TW201329089A - Fused pyrimidineone compounds as TRPV3 modulators - Google Patents

Abstract

The present invention provides transient receptor potential vanilloid (TRPV) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPV3. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPV3.

Description

Fused pyrimidinone compound as a TRPV3 regulator

The present invention relates to fused 'pyrimidinone' compounds having transient receptor potential vanilloid 3 (TRPV3) activity.

Ion movement is achieved through the cell membrane through specialized proteins. The TRP channel is a large family of non-selective cation channels that help regulate ion current and membrane potential. The TRP channel is divided into six subfamilies including the TRPV family. TRPV3 is a member of the TRPV class of the TRP channel.

TRPV3 is a calcium-permeable, non-selective cation channel. In addition to calcium ions, the TRPV3 channel is permeable to other cations such as sodium ions. Thus, the TRPV3 channel regulates membrane potential by modulating the flow of cations such as calcium and sodium ions. The TRPV3 receptor differs in mechanism from the voltage-gated calcium channel. Typically, voltage-gated calcium channels respond to membrane depolarization and open channels to allow calcium ions to flow from the extracellular matrix, causing an increase in intracellular calcium levels or concentrations. In contrast, non-selective long-lasting TRP channels produce longer lasting changes in ion concentration, and the channel is ligand-gated (via chemical reagents such as 2-aminoethoxydiphenylboron) The acid ester [2-APB], vanilloid and heat are adjusted). These differences in mechanism are accompanied by differences in the structure of the voltage-gated channel and the TRP channel. Thus, although there are many different channels in various cell types and in response to numerous stimuli that act to regulate ion flux and membrane potential, it is recognized that the significant differences in structure, function, and mechanism between different types of ion channels are significant. important.

TRPV3 protein is in skin cells (Peier et al, Science (2002), 296, 2046-2049) and dorsal root ganglia, trigeminal ganglia, spinal cord and brain (Xu et al, Nature (2002), 418, 181-185; Smith Etc., Thermosensitive channels expressed in Nature (2002), 418, 186-188). In keratinocyte cell lines, stimulation of TRPV3 causes release of an inflammatory mediator such as interleukin-1. Therefore, TRPV3 also plays an important role in regulating pain and inflammation caused by the release of inflammatory stimuli. As described herein, in particular, the TRPV3 protein can be used in screening assays to identify compounds that modulate the function of TRPV3, including but not limited to human TRPV3, mouse TRPV3, rat TRPV3, and Drosophila TRPV3. The sequence corresponding to human TRPV3, mouse TRPV3 and Drosophila TRPV3 is disclosed in US 2004/0009537 (the '537 application). For example, SEQ ID Nos 106 and 107 of the '537 application correspond to human nucleic acid sequences and amino acid sequences, respectively. SEQ ID Nos 108 and 109 of the '537 application correspond to the nucleic acid sequence and the amino acid sequence of the mouse, respectively.

The function of TRPV3 basically involves the reception and transduction of pain. Therefore, it is desirable to identify and produce compounds that modulate one or more functions of TRPV3.

WO 2007/056124, WO 2008/140750 and WO 2008/033564 disclose TRPV3 modulators, in particular antagonists, for the treatment of a variety of TRPV3-mediated diseases.

In the effort to discover better analgesics, there is still a need for therapeutic treatment of diseases, conditions and/or disorders regulated by TRPV3.

The present invention relates to a compound of formula (I):

Wherein X is O, S or NR ^b ; Y is CR ³ or N; ring A is aryl, heterocyclic or heteroaryl; R may be the same or different and is selected from the group consisting of hydrogen, nitro, cyano, halogen, -OR ^a , substituted or unsubstituted alkyl, alkenyl, haloalkyl, cyanoalkyl, cyanoalkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group; R ¹ and R ³ They may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, -COOH, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl , heteroaryl, heterocyclic group, -NR ⁴ R ⁵ , -S(O) _p NR ⁴ R ⁵ or -S(O) _p R ⁴ ; or R ¹ and R ³ together with the carbon atom to which they are attached Forming a 5-7 membered cyclic ring which may be substituted or unsubstituted, saturated, unsaturated or partially saturated, the cyclic ring optionally comprising a moiety selected from O, NR ^b or S One or more heteroatoms; R ² is an aryl, heteroaryl or heterocyclic group, and each of the above groups may be optionally mono- or polysubstituted with a substituent independently selected from the group consisting of Group consisting of: halogen, hydroxyl, nitro, cyano, -COOH , -NR ⁴ R ⁵ , fluorenyl, substituted or unsubstituted alkyl, alkenyl, alkoxy, cyanoalkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, naphthenic Alkoxy, aryl, heterocyclic and heteroaryl; R ^{a , which} may be the same or different, is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, haloalkyl, cyanide Alkyl, alkenyl, cycloalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl R ^{b is} selected from hydrogen, substituted or unsubstituted alkyl or arylalkyl; R ⁴ and R ⁵ may be the same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, cycloalkane. , n-alkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclylalkyl; 'n' is an integer from 0 to 5 , contains the value of both ends; and 'p' is an integer from 0-2, containing the values at both ends.

It will be understood that formula (I) structurally encompasses all geometric isomers, including enantiomers and diastereomers, that are contemplated by the chemical structures of the classes described herein, and A pharmaceutically acceptable salt.

According to one embodiment, there is specifically provided a compound of formula (I) wherein X is S.

According to another embodiment, there is specifically provided a compound of formula (I), wherein X is NR ^b , wherein R ^b is hydrogen or alkyl (eg methyl).

According to another embodiment, there is provided in particular a compound of formula (I), wherein Y is CR ³ , wherein R ³ is hydrogen, halogen, alkyl or haloalkyl.

According to another embodiment, specifically provided are of formula (I) compounds wherein R ¹ is hydrogen, halo or alkyl.

According to another embodiment, there is provided in particular a compound of formula (I), wherein R ² is a substituted or unsubstituted aryl group, preferably a phenyl group.

According to another embodiment, there is provided in particular a compound of formula (I), wherein R ² is substituted or unsubstituted heteroaryl. In this embodiment, R ² is a substituted or unsubstituted pyridyl group wherein the substituent is a halogen (such as F or Cl).

According to another embodiment, there is specifically provided a compound of formula (I), wherein ring A is aryl.

According to another embodiment, specifically provided are compounds of formula (I), wherein ring A is heteroaryl. In this embodiment Ring A is pyridine.

According to one embodiment, provided is a compound of formula (II):

Wherein R may be the same or different and is selected from the group consisting of hydrogen, nitro, cyano, halogen, -OR ^a , substituted or unsubstituted alkyl, alkenyl, haloalkyl, cyanoalkyl, cyanoalkoxy, ring An alkyl, aryl, heteroaryl or heterocyclic group; R ¹ and R ³ may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, -COOH, substituted or unsubstituted alkyl. , alkenyl, alkynyl, haloalkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic group, -NR ⁴ R ⁵ , -S(O) _p NR ⁴ R ⁵ or -S(O) _p R ⁴ ; or R ¹ and R ³ together with the carbon atom to which they are attached may form a 5-7 membered cyclic ring which may be substituted or unsubstituted, saturated, unsaturated Or partially saturated, the cyclic ring may optionally comprise one or more heteroatoms selected from O, NR ^b or S; R ^a may be the same or different and is selected from the group consisting of: hydrogen , substituted or unsubstituted alkyl, haloalkyl, cyanoalkyl, alkenyl, cycloalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkylalkyl, aryl Alkyl, heteroarylalkyl or heterocyclic Group; R ^b is selected from hydrogen, a substituted or unsubstituted alkyl or aryl group; R ⁴ and R ⁵ may be the same or different, are independently hydrogen, a substituted or unsubstituted alkyl group, alkenyl group, cycloalkyl group , cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclylalkyl; R ⁶ may be the same or different, independently selected From halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , fluorenyl, substituted or unsubstituted alkyl, alkenyl, alkoxy, cyanoalkoxy, haloalkyl, haloalkoxy , cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, aryl, heterocyclic or heteroaryl; 'm' is an integer from 0 to 3, inclusive; 'n' is 0 An integer of -5, containing the value of both ends; and 'p' is an integer of 0-2, including the values at both ends.

It is to be understood that formula (II) structurally encompasses all geometric isomers, including enantiomers and diastereomers, that are contemplated by the chemical structures of the classes described herein, and A pharmaceutically acceptable salt.

According to one embodiment, specifically provided are compounds of formula (II) wherein R ¹ and R ³ are both hydrogen.

According to another embodiment, specifically provided are compounds of formula (II), wherein R ¹ and R ^{3 are,} independently, hydrogen, halogen (eg, F or Cl), substituted or unsubstituted alkyl (eg, methyl) Or a haloalkyl group (eg, trifluoromethyl).

According to another embodiment, specifically provided are compounds of formula (II), wherein R ⁶ is halogen (eg, F or Cl), hydroxy, cyano, decyl (eg, -C(O)CH ₃ ), A substituted or unsubstituted alkyl group (for example, a tert-butyl group), a substituted or unsubstituted alkoxy group (for example, a methoxy group or an ethoxy group), a halogenated alkyl group (for example, a trifluoromethyl group), a halogenated alkoxy group. (eg, difluoromethoxy, trifluoromethoxy or trifluoroethoxy), cyanoalkoxy (eg, cyanopropoxy), cycloalkylalkoxy (eg, cyclopropyl) Oxy) or an alkylamine (for example, -N(CH ₃ ) ₂ ). In this embodiment, 'm' is 1 or 2.

According to another embodiment, specifically provided is a compound of formula (II) wherein 'm' is zero.

According to another embodiment, specifically provided is a compound of formula (II) wherein 'n' is zero.

According to another embodiment, specifically provided are compounds of formula (II), wherein R is halogen, such as F or Cl; and 'n' is 1.

According to another embodiment, specifically provided are compounds of formula (II), wherein R is -OR ^a . In this embodiment, R ^a may be the same or different and are independently selected from hydrogen, alkyl (eg, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isethyl) Or neopentyl), alkoxyalkyl (for example, methoxyethyl or ethoxyethyl), cycloalkyl (for example, cyclopentyl or cyclohexyl), cycloalkylalkyl (for example, Cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl), haloalkyl (for example, difluoromethyl, trifluoropropyl or 4-fluorobutyl), cyanoalkyl (cyanopropyl), substituted Or an unsubstituted arylalkyl group (for example, 3-fluorobenzyl group), a substituted or unsubstituted heteroarylalkyl group (for example, pyridylmethyl group); and 'n' is 1 or 2.

According to another embodiment, specifically provided are compounds of formula (II), wherein R is -OR ^a . In this embodiment, -OR ^a is substituted at the 2-position and the 3-position; and 'n' is 2.

According to another embodiment, specifically provided are compounds of formula (II), wherein R is -OR ^a . In this embodiment -OR ^a is substituted at the 3-position and the 4-position; and 'n' is 2.

According to another preferred embodiment, there is provided a compound of formula (IIa),

R ¹ , R ³ , R ⁶ and 'm' are as defined above; each of R ^a1 and R ^a2 may be the same or different and is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, cyanoalkyl, alkenyl, a cycloalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclic group, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl group; it will be understood that Formula (IIa) structurally encompasses all geometric isomers, including enantiomers and diastereomers, which are contemplated by the chemical structures of the classes described herein, as well as pharmaceutically acceptable salt.

According to one embodiment, specifically provided is a compound of formula (IIa) wherein R ¹ and R ³ are both hydrogen.

According to another embodiment, specifically provided are compounds of formula (IIa), wherein R ¹ and R ^{3 are,} independently, hydrogen, halogen (eg, F or Cl), substituted or unsubstituted alkyl (eg, methyl) Or a haloalkyl group (eg, trifluoromethyl).

According to another embodiment, specifically provided are compounds of formula (IIa), wherein R ⁶ is halogen (eg, F or Cl), hydroxy, cyano, decyl (eg, -C(O)CH ₃ ), a substituted or unsubstituted alkyl group (for example, a third butyl group), a substituted or unsubstituted alkoxy group (for example, a methoxy group or an ethoxy group), a substituted or unsubstituted cycloalkyl alkoxy group (for example, Cyclopropylmethoxy), haloalkyl (for example, trifluoromethyl), haloalkoxy (for example, difluoromethoxy, trifluoromethoxy or trifluoroethoxy), cyanoalkoxy ( For example, cyanopropoxy), cycloalkylalkoxy (e.g., cyclopropylmethoxy), or an alkyl amine _{(e.g., -N (CH 3) 2)} . In this embodiment, 'm' is 1 or 2.

According to another embodiment, specifically provided is a compound of formula (IIa) wherein 'm' is zero.

According to another embodiment, specifically provided are compounds of formula (IIa), wherein R ^a1 and R ^a2 may be the same or different, independently selected from hydrogen, alkyl (eg, methyl, ethyl, n-propyl, n-Butyl, n-pentyl, isobutyl, isopentyl or neopentyl), alkoxyalkyl (eg methoxyethyl or ethoxyethyl), cycloalkyl (eg cyclopentane) Or cyclohexyl), cycloalkylalkyl (for example, cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl), haloalkyl (for example, fluorobutyl, difluoromethyl, trifluoropropyl or 4 -fluorobutyl), cyanoalkyl (for example, cyanopropyl), substituted or unsubstituted arylalkyl (for example 3-fluorobenzyl), substituted or unsubstituted heteroarylalkyl (for example, Pyridylmethyl).

According to another more preferred embodiment, provided is a compound of formula (IIb),

R ^{6 is} independently selected from halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , substituted or unsubstituted alkyl, alkoxy, haloalkyl or haloalkoxy; R ^{a1 is} selected from substituted or Unsubstituted alkyl, alkoxy or cycloalkyl; R ^{a2 is} selected from substituted or unsubstituted alkyl or haloalkyl; and 'q' is an integer from 1 to 4, inclusive.

It will be understood that formula (IIb) structurally encompasses all geometric isomers, including enantiomers and diastereomers, that are contemplated by the chemical structures of the classes described herein, and A pharmaceutically acceptable salt.

According to one embodiment, provided is a compound of formula (III),

'r' is an integer from 0 to 4, inclusive, wherein R ^6a may be the same or different and independently selected from halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , fluorenyl, Substituted or unsubstituted alkyl, alkenyl, alkoxy, cyanoalkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, aryl, heterocyclic a group or a heteroaryl group; R ^{7 is} independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic groups , -NR ⁴ R ⁵ , -S(O) _p NR ⁴ R ⁵ or -S(O) _p R ⁴ ; and R, R ⁴ , R ⁵ , 'm', 'n' and 'p' are as defined above It should be understood that formula (III) structurally encompasses all geometric isomers, including enantiomers and diastereomers, that can be considered by the chemical structures of the species described herein. And a pharmaceutically acceptable salt.

According to one embodiment, specifically provided are compounds of formula (III), wherein R ^6a is cyano, haloalkoxy (eg, trifluoromethoxy). In this embodiment, 'm' is 1.

According to another embodiment, specifically provided are compounds of formula (III), wherein R is -OR ^a . In this embodiment, -OR ^a is substituted at the 2-position and the 3-position; and 'n, is 2.

According to another embodiment, specifically provided are compounds of formula (III), wherein R is -OR ^a . In this embodiment, -OR ^a is substituted at the 3-position and the 4-position; and 'n' is 2.

According to another embodiment, specifically provided are compounds of formula (III), wherein R is -OR ^a . In this embodiment, R ^{a is} independently hydrogen, alkyl (eg, methyl, n-butyl or isopentyl), alkoxyalkyl (eg, methoxyethyl or ethoxyethyl) a cycloalkylalkyl group (for example, cyclopropylmethyl or cyclobutylmethyl), a cyanoalkyl group (for example, a cyanopropyl group) or a heterocycloalkyl group (for example, pyridylmethyl group); and n' is 1 or 2.

The following are representative compounds which are intended to be illustrative only in nature and are not intended to limit the scope of the invention.

