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; -W^1-6, -G^1-4, -P^1-5 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 C_1-6of alkyl, C_2-6alkenyl and C_2-6the quinil;

-R^{2 selected from hydrogen, C_1-10of alkyl, C_1-10haloalkyl,_6-14aryl, C_6-14arylalkyl, -(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 alifaticheskii_1-4alkyl;

-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-W^A;

-W²is an independently-H or-W^A;

-W³is an independently-H or-W^A;

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

-W⁵is an independently-H or-W^A;

-W⁶is an independently-H or-W^A;

where-W^Aindependently chosen from:

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

-IT, -W^A1-O-W^A1,

-NH₂, -NHW^A1and-N(W^A1)₂;

and-W^A1independently chosen from:

unsubstituted saturated aliphatic C_1-4of alkyl,

-CF₃,

-CH₂CH₂OH and

-CH₂CH₂N(Me)₂;

-G¹independently represents-H or-G^A;

-G²independently represents-H or-G^A;

where-G^Aindependently chosen from:

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

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6;

-G³independently represents-H or-G^B;

-G⁴independently represents-H or-G^B,

where-G^Bindependently chosen from:

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

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6;

where:

-R¹independently represents-H or-P^A;

-R²independently represents-H or-P^B;

-R³independently represents-H or-P^C;

-R⁴independently represents-H or-P^B;

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

and where:

each of P^Aeach of P^Band each of P^Cindependently 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 C_1-5alkylen;

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:

-R^A1, -R^A2, -R^A3, -R^A4, -R^A5, -R^A6, -R^A7, -R^A8,

-L^A-R^A4, -L^A-R^A5, -L^A-R^A6, -L^A-R^A7or-L^A-R^A8;

where:

each of R^A1independently represents a saturated aliphatic C_1-6alkyl;

each of R^A2independently represents an aliphatic C_2-6alkenyl;

each of R^A3independently represents an aliphatic C_2-6quinil;

each of R^A4independently represents a saturated_3-6cycloalkyl;

each of R^A5independently represents a C_3-6cycloalkenyl;

each of R^A6independently represents a non-aromatic C_3-7heterocyclyl;

cardys-R ^A7independently represents a C_6-10carbaryl;

each of R^A8independently represents a C_5-10heteroaryl;

each of L^A- independently represents a saturated aliphatic C_1-3alkylen;

and where:

each of R^A4, -R^A5, -R^A6, -R^A7and R^A8possibly substituted, for example, one or more Deputy-R^B1and/or one or more Deputy-R^B2and

each of R^A1, -R^A2, -R^A3and-L^A- may be substituted, for example, one or more Deputy-R^B2,

where:

each of R^B1independently represents a saturated aliphatic C_1-4alkyl, phenyl or benzyl;

each of R^B2independently represents:

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

-CF₃, -OCF₃.

-OH, -L^C-OH, -O-L^C-OH,

-OR^C1, -L^C-OR^C1, -O-L^C-OR^C1,

-SH, -SR^C1,

-CN

-NO₂,

-NH₂-The other^C1, -NR^C1₂, -NR^C2R^C3,

-L^C-NH₂, -L^C-Other^C1, -L^C-NR^C1₂, or-L^C-NR^C2R^C3,

-O-L^C-NH₂, -O-L^C-Other^C1, -O-L^C-NR^C1₂, -O-L^C-NR^C2R^C3,

-C(=O)OH, -C(=O)OR^C1,

-OC(=O)R^C1,

-C(=O)R^C1,

-C(=O)NH₂, -C(=O)other^C1, -C(=O)NR^C1₂, -C(=O)NR^C2R^C3,

-NHC(=O)R^C1, -NR^C1C(=O)R^C1,

-NHS(=O)₂R^C1, -NR^C1S(=O)₂R^C1,

-S(=O)₂NH₂, -S(=O)₂Other^C1, -S(=O)₂NR^C1₂, -S(=O)₂NR^C2R^C3or

-S(=O)₂R^C1;

where:

each of R^C1independently represents an unsubstituted saturated aliphatic C_1-4alkyl, phenyl or benzyl;

each of L^C- independently represents an unsubstituted saturated aliphatic C_1-5alkylen; and

in each of the groups-NR^C2R^C3, -R^C2and R^C3taken 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.	Link	Structure
R-001	Klunk et al. WO 2006/014382

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

No.	Link	Structure
P-010	Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-011	Lee et al. Bioorg. Med. Chem. Lett. 2008, 18,1534
P-012	Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-013	Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-014	Lee et al. Bioorg. Med. Chem. Lett. 2008, 18, 1534
P-015	Lee 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-R^A1; or

(ii) one of R¹, -R², -R³, -R⁴and R⁵is a-R^A7and 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-P^A, -P^Bor-P^Ccontains-F group.

According to one implementation variant, the group T is replaced by-F group or a substituted group containing a-F group. Thus W^Arepresents-F or-W^A1contains-F group.

According to one implementation variant, the group R is substituted by-F group or a substituted group containing a-F group. Thus G^Arepresents-F, or-G^Acontains-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 C_1-4alkyl.

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-W^A.

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-W^A.

According to one implementation variant-W²independently represents-N.

According to one implementation variant-W²independently represents-W^A.

