN (7 ml) to give the title compound as a yellow solid (0.04 g, 43%) after treatment and flash chromatography (2:1 hexane/EtOAc).

1H NMR (250 MHz, CDCl3) δ 3.79 (br s, 2H), 3.89 (s, 3H), 6.68 (d, J=8.2 Hz, 2H), 6.94 (dist (d, J=16.2 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 7.12 (dist (d, J=16.2 Hz, 1H), 7.34 (s, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.2 Hz, 2H);13C I Is R (62.5 MHz, CDCl3/DMSO-d6) δ at 55.20, 103.84, 113.98, 115.24, 121.72, at 122.77, 124.70, 125.80, 126.75, 127.51, 130.32, 130.78, 135.58, 140.04, 147.89, 148.06, 157.05, 164.13.

2-{4-[2-(4-dimethylaminophenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT03-57

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.50 g, 1.28 mmol) and 4-dimethylaminobenzaldehyde (0.21 g, of 1.41 mmol) in dry Meon (10 ml) and 0.5 m of sodium methoxide (3,48 ml of 1.74 mmol) to give the title compound (0.187 g, 38%) as a yellow solid after processing.

1H NMR (250 MHz, CDCl3) δ 2.99 (s, 6N), 3.89 (s, 3H), 6.72 (d, J=8.5 Hz, 2H), 6.93 (d, J=16.2 Hz, 1H), 7.08 (dd, J=8.8, 2.1 Hz, 1H), 7.15 (d, J=16.2 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.2 Hz, 2H).

2-(4-{(E)-2-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]ethynyl}phenoxy)ethanol

no connection SKT08-143

To a stirred solution of 6-methoxy-2-(4-{(E)-2-[4-(2-tert-butyldimethylsilyloxy)phenyl]ethynyl}phenyl)-1,3-benzothiazole (0,200 g, 0,386 mmol) in dry DMF (5 ml) and dry THF (15 ml) at room temperature dropwise added TBAF (1M in THF of 0.85 ml, 0.85 mmol) for 2 minutes. After maturation for 2 hours at room temperature was added a saturated solution of NH4Cl (30 ml) to give a yellow precipitate, which was collected via vacuum is about filtering. The yellow solid was washed with water (2×20 ml) and then left to dry in air for 2 hours. Additional drying at 65°C for 17 hours has led to the title compound (0,136 g, 87%) as a yellow solid.

X 3500-3100 (br), 3017, 2941, 2864, 1601, 1558, 1513, 1485, 1462, 1435, 1299, 1252, 1225, 1175, 1083, 1052, 1022, 967, 830, 816 cm-1;1H NMR (250 MHz, DMSO-d6) δ 3.69-3.80 (m, 2H), 3.86 (s, 3H), 4.00-4.08 (m, 2H), 4.88 (m, 1H), 6.97 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.18 9d, J=15.6 Hz, 1H), 7.35 (d, J=15.6 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.70-7.78 (m, 3H), 7.94 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H).

Fluorinated metaxylene

2-{4-[2-(2-triptoreline)vinyl]phenyl}-6-methoxybenzothiazole

no connection SK2033-44

Received in accordance with section description Receive alcuna using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (100 mg, 0,255 mmol) in dry THF (10 ml), 2-triptoreline (44 mg, 0,255 mmol) in dry THF (5 ml) and t-butoxide potassium (32 mg, 0,280 mmol) in dry THF (5 ml) to give the title compound (77 mg, 73%) as light yellow plates after processing, flash chromatography (3:DHM/hexane) and recrystallization from acetone.

1H NMR (250 MHz, CDCl3) δ 3.89 (s, 3H), 7.07-7.09 (m, 1H), 7.11-7.14 (m, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.51-7.55 (m, 1H), 7.55-7.65 (m, 3H), 7.68 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H); ICSD (ESI+) m/z 412 (M++H, 100%).

2-{4-[2-(4-chlor-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT03-91

Received in accordance with section description Receive alkene with the use of sodium hydride (60% dispersion in mineral oil, 0,077 g, 1.92 mmol), diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.5 g, 1.28 mmol) and 4-chloro-3-nitrobenzaldehyde (0.26 g, of 1.41 mmol) in dry THF (20 ml) to give the title compound (0,251 g, 46%) as a pale orange needle-like particles after treatment and recrystallization from 1,2-dichloroethane.

1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.13 (d, J=8.5 Hz, 1H), 7.45 (d, J=17.7 Hz, 1H), 7.60 (d, J=17.7 Hz, 1H), 7.71-7.81 (m, 4H), 7.94 (d, J=8.2 Hz, 2H), 8.05 (d, J=7.0 Hz, 2H), 8.34 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 56.23, at 105.35, 116.42, 123.38, 123.80, 123.87, is the 127.20, at 127.70, 128.08, 131.55, 131.81, 132.29, 133.21, 136.55, 138.16, 139.10, 148.53, 148.60, 158.09, 164.51.

2-{4-[2-(3-triptoreline)vinyl]phenyl}-6-methoxybenzothiazole

no connection SK2033-42

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (100 mg, 0,255 mmol) in dry THF (10 ml), t-butoxide potassium (32 mg, 0,280 mmol) in dry THF (5 ml) and 3-triptoreline (44 mg, 0,255 mmol) in dry THF (5 ml) to give the title compound (78 mg, 74%) as a colourless solid after processing and flash chromatography (4:1 DHM/hexane).

1H NMR (250 MHz, acetone-d6) δ 3.87 (s, 3H), 7.08 (d, J8.5 Hz, 1H), 7.36 (s, 2H), 7.47-7.59 (m, 3H), 7.75 (d, J=8.2 Hz, 2H), 7.80-7.90 (m, 3H), 8.06 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 55.86, 104.19, 115.83, 123.25, 123.73, 124.40, 127.24, 127.68, 128.56, 129.25, 129.59, 129.76, 131.23 (q, JCF=33.2 Hz), 133.22, 136.40, 137.79, 138.90, 148.65, 157.89, 165.02 (1 missing).

2-{4-[2-(4-triptoreline)vinyl]phenyl}-6-methoxybenzothiazole

no connection SK2033-40

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (100 mg, 0,255 mmol) in dry THF (10 ml), t-butoxide potassium (32 mg, 0,280 mmol) in dry THF (5 ml) and 4-triptoreline (44 mg, 0,255 mmol) in dry THF (5 ml) to give the title compound (51 mg, 49%) as a pale yellow solid after processing, flash chromatography (4:1 DHM/hexane) and recrystallization from acetone.

X 3022,2942,2839, 1606,1556,1487,1462,1437, 1418, 1326, 1268, 1215, 1164, 1120, 1068, 1028, 1014, 966, 844, 829, 812 cm-1;1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.09 (d, J=8.2 Hz, 1H), 7.39 (s, 2H), 7.56 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.74 (d, J=7.9 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 1H), 8.02 (d, J=7.9 Hz, 2H).

2-{4-[2-(4-(2,2,2-triptoreline)phenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-17

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.15 g, 0.38 mmol) in dry Meon (5 ml), a solution of 0.5m of methoxide NAT is FL (1,54 ml, 0.77 mmol) and 4-(2,2,2-triptoreline)benzaldehyde (0,078 g, 0.38 mmol) to give the title compound (0,132 g, 78%) as a slight yellow needle-like particles after processing recrystallization from 1,2-dichloroethane.

1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.80 (q, J=9.0 H, 2H), 7.09 (d, J=8.6 Hz, 2H), 7.13 (dd, J=9.0, 2.3 Hz, 1H), 7.24 (d, J=16.5 Hz, 1H), 7.37 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.93 (d, J=9.0 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H);13With NMR (100 MHz, DMSO-d6) δ 56.28, 65.26 (q, JCF=34.3 Hz), 105.46, 115.75, 116.38, 123.79, 126.63, 127.47, 127.67, 128.64, 129.97, 131.54, 132.26, 136.46, 140.30, 148.64, 157.37, 158.04, 164.78 (1 missing).

2-{4-[2-(4-(4,4,4-triptoreline)phenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-11

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.15 g, 0.38 mmol) in dry Meon (5 ml), a solution of 0.5 m of sodium methoxide (1,54 ml, 0.77 mmol) and 4-(4,4,4-triptoreline)benzaldehyde (0,089 g, 0.38 mmol) to give the title compound (to 0.108 g, 60%) as a slight yellow needle-like particles after processing recrystallization from 1,2-dichloroethane.

X 3019, 2942, 2878, 2837, 1603, 1558, 1510, 1462, 1437, 1386, 1247, 1227, 1176, 1151, 1061, 1025, 966, 832 cm-1;1H NMR (400 MHz, DMSO-d6) δ 1.90-2.00 (m, 2H), 2.36-2.51 (m, 2H), 3.86 (s, 3H), 4.08 (t, J=6.2 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 7.11-7.17 (m, 1H), 7.17 (d, J=16.8 Hz, 1H), 7.33 (d, J=16.8 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.69 (m, 1H), 7.7 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.6 Hz, 1H), 8.10 (d, J=8.2 Hz, 2H).

2-{4-[2-(4-(N-TRIFLUOROACETYL)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-117

To a stirred suspension of 2-{4-[2-(4-AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (0.20 g, 0,558 mmol) in toluene (10 ml) was added TFAA (0.26 g, of 1.23 mmol) and the reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and added DHM (15 ml) and Et2O (40 ml), collected precipitate by filtration, washed Et2O and dried in vacuum at room temperature for 6 hours to obtain the title compound (0,183 g, 72%) as a pale orange solid.

1H NMR (250 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 7.32 (dist (d, J=17.4 Hz, 1H), (7.41 (dist (d, J=17.4 Hz, 1H), 7.67-7.76 (m, 5H), 7.77 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.8 Hz, 1H), 8.05 (d, J=8.2 Hz, 2H), 11.34 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ 56.28, 105.45, 116.25 (q, JCF=289 Hz), 116.40, 121.69, 123.83. 127.68, 127.69, 127.76, 127.97, 129.84, 132.53, 134.67, 136.49, 140.03, 148.64, 154.88 (q, JCF=36.5 Hz), 158.06, 164.71 (1 missing).

2-{4-[2-(4-(N-2,2,2-triptorelin)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-153

To a stirred suspension of 2-{4-[2-(4-(N-TRIFLUOROACETYL)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (0.10 g, 0.22 mmol) in dry THF (20 ml) at room temperature portions added alumag did lithium (0,033 g, 0.88 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then boiled under reflux for 18 hours. The reaction mixture was cooled to 0-5°C and diluted Et2O (5 ml). Slowly added water (1 ml), then added a 15% NaOH (0.2 ml) and the reaction mixture left to warm to room temperature. To the reaction mixture was added MgSO4(30 mg) and after 15 minutes the salt was collected by filtration. The filtrate was concentrated to obtain solid, which was stirred with a catalytic amount of iodine in DHM (5 ml). The reaction mixture was washed with water (10 ml), 10% solution of sodium sulfite (10 ml) and brine (10 ml) and solvent removed under reduced pressure to obtain solid, which was purified using flash chromatography (DHM) to obtain the title compound (to 0.060 g, 62%) as an orange solid.

1H NMR (250 MHz, CDCl3) δ 3.76-3.88 (m, 2H), 3.89 (s, 3H), 4.04 (t, J=2.1 Hz, 1H), 6.69 (d, J=8.5 Hz, 2H), 6.95 (dist (d, J=17.1 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 7.12 (dist (d, J=17.1 Hz, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.5 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H);13C NMR (100.5 MHz, DMSO-d6) δ 44.49 (q, JCF=32.7 Hz), 56.26, 105.45, 113.09, 116.31, 123.38, 123.72, 126.24 (q, JCF=281 Hz), 126.49, 127.00, 127.64, 128.40, 131.07, 131.59, 136.39, 140.97, 148.25, 148.66, 157.99, 164.91.

2-{4-[2-(4-(N-3,3,3-cryptochromes)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-119

To a stirred solution of 2-{4-[2-(4-AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (0,30 g, 0,838 mmol) in THF (13 ml) at room temperature was added in one portion 3,3,3-triterpanes (0,094 g, 0,838 mmol). Then added acetic acid (48 CL, 0,838 mmol) and the reaction mixture was stirred for 5 minutes before adding triacetoxyborohydride sodium (0.25 g at 1.17 mmol) in portions over 15 minutes. Then continued stirring at room temperature. After 48 hours have been spent adding additional 3,3,3-triterpanes (0,094 g, 0,838 mmol) and continued stirring for 24 hours. Then added sodium bicarbonate (15 ml) and the reaction mixture was extracted with EtOAc (4×30 ml), the combined extracts were washed brine (40 ml) and dried (Na2SO4). Removed solvent under reduced pressure and the residue was purified using flash chromatography (10:1 DHM/hexane) to give the title compound (0,149 g, 39%) as an orange solid.

1H NMR (400 MHz, DMSO-d6) δ 2.47-2.59 (m, 2H), 3.33 (q, J=6.7 Hz, 2H), 3.85 (s, 3H), 5.99 (t, J=5.8 Hz, 1H), 6.62 (d, J=8.6 Hz, 2H), 6.99 (d, J=16.4 Hz, 1H), 7.12 (dd, J=8.6, 2.3 Hz, 1H), 7.23 (d, J=16.4 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.66 (d, J=2.3 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.97 (d, J=8.6 Hz, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 32.97 (q, JCF=26.4 Hz), 36.49 (q, JCF=3.1 Hz), 105.43, 112.70, 11629, 122.78, 123.70, 125.59, 126.91, 127.44 (q, JCF=277 Hz), 127.63, 128.59, 131.28, 131.46, 136.38, 141.08, 148.67, 148.80, 157.97, 164.92.

2-{4-[2-(4-(N-4,4,4-trifloromethyl)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-81

To a stirred solution of 2-{4-[2-(4-AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (0.10 g, 0.28 mmol) in 1,2-dichloroethane (5 ml) at room temperature was added in one portion 4,4,4-triptoreline (0.035 g, 0.28 mmol). Then added acetic acid (48 l, 0.28 mmol) and the reaction mixture was stirred for 10 minutes before adding triacetoxyborohydride sodium (0.083 g, 0,39 mmol) in portions over 15 minutes. Then continued stirring at room temperature. After 24 hours spent adding additional 4,4,4-triptoreline (0.035 g, 0.28 mmol) and continued stirring for 72 hours. Then added sodium bicarbonate (15 ml) and the reaction mixture was extracted with EtOAc (3×30 ml), the combined extracts were washed brine (30 ml) and dried (Na2SO4). The crude solid was dissolved in CHCl3(8 ml) and stirred with a catalytic amount of iodine within 24 hours. The reaction mixture was washed with water (10 ml), 10% solution of sodium sulfite (10 ml) and brine (10 ml) and solvent removed under reduced pressure to obtain solid, which was purified using flash XP is matography (DHM) to obtain the title compound (0.06 g, 46%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 1.72-1.79 (m, 2H), 2.27-2.40 (m, 2H), 3.10-3.18 (m, 2H), 3.84 (s, 3H), 5.85-5.97 (m, 1H), 6.59 (d, J=8.6 Hz, 2H), 6.97 (d, J=16.4 Hz, 1H), 7.11 (dd, J=9.0, 2.8 Hz, 1H), 7.21 (d, J=16.4 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.66 (d, J=2.8 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H);13C NMR (100.5 MHz, DMSO-d6) δ at 21.85 (q, JCF=6.2 Hz), 30.89 (q, JCF=28.0 Hz), 41.81, 56.25, 105.43, 112.55, 116.27, 122.42, 123.68, 125.07, 126.84, 127.61, 128.55, 129.59. 131.37, 131.39, 136.36, 141.15, 148.66, 149.44, 157.95, 164.93.

2-{4-[2-(4-forfinal)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT02-137

Received in accordance with section description Receive alkene using NaH (60% dispersion, 0,050 g of 1.02 mmol), diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.25 g, 0.64 mmol) and 4-forventelige (0.08 g, 0.64 mmol) in dry THF (5 ml) to give the title compound (0,122 g, 53%) as a pale yellow solid after treatment and recrystallization from 1,2-dichloroethane.

X 3021, 2963, 2941, 2837, 1600, 1556, 1507, 1487, 1460, 1435, 1319, 1266, 1237, 1212, 1065, 1026, 966, 840, 822, 807 cm-1;1H NMR (250 MHz, CDCl3) δ 3.89 (s, 3H), 7.00-7.11 (m, 4H), 7.17 (dist (d, J=15.9 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H).

2-{4-[2-(4-hydroxy-3-nitrophenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT03-107

Obtained in accordance with the description of the section of the Receipt of the alkene with the use of sodium hydride (60% dispersion in mineral oil, 0,286 g, 7,15 mmol), diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.5 g, 1.28 mmol) and 4-fluoro-3-nitrobenzaldehyde (0.24 g, of 1.41 mmol) in a mixture of dry DMF (5 ml) and THF (20 ml) to give the title compound (0.10 g, 19%) as a red solid after processing and flash chromatography (DHM).

1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 7.08 (dd, J=8.9, 2.4 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.25 (d, J=16.4 Hz, 1H), 7.35 (d, J=16.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.81 (dd,J=8.9, 2.4 Hz, 1H), 7.88 (d,, J=8.9 Hz, 1H), 7.98 (d, J=8.2 Hz, 2H), 8.09 (d, J=2.4 Hz, 1H), 11.2 (br s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ at 56.41, 105.52, 116.65, 120.18, 123.84, 124.01, 127.82, 127.88, 128.65, 129.23, 132.63, 133.45, 136.64, 137.74, 140.11, 148.75, 152.36, 158.19, 164.89 (1 missing).

2-{4-[2-(4-(2-floratone)phenyl)vinyl]phenyl}-6-methoxybenzothiazole

no connection SKT03-77

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.06 g, 0,153 mmol), sodium methoxide (0.5 m solution in MeOH, and 0.46 ml, 0.23 mmol) and 4-(2-floratone)benzaldehyde (0,028 g has 0.168 mmol) in dry MeOH (5 ml) to give the title compound (0,048 g, 77%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.27 (dist d of t, JHF=30.1 Hz, JHH=3.9 Hz, 2H), 4.74 (dist d of t, JHF=48.1 Hz, JHH=3.9 Hz, 2H), 7.00 (d, J=8.6 Hz, 2H), 7.13 (dd, J=9.0, 2.7 Hz, 1H), 7.18 (d, J=16.4 Hz, 1H), 7.33 (d, J=16.4 Hz, 1H), 7.59 (d, J=9.0 is C, 2H), 7.69 (d, J=2.7 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.93 (d, J=9.0 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H).

6-methoxy-2-(4-{(E)-2-[2-methoxy-5-(triptoreline)phenyl]ethynyl}phenyl)-1,3-benzothiazol

no connection SKT04-187

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.75 g, 1.92 mmol), 0.5m solution of sodium methoxide (7.7 ml of 3.84 mmol) and 2-methoxy-5-triphtalocyaninine (0,42 g, 1.92 mmol) in dry MeOH (10 ml) to give the title compound (0,732 g, 83%) as a pale yellow solid after processing.