7-[( E )-2-(4-Chlorophenyl)vinyl]-6-phenyl-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one (Compound 1 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-phenyl-5 H -[1,3]thiazole [3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-6- (6-fluoro-3-pyridyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 6-[4-(t-butylphenyl)]-7 -[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-5 H -[1,3]thiazolo[3,2- a Pyrimidine-5-one; 1-{4-{7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-5- Oxo-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-6-yl}phenyl}-1-ethanone; 6-(4-dimethylaminophenyl)-7 -[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl]-1-vinyl]-5 H -[1,3]thiazolo[3,2- a ] Pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-hydroxyphenyl)- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl )-1-vinyl]-6-(3,5-difluorophenyl)-5 H -[1,3]thiazolo[3,2- a Pyrimidine-5-one; 4-{7-[( E )-2-(2-butoxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H- [ 1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-(3-methoxy-2-pentyloxyphenyl)- 1-vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-( 2-Isopentyloxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl} Benzonitrile; 4-{7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3 Thiazolo[3,2- a ]-pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-(3-methoxy-2-pivaloxyphenyl)-1 -vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-(3 -Methoxy-2-(2-methoxyethoxy)phenyl]-1-vinyl}-5-oxo-5 H -[1,3]-thiazolo[3,2- a ] Pyrimidine-6-yl}benzonitrile; 4-{7-[( E )-2-(2-ethoxyethoxy-3-methoxyphenyl]-1-vinyl}-5-oxo -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-[2-(cyclopropylmethoxy) -3-methoxyphenyl] -l-ethenyl} -5-oxo -5 H - [1,3] thiazolo [3,2- a] pyrimidin-6-yl} benzyl ; 4- {7 - [(E ) -2- (2- methoxy-3-cyclobutyl-methoxy) phenyl-1-ethenyl] -5-oxo -5 H - [1,3] - Thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-(2-cyclopentyloxy-3-methoxy)phenyl-1-ethene yl] -5-oxo -5 H - [1,3] thiazolo - [3,2- a] pyrimidin-6-yl} benzonitrile; 4- {7 - [(E ) -2- (2- Cyclohexylmethoxy-3-methoxy)phenyl-1-vinyl]-5-oxo-5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl} Benzonitrile; 4-{7-[( E )-2-[2-(3-fluorobenzyloxy)-3-methoxyphenyl-1-vinyl]-5-oxo-5 H -[ 1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-{3-methoxy-2-(2-pyridyl) Oxy)phenyl]-1-vinyl]}-5-oxo-5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7 -[( E )-2-{2-(3-Cyanopropoxy)-3-(methoxyphenyl]-1-vinyl]}-5-oxo-5 H -[1,3 ]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{5-oxo-7-[( E )-2-(3-pyridyl)-1-vinyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}-benzonitrile; 7-[( E )-2-(2-cyclopropylmethoxy)-1-ethene 6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2 -(3-methoxy-2-propoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3 , 2- a ] pyrimidin-5-one; 7-[( E )-2-(2-butoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoro Methyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-isobutoxy-3-methyl) Oxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-Isopentyloxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H - [1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(3-methoxy-2-pivaloxy)phenyl-1-vinyl -6-(4-(Trifluoromethyl)phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 3-{2-methoxy-6 -{[( E )-2-{5-oxo-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine-7 -yl}-1-vinyl]phenoxy)propyl cyanide; {7-[( E )-2-(2-methoxyethoxy-3-methoxy)phenyl}vinyl]- 6-[4-(Trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; {7-[( E )-2-(2 -ethoxyethoxy)-3-methoxy)phenyl-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; {7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl] 1-vinyl]-6-[4-(trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclobutylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)-phenyl]-5 H -[1, 3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopentyloxy-3-methoxyphenyl)-1-vinyl]-6 -[4-(Trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one (Compound 35); 7-[( E )-2 -{3-Methoxy-2-(pyridin-2-ylmethoxy)phenylvinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazole And [3,2- a ]pyrimidin-5-one; 7-[( E )-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-vinyl]-6- [4-(Trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(4-ring Propylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3, 2- a ] pyrimidin-5-one; 7-[( E )-2-pyridin-3-ylvinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3 ] thiazolo [3,2- a] pyrimidin-5-one; 7 - [(E) -2- (2- cyclopropylmethoxy 3-methoxyphenyl) -1-ethenyl] -6- [3- (trifluoromethyl) phenyl] -5 H - [1,3] thiazolo [3,2- a] pyrimidin - 5-ketone; 6-(4-dimethylaminophenyl)-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)-1-vinyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 6-(4-dimethylaminophenyl)-7-[( E )-2-(3-A Oxy-2-p-pentyloxy)phenyl-1-vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one (Compound 42); 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-methoxyphenyl)-5 H -[1,3] Thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6 -(4-ethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropyl A Oxy-3-methoxyphenyl)-1-vinyl]-6-(4-(2,2,2-trifluoroethoxy)phenyl]-5 H -[1,3]thiazole [3,2- a ]pyrimidin-5-one;3-4-{7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl ]-5 H -[1,3]thiazolo-[3,2- a ]pyrimidin-6-yl}phenoxy)propyl cyanide; 7-[( E )-2-(2-cyclopropyl-methyl) Oxy-3-methoxyphenyl)-1-vinyl]-6-(4-cyclopropylmethoxy Phenyl]-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methyl) Oxyphenyl)-1-vinyl]-6-(4-difluoromethoxyphenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; -[( E )-2-(2-cyclopropylmethoxy-3-fluorophenyl)-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-{2-isopentyloxy-3-methoxyphenyl}-1-ethene 6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2 -(2-isobutoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazole [3,2- a ]pyrimidin-5-one; 7-[( E )-2-{3-methoxy-2-pivaloxyphenyl}-1-vinyl]-6-[4- (trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-{2-(2- Ethoxyethoxy)-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazole [3,2- a ]pyrimidin-5-one; 7-[( E )-2-(3-methoxy-2-propoxyphenyl)-1-vinyl]-6-[4-( Trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E ) -2-(3-methoxy-2-pentyloxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazole And [3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-{2-(4-fluorobutoxy)-3-methoxyphenyl}-1-ethene 6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )- 2-(2-Butoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazole [3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl}-1-vinyl]-6 -(4-trifluoromethoxy-phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-(2,3-di Hydroxy)phenyl}-1-vinyl]-6-(4-trifluoromethoxy-phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-(2-cyclopropylmethoxy-3-hydroxy)phenyl]-1-vinyl}-6-(4-trifluoro-methoxyphenyl)-5 H -[ 1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-ethoxyphenyl}-1 -vinyl]-6-(4-trifluoromethoxy-phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )- 2-[2-(cyclopropylmethoxy)-3-(2-ethoxyethoxy)phenyl]-1-vinyl}-6- (4-trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropane Methoxy)-3-difluoromethoxyphenyl]-1-vinyl}-6-(4-trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3, 2- a ] pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-(cyclopropylmethoxy)phenyl]-1-vinyl} -6-(4-trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2- (cyclopropylmethoxy)-3-(3-cyanopropoxy)phenyl]-1-vinyl}-6-(4-trifluoromethoxyphenyl)-5 H -[1, 3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-propoxyphenyl}-1-ethylene 6-(4-Trifluoromethoxy-phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2- {2-Cyclobutylmethoxy-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazole [3,2- a ]pyrimidin-5-one; 7-[( E )-2-{2-(cyclopentyloxy-3-methoxyphenyl}-1-vinyl]-6-[4 -(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-hydroxy- 3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)benzene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-{3-methoxy-2-(2- Trifluoromethylethoxy)phenyl}-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a Pyrimidine-5-one; 7-[( E )-2-(2-cyclohexylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy) -phenyl]-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclohexyloxy-3-methyl Oxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine-5- Ketone; 7-[( E )-2-{3-methoxy-2-(2-methoxyethoxy)phenyl}-1-vinyl]-6-[4-(trifluoromethoxy) -phenyl]-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-{(3-cyanopropoxy) 3-methoxy}phenylvinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine -5-keto; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-2-methyl-6-[4-( Trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy) 3-methoxyphenyl)-1-vinyl]-3-methyl-6-[4-(trifluoromethoxy)phenyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl) 1-vinyl]-2,3-dimethyl-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine- 5-ketone; 2-chloro-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methoxyphenyl)vinyl]-6-[4- (trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 2-chloro-6-[4-(dimethylamino) Phenyl]-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methoxy-phenyl)vinyl]-5 H -[1,3] Thiazolo[3,2- a ]pyrimidin-5-one; 4-{2-chloro-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methyl Oxyphenyl)vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 2-chloro-6-[4-( Dimethylamino)phenyl]-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]thiazolo[ 3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-5-oxo -3- (trifluoromethyl) -5 H - [1,3] thiazolo [3,2- a] pyrimidin-6-yl} benzonitrile; 4- (2 - {(E ) -2- [ 2- (3-cyano-propoxy) -3-methoxyphenyl} -l-ethenyl} -4-oxo -4 H - benzo [4,5] - [1,3] Pyrazolo - [3,2] pyrimidin-3-yl) benzonitrile; 4- (2 - {(E ) -2- [3- methoxy-2- (methoxyethoxy) phenyl} - 1-vinyl}-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[ ( E )-2-[2-(2-ethoxyethoxy)-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5 ]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[2-cyclopropylmethoxy-3-methoxy Phenyl]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[2-Butoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5] -[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[2-(3-methylbutoxy-3-methyl) Oxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile 4-{2-[( E )-2-[2-cyclobutylmethoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4, 5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[3-methoxy-2-pyridine-2- Methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl) Benzonitrile; 2-{( E -2-[(2-cyclopropylmethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethyl-phenyl)-4 H -benzo [4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2-[(2-methoxyethoxy)-3-methyl Oxyphenyl]-1-vinyl}-3-(4-trifluoromethyl-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a Pyrimidine-4-one; 2-{( E )-2-[(2-ethoxyethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoro Methyl-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2-[(3 -Cyanopropoxy-3-methoxy)phenyl]-1-vinyl}-3-(4-trifluoromethyl-phenyl)-4 H -benzo[4,5][1, 3] Thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2-[2-cyclopropylmethoxy-3-methoxyphenyl]-1-vinyl }-3-(4-Trifluoromethoxy-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2- {( E )-2-[3-Methoxy-2-(2-methoxyethoxy)phenyl]-1-vinyl}-3-(4-trifluoromethoxy-phenyl) -4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2-[(2-ethoxyethoxy) 3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethoxy-phenyl)-4 H -benzo[4,5][1, 3] thiazolo-[3,2- a ]pyrimidin-4-one; and 2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]- 3-(4-Trifluoromethoxyphenyl)-10-methylpyrimido[1,2- a ]benzimidazole-4(10 H )-one; or analog, tautomerization of compound 1-98 Constructs, regiomers, geometric isomers, stereoisomers, enantiomers, diastereomers or pharmaceutically acceptable salts are also contemplated.

According to another embodiment, specifically provided are compounds of formula (I), formula (II), formula (IIa), formula (IIb) or formula (III) or salts thereof, which compounds or salts thereof are less than 10,000 nM The IC ₅₀ value inhibits TRPV3 function. In other embodiments, as specifically provided it is a compound of formula (I) or a salt thereof, the compound or a salt thereof IC ₅₀ values of less than 1000 nM inhibition of TRPV3 function.

Also provided herein are methods of making the compounds described herein.

detailed description

The present invention provides fused pyrimidinone compounds which are useful as TRPV3 modulators and methods of synthesizing these compounds. The inventors have separately considered the pharmaceutically acceptable salts, enantiomers and diastereomers of the compounds described herein. Pharmaceutical compositions comprising the compound together with a pharmaceutically acceptable carrier, excipient or diluent are also contemplated, respectively, which are useful for treating diseases, disorders and/or disorders mediated by TRPV3.

The invention is defined by the scope of the claims, and not by the description provided below. The terms used in the scope of the appended claims are defined in the vocabulary section herein, but the terms of the claims may be used in different ways, if explicitly stated otherwise.

The term "halogen" or "halo" includes fluoro, chloro, bromo or iodo.

The term "alkyl" refers to a hydrocarbon chain radical having from 1 to 8 carbon atoms consisting solely of carbon and hydrogen atoms and having no unsaturation, and is attached to the remainder of the molecule by a single bond, for example: methyl , ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl). The term " _C1-6 alkyl" refers to an alkyl chain having from 1 to 6 carbon atoms. Unless otherwise stated or stated, all alkyl groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2- Butyl. Unless otherwise stated or stated, all alkenyl groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbyl group having from 2 to about 12 carbon atoms and having at least one carbon-carbon triple bond (groups having from 2 to about 10 carbon atoms are preferred). Non-limiting examples of alkynyl groups include ethynyl, propynyl and butynyl. Unless stated or stated to the contrary, all alkynyl groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen linkage. Representative examples of such groups are -OCH ₃ and -OC ₂ H ₅ . Unless otherwise stated or stated, all alkoxy groups described or protected herein may be straight or branched, substituted or unsubstituted.

The term "cycloalkyl" denotes a non-aromatic monocyclic or polycyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, bridged ring groups or spirobicyclic groups (eg, spiro(4,4)壬-2- base). Unless stated or stated to the contrary, all cycloalkyl groups described or protected herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a cyclic ring-containing group having from 3 to about 8 carbon atoms attached directly to an alkyl group. A cycloalkylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to produce a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless stated or stated to the contrary, all cycloalkylalkyl groups described or protected herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to cyclic ring-containing groups having from 3 to about 8 carbon atoms having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless stated or stated to the contrary, all cycloalkenyl groups described or protected herein may be substituted or unsubstituted.

The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms, including monocyclic, bicyclic or tricyclic aromatic systems such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. base. All aryl groups described or protected herein may be substituted or unsubstituted, unless stated or stated to the contrary.

The term "arylalkyl" means a direct bonded as above defined aryl radical as defined above in the alkyl group, e.g. -CH ₂ C ₆ H ₅ or _{-C 2 H 4 C 6 H 5} .

The terms "heterocyclyl" and "heterocyclic ring", "heterocyclic group" refer to a stable 3-15 membered ring consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. base. For the purposes of the present invention, a heterocyclic ring group may be a monocyclic, bicyclic or tricyclic ring system, and may include a fused ring system, a bridged ring system or a spiro ring system and nitrogen, phosphorus, carbon in the heterocyclic ring group. The oxygen or sulfur atom can optionally be oxidized to various oxidation states. Additionally, the nitrogen atom can be optionally quaternized; and the ring group can be partially or fully saturated (ie, heterocyclic or heteroaryl). Examples of such heterocyclic ring groups include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, oxazolyl, anthracene Polinyl, dioxolane, pyridazinyl, naphthyridyl, perhydroaza Base, phenazinyl, phenothiazine, phenoxazinyl, pyridazinyl, pyridyl, pteridinyl, fluorenyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetra Azyl, imidazolyl, tetrahydroisoquinolinyl, acridinyl, pyridazinyl, 2-oxooxazinyl, 2-oxoacridinyl, 2-oxopyrrolidinyl, 2-oxonitrogen miscellaneous Base, aza , pyrrolyl, 4-acridone, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolyl, oxazolidinyl, triazolyl, indanyl, iso Oxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isodecyl, anthracene Lolinyl, isoindolyl, octahydrofluorenyl, octahydroisodecyl, quinolyl, isoquinolyl, decahydroisoquinolinyl, benzimidazolyl, thio Diazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, Thiomorpholinyl hydrazide, thiomorpholinyl hydrazine, dioxaphospholyl, oxadiazolyl, chromanyl and isochroman. A heterocyclic ring group can be attached to the main structure at any heteroatom or carbon atom, resulting in a stable structure. Unless stated or stated to the contrary, all heterocyclyl groups described or protected herein may be substituted or unsubstituted, including heterocyclyl groups contained in more complex substructures.

The term "heterocyclylalkyl" refers to a heterocyclic ring group attached directly to an alkyl group. The heterocyclylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to give a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring group. A heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom, resulting in a stable structure. Unless stated or stated to the contrary, all heteroaryl groups described or protected herein may be substituted or unsubstituted, including heteroaryl groups contained in more complex substructures.

The term "heteroarylalkyl" refers to a heteroaryl ring radical attached directly to an alkyl group. A heteroarylalkyl group can be attached to the main structure at any carbon atom in the alkyl group to produce a stable structure.

The term "substituted" as used herein, unless otherwise specified, refers to a group or moiety having one or more substituents attached to the structural backbone of the group or moiety, including but not limited to: hydroxy, halo, Carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or not Substituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl Alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, Substituted or unsubstituted heterocyclic ring, substituted or unsubstituted anthracene, -COOR ^x , -C(O)R ^x , -C(S)R ^x , -C(O)NR ^x R ^y , -C(O ONR ^x R ^y , -NR ^x CONR ^y R ^z , -N(R ^x )SOR ^y , -N(R ^x )SO ₂ R ^y , -(=NN(R ^x )R ^y ), -NR ^x C ^{(O) OR y, -NR x} R y, -NR x C (O) R y, -NR x C (S) R y ^{-NR x C (S) NR y} R z, -SONR x R y, -SO 2 NR x R y, -OR x, -OR x C (O) NR y R z, -OR x C (O) OR ^y , -OC(O)R ^x , -OC(O)NR ^x R ^y , -R ^x NR ^y C(O)R ^z , -R ^x OR ^y , -R ^x C(O)OR ^y , -R ^x C(O)NR ^y R ^z , -R ^x C(O)R ^y , -R ^x OC(O)R ^y , -SR ^x , -SOR ^x , -SO ₂ R ^x and -ONO ₂ , where R ^x , R ^y and R ^{z are} independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituent in the above "substituted" group cannot be further substituted. For example, when the substituent on the "substituted alkyl group" is a "substituted aryl group", the substituent on the "substituted aryl group" cannot be a "substituted alkenyl group".

The term "treatment" state, disorder or condition includes: (a) preventing or delaying the onset of a clinical condition of a condition, disorder or condition in which the state, disorder or condition is or susceptible to having the condition, disorder or condition. (c) inhibiting the state, disorder, or condition, ie, preventing or alleviating the disease, or at least one of its clinical or sub-therapies, in the subject but not yet undergoing or exhibiting clinical or subclinical symptoms of the state, disorder, or condition; Development of clinical symptoms; or (c) elimination of the disease, ie, causing the state, disorder or condition or at least one of its clinical or subclinical symptoms to subside.

The term "subject" includes mammals (especially humans) and other animals, such as livestock (eg, domestic pets, including cats, dogs) and non-live animals (such as wild animals).

"Therapeutically effective amount" refers to an amount of a compound that, when administered to a subject in need of a therapeutic state, disorder or condition, is sufficient to produce an effect on the subject being targeted for administration. A "therapeutically effective amount" will vary with the compound, the disease, its severity, and the age, weight, physical condition, and responsiveness of the subject to be treated.

The compounds described in the present invention can form salts. Non-limiting examples of pharmaceutically acceptable salts that form part of the invention include inorganic hydrazine derived salts, organic hydrazine salts, chiral guanidine salts, salts of natural amino acids, and salts of unnatural amino acids. With respect to all compounds of formula (I), the invention extends to its stereoisomeric forms and mixtures thereof. The various stereoisomeric forms of the invention may be separated from one another by methods known in the art, or may be obtained by stereospecific or asymmetric synthesis, as long as the prior art teaches the synthesis or isolation of particular stereoisomers. isomer. Tautomeric forms and mixtures of the compounds described herein are also contemplated.

Drug composition

The pharmaceutical compositions of the present invention comprise at least one compound described herein and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition contemplated comprises a compound described herein in an amount sufficient to inhibit the TRPV3 receptor in the subject.

Subjects considered include, for example, living cells and mammals including humans. The compounds of the invention may be combined with or diluted with a pharmaceutically acceptable excipient such as a carrier or diluent, or enclosed in a carrier in the form of a capsule, sachet, paper or other container.

Examples of suitable carriers include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, gypsum powder, sucrose, dextrin, carbonic acid Magnesium, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose low alkyl ether, citric acid, fatty acid, fatty acid amine, fatty acid single Glycerides and diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

The carrier and diluent may comprise a sustained release material such as glyceryl monostearate or glyceryl distearate (alone or mixed with paraffin).

The pharmaceutical composition may further comprise one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, salts which affect the osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents or Any combination of the above. The pharmaceutical compositions of the present invention may also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art.

The pharmaceutical compositions described herein can be prepared by conventional techniques known in the art. For example, the active compound may be mixed with the carrier or diluted in a carrier or enclosed in a carrier in the form of an ampule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as an excipient, excipient or medium for the active compound. The active compound can be adsorbed onto a granular solid container, such as in a sachet.

The pharmaceutical composition may be in a conventional form such as a capsule, a tablet, an aerosol, a solution, a suspension or a topically applied product.

The route of administration can be any route that effectively delivers the active compound of the invention to the appropriate or desired site of action. Suitable administration routes include, but are not limited to, oral administration, nasal administration, pulmonary administration, buccal administration, subdermal administration, intradermal administration, transdermal administration, parenteral administration. Medicine, rectal administration, depot administration, subcutaneous administration, intravenous administration, intraurethral administration, intramuscular administration, intranasal administration, ocular administration (eg use of ophthalmic solution) Or local administration (such as the use of topical ointment).

Solid oral preparation forms include, but are not limited to, tablets, capsules (soft gelatin or hard gelatin), dragees (containing active ingredients in powder or pellet form), lozenges (troches and lozenges). Tablets, dragees or capsules having talc and/or carbohydrate carriers or binders and the like are especially suitable for oral use. Liquid preparations include, but are not limited to, syrups, emulsions, soft gelatin, and sterile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions. For parenteral applications, injectable solutions or suspension formulations are especially suitable.

Liquid preparations include, but are not limited to, syrups, emulsions, soft gelatin, and sterile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions.

For parenteral use, injectable solutions or suspension formulations are especially suitable, preferably aqueous solutions with active compound in polyhydroxylated castor oil.

Suitable dosages of the compounds used to treat the diseases and disorders described herein can be determined by those skilled in the relevant art. The therapeutic dose is usually determined by a human dose range study based on prima facie evidence from animal studies. The dose must be sufficient to produce the desired therapeutic benefit without causing unwanted side effects. For example, the daily dose of the TRPV3 modulator can range from 0.1 mg/kg to about 30.0 mg/kg. Modes of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can be utilized and adjusted by those skilled in the art. All changes and modifications are considered to be within the scope of the invention.

treatment method

The invention provides compounds and pharmaceutical formulations thereof for use in the treatment of diseases, disorders and or disorders modulated by TRPV3. The invention further provides a method of treating a disease, disorder, and/or disorder modulated by TRPV3 in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

Diseases, disorders, and/or disorders that are thought to be modulated by TRPV3 include, but are not limited to, pain; nociceptive pain; toothache; heartache caused by ischemic myocardium; pain caused by migraine; acute pain; chronic pain; Neuropathic pain; postoperative pain; pain due to neuralgia (eg, postherpetic neuralgia or trigeminal neuralgia); pain due to diabetic neuropathy; toothache and cancer pain; inflammatory pain conditions (eg arthritis and Osteoarthritis); joint pain; neuropathy; neurodegenerative diseases; retinopathy; neuropathic skin disorders; stroke; bladder allergy; urinary incontinence; vulvodynia; gastrointestinal disorders, such as irritable bowel syndrome, stomach - esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease; inflammatory diseases such as pancreatitis; respiratory disorders such as allergic and non-allergic Rhinitis, asthma or chronic obstructive pulmonary disease; irritation of the skin, eyes or mucous membranes; dermatitis; pruritus, such as uremia, itching; fever; muscle spasm; Sputum; dyskinesia; depression; Huntington's disease; memory loss; brain function limitation; amyotrophic lateral sclerosis (ALS); dementia; arthritis; osteoarthritis; diabetes; obesity; urticaria; Keratocarcinoma; keratocanthoma; alopecia; Ménière's disease; tinnitus; hyperacusis; anxiety; and benign prostatic hyperplasia. Other diseases, disorders and/or disorders modulated by TRPV3 are described, for example, in WO2007/056124; Wissenbach, U. et al., Biology of the cell (2004), 96, 47-54; Nilius, B. et al., Physiol Rev (2007). ), 87, 165-217; Okuhara, DY, et al, Expert Opinion on Therapeutic Targets (2007), 11, 391-401; Hu, HZ et al, Journal of Cellular Physiology , (2006), 208, 201-212; In the cited references; all documents are hereby incorporated by reference in their entirety for their purposes.

Preparation

The compounds described herein, including compounds of formula (I), (II), (IIa), (IIb), (III) and specific examples, are prepared using techniques known to those of ordinary skill in the art. The compounds described herein are prepared by the reaction sequences described in Schemes 1-7. It is envisioned that all possible stereoisomers are also included within the scope of the invention.