Group-W³

According to one implementation variant-W³independently represents-H or-W^A.

According to one implementation variant-W³independently represents-N.

According to one implementation variant-W³independently represents-W^A.

Group-W⁴

According to one implementation variant-W⁴independently represents-H or-W^A.

According to one implementation variant-W⁴independently represents-N.

According to one implementation variant-W⁴independently represents-W^A.

Group-W⁵

According to one implementation variant-W⁵independently represents-H or-W^A.

According to one implementation variant-W⁵independently represents-N.

According to one implementation variant-W⁵independently represents-W^A.

Group-W⁶

According to one implementation variant-W⁶independently represents-H or-W^A.

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

According to one implementation variant-W⁶independently represents-W^A.

Group-W²and-W³

According to one implementation variant, at least one of-W²and-W³represents-W^A.

According to one implementation variant, one of the-W²and-W³represents-W^A.

According to one implementation variant-W²represents-W^A.

According to one implementation variant-W³represents-W^A.

Group-W⁴, -W⁵and-W⁶

According to one implementation variant, at least one of-W⁴, -W⁵and-W⁶represents-W^A.

According to one implementation variant, one of the-W⁴, -W⁵and-W⁶represents-W^A.

According to one implementation variant-W⁴represents-W^A.

According to one implementation variant-W⁵represents-W^A.

According to one implementation variant-W⁶represents-W^A.

Group-W^A

According to one implementation variant-W^Aif present, independently selected from:

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

-IT, -W^A1-O-W^A1,

-NH₂, -NHW^A1and-N(W^A1)₂.

According to one implementation variant-W^{A/sup> if present, independently selected from:}

^{-OH, -WA1-O-WA1,}

-NH₂, -NHW^A1and-N(W^A1)₂.

According to one implementation variant-W^Aif present, independently selected from-OH, -W^A1and-O-W^A1.

According to one implementation variant-W^Aif present, independently selected from W^A1and-O-W^A1.

According to one implementation variant-W^Aif present, independently selected from-HE-O-W^A1.

According to one implementation variant-W^Aif present, independently represents-W^A1.

According to one implementation variant-W^Aif present, independently represents-O-W^A1.

According to one implementation variant-W^Aif present, independently represents-HE.

According to one implementation variant-W^Aif present, independently selected from-NH₂, -NHW^A1and-N(W^A1)₂.

According to one implementation variant-W^Aif present, independently represents-NH₂.

According to one implementation variant-W^Aif present, independently represents-NHW^A1.

According to one implementation variant-W^Aif presets is there, independently represents-N(W^A1)₂.

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

According to one implementation variant-W^Aif present, independently represents a-F or a-I.

According to one implementation variant-W^Aif present, independently represents-F.

Group-W^A1

According to one implementation variant-W^A1if present, independently selected from:

unsubstituted saturated aliphatic C_1-4of alkyl,

-CF₃,

-CH₂CH₂OH and

-CH₂CH₂N(Me)₂.

According to one implementation variant-W^A1if present, independently selected from unsubstituted saturated aliphatic C_1-4the alkyl and-CF₃.

According to one implementation variant-W^A1if present, independently represents an unsubstituted saturated aliphatic C_1-4alkyl.

According to one implementation variant-W^A1if present, independently represents-Me.

According to one implementation variant-W^A1if present, independently represents-Et.

According to one implementation variant-W^A1if present, represent the screens a-CF ₃.

According to one implementation variant-W^A1if present, represents-CH₂CH₂OH.

According to one implementation variant-W^A1if 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-G^A.

According to one implementation variant-G¹independently represents-N.

According to one implementation variant-G¹independently represents-G^A.

Group-G²

According to one implementation variant-G²independently represents-H or-G^A.

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-G^B.

According to one implementation variant-G³independently represents-N.

According to one implementation variant-G³independently represents-G^B.

Group-G⁴

According to one implementation variant-G⁴independently represents-H or-G^B.

According to one implementation variant-G⁴independently represents-N.

According to one implementation variant-G⁴independently represents-G^B.

Group-G^A

According to one implementation variant-G^Aif present, independently selected from

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

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

According to one implementation variant-G^Aif present, independently selected from

-F

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

According to one implementation variant-G^Aif present, independently selected from

-F

-CF₃, -OCF₃,

-OH, -OR².

According to one implementation variant-G^Aif present, it is not avisio selected from the

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

-OH, -OR².

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

According to one implementation variant-G^Aif present, independently represents-F.

According to one implementation variant-G^Aif present, independently selected from-HE-OR².

According to one implementation variant-G^Aif present, independently represents-HE.

According to one implementation variant-G^Aif present, independently represents-OR².

According to one implementation variant-G^Aif present, independently represents -[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

Group-G^B

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

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

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

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

-F

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

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

-CF₃, -OCF₃,

-OH, -OR²;

-[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

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

-CF₃, -OCF₃,

-OH, -OR².

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

According to one implementation variant-G^Bif present, independently represents-F.

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

According to one implementation variant-G^Bif present, independently represents-CF₃and-OCF₃.

According to one implementation variant-G^Bif present, independently represents-OCF₃.

According to one implementation variant-G^Bif present, independently selected from-HE-OR².