1H NMR (250 MHz, CDCl3) δ 3.87 (s, 3H), 3.89 (s, 3H), 6.86 (d, J=8.8 Hz, 1H), 7.06-7.14 (m, 3H), 7.33 (d, J=2.1 Hz, 1H), 7.45 (s, 1H), 7.49 (d, J=17 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 55.81, 55.98, 104.16, 111.61, 115.71, 119.26, 120.67 (q, JCF=256 Hz), 121.39, 123.58, 123.69, 127.21. 127.40, 127.54, 129.53, 132.96, 136.45, 139.57, 142.88, 148.81, 155.46, 157.82, 165.13.

6-methoxy-2-(4-{(E)-2-[4-methoxy-2-(trifluoromethyl)phenyl]ethynyl}phenyl)-1,3-benzothiazol

no connection SKT04-159

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0,89 g, 2.28 mmol), 0.5m solution of sodium methoxide (9,2 ml, 4,56 mmol) and 4-methoxy-2-triphtalocyaninine (0,47 g, 2.28 mmol) in dry MeOH (10 ml) to give the title compound (0,67 g, 6%) as a yellow/green solid after processing.

1H NMR (250 MHz, DMSO-d6) δ 3.86 (s, 3H), 3.89 (s, 3H), 6.99 (d, J=16.2 Hz, 1H), 7.05-7.11 (m, 2H), 7.19 (d, J=2.1 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.48 (d, J=16.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.94 (d,, J=8.8 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 55.62, 55.84, 104.16, 111.61 (q, JCF=5.9 Hz), 115.72, 117.51, 123.73, 124.16 (q, JCF=274 Hz), 125.32, 127.18, 127.60, 128.31, 128.49, 128.79 (q, JCF=29.8 Hz), 129.77, 133.03, 136.47, 139.35, 148.83, 157.82, 158.98, 165.08.

6-methoxy-2-(4-{(E)-2-[4-methoxy-3-(trifluoromethyl)phenyl]ethynyl}phenyl)-1,3-benzothiazol

no connection SKT03-167

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0,89 g, 2.28 mmol), 0.5m solution of sodium methoxide (9,2 ml, 4,56 mmol) and 4-methoxy-3-triphtalocyaninine (0,47 g, 2.28 mmol) in dry Meon (15 ml) to give the title compound (0,683 g, 68%) as a pale yellow solid after processing.

1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 3.92 (s, 3H), 7.13 (dd, J=8.6, 2.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.30 (d, J=16.4 Hz, 1H), 7.40 (d, J=16.4 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.86-7.91 (m, 2H), 7.92 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 56.28, 56.83, 105.46, at 113.91, at 116.39, 117.87 (q, JCF=30.4 Hz), 123.81, 124.14 (q, JCF=272 Hz), 125.51 (q, JCF=5.4 Hz), 127.51, 127.60, 127.68, 128.96, 128.98, 129.87, 132.45, 132.51, 136.48, 140.06, 148.63, 157.18, 158.06, 163.79, 164.74.

Monitor and fluorinated hydroxyalkoxy

2-{4-[2-(4-Fortini is)vinyl]phenyl}-6-hydroxybenzothiazole

no connection SKT02-165

Obtained in accordance with the description of the Demethylation section above using 2-{4-[2-(4-forfinal)vinyl]phenyl}-6-methoxybenzothiazole (0,080 g, 0,222 mmol) in dry DHM (10 ml) and BBr3in DHM (1,Ω, of 1.10 ml, 1.10 mmol) to give the title compound (0,087 g, 78%) as a yellow solid after processing and flash chromatography (15:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 5.11 (br s, 1H), 6.96-7.09 (m, 4H), 7.17 (d, J=16.2 Hz, 1H), 7.32 (s, 1H), 7.48-7.53 (m, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.8 Hz, 1H), 8.02 (d, J=7.9 Hz, 2H);13C NMR (100.5 MHz, DMSO-d6) δ 107.24, 116.13 (d, JCF=21.0 Hz), 116.67, 123.91, 127.54, 127.63, 127.86 (d, JCF=2.3 Hz), 129.06, 129.14, 129.32, 132.59, at 133.86 (d, JCF=3.1 Hz), 136.43, 139.78, 147.68, 156.28, 162.31 (d, JCF=242.9 Hz).

2-{4-[2-(4-(N-2,2,2-triptorelin)AMINOPHENYL)vinyl]phenyl}-6-hydroxybenzothiazole

no connection SKT02-155

Obtained in accordance with the description of the Demethylation section above using 2-{4-[2-(4-(N-2,2,2-triptorelin)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (0,049 g, 0,111 mmol) in dry DHM (10 ml) and BBr3in DHM (1,Ω, 0.6 ml, of 0.60 mmol) to give the title compound (0.037 g, 78%) as a yellow solid after processing and flash chromatography (15:1 DHM/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 3.90-4.02 (m, 2H), 6.50 (t, J=1.5 Hz, 1H), 6.76 (d, J=8.2 Hz, 2H), 6.99 (dd, J=1.6, 8.0 Hz, 1H), 7.0 (d, J=16.4 Hz, 1H), 7.24 (d, J=16.4 Hz, 1H), 7.38-7.45 (m, 3H), 7.66 (d, J=8.2 Hz, 2H), 7.83 (d, J=9.0 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 9.88 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 44.49 (q, JCF=32.8 Hz), 107.24, 113.10, 116.61, 123.41, 123.77, 126.24 (q, JCF=281 Hz), 126.51, 126.98, 127.51, 128.38, 130.95, is 131.75, 136.36, 140.75, 147.77, 148.23, 156.20, 163.72.

2-{4-[2-(4-(N-3,3,3-cryptochromes)AMINOPHENYL)vinyl]phenyl}-6-hydroxybenzothiazole

no connection SKT02-127

Obtained in accordance with the description above section Dmitrievna using 2-{4-[2-(4-(N-3,3,3-cryptochromes)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (0.10 g, 0.22 mmol) in dry DHM (10 ml) and BBr3in DHM (1.0m, of 1.10 ml, 1.10 mmol) to give the title compound (0,050 g, 52%) as a yellow solid after processing and flash chromatography (4:3 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.53-2.66 (m, 2H), 3.37-3.51 (m, 2H), 6.14 (br s, 1H), 6.68 (d, J=8.6 Hz, 2H), 7.05 (dd, J=9.0, 2.3 Hz, 1H), 7.07 (d, J=16.5 Hz, 1H), 7.30 (d, J=16.5 Hz, 1H), 7.46 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.47 (s,, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.89 (d, J=9.0 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 9.95 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 32.98 (q, JCF=27.2 Hz), 36.49 (q, JCF=3.8 Hz), 107.24, 112.71, 116.60, 122.82, 123.76, 125.62, 126.89, 127.44 (q, JCF=277.1 Hz), 127.51, 128.57, at 131.17, 131.62, 136.35, 140.88, 147.78, 148.77, 156.19, 163.74.

2-{4-[2-(4-(N-4,4,4-trifloromethyl)AMINOPHENYL)vinyl]phenyl}-6-hydroxybenzothiazole

no connection SKT02-111

Obtained in accordance with the description vichar the led section Demethylation using 2-{4-[2-(4-(N-4,4,4-trifloromethyl)AMINOPHENYL)vinyl]phenyl}-6-methoxybenzothiazole (was 0.138 g, 0,295 mmol) in dry DHM (10 ml) and BBr3in DHM (1.0m, 1.50 ml, 1.50 mmol) to give the title compound (0,095 g, 71%) as a yellow solid after processing and flash chromatography (3:2 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 1.71-1.79 (m, 2H), 2.27-2.40 (m, 2H), 3.13 (q, J=6.3 Hz, 2H), 5.94 (t, J=5.9 Hz, 1H), 6.59 (d, J=8.6 Hz, 2H), 6.96 (d, J=16.0 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 7.20 (d, J=16.0 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.38 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.81 (d, J=8.6 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 9.76 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 21.84 (q, J=Hz), 30.89 (q, J=28.05 Hz), 41.81, 107.23, 112.55, 116.58, 122.45, 123.74, 125.09, 126.82, 127.50, 128.53, 131.27, 131.53, 136.33, 140.94, 147.77, 149.42, 156.17, 163.74.

2-{4-[2-(4-(2,2,2-triptoreline)phenyl)vinyl]phenyl}-6-hydroxybenzothiazole

no connection SKT02-51

Obtained in accordance with the description of the Demethylation section above using 2-{4-[2-(4-(2,2,2-triptoreline)phenyl)vinyl]phenyl}-6-methoxybenzothiazole (0,097 g, 0.22 mmol) in dry DHM (5 ml) and BBr3in DHM (1.0m, of 1.10 ml, 1.10 mmol) to give the title compound (0,078 g, 83%) as a yellow solid after processing and flash chromatography (100:1 DHM/Meon).

1H NMR (250 MHz, acetone-d6) δ 4.72 (q, J=9.1 Hz, 2H), 7.01-7.18 (m, 3H), 7.23 (d, J=15.9 Hz, 1H), 7.38 (d, J=15.9 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 7.87 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.2 Hz, 2H), 8.83 (s, 1H)

2-(4-{(E)-2-[2-hydroxy-5-(triptoreline)phenyl]ethynyl}phenyl)-1,3-benzothiazol-6-on the Sabbath.

no connection SKT05-5

Obtained in accordance with the description of the Demethylation section above using 6-methoxy-2-(4-{(E)-2-[2-methoxy-5-(triptoreline)phenyl]ethynyl} phenyl). 1,3-benzothiazole (0,097 g, 0.22 mmol) in dry DHM (5 ml) and BBr3in DHM (1.0m, 1.90 ml, 1,90 mmol) at -78°C To produce the title compound (0,308 g, 82%) as a yellow solid after processing and flash chromatography (20:1 DHM/Meon).

1H NMR (250 MHz, CD3OD) δ 6.86 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.26 (d, J=16.5 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.55 (d, J=16.5 Hz, 1H), 7.67 (d,J=8.2 Hz, 1H), 7.81 (d,J=8.8 Hz, 1H), 7.98 (d,J=8.2 Hz, 1H);13With NMR (100 MHz, DMSO-d6) δ 107.24, 116.69, 117.39, 119.69, 120.80 (q, JCF=255 Hz), 121.92, 123.89, 124.45, 125.42, 127.58, 127.62, 129.21, 132.75, 136.49, 140.06, 141.56, 147.79, 154.65, 156.33, 163.54.

2-(4-{(E)-2-[4-hydroxy-2-(trifluoromethyl)phenyl]ethynyl}phenyl)-1,3-benzothiazol-6-ol

no connection SKT04-169

Obtained in accordance with the description of the Demethylation section above using 6-methoxy-2-(4- {(E)-2- [4-methoxy-2-(trifluoromethyl)phenyl]ethynyl} phenyl)-1,3-benzothiazole (0,30 g of 0.68 mmol) in dry DHM (10 ml) and BBr3in DHM (1.0m, 1,40 ml of 1.40 mmol) at -78°C To produce the title compound (0,229 g, 81%) as a yellow solid after processing and flash chromatography (1:1 hexane/EtOAc).

1H NMR (250 MHz, DMSO-d6 ) δ 6.99 (dd, J=2.1, 8.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.11 (s, 1H), 7.24 (d, J=17.1 Hz, 1H), 7.31-7.44 (m, 2H), 7.70 (d,J=8.5 Hz, 2H), 7.83-7.91 (m, 2H), 8.03 (d, J=8.5 Hz, 2H), 9.97 (br s, 1H), 10.30 (br s, 1H);13C NMR (100.5 MHz, DMSO-d6) δ 107.24, 112.97 (q, JCF=6.2 Hz), 116.72, 120.06, 123.92, 124.70 (q, JCF=274 Hz), 124.97 (q, JCF=1.6 Hz), 126.30 (q, JCF=1.6 Hz), 127.62, at 127.70, 127.72 (q, JCF=29.6 Hz), 129.60, 129.73, 132.93, 136.48, 139.55, 147.75, 156.32, 157.86, 163.44.

Non-fluorinated methylalkanes

6-methyl-2-{4-[(E)-2-phenylethenyl]phenyl}-1,3-benzothiazol

no connection SK696-39

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0,30 g, 0.80 mmol) in dry THF (15 ml), tert-butoxide potassium (0.10 g, 0.88 mmol) and benzaldehyde (of 0.085 g, 0.80 mmol) in dry THF (5 ml) to give the title compound (0.16 g, 60%) as a pale yellow solid after processing and flash chromatography (2:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 7.28-7.42 (m, 6H), 7.65 (d, J=7.4 Hz, 2H), 7.78 (d, J=7.8 Hz, 2H), 7.92 (s, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.07 (d, J=8.2 Hz, 2H).

2-{4-[2-(2-nitrophenyl)vinyl]phenyl}-6-methylbenzothiazol

no connection SKT01-15

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0,30 g, 0.80 mmol), 2-nitrobenzaldehyde (0.12 g, 0.80 mmol) and 0.5m solution of sodium methoxide (3.2 m is, to 1.60 mmol) in dry Meon (10 ml) to give the title compound (0,185 g, 62%) as a slight yellow needle-like particles after treatment and recrystallization from 1,2-dichloroethane.

1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 7.36 (dd, J=8.2, 1.2 Hz, 1H), 7.39 (d,.7=16.0 Hz, 1H), 7.54-7.58 (m, 1H), 7.60 (d, J=16.0 Hz, 1H), 7.74-7.77 (m, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.92 (brs, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 8.00 (dd, J=8.2, 1.2 Hz, 1H), 8.09 (d, J=8.2 Hz, 2H);13With NMR (100 MHz, DMSO-d6) δ 21.51, 122.28, 122.92, 124.97, 125.14, 128.00, 128.27, 128.65, 128.74, 129.37, 132.00. 132.85, 133.24, 133.93, 135.16, 135.91, 139.53, 148.50, 152.30, 166.05.

2-{4-[2-(3-nitrophenyl)vinyl]phenyl}-6-methylbenzothiazol

no connection SKT01-53

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.16 g, 0.43 mmol), 3-nitrobenzaldehyde (0,064 g, 0.43 mmol) and 0.5m solution of sodium methoxide (1.7 ml, 0.85 mmol) in dry Meon (10 ml) to give the title compound (0,149 g, 94%) as a slight yellow needle-like particles after treatment and recrystallization from 1,2-dichloroethane.

1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 7.36 (d, J=8.6 Hz, 1H), 7.55 (d, J=17.2 Hz, 1H), 7.59 (d, J=17.2 Hz, 1H), 7.66-7.70 (m, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.92 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.08 (d, J=8.2 Hz, 2H), 8.11-8.13 (m, 2H), 8.47 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ 21.54, 121.49, 122.31, 122.79, 122.88, 127.92, 128.12, 128.49, 128.65, 130.69, 130.79, 132.90, 133.23, 135.09, 135.86, 139.22, 139.67, 148.83, 152.24, 166.12.

2-{4-[2-(4-nitrophenyl)is inyl]phenyl}-6-methylbenzothiazol

no connection SKT01-3

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0,324 g, 0.86 mmol), 4-nitrobenzaldehyde (of 0.13 g, 0.86 mmol) and 0.5m solution of sodium methoxide (3.5 ml, about 1.75 mmol) in dry MeOH (10 ml) to give the title compound (0,221 g, 69%) as a slight yellow needle-like particles after treatment and recrystallization from 1,2-dichloroethane.

X 3023, 1635, 1596, 1587, 1502, 1483, 1332, 1258, 1194, 1109, 968, 943, 873, 834, 825, 810, 748, 722 cm-1;1H NMR (250 MHz, DMSO-d6) δ 2.47 (s, 3H), 7.38 (d, J=7.9 Hz, 1H), 7.57 (d, J=17.4 Hz, 1H), 7.65 (d, J=17.4 Hz, 1H), 7.86 (d, J=7.9 Hz, 2H), 7.90-7.97 (m, 4H), 8.12 (d, J=8.2 Hz, 2H), 8.26 (d, J=8.2 Hz, 2H).

2-{4-[2-(2-AMINOPHENYL)vinyl]phenyl}-6-methylbenzothiazol

no connection SKT01-55

Received in accordance with section description restoration of the nitro group using 2-{4-[2-(2-nitrophenyl)vinyl]phenyl}-6-methylbenzothiazole (0.10 g, 0,268 mmol) and chloride dihydrate tin (II) (0,48 g of 2.15 mmol) in EUN (3 ml) to give the title compound (0.036 g, 39%) as a yellow solid after processing and flash chromatography (20:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.49 (s, 3H), 3.84 (br s, 2H), 6.73 (d, J=7.9 Hz, 1H), 6.79-6.85 (m, 1H), 7.02 (d, J=16.2 Hz, 1H), 7.09-7.15 (m, 1H), 7.27 (d, J=16.2 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.68 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 21.62, 116.47, 119.29, 121.39, 122.65, 125.64, 125.78, 126.92, 127.29, 127.77, 128.00, 129.11, 129.32, 132.69, 135.19, 135.39, 140.10 is expected, 144.18, 152.35, 166.63.

2-{4-[2-(3-AMINOPHENYL)vinyl]phenyl}-6-methylbenzothiazol

no connection SKT01-69

Received in accordance with section description restoration of the nitro group using 2-{4-[2-(3-nitrophenyl)vinyl]phenyl}-6-methylbenzothiazole (0.12 g, 0,322 mmol) and chloride dihydrate tin (II) (0,58 g, 2.58 mmol) in EtOH (3 ml) to give the title compound (0,078 g, 71%) as a pale yellow solid after processing and flash chromatography (20:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 2.49 (s, 3H), 3.71 (br s, 2H), 6.63 (dd, J=7.9, 1.8 Hz, 1H), 6.87 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.05-7.20 (m, 3H), 7.29 (dd, J=8.2, 1.8 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.68 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 21.63, 113.02, 115.12, 117.54, 121.41, 122.66, 126.98, 127.58, 127.76, 127.99, 129.71, 130.46, 132.66, 135.19, 135.38, 138.03, 139.90, 146.73, 152.37, 166.68.

2-{4-[2-(4-AMINOPHENYL)vinyl]phenyl}-6-methylbenzothiazol

no connection SKT01-17

Received in accordance with section description restoration of the nitro group using 2-{4-[2-(4-nitrophenyl)vinyl]phenyl}-6-methylbenzothiazole (0.15 g, 0,403 mmol) and chloride dihydrate tin (II) (0.73 g, up 3.22 mmol) in EtOH (5 ml) to give the title compound (0,113 g, 82%) as a pale yellow solid after processing and flash chromatography (20:1 DHM/EtOAc).

13) δ 2.48 (s, 3H), 3.73 (br s, 2H), 6.68 (d, J=8.2 Hz, 2H), 6.94 (d, J=16.0 Hz, 1H), 7.12 (d, J=16.0 Hz, 1H), 7.22-7.41 (m, 3H), 7.57 (d, J=8.2 Hz, 2H), 7.69 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H).

2-{4-[2-(4-dimethylaminophenyl)vinyl]phenyl}-6-methylbenzothiazol

no connection SK2033-30

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.05 g, 0.133 mmol) in dry THF (5 ml), tert-butoxide potassium (0.03 g, 0,266 mmol) and 4-dimethylaminobenzaldehyde (0.02 g, 0.133 mmol) in dry THF (5 ml) to give the title compound (0.037 g, 75%) as an orange solid after processing and flash chromatography (4:1 hexane/USD).