Starting materials for the reaction schemes described below are either commercially available or can be prepared according to methods known to those skilled in the art or by the methods disclosed herein. In general, the compounds of the invention can be prepared by the following reaction scheme in which all the symbols are as defined above.

A general method for the synthesis of the general formula (I) is shown in Schemes 1-3. The amine of formula (1) is either commercially available or prepared according to methods known in the art: in the presence of iodine or hydrobromic acid and bromine in a polar protic solvent such as ethanol, the thiourea is suitably substituted The carbonyl compound is reacted at reflux temperature. (Foulis, MJ et al, J. Med. Chem ., (1971), 14, 1075-1077; Kikugawa, Y. et al., Synthesis ., (1981), 124-125; Tanaka, K. et al., J. Het. Chem ., (1991), 28, 907-911; Kauffman JM et al, J. Org. Chem ., (2003), 68, 839-853).

plan 1:

According to one embodiment, the compound of formula (I) is prepared by the method described in Scheme 1. In the presence of a suitable solvent (eg, acetic acid, polyphosphoric acid, etc.), the amine of formula (1) is converted to formula (3) by reacting with a compound of formula (2) wherein R' is H or an alkyl group. Compounds (Allen, CFH et al, J. Org. Chem. , (1959), 24, 779-787; Andrew, HF et al, J. Het. Chem. , (1967), 4, 577-581; Hermecz, I. Etc. Synthesis. , (1984) 155-158). In a suitable polar aprotic solvent (eg, acetonitrile, tetrahydrofuran, etc.), a suitable halogenating agent is used [eg, N -iodobutylimine (NIS), N -bromosuccinimide (NBS) , iodine and ammonium cerium nitrate (CAN), etc.] halogenate the intermediate of formula (3) to give a halogenated compound of formula (4) wherein L is a halogen; the compound is then reacted with a suitable boric acid of formula (5) Palladium (O) catalyzed CC coupling (eg, Suzuki coupling) reaction produces a compound of formula (6). Then, in the presence of a suitable hydrazine (eg, sodium acetate, sodium ethoxide, potassium butoxide, sodium hydride, etc.), in a suitable polar solvent (eg, ethanol, dimethylformamide, tetrahydrofuran, etc.) In the formula (6), the compound of the formula (I) is converted into a compound of the formula (I) by a classically modified Knoevenagel reaction with a suitable aldehyde of the formula (7).

Scenario 2:

According to another embodiment, the compound of formula (I) is prepared by the method described in Scheme 2. In the presence of a suitable solvent (for example, acetic acid, polyphosphoric acid, etc.), the amine of the formula (1) is reacted with a compound of the formula (8) wherein R' is H or an alkyl group; and L is a halogen, Conversion to a compound of formula (9) (Vanelle, P. et al, J. Het. Chem ., (2006), 43, 1225-1229). Then, in the presence of a suitable solvent (for example, acetonitrile, toluene, etc.), the compound of formula (9) is converted to the corresponding phosphonium salt of formula (10) by reaction with triphenylphosphine (TPP) (wherein L For halogen). In the presence of a suitable hydrazine (eg, triethylamine, potassium butoxide, sodium hydride, etc.), in a suitable polar aprotic solvent (eg, dimethylformamide, tetrahydrofuran, etc.), corresponding The hydrazine salt of formula (10) is prepared from the aldehyde of formula (7) by a classical Wittig reaction to prepare a compound of formula (11). In a suitable polar aprotic solvent (eg, acetonitrile, tetrahydrofuran, etc.), a suitable halogenating agent is used [eg, N -iodobutylimine (NIS), N -bromosuccinimide (NBS) , iodine and ammonium cerium nitrate (CAN), etc.] halogenating the intermediate of formula (11) to give an intermediate of formula (12) wherein L is a halogen; this intermediate is further reacted with a suitable boric acid of formula (5) Palladium (0) catalyzed CC coupling (e.g., Suzuki coupling) reaction to form a compound of formula (I).

Option 3:

According to another embodiment, the compound of formula (I) is prepared by the method described in Scheme 3. In a suitable polar aprotic solvent (eg, acetonitrile, tetrahydrofuran, etc.), a suitable halogenating agent is used [eg, N -iodobutylimine (NIS), N -bromosuccinimide (NBS) , iodine and ammonium cerium nitrate (CAN), etc.] halogenate the intermediate of formula (3) to give a halogenated compound of formula (4) wherein L is a halogen; the compound is then reacted with a suitable boric acid of formula (5) Palladium (0) catalyzed CC coupling (eg, Suzuki coupling) reaction produces an intermediate of formula (6). Then, in the presence of a suitable hydrazine [eg, lithium diisopropyl guanamine (LDA), hexamethyldioxane diazo lithium (LHMDS), sodium hydride, etc.], in a suitable polar solvent (eg, tetrahydrofuran) In the formula, the compound of the formula (6) is converted to the alcohol of the formula (13) by reacting with an appropriate aldehyde of the formula (7). The resulting alcohol of formula (13) is dehydrated with a suitable dehydrating agent (e.g., trifluoroacetic acid) according to methods known in the art to yield compounds of formula (I) (Philipova, P. et al., J. Het Chem ., (2006), 43, 1057-1063).

Option 4:

According to another embodiment, the compound of formula (III) is prepared by the method described in Scheme 4. In the presence of a suitable solvent (eg, acetic acid, polyphosphoric acid, etc.), the amine of formula (14) is converted to formula (15 by reaction with a compound of formula (2) wherein R' is H or an alkyl group. Compounds (Hermecz, I. et al., Synthesis., (1984), 155-158). In a suitable polar aprotic solvent (eg, acetonitrile, tetrahydrofuran, etc.), a suitable halogenating agent is used [eg, N -iodobutylimine (NIS), N -bromosuccinimide (NBS) , iodine and ammonium cerium nitrate (CAN), etc.] halogenate the intermediate of formula (15) to give a halogenated compound of formula (16) wherein L is a halogen; the compound is then reacted with a suitable boric acid of formula (5a) Palladium (0) catalyzed CC coupling (eg, Suzuki coupling) reaction produces an intermediate of formula (17). Then, in the presence of a suitable hydrazine (eg, sodium acetate, sodium ethoxide, potassium butoxide, sodium hydride, etc.), in a suitable polar solvent (eg, ethanol, dimethylformamide, tetrahydrofuran, etc.) In the intermediate, the intermediate of formula (17) is converted to the compound of formula (III) by a classically modified Knoevenagel reaction with a suitable aldehyde of formula (7a).

Option 5:

Specific compounds related to the present invention were prepared by the method described in Scheme 5. According to the method described in Scheme 1, the amine of formula (1) is converted to the compound of formula (4) by reaction with a compound of formula (2) wherein R' is H or an alkyl group. The compound of formula (4) is then reacted with a suitably substituted aryl boronic acid of formula (5b) via a palladium (0) catalyzed C-C coupling (e.g., Suzuki coupling) to yield a compound of formula (18). Then, in the presence of a suitable hydrazine (eg, sodium acetate, sodium ethoxide, potassium butoxide, sodium hydride, etc.), in a suitable polar solvent (eg, ethanol, dimethylformamide, tetrahydrofuran, etc.) In the formula (18), the compound of the formula (II) is converted into a compound of the formula (II) by a classically modified Knoevenagel reaction with an appropriately substituted aromatic aldehyde of the formula (7a).

Alternatively, an amine of formula (1) can be converted to a compound of formula (19) using an appropriately substituted aromatic aldehyde of formula (7a) according to the procedure described in Scheme 2. In a suitable polar aprotic solvent (eg, acetonitrile, tetrahydrofuran, etc.), a suitable halogenating agent is used [eg, N -iodobutylimine (NIS), N -bromosuccinimide (NBS) , iodine and ammonium cerium nitrate (CAN), etc.] halogenate the intermediate of formula (19), followed by palladium (0) catalyzed CC coupling with an appropriately substituted aryl boronic acid of formula (5b) (eg, Suzuki coupling) The reaction produces a compound of the formula (II).

Option 6:

Specific compounds related to the present invention are prepared by the method described in Scheme 6. According to the method described in Scheme 1, the amine of formula (1) is converted to the compound of formula (4) by reaction with a compound of formula (2) wherein R' is H or an alkyl group. The compound of formula (4) is then reacted with a suitably substituted aryl boronic acid of formula (5b) via a palladium (0) catalyzed C-C coupling (e.g., Suzuki coupling) to yield a compound of formula (18). Then, in the presence of a suitable hydrazine (eg, sodium acetate, sodium ethoxide, potassium butoxide, sodium hydride, etc.), in a suitable polar solvent (eg, ethanol, dimethylformamide, tetrahydrofuran, etc.) In the formula (18), the compound of the formula (II) is converted into a compound of the formula (IIa) by a classically modified Knoevenagel reaction with an appropriately substituted aromatic aldehyde of the formula (7b).

Alternatively, the amine of formula (1) can be converted to the compound of formula (20) using an appropriately substituted aromatic aldehyde of formula (7b) according to the procedure described in Scheme 2. In a suitable polar aprotic solvent (eg, acetonitrile, tetrahydrofuran, etc.), a suitable halogenating agent is used [eg, N -iodobutylimine (NIS), N -bromosuccinimide (NBS) , iodine and ammonium cerium nitrate (CAN), etc.] halogenate the intermediate of formula (20); followed by palladium (0) catalyzed CC coupling with an appropriately substituted aryl boronic acid of formula (5b) (eg, Suzuki coupling) The reaction produces a compound of the formula (IIa).

Option 7:

Further, specific compounds related to the present invention are prepared by the method described in Scheme 7. O-dealkylation of a compound of formula (IIa) under acidic conditions (for example, a mixture of 48% hydrobromic acid and acetic acid) or using a Lewis acid (for example, boron tribromide) A dihydroxy compound of the formula (21) is obtained. In a suitable polar solvent (for example, dimethylformamide, tetrahydrofuran, dimethylhydrazine, etc.), a compound of formula (21) is reacted with a suitable hydrazine (for example, potassium carbonate, sodium hydride, cesium carbonate, etc.). Alkylation of a suitable alkyl halide of R ^a1 X affords a compound of formula (22). Then, in a suitable polar solvent (for example, dimethylformamide, tetrahydrofuran, dimethylhydrazine, etc.), a suitable hydrazine (for example, potassium carbonate, sodium hydride, cesium carbonate, etc.) is used to make the formula (22) The compound is alkylated with a suitable haloalkane of the formula R ^a2 X and converted to a compound of the formula (IIa). Alternatively, as described in Scheme 6, in the presence of a suitable hydrazine (eg, sodium acetate, sodium ethoxide, potassium butoxide, sodium hydride, etc.) in a suitable polar solvent (eg, ethanol, dimethyl In the case of meglumine, tetrahydrofuran, etc., the compounds of the formula (21) and the formula (22) can be produced by a classical modified Knoevenagel reaction (particularly with a monohydroxy aldehyde or a dihydroxy aldehyde of the formula (7b)).

experiment

Intermediate 1: 7-[( E )-2-(4-fluorophenyl)vinyl]-6-iodo-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one :

Step 1: 7-Methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: 2-aminothiazole (5 g, 49.931 mmol) in acetic acid at room temperature Ethyl acetate (9.48 ml, 74.843 mmol) was added to the stirred solution (40 ml). The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was cooled to room temperature. After concentrated under reduced pressure to give the residue was basified with saturated NaHCO ₃ solution with ethyl acetate (50ml) was diluted. The organic layer was washed with brine (100ml), then dried (Na ₂ SO ₄₎ and concentrated to give a crude product which was used in 1% methanol in chloroform, the crude product was purified by silica gel column chromatography, 3.3g of a white solid product ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H).

Step 2: 7-[( E )-2-(4-Chlorophenyl)vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one: at room temperature Add 4-chlorobenzaldehyde (253 mg, 1.795 mmol) to a stirred solution of the intermediate (200 mg, 1.206 mmol) in EtOAc (30 mL). . The reaction mixture was heated to reflux for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue obtained was partitioned between chloroform (100 ml) and water (50 ml). The organic layer was washed (100ml) washed with brine, then dried (Na ₂ SO ₄₎ and concentrated to give the crude product; used in chloroform with 2% acetone The crude was purified by silica gel column chromatography, a white solid product 59mg of; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.25 (s, 1H), 6.87 (d, J = 15.6 Hz, 1H), 6.94 (d, J = 4.8 Hz, 1H), 7.33 (d, J = 9.0 Hz , 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.90 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 289.37 ( M+H) ⁺ .

Step 3: 7-[( E )-2-(4-Chlorophenyl)vinyl]-6-iodo-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: at 80 ℃, the mixture in step 2 intermediate (3.0 g, 0.018 mmol), iodine (2.75g, 0.018mmol), and ceric ammonium nitrate (CAN) (4.93g, 0.009mmol) in CH ₃ CN (30ml) Stir for 2 h. The reaction mixture was cooled to room temperature. Distilled water (50 ml) was added to the residue obtained after the reaction mixture was concentrated, and stirred at room temperature for 1 h. The reaction mixture was filtered, dried under vacuum to produce 5.30g of product as a pale yellow ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 6.87 (d, J = 15.6 Hz, 1H), 6.94 (d, J = 4.8 Hz, 1H), 7.33 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.90 (d, J = 4.8 Hz, 1H) ; ESI-MS (m/z) 289.37 (M+H) ⁺ .

Intermediate 2: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxy]vinyl}-6-iodo-5 H- [1,3]thiazolo[ 3,2- a ]pyrimidin-5-one:

Step 1: 7-(Chloromethyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one: treated with ethyl chloroacetate (11.176 g, 67.866 mmol) A solution of 2-aminothiazole (5.0 g, 49.993 mmol) in polyphosphoric acid (40.0 g) was heated at 110 ° C for 5.0 h. The reaction mixture was cooled to room temperature and adjusted to pH 7 with a 10% aqueous NaOH. The solid which formed was filtered and purified by column chromatography using ethyl acetate in dichloromethane to afford 2.6 g of the desired brown solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 4.59 (s, 2H), 6.41 (s, 1H), 7.56 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 200.42 (M+ H) ⁺ .

Step 2: 5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-ylmethyl(triphenyl)phosphonium chloride: at room temperature, to the middle of step 1 Triphenylphosphine (8.6 g, 32.89 mmol) was added to a suspension of the mixture (6.0 g, 29.90 mmol) in acetonitrile. The resulting reaction mixture was slowly heated and refluxed for 30 min. The solvent was concentrated in vacuo and the residue was crystallised eluted with diisopropylethyl ether. The solid was dried under vacuum to afford 13.5g of the desired compound of an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 4.96 (d, J = 15.0 Hz, 2H), 6.15 (br s, 1H), 7.32 (br s, 1H), 7.60-7.74 (m, 15H), 7.86 (br s, 1H); ESI-MS (m/z) 427.33 (M+H) ⁺ .

Step 3: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-ethylphenyl]ethenyl}-5 H -[1,3]thiazolo[3,2- a ] Pyrimidine-5-one: NaH (1.2 g, 30.88) in dry DMSO (75 mL) was added to a stirred portion of intermediate 2 (13.0 g, 28.08) and stirred for 0.5 h. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (6.3 g, 30.88 mmol) in DMSO was added dropwise to the solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over anhydrous Na ₂ SO _4, to give a crude solid; used in 10% ethyl acetate in DCM, the solid was purified by column chromatography to give 7.5g of the desired White solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.30-0.33 (m, 2H), 0.52-057 (m, 2H), 1.10-1.20 (brm, 1H), 3.72-3.90 ( m, 5H), 6.29 (s, 1H), 7.00-7.11 (m, 3H), 7.34 (d, J = 6.3 Hz, 1H), 7.44 - 7.50 (m, 1H), 7.90-8.00 (m, 1H) , 8.14 (d, J = 6.2 Hz, 1H); ESI-MS (m/z) 355.17 (M+H) ⁺ .

Step 4: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-ethylphenyl]ethenyl}-6-iodo-5 H- [1,3]thiazolo[ 3,2- a ]pyrimidin-5-one: N -iodobutanediimide (2.69 g, in acetonitrile) was added to a solution of the intermediate 3 (3.89 g, 10.72 mmol) in EtOAc. 11.79mmol). The reaction temperature was then raised to 60 ° C and stirred for 4 h. The reaction mixture was then cooled to room temperature, diluted with water and stirred for 20 min. The filtered solid was washed with water and dried to give 5.19 g of desired compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.32-0.33 (m, 2H), 0.54-0.56 (d, J = 7.2 Hz, 2H ), 1.22 (br s, 1H), 3.77-3.81 (m, 5H), 7.06-7.14 (m, 2H), 7.27-7.29 (d, J = 7.2 Hz, 1H), 7.49-7.52 (m, 1H) , 7.57 (s, 1H), 7.96 (d, J = 3.9 Hz, 1H), 8.18 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 481.45 (M+H) ⁺ .

Intermediate 3: 6-(3,5-difluorophenyl)-7-methyl-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Step 1: 7-Methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: at room temperature, to 2-aminothiazole (5.0 g, 49.930 mmol) Ethyl acetate (9.746 g, 74.90 mmol) was added to a stirred solution of acetic acid (40 ml). The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was cooled to room temperature. The residue obtained after concentrating of EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a crude product which was used in 1% methanol in chloroform, purified by silica gel column chromatography of the crude product, 4.20g of a white solid product; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H).

Step 2: 6-Iodo-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: according to the method described in Step 3 of Intermediate 1, in the chamber The solution of the intermediate of Step 1 (20 g, 120.463 mmol) in acetonitrile (200 mL) was worked-up with EtOAc (3 g, 60.233 mmol) to afford 35 g of pale yellow solid product; ¹ H NMR (300) MHz, DMSO- d ₆ ) δ 2.56 (s, 3H), 7.52 (d, J = 5.1 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 291.29 (MH) ) ^- .

Step 3: 6-(3,5-Difluorophenyl)-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: To the intermediate of step 2 ( A solution of Na ₂ CO ₃ (0.653 g, 6.162 mmol) in water (4 ml) and Pd[(C ₆ H ₅ ) ₃ P] ₄ [4] was added to a solution of 0.300 g, 1.027 mmol) in toluene (10 ml) (Triphenylphosphine)palladium(0)] (0.048 g, 0.042 mmol). A solution of 3,5-difluorophenylboronic acid (6.5 g, 44.235 mmol) in EtOAc (6 mL) was evaporated. After the reaction mixture was completed, EtOAc was evaporated. The organic layer was washed (50ml) with brine, then dried over anhydrous Na ₂ SO ₄ to give a crude product; used in 10% ethyl acetate in chloroform, purified by silica gel column chromatography of the crude product as an off-white solid 280mg of product; ¹ H NMR (300 MHz, DMSO- d 6) δ 2.19 (s, 3H), 7.53 (d, J = 7.8 Hz, 3H), 7.88 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 276.31 (MH) ^- .

Intermediate 4: 4-(7-Methyl-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl)benzonitrile:

Step 1: 7-Methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: 2-aminothiazole according to the procedure described in Step 1 of Intermediate 3 A solution of (50 g, 499.301 mmol), ethyl acetate (96 ml, 748.885 mmol) and acetic acid (400 ml) were combined to give a crude product. The crude product was purified by silica gel column chromatography using 1% methanol in chloroform. 40g of white solid product; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J = 4.8 Hz, 1H), 7.94 (d, J =4.8 Hz, 1H).

Step 2: 6-iodo-7-methyl -5 H - [1,3] thiazolo [3,2- a] pyrimidin-5-one: The procedure described in step 1 of Intermediate 3, the step of 1 The solution of the intermediate 1 (20 g, 120.463 mmol) in acetonitrile (200 ml) was firstly reacted with ammonium cerium nitrate (33 g, 60.233 mmol) and then reacted with iodine (18 g, 72.281 mmol) to give 35 g of pale yellow solid ^{product; 1 H NMR (300MHz, DMSO-} d 6) δ 2.56 (s, 3H), 7.52 (d, J = 5.1 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H); ESI-MS (m /z) 291.29 (MH) ^- .

Step 3: 4-(7-Methyl-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl)benzonitrile: according to Step 3 in Intermediate 3 The procedure described in the preparation of this compound: Step 2 intermediate (10 g, 34.234 mmol), 4-cyanophenylboronic acid (6.5 g) in a mixture of toluene (250 ml), ethanol (150 ml) and water (100 ml) , 44.235 mmol), Pd[(C ₆ H ₅ ) ₃ P] ₄ (1.62 g, 1.401 mmol) and Na ₂ CO ₃ (21.7 g, 2.051 mmol) afforded crude product; using 10% ethyl acetate in chloroform The ester was purified by silica gel column chromatography to give 5 g of pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.19 (s, 3H), 7.53 (d, J = 7.8 Hz, 3H) , 7.88 (d, J = 7.8 Hz, 2H), 8.02 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 265.31 (MH) ^- .