According to one implementation variant-G^Bif present, independently represents-HE.

According to one implementation variant-G^Bif present, independently represents-OR².

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

According to one implementation variant-G^Bif present, independently represents -[O-CH₂CH₂]_n-R^B2where n takes values from 2 to 6.

According to one implementation variant-G^Bif 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-P^A, -P^Bor-P^Cin appropriate cases.

According to one implementation variant, one of R¹, -R², -R³, -R⁴and-R⁵if there is a-P^A, -P^Bor-P^Cin 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-P^A.

According to one implementation variant-R¹independently represents-N.

According to one implementation variant-R¹independently represents-P^A.

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

Group-P²

According to one implementation variant-R²independently represents-H or-P^B.

According to one implementation variant-R²independently represents-N.

According to one implementation variant-R²independently represents-P^B.

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

Group-P³

According to one implementation variant-R³independently represents-H or-P^C.

According to one implementation variant-R³independently represents-N.

According to one implementation variant-R independently represents-P^C.

Group-P⁴

According to one implementation variant-R⁴independently represents-H or-P^B.

According to one implementation variant-R⁴independently represents-N.

According to one implementation variant-R⁴independently represents-P^B.

Group-P⁵

According to one implementation variant-R⁵if present, independently represents-H or-P^A.

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

According to one implementation variant-R⁵if present, independently represents-P^A.

Group-P^A, -P^Band-P^C

According to one implementation variant, each of P^Aeach of P^Band each of P^Cif present, independently selected from:

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

-R²,

-CF₃, -OCF₃,

-OH, -L¹HE

-OR², -L¹-OR², -O-L^{1 -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 P^Aeach of P^Band each of P^Cif 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-P^A

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

According to one implementation variant, each of P^Aif present, independently selected from-f

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

According to one implementation variant, each of P^Aif present, independently represents-CF₃.

According to one implementation variant, each of P^Aif present, independently represents-OCF₃.

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

According to one implementation variant, each of P^Aif present, independently represents-HE.

According to one implementation variant, each of P^Aif present, independently represents-L¹HE.

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

According to one implementation variant, each of P^Aif present, independently represents-OR².

According to one implementation variant, each of P^Aif present, independently represents-OMe.

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

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

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

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

According to one implementation variant, each of P^Aif present, independently selected from:

-NO₂,

-NH₂-The other², -NR²₂, -NR³R⁴.

According to one implementation variant, each of P^Aif present, independently represents-NO₂.

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

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

According to one implementation variant, each of P^Aif present, independently represents-NR³R⁴.

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

According to one implementation variant, each of P^Aif present, independently represents-NH₂.

According to one implementation variant, each of P^Aif present, independently represents-other².

According to one implementation variant, each of P^Aif present, independently represents-NHMe.

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

According to one implementation variant, each of P^Aif 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 P^Aif present, independently represents-NMe₂.

According to one implementation variant, each of P^Aif present, independently represents-R².

Group-P^B

According to one implementation variant, each of P^Bif 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 P^Bif present, independently selected from:

-F

-CF₃, -OCF₃,

HE

-OR²,

-NO₂,

-NH₂-The other², -NR²₂, -NR³R⁴.

According to one implementation variant, each of P^Bif present, independently selected from:

-F

-CF₃, -OCF₃,

-NO₂,

-NH₂-The other², -NR²₂, -NR³R⁴.

According to one implementation variant, each of P^Bif 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 P^B, if present, is independently chosen from-CF₃and-OCF₃.

According to one implementation variant, each of P^Bif present, independently represents-CF₃.

According to one implementation variant, each of P^Bif present, independently represents-OCF₃.

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

According to one implementation variant, each of P^Bif present, independently represents-HE.

According to one implementation variant, each of P^Bif present, independently represents-L¹HE.

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

According to one implementation variant, each of P^Bif present, independently represents-OR².

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

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

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

According to one implementation variant, each of P^Bif present, independently selected from

-NO₂,

-NH₂-The other², -NR²₂, -NR³R⁴.

According to one implementation variant, each of P^Bif present, independently represents-NO₂.

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

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

According to one implementation variant, each of P^Bif present, independently represents-NR³R⁴.

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

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

According to one implementation variant, each of P^Bif present, independently represents-other².

According to one implementation variant, each of P^Bif present, independently represents-NHMe.

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

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

According to one implementation variant, each of P^Bif present, independently represents-NR²₂.

According to one implementation variant, each of P^Bif present, independently represents-NMe₂.

According to one implementation variant, each of P^Bif present, independently represents-R².

Group-P^C

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

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

According to one implementation variant, each of P^Cif present, independently represents-F.

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

According to one implementation variant, each of P^Cif present, independently represents-CF₃.

According to one implementation variant, each of P^Cif present, independently represents-OCF₃.

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

According to gnome implementation variant, each of P^Cif present, independently represents-HE.

According to one implementation variant, each of P^Cif present, independently represents-L¹HE.

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

According to one implementation variant, each of P^Cif present, independently represents-OR².

According to one implementation variant, each of P^Cif present, independently represents-OMe.

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

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

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

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

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

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

According to one implementation variant, each of P^Cif present, independently selected from:

-NO₂,

-NH₂-The other², -NR²₂, -NR³R⁴,

-NHOH.