X 3020, 2915, 1605, 1591. 1554, 1523, 1479, 1452, 1415, 1359, 1309, 1256, 1224, 1190, 1180, 1164, 1115, 1062, 965, 949, 827, 812 cm-1;1H NMR (400 MHz, acetone-d6) δ 2.49 (s, 3H), 3.00 (s, 6N), 6.77 (d, J=8.6 Hz, 2H), 7.08 (d, J=16.4 Hz, 1H), 7.32 (d, J=16.4 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.2 Hz, 2H), 7.86 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 8.08 (d, J=8.2 Hz, 2H).

2-{(E)-2-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]ethynyl}phenol

no connection SK696-62

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0,30 g, 0.80 mmol) in dry THF (25 ml), tert-butoxide potassium (0,19 g, by 1.68 mmol) and 2-hydroxybenzaldehyde (0,097 g, 0.80 mmol) in dry THF (10 ml) to give the title compounds is based (0.16 g, 60%) as a yellow solid after processing and flash chromatography (1:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 6.81-6.85 (m, 1H). 6.89 (d, J=7.8 Hz, 1H), 7.10-7.14 (m, 1H), 7.29 (d, J=16.5 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.56 (d, J=16.5 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.89 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H),9.87(s, 1H);13With NMR (100 MHz, DMSO-d6) δ 21.54, at 116.39, 119.81, 122.29, 122.79, 123.87, 126.01, 127.23, 127.42, 127.92, 128.59, 129.63, 131.96, 135.00, 135.72, 141.02, 152.27, 155.76, 166.29 (1 missing).

3-{(E)-2-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]ethynyl}phenol

no connection SK696-57

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0,30 g, 0.80 mmol) in dry THF (25 ml), tert-butoxide potassium (0,19 g, by 1.68 mmol) and 3-hydroxybenzaldehyde (0,097 g, 0.80 mmol) in dry THF (10 ml) to give the title compound (0.12 g, 44%) as a yellow solid after processing and flash chromatography (2:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.43 (s, 3H), 6.72 (dd, J=7.8, 1.6 Hz, 1H), 7.02 (s, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.22 (d, J=16.0 Hz, 1H), 7.31 (d, J=16.0 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H,), 7.87 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H), 9.48 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ 21.53, 113.79, 115.78, 118.26, 122.26, 122.82, 127.65, 127.71, 127.83, 128.59, 130.16, 130.98, 132.27, 135.03, 135.75, 138.51, 140.33, 152.26, 158.13, 166.23.

4-{(E)-2-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]ethynyl}phenol

no soy is inane SK696-43

Received in accordance with section description Receive alkene using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.10 g, 0,266 mmol) in dry THF (10 ml), tert-butoxide potassium (0,063 g, 0,559 mmol) and 4-hydroxybenzaldehyde (0,033 g 0,266 mmol) in dry THF (5 ml) to give the title compound (0,061 g, 67%) as a pale orange solid after processing and flash chromatography (2:1 hexane/EtOAc).

1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 6.79 (d, J=8.3 Hz, 2H), 7.08 (d, J=16.5 Hz, 1H), 7.28 (d, J=16.5 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.2 Hz. 2H), 7.88 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H), 9.57 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 21.49, 116.14, 122.21, at 122.77, 124.61, 127.19, 127.71, 127.85, 128.33, 128.53, 128.69, 130.96, 131.76, 135.67, 140.98, 152.33, 158.25, 166.34.

2-{4-[2-(3-methoxyphenyl)vinyl]phenyl}-6-methylbenzothiazol

no connection SK2033-29

Received in accordance with section description Receive alkene using diethyl 4-(6-methoxybenzothiazole-2-yl)benzylphosphonate (0.05 g, 0.133 mmol) in dry THF (5 ml), tert-butoxide potassium (0.03 g, 0,266 mmol) and 3-methoxybenzaldehyde (0,018 g, 0.133 mmol) in dry THF (5 ml) to give the title compound (0,016 g, 34%) as a pale yellow solid after processing and flash chromatography (4:1 hexane/Et2O).

1H NMR (250 MHz, CDCl3) δ 2.49 (s, 3H), 3.86 (s, 3H), 6.85 (dd, J=8.2, 1.8 Hz, 1H), 7.61 (d, =8.2 Hz, 2H), 7.68 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H);13C NMR (62.5 MHz, CDCl3) δ 21.6, 55.31, 111.90, 113.81, 119.46, 121.39, 122.68, 127.04, 127.77, 128.00, 129.76, 130.18, 132.82, 135.21, 135.41, 138.44, 139.71, 152.35, 159.96, 166.62.

Intermediate compounds in obtaining imidazo[1,2-a]pyridine compounds

4-Bromeliaceae

no connection SKT05-187

To a stirred solution of 4-methylacetophenone (2.16 g, 15,32 mmol) in MeCN (20 ml) was added N-bromosuccinimide (3.00 g, 16,85 mmol) and AIBN (0.25 g, 1.53 mmol) in argon atmosphere. Then the reaction mixture was heated at 90°C for 1.5 hours. After cooling to room temperature the solvent was removed under reduced pressure and added toluene (25 ml) to the residue, which was then filtered under vacuum. The filtrate was concentrated and purified using flash chromatography (10:1 hexane/EtOAc, then 5:1 hexane/EtOAc) to give the title compound (2,80 g, 86%) as a colorless oily liquid.

X 3034, 3003, 2969, 1683, 1606, 1573, 1412, 1358, 1267, 1229, 1202, 1181, 1102, 1075, 1017, 959, 843, 821 cm-1;1H NMR (250 MHz, CDCl3) δ 2.59 (s, 3H), 4.49 (s, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.2 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 26.77, 32.22, 128.89, 129.29, 136.87, 142.85, 197.50.

Diethyl ether (4-acetylphenyl)phosphonic acid

no connection SKT05-191

Stir a mixture of 4-bromochloroethane (2.50 g, 11,74 mmol) and triethylphosphite (10 ml) heating the at 140°C for 3 hours. After cooling to room temperature the excess triethylphosphite removed by distillation and the residue was purified using flash chromatography (EtOAc) to give the title compound (2,49 g, 79%) as a colorless oily liquid.

1H NMR (250 MHz, CDCl3) δ 1.19 (t, J=7.0 Hz, 6N), 2.53 (s, 3H), 3.15 (d, JHP=22.2 Hz, 2H), 3.91-4.02 (m, 4H), 7.34 (d, J=7.9 Hz, 2H), 7.85 (d, J=7.9 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 16.37 (d, JCP=5.9 Hz), 26.62, 33.94 (d, JCP=137.7 Hz), at 62.27 (d, JCP=6.8 Hz), 128.56, 129.99 (d, JCP=5.9 Hz), 135.73 (d, JCP=2.9 Hz), 137.43 (d, JCP=9.8 Hz), 197.70.

Diethyl ether (4-bromacleanse)phosphonic acid

no connection SKT06-87

To a mixed solution of diethyl ether (4-acetylphenyl)phosphonic acid (2,56 g, 9,48 mmol) in DHM (100 ml) and Meon (40 ml) at room temperature was added tribromide Tetra-n-butylamine (of 5.03 g, 10,43 mmol) followed by adding drops of concentrated chloroethanol acid. The reaction mixture was stirred at room temperature for 18 hours. Then solvents were removed under reduced pressure and the residue was divided in Et2O (100 ml) and a saturated solution of NaHCO3(60 ml). The aqueous phase was separated and the organic phase is washed with saline (60 ml) and dried (Na2SO4). Removed solvent under reduced pressure to obtain light yellow is Oh oily liquid which was purified using flash chromatography (3:1 EtOAc/DHM) to obtain the title compound (2,01 g, 61%) as a colorless oily liquid.

1H NMR (250 MHz, CDCl3) δ 1.23 (t, J=7.0 Hz, 6N), 3.19 (d, JHP=22.3 Hz, 2H), 3.95-4.10 (m, 4H), 4.42 (s, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.2 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 16.38 (d, JCP=5.9 Hz), 31.01, at 34.08 (d, JCP=137 Hz), 39.78, 62.35 (d, JCP=6.8 Hz), 129.17, 129.94, 130.24, 130.33, 132.58 (d, JCP=2.9 Hz), 138.55 (d, JCP=8.8 Hz), 139.21 (d, JCP=8.8 Hz), 190.84.

Diethyl-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzyl]phosphonate

no connection SKT06-31

To a stirred mixture of 2-amino-5-picoline (0,62 g, USD 5.76 mmol) and sodium bicarbonate (0,48 g, USD 5.76 mmol) in CHCl3(35 ml) was added a solution of diethyl ether (4-bromacleanse)phosphonic acid in CHCl3(8 ml). Stir the reaction mixture is boiled under reflux for 17 hours. After cooling to room temperature, to the reaction mixture was added CHCl3(20 ml), then washed with water (60 ml). The separated aqueous phase was extracted with CHCl3(2×50 ml) and the combined organic phases are washed with salt solution (80 ml) and dried (Na2SO4). Removed solvent under reduced pressure to obtain an orange viscous oily liquid, which was purified using flash chromatography (EtOAc, then EtOAc/Meon 20:1) obtained with the eating of the title compound (1.29 g, 63%) as a colourless solid.

1H NMR (250 MHz, CDCl3) δ 1.23 (t, J=7.0 Hz, 6N), 2.32 (s, 3H), 3.18 (d, JH,P=21.7 Hz, 2H), 4.00 (m, 4H), 7.05 (d, J=9.2 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.57 (d, J=9.2 Hz, 1H), 7.76 (s, 1H), 7.89 (d, J=7.9 Hz, 2H), 7.90 (s, 1H);13With NMR (62.5 MHz, CDCl3) δ 16.41 (d, JC P=5.8 Hz), 18.15, 33.65 (d, JC P=138.7 Hz), 62.24 (d, JC P=6.8 Hz), 107.87, 116.76, 122.10, 123.33, 126.05, 127.96. 130.15 (d, JC P=6.8 Hz), 131.13 (d, JC P=8.8 Hz), 132.57 (d, JC P=3.9 Hz), 144.73, 145.08.

2-hydroxy-4-nitrobenzaldehyde

Obtained in accordance with the description of the Demethylation section above using 2-methoxy-4-nitrobenzaldehyde (1.0 g, 5,52 mmol) in dry DHM (25 ml) and BBr3in DHM (1.0m, 16 ml, 16 mmol) to give the title compound (0,70 g, 78%) as a brownish plates after recrystallization from EtOH.

1H NMR (250 MHz, CDCl3) δ 7.76-7.85 (m, 3H), 10.04 (s, 1H), 11.14 (s, 1H);13C NMR (100.5 MHz, CDCl3) δ 113.49, 114.36, 123.70, 134.79, 152.47, 161.91, 196.01.

2-(2-floratone)-4-nitrobenzaldehyde

To a stirred solution of 2-hydroxy-4-nitrobenzaldehyde (0.50 g, 2,99 mmol) in dry DMF (15 ml) was added To a2CO3(1.24 g, 8.98 mmol) at room temperature in argon atmosphere. To this stirred suspension is dropwise added 2-foradil-(4-methylbenzoyl)sulfonate (0,78 g and 3.59 mmol). The reaction mixture was heated at 100°C in those who tell 6 hours. The cooled reaction mixture was added to water (250 ml) and was extracted with EtOAc (3×75 ml). The combined organic phases are washed with salt solution (50 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a brown solid, which was purified using flash chromatography (3:1 DHM/hexane) to give the title compound (0,493 g, 77%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 4.47 (dist d of t, JHF=27 Hz, JHH=3.7 Hz, 2H), 4.87 (dist d of t, JHF=47 Hz, JHH=3.6 Hz, 2H), 7.86 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 10.56 (s, 1H);13With NMR (100.5 MHz, CDCl3) δ 68.58 (d, JCF=20.5 Hz), 81.15 (d, JCF=173 Hz), 108.05, 116.25, 128.87, 129.70, 152.05, 160.64, 188.11.

2-([2-tert-butyldimethylsiloxy]ethoxy)-4-nitrobenzaldehyde

To a stirred suspension of 2-hydroxy-4-nitrobenzaldehyde (0,500 g 2,992 mmol) and anhydrous potassium carbonate (0,621 g 4,488 mmol) in dry MeCN (20 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxy (83%, 1,293 g 4,488 mmol) and the reaction mixture is boiled under reflux for 40 minutes to obtain a viscous dark red precipitate. The reaction mixture is left to cool to room temperature and added dry DMF (10 ml). The reaction mixture was heated at 100°C for 4 hours and after cooling, was added to water (250 is l) and was extracted with EtOAc (3×80 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml) and dried (Na2SO4) and solvent removed under reduced pressure to obtain a light brown solid, which was purified using flash chromatography AI (2:1 hexane/Et2O). Recrystallization from hexane led to the title compound (0,621 g, 64%) as light yellow crystals.

1H NMR (250 MHz, CDCl3) δ 0.08 (s, 6N), 0.87 (s, 9H), 4.05 (t, J=4.6 Hz, 2H), 4.30 (t, J=4.6 Hz, 2H), 7.83-7.98 (m, 3H), 10.54 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 5.34, 18.32, at 25.79, 61.61, 71.08, 108.64, 115.63, 128.81, 129.37, 152.12, 161.53, 188.43.

Method adapted from the work of Kawabe with co-authors (Kuwabe et al.).

4-[2-(hydroxyethyl)(methyl)amino]benzaldehyde

To a stirred solution of 4-forventelige (5.0 g, 40,29 mmol) and 2-(methylamino)ethanol (3,63 g, 48,34 mmol) in dry DMSO (35 ml) was added To a2CO3(of 6.68 g, 48,34 mmol) in argon atmosphere. Then the reaction mixture was heated at 120°C for 3days. The cooled reaction mixture was added to water (400 ml) and was extracted with EtOAc (7×100 ml). The combined organic phases are washed with salt solution (2×10 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a viscous orange oily liquid, which slowly otverdel at room temperature. Pointed to by the e solid was dissolved in DHM (40 ml) and this solution is then added to hexane (200 ml) with precipitation of a yellow solid, which was collected by filtration under vacuum. Recrystallization from toluene led to the title compound (4,47 g, 62%) in the form of small yellow plates.

1H NMR (250 MHz, CDCl3) δ 2.73 (br s, 1H), 3.07 (s, 3H), 3.58 (t, J=5.5 Hz, 2H), 3.82 (t, J=5.5 Hz, 2H), 6.69 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 9.60 (s, 1H);13With NMR (100.5 MHz, CDCl3) δ 39.25, 54.38, 59.92, 111.16, 125.05, 132.24, 153.96, 190.58.

Method adapted from the work of Lo MEO with co-authors (Lo Meo et al.).

4-[N-(2-tert-butyldimethylsilyloxy)-N-methylamino]benzaldehyde

To a stirred solution of 4-[2-(hydroxyethyl)(methyl)amino]benzaldehyde (1.50 g, scored 8.38 mmol) in dry DMF (35 ml) was added imidazole (1,71 g, 25,14 mmol) in argon atmosphere. The reaction mixture was stirred at room temperature until complete dissolution of all components of the solution, then added tert-butyldimethylsilyloxy (2,53 g, 16,76 mmol). The reaction mixture was stirred at room temperature for 3 days, added to water (300 ml) and was extracted with Et2O (3×40 ml). The combined organic phases are washed with water (3×60 ml), brine (60 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a yellow oily liquid, which was purified using flash chromatography to obtain the title compound (2,22 g, 90%) as a yellow oily liquid.

1H NMR (250 MHz, CDCl3) δ-0.01 (s, 6H), 0.85 (s, 9H), 3.09 (s, 3H), 3.57 (t, J=5.5 Hz, 2H), 3.79 (t, J=5.5 Hz. 2H), 6.71 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 9.72 (s, 1H);13With NMR (100.5 MHz, CDCl3) δ 5.42, 18.23, 25.85, 39.56, 54.52, 60.43, 111.03, 125.16, 132.10, 153.64, 190.31.

4-N-(2-tert-butyldimethylsilyloxy)-N-methyl-4-{(E)-2-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]ethynyl}aniline

no connection SKT07-107

Received in accordance with section description Receive alkene with the use of sodium hydride (60% dispersion in oil, 27 mg, 0.67 mmol), diethyl 4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzylphosphonate (200 mg, 0,559 mmol) and 4-[N-(2-tert-butyldimethylsilyloxy)-N-(methyl)amino]benzaldehyde (164 mg, 0,559 mmol) in dry THF (15 ml) to give the title compound (210 mg, 75%) a pale yellow solid after processing and flash chromatography (4:1 DHM/EtOAc).

1H NMR (250 MHz, CDCl3) δ 0.02 (s, 6N), 0.88 (s, 9H), 2.32 (s, 3H), 3.02 (s, 3H), 3.49 (t, J=5.5 Hz, 2H), 3.77 (t, J=5.5 Hz, 2H), 6.68 (d, J=7.9 Hz, 2H), 6.91 (d, J=15.6 Hz, 1H), 7.04 (d, J=7.9 Hz, 1H), 7.08 (d, J=15.6 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.54-7.59 (m, 1H), 7.76 (s, 1H), 7.89-7.92 (m, 3H);13With NMR (100.5 MHz, CDCl3) δ 5.32, 18.20, 18.32, 25.95, 39.30, 54.78, at 60.51, 107.79, 111.86, 116.65, 122.15, 123.35, 123.73, 125.29, 126.11, 126.33, 127.74, 127.99, 128.80, 131.89, 137.86, 144.65, 145.19, 148.81.

6-methyl-2-(4-{(E)-2-[4-nitro-2-(2-tributyltinoxide)phenyl]ethynyl}phenyl)imidazo[1,2-a]pyridine

no connection SKT08-115

Received in accordance with section description Receive alkene with the use of sodium hydride (40 mg, 60% dispersion in mineral oil, 1.00 mmol), diethyl [4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzyl]phosphonate (0,300 g, 0,837 mmol) and 2-([tert-butyldimethylsiloxy]ethoxy)-4-nitrobenzaldehyde (0,272 g, 0,837 mmol) in dry THF (30 ml) to give the title compound (0,285 g, 64%) as an orange solid substances after treatment and flash chromatography (2:1 EtOAc/hexane).

1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6N), 0.92 (s, 9H), 3.96 (t, J=5.1 Hz, 2H), 4.10 (t, J=5.1 Hz, 2H), 7.29 (d, J=16.4 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.86 (dd, J=8.2, 2.0 Hz, 1H), 7.93 (br s, 1H), 7.98 (d, J=8.2 Hz, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 5.20, 18.17, 18.40, 25.90, 61.78, 70.57, 107.17, 108.19, 116.27, 116.82, at 121.30, 122.32, 123.33, 126.08, 126.19, 127.51, 128.17, 132.89, 133.58, 133.97, 136.40, 144.85, 147.37, 156.20 (1 missing).