Intermediate 5: 7-Methyl-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Step 3 of Intermediate 3, in the presence of Pd[(C ₆ H ₅ ) ₃ P] ₄ (1.72 g, 1.491 mmol) and sodium carbonate (23.7 g, 223.891 mol) in toluene The title compound was prepared by a coupling reaction of the intermediate 2 (10.9 g, 37.312 mmol) with 4-(trifluoromethyl)phenylboronic acid (9.9 g, 52.241 mmol). , 18.5 g of the desired pale yellow solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.18 (s, 3H), 7.53-7.59 (m, 4H), 7.58-7.80 (m, 1H), 8.01 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H) ⁺ .

Intermediate 6: 7-Methyl-6-[3-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the procedure described in Step 31.21g of Intermediate 3, in the presence of Pd[(C ₆ H ₅ ) ₃ P] ₄ (92 mg, 0.0812 mmol) and sodium carbonate (1.27 g, 12.061 mol) in toluene The title compound was prepared by a coupling reaction of the intermediate 2 (600 mg, 2.001 mmol) with 3-(trifluoromethyl)phenylboronic acid (585 g, 3.020 mmol). 18.5g of the desired pale yellow solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.18 (s, 3H), 7.53-7.59 (m, 4H), 7.58-7.80 (m, 1H), 8.01 ( d, J = 4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H) ⁺ .

Intermediate 7: 6-iodo-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]thiazolo-[3 , 2- a ] pyrimidin-5-one:

Step 1: 7-[( E )-2-(2-Isobutoxy-3-methoxyphenyl)ethenyl]-5 H- [1,3]thiazolo[3,2- a ]pyrimidine -5-one: This compound was prepared according to the procedure described in Step 3 of Intermediate 2: Step 2 Intermediate (1.00 g, 2.160 mmol) of Intermediate 2 in dry DMSO (10 mL). Isobutoxy-3-methoxy)benzaldehyde (494 mg, 2.376 mmol) and NaH (95 mg, 3.958 mmol) elute the residue, to give 500mg of the desired compound as a white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.05 (d, J = 6.9 Hz, 6H), 2.01-2.06 (m, 1H), 3.69 (d, J = 6.3 Hz, 2H), 3.80 (s, 3H), 6.28 (s, 1H), 6.94 - 7.18 (m, 3H), 7.34 (d, J = 6.3 Hz, 1H), 7.47 (d, J = 5.1) Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 16.2 Hz, 1H).

Step 2: 6-Iodo-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]thiazolo[3,2 -a]pyrimidin-5-one: The intermediate of step 1 was treated with N -iodobutaneimine (416 g, 1.851 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2. 600 mg, 1.683 mmol) gave 600 mg of the desired yellow solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.05 (d, J = 6.9 Hz, 6H), 2.04-2.08 (m, 1H) , 3.71 (d, J = 6.3 Hz, 2H), 3.81 (s, 3H), 7.10-7.12 (m, 2H), 7.27-7.30 (m, 1H), 7.48-7.53 (m, 2H), 7.96 (d , J = 4.8 Hz, 1H), 8.17 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 483.16 (M+H) ⁺ .

Intermediate 8: 7-{( E )-2-[2-(2,2-dimethylpropoxy)-3-methoxyphenyl]ethenyl}-6-iodo-5 H- [1 , 3] thiazolo-[3,2-a]pyrimidin-5-one:

Step 1: 7-{( E )-2-[2-(2,2-Dimethylpropoxy)-3-methoxyphenyl]ethenyl}-5H-[1,3]thiazolo- [3,2-a]pyrimidin-5-one: This compound was prepared according to the procedure described in Step 3 of Intermediate 2: Step 2 Intermediate (1.00 g, using Intermediate 2 in dry DMSO (10 mL) 2.160 mmol), [2-(2,2-dimethylpropoxy)-3-methoxy)]benzaldehyde (527 mg, 2.316 mmol) and NaH (92 mg, 2.685 mmol) use in 2% ethyl acetate in chloroform, the residue was purified by column chromatography to give 1.416g of the desired compound as a white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) 1.08 (s, 9H), 3.56 ( s, 2H), 3.79 (s, 3H), 6.26 (s, 1H), 7.01-7.17 (m, 2H), 7.33 - 7.35 (m, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 8.11-8.16 (m, 1H); ESI-MS (m/z) 371.52 (M+H) ⁺ .

Step 2: 7-{( E )-2-[2-(2,2-Dimethylpropoxy)-3-methoxyphenyl]ethenyl}-6-iodo-5 H- [1, 3] Thiazolo[3,2- a ]pyrimidin-5-one: N -iodobutadiene imine (143 g, 6.327) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 Methyl) The title compound (275 mg, 5.816 mmol) was obtained as a crude material. Yellow solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) 1.08 (s, 9H), 3.58 (m, 2H), 3.81 (m, 3H), 7.07-7.12 (m, 2H), 7.30-7.33 (m, 2H), 7.41-7.48 (m, 1H), 7.94-7.96 (m,)H), 8.23-8.29 (m, 1H); ESI-MS (m/z) 497.21. (M+H) ⁺ .

Intermediate 9: 6-(4-Methoxyphenyl)-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Step 3 of Intermediate 3, in the presence of Pd[(C ₆ H ₅ ) ₃ P] ₄ (1.076 g, 0.931 mmol) and sodium carbonate (14.812 g, 139.071 mmol) in toluene The title compound was prepared by a coupling reaction of the intermediate 2 (6.8 g, 23.271 mmol) and 4-methoxyphenyl boronic acid (4.95 g, 32.490 mmol) g desired grayish solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.29 (s, 3H), 3.83 (s, 3H), 6.92-6.96 (m, 3H), 7.20-7.23 (m, 2H), 7.94 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 273.51 (M+H) ⁺ .

Intermediate 10: 6-(4-ethoxyphenyl)-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Step 1: 6-(4-Hydroxyphenyl)-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: HBr (35 ml) at room temperature Intermediate 9 (4.8 g, 17.726 mmol) was treated with EtOAc (35 mL). After the reaction was completed, the mixture was concentrated and evaporated with NaHCO _? The organic layer was washed with water combined with brine, dried over anhydrous Na ₂ SO _4, in chloroform using 5% CH ₃ OH to give 3.0g of the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6 δ 2.17 (s, 3H), 6.76-6.79 (m, 2H), 7.05-7.08 (m, 2H), 7.48 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 5.1 Hz, 1H) , ESI-MS (m/z) 259.50 (M+H) ⁺ .

Step 2: 6-(4-Ethoxyphenyl)-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: To the intermediate of step 1 (250 mg Ethyl bromide (0.147 g, 1.355 mmol) and NaH (0.053 g, 1.355 mmol) were added to a solution of <RTI ID=0.0>> After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water, brine, then dried over anhydrous Na ₂ SO _4, to give 300mg of the desired compound as a white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.34 (t, J = 6.6 Hz, 3H), 2.17 (s, 3H), 4.05 (q, J = 6.6 Hz, 2H), 6.93 - 6.96 (m, 2H), 7.17 - 7.20 (m, 2H), 7.50 ( d, J = 4.5 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H) ⁺ .

Intermediate 11: 7-Methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine- 5-ketone:

Add 1,1,1-trifluoro-2-iodoethane (1.131 g, 5.413 mmol) to a solution of the intermediate 1 (400 mg, 2.712 mmol) Then, Cs ₂ CO ₃ (2.63 g, 8.120 mmol) was added, and the reaction temperature was brought to 80 ° C by heating, and maintained for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the compound of 1% methanol in chloroform and purified by column chromatography to give the desired in ^{use; 1 H NMR (300 MHz,} CDCl 3) δ 2.17 (s, 3H ), 4.79 (q, J = 9.3 Hz, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 4.5 Hz, 1H).

Intermediate 12: 4-[4-(7-Methyl-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl)phenoxy]-butyronitrile :

At room temperature, was added 4-bromo-butyronitrile (280mg, 1.897mmol) in solution (10ml) DMF in the step 1 of Intermediate 10, Intermediate (350mg, 1.355mmol), followed by addition of K ₂ CO ₃ (560mg , 4.065 mmol), heating to bring the reaction temperature to 80 ° C for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and purified by column chromatography to afford 250mg of the desired compound as a white ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 2.17 (s, 3H), 3.80-3.85 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 4.5 Hz, 1H).

Intermediate 13: 6-(4-cyclopropylmethoxyphenyl)-7-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one:

At room temperature, cyclopropylmethylbromide to step 1 of Intermediate 10, Intermediate (500mg, 1.932mmol) in solution (5ml) DMF in (0.313g, 2.321mmol), followed by addition of Cs ₂ CO ₃ (1.88 g, 5.770 mmol), heating to bring the reaction temperature to 80 ° C, maintaining 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the compound of 1% methanol in chloroform and purified by column chromatography to give the desired in ^{use; 1 H NMR (300 MHz,} CDCl 3) δ 0.35-0.37 (m , 2H), 0.59-0.61 (m, 2H), 1.01-1.03 (m, 1H), 2.19 (s, 3H), 3.80-3.85 (m, 2H), 7.09-7.11 (m, 2H), 7.26-7.29 (m, 2H), 7.52 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 4.5 Hz, 1H); MS (m/z) 313.25 (M+H) ⁺ .

Intermediate 14: 6-[4-(Difluoromethoxy)phenyl]-7-methyl-5 H- [1,3]thiazolo[3,2- a ]-pyrimidin-5-one:

At room temperature, the intermediate step 10 of intermediate 1 (400mg, 1.548mmol) slowly treated in solution (15ml) DMF with _{Cs 2 CO 3 (1.513g, 4.645mmol} ). The reaction temperature was raised to 80 ° C, and a chlorodifluoromethane (ClCHF ₃ ) gas was introduced into the reaction mixture at this temperature until TLC indicated the reaction was completed. The reaction mixture was diluted with ethyl acetate, then washed with water and brine, then dried over anhydrous Na ₂ SO _4, and then purified using column chromatography to give the desired ^{compound; 1 H NMR (300 MHz,} CDCl 3) δ 2.20 (s , 3H), 7.18-7.22 (m, 2H), 7.25 (s, 1H), 7.37-7.40 (m, 2H), 7.55 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 303.45 (M+H) ⁺ .

Intermediate 15: 7-Methyl-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]-pyrimidin-5-one:

According to the method described in Step 3 of Intermediate 3, in the presence of Pd[(C ₆ H ₅ ) ₃ P] ₄ (1.5 g, 1.301 mmol) and sodium carbonate (20.6 g, 195.13 mol) in toluene In the mixture of ethanol and water, the title was prepared by the coupling reaction of the intermediate 2 (9.5 g, 37.312 mmol) of intermediate 4 with 4-(trifluoromethoxy)phenylboronic acid (9.5 g, 32.523 mmol). Compound 7.3 g of the desired pale yellow solid compound; IR (KBr) 3088, 1658, 1646, 1513, 1269, 1160 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.18 (s, 3H), 7.42-7.4 (m, 4H), 7.53 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 327.16 (M +H) ⁺ .

Intermediate 16:7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-iodo-2-methyl-5 H- [ 1,3]-thiazolo[3,2- a ]pyrimidin-5-one:

Step 1: 7- (chloromethyl) -2-methyl -5 H - [1,3] thiazolo [3,2- a] pyrimidin-5-one: Step 2 described in Intermediate 1 Method: This compound was synthesized from 2-amino-5-methylthiazole (5.0 g, 43.710 mmol) and ethyl chloroacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g). g desired black solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.43 (s, 3H), 4.58 (s, 2H), 6.39 (s, 1H), 7.87 (s, 1H); - MS (m/z) 215.37 (M+H) ⁺ .

Step 2: 2-Methyl-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-ylmethyl(triphenyl)-phosphonium chloride: according to the intermediate the method described in step 2 of 2, using in acetonitrile (70ml) of triphenylphosphine (2.688g, 10.249mmol) the processing of step 1 intermediate (2.0g, 9.317mmol), to give 3.5g of the desired ^compound; H NMR (300 MHz, DMSO- d ₆ ) δ 2.36 (s, 3H), 2.20-2.26 (m, 2H), 6.17 (s, 1H), 7.71-7.84 (m, 15H); ESI-MS (m/) z) 441.37 (M+H) ⁺ .

Step 3: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-2-methyl-5 H -[1,3]- Thiazolo[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 3 of Intermediate 2, using NaH (92mg, 2.306mmol) and 2-(cyclopropylmethoxy)-3- The methoxybenzaldehyde (475 mg, 2.306 mmol) was treated with a suspension of the intermediate from step 2 (1.0 g, 2.096 mmol) in dry DMSO (12 mL) to give a crude solid; using 2% in DCM ethyl acetate, the solid was purified by column chromatography to give 600mg of the desired compound of an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H) , 0.84-0.86(s,1H), 2.42(s,1H),3.74-3.76(m,2H),3.79(s,3H),6.25(s,1H),7.00-7.16(m,2H),7.31 -7.33 (m, 1H), 7.80 (s, 1H), 8.06-8.11 (m, 1H); ESI-MS (m/z) 369.24 (M+H) ⁺ .

Step 4: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-iodo-2-methyl-5 H- [1 , 3]thiazolo[3,2- a ]pyrimidin-5-one: a solution of the intermediate of step 3 (700 mg, 1.810 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 N -iodobutanediimine (641 mg, 2.841 mmol) was added and reacted to give 600 mg of the desired compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.31-0.33 (m, 2H), 0.53- 0.56 (m, 2H), 1.22 (brs, 1H), 2.43 (s, 3H), 3.76-3.81 (m, 2H), 3.81 (s, 3H), 7.05-7.11 (m, 2H), 7.25-7.28 ( m,1H), 7.51 (d, J = 15.6 Hz, 1H), 7.80 (s, 1H), 8.14 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 495.10 (M+H) ⁺ .

Intermediate 17: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-iodo-3-methyl-5 H- [ 1,3]-thiazolo[3,2- a ]pyrimidin-5-one:

Step 1: 7-(Chloromethyl)-3-methyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: according to the description in Step 1 of Intermediate 2 Method: This compound was synthesized from 2-amino-4-methylthiazole (5.0 g, 43.710 mmol) and ethyl chloroacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g). g desired black solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.67 (s, 3H), 4.53 (s, 2H), 6.27 (s, 1H), 7.05 (s, 1H); -MS (m/z) 215.39 (M+H) ⁺ .

Step 2: 3-methyl-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-ylmethyl(triphenyl)-phosphonium chloride: according to the middle the method described in step 2 of 2, useful in acetonitrile (70ml) of triphenylphosphine (2.688g, 10.249mmol) the processing of step 1 intermediate (2.0g, 9.317mmol), to give 4.0g of the desired ^compound; H NMR (300 MHz, DMSO- d ₆ ) δ 2.07 (s, 3H), 5.17-5.22 (m, 2H), 6.07 (s, 1H), 7.01 (m, 1H), 7.75-7.85 (m, 15H) ;ESI-MS (m/z) 441.46 (M+H) ⁺ .

Step 3: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-3-methyl-5 H -[1,3]- Thiazolo[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 3 of Intermediate 2, using NaH (92mg, 2.306mmol) and 2-(cyclopropylmethoxy)-3- The methoxybenzaldehyde (475 mg, 2.306 mmol) was treated with a suspension of the intermediate from step 2 (1.0 g, 2.096 mmol) in dry DMSO (12 mL) to give a crude solid; using 2% in DCM ethyl acetate, the solid was purified by column chromatography to give 260mg of the desired compound of an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H) , 1.18-1.22 (m, 1H), 2.66 (s, 3H), 3.73-3.76 (m, 2H), 3.79 (s, 3H), 6.15 (s, 1H), 6.97-7.13 (m, 4H), 7.30 -7.33 (m, 1H), 8.07 (d, J = 16.2 Hz 1H); ESI-MS (m/z) 369.26 (M+H) ⁺ .

Step 4: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-iodo-3-methyl-5 H- [1 , 3]thiazolo[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 4 of Intermediate 2, to Step 3 Intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) N -iodobutanediamine (641 mg, 2.841 mmol) was added to the solution and reacted to give 600 mg of the desired compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.32-0.35 (m, 2H) ), 0.52-0.58 (m, 2H), 1.18-1.22 (m, 1H), 2.64 (s, 3H), 3.76-3.78 (m, 2H), 7.01-7.14 (m, 3H), 7.25-7.28 (m , 1H), 7.49 (d, J = 15.6 Hz, 1H), 8.10-8.16 (d, J = 15.9 Hz, 1H); ESI-MS (m/z) 494.99 (M+H) ⁺ .

Intermediate 18: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-iodo-2,3-dimethyl-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Step 1: 7-(Chloromethyl)-2,3-dimethyl-5 H- [1,3]thiazolo[3,2- a ]pyrimidin-5-one: according to Step 1 in Intermediate 2 The compound was synthesized by the method described in the following: 2-amino-4,5-dimethylthiazole (5.0 g, 30.365 mmol) and ethyl chloroacetate (6.519 g, in polyphosphoric acid (40.0 g), 42.511 mmol), 10.0 g of the desired compound as a dark solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 ( s, 1H); ESI-MS (m/z) 229.60 (M+H) ⁺ .

Step 2: 2,3-Dimethyl-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-ylmethyl(triphenyl)-ruthenium chloride: The intermediate of Step 1 (2.0 g, 8.746 mmol) was treated with triphenylphosphine (2.520 g, 9.461 mmol) in EtOAc (50 mL) ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 2.22 (s, 3H), 2.53 (m, 3H), 5.19-5.24 (m, 2H), 6.07-6.08 (m, 1H), 7.68- 7.87 (m, 15H); ESI -MS (m / z) 455.35 (m + H) +.

Step 3: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-2,3-dimethyl-5 H- [1, 3] Thiazolo[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 3 of Intermediate 2, using NaH (89 mg, 2.240 mmol) and 2-(cyclopropylmethoxy)- 3-Methoxybenzaldehyde (462 mg, 2.240 mmol) was treated with a suspension of EtOAc (EtOAc, EtOAc (EtOAc) 2% ethyl acetate, the solid was purified by column chromatography to give 600mg of the desired compound of an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.32-0.35 (m, 2H), 0.54-0.58 (m, 2H), 1.15 - 1.21 (m, 1H), 2.26 (s, 3H), 2.59 (s, 3H), 3.73 - 3.75 (m, 2H), 3.79 (s, 3H), 6.13 (s, 1H), 6.99 - 7.00 (m, 3H), 7.29 - 7.31 (m, 1H), 8.03 (d, J = 16.2 Hz, 1H).

Step 4: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-iodo-2,3-dimethyl- 5H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 4 of Intermediate 2, to Step 3 Intermediate (500 mg, 1.568 mmol) in acetonitrile (10 mL) N -iodobutanediimide (494 mg, 2.195 mmol) was added to the solution and reacted to give 600 mg of the desired compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.32-0.34 (m, 2H) , 0.54-0.56 (m, 2H), 1.17- 1.20 (m, 1H), 2.29 (s, 3H), 2.58 (s, 3H), 3.75-3.77 (m, 2H), 3.80 (s, 3H), 7.04 -7.13 (m, 2H), 7.25-7.27 (m, 1H), 7.47 (d, J = 15.9 Hz, 1H), 8.12 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 509.01 (M+H) ⁺ .

Intermediate 19: 2-Chloro-7-{( E )-2-[2-(2,2-dimethylpropoxy)-3-methoxyphenyl]ethenyl}-6-iodo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Step 1: 2-Chloro-7-(chloromethyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one: Step 1: According to Step 1 in Intermediate 2 The method described was used to prepare this compound: 5-chloro-1,3-thiazol-2-amine hydrochloride (3.01 g, 17.482 mmol), polyphosphoric acid (81.0 g) and ethyl chloroacetate (4.03 g, 24.475mmol), to give 5.1g of the desired compound as a brown ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 4.55 (s, 2H), 6.45 (s, 1H), 8.31 (s, 1H); ESI- MS (m/z) 235.57 (M+H) ⁺ .