According to one implementation variant, each of P^Cif present, independently represents-NO₂.

According to one implementation variant, each of P^Cif present, independently represents-NHOH.

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

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

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

According to one implementation variant, each of P^Cif present, independently represents-NR³R⁴.

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

According to one implementation variant, each of P^Cif present, independently represents-NH₂.

According to one implementation variant, each of P^Cif present, independently represents-other².

According to one implementation variant, each of P^Cif present, independently represents-NHMe.

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

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

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

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

According to one implementation variant, each of P^Cif present, independently represents-NMe₂.

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

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

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

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

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

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

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

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

According to one implementation variant, each of P^Cif present, independently represents-R².

Group-L¹-

According to one implementation variant, each of the-L¹-, if present, independently represents an unsubstituted saturated aliphatic C_1-5alkylen.

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:

-R^A1, -R^A2, -R^A3, -R^A4, -R^A5, -R^A6, -R^A7, -R^A8,

-L^A-R^A4, -L^A-R^A5, -L^A-R^A6, -L^A-R^A7or-L^A-R^A8;

and each of R^A4, -R^A5, -R^A6, -R^A7and R^A8is a possibly substituted, for example, one or more Deputy-R^B1and/or one or more Deputy-R^B2and

each of R^A1, -R^A2, -R^A3and-L^A- is a possibly substituted, for example, one or more Deputy-R^B2.

According to one variant the NTU implementation, each of R²if present, independently represents-R^A1.

The group-R^A1

According to one implementation variant, each of R^A1if present, independently represents a possibly substituted saturated aliphatic C_1-6alkyl.

According to one implementation variant, each of R^A1if present, independently represents a possibly substituted saturated aliphatic C_1-4alkyl.

According to one implementation variant, each of R^A1if present, independently represents an unsubstituted saturated aliphatic C_1-6alkyl.

According to one implementation variant, each of R^A1if present, independently represents an unsubstituted saturated aliphatic C_1-4alkyl.

According to one implementation variant, each of R^A1if present, independently represents an unsubstituted-Me.

According to one implementation variant, each of R^A1if present, independently represents an unsubstituted-Et.

According to one implementation variant, each of R^A1if present, independently represents an unsubstituted-Pr.

According to one implementation variant, each of R^A1that is the case, if present, independently represents a possibly substituted-Me.

According to one implementation variant, each of R^A1if present, independently represents a possibly substituted-Et.

According to one implementation variant, each of R^A1if present, independently represents a possibly substituted-Pr.

According to one implementation variant, each of R^A1if present, independently represents a possibly substituted-Bu.

According to one implementation variant, each of R^A1if present, independently represents-CF₃.

According to one implementation variant, each of R^A1if present, independently represents-CH₂CF₃.

According to one implementation variant, each of R^A1if present, independently represents-CH₂CH₂CF₃.

According to one implementation variant, each of R^A1if present, independently represents-CH₂CH₂CH₂CF₃.

According to one implementation variant, each of R^A1if present, independently represents-CH₂F.

According to one implementation variant, each of R^A1if present, independently presented yet a-CH ₂CH₂F.

According to one implementation variant, each of R^A1if present, independently represents-CH₂CH₂CH₂F.

According to one implementation variant, each of R^A1if present, independently represents-CH₂CH₂N(Me)₂.

The group-R^B2

According to one implementation variant, each of R^B2if present, independently selected from:

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

-CF₃, -OCF₃,

-OH, -L^C-OH, -O-L^C-OH,

-OR^C1, -L^C-OR^C1, -O-L^C-OR^C1,

-NHS(=O)₂R^C1, -NR²S(=O)₂R^C1.

According to one implementation variant, each of R^B2if present, independently selected from:

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

-CF₃, -OCF₃,

-OH, -L_C-OH, -O-L^C-OH,

-OR^C1, -L^C-OR^C1, -O-L^C-OR^C1.

According to one implementation variant, each of R^B2if present, independently selected from:

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

-CF₃, -OCF₃,

-OH, -O-L^C-OH,

-OR^C1, -L^C-OR^C1, -O-L^C-OR^C1.

According to one implementation variant, each of R^B2if present, independently selected from:

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

-CF₃, -OCF₃.

According to one implementation variant, each of R^{B2 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 R^B2if present, independently selected from-F and-CF₃.

According to one implementation variant, each of R^B2if present, independently represents-F.

According to one implementation variant, each of R^B2if present, independently represents-CF₃.

According to one implementation variant, each of R^B2if present, independently selected from:

-OH, -L^C-OH, -O-L^C-OH,

-OR^C1, -L^C-OR^C1, -O-L^C-OR^C1.

According to one implementation variant, each of R^B2if present, independently selected from:

-OH, -O-L^C-OH,

-OR^C1, -O-L^C1-OR^C1.

According to one implementation variant, each of R^B2if present, independently selected from-HE-OR^C1.

According to one implementation variant, each of R^B2if present, independently selected from-O-L^C-OH and-O-L^C-OR^C1.

According to one implementation variant, each of R^B2if present, it is not avisio represents-O-L ^CHE.

According to one implementation variant, each of R^B2if present, independently represents-O-L^C-OR^C1.