2-(2-{(E)-2-[4-(6-methyl-1H-imidazo[1,2-a]pyridine-2-yl)phenyl]vinyl}-5-nitrophenoxy)ethyl ester methanesulfonic acid

no connection SKT08-175

To a stirred solution of 2-(2-{(E)-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]ethynyl}-5-nitrophenoxy)ethanol (40,2 mg, 0,0968 mmol) in dry pyridine (4 ml) at room temperature was added methanesulfonamide (15,9 l, 0,203 mmol). After 2.25 hours at room temperature was added water (25 ml) to give a yellow precipitate, which was collected with p the power vacuum filtration, washed with water (2×10 ml) and then dried in an oven at 85°C for 3 hours. The yellow solid was purified using flash chromatography (1:1 EtOAc/DHM) to obtain the title compound (31 mg, 65%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.29 (s, 3H), 4.49-4.52 (m, 2H), 4.69-4.71 (m, 2H), 7.11 (dd, J=9.0, 1.9 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.55 (d, J=16.4 Hz, 1H), 7.60 (d, J=16.4 Hz, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.84 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.6, 1.9 Hz, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.60-8.00 (m, 1H), 8.31 (br s, 1H), 8.35 (s, 1H);13With NMR (100.5 MHz, DMSO-d6) δ 17.95, 37.54, 67.63, 68.98, 108.18, 109.72, 116.46, 116.99, at 121.30, 122.09, 124.70, 126.31, 127.54, 127.87, 128.59, 133.61, 133.93, 134.67, 136.42, 144.14, 144.45, 147.39, 155.69.

Imidazo[1,2-a]pyridine compounds

6-methyl-2-{4-[(E)-2-(4-nitrophenyl)ethynyl]phenyl}imidazo[1,2-a]pyridine

no connection SKT06-117

Received in accordance with section description Receive alkene with the use of sodium hydride (60% dispersion in mineral oil, 7 mg, 0,307 mmol), diethyl 4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzylphosphonate (100 mg, 0,279 mmol) and 4-nitrobenzaldehyde (42 mg, 0,279 mmol) in THF (5 ml) to give the title compound (24 mg, 24%) as a yellow solid after processing and flash chromatography (100:1 DHM/Meon).

1H NMR (250 MHz, DMSO-d6) δ 2.29 (s, 3H), 7.12 (d, J=8.8 Hz, 1H), 7.49 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 8.01 (d, J=7.5 Hz, 2H), 8.25 (d, J8.5 Hz, 2H), 8.33 (s, 1H), 8.37 (s, 1H).

6-methyl-2-{4-[(E)-2-pyridine-4-retinyl]phenyl}imidazo[1,2-a]pyridine

no connection SKT06-161

Received in accordance with section description Receive alkene with the use of sodium hydride (60% dispersion in mineral oil, 25 mg, of 0.615 mmol), diethyl 4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzylphosphonate (0.20 g, 0,559 mmol) and pyridine-4-aldehyde (0.06 g, 0,559 mmol) in dry THF (10 ml) to give the title compound (0,074 g, 42%) as a pale orange solid after processing and flash chromatography (7:7:1 DHM/EtOAc/Meon).

X 3132, 3022, 2919, 1629, 1606, 1590, 1417, 1340, 1273, 1213, 1186, 980, 971, 874, 844, 813, 803, 750 cm-1;1H NMR (250 MHz, DMSO-d6) δ 2.29 (s, 3H), 7.12 (dd, J=9.5, 0.6 Hz, 1H), 7.29 (d, J=16.8 Hz, 1H), 7.50 (dd, J=9.5, 0.9 Hz, 1H), 7.52-7.65 (m, 3H), 7.73 (d, J=7.3 Hz, 2H), 8.00 (d, J=7.3 Hz, 2H), 8.34 (dd, J=8.9, 0.6 Hz, 2H), 8.53-8.56 (m, 2H).

2-{4-[(E)2-(2-methoxy-4-nitrophenyl)ethynyl]phenyl}-6-methylimidazo[1,2-a]pyridine

no connection SKT07-81

Received in accordance with section description Receive alkene with the use of sodium hydride (60% dispersion in mineral oil, 33 mg, 0,838 mmol), diethyl 4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzylphosphonate (250 mg, 0,698 mmol) and 2-methoxy-4-nitrobenzaldehyde (126 mg, 0,698 mmol) in dry THF (15 ml) to give the title compound (199 mg, 74%) as an orange solid after processing and flash chromatog is the her (25:1 DHM/Meon).

1H NMR (250 MHz, CDCl3) δ 2.33 (s, 3H), 3.99 (s, 3H), 7.05 (d, J=8.8 Hz, 1H), 7.28 (d, J=16.2 Hz, 1H), 7.50 (d, J=16.2 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.75 (br s, 1H), 7.81 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.97 (d, J=8.2 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 18.17, at 56.08, 105.99, 108.18, 116.27, 116.78, 121.28, 122.45, 123.35, 126.16, 126.27, 127.51, 128.31, 133.03, 133.39, at 133.86, 136.45, 144.73, 147.49, 156.81 (1 missing).

2-(4-{(E)-2-[4-nitro-2-(2-floratone)phenyl]ethynyl}phenyl)-6-methylimidazo[1,2-a]pyridine

no connection SKT07-115

Received in accordance with section description Receive alkene with the use of sodium hydride (60% dispersion in mineral oil, 27 mg, 0.67 mmol), diethyl 4-(6-methylimidazo[1,2-a]pyridine-2-yl)benzylphosphonate (200 mg, 0,559 mmol) and 2-(2-floratone)-4-nitrobenzaldehyde (119 mg, 0,559 mmol) in dry THF (15 ml) to give the title compound (174 mg, 74%) as an orange solid after processing and flash chromatography (50:1 DHM/Meon).

1H NMR (250 MHz, CDCl3) δ 2.32 (s, 3H), 4.39 (dist d of t, JHF=28 Hz, JHH=3.7 Hz, 2H), 4.89 (dist d of t, JHF=47 Hz, JHH=3.7 Hz, 2H), 7.04 (d, J=8.8 Hz, 1H), 7.33 (d, J=16.8 Hz, 1H), 7.51 (d, J=16.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.62 (d, J=7.9 Hz, 2H), 7.71-7.75 (m, 2H), 7.82 (s, 1H), 7.88-7.91 (m, 2H), 7.96 (d, J=8.2 Hz, 2H);13C NMR (100.5 MHz, CDCl3) δ 18.22, 68.25 (d, JCF=20.5 Hz), 81.52 (d, JCF=172 Hz), at 96.13, 107.15, 108.24, 116.79, 116.92, 121.05, 122.46, 123.36, 126.28, 126.56, 127.60, 128.35, 133.52, at 133.86, 136.33, 144.74, 147.23, 155.53 (1 missing).

-(2 floratone)-4-{(E)-2-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]ethynyl}aniline

no connection SKT07-131

Received in accordance with section description restoration of the nitro group using 2-(4-{(E)-2-[4-nitro-2-(2-floratone)phenyl]ethynyl}phenyl)-6-methylimidazo[1,2-a]pyridine (81 mg, 0,194 mmol) and chloride dihydrate tin (II) (219 mg, 0,970 mmol) in EtOH (12 ml) to give the title compound (36 mg, 48%) as an orange solid after processing and flash chromatography (2:1 EtOAc/DHM).

1H NMR (250 MHz, CDCl3) δ 2.31 (s, 3H), 3.79 (br s, 2H), 4.22 (dist d of t, JHF=27 Hz, JHH=3.7 Hz, 2H), 4.81 (dist d of t, JHF=48 Hz, JHH=3.7 Hz, 2H), 6.23 (s, 1H), 6.34 (d, J=7.3 Hz, 1H), 6.99 (d, J=16.5 Hz, 1H), 7.02 (m, 1H), 7.39 (d, J=3.7 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.55 (d, J=16.5 Hz, 1H), 7.55 (m, 2H), 7.77 (s, 1H), 7.88-7.91 (m, 3H);13With NMR (100 MHz, DMSO-d6) δ 17.97, 68.02 (d, JCF=18.7 Hz), 82.76 (d, JCF=166.5 Hz), 98.94, 107.89, 109.04, 114.47, 116.42, 121.81, 123.63, 124.21, 124.63, 126.24, 126.33, 128.18, 128.24, 132.55, 138.34, 144.69, 150.64, 157.41 (1 missing).

N-(2-hydroxyethyl)-N-methyl-4-{(E)-2-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]ethynyl}aniline

no connection SKT07-113

To a stirred suspension of 4-N-(2-tributyltinoxide)-N-methyl-4-{(E)-2-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]ethynyl}aniline (0.18 g, 0,362 mmol) in a mixture of dry THF (5 ml) and dry DMF (3 ml) at 0-5°C was added a solution of TBAF in THF (1M, 800 l HDI, 0.800 mmol). The reaction mixture was stirred at 0-5°C for 5 minutes, and then forgive and to warm to room temperature and was further stirred for 50 minutes. To the reaction mixture were added a saturated solution of ammonium chloride (25 ml), the resulting solution was extracted with a mixture DHM/Meon (1:1, 5×30 ml). The combined organic phases are washed with salt solution (40 ml), dried (Na2SO4) and solvent removed under reduced pressure to obtain a yellow oily liquid, which slowly solidify at room temperature. The solid was purified using flash chromatography (10:1 DHM/Meon) to obtain the title compound (0,136 g, 98%) as a yellow solid.

1H NMR (250 MHz, CDCl3) δ 2.28 (s, 3H), 2.96 (s, 3H), 3.42 (t, J=5.2 Hz, 2H), 3.54 (t, J=5.2 Hz, 2H), 4.71 (t, J=5.2 Hz, 1H), 6.70 (d, J=8.5 Hz, 2H), 6.96 (d, J=16.2 Hz, 1H), 7.08-7.19 (m, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.48 (d,, J=9.5 Hz, 1H), 7.57 (d,J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.29 (s, 2H);13With NMR (100.5 MHz, DMSO-d6) δ 17.96, 39.04, 54.66, 58.68, 109.09, 112.24, 116.44, 121.80, 123.47, 124.60, 124.99, 126.19, 126.53, 128.07, 128.23, 129.13, 132.75, 137.70, 144.42, 144.69, 149.42

2-(2-{(E)-2-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]ethynyl}-5-nitrophenoxy)ethanol

no connection SKT08-137

To a stirred solution of 6-methyl-2-(4-{(E)-2-[4-nitro-2-(2-tert-butylethylenediamine)phenyl]ethynyl}phenyl)imidazo[1,2-a]pyridine (0,200 g, 0,377 mmol) in dry THF (7 ml) at 0-5°C dropwise added TBAF (1M solution in THF, or 0.83 ml, 0.83 mmol) for 5 minutes. The reaction mixture was stirred at 0-5°C for 5 minutes, and then removed the cooling is Yu bath. After 1.5 hours was added a saturated solution of NH4Cl (15 ml) and the mixture was transferred into a separating funnel and was extracted with a mixture DHM/Meon (3:1, 5×40 ml). The combined organic extracts were washed brine (2×60 ml) and dried (Na2SO4) and solvent removed under reduced pressure to obtain an orange residue, which was purified using flash chromatography (10:1 EtOAc/hexane) to give the title compound (is 0.102 g, 65%) as an orange solid.

1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.81-3.88 (m, 2H), 4.19-4.24 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.57 (s, 2H), 7.70 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.98 (d, J=7.8 Hz, 2H), 8.30 (s, 1H), 8.34 (s, 1H);13With NMR (100 MHz, DMSO-d6) δ 17.99, 59.95, 71.52, 107.75, 109.72, 116.41, 116.53, 121.44, 122.02, 124.69, 126.25, 127.27, 127.95, 128.50, 133.51, 133.67, 134.67, 136.40, 144.18, 144.45, 147.35, 156.44.

Compounds in which Q represents-N=N-

The intermediate receiving benzothiazole

N-(3-methoxyphenyl)-4-nitrobenzamide

no connection LS-T203

Received in accordance with section description Amide binding.

Orange solid (87%).1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 6.74 (dd, J=2.4 Hz, 8.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.28-7.38 (m, 1H), 7.38 (s, 1H), 7.86 (s, 1H), 8.03 (d, J=8.5 Hz, 2H), 8.35 (d, J=8.5 Hz, 2H); ICSD (ESI-) m/z 271.09 (M+-N, 41%), 325.03 (100%).

4-nitro-N-[3-(triptoreline)phenyl]ansamed

no connection LS-T204

Received in accordance with section description Amide binding.

Whitish solid (98%).1H NMR (400 MHz, CDCl3) δ 7.05 (d, J=7.7 Hz, 1H), 7.41 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.89 (s, 1H), 8.02 (d, J=8.5 Hz, 2H), 8.34 (d, J=8.5 Hz, 2H); ICSD (ESI-) m/z 325.02 (M+-H, 100%).

4-nitro-N-[4-(triptoreline)phenyl]benzamide

no connection LS-T197

Received in accordance with section description Amide binding.

Whitish solid (97%).1H NMR (250 MHz, CDCl3) δ 7.20-7.28 (m, 2H), 7.67 (d, J=9.1 Hz, 2H), 7.88 (bs, 1H), 8.03 (d, J=8.9 Hz, 2H), 8.35 (d, J=8.9 Hz, 2H).

4-nitro-N-(3-methoxyphenyl)escarbotin

no connection LS-T205

Column chromatography (1:5 EtOAc/40:60 petroleum ether) yielded the product as a red/orange solid (82%).1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 6.91-7.07 (m, 2H), 7.17-7.37 (m, 1H), 7.54 (s, 1H), 7.95-8.11 (m, 2H), 8.11-8.29 (m, 2H), 9.09 (s, 1H).

4-nitro-N-[3-(triptoreline)phenyl]escarbotin

no connection LS-T206

Received in accordance with section description Receive thioamide.

Column chromatography (1:5 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (87%). ICSD (ESI-) m/z 341.00 (M+-H, 85%), 466.92 (100%).

4-nitro-N-[4-(triptoreline)Fe is Il]escarbotin

no connection LS-T198

Received in accordance with section description

Getting thioamide.

Column chromatography (1:5 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (89%).1H NMR (250 MHz, CDCl3) δ 7.29 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 8.22 (d, J=8.5 Hz, 2H), 9.30 (bs, 1H);13C NMR (62.5 MHz, CDCl3) δ 121.3 (2C), 121.9 (2C), 125.2 (2C), 126.1 (2C), 137.4, 147.1, 147.8, 148.7; MCHP (ESI-) m/z 341.04 (M+-H, 100%).

5-methoxy-2-(4-nitrophenyl)-1,3-benzothiazol

no connection LS-T232

Received in accordance with section description

Getting benzothiazole using potassium ferricyanide.

Column chromatography (100% toluene) yielded the product as yellow solid (13%). X (KBr)/cm-1: 1603, 1517, 1457, 1344, 1311, 1281, 1159, 1149, 852;1H NMR (250 MHz, CDCl3) δ 3.90 (s, 3H), 7.08 (dd, J=Hz, 2.4 Hz, 8.8 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.5 Hz, 2H), 8.30 (d, J=8.5 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 55.6, 105.7, 116.8, 122.0, 124.3, 127.4, 128.0, 139.2, 148.9, 155.4, 159.5, 165.9; MCHP (ESI+) m/z 287.42 (M+, 97%), 309.40 (100%).

2-(4-nitrophenyl)-5-(triptoreline)-1,3-benzothiazol

no connection LS-T208

Received in accordance with section description

Getting benzothiazole using potassium ferricyanide.

Column chromatography (1:4 EtOAc/40:0 petroleum ether) yielded the product as yellow solid (10%). X (KBr)/cm-1: 1607, 1514, 1356, 1302, 1260, 1211, 1151, 1109;1H NMR (250 MHz, CDCl3) δ 7.33 (d, J=8.9 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.96 (s, 1H), 8.23 (d, J=8.5 Hz, 2H), 8.34 (d, J=8.5 Hz, 2H).

2-(4-nitrophenyl)-6-(triptoreline)-1,3-benzothiazol

no connection LS-T199

Received in accordance with section description

Getting benzothiazole using potassium ferricyanide.

Column chromatography (1:5 EtOAc/40:60 petroleum ether) yielded the product as yellow solid (10%).1H NMR (250 MHz, CDCl3) δ 6.43 (dd, J=1.5 Hz, 9.1 Hz, 1H), 7.81 (d, J=0.9 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 8.24 (d, J=8.8 Hz, 2H), 8.36 (d, J=8.8 Hz, 2H); MCHP (ESI+) m/z 340.94 (M++H, 100%).

4-[5-methoxy-1,3-benzothiazol-2-yl]aniline

no connection LS-T226B

Received in accordance with section description restoration of the nitro-group.

Column chromatography (1:3 EtOAc/40:60 petroleum ether) yielded the product as yellow solid (45%).1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 3.91 (bs, 2H), 6.68 (d, J=Hz, 8.5 Hz, 2H), 6.92 (dd, J=2.7 Hz, 8.9 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 7.83 (d, J=8.5 Hz, 1H);13With NMR (100 MHz, CDCl3) δ 55.5, 105.2, 114.4, 114.7, 121.6, 124.0, 126.3, 128.9, 149.2, 155.4, 158.9, 169.8.

4-[4-methoxy-1,3-benzothiazol-2-yl]aniline

no connection LS-T234

Received in accordance with section description restoration of the nitro-group.

Colo is full-time chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as yellow solid (39%). X (KBR)/cm-1: 3345, 3211, 1620, 1602, 1567, 1433, 1333, 1308, 1262, 1177, 1051, 973, 826, 729;1H NMR (400 MHz, CDCl3) δ3.92 (bs, 2H), 4.03 (s, 3H), 6.68 (d, J=Hz, 8.5 Hz, 2H), 6.85 (dd, J=1.0 Hz, 8.6 Hz, 1H), 7.20-7.24 (m, 2H), 7.40 (dd, J=1.0 Hz, 8.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 2H); ICSD (ESI+) m/z 257.48 (M++H, 100%).

4-[5-(triptoreline)-1,3-benzothiazol-2-yl]aniline

no connection LS-T225

Received in accordance with section description restoration of the nitro-group.

Column chromatography (1:2,8 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (33%).1H NMR (400 MHz, CDCl3) δ 4.06 (bs, 2H), 6.71 (d,J=8.5 Hz, 2H), 7.16 (d,J=8.5 Hz, 1H), 7.79 (d,J=8.5 Hz, 1H), 7.86 (d,J=8.5 Hz, 2H), 7.77-7.88 (hidden, 1H).

4-[6-(triptoreline)-1,3-benzothiazol-2-yl]aniline

no connection LS-T201

Received in accordance with section description restoration of the nitro-group.

Yellow solid (37%).1H NMR (250 MHz, CDCl3) δ 4.02 (bs, 2H), 6.72 (d, J=Hz, 8.5 Hz, 2H), 7.31 (d, J=8.9 Hz, 1H), 7.72 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.93 (d,J=8.9 Hz, 1H); ICSD (ESI+) m7z 310.99 (M++N, 20%), 455.95 (100%).

4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]aniline

no connection LS-T247

Received in accordance with section description restoration of the nitro-group.