Step 2: 2-Chloro-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-ylmethyl(triphenyl)-phosphonium chloride: based on the intermediate Step 2 The intermediate (3.01 g, 12.761 mmol) was reacted with triphenylphosphine (3.68 g, 14.037 mmol) in acetonitrile (75 mL) to give 3.4 g of desired desired white. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 5.24 (d, J = 16.5 Hz, 2H), 6.23 (s, 1H), 7.43-7.86 (m, 15H), 8.28 (s, 1H) ;ESI-MS (m/z) 461.42 (M+H) ⁺ .

Step 3: 2-Chloro-7-{( E )-2-[2-(2,2-dimethylpropoxy)-3-methoxyphenyl]-5 H -[1,3]- Thiazolo[3,2- a ]pyrimidin-5-one: Step 2 intermediate (1.5 g, 3.015 mmol) with 2 in dry DMSO (20 mL) according to the procedure described in Step 3 of Intermediate 2 -(2,2-Dimethylpropoxy)-3-methoxybenzaldehyde (0.736 g, 3.317 mmol) and NaH (60% dispersion in mineral oil, 0.079 g, 3.317 mmol), Yield 5.5 g of the desired white solid compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.12 (s, 9H), 3.61 (s, 2H), 3.84 (s, 3H), 6.21 (s, 1H), 6.87 (d, J = 6.9 Hz, 1H), 6.90 (d, J = 15.0 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.80 (s) , </ RTI>^<RTIgt;

Step 4: 2-Chloro-7-{( E )-2-[2-(2,2-dimethylpropoxy)-3-methoxyphenyl]ethenyl}-6-iodo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

This compound was prepared according to the procedure described in Step 4 of Intermediate 2: using N -Iodobutanediamine (0.416 g, 1.852 mmol) in acetonitrile (10 mL) and Step 3 intermediate (0.501 g, 1. 234 mmol) gave 0.601 g of the desired compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.12 (s, 9H), 3.62 (s, 2H), 3.85 (s, 3H), 6.89 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 15.0 Hz, 1H), 7.79 (s, 1H), 8.35 (d, J = 15.0 Hz, 1H); ESI-MS (m/z) 405.56 (M+H) ⁺ .

Intermediate 20: 2-Chloro-6-iodo-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]thiazole And [3,2- a ]pyrimidin-5-one:

Step 1: 2-Chloro-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]thiazolo[3,2 - a ] pyrimidin-5-one: Step 2 intermediate (1.2 g, 2.412 mmol) of intermediate 19 was combined with 2-isoform in anhydrous DMSO (20 ml) according to the procedure described in Step 3 of Intermediate 2. Butoxy-3-methoxybenzaldehyde (546 mg, 2.412 mmol) and NaH (60% dispersion in mineral oil, 105 mg, 2.610 mmol) were reacted to yield 5.5 g of the desired white solid compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.03 (d, J = 6.6 Hz, 6H), 1.98-2.06 (m, 1H), 3.68 (d, J = 6.6 Hz, 2H), 3.79 (s, 3H), 6.30 (s, 1H), 6.98-7.16 (m, 3H), 7.30-7.33 (m, 1H), 8.05 (d, J = 16.2 Hz, 1H), 8.23 (s, 1H).

Step 2: 2-Chloro-6-iodo-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]-thiazole And [3,2- a ]pyrimidin-5-one: This compound was prepared according to the procedure described in Step 4 of Intermediate 2: using N -iodobutanediamine in acetonitrile (10 ml) (227 g , 1.012 mmol) and the above-mentioned step 1 intermediate (0.360 g, 0.928 mmol) afforded 0.61 g of the desired compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.04 (d, J = 6.6 Hz, 6H), 2.04 -2.11(m,1H),3.72(d,J=6.3 Hz,2H),3.82(s,3H),7.12-7.17(m,2H),7.29-7.31(m,1H),7.50(d,J =1 5.6 Hz, 1H), 8.15 (d, J = 15.3 Hz, 1H), 8.26 (s, 1H); ESI-MS (m/z) 517.10, 519.29 (M+H) ⁺ .

Intermediate 21: 6-iodo-7-{( E )-2-[3-(methoxy)-2-pivaloxyphenyl)-1-vinyl]-3-trifluoromethyl-5 H- 1,3-thiazolo-[3,2- a ]pyrimidin-5-one:

Step 1: 4-(Trifluoromethyl)-1,3-thiazol-2-amine: 3-bromo-1,1,1-trifluoroacetone (5.0 g, 26.184 mmol) and thiourea (2.0 g, A solution of 26.184 mmol) in ethanol was heated to 50-55 ° C for 2.0 h until TLC indicated the reaction was complete. The reaction mixture was concentrated and the residue was made basic with 5% NaOH. The mixture was then extracted with ethyl acetate, and then concentrated to give compound residue, and the residue was subjected to column purification to obtain desired ^{3.8g; 1 H NMR (300 MHz,} DMSO- d 6) δ 7.25 (s, 1H) , 7.43 (br s, 2H); ESI-MS (m/z) 169.37 (M+H) ⁺ .

Step 2: 7-(Chloromethyl)-3-(trifluoromethyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

This compound was synthesized according to the procedure described in Step 1 of Intermediate 2: ethyl chloroacetate (5.194 g, 31.558 mmol), 2-amino-4-trifluoroacetate in polyphosphoric acid (30.0 g) methylthiazole and step 1 of intermediate (3.70g, 22.541mmol), to give 4.0g of the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 2.28 (s, 3H), 2.60 (s, 3H) , 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 269.22 (M+H) ⁺ .

Step 3: 5-Oxo-3-trifluoromethyl-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-ylmethyl-(triphenyl)phosphonium chloride: according to The intermediate of step 2 (2.0 g, 7.472 mmol) was treated with triphenylphosphine (2.150 g, 8.219 mmol) in acetonitrile (75 mL). compound black ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 5.20-5.25 (m, 2H), 6.24 (s, 1H), 7.20 (s, 1H), 7.36 (br s, 3H), 7.74- 7.86 (m, 15H); ESf-MS (m/z) 495.15 (M+H) ⁺ .

Step 4: 7-{( E )-2-[3-(Methoxy)-2-pivaloxyphenyl)-1-vinyl]-3-trifluoromethyl-5 H -1,3 -thiazolo-[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 3 of Intermediate 2, using NaH (83 mg, 2.075 mmol) and 3-methoxy-2,2- Methylpropoxy-benzaldehyde (460 mg, 2.075 mmol) was treated with a suspension of the intermediate from step 3 (1.0 g, 1.86 mmol) in dry DMSO (10 mL) to give a crude solid. 10% ethyl acetate, the solid was purified by column chromatography to give 300mg of the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.08 (s, 9H), 3.56 (s, 2H), 3.79 (s, 3H), 6.13 (s, 1H), 7.02-7.18 (m, 3H), 7.32-7.35 (m, 1H), 8.15 (d, J = 15.6 Hz 1H), 8.25 (s, 1H); - MS (m/z) 439.11 (M+H) ⁺ .

Step 5: 6-Iodo-7-{( E )-2-[3-(methoxy)-2-pivaloxyphenyl)-1-vinyl]-3-trifluoro-methyl-5 H- 1,3-thiazolo-[3,2- a ]pyrimidin-5-one: according to the procedure described in Step 4 of Intermediate 2, to Intermediate 4 (270 mg, 0.615 mmol) in acetonitrile (10 ml) N -iodobutanediimide (193 mg, 0.862 mmol) was added to the solution and the reaction was carried out to give 225 mg of the desired compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.08 (s, 9H), 3.58 (s, 2H), 3.80 (s, 3H), 7.10-7.12 (m, 2H), 7.31 - 7.34 (m, 1H), 7.42 (d, J = 15.6 Hz, 1H), 8.24 - 8.29 (m, 2H); ESI-MS (m/z) 565.05 (M+H) ⁺ .

Intermediate 22: 4-(2-methyl-4-oxo- 4H -pyrimido[2,1- b ][1,3]benzothiazol-3-yl)benzonitrile:

Step 1: 2-Methyl- 4H -pyrimido[2,1- b ][1,3]benzothiazol-4-one: acetonitrile acetic acid according to the method described in Step 1 of Intermediate 3 A solution of ethyl ester (25.96 g, 0.199 mmol), acetic acid (150 ml) and 1,3-benzothiazol-2-amine (20 g, 0.133 mmol) was combined to give 9 g of the desired pale yellow solid product; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H).

Step 2: 3-iodo-2-methyl- 4H -pyrimido[2,1- b ][1,3]benzothiazol-4-one: according to the method described in Step 3 of Intermediate 1, The solution of the intermediate 1 (9 g, 41.613 mmol) in EtOAc (150 mL) was reacted with EtOAc (11 g, 20.803 mmol) and then reacted with iodine (6 g, 24.961 mmol) to give 9 g of pale yellow solid ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.15 (s, 3H), 7.54-7.60 (m, 2H), 8.00-8.07 (m, 1H), 8.84-8.90 (m, 1H).

Step 3: 4-(2-Methyl-4-oxo- 4H -pyrimido[2,1- b ][1,3]benzothiazol-3-yl)benzonitrile: according to intermediate 3 This compound was prepared by the method described in Step 3: in a mixture of toluene, ethanol and water, from Step 2 intermediate (800 mg, 2.331 mmol), 4-cyanophenylboronic acid (480 mg, 8.271 mmol), Pd[( C ₆ H ₅ ) ₃ P] ₄ (108 mg, 0.093 mmol) and Na ₂ CO ₃ (1.48 g, 14.023 mol) gave the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.49 (s, 3H), 7.53-7.59 (m, 4H), 7.91 (d, J = 7.8 Hz, 2H), 8.03-8.10 (m, 1H), 8.80-8.90 (m, 1H); ESI-MS (m) /z) 318.30(M+H) ⁺ .

Intermediate 23: 2-methyl-3-[4-(trifluoromethyl)phenyl]-4 H -pyrimido[2,1- b ][1,3]benzothiazol-4-one:

In the presence of Pd[(C ₆ H ₅ ) ₃ P] ₄ (270 mg, 0.233 mmol) and sodium carbonate (3.71 g, 35.07 mol), in a mixture of toluene, ethanol and water, 4-trifluoromethyl step phenylboronic acid (1.50g, 8.18mmol) of intermediate 2. intermediate 22 (2.0g, 5.845mmol) to prepare the title compound, to give 2.27g of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO - d ₆ ) δ 2.30 (s, 3H), 7.42-7.48 (m, 2H), 7.65-7.67 (m, 2H), 8.00-8.03 (m, 2H), 8.86-8.88 (m, 2H); MS (m/z) 361.32 (M+H) ⁺ .

Intermediate 24: 2-methyl-3-[4-(trifluoromethoxy)phenyl]-4 H -pyrimido[2,1- b ][1,3]benzothiazol-4-one:

In the presence of Pd[(C ₆ H ₅ ) ₃ P] ₄ (270 mg, 0.233 mmol) and sodium carbonate (3.11 g, 35.07 mol), in a mixture of toluene, ethanol and water, 4-trifluoromethyl step phenylboronic acid (1.684g, 8.183mmol) of intermediate 2. intermediate 22 (2.0g, 5.845mmol) the title compound was prepared, to give 1.5g of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO - d ₆ ) δ 2.02 (s, 3H), 7.41 - 7.59 (m, 3H), 7.53 - 7.56 (m, 3H), 8.03 - 8.07 (m, 1H), 8.84 - 8.87 (m, 1H); MS (m/z) 377.17 (M+H) ⁺ .

Intermediate 25: 2,10-Dimethyl-3-[4-(trifluoromethoxy)phenyl]pyrimido[1,2- a ]benzimidazole-4(10 H )-one:

Step 1:1-Methyl-1 H -benzimidazol-2-amine To a solution of 2-aminobenzimidazole (3.0 g, 0.0225 mol) in acetone (30 ml), KOH (6.32 g, 0.112 mol) Then, methyl iodide (3.51 g, 0.025 mol) was added and stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water, brine, and dried over anhydrous Na ₂ SO _4, to obtain the crude residue, the residue was purified by column to produce the desired product; ¹ H NMR ( 300 MHz, DMSO- d ₆ ) δ 3.47 (s, 3H), 6.34 (br s, 2H), 6.82-6.92 (m, 2H), 7.06-7.09 (m, 2H); ESI-MS (m/z) 148.49 (M+H) ⁺ .

Step 2: 2,10-Dimethylpyrimido[1,2- a ]benzimidazole-4(10 H )-one: The intermediate of step 1 (1.8 g, 0.0122 mol) was added to POCl ₃ (5.0 ml) It was treated with polyphosphoric acid (2 g), then treated with ethyl acetate ethyl acetate and stirred at 130 ° C for 3.0 h. The reaction mixture was neutralized with sodium bicarbonate, and the precipitated solid was filtered under vacuum, then purified by column to afford the desired compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.31 (s, 3H), 3.73 (s, 3H), 5.93 (s, 1H), 7.30-7.35 (m, 1H), 7.48-7.53 (m, 1H), 7.63-7.66 (s, 1H), 8.39-8.42 (s, 1H); - MS (m/z) 214.48 (M+H) ⁺ .

Step 3: 3-Iodo-2,10-dimethyl-pyrimido [1,2- a] benzimidazole--4 (10 H) - one: To a solution of Intermediate Step 2 (1.2g, 5.620mmol) in acetonitrile ( Ammonium cerium nitrate (1.53 g, 2.812 mmol) was added to the solution in 15 ml), followed by iodine (0.857 g, 3.325 mmol) and refluxed for 2.0 h. After the reaction was completed, the solvent was evaporated and the residue was dissolved in ethyl acetate. The combined organic layer was washed with water, saturated NaHSO ₃ solution, brine, dried and purified to give the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 2.61 (s, 3H), 3.75 (s, 3H), 7.39-7.42 (s, 1H), 7.52-7.58 (m, 1H), 7.68-7.70 (m, 1H), 8.38-8.41 (s, 1H); ESI-MS (m/z) 340.48 (M +H) ⁺ .

Step 4: 2,10-Dimethyl-3-[4-(trifluoromethoxy)phenyl]pyrimido[1,2- a ]benzimidazole-4(10 H )-one: according to the middle In the mixture of toluene (20 ml), ethanol (5 ml) and water (5 ml), Na ₂ CO ₃ (2.32 g), Pd[(C ₆ H ₅ ) ₃ P ₄ (0.161 g, 1.420 mmol), 4-trifluoromethoxyphenylboronic acid (0.864 g, 4.212 mmol) and a solution of the intermediate from step 3 (1.2 g, 3.512 mmol), to give the desired compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.24 (s, 3H), 3.78 (s, 3H), 7.33-7.46 (m, 4H), 7.52-7.57 (m, 1H), 7.68-7.71 (m) , 1H), 8.40-8.43 (s, 1H); ESI-MS (m/z) 374.62 (M+H) ⁺ .

Example

Examples 1-9 mentioned in Table 1 below were prepared according to the procedure described in Example 1, using the appropriate intermediates and the appropriate aldehydes.

Table 1: Details of the structure of Examples 1-9.

Example 1: 7-[( E )-2-(4-Chlorophenyl)vinyl]-6-phenyl-5 H -[1,3]thiazolo[3,2- a ]pyrimidine-5- ketone:

To a solution of the intermediate 1 (100 mg, 0.231 mmol) in toluene (20 ml) and ethanol (10 ml) was added phenyl boronic acid (33 mg, 0.276 mmol) and Pd[(C ₆ H ₅ ) ₃ P] ₄ ( 26 mg, 0.023 mmol), followed by the addition of sodium carbonate (Na ₂ CO ₃ ) (48 mg, 0.461 mmol) in water (10 ml). The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was cooled to room temperature. The residue obtained after evaporation was partitioned between ethyl acetate (500 ml) and water (100 ml). The organic layer was washed with brine (100ml), dried (Na ₂ SO ₄₎ and concentrated to give the crude product; used in 10% ethyl acetate in chloroform, purified by silica gel column chromatography of the crude product as a pale yellow solid generated 5g ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.19 (s, 3H), 6.85 (d, J = 4.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 3H), 7.77 (m, 4H), 7.88 (d, J = 7.8 Hz, 1H), 7.8.0 (d, J = 4.8 Hz, 1H); ESI-MS (m/z) 265.31 (MH) ^- .

Example 2: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]vinyl}-6-phenyl-5 H -[1,3] Thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (26 mg, 0.023 mmol) in toluene (5 ml) and ethanol (2 ml) and water (2 ml) sodium carbonate (48mg, 0.461mmol), produced from intermediate 2 (100mg, 0.231mmol) and phenylboronic acid (33mg, 0.276mmol) the crude product; purification by column chromatography the crude product was 15mg of the desired product; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.32 (d, J = 4.2 Hz, 2H), 0.57 (d, J = 7.2 Hz, 2H), 0.99-1.70 (m, 1H), 3.76-3.82 (m, 5H) , 6.78-6.82 (m, 3H), 6.91-6.98 (m, 3H), 7.36-7.43 (m, 4H), 7.93 (d, J = 6.5 Hz, 1H), 8.27 (d, J = 15.6 Hz, 1H ESI-MS (m/z) 431.33 (M+H) ⁺ .

Example 3: 7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-6-(6-fluoro-3-pyridyl )-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (9 mg, 0.008 mmol) in toluene (5 ml), ethanol (2 ml) and water (2 ml) Sodium carbonate (133 mg, 1.2 mmol), mpjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Desired product; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.28 (br s, 2H), 0.52-0.54 (m, 2H), 1.04-1.07 (m, 1H), 3.69-3.71 (m, 2H) ), 3.77 (s, 3H), 6.88 (d, J = 15.6 Hz, 1H), 7.00 (br s, 3H), 7.29-7.31 (m, 1H), 7.54 (br s, 1H), 7.97-8.00 ( m, 2H), 8.18-8.21 (m, 2H); ESI-MS (m/z) 450.28 (M+H) ⁺ .

Example 4: 6-[4-(Third butylphenyl)]-7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1- Vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (20 mg, 0.010 mmol) in toluene (10 ml), ethanol (5 ml) and water (4 ml) Sodium carbonate (265 mg, 2.49 mmol) was obtained from EtOAc (EtOAc: EtOAc (EtOAc) The desired off-white solid product; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.23-0.25 (m, 2H), 0.46-0.48 (m, 2H), 0.90-1.10 (m, 1H), 1.33 (s , 9H), 3.67 (d, J = 7.2 Hz, 2H), 3.76 (s, 3H), 6.87-6.89 (m, 1H), 6.96-7.01 (m, 3H), 7.25-7.28 (m, 2H), 7.46-7.49 (m, 2H), 7.96-7.98 (m, 2H), 8.09 (d,J = 16.2 Hz, 1H); ESI-MS (m/z) 487.51 (M+H) ⁺ .

Example 5: 1-{4-{7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-5-oxo- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}phenyl}-1-ethanone:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (24 mg, 0.020 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) Sodium carbonate (331 mg, 3.122 mmol) from EtOAc (EtOAc: EtOAc (EtOAc) The product is obtained as an off-white solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.24-0.26 (m, 2H), 0.47-0.49 (m, 2H), 0.9-1.10 (m, 1H), 2.63 (s, 3H), 3.68 (d, J = 7.5 Hz, 2H), 3.76 (s, 3H), 6.86-6.90 (m, 1H), 6.91-6.93 (m, 1H), 7.48-7.51 (m, 4H), 7.99 - 8.04 (m, 4H), 8.17 (d,J = 15.6 Hz, 1H); ESI-MS (m/z) 473.13 (M+H) ⁺ .

Example 6: 6-(4-Dimethylaminophenyl)-7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl]-1-vinyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1: Intermediate 2 (150 mg, 31 mmol), 4- N,N -dimethylaminophenylboronic acid (61 mg, 37 mmol) in a mixture of toluene, ethanol and water. , Pd[(C ₆ H ₅ ) ₃ P] ₄ (61 mg, 37 mmol) and sodium carbonate (206 mg, 1.91 mmol) yielded crude product: EtOAc (EtOAc) The product obtained 110 mg of the product; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.26-0.28 (m, 1H), 0.50 (d, J = 7.8 Hz, 2H), 1.06-1.08 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.88-6.90 (m, 1H), 6.97-7.04 (m, 3H), 7.14 (d, J = 5.1 Hz, 2H), 7.95 (d, J = 5.1 Hz) , 1H), 8.10 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 474.19 (M+H) ⁺ .