Group-L^C-

According to one implementation variant, each of L^C-, if present, independently represents an unsubstituted saturated aliphatic C_1-5alkylen.

According to one implementation variant, each of L^C-, if present, independently represents-CH₂CH₂-.

The group-R^C1

According to one implementation variant, each of R^C1if present, independently represents an unsubstituted saturated aliphatic C_1-4alkyl, phenyl or benzyl.

According to one implementation variant, each of R^C1if present, independently represents an unsubstituted saturated aliphatic C_1-4alkyl.

According to one implementation variant, each of R^C1if present, independently represents-Me.

According to one implementation variant, each of R^C1if present, independently represents an unsubstituted phenyl.

According to one implementation variant, each of R^C1if 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 Ų.

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 Ųor less.

According to one implementation variant DSB compound has a surface area of topological polar region, is equal to 70 Ųor 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 name	No. of connections	Structure
AVM is -01	SKT01-13
AVMA-02	SKT01-23
AVMA-03	SKT01-9
AVMA-04	SKT01-99
AVMA-05	SKT01-41
AVMA-06	SKT01-21
AVMA-07	SKT01-103

Abbreviated name	No. of connections	Structure
AVMA-08	SKT01-63
AVMA-09	SKT01-61
AVMA-1	SKT01-155
AVMA-11	SKT01-161
AVMA-12	SKT04-87
AVMA-13	SKT04-89
AVMA-14	SKT03-141
AVMA-15	SKT03-137
AVMA-16	SKT03-33

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 connections	Structure
ABFMA-01	SK2033-50
ABFMA-02	SK2033-49
ABFMA-03	SK2033-47
ABFMA-04	SKT04-155
ABFMA-05	SKT05-7
ABFMA-06	SKT05-9
ABFMA-07	SKT04-173

Abbreviated name	No. of connections	Structure
ABFMA-08	SKT05-33
ABFMA-09	SKT05-31
ABFMA-10	SKT05-21
ABFMA-11	SKT04-175
ABFMA-12	SKT02-103
ABFMA-13	SKT02-169
ABFMA-14	SKT03-39
ABFMA-15	SKT01-157
ABFMA-16	SKT01-149

Abbreviated name	No. of connections	Structure
ABFMA-17	SKT02-31
ABFMA-18	SKT01-159
ABFMA-19	SKT02-25
ABFMA-20	SKT01-137

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 name	No. of connections	Structure
ABMFMA-01	SKT02-135
ABMFMA-02	SKT04-137

Abbreviated name	No. of connections	Structure
ABMFMA-03	SKT04-111
ABMFMA-04
ABMFMA-05	SKT03-99
ABMFMA-06	SKT03-75
ABMFMA-07	SKT03-93
ABMFMA-08	SKT04-33
ABMFMA-09	SKT04-29
ABMFMA-10	SKT05-37

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

Abbreviated name	No. of connections	Structure
AVNA-01
AVNA-02	SKT01-77
AVNA-03	SKT01-57
AVNA-04	SKT01-111
AVNA-05	SKT02-177

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 name	No. of connections	Structure
ABFHA-01	SKT03-07
ABFHA-02	SKT02-45
ABFHA-03	SKT02-149/td>
ABFHA-04	SKT03-41
ABFHA-05	SKT02-171
ABFHA-06	SKT05-39
ABFHA-07	SKT02-163
ABFHA-08	SKT05-17
ABFHA-09	SKT05-13

Abbreviated name	No. of connections	Structure
ABFHA-10	SKT04-179
ABFHA-11	SKT03-129

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 name	No. of connections	Structure
AVA-01	SK2033-51
AVA-02	SK2033-46
AVA-03	SK2033-67
AAA-04	SK2033-55

Abbreviated name	No. of connections	Structure
AAA-05	SK2033-72
AAA-06	LS-T107
AVA-07	SKT01-5
AVA-08	SK2033-93
AAA-09	SK2033-71
AAA-10	SK696-32
AVA-11	SK696-54
AVA-12	SK2033-94

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 name	No. of connections	Structure
ABDMAA-01	SKT03-171
ABDMAA-02	SKT03-171.01

Unsubstituted amides

Abbreviated name	No. of connections	Structure
AUB-01	SKT04-127
AUB-02	SKT04-143

Abbreviated name	No. of connections	Structure
AUB-03	SKT04-163

Imidazo[1,2-a] pyridine compounds

Abbreviated name	No. of connections	Structure
AIPN-01	SKT05-123
AIPN-02	SKT05-93
AIPN-03	SKT05-107
AIPN-04	SKT05-171
AIPN-05	SKT06-5
AIPN-06	SKT05-169
AIPN-07	SKT06-53

Abbreviated name	No. of connections	Structure
AIPN-08	SKT06-63
AIPN-09	SKT05-165
AIPN-10	SKT05-173
AIPN-11	SKT06-71
AIPN-12	SKT06-67
AIPN-13	SKT06-7
AIPN-14	SKT06-11
AIPN-15	SKT06-25
AIPN-16	SKT06-29