Yellow solid (47%). %).1H NMR (250 MHz, CDCl3) δ 3.00 (s, 6H), 6.71 (d, J=8.5 Hz, 2H), 6.93 (dd, J=2.7 Hz, 8.9 Hz, 1H). 7.08 (d, J=Hz, 1H), 7.74-7.85 (m, 1H), 7.82 (d, J=8.5 Hz, 2H).

2-(4-{(E)-[4-(6-methoxybenzothiazole-2-yl)phenyl]diazenyl}phenoxy)ethylmethanesulfonate

no connection SC597

2-(4-{(E)-[4-(6-methoxybenzothiazole-2-yl)phenyl]diazenyl}phenoxy)ethanol (260 mg, 0,642 mmol) was added pyridine (26 ml) in an atmosphere of N2. Was cooled to 6°C and dropwise added methanesulfonamide (441 mg, of 3.85 mmol). Left to warm to room temperature, then was stirred for 6 hours. Added H2O (60 ml) and the precipitate was collected by filtration, washed H2O (2×5 ml) and then dried in vacuum overnight to obtain the product as an orange solid. Output: 251 mg, 81%;1H NMR (250 MHz, DMSO-d6) δ 3.26 (s, 3H), 3.87 (s, 3H), 4.39-4.41 (m, 2H), 4.57-4.59 (m, 2H), 7.12-7.26 (m, 3H), 7.75 (s, 1H), 7.88-8.06 (m, 5H), 8.23 (d, J=8.5 Hz, 2H).

Benzothiazoline connection

2-(4-{(E)-[4-(2-floratone)phenyl]diazenyl}phenyl)-6-methoxy-1,3-benzothiazole

no connection SC598

Dry THF (6 ml) was added 2-(4-{(E)-[4-(6-methoxybenzothiazole-2-yl)phenyl]diazenyl}phenoxy)ethylmethanesulfonate (50 mg, 0,103 mmol) in an atmosphere of N2. Added TBAF (310 l, 1M solution in THF) and the reaction mixture was heated at 50°C for 1 hour. The reaction mixture was cooled to room temperature and added in H2O (15 ml). The solid is collected by filtration, industrial and H 2O (2×2 ml) and dried in vacuum over night. Column chromatography (3:7 EtOAc/hexane) yielded the product (24 mg, 57%) as an orange solid.

4-{(E)-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T192

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:3 EtOAc/40:60 petroleum ether) yielded the product as yellow solid (24%). X (KBr)/cm-1: 1616, 1481, 1326, 1263, 1225, 1167, 1126;1H NMR (250 MHz, methanol-d4) δ 2.52 (s, 3H), 7.09 (d, J=8.9 Hz, 1H), 7.26 (s, 1H), 7.38 (d, J=8.9 Hz, 1H), 7.83 (s, 1H), 7.91-7.98 (m, 2H), 8.02 (d, J=7.9 Hz, 2H), 8.25 (d, J=7.9 Hz, 2H); MCHP (ESI+) m/z 413.87 (M++H, 45%), 326.09 (100%).

2-{(E)-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]diazenyl}-4-(trifluoromethyl)phenol

no connection LS-T191

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:20 EtOAc/40:60 petroleum ether, then 100% EtOAc) yielded the product as yellow solid (29%).1H NMR (250 MHz, CDCl3) δ 2.50 (s, 3H), 7.13 (d, J=8.9 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.71 (s, 1H), 7.91-8.04 (m, 3H), 8.17-8.29 (m, 3H), 13.07 (s, 1H);13C NMR (62.5 MHz, CDCl3) δ 21.6, 119.2, 121.5, 123.1, 127.9, 128.1, 128.4, 128.5, 129.0, 130.0 (2C), 130.8 (2C), 135.5, 136.1, 136.4, 136.7, 151.3, 152.4, 155.3, 165.2; MCHP (ESI-) m/z 411.99 (M+-H, 100%).

4-{(E)-[4-(6-methyl-1,3-benzothiazol the-2-yl)phenyl]diazenyl}for 3,5-bis(trifluoromethyl)phenol

no connection LS-T214

Obtained in accordance with the description section Diazomethane.

Column chromatography (3:2 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (20%).1H NMR (250 MHz, CDCl3) δ 2.51 (s, 3H), 7.32 (d, J=8.9 Hz, 1H), 7.53 (s, 1H), 7.62 (s, 1H), 7.72 (s. 1H), 7.98 (d, J=8.9 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 8.26 (d, J=8.5 Hz, 2H); ICSD (ESI-) m/z 480.00 (M+-H, 100%).

4-{(E)-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T209

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:3 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (32%). X (KBr)/cm-1: 1604, 1484, 1326, 1264, 1226, 1165, 1127, 1043, 1029;1H NMR (400 MHz, acetone-d6) δ 3.89 (s, 3H), 7.13 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.21 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.61 (d, J=3.4 Hz, 1H), 7.93 (d, J=8.90 Hz, 1H), 8.01 (d, J=8.9 Hz, 2H), 8.25 (d, J=8.9 Hz, 2H), 9.80 (bs, 1H);13C NMR (62.5 MHz, acetone-d6) δ 60.7, 109.7, 118.6 (2C), 121.6, 123.5, 125.0, 129.0 (2C), 129.3, 133.4 (2C), 141.4, 142.2, 147.7, 154.2, 159.0, 163.8, 166.1, 168.9; ICSD (ESI+) m/z 429.96 (M+-H, 100%).

no connection LS-T235A and LS-T235B

4-{(E)-[4-(5-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T235A

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (11%). 1H NMR (250 MHz, CDCl3) δ 3.92 (s, 3H), 7.07 (d, J=7.6 Hz, 1H), 7.25-7.30 (m, 1H), 7.32 (d, J=6.1 Hz, 1H), 7.42 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.5 Hz, 2H), 8.24 (d, J=8.5 Hz, 2H).

2-{(E)-[4-(5-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-5-(trifluoromethyl)phenol

no connection LS-T235B

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (43%).1H NMR (250 MHz, CDCl3) δ 3.91 (s, 3H), 7.03 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.04-7.10 (m, 1H), 7.53-7.64 (m, 4H), 7.74 (d, J=8.9 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.25-7.30 (m, 1H), 7.32 (d,J=6.1 Hz, 1H), 7.42 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.75-7.78 (m, 1H), 7.77 (1H, d, J=8.8 Hz, 1H), 8.01 (d, J=8.5 Hz, 2H), 8.24 (d, J=8.5 Hz, 2H).

4-{(E)-[4-(4-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T236

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (40%). X (KBr)/cm-1: 3121, 1606, 1465, 1335, 1265, 1226, 1155, 1127;1H NMR (400 MHz, acetone-d6) δ 4.04 (s, 3H), 7.06 (dd, J=0.7 Hz, 8.2 Hz, 1H), 7.22 (dd, J=2.7 Hz, 8.9 Hz, 1H), 7.34 (d, J=17 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.62 (dd, J=1.0 Hz, 8.2 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 8.03 (d, J=8.9 Hz, 2H,), 8.30 (d, J=8.5 Hz, 2H);13With NMR (62.5 MHz, acetone-d6) δ 55.8, 107.9, 108.1, 114.0, 118.1, 119.7, 123.6, 124.0, 128.3 (2C), 128.7 (2C), 130.8, 136.1, 137.2, 142.5, 144.7, 153.9, 154.4, 161.0, 164.4; M is HP (ESI+) m/z 430.41 (M ++H, 70%), 64.42 (100%).

4-{(E)-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}phenol

no connection LS-T210a

Obtained in accordance with the description section Diazomethane.

The substance crystallized from acetone (80 about. shares) to give the product as an orange solid (70%).1H NMR (250 MHz, DMSO-d6) δ 3.85 (s, 3H), 6.96 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.9 Hz, 1H), 7.71 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.84-7.95 (m, MN), 8.19 (d,.7=8.0 Hz, 2H).

4-[(E)-{4-[5-(triptoreline)-1,3-benzothiazol-2-yl]phenyl}diazenyl]phenol

no connection LS-T229

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:2 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (37%).1H NMR (250 MHz, acetone-d6and CDCl3) 5 6.92 (d, J=8.9 Hz, 1H), 7.22 (m, 1H), 7.71-7.96 (m, 6H), 8.01-8.19 (m, 2H), 8.44 (bs, 1H).

4-[(E)-{4-[6-(triptoreline)-1,3-benzothiazol-2-yl]phenyl}diazenyl]phenol

no connection LS-T210b

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:2 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (32%). X (KBr)/cm-1: 1633, 1595, 1454, 1324, 1297, 1247, 1219, 1163, 1106;1H NMR (250 MHz, acetone-d6) δ 7.06, (d, J=8.9 Hz, 2H), 7.55 (d, J=9.2 Hz, 1H), 7.93 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.5 is C, 2H), 8.14-8.20 (m, 2H), 8.33 (d, J=8.2 Hz, 2H), 9.38 (bs, 1H); MCHP (ESI-) m/z 413.99 (M+-H, 100%).

4-{(E)-[4-(6-dimethylamino-1,3-benzothiazol-2-ID)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T256

Obtained in accordance with the description section Diazomethane.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (26%).1H NMR (250 MHz, acetone-d6) δ 3.07 (s, 6N), 7.08 (dd, J=2.7 Hz, 9.1 Hz, 1H), 7.26 (dd, J=2.7 Hz, 9.1 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.98 (d, J=9.1 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H), 8.26 (d, J=8.5 Hz, 2H).

2-(4-{(E)-[4-(6-methoxybenzothiazole-2-yl)phenyl]diazenyl}phenoxy)ethanol

no connection SC588

4-[(E)-{4-[6-(triptoreline)-1,3-benzothiazol-2-yl]phenyl}diazenyl]-3-(trifluoromethyl)phenol (400 mg, 1.11 mmol) was added in DMF (5 ml). Added To2CO3(535 mg, 3.88 mmol), then 2-chloroethanol (134 mg, of 1.66 mmol) and the reaction mixture was heated at 80°C for 48 hours. Cooled to room temperature and added H2O (20 ml). The obtained solid substance was collected by filtration, washed H2O (2×5 ml) and dried in vacuum overnight to obtain the product as an orange solid. Output: 397 mg, 88%;1H NMR (250 MHz, DMSO-d6) δ 3.69-3.78 (m, 2H), 3.86 (s, 3H), 4.07-4.16 (m, 2H), 7.08-7.20 (m, 3H), 7.75 (s, 1H), 7.85-8.04 (m, 5H), 8.22 (d, J=8 Hz, 2H).

<> 1H NMR (250 MHz, DMSO-d6) δ 3.69-3.78 (m, 2H), 3.86 (s, 3H), 4.07-4.16 (m, 2H), 7.08-7.20 (m, 3H), 7.75 (s, 1H), 7.85-8.04 (m, 5H), 8.22 (d, J=8 Hz, 2H).

4-{(E)-[4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T213

Received in accordance with section description Demethylation.

Column chromatography (1:2 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (36%). X (KBr)/cm-1: 1600, 1481, 1454, 1327, 1264, 1229, 1158, 1131, 1043;1H NMR (400 MHz, acetone-d6) δ 7.08 (dd, J=8.9 Hz, 2.4 Hz, 1H), 7.22 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 8.01 (d, J=8.5 Hz, 2H), 8.24 (d, J=8.9 Hz, 2H);13With NMR (62.5 MHz, acetone-d6) δ 106.9, 113.4, 116.7, 118.6, 119.7, 124.0 (2C), 124.4, 128.3 (2C), 130.8, 136.3, 137.1, 142.5, 148.5, 153.7, 156.4, 160.9, 163.0; MCHP (ESI-) m/z 414.05 (M+-H, 100%).

4-{(E)-[4-(5-hydroxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T245

Received in accordance with section description Demethylation.

Column chromatography (1:2 EtOAc/40:60 petroleum ether) yielded the product as an orange solid (39%).1H NMR (250 MHz, acetone-d6) δ 7.09 (dd, J=2.1 Hz, 8.5 Hz, 1H), 7.28 (dd, J=2.4 Hz, 8.85 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H). 7.53 (d, J=2.1 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 8.08 (d, J=8.5 Hz, 2H), 8.34 (d, J=8.5 Hz, 2H), 8.83 (s, 1H), 9.84 (s, 1H).

4-{(E)-[3-methoxy-4-(6-what ethoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T273

Received in accordance with section Diazomethane.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a pink solid (25%). X (KBr)/cm-1: 1609, 1498, 1476, 1403, 1338, 1263, 1234, 1138, 1123, 1043, 1027;1H NMR (400 MHz, acetone-d6) δ 3.89 (s, 3H), 4.18 (s, 3H), 7.13 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.23 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.59 (d,J=2.7 Hz, 1H), 7.68 (dd, J=1.7 Hz, 8.8 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.93 (d,, J=8.9 Hz, 2H), 8.66 (d, J=8.2 Hz, 1H);13With NMR (100 MHz, acetone-d6) δ 55.5, 55.7, 103.6, 105.9, 113.5, 116.3, 118.3, 119.8, 123.7, 124.8, 129.7, 138.0, 142.5, 147.1, 154.6, 157.8, 158.2, 159.2, 160.9.

4-{(E)-[3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(4,4,4-triptoreline)phenol

no connection LS-T271

Received in accordance with section Diazomethane.

Column chromatography (1:2 EtOAc/40:60 petroleum ether) yielded the product as a pink solid (3%).1H NMR (250 MHz, acetone-d6) δ 2.15-2.22 (m, 2H), 2.56-2.68 (m, 2H), 3.93 (s, 3H), 4.19 (s, 3H), 4.33 (t, J=6.0 Hz, 2H), 6.60 (dd, J=2.1 Hz, 8.5 Hz, 1H), 6.71 (d, J=2.1 Hz, 1H), 7.16 (dd, J=2.4 Hz. 8.5 Hz, 1H), 7.63-7.68 (m, 3H), 7.77 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.66 (d, J=8.9 Hz, 1H), 9.36 (bs, 1H).

4-{(E)-[2-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T286

Received in accordance with section Diazo Azania.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a pink solid (21%).1H NMR (250 MHz, acetone-d6) δ 3.92 (s, 3H), 4.16 (s, 3H), 7.16 (d, J=8.9 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.36 (s, 1H), 7.64 (s, 1H), 7.65-7.78 (m, 2H), 7.88-7.98 (m, 3H).

4-{(E)-[2-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(triptoreline)phenol

no connection LS-T287

Received in accordance with section Diazomethane.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a pink solid (24%).1H NMR (400 MHz, acetone-d6) δ 3.88 (s, 3H), 4.11 (s, 3H), 6.97-7.00 (m, 2H), 7.13 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.65-7.68 (m, 2H), 7.80 (d, J=9.2 Hz, 1H), 7.89 (d, J=1.4 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H); NMR (100 MHz, acetone-d6) δ 55.5, 56.1, 104.5, 109.6, 111.2, 115.5, 116.4, 117.4, 119.0, 119.6, 120.0, 122.2, 124.0, 137.0, 137.3, 139.1, 143.7, 148.6, 148.9, 157.7, 158.6, 161.8, 163.9.

4-{(E)-[3-hydroxy-4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T274

Received in accordance with section description Demethylation.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a purple solid (31%). X (KBr)/cm-1: 1651, 1615, 1486, 1427, 1324, 1226, 1130, 1041;1H NMR (250 MHz, acetone-d6) δ 7.17 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.26 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.5 (m, 3H), 7.97 (m, 3H), 9.13 (bs, 1H).

4-{(E)-[3-hydroxy-4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(4,4,4-triptoreline)phenol

no connection LS-T272

Obtained in accordance with the description section Dmitrievna.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a purple solid (29%). X (KBr)/cm-1: 1626, 1564, 1505, 1417, 1271, 1135, 1049, 1012;1H NMR (400 MHz, acetone-d6) δ 2.13 (m, 2H, 2.54 (m, 2H), 4.28 (t, J=6.2 Hz, 2H), 6.54 (dd, J=2.4 Hz, 8.8 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 7.11 (dd, J=2.4 Hz, 8.9 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 7.46 (dd, J=1.9 Hz, 8.9 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.55 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 9.04 (bs, 1H), 9.34 (bs, 1H);13With NMR (100 MHz, acetone-d6) δ 22.4, 30.4, 67.7, 101.8, 107.0, 108.9, 110.6, 114.5, 116.8, 118.3, 123.1, 129.0, 134.7, 136.5, 145.8, 155.7, 156.6, 158.4, 159.4, 163.3, 165.5.

4-{(E)-[2-hydroc:si-4-(6-hydroxy-1,3-benzothiazol-2-yl)phenyl]diazenyl}-3-(trifluoromethyl)phenol

no connection LS-T288

Received in accordance with section description Demethylation.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a purple solid (31%). X (KBr)/cm-1: 1603, 1562, 1483, 1323, 1248, 1159, 1126, 1043;1H NMR (250 MHz, acetone-d6) δ 7.09-7.24 (m, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.36 (s, 1H), 7.47 (s, 1H), 7.63 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.99-8.13 (m, 1H).

4-{(E)-[2-hydroxy-4-(6-hydroxy-1,3-benzothiazol--yl)phenyl]diazenyl}-3-(triptoreline)phenol

no connection LS-T289

Received in accordance with section description Demethylation.

Column chromatography (1:1 EtOAc/40:60 petroleum ether) yielded the product as a purple solid (20%). X (KBr)/cm-1: 1614, 1564, 1484, 1463, 1383, 1261, 1125, 1101;1H NMR (250 MHz, acetone-d6) δ 6.97-7.29 (m, 3H), 7.43 (s, 1H), 7.62 (s, 1H), 7.70-7.82 (m, 1H), 7.83-8.09 (m, 3H).

Imidazo[1,2-a]pyridine compounds

N,N-dimethyl-4-{(E)-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]diazenyl}aniline

no connection SKT05-163

To a mixed solution of concentrated HCl (0.4 ml) in water (20 ml) at 0°C was added a suspension of 4-(6-methylimidazo[1,2-a]pyridine-2-yl)aniline (80 mg, 0,359 mmol) in acetone (5 ml). The reaction mixture was stirred at 0°C for 15 minutes, then dropwise added a pre-cooled solution of NaNO2(26 mg, 0,380 mmol) in water (2 ml). After 15 minutes, added a few crystals of urea. To the specified light yellow solution was dropwise added a solution of N,N-dimethylaniline (43 mg, 0,359 mmol) in Asón (1.5 ml). The reaction mixture was additionally stirred for 10 minutes at 0°C, then added a saturated solution of NaOAc (10 ml), collected orange precipitate by filtration under vacuum and dried in air. The solid was purified using flash chromatography (1:1 DHM/EtOAc) to the floor is the group of the title compound (40 mg, 31%) as a red/orange solid.

1H NMR (250 MHz, CDCl3) δ 2.32 (s, 3H), 3.09 (s, 6N), 6.76 (d,J=9.2 Hz, 1H), 7.02 (d, J=9.5 Hz, 1H), 7.54 (d, J=9.2 Hz, 1H), 7.84-7.92 (m, 7H), 8.05 (d, J=8.5 Hz, 2H);13With NMR (62.5 MHz, CDCl3) δ 18.17, 40.36, 108.39, 111.56, 116.86, 122.31, at 122.77, 123.35, 124.99, 126.45, 128.17, 128.73, 134.76, 143.86, 144.88, 152.40, 152.74.