Example 7: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-hydroxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Intermediate 2 (500 mg, 1.040 mmol), 4-hydroxyphenylboronic acid (172 mg, 1.249 mmol), Pd[(C ₆ H ₅ ) ₃ P] ₄ (120 mg, 0.104 mmol) and cesium fluoride (506 mg, 3.331) The solution in mmol of dry THF was heated to reflux for 4.0 h. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water dried, washed with brine, dried over anhydrous Na ₂ SO _4, to give a crude residue; in CHCl ₃ using 1% CH ₃ OH The residue is purified to afford 271mg of the desired Yellow solid compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.26-0.28 (m, 2H), 0.48-0.54 (m, 2H), 1.03-1.07 (m, 1H), 3.67-3.70 (m, 2H), 3.76 (s, 3H), 6.81-6.92 (m, 3H), 6.97-7.03 (m, 3H), 7.10-7.13 (m, 2H), 7.47 (d, J = 4.5 Hz, 1H), 7.95 (d, J = 5.1 Hz, 1H), 8.10 (d, J = 15.6 Hz, 1H), 9.57 (s, 1H); ESI-MS (m/z) 447.20 (M+H) ⁺ .

Example 8: 7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-6-(3,5-difluorophenyl )-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Intermediate 3 (200 mg, 0.719 mmol), 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (205 mg, 1.078 mmol) and sodium ethoxide (98 mg, 1.438 mmol) in ethanol (20 ml) The solution was refluxed for 15 h. The reaction mixture was concentrated, EtOAc EtOAc m. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.29-0.33 (m, 2H), 0.57-0.59 (m, 2H), 1.20-1.30 (m, 1H), 3.79 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 6.80-6.86 (m, 2H), 6.90-7.23 (m, 6H), 7.93 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 15.3 Hz, 1H); ESI - MS (m/z) 467.31 (M+H) ⁺ .

Example 9: 4-{7-[( E )-2-(2-Butoxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3 Thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

The title compound was prepared according to the method described in Example 8: Intermediate 4 (350 mg, 1.304 mmol), (2-butoxy-3-methoxy)benzaldehyde (354 mg, 1.601) in ethanol (25 ml) mmol) and sodium ethoxide (176mg, 2.301mmol) to obtain a crude product; used in 1% acetone in chloroform, purified by silica gel column chromatography of the crude product as a light yellow solid product was 260 mg generating ^{a; 1 H NMR (300 MHz,} DMSO - d ₆ ) δ 0.92-0.99 (m, 3H), 1, 45-1.52 (m, 4H), 3.77 (s, 3H), 3.80-3.85 (m, 2H), 6.88 (d, J = 15.6 Hz, 1H), 6.95-7.01 (m, 3H), 7.52-7.57 (m, 3H), 7.92 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 8.10 (d, J) </ RTI></RTI></RTI></RTI></RTI>^<RTIgt;

Examples 10-22 mentioned in Table 2 below were prepared according to the procedure described in Example 9, using Intermediate 4 and a suitable aldehyde.

Example 10: 4-{7-[( E )-2-(3-methoxy-2-pentyloxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3 ]-thiazo[3,2- a ]pyrimidin-6-yl}benzonitrile:

Intermediate 4 (400 mg, 1.4 mmol), (3-methoxy-2-pentyloxy)benzaldehyde (498 mg, 2.22 mmol) in ethanol (25 ml) and according to the procedure described in Example 9 sodium ethoxide (190mg, 2.8mmol) was prepared the title compound as a light yellow solid generated 300mg of ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.90-1.00 (m, 3H), 1.25-1.45 (m, 4H) , 1.46-1.60 (m, 2H), 3.77 (s, 3H), 3.65-3.85 (m, 2H), 6.87 (d, J = 16.2 Hz, 1H), 6.96-7.00 (m, 3H), 7.54 - 7.57 (m, 3H), 7.93 (d, J = 7.5 Hz, 1H), 8.00-8.01 (m, 2H), 8.09 (d, J = 14.7 Hz, 1H); ESI-MS (m/z) 472.27 (M +H) ⁺ .

Example 11: 4-{7-[( E )-2-(2-isopentyloxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H- [1, 3] Thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (350 mg, 1.305 mmol) and (2-isopentyloxy-3-methoxy)benzaldehyde were obtained in the presence of sodium ethoxide (178 mg, 2.604 mmol). 436mg, 1.961mmo1) the title compound was prepared condensation, generating 256mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.94 (d, J = 6.3 Hz, 6H), 1.43 (d, J=5.7 Hz, 2H), 1.88 (br s, 1H), 3.77 (s, 3H), 3.85 (br s, 2H), 6.88 (d, J = 16.2 Hz, 1H), 6.91-7.00 (m, 3H) ), 7.53 - 7.58 (m, 3H), 7.92 - 8.04 (m, 3H), 8.09 (d, J = 15.0 Hz, 1H); ESI-MS (m/z) 472.30 (M+H) ⁺ .

Example 12: 4-{7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H- [1, 3] Thiazolo[3,2- a ]-pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (350 mg, 1.325 mmol) and 2-isobutoxy-3-methoxybenzaldehyde (409 mg, in the presence of sodium ethoxide (178 mg, 2.264 mmol) 1.961mmol) of the title compound was prepared by reacting, generating 270mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.85 (d, J = 3.9 Hz, 4H), 2.03 (d, J = 7.8 Hz, 3H), 3.77 (s, 3H), 3.83 (d, J = 6.3 Hz, 2H), 6.84 (d, J = 15.6 Hz, 1H), 6.95-7.00 (m, 3H), 7.50-7.58 ( m, 3H), 7.92-8.04 (m, 3H), 8.14 (d,J = 15.3 Hz, 1H); ESI-MS (m/z) 470.45 (M+H) ⁺ .

Example 13: 4-{7-[( E )-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-5-oxo-5 H- [1, 3] Thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

Intermediate 4 (400 mg, 1.496 mmol), 3-methoxy-2-pivaloxybenzaldehyde (465 mg, 2.094 mmol) and ethanol in ethanol (25 ml) according to the procedure described in Example 9. the title compound was prepared sodium (203mg, 2.992mmol), 290mg of the product generated as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.03 (s, 9H), 3.53 (s, 2H), 3.77 (s, 3H), 6.77 (d, J = 15.6 Hz, 1H), 6.99 (br s, 3H), 7.51-7.57 (m, 3H), 7.91-7.99 (m, 3H), 8.26 (d, J = 15.0 Hz, 1H); ESI-MS (m/z) 472.26 (M+H) ⁺ .

Example 14: 4-{7-[( E )-2-(3-methoxy-2-(2-methoxyethoxy)phenyl]-1-vinyl}-5-oxo- 5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (350 mg, 1.312 mmol) and 3-methoxy-2-(2-methoxyethoxy) in the presence of sodium ethoxide (178 mg, 2.624 mmol) yl) benzaldehyde the title compound was prepared by condensing (385mg, 1.833mmol) to afford 243mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.47-3.53 (m, 2H), 3.70 (s , 3H), 3.78 (s, 3H), 3.99-4.05 (m, 2H), 6.79 (d, J = 15.6 Hz, 1H), 6.93-7.01 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 15.9 Hz, 1H); ESI-MS (m/z) 460.50 (M+H) ⁺ .

Example 15: 4-{7-[( E )-2-(2-ethoxyethoxy-3-methoxyphenyl]-1-vinyl}-5-oxo-5 H- [ 1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (335 mg, 1.252 mmol) and 2-(2-ethoxyethoxy)-3-methoxy in the presence of sodium ethoxide (170 mg, 2.506 mmol) yl - benzaldehyde (339mg, 1.753mmol) condensation of the title compound was prepared, to produce 231mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.16 (t, J = 6.6 Hz, 3H) , 3.45-3.52 (m, 4H), 3.78 (s, 3H), 4.00-4.08 (m, 2H), 6.78 (d, J = 15.6 Hz, 1H), 6.94-7.01 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J = 7.8 Hz, 2H), 8.02 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 474.45 (M+H) ⁺ .

Example 16: 4-{7-[( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]-1-vinyl}-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

Intermediate 4 (180 mg, 0.673 mmol), 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (192 mg, 1.010) in ethanol (15 ml) according to the procedure described in Example 9. mmol) and sodium ethoxide (92mg, 1.346mmol) was prepared the title compound as a light yellow solid generated 135mg of ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25-0.27 (m, 2H), 0.49-0.51 (m , 2H), 0.90-1.10 (m, 1H), 3.68 (d, J = 7.8 Hz, 2H), 3.77 (s, 3H), 6.85 (d, J = 15.6 Hz, 1H), 6.96-7.00 (m, 3H), 7.51-7.57 (m, 3H), 7.92 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 5.1 Hz, 2H), 8.17 (d, J = 15.6 Hz, 1H); MS (m/z) 456.23 (M + H) ⁺ .

Example 17: 4-{7-[( E )-2-(2-cyclobutylmethoxy-3-methoxy)phenyl-1-vinyl]-5-oxo-5 H- [1, 3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, sodium ethoxide (176 mg, 2.604 mmol), intermediate 4 (350 mg, 1.304 mmol) and 2-cyclobutylmethoxy-3-methoxybenzene were obtained in ethanol (15 ml). carbaldehyde (374mg, 1.713mmol) the title compound was prepared a reaction occurs to produce 240mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.85 (d, J = 3.9 Hz, 4H), 2.03 ( d, J = 7.8 Hz, 3H), 3.77 (s, 3H), 3.83 (d, J = 6.3 Hz, 2H), 6.84 (d, J = 15.6 Hz, 1H), 6.95-7.00 (m, 3H), 7.50-7.58 (m, 3H), 7.92-8.04 (m, 3H), 8.14 (d,J = 15.3 Hz, 1H); ESI-MS (m/z) 470.45 (M+H) ⁺ .

Example 18: 4-{7-[( E )-2-(2-cyclopentyloxy-3-methoxy)phenyl-1-vinyl]-5-oxo-5 H- [1, 3] Thiazolo-[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (300 mg, 1.122 mmol) and 2-(cyclopentyloxy)-3-methoxybenzaldehyde (in the presence of sodium ethoxide (152 mg, 2.422 mmol)) Condensation of 310 mg, 1.683 mmol) to give the title compound to give 181 mg of desired desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.50-1.60 (m, 6H), 1.78-1.85 (m, 2H) ), 3.78 (s, 3H), 4.83-4.89 (m, 1H), 6.80 (d, J = 15.0 Hz, 1H), 6.89-6.99 (m, 3H), 7.51 - 7.57 (m, 3H), 7.93 ( d, J = 8.4 Hz, 2H), 8.00 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 485.18 (M+H) ⁺ .

Example 19: 4-{7-[( E )-2-(2-cyclohexylmethoxy-3-methoxy)phenyl-1-vinyl]-5-oxo-5 H -[1 , 3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

Intermediate 4 (325 mg, 1.212 mmol) and 2-(cyclohexylmethoxy)-3-methoxybenzaldehyde were obtained according to the procedure described in Example 9 in the presence of sodium ethoxide (165 mg, 2.484 mmol). the title compound is prepared by reacting, generating 256mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.08 (t, J = 7.2 Hz, 3H), 1.22-1.30 (m, 3H), 1.65-1.85 (m, 5H), 3.32-3.40 (m, 1H), 3.65 (d, J = 6.6 Hz, 1H), 3.76 (s, 3H), 6.81 (d, J = 15.6 Hz, 1H), 6.94 -7.00 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 495.37 (M+H) ⁺ .

Example 20: 4-{7-[( E )-2-[2-(3-Fluorobenzyloxy)-3-methoxyphenyl-1-vinyl]-5-oxo-5 H - [1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (350 mg, 1.09 mmol) and 2-(3-fluorobenzyloxy-3-methoxy)benzene in the presence of sodium ethoxide (178 mg, 2.618 mmol) carbaldehyde (477mg, 1.833mmol) condensation title compound was prepared in ethanol (15ml) is generated 241mg of the desired product as a pale yellow ^{solid; 1 H NMR (300MHz, DMSO-} d 6) δ 3.83 (s, 3H), 4.94 ( s, 2H), 6.76 (d, J = 16.2 Hz, 1H), 6.90-6.98 (m, 1H), 7.02-7.09 (m, 2H), 7.17-7.26 (m, 3H), 7.38-7.44 (m, 1H), 7.50-7.55 (m, 3H), 7.86 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 5.1 Hz, 1H), 8.09 (d, J = 15.6 Hz, 1H); MS (m/z) 526.15 (M+H) ⁺ .

Example 21: 4-{7-[( E )-2-{3-Methoxy-2-(2-pyridylmethoxy)phenyl]-1-vinyl]}-5-oxo- 5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

By intermediate 4 (400 mg, 1.496 mmol) with 3-methoxy-2-(pyridylmethoxy)benzaldehyde according to the procedure described in Example 9 in the presence of sodium ethoxide (200 mg, 2.939 mmol) (546mg, 2.244mmol) condensation title compound was prepared in ethanol (15ml) is generated 275mg of the desired product as a pale yellow ^{solid; IR (KBr) 2837,2226,1652,1478,1270 cm -1} ; 1 H NMR (300 MHz, DMSO- d ₆ ) δ 3.81 (s, 3H), 4.99 (s, 2H), 6.78 (d, J = 15.6 Hz, 1H), 6.97-7.06 (m, 3H), 7.30-7.36 (m, 1H) ), 7.45-7.59 (m, 4H), 7.80-7.88 (m, 3H), 8.00 (d, J = 5.9 Hz, 1H), 8.08 (d, J = 15.0 Hz, 1H), 8.49-8.55 (m, 1H); ESI-MS (m/z) 495.56 (M+H) ⁺ .

Example 22: 4-{7-[( E )-2-{2-(3-Cyanopropoxy)-3-(methoxyphenyl]-1-vinyl]}-5-oxo -5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 9, intermediate 4 (400 mg, 1.496 mmol) and 2-(3-cyanopropoxy)-3-methoxy in the presence of sodium ethoxide (203 mg, 2.990 mmol) benzaldehyde (492mg, 2.244mmol) the title compound was prepared in the condensation (15ml) in ethanol to produce 270mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.84-1.90 (m, 2H ), 2.68-2.78 (m, 2H), 3.79 (s, 3H), 3.89-3.95 (m, 2H), 6.84 (d, J = 15.6 Hz, 1H), 6.98-7.05 (m, 3H), 7.52 7.60 (m, 3H), 7.93 (d, J = 6.9 Hz, 2H), 8.00-8.08 (m, 2H); ESI-MS (m/z) 469.12 (M+H) ⁺ .

Example 23: 4-{5-oxo-7-[( E )-2-(3-pyridyl)-1-vinyl]-5 H -[1,3]thiazolo[3,2- a Pyrimidine-6-yl}-benzonitrile:

According to the method described in Example 9, in the presence of sodium ethoxide (178 mg, 2.618 mmol), intermediate 4 (350 mg, 1.309 mmol) and nicotinaldehyde (196 mg, 1.833 mmol) in ethanol (15 ml) the title compound was prepared in the condensation, generating 266mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 6.88 (d, J = 15.6 Hz, 1H), 7.30-7.38 (m, 1H) , 7.50-7.58 (m, 3H), 7.84-7.93 (m, 4H), 8.02 (d, J = 4.8 Hz, 1H), 8.47 (d, J = 3.9 Hz, 1H), 8.70 (s, 1H); ESI-MS (m/z) 357.32 (M+H) ⁺ .

Example 24: 7-[( E )-2-(2-cyclopropylmethoxy)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1 , 3]-thiazolo[3,2- a ]pyrimidin-5-one:

A solution of intermediate 5 (400 mg, 1.289 mmol), (2-cyclopropyl methoxy)benzaldehyde (356 mg, 2.025 mmol) and sodium ethoxide (183 mg, 2. The reaction mixture was concentrated and residue was extracted with ethyl acetate, washed with water and brine to afford crude solid: This solid was purified by column chromatography to afford 241mg of the desired compound of an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.12-0.20 (m, 2H), 0.27-0.32 (m, 2H), 0.78-0.83 (m, 1H), 3.74 (d, J = 6.9 Hz, 2H), 6.90-6.97 (m, 2H), 7.18 -7.26 (m, 2H), 7.39 (d, J = 6.9 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.5 Hz, 2H), 7.91-7.97 (m, 1H), 8.00 (d, J = 4.5 Hz, 1H); ESI-MS (m/z) 469.22 (M+H) ⁺ .

Examples 25-36 described in Table 3 were prepared from the intermediate 5 with the appropriate aldehyde in a single step using the methods described herein.

Example 25: 7-[( E )-2-(3-Methoxy-2-propoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Intermediate 5 (400 mg, 1.289 mmol) and 3-methoxy-2-propoxybenzaldehyde (375 mg, 1.933) in the presence of sodium ethoxide (175 mg, 2.478 mmol) according to the procedure described in Example 24 mmol) in ethanol (condensation title compound was prepared 15ml) was generated 310mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.93 (t, J = 6.6 Hz, 3H), 1.48 ( q, J=6.9 Hz, 2H), 3.77 (s, 5H), 6.93-7.00 (m, 4H), 7.52-7.59 (m, 3H), 7.82 (d, J = 7.8 Hz, 2H), 7.98-8.02 (m, 2H); ESI-MS (m/z) 495.35 (M+H) ⁺ .

Example 26: 7-[( E )-2-(2-Butoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, intermediate 5 (400 mg, 1.289 mmol) and 2-butoxy-3-methoxybenzaldehyde (400 mg, 1.922) in the presence of sodium ethoxide (175 mg, 2.579 mmol) mmol) in a condensation title compound was prepared (15ml) in ethanol, to give 271mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.95 (t, J = 6.3 Hz, 3H), 1.42- 1.48 (m, 4H), 3.77 (s, 3H), 3.79-3.85 (m, 2H), 6.91-7.01 (m, 4H), 7.52 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 501.18(M+H) ⁺ .

Example 27: 7-[( E )-2-(2-Isobutoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Intermediate 5 (400 mg, 1.289 mmol) and 2-isobutoxy-3-methoxybenzaldehyde (400 mg, in the presence of sodium ethoxide (175 mg, 2.478 mmol) according to the procedure described in Example 24 1.922mmol) condensation title compound was prepared in ethanol (15ml) is generated 285mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.93 (d, J = 3.6 Hz, 6H), 1.72(br s,1H),3.58(br s,2H),3.77(s,3H),6.91-7.00(m,4H),7.53-7.58(m,3H),7.78-7.84(m,2H), 8.00 (br s, 1H), 8.12 (d, J = 15.3 Hz, 1H); ESI-MS (m/z) 501.24 (M+H) ⁺ .

Example 28: 7-[( E )-2-(2-Isopentyloxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (163 mg, 2.418 mmol), Intermediate 5 (400 mg, 1.289 mmol) and 2-isopentyloxy-3-methoxybenzaldehyde (400 mg, 1.812 mmol) of the title compound is synthesized by condensation in ethanol (15ml) is generated 308mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.92 (d, J = 6.3 Hz, 6H), 1.42 (q, J = 6.3 Hz, 2H), 1.80-1.90 (m, 1H), 3.77 (s, 3H), 3.84 (t, J = 6.3 Hz, 2H), 6.90-7.00 (m, 4H), 7.51 ( d, J = 4.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 515.52 (M+H) ⁺ .

Example 29: 7-[( E )-2-(3-Methoxy-2-pivalyloxy)phenyl-1-vinyl]-6-(4-(trifluoromethyl)phenyl) -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (183 mg, 2.70 mmol), intermediate 5 (400 mg, 1.350 mmol) and 3-methoxy-2-pivaloxybenzaldehyde (419 mg, 1.890mmol) in ethanol analogously title (15ml) of the compound, to generate the desired product ^{290mg; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.00 (s, 9H), 3.52 (s, 2H), 3.77 (s, 3H), 6.82 (d, J = 15.9 Hz, 1H), 6.95-6.99 (m, 3H), 7.50 (d, J = 3.9 Hz 1H), 7.57-7.59 (m, 2H), 7.81 - 7.83 (m, 2H), 8.00 (d, J = 3.9 Hz, 1H), 8.25 (m, J = 15.0 Hz, 1H); ESI-MS (m/z) 515.45 (M+H) ⁺ .