Abbreviated name	No. of connections	Structure
AIPN-17	SKT06-15
AIPN-18	SKT06-13
AIPN-19	SKT06-35
AIPN-20	SKT06-55
AIPN-21	SKT06-59
AIPN-22	SKT06-39
AIPN-23	SKT06-49
AIPN-24	SKT06-45
AIPN-25	SKT06-79

Abbreviated name	No. of connections	Structure
AIPN-26	SKT06-51
AIPN-27	SKT06-57
AIPN-28	SKT06-61
AIPN-29	SKT06-103
AIPN-30	SKT06-99
AIPN-31	SKT06-81

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 name	No. of connections	Structure
AIPN-32	SKT08-153
AIPN-33	SKT08-165
AIPN-34	SKT06-155
AIPN-35	SKT06-153
AIPN-36	SKT06-141
AIPN-37	SKT06-137
AIPN-38	SKT06-131
AIPN-39	SKT06-165

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 name	No. of connections	Structure
AIPM-01	SKT05-95

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

Abbreviated name	No. of connections	Structure
AIT-01	SKT05-149
AIT-02	SKT05-143

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

Benzothiazoline connection

Non-fluorinated methylalkanes

Abbreviated name	No. of connections	Structure
VEMA-01	SK696-39
VEMA-02	SKT01-15

Abbreviated name	No. of connections	Structure
VEMA-03	SKT01-53
VEMA-04	SKT01-3
VEMA-05	SKT01-55
VEMA-06	SKT01-69
VEMA-07	SKT01-17
VEMA-08	SK2033-30
VEMA-09	SK696-62
VEMA-10	SK696-57
VEMA-11	SK696-43
VEMA-12	SK2033-29

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 name	No. of connections	UEMOA-01	SKT01-71
UEMOA-02	SKT01-73
UEMOA-03	SKT02-67
UEMOA-04	SKT01-109
UEMOA-05	SKT01-107
UEMOA-06	SKT01-189
UEMOA-07	SKT03-57
UEMOA-08	SKT03-91

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 name	No. of connections	Structure
UEMOA-10	SKT08-143

Fluorinated metaxylene

Abbreviated name	No. of connections	Structure
BEFA-01	SK2033-44
BEFA-02	SK2033-42

Abbreviated name	No. of connections	Structure
BEFA-03	SK2033-40
BEFA-04	SKT02-17
BEFA-05	SKT02-11
BEFA-06	SKT02-117
BEFA-07	SKT02-153
BEFA-08	SKT02-119
BEFA-09	SKT02-81
BEFA-10	SKT02-137
BEFA-11	SKT03-167
BEFA-12	SKT03-77

Abbreviated name	No. of connections	Structure
BEFA-13	SKT04-187
BEFA-14	SKT04-159

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 name	No. of connections	Structure
BEHF-01	SKT02-165
BEHF-02	SKT02-155
BEHF-03	SKT02-127
BEHF-04	SKT02-111

Abbreviated name	No. of connections	Structure
BEHF-05	SKT02-51
BEHF-06	SKT05-05
BEHF-07	SKT04-169

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 name	No. of connections	Structure
IEPN-01	SKT06-117

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

Abbreviated name	No. of connections	IEPN-02	SKT06-161
IEPN-03	SKT07-81
IEPN-04	SKT07-115
IEPN-05	SKT07-131
IEPN-06	SKT07-113
IEPN-07	SKT08-137

Compounds in which Q represents-N=N-

Benzothiazoline connection

Abbreviated name	No. of connections	Structure
BDF-09	LS-T229
BDF-10	LS-T235A
BDF-11	LS-T235B
BDF-12	LS-T236A
BDF-13	LS-T236B
BDF-14	LS-T274
BDF-15	LS-T272

Abbreviated name	No. of connections	Structure
BDF-16	LS-T288
BDF-17	LS-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 name	No. of connections	Structure
BDF-18	SC598
BDF-19	SC588

Imidazo[1,2-a]pyridine compounds

Abbreviated name	No. of connections	Structure
DPN-001	SKT05-163

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, C_1-7alkyl 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); C_1-7haloalkaline of ester (for example, C_1-7trihalogenmethanes of ester); Tris_1-7alkylsilane-C_1-7alkyl ether complex; or (C_5-20aryl-C_1-7alkyl 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 to	Structure
DL-001	ABMFMA-05
DL-002	ABMFMA-02
DL-003	AIPN-33

Abbr.	Applies to	Structure
DL-004	AIPN-06
DL-005	IEPN-04
DL-006	BEFA-12
DL-007	BDF-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, 18^thedition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5^thedition, 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-P^Aand-P^Brepresents 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-P^Aand-P^Brepresent 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-P^Aand-P^Bcan represent-C(O)IT or its activated form, and the other may represent-NH₂or other¹.

According to one implementation variant-P^Arepresents-NH₂or other¹. According to one implementation variant, -P^Arepresents-NH₂.

According to one implementation variant-P^Brepresents-C(O)HE or-C(O)Cl.

According to one implementation variant-P^Aand-P^Bare 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-P^Aand-P^Bmay represent a linking group by Wittig or group, the same groups Wittig, for example, linking groups Horner-Watford-Emmons. Thus, one of the-P^Aand P^Bcan represent-C(O)H or-C(O)R¹and the other may be a phosphonate.