Diagnostic ligands

4-[18F]fluoro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]-3-nitrobenzamide

Water [18F]Fluoride (1,8 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 5 mg2.2.20.95 ml of MeCN + 1 mg2CO350 l water in the vials Wheaton (5 ml). The solvent was removed by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of precursor of 4-bromo-3-nitro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]benzamide (SKT04-33) (5 mg) in 500 (al anhydrous DMSO. After heating at 180°C for 20 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve a total volume of 5 ml, and purified using preparative HPLC: ACE 5-C18-HL 250 mm × 10 mm, Advanced Chromatography Technologies; Cat. No. ACE 321-2510; gradient from 50% acetonitrile in 0.1% triperoxonane acid to 80% acetonitrile in 0.1% triperoxonane acid for 20 minutes, 20 to 30 minutes in isocratic mode 80% acetonitrile in 0.1% triperoxonane acid; p is current: 4 ml/min, tR=22,5 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak light With 18 cartridge (Waters, WAT023501), which was washed in 5 ml of water and was suirable 1 ml ethanolic getting 134 MBq product (12%, the correction for decay; radiochemical purity >95%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SKT03-99) using analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in 0.1% triperoxonane acid after 7 minutes, flow: 2 ml/min (tR=5,6 min), RHC>95% (HPLC).

6-[18F]fluoro-N-[4-(6-methoxybenzothiazole-2-yl)phenyl]nicotinamide

Water [18F]Fluoride (1,8 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 5 mg2.2.20.95 ml of MeCN + 1 mg2CO350 l water in the vials Wheaton (5 ml). The solvent was removed by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of precursor of 6-chloro-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]pyridine-3-carboxamide (SKT04-111) (5 mg) in 500 CL anhydrous DMSO. After heating at 180°C for 20 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve a total volume of 5 ml, and purified using preparative VAG IS: ACE 5-C18-HL 250 mm × 10 mm Advanced Chromatography Technologies; Cat. No. ACE 321-2510; gradient from 50% acetonitrile in 0.1% triperoxonane acid to 80% acetonitrile in 0.1% triperoxonane acid over 20 minutes; flow: 4 ml/min, tR=17,5 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak light C18 cartridge (Waters, WAT023501), which was washed in 5 ml of water and was suirable 1 ml of ethanol to obtain 168 MBq product (15%, the correction for decay; radiochemical purity >95%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SKT04-137) using analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in 0.1% triperoxonane acid after 7 minutes, flow: 2 ml/min (tR=5,1 min), RHC>95% (HPLC).

4-[+F]fluoro-N-[4-(6-methoxyimino[1,2-a]pyridine-2-yl)phenyl]-3-nitrobenzamide

Water [18F]Fluoride (2,4 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 5 mg2.2.20.95 ml of MeCN + 1 mg2CO350 l water in the vials Wheaton (5 ml). The solvent was removed by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of precursor of 4-bromo-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]-3-nitrobenzamide (SKT08-153) (5 mg) in 500 CL anhydrous DMSO. After load, the cation at 130°C for 20 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve the total volume, equal to 5 ml and purified using preparative HPLC: ACE 5-C18-HL 250 mm × 10 mm Advanced Chromatography Technologies; Cat. No. ACE 321-2510; gradient from 40% acetonitrile in 0.1% triperoxonane acid to 70% acetonitrile in 0.1% triperoxonane acid over 20 minutes; flow: 4 ml/min, tR=9 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak light C18 cartridge (Waters, WAT023501), which was washed in 5 ml of water and was suirable 1 ml of ethanol with 80 MBq product (5%, adjusted for decay; radiochemical purity >95%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SKT08-165) using analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in 0.1% triperoxonane acid after 7 minutes, flow: 2 ml/min (tR=3,8 min), RHC>95% (HPLC).

6-[18F]fluoro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)phenyl]nicotinamide

Water [18F]Fluoride (1,1 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 2 ml TBAH solution (8 l TBAG (40%) in 1.5 ml MeCN + 0.5 ml of water) in ampoule of Wheaton (5 ml). The solvent was removed by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of precursor of 6-chloro-N-[4-(6-methylimidazo[1,2-a]pyridine-2-yl)Hairdryer is l]pyridine-3-carboxamide (SKT06-13) (5 mg) in 500 l anhydrous DMSO. After heating at 180°C for 10 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve a total volume of 5 ml, and purified using preparative HPLC: ACE 5-C18-HL 250 mm × 10 mm, Advanced Chromatography Technologies; Cat. No. ACE 321-2510; gradient from 30% acetonitrile in 0.1% triperoxonane acid to 70% acetonitrile in 0.1% triperoxonane acid over 20 minutes; flow: 4 ml/min, tR=7 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak light C18 cartridge (Waters, WAT023501), which was washed in 5 ml of water and was suirable 1 ml of ethanol to obtain 296 MBq product (38%, the correction for decay; radiochemical purity >99%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SKT05-169) using analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in 0.1m K2HPO4after 7 min, flow: 2 ml/min (tR=5,0 min), RHC>99% (HPLC).

2-(4-{(E)-2-[2-(2-[18F]floratone)-4-nitrophenyl]vinyl}phenyl)-6-methyl-3H-imidazo[1,2-a]pyridine

Water [18F]Fluoride (0,255 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 1.5 ml To2.2.2/K2CO3(5 mg2220.95 ml of MeCN, 1 mg2CO3in 0.05 ml water) in ampoule of Wheaton (5 ml). The remove solvent and by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of the precursor 2-(2-{(E)-2-[4-(6-methyl-1H-imidazo[1,2-a]pyridine-2-yl)phenyl]vinyl}-5-nitrophenoxy)ethyl ether of methanesulfonamido acid (SKT08-175) (3 mg) in 500 l anhydrous DMF. After heating at 130°C for 15 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve a total volume of 5 ml, and purified using preparative HPLC: ACE 5-C18-HL 250 mm × 10 mm, Advanced Chromatography Technologies; Cat. No. ACE 321-2510; gradient from 40% acetonitrile in 0.1% triperoxonane acid to 70% acetonitrile in 0.1% triperoxonane acid over 20 minutes; flow: 4 ml/min, tR=14 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak Plus tC18 cartridge (Waters, WAT036810), which was washed in 5 ml of water and was suirable 2 ml of ethanol to obtain 55 MBq product (40%, the correction for decay; radiochemical purity >95%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SKT07-115) using analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in 10 mm Na2HPO4(pH 7,4) after 7 min, flow: 2 ml/min (tR=5,7 min), RHC>95% (HPLC).

2-(4-{(E)-2-[4-(2-[18F]floratone)phenyl]vinyl}phenyl)-6-methoxybenzothiazole

Water [18/sup> F]Fluoride (0,250 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 1.5 ml To2CO3(5 mg2220.95 ml of MeCN, 1 mg2CO3in 0.05 ml water) in ampoule of Wheaton (5 ml). The solvent was removed by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of the precursor 2-(4-{(E)-2-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]vinyl} phenoxy)ethyl ether of methanesulfonamido acid (SKT08-179) (3 mg) in 500 l anhydrous DMF. After heating at 130°C for 15 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve a total volume of 5 ml, and purified using preparative HPLC: ACE 5-C18-HL 250 mm × 10 mm, Advanced Chromatography Technologies; Cat. No. ACE 321-2510; gradient from 60% acetonitrile in 0.1% triperoxonane acid to 90% acetonitrile in 0.1% triperoxonane acid for 30 minutes; 30-40 minutes at 100% acetonitrile (0.1% of triperoxonane acid), flow: 4 ml/min, tR=31 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak Plus tC18 cartridge (Waters, WAT036810), which was washed in 5 ml of water and was suirable 2 ml of ethanol to obtain 13 MBq product (9%, the correction for decay; radiochemical purity >95%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SKT03-77) with what emeniem analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in 10 mm Na2HPO4(pH 7,4) after 7 min, flow: 2 ml/min (tR=6,9 min), RHC>95% (HPLC).

[4-(2-[l8F]floratone)phenyl}-[4-(6-methoxybenzothiazole-2-yl)phenyl}diazen

Water [18F]Fluoride (0,350 GBq) was placed in a QMA cartridge (Waters, Sep-Pak Light QMA Part. No.: WAT023525) and suirable 1.5 ml To2.2.2/K2CO3(5 mg2220.95 ml of MeCN, 1 mg2CO3in 0.05 ml water) in ampoule of Wheaton (5 ml). The solvent was removed by heating at 120°C for 10 minutes in a stream of nitrogen. Added anhydrous MeCN (1 ml) and boiled away, as described above. Added a solution of the precursor 2-(4-{(E)-2-[4-(6-methoxybenzothiazole-2-yl)phenyl]diazenyl}phenoxy)ethylmethanesulfonate (SC597) (1 mg) 500 CL of anhydrous DMF. After heating at 130°C for 10 minutes, the crude reaction mixture was diluted with a mixture of water/MeCN (1/1) to achieve a total volume of 5 ml, and purified using preparative HPLC: Phenomenex Synergy Hydro-RP 250 mm × 10 mm; gradient of 80% acetonitrile in 0.1% triperoxonane acid to 85% acetonitrile in 0.1% triperoxonane acid for 20 minutes, flow: 4 ml/min, tR=19 minutes Collected in the HPLC fraction was diluted with 40 ml of water and was immobilized on a Sep-Pak Plus tC18 cartridge (Waters, WAT036810), which was washed in 5 ml of water and was suirable 2 ml of ethanol with getting 65 M is to the product (35%, the correction for decay; radiochemical purity of >85%). The target product was characterized using joint injection with non-radioactive F-19 standard fluoride (SC598) using analytical HPLC: ACE-C18 50 mm × 4.6 mm; gradient solvent: start 5% acetonitrile to 95% acetonitrile in Umm Na2HPO4(pH 7.4) after 7 min, flow: 2 ml/min (tR=min 7,1), RHC>85% (HPLC).

Biological results

The study of competitive binding

Investigated the ability JB connections to contact PHF in uslovijahrekomenduetsja binding.

In the study of ligand used control ligand that exhibits increased fluorescence in the case of specified binding ligand with PHF. Adding the compounds, which is also associated with PHF with similar or higher affinity, this connection replaces the reference ligand and reduces the fluorescence signal. In this study the reference ligand is primulin, which was added to TSM concentration. The investigated compounds were added at concentrations from 0.05 to 1 μm. A value of P50for the studied compounds is defined as the concentration of a compound that reduces the signal primulina up to 50% of the initial value. The specified value, therefore, is not absolutisation, but the relative affinity cf is the ranking, with affinity primulina.

Way

Allocated PHF from the brain of a patient suffering from Alzheimer's disease, essentially in accordance with the description provided in the work of vesica with co-authors (Wischik et al.) (Neurobiology of Aging, Vol.16, pp.409-431, 1995). IFII fraction was isolated by centrifugation in a density gradient of sucrose in accordance with the description of the proposed doctoral thesis Kmicic, and additionally were extracted in "abc-sup" in accordance with the description provided in the work Kmicic (Thesis "The structure and biochemistry of paired helical filaments in Alzheimer's disease" Part I and II; Cambridge University, 1989).

The research activity of the ligands was performed in 96-well plates (Nunc Cat. No. 236108). The compounds at the desired concentration was mixed with PHF, then added primulin to achieve a final concentration of 1 µm and a total volume of 100 l. The concentration of added PHF was determined for each experiment to obtain adequate fluorescence signal and was typically in the range 1-2 l/100 l. Tested compound, usually dissolved in DMSO to achieve a final concentration of 10% DMSO in the study. Background fluorescence in the absence of PHF, also measured in the presence of 10% DMSO.

Fluorescence was measured on a Varian Carey Eclipse Fluorescence Spectrophotometer with wavelength emission, equal to 480 nm. Got excitation spectra, which were adjusted using the citania signal, measured in the absence of PHF, with application software Varian. For the corrected spectra measured fluorescence signal in the peak wavelength of emission at 420 nm. The values of fluorescence was built on a graph as a function of the concentration of the compounds, and values of P50determined from the graphs.

Values of P50

Data P50presented in parentheses, measured in 10% DMSO)

The control connection

Abbreviated nameConnectionP50(µM)
Primulin(1)

JB connection

Compounds in which Q represents-NHC(O)-; -NR1C(O)-; -C(O)NH-; or-C(O)NR1-

Benzothiazoline connection

The non-fluorinated methoxyamine

SacramentosanNo. of connectionsP50(µm)
AVMA-04SKT01-990.87
AVMA-05SKT01-410.85
AVMA-06SKT01-210.37
AVMA-07SKT01-1031.35
AVMA-08SKT01-63-1.2
AVMA-09SKT01-610.17
AVMA-10SKT01-1550.31
AVMA-11SKT01-1610.43
AVMA-13SKT04-890.31

Fluorinated methoxyamine

SacramentosanNo. of connectionsP50(µM)
ABFMA-01SK2033-50Unchanged
ABFMA-02SK2033-49Unchanged
ABFMA-03SK2033-47Unchanged
ABFMA-10SKT05-21 Unchanged

Abbreviated nameNo. of connectionsP50(µm)
ABFMA-12SKT02-1030.17
ABFMA-13SKT02-169Unchanged
ABFMA-15SKT01-1570.43
ABFMA-16SKT01-149Unchanged
ABFMA-16aSKT01-149aUnchanged
ABFMA-16bSKT01-149bUnchanged
ABFMA-18SKT01-159Unchanged
ABFMA-19SKT02-25Unchanged

Monitor-methoxyamine

SacramentosanNo. of connectionsP50(µm)
ABMFMA-01 SKT02-135Unchanged
ABMFMA-02SKT04-1370.89
ABMFMA-03SKT04-1110.34
ABMFMA-05SKT03-990.20
ABMFMA-06SKT03-75Unchanged
ABMFMA-08SKT04-33>1
ABMFMA-09SKT04-290.21

The non-fluorinated hydroxyamide

SacramentosanNo. of connectionsP50(µm)
AVNA-01SKT01-1010.90
AVNA-02SKT01-770.56
AVNA-03SKT01-570.45
AVNA-04SKT01-111Without edit the settings

Fluorinated hydroxyamide

SacramentosanNo. of connectionsP50(µm)
ABFHA-01SKT03-070.19
ABFHA-02SKT02-450.34
ABFHA-03SKT02-1490.1
ABFHA-04SKT03-41Unchanged
ABFHA-05SKT02-1710.4
ABFHA-06SKT05-390.39
ABFHA-07SKT02-1630.1
ABFHA-08SKT05-17>1
ABFHA-09SKT05-13>1
ABFHA-10SKT04-179>1
ABFHA-11SKT03-129 0.31

The non-fluorinated methylamide

SacramentosanNo. of connectionsP50(µM)
AAA-04SK2033-55Unchanged
AAA-05SK2033-72Unchanged
AVA-LS-T1070.52
AVA-07SKT01-5Unchanged
AVA-08SK2033-93Unchanged
AAA-10SK696-32-1.2
AVA-11SK696-54-1.2
AVA-12SK2033-94Unchanged

Dimethylamine-amides

Abbreviated nameNo. of connectionsP50(µm)
ABDMAA-01SKT03-1710.98
ABDMAA-02SKT03-171.01>1

Unsubstituted amides

SacramentosanNo. of connectionsP50(µm)
AUB-01SKT04-127>1
AUB-02SKT04-143>1
AUB-03SKT04-163>1

Imidazo[1,2-a]pyridine compounds

AIPN-20
SacramentosanNo. of connectionsP50(µm)
AIPN-01SKT05-123>1
AIPN-02SKT05-930.31
AIPN-03SKT05-107Unchanged
AIPN-04SKT05-171Without the of izmenenii
AIPN-05SKT06-50.51
AIPN-06SKT05-169Unchanged
AIPN-07SKT06-53>1
AIPN-08SKT06-630.10
AIPN-09SKT05-1650.34
AIPN-10SKT05-1730.18
AIPN-11SKT06-710.66
AIPN-12SKT06-670.33
AIPN-13SKT06-70.63
AIPN-14SKT06-110.5
AIPN-16SKT06-29>1
AIPN-17SKT06-15Unchanged
AIPN-18SKT06-13>1
SKT06-550.27
AIPN-21SKT06-590.46

SacramentosanNo. of connectionsP50(µM)
AIPN-22SKT06-390.76
AIPN-23SKT06-49095
AIPN-24SKT06-45-1.0
AIPN-25SKT06-79>1
AIPN-26SKT06-51>1
AIPN-27SKT06-57>1
AIPN-28SKT06-61>1
AIPN-29SKT06-1030.70

Imidazo[2,1-a]pyrimidine compounds

SacramentosanP50(µm)
AIPM-01SKT05-95Unchanged

Compounds in which Q represents-CH=CH-; -CR1=CH-; -CH=CR1-; or-CR1=CR1-

Benzothiazoline non-fluorinated compounds methylalkanes

SacramentosanNo. of connectionsP50(µm)
VEMA-01SK696-39Unchanged

SacramentosanNo. of connectionsP50(µm)
VEMA-05SKT01-55Unchanged
VEMA-06SKT01-69Unchanged
VEMA-08SK2033-30PL.
VEMA-09SK696-62Unchanged
VEMA-10 SK696-57-1.2
VEMA-11SK696-43Unchanged
VEMA-12SK2033-29Unchanged

FL. means that the compound is fluorescent. Therefore, the level of binding of the compounds in the study of competitive binding cannot be determined using fluorescence spectroscopy. As an alternative, the binding of ligand to aggregated Tau protein can be determined using cell research or analysis of tissue slices subjected to a ligand, as described in this patent application.

Non-fluorinated metaxylene

SacramentosanNo. of connectionsP50(µm)
UEMOA-03SKT02-670.04
UEMOA-05SKT01-1070.28
UEMOA-06SKT01-189Unchanged
UEMOA-09SKT03-07 0.03

Fluorinated metaxylene

SacramentosanNo. of connectionsP50(µM)
BEFA-01SK2033-44Unchanged
BEFA-02SK2033-42Unchanged
BEFA-03SK2033-40Unchanged
BEFA-04SKT02-17Unchanged
BEFA-06SKT02-117PL.
BEFA-09SKT02-81Unchanged
BEFA-10SKT02-137PL.
BEFA-12SKT03-77Unchanged

FL. means that the compound is fluorescent. Therefore, the level of binding of the compounds in the study of competitive binding cannot be determined using fluorescent is Oh spectroscopy. As an alternative, the binding of ligand to aggregated Tau protein can be determined using cell research or analysis of tissue slices subjected to a ligand, as described in this patent application.

Monitor and ftorirovannym hydroxyalkoxy

SacramentosanNo. of connectionsP50(µm)
BEHF-01SKT02-165PL.
BEHF-02SKT02-155PL.
BEHF-04SKT02-111Unchanged
BEHF-06SKT05-05PL.
BEHF-07SKT04-169PL.