Example 30: 3-{2-methoxy-6-{[( E )-2-{5-oxo-6-[4-(trifluoromethyl)phenyl]-5 H -[1, 3] Thiazolo[3,2- a ]pyrimidin-7-yl}-1-vinyl]phenoxy)propyl cyanide:

According to the method described in Example 24, in the presence of sodium ethoxide (152 mg, 2.247 mmol), Intermediate 5 (330 mg, 1.114 mmol) and 4-(2-carbamido-6-methoxyphenoxy) ) butyronitrile (366mg, 1.671mmol) the title compound was prepared in the condensation (15ml) in ethanol, 222mg generating a desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ1.82 (t, J =6.0 Hz, 2H), 2.67 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.85-3.91 (m, 2H), 6.86-6.91 (m, 2H), 6.96-7.02 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 2H), 8.03 - 8.08 (m, 2H); MS (m/z) 512.18 (M+H) ⁺ .

Example 31: {7-[( E )-2-(2-methoxyethoxy-3-methoxy)phenyl}vinyl]-6-[4-(trifluoromethyl)phenyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (175 mg, 2.573 mmol), Intermediate 5 (400 mg, 1.281 mmol) and (2-methoxyethoxy)-3-methoxy) benzaldehyde (406mg, 1.932mmol) the title compound was prepared in a condensation (15ml) in ethanol, to give 107mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ3.46-3.52 (m, 3H) , 3.60-3.70 (m, 2H), 3.80-3.89 (m, 3H), 4.10-4.20 (m, 2H), 6.86-6.95 (m, 5H), 7.49-7.56 (m, 2H), 7.65-7.71 ( m, 2H), 7.90-7.97 (m, 1H), 8.30-8.40 (m, 1H); ESI-MS (m/z) 503.43 (M+H) ⁺ .

Example 32: {7-[( E )-2-(2-ethoxyethoxy)-3-methoxy)phenyl-1-vinyl]-6-[4-(trifluoromethyl) Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, intermediate 5 (350 mg, 1.072 mmol) and (2-ethoxyethoxy)-3-methoxybenzene in the presence of sodium ethoxide (146 mg, 2.147 mmol) carbaldehyde (372mg, 1.501mmol) the title compound was prepared in the condensation (15ml) in ethanol provided 261mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ1.15 (t, J = 6.6 Hz,3H),3.44-3.53(m,4H),3.77(s,3H),4.00-4.06(m,2H),6.79(d,J=15.0 Hz,1H),6.88(d,J=5.1 Hz , 1H), 6.99 (d, J = 4.5 Hz, 2H), 7.52 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H ), 8.01 (d, J = 5.1 Hz, 1H), 8.19 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 515.80 (M+H) ⁺ .

Example 33: {7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl]-1-vinyl]-6-[4-(trifluoromethyl) Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, intermediate 5 (210 mg, 0.670 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (in the presence of sodium ethoxide (91 mg, 1.310 mmol) 207mg, 1.00mmol) in the title compound was prepared by condensing (15ml) in ethanol, to produce 106mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.23-0.25 (m, 2H), 0.46 -0.49 (m, 2H), 3.65-3.68 (m, 2H), 3.76 (s, 3H), 6.88-6.98 (m, 4H), 7.51-7.59 (m, 3H), 7.80-7.83 (m, 2H) , 7.99-8.01 (m, 1H), 8.16 (d, J = 16.2 Hz, 1H); ESI-MS (m/z) 499.36 (M+H) ⁺ .

Example 34: 7-[( E )-2-(2-Cyclobutylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (163 mg, 2.411 mmol), Intermediate 5 (400 mg, 1.289 mmol) and 2-cyclobutylmethoxy-3-methoxybenzaldehyde (368 mg, 1.603mmol) in ethanol analogously title (15ml) of the compound, to generate 310mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.80-1.86 (m, 5H), 1.98-2.04 ( m, 2H), 3.77 (s, 3H), 3.82 (d, J = 6.9 Hz, 2H), 6.87-7.00 (m, 4H), 7.51 (d, J = 7.5 Hz, 1H), 7.59 (d, J) = 7.8 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 15.6 Hz, 1H); ESI-MS (m/z ) 513.30 (M+H) ⁺ .

Example 35: 7-[( E )-2-(2-Cyclopentyloxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (163 mg, 2.411 mmol), Intermediate 5 (400 mg, 1.289 mmol) and 2-cyclopentyloxy-3-methoxybenzaldehyde (398 mg, 1.813mmol) the title compound was prepared in the condensation (15ml) in ethanol provided 296mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.50-1.60 (m, 6H), 1.74-1.81 ( m, 2H), 3.77 (s, 3H), 4.83 (s, 1H), 6.85-6.99 (m, 4H), 7.51 (d, J = 5.1 Hz, 1H), 7.58 (d, j = 8.1 Hz, 2H ), 7.83 (d, J = 7.2 Hz, 2H), 8.00 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 529.30 (M+ H) ⁺ .

Example 36: 7-[( E )-2-{3-Methoxy-2-(pyridin-2-ylmethoxy)phenylvinyl]-6-[4-(trifluoromethyl)benzene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (153 mg, 2.207 mmol), Intermediate 5 (350 mg, 1.127 mmol) and 3-methoxy-2-(pyridin-2-ylmethoxy) ) benzaldehyde (411mg, 1.692mmol) the title compound is synthesized by condensation in ethanol (20ml) is generated 289mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.81 (s, 3H), 5.00 (s, 2H), 6.79 (d, J = 16.2 Hz, 1H), 6.90-6.98 (m, 1H), 7.05 (d, J = 4.5 Hz, 2H), 7.30-7.36 (m, 1H), 7.46 -7.60 (m, 4H), 7.72-7.84 (m, 3H), 7.99-8.04 (m, 1H), 8.10 (d, J = 15.6 Hz, 1H), 8.48-8.56 (m, 1H); ESI-MS (m/z) 512.18(M+H) ⁺ .

Example 37: 7-[( E )-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)- Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (183 mg, 2.701 mmol), intermediate 5 (400 mg, 1.350 mmol) and 3-cyclopropylmethoxy-4-methoxybenzaldehyde ( 417mg, 2.025mmol) the title compound is synthesized by condensation in ethanol (20ml) is generated 289mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.23-0.30 (m, 2H), 0.50- 0.58 (m, 2H), 1.12-1.18 (m, 1H), 3.72-3.80 (m, 5H), 6.60 (d, J = 15.6 Hz, 1H), 6.94-7.00 (m, 3H), 7.48-7.53 ( m,1H), 7.58-7.64 (m, 2H), 7.78-7.84 (m, 3H), 7.98-8.05 (m, 1H); ESI-MS (m/z) 499.12 (M+H) ⁺ .

Example 38: 7-[( E )-2-(4-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)- Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, intermediate 5 (400 mg, 1.289 mmol) and 4-cyclopropylmethoxy-3-methoxybenzaldehyde (in the presence of sodium ethoxide (163 mg, 2.418 mmol)) 345mg, 1.602mmol) the title compound is synthesized by condensation in ethanol (20ml) is generated 297mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.35 (d, J = 4.2 Hz, 2H) , 0.64 (d, J = 7.8 Hz, 2H), 1.30 - 1.38 (m, 1H), 3.83 (s, 3H), 3.84 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 15.6 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.85-6.92 (m, 1H), 6.94-7.00 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 15.0 Hz, 1H), 7.95 (d, J = 5.1 Hz, 1H); ESI-MS (m/z) 499.32 (M+H) ⁺ .

Example 39: 7-[( E )-2-Pyridin-3-ylvinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3, 2- a ] pyrimidine-5-one:

Intermediate 5 (400 mg, 1.289 mmol) and pyridine-3-carbaldehyde (200 mg, 1.867 mmol) in ethanol (20 ml), EtOAc (EtOAc) Condensation of the title compound to give 267 mg of the desired product as a pale yellow solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 6.91 (d, J = 15.6 Hz, 1H), 7.31 - 7.38 (m, 1H), 7.55-7.61 (m, 3H), 7.80-7.88 (m, 4H), 8.00-8.06 (m, 1H), 8.41-8.49 (m, 1H), 8.65-8.72 (m, 1H); ESI-MS (m) /z) 400.25(M+H) ⁺ .

Example 40: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[3-(trifluoromethyl)benzene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (76 mg, 1.118 mmol), intermediate 6 (175 mg, 0.561 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde ( 150mg, 0.783mmol) the title compound was prepared in the condensation (10ml) in ethanol provided 115mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.24 (d, J = 4.2 Hz, 2H) , 0.48 (d, J = 5.7 Hz, 2H), 0.93-0.99 (m, 1H), 3.67 (d, J = 6.6 Hz, 2H), 3.77 (s, 3H), 6.85-7.01 (m, 4H), 7.53 (d, J = 4.8 Hz, 1H), 7.66-7.76 (m, 4H), 8.00 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 15.3 Hz, 1H); ESI-MS (m) /z) 499.13(M+H) ⁺ .

Example 41: 6-(4-Dimethylaminophenyl)-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)-1-vinyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the procedure described in Example 1 in a mixture of toluene, ethanol and water from sodium carbonate (131 mg, 1.244 mmol), intermediate 7 (100 mg, 0.207 mmol), 4- N, N - Methylaminophenylboronic acid (47 mg, 0.290 mmol) and Pd[(C ₆ H ₅ ) ₃ P] ₄ (10 mg, 0.009 mmol) afforded crude product: using 10% ethyl acetate in chloroform. the crude product was purified by chromatography, 75mg of the resulting ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.98 (d, J = 6.9 Hz, 6H), 1.85-1.89 (m, 1H), 2.95 (s, 6H ), 3.62 (d, J = 6.3 Hz, 2H), 3.77 (s, 3H), 6.77 (d, J = 9.0 Hz, 2H), 6.82-6.92 (m, 1H), 6.98-7.04 (m, 3H) , 7.15 (d, J = 9.0 Hz, 1H), 7, 45 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 15.6 Hz, 1H) ; ESI-MS (m/z) 476.46 (M+H) ⁺ .

Example 42: 6-(4-Dimethylaminophenyl)-7-[( E )-2-(3-methoxy-2-pivalyloxy)phenyl-1-vinyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the procedure described in Example 1 in a mixture of toluene, ethanol and water from sodium carbonate (133 mg, 1.244 mmol), Intermediate 8 (100 mg, 0.207 mmol), 4- N, N - Methylaminophenylboronic acid (36 mg, 0.221 mmol) and Pd[(C ₆ H ₅ ) ₃ P] ₄ (9 mg, 0.008 mmol) afforded crude product: using 50% ethyl acetate in DCM the crude product was purified by column chromatography, 79mg of the resulting ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.04 (s, 9H), 2.96 (s, 6H), 3.53 (s, 2H), 3.77 (s, 3H ), 6.82 (s, 1H), 6.87-6.89 (m, 2H), 6.90-6.98 (m, 3H), 7.14 - 7.17 (m, 2H), 7.44 (d, J = 4.8 Hz, 1H), 7.94 ( d, J = 4.2 Hz, 1H), 8.16-8.21 (m, 1H); ESI-MS (m/z) 490.43 (M+H) ⁺ .

Example 43: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-methoxy-phenyl) -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, intermediate 9 (350 mg, 1.283 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (in the presence of sodium ethoxide (174 mg, 2.570 mmol) 371mg, 1.799mmol) the title compound was prepared in the condensation (10ml) in ethanol, to give 255mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25-0.27 (m, 2H), 0.49 -0.51 (m, 2H), 1.03-1.05 (m, 1H), 3.67-3.70 (m, 2H), 3.77-3.81 (m, 3H), 6.89-6.91 (m, 2H), 6.98-7.02 (m, 4H), 7.23-7.26 (m, 2H), 7.47-7.49 (m, 1H), 7.96-8.10 (m, 1H), 8.10-8.15 (m, 1H); ESI-MS (m/z) 461.39 (M +H) ⁺ .

Example 44: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-ethoxyphenyl)- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, intermediate 10 (300 mg, 1.047 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (in the presence of sodium ethoxide (142 mg, 2.090 mmol)) 302mg, 1.466mmol) the title compound was prepared in the condensation (10ml) in ethanol, to give 200mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25-0.27 (m, 2H), 0.49 -0.51 (m, 2H), 1.03-1.05 (m, 1H), 3.67-3.70 (m, 2H), 3.77-3.81 (m, 3H), 6.89-6.91 (m, 2H), 6.98-7.02 (m, 4H), 7.23-7.26 (m, 2H), 7.47-7.49 (m, 1H), 7.96-8.10 (m, 1H), 8.10-8.15 (m, 1H); ESI-MS (m/z) 461.39 (M +H) ⁺ .

Example 45: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-(2,2,2- Trifluoroethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (129 mg, 1.90 mmol), intermediate 11 (325 mg, 0.95 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde ( 255mg, 1.20mmol) in ethanol analogously title (25ml) of the compound, to generate the desired product ^{235mg; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.27 (br s, 2H), 0.51 (br s, 2H), 1.04-1.06 (m, 1H), 3.68-3.70 (m, 2H), 3.77 (m, 3H), 4.81-4.83 (m, 2H), 6.89-6.98 (m, 4H), 7.13-7.15 ( m, 2H), 7.27-7.29 (m, 2H), 7.49 (br s, 1H), 7.98 (br s, 1H), 8.14 (d, J = 16.2 Hz, 1H); ESI-MS (m/z) 529.23 (M+H) ⁺ .

Example 46: 3-4-{7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-5 H -[1,3 Thiazolo-[3,2- a ]pyrimidin-6-yl}phenoxy)propyl cyanide:

The intermediate 12 (200 mg, 0.614 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (27 mg, 0.676) were obtained according to the procedure of Example 24 in the presence of sodium hydride (16 mg, 0.676 mmol). mmol) of the title compound is synthesized by condensation to produce 106mg of the desired ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25-0.27 (m, 2H), 0.49-0.51 (m, 2H), 1.02-1.06 ( m,1H), 2.04-2.06 (m, 2H), 2.66-2.71 (m, 2H), 3.67-3.69 (m, 2H), 3.76 (s, 3H), 4.07-4.08 (m, 2H), 6.80- 6.91 (m, 2H), 6.96-7.03 (m, 4H), 7.23-7.26 (m, 2H), 7.47-7.49 (m, 1H), 7.96-7.98 (m, 1H), 8.12 (d, J = 15.9) Hz, 1H); ESI-MS (m/z) 514.24 (M+H) ⁺ .

Example 47: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-cyclo-propylmethoxy) Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

By intermediate method 13 (475 mg, 1.5 mmol) and (2-cyclopropylmethoxy-3-methoxy)benzaldehyde (407 mg) in the presence of sodium ethoxide (204 mg, 3.0 mmol) , 1.9 mmol) in ethanol analogously title (25ml) of the compound, to generate the desired product ^{320mg; 1 H NMR (300 MHz} , DMSO- d 6) δ 0.27-0.35 (m, 4H), 0.50-0.59 (m , 4H), 1.05 (br s, 1H), 1.25 (br s, 1H), 3.69-3.85 (m, 7H), 6.8-6.99 (m, 6H), 7.22 (br s, 2H), 7.49 (br s , 1H), 7.97 (br s, 1H), 8.05-8.15 (m, 1H); ESI-MS (m/z) 501.30 (M+H) ⁺ .

Example 48: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-difluoromethoxyphenyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Intermediate 14 (250 mg, 0.811 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (234 mg, 1.136) in the presence of sodium ethoxide (110 mg, 1.623 mmol) Condensation of the title compound to give 158 mg of the desired product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.26-0.28 (m, 2H), 0.49-0.51 (m, 2H), 1.02-1.04 ( m,1H), 3.69 (m, 2H), 3.77 (s, 3H), 6.93-7.08 (m, 4H), 7.27-7.57 (m, 6H), 7.99 (brs, 1H), 8.15 (d, J = 16.2 Hz, 1H); ESI-MS (m/z) 495.28 (M+H) ⁺ .

Example 49: 7-[( E )-2-(2-cyclopropylmethoxy-3-fluorophenyl)-1-vinyl]-6-[4-(trifluoromethoxy)-benzene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Intermediate 15 (350 mg, 1.071 mmol) and 2-cyclopropylmethoxy-3-fluorobenzaldehyde (291 mg, in the presence of sodium ethoxide (146 mg, 2.147 mmol) according to the procedure described in Example 24 1.501mmol) in ethanol analogously title (15ml) of the compound, to generate 241mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.23 (d, J = 4.8 Hz, 2H), 0.48 (d, J = 6.6 Hz, 2H), 0.95-1.05 (m, 1H), 3.77 (d, J = 6.9 Hz, 2H), 7.00-7.09 (m, 2H), 7.15-7.23 (m, 2H) , 7.42-7.50 (m, 4H), 7.53 (d, J = 4.8 Hz, 1H), 7.98-8.08 (m, 2H); ESI-MS (m/z) 503.55 (M+H) ⁺ .

Example 50: 7-[( E )-2-{2-Isopentyloxy-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)phenyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (146 mg, 2.147 mmol), intermediate 15 (350 mg, 1.071 mmol) with 2-isopentyloxy-3-methoxybenzaldehyde ( 334mg, 1.501mmol) the title compound was prepared in the condensation (15ml) in ethanol, to give 280mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.93 (d, J = 6.3 Hz, 6H ), 1.45 (q, J = 6.6 Hz, 2H), 1.85-1.91 (m, 1H), 3.77 (s, 3H), 3.86 (t, J = 6.6 Hz, 2H), 6.86-6.94 (m, 2H) , 7.00-7.06 (m, 2H), 7.46-7.51 (m, 5H), 7.99 (d, J = 4.8 Hz, 1H), 8.07 (d, J = 15.6 Hz, 1H); ESI-MS (m/z ) 531.20(M+H) ⁺ .

The examples 51-74 described in Table 4 were prepared in a single step from Intermediate 15 with the appropriate aldehyde using a procedure analogous to Example 24.

Example 51: 7-[( E )-2-(2-Isobutoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The intermediate 15 (350 mg, 1.071 mmol) and 2-isobutoxy-3-methoxybenzaldehyde (312 mg, 1.516) were obtained according to the method of Example 24 in the presence of sodium ethoxide (146 mg, 2.147 mmol). mmol) of the title compound is synthesized by condensation in ethanol (15ml) is generated 187mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.90-0.99 (m, 6H), 1.80-1.86 ( m,1H), 3.58-3.65 (m, 2H), 3.77 (s, 3H), 6.85-6.93 (m, 2H), 6.99-7.06 (m, 2H), 7.40-7.50 (m, 5H), 7.96- 8.02 (m, 1H), 8.09-8.14 (m, 1H); ESI-MS (m/z) 517.18 (M+H) ⁺ .

Example 52: 7-[( E )-2-{3-Methoxy-2-pivalyloxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)phenyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (163 mg, 2.40 mmol), intermediate 15 (400 mg, 1.225 mmol) and 3-methoxy-2-pivaloxybenzaldehyde ( 353mg, 1.50mmol) in the title compound was prepared by condensing (15ml) in ethanol, to give 320mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.01 (s, 9H), 3.52 (s , 2H), 3.77 (s, 3H), 6.82 (d, J = 16.2 Hz, 1H), 6.92-6.94 (m, 1H), 6.99 (s, 2H), 7.48 (m, 5H), 7.98 (d, J = 5.1 Hz, 1H), 8.22 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 531.35 (M+H) ⁺ .

Example 53: 7-[( E )-2-{2-(2-ethoxyethoxy)-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoro Methoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method of Example 24, in the presence of sodium ethoxide (166 mg, 2.471 mmol), Intermediate 15 (400 mg, 1.225 mmol) and [2-(2-ethoxyethoxy)-3-methoxy] The title compound was synthesized by condensation of benzaldehyde (384 mg, 1.716 mmol) in EtOAc (15 mL) to yield 291 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.15 (t, J = 7.2 Hz, 3H), 3.45-3.51 (m, 4H), 3.78 (s, 3H), 4.00-4.08 (m, 2H), 6.80 (d, J = 15.6 Hz, 1H), 6.82-6.89 (m, 1H) , 6.99 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 4.2 Hz, 2H), 7.40-7.48 (m, 4H), 7.51 (d, J = 6.3 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 8.17 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 533.25 (M+H) ⁺ .

Example 54: 7-[( E )-2-(3-Methoxy-2-propoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (176 mg, 2.301 mmol), intermediate 15 (400 mg, 1.225 mmol) and 3-methoxy-2-propoxybenzaldehyde (333 mg) Condensation in ethanol (25 ml) to give the title compound to give 295 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.94 (t, J = 7.2 Hz, 3H) , 1.53 (q, J = 6.9 Hz, 2H), 3.31 (s, 1H), 3.77 (s, 3H), 3.80 (s, 1H), 6.91-6.99 (m, 4H), 7.40-7.46 (m, 4H) ), 7.50 (d, J = 4.8 Hz, 1H), 7.95-8.07 (m, 2H); ESI-MS (m/z) 503.51 (M+H) ⁺ .