According to one implementation variant, one of the-P^Aand-P^Brepresents-C(O)N.

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

According to one implementation variant-P^Brepresents-C(O)N.

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

According to one implementation variant alkenone linking group-P^Aand-P^Bmay represent a linking group Hake or group, the same groups Hake.

Thus, one of the-P^Aand-P^Bmay 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-P^Aand-P^Bare diazo-binding group. The reaction product link is a diazo-communication, i.e. Q-represents-N=N-.

According to one implementation variant-P^Aand-P^Bare minovia linking group. The reaction product link is kinoway communication, i.e. Q-represents-N-CH - or-CH=N-. Thus, one of the-P^Aand-P^Bcan 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 C_1-6alkyl groups, substituted-HE, or group linking-Oh group, such as saturated aliphatic C_1-5alkylenes group, associate IT with the group.

Examples of groups suitable for use include groups in which-W^A1represents-CH₂CH₂OH, one of the-P^A, -P^Bor-P^Crepresents-L¹-OH, -G^Aor-G^Bis a -[O-CH₂CH₂]_n-R^B2and R^B2represents-L^C-OH, -O-L^C-OH, or-IT, or in which R^B2represents-L^C-OH, or-O-L^C-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.

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, J_CF=274 Hz), 122.63 (q, J_CF=5.9 Hz), 124.81, 126.39, 130.61 (q, J_CF=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, J_CF=274 Hz), 124.68, 124.75 (q, J_CF=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, J_CF=4.9 Hz), 115.61, 116.78, 122.01, 123.59 (q, J_CF=274 Hz), 124.00, 130.00 (q, J_CF=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, J_CF=30.3 Hz), 115.54, 117.26, 123.22, 123.41, 124.55 (q, J_CF=272 Hz), 125.99 (q, J_CF=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, J_CF=36 Hz), 115.02, 123.02 (q, J_CF=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, J_CF=35 Hz), 115.36, 124.72 (q, J_CF=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, J_CF=28.3 Hz), 60.87, 113.87, 123.91, 125.79 (q, J_CF=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, J_CF=29.3 Hz), 60.80, 113.83, 123.84, 125.78 (q, J_CF=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, J_CF=2.9 Hz), at 30.67 (q, J_CF=29 Hz), 60.70, at 66.15, 113.95, 123.30, 127.06 (q, J_CF=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, J_CF=1.9 Hz), 30.41 (q, J_CF=29 Hz), 65.93, 113.77, 123.39, 127.00 (q, J_CF=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, J_HF=28 Hz, J_HH=4.0 Hz, 2H), 4.77 (dist d oft, J_HF=47 Hz, J_HH=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, J_CF=19.5 Hz), 81.59 (d, J_CF=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, J_HF=28 Hz, J_HH=3.0 Hz, 2H), 4.59 (dist d of t, J_HF=47 Hz, J_HH=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, J_CF=19.5 Hz), 81.64 (d, J_CF=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, J_CF=274 Hz), 126.30 (q, J_CF=31.1 Hz), 126.86 (q, J_CF=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, J_CF=272.5 Hz), 124.81 (q, J_CF=3.9 Hz), 127.99, 128.79, 128.99, 129.66 (q, J_CF=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, J_CF=272.4 Hz), 125.91 (q, J_CF=3.9 Hz), 127.98, 128.79, 129.01, 129.17, 131.99 (q, J_CF=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, J_CF=31.2 Hz), 120.40, 122.93, 123.12 (q, J_CF=273 Hz), 126.27, 126.87 (q, J_CF=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, J_CF=4.9 Hz), 115.26, 116.02, 119.65, 122.85, 122.99 (q, J_CF=274 Hz), is the 127.20, 128.04, 128.40 (q, J_CF=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, J_CF=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, J_CF=4.9 Hz), 122.45, 123.32 (q, J_CF=274 Hz), 124.22, 126.14, 127.94, 129.15, 129.69 (q, J_CF=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, J_CF=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, J_CF=5 Hz), 115.19, 116.06, 117.32, 122.55, 123.14 (q, J_CF=274 Hz), 128.19, 128.76 (q, J_CF=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, J_CF=3.9 Hz), 115.23, 116.33, 119.81, 120.16, 122.88, 122.97 (q, J_CF=273 Hz), 127.40, 128.14 (q, J_CF=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, J_CF=32 Hz), 119.56, 121.16, 123.12 (q, J_CF=273 Hz), 123.44, 126.55 (q, J_CF=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, J_CF=33.5 Hz), 122.37 (q, J_CF=274 Hz), 123.67, 126.13, 127.86 (q, J_CF=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, J_CF=274 Hz), 123.11, 126.62, 127.52, 128.71 (q, J_CF=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, J_CF=30.3 Hz), 123.50, 124.08 (q, J_CF=273.4 Hz), 126.37, 127.74 (q, J_CF=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, J_CF=5.4 Hz), 114.41, 116.18, 120.25, 122.91, 123.60, 124.45 (q, J_CF=274 Hz), 127.99, 128.07 (q, J_CF=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, J_CF=8 Hz), 65.21 (q, J_CF=34 Hz), 105.50 (q, J_CF=6 Hz), 115.19, 116.45, 121.12, 123.82, 124.55 (q, J_CF=278 Hz), 128.09, 128.74, 128.81, 130.50 (q, J_CF=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, J_CF=27 Hz), 56.40, 61.85, 105.56, 114.85, 116.44, 121.85, 123.79, 127.34 (q, J_CF=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, J_CF=6.3 Hz), 29.97 (q, J_CF=28.05 Hz), 56.24, 66.60, 105.46, 114.66, 116.16, 120.86, 123.58, 127.38, 127.85, 128.05 (q, J_CF=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, J_CF=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, J_CF=21.5 Hz), 115.16, 120.01, 122.68, 126.93, 128.10, 130.03 (d, J_CF=8.8 Hz), 130.67 (d, J_CF=2.9 Hz), 135.53, 141.16, 147.86, 156.99, 163.97 (d, J_CF=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, J_CF=37 Hz), 116.51, 121.14, 123.85, 128.20, 129.20, 129.77 (d, J_CF=3.8 Hz), 136.51, 141.79, 142.72 (d, J_CF=9.2 Hz), 148.58 (d, J_CF=16.8 Hz), 148.69, 158.04, 163.79, 164.90, 165.04 (d, J_CF=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, J_CF=21 Hz), at 121.30, 123.84, 126.53, 128.16, 129.33, 132.02 (d, J_CF=3.8 Hz), 136.42, 136.53, 137.31 (d, J_CF =8 Hz), 141.69, 148.72, 157.13 (d, J_CF=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, J_CF=19.4 Hz), 126.89 (d, J_CF=10.9 Hz), 127.32 (d, J_CF=8.5 Hz), 129.80 is awaited, 131.03, 131.35, 134.28, 136.44 (d, J_CF=3.9 Hz), 140.29, 141.05, 141.82 (d, J_CF=7.8 Hz), 147.69, 156.79, 161.72 (d, J_CF=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, J_CF=21 Hz), 122.05, 122.59, 125.07, 126.28, 126.58, 129.63, 131.72 (d, J_CF=3.9 Hz), 135.76, 136.26 (d, J_CF=10 Hz), 137.10 (d, J_CF=7.7 Hz), 142.82, 152.02, 156.93, 156.98 (d, J_CF=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, J_HF=30 Hz, J_HH=3.7 Hz, 2H), 4.73 (dist d of t, J_HF=48 Hz, J_HH=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, J_CF=19 Hz), 82.70 (d, J_CF=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, J_CF=32.7, 13.3 Hz), 117.99 (d, J_CF=21.0 Hz), 121.14, 122.84 (q, J_CF=272.5 Hz), 123.63, 127.54 (d of q, J_CF=4.6, 1.5 Hz), 127.92, 129.14, 131.97 (d, J_CF=3.8 Hz), 135.58 (d, J_CF=10.1 Hz), 136.37, 141.60, 148.61, 157.92, 161.19 (d of q, J_CF=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, J_CF=35 Hz), 106.24, 113.94, 115.63, 120.10, 122.74, 123.07 (q, J_CF=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, J_CF=28 Hz), 60.67 (q, J_CF=3.9 Hz), 106.27, 113.61, 115.63, 120.10, 122.76, 125.73 (q, J_CF=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, J_CF=3.1 Hz), 29.95 (q, J_CF=28.0 Hz), 66.60, 107.24, 114.69 last, 116.53, 120.94, 123.64, 127.34, 127.73, 128.04 (q, J_CF=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, J_CF=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, J_CF=22.5 Hz). 115.69, 120.23, 122.80, 127.04, 128.56, 130.12 (d, J_CF=8.8 Hz), 130.84 (d, J_CF=1.9rn), 135.71, 141.03, 147.18, 155.33, 163.34, 164.21 (d, J_CF=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, J_CF=3.9 Hz), 115.55, 117.77, 119.43, 122.1, 123.04 (q, J_CF=274 Hz), 126.37, 126.93, 128.04 (q, J_CF=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, J_CF=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, J_CF=2.9 Hz), 122.54, 123.54 (q, J_CF=274 Hz), 123.83. 125.41, 126.98, 128.87 (q, J_CF=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, J_HH=1.2, J_HF=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, J_CFCF=3.9 Hz), 135.52 (d, J_CF=11.7 Hz), 135.61, 136.36 (d, J_CF=7.8 Hz), 140.43, 147.09, 155.33, 156.41 (J_CF=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, J_CF=Hz), 114.30 (d, J_CF=42.0 Hz), 118.17 (d, J_CF=26.4 Hz), 118.23 (d, J_CF=10.2 Hz), 124.51, 126.77, 140.61, 143.66, 143.75 (d, J_CF=Hz), 147.08, 153.26 (d, J_CF=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, J_CF=1.5 Hz), 113.48 (d, J_CF=41 Hz), 114.39, 115.90 (d, J_CF=25.7 Hz), 117.00 (d, J_CF=10.1 Hz), 121.90, 142.99, 147.63, 149.18, 152.80 (d, J_CF=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, J_HF=27 Hz, J_HH=4.3 Hz, 2H), 4.56 (dist d of t, J_HF=47 Hz, J_HH=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, J_CF=21.5 Hz), 80.57 (d, J_CF=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.