FL. means that the compound is fluorescent. Therefore, the level of binding of the compounds in the study of competitive binding cannot be determined using fluorescence spectroscopy. As an alternative, the binding of ligand to aggregated Tau protein can be determined using cell research is whether the analysis of the tissue section, subjected to a ligand, as described in this patent application.

Imidazo[1,2-a]pyridine compounds

Abbreviated nameNo. of connectionsP50(µm)
IEPN-01SKT06-1170.05

Compounds in which Q represents-N=N-

Benzothiazoline connection

Abbreviated nameNo. of connectionsP50(µm)
BDF-01LS-T1920.29
BDF-02LS-T1910.46
BDF-03LS-T2090.13
BDF-04LS-T2130.08
BDF-05LS-T2450.09
BDF-06LS-T2560.04
BDF-07LS-T210 0.72
BDF-08LS-T214Unchanged
BDF-09LS-T229Unchanged

SacramentosanNo. of connectionsP50(µM)
BDF-10LS-T235A0.87
BDF-11LS-T235B0.6
BDF-12LS-T236A0.70
BDF-13LS-T236B0.35
BDF-14LS-T2740.02
BDF-15LS-T2720.14
BDF-16LS-T2880.03
BDF-17LS-T2890.03

Imidazo[1,2-a]pyridine compounds

Sacramentosan
No. of connectionsP50(µm)
DPN-001SKT05-1630.03

Calculated logP and TPSA (Å2)

The area of the polar surface of the molecule (PSA) or the total area of the polar surface area (TPSA), i.e, the surface owned by polar atoms (mainly N, O and associated hydrogen atoms) is a descriptor that has been shown to be well correlated with passive molecular transfer through membranes, and thus makes possible the prediction of properties transfer of drugs, which were successfully applied to predict the internal absorption and penetration through the blood-brain barrier. Differences between CNS and non-CNS drugs were studied by means of PHF, and it was shown that on average PSA for drugs that act on the CNS is lower.

Computational methods for estimating logP are high, but their database is limited by the fact that the values computed for each structure are dependent on the information contained in the library program. In addition most of the calculations reflect only the distribution of neutral particles, and, consequently, often the value calculated logP is higher than the structure with the experimentally determined values for the specified connection.

Published various works on the calculation of the PSA, which differ in the definition of "polar atoms, various methods of obtaining 3D structures or directly to the surface. However, the results of the numerous approaches correlate well with each other, even if the absolute values may differ due to differences in computational protocols and different sets of used nuclear radii. The calculation of the topological PSA (TPSA) is based on the summation of listed in the table of contributions of polar fragments (i.e., atoms, considered with regard to binding to the surface and ensures fast direct calculation PSA-based 2D patterns. Preferred is a computer system "molinspirations cheminformatics" (http://www.molinspiration.com/).

Thus, the following tables miLog P refers to the values of log P calculated by applying computational tools Molinspiration.

Imidazo[1,2-a]pyridine compounds

Abbreviated nameno connection in the applicationmiLog PTPSA (Å2)
AIPN-02SKT05-934.3749.6
AIPN-03SKT05-1072.9759.3
AIPN-04SKT05-1713.0359.3
AIPN-05SKT06-53.0959.3
AIPN-06SKT05-1693.5359.3
AIPN-07SKT06-533.659.3

Abbreviated nameno connection in the applicationmiLog PTPSA (Å2)
AIPN-08SKT06-634.2292.2
AIPN-09SKT05-1655.0592.2
AIPN-10SKT05-1734.6378.7
AIPN-11SKT06-71 3.3472.4
AIPN-12SKT06-674.1258.4
AIPN-13SKT06-74.3255.6
AIPN-14SKT06-113.7866.6
AIPN-16SKT06-294.5549.6
AIPN-18SKT06-134.0559.3
AIPN-20SKT06-554.2158.4
AIPN-21SKT06-594.3058.4
AIPN-22SKT06-394.4649.6
AIPN-23SKT06-494.4155.6
AIPN-24SKT06-454.5055.6
AIPN-26SKT06-514.2366.6
AIPN-27SKT06-574.4166.6
AIPN-28SKT06-615.1455.6

The research sections of tissue and cells

Ligand binding to aggregated Tau protein in tissue sections or cells containing these aggregates can also be used to determine that these connections may (i) to enter cells and (ii) to contact aggregated Tau protein. In addition this study is suitable for the determination of fluorescent ligands that can't be examined in fluorescence study of competitive binding.

Used slices of brain tissue from transgenic mice expressing a full-sized human Tau protein, which contained double the P301S mutation/G335D (mouse line 66). Pathological aggregated Tau proteins accumulate in the neurons of these animals. The specified fabric used after inclusion in paraffin or after freezing in the presence of critising substances.

Aggregated Tau protein obtained in cell lines, ACC is accordance with the description of WO 02/055720. Essentially fibroblast cells (T) Express full-Tau-protein ("t") under control of the inducible promoter and a small amount of PHF-core fragment of the Tau protein (12 KD fragment). Then the expression t reduced, as this protein undergoes dependent aggregation processing inside the cell, the N-terminal ~ αα 295 and C-terminal ~ αα 390, leading, thus, to higher levels of the 12 KD PHF-core fragment of the domain.

Included in paraffin sections of brain

The brain slices of mice expressing full-Tau protein, which contains the double mutation P301S/G335D located in the fronto-temporal lobes of the brain were cut with a layer thickness of 5 μm. Slices were deparaffinization and rehydratable in the water. Characteristic fluorescence repaid by sodium permanganate followed by the application of sodium borohydride. Added primulin or SK2033-30 in 50% ethanol. In the second experiment added SK2033-30 in 50% ethanol containing 10% DMSO. Slices were compared with sections stained using standard immunohistochemical processing using mAb 7/51, antibodies that can recognize duplicate domain truncated Tau protein (the work of Nowak and co-authors (Novak et al.), 1993; the work of vesica with co-authors (Wischik et al.), 1996).

Connection SK2033-30 is fluorescent, but there was no reason to put on the inclusion of the specified connection in CL the TCI slices of the brain of mice 66 compared with primulinum or immune staining antibodies (Figure 2A). When the solubility of the compounds increased using the inclusion of DMSO (10%) SK2033-30 resulted in staining, similar to the staining observed in the case primulina or antibodies (Figure 2B).

Sections of frozen brain

Take slices of mice of 6, which was mixed with 4% formaldehyde and then subjected createsite in 30% sucrose. Sections (30 µm) were collected and used in free-floating condition. Ligand LST-213 dissolved in 1% trinitrotoluene or 50% ethanol (residual DMSO concentration of stock solution was 1%).

When frozen sections of brain were incubated with LST-213, sliced yellow and, after 24 hours, adsorbing almost all compound that has been shown considering the fact that the environment has become colorless. These slices were studied using BioRad confocal laser scanning microscope settings used for the detection of fluorescein. Watched some staining structures in the cortex and hippocampus (Figure 3), which is consistent sites of Tau-positive neurons in these sections.

Cells tissue culture

In a study of tissue culture used ST cells of mice designed to ekspressirovali full-sized human Tau protein (htau40) under control of the inducible promoter (pOPRSVI) and ekspressirovali small amounts of truncated Tau protein (295-30 dGA) under control of the constitutive promoter (pcDNA3.1). The expression of large quantities of htau40 induce by adding isopropyl β-D-1-thiogalactopyranoside (IPTG, 10-50 µm), which in turn lead to additional amounts of truncated Tau protein at the expense of the process in which the aggregation and formirovaniyabrenda Tau protein are in the presence of the dGA of the Tau protein, which acts as a matrix. The aggregation of the Tau protein in this study are presented in Figure 1.

Mouse T fibroblast cells were grown to ~80% of the population in 10-cm tablets, before separating in 2×24-hole plates and left for additional growth within 24 hours, then added IPTG. After incubation over night removed the medium and the cells were washed in PBS.

In the study by light microscopy observed a significant increase in capture LST-213 cultured cells after 24 hours compared to the seizure within 2 to 4 hours (Figure 4). On the upper sections of the figure one can observe a large amount of undissolved substances in the environment. After washing, however, it was found that some compounds of the captured cells.

A similar experiment was conducted with cells, placed on a cover glass in 24-well plates. After 24 hours, cells were incubated with ligand for 20 hours in the presence or absence of IPTG (100 μm), i.e. the Indus is new or neindutsirovannom.

LST-213 has been far more intense staining in cells induced by IPTG, compared with neindutsirovannom cells (Figure 5). LST-213, in the presence of β-cyclodextrin (used to aid in the transfer of hydrophobic compounds through the membrane), did not show a significant improvement in the labeling. Also defined the capture and marking of aggregated Tau protein in induced cells for SK2033-30 (Figure 5).

It can be shown that the ligands are associated with aggregated Tau protein in vivo and that they are able to incorporate into the cells, which can be shown to aggregated Tau protein using specific tissues or cells grown in culture.

The study bearsdley

Research bearsdley and excretion ligands were carried out in male NMRI mice (body weight of approximately 30 g, 3 animals per time unit). Animals were kept under normal laboratory conditions at a temperature of 22±2°C and with the mode of darkness/light, equal to 12 hours. Food and water were supplied in full. During acclimatization less than 3 days before the study was conducted clinical examination of animals for reliable determination of the absence of abnormal clinical signs.

After 2, 5, 30, 60 and 120 minutes after intravenous injection into the tail vein of approximately 150 kBq 100 l research is imago connection quantitatively collected urine and feces. In the same time intervals the animals were anestesiologi by isoflurane, slew by using decapitate and removed for determination of radioactivity using a gamma counter-radiation following organs and tissues: spleen, liver, kidney, lung, bone, heart, brain, fat, thyroid, muscle, skin, blood, tail, stomach (without content), testis, intestine (with contents), pancreas, adrenal gland, skull and the rest of the body. Analysis calculated the percentage of the administered dose relative to tissue mass (% BM/g ± standard deviation) adjusted for decay.

The biodistribution SKT04-137, labeled18F (below), in mice indicates a good inclusion in the brain (3,99% injected dose/g tissue after 2 minutes) and a significant excretion from the brain (left 1,43% injected dose/g tissue after 60 minutes, the% excretion).

The distribution of the signal F-18 SKT04-137 in the organs of mice (% VD. % injected dose)

Fat 1.04
BodyTime
2 min5 min30 min60 min120 min
% VD/gSKO% VD/gSKO% VD/gSKO% VD/gSKO% VD/gSKO
Spleen2.950.842.440.121.190.110.600.100.300.03
Liver11.523.1013.302.377.031.694.260.792.411.14
Kidney9.602.827.100.506.380.703.780.691.490.52
Easy6.912.254.550.081.830.250.970.060.400.01
Bone1.540.371.500.341.200.101.960.241.650.22
Heart6.681.983.720.181.620.260.810.040.390.04
The brain3.990.623.540.453.190.421.430.180.600.10
1.250.511.570.517.211.414.510.411.760.25
Thyroid gland3.973.092.591.041.060.070.590.110.370.07
Muscle1.980.501.800.131.110.140.630.060.200.02
Leather1.010.251.280.181.870.171.110.080.450.06/td>
Blood1.690.411.120.020.740.130.390.040.160.01
Tail15.8910.067.401.023.741.267.706.064.932.66
Stomach3.670.572.280.462.481.142.170.680.980.57
Testicles0.970.101.100.191.680.191.180.400.61 0.17
The adrenal glands10.845.509.594.975.620.962.830.551.040.07
Intestine1.990.392.450.249.360.2317.431.2320.082.55
Pancreas4.340.883.170.391.740.081.110.430.330.05
Skull1.930.551.280.310.950.151.440.110.28

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WO 02/055720

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1. Labelling of paired helical filaments (PHF), including interaction with PHF connection and detecting the presence of the specified connection, and the connection specified is a compound of the formula:

where
R is independently selected from:br/>
where (T) denotes the place of joining-T;
and (Q) indicates the place of attachment to Q;
-Q - is independently chosen from:
-NHC(O)-;
-N=N-;
-CH=CH-;
-P is independently selected from:

where * indicates the place of attachment;
-T is independently selected from:

where * indicates the place of attachment;
and X independently represents N or CH;
-W1independently represents-H or-WA;
-W2independently represents-H or-WA;
-W3independently represents-H or-WA;
-W4independently represents-H or-WA;
-W5independently represents-H or-WA;
-W6independently represents-H or-WA;
where-WAindependently chosen from:
-F, -Cl, -Br, -I,
-OH, -WA1-O-WA1,
-N(WA1)2;
and-WA1independently chosen from:
unsubstituted saturated aliphatic C1-4of alkyl;
-CF3and
-CH2CH2N(Me)2;
-G1independently represents-H or-GA;
-G2independently represents-H or-GA;
where-GArepresents-OR2;
-G3independently represents-H or-GB;
-G4independently represents-H or-GB;
where-GBindependently SEL is an from:
-CF3,
-OH, -OR2;
-[O-CH2CH2]n-RB2where n is from 2 to 6;
where:
-P1independently represents-H or-PA;
-P2independently represents-H or-PB;
-P3independently represents-H or-PC;
-P4independently represents-H or-PB;
-P5independently represents-H or-PA;
and where:
each of PAeach of PBand each of PCindependently represents:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH,
-OR2,
-NO2,
-NH2-The other2, -NR22,
-NHOH,
-OC(=O)R2,
-NHC(=O)R2,
where:
each of R2independently represents-RA1,
where:
each of RA1independently represents a saturated aliphatic C1-6alkyl;
and where:
each of RA1is a possibly substituted, for example, one or more Deputy-RB2;
where:
each of RB2independently represents:
-F, -Cl, -Br, -I,
-CF3,
-OH,
-ORC1,
-NRC12,
where:
each of RC1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
and their pharmaceutically and physiologically acceptable salts.

2. The method according to claim 1, characterized in that the-G1independently represents-H

3. The method according to claim 1, characterized in that at least one of the-G1and-G2independently represents-GAand/or wherein at least one of the-G3and-G4independently represents-GB

4. The method according to claim 1, characterized in that each of the-G1, -G2, -G3and-G4independently represents-h

5. The method according to claim 1, characterized in that the-P independently represents:

6. The method according to claim 5, characterized in that-P1independently represents-h

7. The method according to claim 6, characterized in that at least one of P1and-P5independently represents-PAand/or wherein at least one of P2and-P4independently represents-PBand/or wherein-P3independently represents-PC.

8. The method according to claim 5, characterized in that at least one of P1, -P2, -P3, -P4and-P5is not-H.

9. The method according to claim 1, wherein P is independently selected from:

10. The method according to claim 9, characterized in that each of P1, -P2, -P3and-P4independently represents-h

11. The method according to claim 1, wherein T independently represents:
.

12. The method according to claim 11, characterized in that at least one-W4, -W5and-W6independently represents-h

13. The method according to claim 11, characterized in that-W4independently represents-WA.

14. The method according to claim 1, wherein T independently represents:

15. The method according to 14, wherein T independently represents:

16. The method according to 14, wherein T independently represents:

17. The method according to any of p-16, characterized in that-W1independently represents-h

18. The method according to 14, characterized in that-W1independently represents-WA.

19. The method according to claim 1, wherein T independently represents:
.

20. The method according to claim 19, characterized in that-W2independently represents-h

21. The method according to claim 19, characterized in that-W2independently represents-WA.

22. The method according to any of p, 18 or 21, characterized in that-WAindependently selected from-OH, -WA1and-O-WA1.

23. The method according to item 22, wherein-WAindependently represents-WA1or-O-WA1and WA1independently represents Me.

24. A way of marking agreg is one of the Tau protein, including the interaction of aggregated molecules of the Tau protein with a compound and detecting the presence of the specified connection, where the connection is defined in accordance with any of claims 1 to 23.

25. The compound of the formula:

where
R is independently selected from:

where (T) denotes the place of joining-T;
and (Q) indicates the place of attachment to Q;
-Q - is independently chosen from:
-N=N-;
-CH=CH-;
each of R1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
-P is independently selected from:

where * indicates the place of attachment;
-T is independently selected from:

where * indicates the place of attachment;
and X independently represents CH;
-W1independently represents-WA;
-W2independently represents-H or-WA;
-W3independently represents-H or-WA;
-W4independently represents-H or-WA;
-W5independently represents-H or-WA;
-W6independently represents-H or-WA;
provided that at least one-W4, -W5and-W6represents-WA,
where-WAindependently chosen from:
-F, -Cl, -Br, -I,
-OH, -WA1-O-WA1,
-N(W A1)2;
and-WA1independently chosen from:
unsubstituted saturated aliphatic C1-4of alkyl,
-CF3and
-CH2CH2N(Me)2;
-G1independently represents-H or-GA;
-G2independently represents-H or-GA;
where-GArepresents-OR2;
-G3independently represents-H or-GB;
-G4independently represents-H or-GB
where-GBindependently chosen from:
-CF3,
-OH, -OR2;
-[O-CH2CH2]n-RB2where n is from 2 to 6;
where:
-P1independently represents-H or-PA;
-P2independently represents-H or-PB;
-P3independently represents-H or-PC;
-P4independently represents-H or-PB;
-P5independently represents-H or-PA;
and where:
each of PAeach of PBand each of PCindependently represents:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH,
-OR2,
-NO2,
-NH2-The other2, -NR22,
-NHOH,
-OC(=O)R2,
-NHC(=O)R2,
where:
each of R2independently represents-RA1;
where:
each of RA1independently represents a saturated aliphatic C1-6alkyl;
and where:
each of the C-R A1is a possibly substituted, for example, one or more Deputy-RB2;
where
each of RB2independently represents:
-F, -Cl, -Br, -I,
-CF3,
-OH,
-ORC1,
-NRC12,
where:
each of RC1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
and their pharmaceutically and physiologically acceptable salts, with the proviso that the specified connection is not a connection:
(a)

No.Structure
P-002
P-003
P-004
P-005
P-006
P-007
P-008

No. Structure
P-009
P-010
P-011
P-012
P-013
P-014
P-015

and
(b) where-T is a:

-R represents a

and-P is a:

and-W4represents-H, -Q - represents-CH=CH-, all G1, -G2, -G3and-G4represent-H, and
(i) all P1, -P2, -P4and-P5represent-H, and-P3is a-RA1; or
(ii) one-P1, -P2, -P3, -P4and-P5is a-RA7and the other of P1, -P2, -P3, -P4and-P5represent-H.

26. The compound of the formula:

where
R is independently selected from:

where (T) denotes the place of joining-T;
and (Q) indicates the place of attachment to Q;
-Q - is independently chosen from:
-NHC(O)-;
each of R1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
-P is independently selected from:

where * indicates the place of attachment;
-T is independently selected from:

where * indicates the place of attachment;
and X independently represents CH;
-W1independently represents-WA;
-W2independently represents-H or-WA;
-W3independently represents-H or-WA;
where-WAindependently chosen from:
-F, -Cl, -Br, -I,
-OH, -WA1-O-WA1and
-N(WA1)2;
and-WA1independently chosen from:
unsubstituted saturated aliphatic C1-4of alkyl;
-CF3,
-CH2CH2OH and
-CH2CH2N(Me)2;
-G1independently represents-H or-GA;
-G2independently represents-H or-GA;
where-GArepresents-OR2;
-G3independently represents-H or-GB;
-G4independently represents-H or-GB;
where-GBindependently chosen from:
-CF3,
-OH, -OR2 ;
-[O-CH2CH2]n-RB2where n is from 2 to 6;
where:
-P1independently represents-H or-PA;
-P2independently represents-H or-PB;
-P3independently represents-H or-PC;
-P4independently represents-H or-PB;
-P5independently represents-H or-PA;
and where:
each of PAeach of PBand each of PCindependently represents:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH,
-OR2,
-NO2,
-NH2-The other2, -NR22,
-NHOH,
-OC(=O)R2,
-NHC(=O)R2,
where:
each of R2independently represents-RA1,
where:
each of RA1independently represents a saturated aliphatic C1-6alkyl;
and where:
each of RA1is a possibly substituted, for example, one or more Deputy-RB2;
where:
each of RB2independently represents:
-F, -Cl, -Br, -I,
-CF3,
-OH,
-ORC1,
-NRC12,
where:
each of RC1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
and its pharmaceutically and physiologically acceptable salts.

27. The compound of the formula:

where
R is independently selected from:

where (T) denotes the place of joining-T;
and (Q) indicates the place of attachment to Q;
-Q - is independently chosen from:
-NHC(O)-;
each of R1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
-P is independently selected from:

where * indicates the place of attachment;
-T is independently selected from:

where * indicates the place of attachment;
-W4independently represents-H or-WA;
-W5independently represents-H or-WA;
-W6independently represents-H or-WA;
provided that at least one-W4, -W5and-W6represents-WA,
where-WAindependently chosen from:
-F, -Cl, -Br, -I,
-OH, -WA1-O-WA1,
-N(WA1)2;
and-WA1independently chosen from:
unsubstituted saturated aliphatic C1-4of alkyl;
-CF3and
-CH2CH2N(Me)2;
-G1independently represents-H or-GA;
-G2independently represents-H or-GA;
where-GArepresents-OR2;
-G3independently represents-H or-GB;
-G4independently represents-H or-GB;
where-GBindependently chosen from:
-F, -Cl, -Br, -I.
-CF3,
-OH, -OR2;
-[O-CH 2CH2]n-RB2where n is from 2 to 6;
where:
-P1independently represents-H or-PA;
-P2independently represents-H or-PB;
-P3independently represents-H or-PC;
-P4independently represents-H or-PB;
-P5independently represents-H or-PA;
and where:
each of PAeach of PBand each of PCindependently represents:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH,
-OR2,
-NO2,
-NH2-The other2, -NR22,
-NHOH,
-OC(=O)R2,
-NHC(=O)R2,
where:
each of R2independently represents-RA1;
where:
each of RA1independently represents a saturated aliphatic C1-6alkyl;
and where:
each of RA1is a possibly substituted, for example, one or more Deputy-RB2;
where:
each of RB2independently represents:
-F, -Cl, -Br, -I,
-CF3,
-OH,
-ORC1,
-NRC12,
where:
each of RC1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
moreover, the specified compound contains the group-F;
and its pharmaceutically and physiologically acceptable salts;
provided that the compound is not a compound P-001.

28. The compound of the formula:

where
R is independently selected from:

where (T) denotes the place of joining-T;
and (Q) indicates the place of attachment to Q;
-Q - is independently chosen from:
-NHC(O)-;
-N=N-;
-CH=CH-;
each of R1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
-P is independently selected from:

where * indicates the place of attachment;
-T is independently selected from:

where * indicates the place of attachment;
and X independently represents N;
-W1independently represents-H or-WA;
where-WAindependently chosen from:
-F, -Cl, -Br, -I,
-OH, -WA1-O-WA1,
-N(WA1)2;
and-WA1independently chosen from:
unsubstituted saturated aliphatic C1-4of alkyl;
-CF3and
-CH2CH2N(Me)2;
-G1independently represents-H or-GA;
-G2independently represents-H or-GA;
where-GArepresents-OR2;
-G3independently represents-H or-GB;
-G4independently represents-H or-GB;
where-GBindependently chosen from:
-CF3,
-OH, -OR2;
-[O-CH2CH2]n-RB2where n is from 2 d is 6;
where:
-P1independently represents-H or-PA;
-P2independently represents-H or-PB;
-P3independently represents-H or-PC;
-P4independently represents-H or-PB;
-P5independently represents-H or-PA;
and where:
each of PAeach of PBand each of PCindependently represents:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH,
-OR2,
-NO2,
-NH2-The other2, -NR22,
-NHOH,
-OC(=O)R2,
-NHC(=O)R2,
where:
each of R2independently represents-RA1,
where:
each of RA1independently represents a saturated aliphatic C1-6alkyl;
and where:
each of RA1is a possibly substituted, for example, one or more Deputy-RB2;
where:
each of RB2independently represents:
-F, -Cl, -Br, -I,
-CF3,
-OH,
-ORC1,
-NRC12,
where:
each of RC1independently represents an unsubstituted saturated aliphatic C1-4alkyl;
and their pharmaceutically and physiologically acceptable salts.



 

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FIELD: medicine.

SUBSTANCE: venous blood of a patient suffering from sepsis of abdominal origin is analysed twice every 1 to 7 days; vascular endothelial growth factor (VEGF) is evaluated in pg/ml using an enzyme-immunoassay, a prognostic index (PI) of the clinical outcome of sepsis of abdominal origin is calculated by formula. If the PI index is less than 100%, the unfavourable outcome of sepsis of abdominal origin is predicted.

EFFECT: using the declared method enables providing higher accuracy and simplifying the prediction of the clinical outcome of sepsis of abdominal origin.

4 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to the field of medicine, namely to clinical laboratory diagnostics, and describes a method of differential diagnostics of post operational development of ischemic or necrotic changes of the liver in case of the acute liver failure.A method includes biochemical postoperative test of blood serum, carried out on 3-rd day, determination of lactate dehydrogenase and dehydrogenase glutamate concentration and calculation of index of ischemic change of the liver (ICL). Necrotic change of the liver is diagnosed in case if the values of ICL indexes are less than the values of indexes, characteristic of the norm.

EFFECT: ischemic change of the liver is diagnosed in case if the values of ICL indexes are larger than the values of indexes, characteristic of the norm.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: enzyme-immunoassay is used to measure blood plasma α-defensin (αD), ng/ml and fecal β-defensin (βD), ng/g and calprotectin (FC), mcg/g in the patients suffering inflammatory intestinal diseases; a probability of developing recurrent inflammatory intestinal disease (p), % is calculated by formula. If the derived probability is equal to 50% or more, a high risk of developing a recurrence is predicted, and if the probability is less than 50%, a low risk of developing the recurrence is predicted.

EFFECT: using the declared method enables the timely prediction of developing the recurrence of the inflammatory intestinal diseases.

2 ex

FIELD: medicine.

SUBSTANCE: method involves pre- and post-therapeutic blood serum examination that is additionally preceded by three-time 20-minute freezing and 10-minute thawing cycles, disintegration, apolipoprotein B and lipoprotein (a) tests, determination of their relation, total cholesterol and triacylglycerol tests. If observing an increase of apolipoprotein B to lipoprotein (a) relation by 40% and more, a decrease of total cholesterol by 25% and more as compared to a reference and a decrease of triacylglycerol by 20% and more, the clinical course of lipidemia is predicted to be favourable.

EFFECT: more accurate and effective prediction of the clinical course of lipidemia.

1 ex

FIELD: medicine.

SUBSTANCE: bronchial epithelium of dead fetuses or newborns of 22-40 weeks of gestation is examined by immunohistochemical method; there are also evaluated expression indices of epidermal growth factor (EGF) and insulin-like growth factor I (ILGF-I). If the relation of the EGF expression index to the ILGF-I expression index is more than 1.0, a morphofunctional maturity of the lungs is diagnosed, and if the relation is less than 1.0, the lung development delay is stated.

EFFECT: technique enables diagnosing the lung tissue development delay without regard to the antropometric parameters and gestation term, providing the objective death mechanism of the foetuses and newborns.

3 ex

FIELD: medicine.

SUBSTANCE: there are presented recombinant chimeric polypeptides rmBmpA-frp83, rmOspA-frp83, rmDbpB-rmOspA, rmFlaA-frFlaB and rmOspCBg-rmOspCBa, prepared on the basis of gene expression amplified by PCR on the DNA of Borrelia garinii 20047T Western-Siberian isolate or in case of the protein rmOspCBa, on the DNA of Borrelia afzelii isolate.

EFFECT: invention extends the range of recombinant polypeptides applicable for the serum diagnosis of ixodic tick-borne borreliosis, providing higher specificity and sensitivity of the ITBB, including the differential diagnosis of the early stage and the stage of a disseminated infection in the territories of Borrelia burgdorferi s1 Western-Siberian isolates.

8 cl, 2 dwg, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: early diagnosis of pulmonary artery thromboembolia in the presence of the clinical signs of potential pulmonary artery thromboembolia PATE (tachypnea, tachyrhythmia, thoracodynia, bloody expectoration) is ensured by measuring blood serum fibrin D-dimer. If the fibrin D-dimer content is less than 0.5 mg/l, suspended PATE is discarded. If the blood plasma fibrin D-dimer content is 0.5 mg/l and more, an additional enzyme immunoassay is used to measure blood serum interleukin-6, and if the derived concentration is 21.3 pg/ml and more, pulmonary artery thromboembolia is diagnosed.

EFFECT: using the technique enables higher accuracy and information value of diagnosing pulmonary artery thromboembolia.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: blood serum is examined for TNFα; erythrocyte membrane lipids are analysed for ω-6 and ω-3 polyunsaturated fatty acids; that is followed by calculating the relation K=Σω-6/Σω-3, wherein Σω-6 is an amount sum of linoleic and arachidonic acid, %, Σω-3 is an amount sum of α-linolenoic, eicosapentanoic and docosahexaenoic acid, %. If blood serum TNFα is 110±1.97 pg/ml, while K is more than 0.67, developing hemic hypoxia is predicted.

EFFECT: method has enabled the high-accuracy prediction of developing unstable erythrocytes in the pregnant women suffering aggravated cytomegaloviral infection at the early stages of the clinical manifestations of hemic hypoxia.

1 ex

FIELD: medicine.

SUBSTANCE: method for the prediction of the length of abscess formation accompanying a sequestration phase of acute pancreatitis involves the DNA recovery from peripheral venous blood, the polymorphism analysis of +250 A/G Ltα, and if observing the genotypes +250 GG or +250 AG Ltα, a risk of early abscess formation accompanying the sequestration phase of acute pancreatitis is predicted.

EFFECT: higher prediction accuracy.

1 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to medicine, namely to medical genetics and psychiatry, and may be used for the prediction of a risk of paranoid schizophrenia. Substance of the method: DNA is recovered by phenol-chloroform extraction that is followed by genetic typing of polymorphous locus rs 1443445 of NTRK2 gene, locus rs 1946698, locus rs 7170062, locus rs 11631508 of NTRK3 gene, locus rs 1469794 of NRXN1 gene; if observing the genetic type NTRK2*C/*C (rs 1443445), the genetic type NTRK3*G/*G (rs 1946698), the genetic type NTRK3*T7*T (rs 7170062), the genetic type NTRK3*A/*A (rs 11631508) in Russian people; the genetic type NRXN1*A/*A (rs 1469794) in the Tatar people, the risk of paranoid schizophrenia is predicted.

EFFECT: using the invention enables the more accurate, objective prediction of the disease.

1 tbl, 2 ex, 5 dwg

FIELD: biotechnologies.

SUBSTANCE: invention proposes a detection method of proteins in amyloid state, in which a specimen of lysate of yeast culture or tissue of a mammal is obtained, ionic detergent is added to the specimen, proteins are concentrated in an amyloid shape on a cellulose acetate membrane, and they are detected by means of aptomeres, their conjugates or antibodies specific to amyloid shape of proteins. Besides, a set for detection of proteins in amyloid state is proposed.

EFFECT: invention can be used in medicine for diagnostics of amyloid diseases.

9 cl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: visualisation agent contains a conjugate of formula (I) of benzopyrylium dye through a linker group with a 3-100-dimensional synthetic peptide which provides directed delivery to the biological target. Also disclosed is a pharmaceutical composition which contains said conjugate of formula (I), a set for preparing said pharmaceutical composition and methods for visualisation of a mammal body in vivo.

EFFECT: invention provides efficient visualisation of a mammal body in vivo while monitoring diseased state thereof.

24 cl, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: detection system for detecting target molecules includes a sensor chip (1), having on its detecting surface (33) an immobilised target molecule or a capturing molecule for target molecules and a soluble reagent layer (5), having a labelled molecule for binding with the target. The group of inventions also relates to a sensor chip (1) and a method of detecting target molecules in a sample using said sensor chip.

EFFECT: high sensitivity and accuracy of analysis while cutting duration of analysis.

19 cl, 8 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to methods and systems of analysis based on enzymatic degradation following protein-protein interaction for reporter modulation (activation or inactivation).

EFFECT: group of inventions provides simple high-efficiency identification of protein-protein interaction modelling.

34 cl, 17 dwg, 17 ex

FIELD: medicine.

SUBSTANCE: there is offered a method of discrimination and calculation of at least two populations of biological elements - carriers of specific signs, probably presented in a sample. The method provides the use of three different probes, each of which is specifically fixed with one of the populations of biological elements which are required to be detected. Each probe itself becomes detectable due to its proper marker, and two different markers specified have two emission spectra containing at least one common part (overlapping emission spectra), and the third one has the emission spectrum which essentially contain no common parts with two others (nonoverlapping spectrum).

EFFECT: invention allows definitely detecting three populations of biological elements by using only two detection devices that assumes that two populations of biological elements will be detected by the same detection device.

9 cl, 2 ex, 1 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: device comprises a measuring cavity for receiving and introducing a fluid sample. The measuring cavity has a set fixed thickness not exceeding 170 micrometres. The measuring cavity has a section fit for acquisition of its image. Within the measuring cavity, there is a dry reagent. The reagent contains as a component, a molecule conjugate with phosphor used for binding with biological components and with all other reacting components. The reacting components are soluble and/or suspended in the fluid sample. The method involves mixing of the reagent with the liquid sample to be introduced in the measuring cavity. A section of the sample in the measuring cavity is exposed to electromagnetic radiation of wavelength corresponding to wavelength of phosphor excitation. Phosphor marked biological components are detected through-thickness of the measuring cavity. Further, numerical analysis of the digital image follows to identify the biological components showing phosphor and to determine amounts of the biological components showing phosphor in the sample. The biological components are discernible on the digital image as fluorescing points emitting electromagnetic radiation of wavelength corresponding wavelength of phosphor emission.

EFFECT: device and method allow for higher effectiveness of numerical volume concentration of fluorescent marked biological components of the fluid sample.

24 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to biology and medicine, namely to immunodiagnosis. There is offered method of multianalytic immune assay based on immunochemical, genetic and other types of reactions of biospecific binding analyte and ligands. There are mixed various categories of microparticles coated with biospecific reagents for binding of various required analytes and marked with one or more fluorochromes in various concentrations emitting a long-living fluorescence. The analysed sample and biospecific developing reagent marked with a detecting fluorochrome with a short-living fluorescence with its excitation area being outside that of fluorochromes with long-living fluorescence are added to the particle mixture. It is followed with reaction for biospecific complex formation. The prepared biospecific complexes are deposited on a solid-phase carrier. The fluorescence emission of all fluorochromes is excited with emitters in two spectral ranges herewith measuring an amount of long-living fluorescence in a time resolution mode to identify the microparticle and an amount of short-living fluorescence of detecting fluorochrome for measuring concentration of required analytes. Thus the concentration ratio of long fluorescing fluorochromes in microparticles for detecting the same type of analyte is constant, and for determining different types of analytes, the concentration ratio differs at least twice.

EFFECT: possibility of simultaneous analysis of great array of microparticles on a solid phase, ie increased multiplexity of the analysis, and wide-range measurement of concentration of required analytes.

6 cl; 3 ex, 10 dwg

FIELD: medicine.

SUBSTANCE: on surface of porous membrane apply the reactionary admixture containing analyte, the first binding molecules bound to detecting substance and specific to analyte, the investigated sample and the particles, not capable to pass through the pores of a membrane covered with the second binding molecules, also specific to analyte, incubate an admixture for formation of a biospecific complex, wash an admixture from not bound reagents and register in a regimen of the time permission phosphorescence signals in spectral ranges of the detecting substances corresponding to a constant of time of attenuation of these substances. Determine the required analyte on a parity of measured phosphorescence signals, thus use on two kinds of the first and second binding molecules, each kind of the first binding molecule is bound to two detecting is long luminescing substances, for example chelate of europium and platinaporphyrine which parity of concentration in each first binding molecule is chosen in advance and corresponds to defined analyte.

EFFECT: method allows finding out and quantitatively to detect low concentration biological analytes in assays at carrying out of researches on solid surface.

5 cl, 5 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves determining estradiol- and progesterone receptors concentration in mononuclear cells fraction of peripheral blood. The value being greater than 210 and 2050 receptors per cell, estrogen- and progesteron-dependent genitalia abnormalities are diagnosed, respectively.

EFFECT: high diagnosis accuracy; no biopsy needed.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing radioisotope to animals and further repeatedly determining radioisotope inclusions percent in blood and in and in non-mineralized organs in given time intervals, calculating relative radio-activity RRA for an animal examined at each time as ratio between radioisotope inclusions percent in non-mineralized organs to radioisotope inclusions percent in blood. Then transport intensity is determined in prevailing directions in each examination time by applying RRA difference factor (DFRRA), calculated as difference between the subsequent and previous RRA values. The received values of DFRRA factor changes are interpreted in terms of intensity time fluctuations and radioisotope transport direction for each organ.

EFFECT: enhanced effectiveness in determining intensity dynamics and prevailing direction of substance transport between non-mineralized organ and blood.

3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bicyclic heterocyclic compounds of formula (I), which can be applied in prevention or treatment of abnormal or pathological condition, mediated by FGFR kinase, such as cancer. In formula compound, (i) in case when R1 and R2 independently represent hydrogen or C3-8cycloalkyl; A is group Aa, which represents aromatic group, representing phenyl; R3 represents hydrogen or C1-6alkyl; R4 represents group R4a, which represents amino, halogen, C1-6alkyl, -X-R5, phenyl or aromatic heterocyclic group, where said heterocyclic group represents 5- or 6-membered heterocyclyl group and contains 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen or sulphur, where said phenyl or said heterocyclyl group can be optionally substituted with one or two Rb groups; or (ii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ab, which represents aromatic 5-membered heterocyclic group; R3 represents hydrogen or C1-6alkyl; R4 is group R4a, which represents halogen; or (iii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ac, which represents aromatic 6-membered heterocyclic group, containing one nitrogen atom as heteroatom; R3 represents hydrogen or C1-6alkyl; R4 is group R4b, which represents halogen, C1-6alkyl, -X-R5 or aromatic heterocyclic group, containing 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Other values of radicals are given in the invention formula.

EFFECT: obtaining novel derivatives of bicyclic heterocyclic compounds.

21 cl, 7 tbl, 250 ex

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