Example 55: 7-[( E )-2-(3-Methoxy-2-pentyloxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The intermediate 15 (350 mg, 1.071 mmol) and 3-methoxy-2-pentyloxybenzaldehyde (333 mg, 1.501 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol). The title compound was synthesized by condensation in ethanol (15 ml) to give 261 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.91 (t, J = 6.6 Hz, 3H), 1.33 1.42 (m, 4H), 1.50-1.58 (m, 2H), 3.77 (s, 3H), 3.83 (t, J = 6.3 Hz, 2H), 6.85-6.90 (m, 2H), 6.96-7.02 (m, 2H), 7.40-7.47 (m, 4H), 7.51-7.90 (m, 1H), 7.95-8.02 (m, 1H), 8.06-8.12 (m, 1H); ESI-MS (m/z) 531.26 (M +H) ⁺ .

Example 56: 4-{7-[( E )-2-{2-(4-Fluorobutoxy)-3-methoxyphenyl}-1-vinyl]-6-[4-(three Fluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The intermediate 15 (400 mg, 1.225 mmol) and [2-(4-fluorobutoxy)-3-methoxy]benzaldehyde were obtained according to the method of Example 24 in the presence of sodium ethoxide (166 mg, 2.471 mmol). (384mg, 1.716mmol) condensation title compound was prepared in ethanol (25ml) is generated 321mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.60-1.67 (m, 2H), 1.79-1.88 (m, 2H), 3.77 (s, 3H), 3.86 (t, J = 6.0 Hz, 2H), 4.42 (t, J = 5.4 Hz, 1H), 4.58 (t, J = 6.0 Hz, 1H) ), 6.85-6.91 (m, 2H), 6.99-7.05 (m, 2H), 7.40-7.48 (m, 4H), 7.51 (d, J = 4.8 Hz, 1H), 7.95-8.02 (m, 1H), 8.06-8.12 (m, 2H); ESI-MS (m/z) 536.00 (M+H) ⁺ .

Example 57: 7-[( E )-2-(2-Butoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl] -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (166 mg, 2.457 mmol), Intermediate 15 (400 mg, 1.225 mmol) and 2-butoxy-3-methoxybenzaldehyde (337 mg, 1.716) mmol) of the title compound is synthesized by condensation in ethanol (25 ml) is generated 281mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.94 (t, J = 6.9 Hz, 3H), 1.40-1.52 (m, 4H), 3.77 (s, 3H), 3.80-3.90 (m, 2H), 6.80-6.90 (m, 2H), 6.98-7.05 (m, 2H), 7.40-7.46 (m, 4H) ), 7.50 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 517.15 (M+ H) ⁺ .

Example 58: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-methoxyphenyl}-1-vinyl]-6-(4-trifluoromethoxy Phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Sodium ethoxide (154 mg, 2.264 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (327 mg, 1.583 mmol) in ethanol (15 ml) were obtained according to the procedure described in Example 24 intermediate] 5 (370mg, 1.132mmol) the title compound was prepared by condensation, to give 276mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} CDCl 3) δ 0.30-0.34 (m, 2H), 0.54-0.60 (m , 2H), 1.17.14.24 (m, 1H), 3.79 (d, J = 7.2 Hz, 2H), 3.84 (s, 3H), 6.84-6.87 (m, 1H), 6.96-7.00 (m, 4H), 7.31 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 15.6 Hz, 1H); ESI- MS (m/z) 515.18 (M+H) ⁺ .

Example 59: 7-{( E )-(2,3-Dihydroxy)phenyl}-1-vinyl]-6-(4-trifluoromethoxy-phenyl)-5 H -[1, 3] Thiazolo[3,2- a ]pyrimidin-5-one:

Was added to Example 58 (0.500g, 0.971mmol) in DCM was cooled to -75 ℃ slowly in a solution in DCM BBr _3, and stirred for 0.5h. The reaction mixture was then warmed to room temperature and further stirred for 2.0 h. The mixture was concentrated in vacuo. And extracted with ethyl acetate and saturated NaHCO ₃ residue. The organic layer was dried over anhydrous Na ₂ SO _4, and then distilled off the solvent, to give the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 6.54-6.59 (m, 1H), 6.67-6.73 (m, 2H ), 6.81 (d, J = 15.6 Hz, 1H), 7.37-7.51 (m, 5H), 7.99 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 15.6 Hz, 1H), 8.87 (br) s, 1H), 9.56 (br s, 1H); ESI-MS (m/z) 447.24 (M+H) ⁺ .

Example 60: 7-{( E )-(2-Cyclopropylmethoxy-3-hydroxy)phenyl]-1-vinyl}-6-(4-trifluoro-methoxyphenyl)- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Example 59 (850mg, 1.9mmol) will be implemented, bromomethyl cyclopropane (283mg, 2.0mmol) and _{K 2 CO 3 (315mg, 2.2mmol} ) in DMF was heated at 60 deg.] C overnight 18.0h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried, and then purified by column chromatography to afford 560mg of the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) 0.26 (d, J = 3.6 Hz, 2H), 0.48 (d, J=6.9 Hz, 2H), 1.0-1.10 (m, 1H), 3.68 (d, J=6.9 Hz, 2H), 6.76-6.91 (m, 4H), 7.46-7.50 (m, 5H), 8.00 (d) , J = 4.8 Hz, 1H), 8.13 (d, J = 16.2 Hz, 1H), 9.42 (s, 1H).

Example 61: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-ethoxyphenyl}-1-vinyl]-6-(4-trifluoromethoxy -phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

A solution of Example 60 (60 mg, 0.119 mmol) in DMF (5 mL). Then, the reaction mixture was heated to room temperature, then heated to 60 ° C and heated at this temperature for 1.0 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, in 5% ethyl acetate in chloroform was purified by column chromatography to give 30mg of the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25 (d, J = 4.5 Hz, 2H), 0.48 (d, J = 7.2 Hz, 2H), 0.90-1.01 (m, 1H), 1.33 (t, J = 6.9 Hz, 3H), 3.70 (d, J) = 7.2 Hz, 2H), 4.00 (q, J = 6.6 Hz, 2H), 6.89-6.96 (m, 3H), 7.46 (s, 3H), 7.51 (d, J = 4.8 Hz, 1H), 7.99 (d , J = 5.1 Hz, 1H), 8.12 (d, J = 15.3 Hz, 1H); ESI-MS (m/z) 529.43 (M+H) ⁺ .

Example 62: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-(2-ethoxyethoxy)phenyl]-1-vinyl}-6-( 4-Trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

Example 60 (70 mg, 0.130 mmol) and 2-bromoethylethyl ether (29 mg, 0.191 mmol) in DMF (yield: The title compound was synthesized in 2 ml) to give 50 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.23 (d, J = 4.2 Hz, 2H), 0.47 (d, J = 7.2 Hz, 2H), 0.96-0.99 (m, 1H), 1.118 (t, J = 6.3 Hz 3H), 3.50 (q, J = 6.3 Hz, 2H), 3.69-3.73 (m, 4H), 4.07 (s) , 2H), 6.92-6.98 (m, 4H), 7.46 (s, 3H), 7.51 (d, J = 4.2 Hz, 2H), 8.00 (d, J = 3.9 Hz, 1H), 8.12 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 573.76 (M+H) ⁺ .

Example 63: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-difluoromethoxyphenyl]-1-vinyl}-6-(4-trifluoromethyl) Oxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The method described in Intermediate 14, Example 60 (70mg, 0.13mmol) using the embodiment, the title compound _{Cs 2 CO 3 (84mg, 0.26mmol} ) and ClCHF ₂ gas is prepared in DMF (2ml), to give 58mg of the desired ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.25-0.28 (m, 2H), 0.51 (d, J = 7.8 Hz, 2H), 0.80-1.10 (m, 1H), 3.69 (d, J) =6.9 Hz, 2H), 6.90-7.00 (m, 1H), 7.10-7.15 (m, 2H), 7.27 (d, J = 6.9 Hz, 1H), 7.46-7.53 (m, 5H), 8.00 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 15.0 Hz, 1H); ESI-MS (m/z) 551.36 (M+H) ⁺ .

Example 64: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-(cyclopropylmethoxy)phenyl]-1-vinyl}-6-(4- Trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 61, using Cs ₂ CO ₃ (84 mg, 0.26 mmol), by example 60 (70 mg, 0.13 mmol) and bromomethylcyclopropane (26 mg, 0.19 mmol) in DMF (2 ml) The title compound was prepared by condensing to give 60 mg of the desired compound: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.29 (d, J = 3.9 Hz, 2H), 0.31 (d, J = 3.9 Hz, 2H ), 0.48 (d, J = 6.9 Hz, 2H), 0.56 (d, J = 7.2 Hz, 3H), 0.90-1.10 (m, 1H), 1.20 - 1.30 (m, 1H), 3.73 (d, J = 6.9 Hz, 2H), 3.81 (d, J = 6.3 Hz, 2H), 6, 90-6.95 (m, 4H), 7.46-7.52 (m, 5H), 8.00 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 15.6 Hz, 1 H); ESI-MS (m/z) 555.40 (M+H) ⁺ .

Example 65: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-(3-cyanopropoxy)phenyl]-1-vinyl}-6-(4 -trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The method described in Example 61, the title compound was synthesized by (60mg, 0.130mmol) and 4-bromo-butyronitrile with NaH (28mg, 0.191mmol) reaction of Example 60, to give the desired compound 50mg; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.25-0.26 (m, 2H), 0.50 (d, J = 7.8 Hz, 2H), 0.90-1.10 (m, 1H), 2.04 (t, J = 5.7 Hz 2H) , 2.65 (t, J = 6.9 Hz 2H), 3.70 (d, J = 6.9 Hz, 2H), 4.03 (t, J = 5.1 Hz 2H), 6.89-7.01 (m, 4H), 7.46-7.52 (m, 5H), 8.00 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 15.9 Hz, 1H); ESI-MS (m/z) 568.64 (M+H) ⁺ .

Example 66: 7-{( E )-2-[2-(Cyclopropylmethoxy)-3-propoxyphenyl}-1-vinyl]-6-(4-trifluoromethoxy -phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was synthesized by the reaction of EtOAc (EtOAc (EtOAc,MeOHMeOHMeOHMeOH 55 mg of the desired compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.24-0.26 (m, 2H), 0.49 (d, J = 7.2 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H ), 1.70-1.77 (m, 2H), 3.70 (d, J = 3.9 Hz, 2H), 3.89-3.93 (m, 2H), 6.89-6.97 (m, 4H), 7.46-7.52 (s, 5H), 8.00 (d, J = 4.5 Hz, 1H), 8.13 (d, J = 16.2 Hz, 1H); ESI-MS (m/z) 543.26 (M+H) ⁺ .

Example 67: 7-[( E )-2-{2-Cyclobutylmethoxy-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-benzene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (146 mg, 2.147 mmol), Intermediate 15 (350 mg, 1.012 mmol) and 2-cyclobutylmethoxy-3-methoxybenzaldehyde ( 330mg, 1.501mmol) the title compound was prepared in the condensation (15ml) in ethanol to produce 292mg of the desired product was an off-white ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.80-1.90 (m, 5H), 2.00- 2.08 (m, 2H), 3.77 (s, 3H), 3.83 (d, J = 6.9 Hz, 2H), 6.80-6.87 (m, 2H), 6.91-6.99 (m, 2H), 7.40-7.46 (m, 4H), 7.51 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 8.12 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 529.13 (M +H) ⁺ .

Example 68: 7-[( E )-2-{2-(Cyclopentyloxy-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)- Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The intermediate 15 (350 mg, 1.012 mmol) and 2-cyclopentyloxy-3-methoxybenzaldehyde (330 mg, 1.501) were obtained according to the method of Example 24 in the presence of sodium ethoxide (146 mg, 2.147 mmol). mmol) of the title compound is synthesized by condensation in ethanol (15ml) is generated 251mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.54-1.62 (m, 6H), 1.75-1.82 ( m, 2H), 3.77 (s, 3H), 4.80-4.87 (m, 1H), 6.84-6.93 (m, 2H), 6.98 (d, J = 4.8 Hz, 2H), 7.46-7.52 (m, 5H) , 7.98 (d, J = 4, 2 Hz, 1H), 8.10 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 529.49 (M+H) ⁺ .

Example 69: 7-[( E )-2-(2-Hydroxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

By treatment with 48% hydrogen bromide and acetic acid: The title compound was prepared process (1 1) (2ml) Example 68 (38mg, 0.071mmol) embodiment, to give 14mg of the desired product as a pale yellow solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.78 (s, 3H), 6.71 (t, J = 8.1 Hz, 1H), 6.85-6.91 (m, 4H), 7.40-7.46 (m, 3H), 7.51 (d, J = 6.1 Hz, 1H), 8.00 (d, J = 4.8 Hz, 1H), 8.10 (d, J = 15.6 Hz, 1H), 9.17 (br s, 1H); ESI-MS (m/z) 461.35 (M+ H) ⁺ .

Example 70: 4-{7-[( E )-2-{3-Methoxy-2-(2-trifluoromethylethoxy)phenyl}-1-vinyl]-6-[4 -(Trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 61, treatment with Cs ₂ CO ₃ (136 mg, 0.421 mmol) and 1,1,1-trifluoro-3-iodopropane (121 mg, 0.542 mmol) in DMF (3 mL) Example 69 (100mg, 0.210mmol) the title compound was prepared, to give the desired ^{compound; 1 H NMR (300 MHz,} DMSO- d 6) δ 2.25-2.63 (m, 2H), 3.80 (s, 3H), 4.04-4.08 ( m, 2H), 6.89-6.98 (m, 2H), 6.98-7.08 (m, 2H), 7.49-7.54 (m, 5H), 8.01-8.03 (m, 1H), 8.09 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 558.81 (M+H) ⁺ .

Example 71: 7-[( E )-2-(2-Cyclohexylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)benzene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (146 mg, 2.147 mmol), Intermediate 15 (350 mg, 1.072 mmol) and 2-cyclohexylmethoxy-3-methoxybenzaldehyde (372 mg) Condensation in ethanol (15 ml) to give the title compound to give 281 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.03-1.10 (m, 2H), 1.18- 1.25 (m, 3H), 1.68-1.79 (m, 6H), 3.60-3.68 (m, 2H), 3.77 (s, 3H), 6.81-6.88 (m, 2H), 6.91-6.96 (m, 3H), 7.40-7.46 (m, 5H), 7.98 (d, J = 6.3 Hz, 1H), 8.14 (d, J = 15.0 Hz, 1H); ESI-MS (m/z) 557.44 (M+H) ⁺ .

Example 72: 7-[( E )-2-(2-Cyclohexyloxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl ]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (146 mg, 2.147 mmol), intermediate 15 (350 mg, 1.072 mmol) and (2-cyclohexyloxy-3-methoxy)benzaldehyde ( 351mg, 1.501mmol) the title compound is synthesized by condensation in ethanol (15ml) is generated 251mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.15-1.21 (m, 4H), 1.33 -1.49(m,2H), 1.68-1.79(m,2H),1.76-1.83(m,2H),3.74(s,3H),3.95-4.05(m,1H),6.87(d,J=6.3 Hz , 2H), 6.97 (d, J = 7.2 Hz, 4H), 7.40-7.46 (m, 2H), 7.50 (d, J = 6.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H), 8.08 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 543.57 (M+H) ⁺ .

Example 73: 7-[( E )-2-{3-Methoxy-2-(2-methoxyethoxy)phenyl}-1-vinyl]-6-[4-(trifluoro Methoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the procedure described in Example 24, intermediate 15 (350 mg, 1.072 mmol ) benzaldehyde (316mg, 1.501mmol) the title compound is synthesized by condensation in ethanol (15ml) is generated 286mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.33-3.40 (m, 3H), 3.45-3.51 (m, 2H), 3.78 (s, 3H), 3.95-4.03 (m, 2H), 6.82 (d, J = 15.6 Hz, 1H), 6.85-6.91 (m, 1H), 7.00 (d, J = 4.2 Hz, 2H), 7.45-7.52 (m, 5H), 8.00 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 15.6 Hz, 1H); ESI-MS (m/) z) 518.19(M+H) ⁺ .

Example 74: 4-{7-[( E )-2-{(3-Cyanopropoxy)-3-methoxy}phenylvinyl]-6-[4-(trifluoromethoxy) Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 24, in the presence of sodium ethoxide (145 mg, 2.145 mmol), Intermediate 15 (350 mg, 1.012 mmol) and 2-(3-cyanopropoxy)-3-methoxy - benzaldehyde (329mg, 1.501mmol) of the title compound is synthesized by condensation to produce 250mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.82-1.87 (m, 2H), 2.67 (t , J=7.2 Hz, 2H), 3.89 (t, J=6.9 Hz, 1H), 6.86-6.91 (m, 2H), 7.02 (s, 2H), 7.46 (s, 4H), 7.52 (d, J = 4.8 Hz, 1H), 7.99-8.03 (m, 2H); ESI-MS (m/z) 528.48 (M+H) ⁺ .

Example 75: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-2-methyl-6-[4-(three Fluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (90 mg, 0.008 mmol) in toluene (10 ml), ethanol (5 ml) and water (4 ml) And a sodium carbonate (128 mg, 1.213 mmol) from Intermediate 16 (100 mg, 0.202 mmol) and 4-trifluoromethoxyphenylboronic acid (58 mg, 0.283 mmol). 60 mg of the desired product are obtained; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.22-0.27 (m, 2H), 0.46-0.52 (m, 3H), 0.98-1.01 (m, 1H), 2.44 (s) , 3H), 3.67 (d, J = 6.9 Hz, 2H), 3.76 (s, 3H), 6.86-6.92 (m, 2H), 6.99-7.00 (m, 2H), 7.45 (m, 1H), 7.84 ( s, 1H), 8.12 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 529.23 (M+H) ⁺ .

Example 76: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-3-methyl-6-[4-(three Fluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (90 mg, 0.008 mmol) in toluene (10 ml), ethanol (5 ml) and water (4 ml) Sodium carbonate (128 mg, 1.213 mmol) from Intermediate 17 (100 mg, 0.202 mmol) and 4-trifluoromethoxyphenylboronic acid (58 mg, 0.283 mmol) afforded crude residue of 10% acetic acid in petroleum ether ethyl ester, the residue was purified by column chromatography to afford 50mg of the desired ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.24-0.26 (m, 2H), 0.48-0.50 (m, 2H), 0.90 -1.10 (m, 1H), 2.65 (s, 3H), 3.67 (d, J = 6.9 Hz, 2H), 3.76 (s, 3H), 6.83 (d, J = 15.6 Hz, 2H), 6.90-6.91 ( m, 2H), 6.98-7.01 (m, 4H), 7.43 (s, 4H), 8.10 (d,J = 15.6 Hz, 1H); ESI-MS (m/z) 529.19 (M+H) ⁺ .

Example 77: 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-2,3-dimethyl-6-[4 -(Trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (90 mg, 0.009 mmol) in toluene (10 ml), ethanol (5 ml) and water (4 ml) Sodium carbonate (125 mg, 1.187 mmol) from Intermediate 18 (100 mg, 0.196 mmol) and 4-trifluoromethoxyphenylboronic acid (56 mg, 0.275 mmol) afforded crude residue of 10% acetic acid in petroleum ether ethyl ester, the residue was purified by column chromatography to afford 80mg of the desired ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25-0.28 (m, 2H), 0.46-0.52 (m, 2H), 0.90 -1.01 (m, 1H), 2.30 (s, 3H), 2.59 (s, 3H), 3.67 (d, J = 7.5 Hz, 2H), 3.76 (s, 3H), 6.82 (d, J = 15.6 Hz, 2H), 6.88-6.91 (m, 1H), 6.98-7.00 (m, 4H), 7.43 (s, 4H), 8.08 (d, J = 15.6 Hz, 1H); ESI-MS (m/z) 543.19 ( M+H) ⁺ .

Example 78: 2-Chloro-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methoxyphenyl)vinyl]-6-[4- (trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 1, Pd[(C ₆ H ₅ ) ₃ P] ₄ (5 mg, 0.004 mmol) in toluene (10 ml) and ethanol (5 ml) was used first, and then used in water (4 ml) sodium carbonate (77mg, 0.734mmol), from intermediate 19 (65mg, 0.122mmol) and 4-trifluoromethoxyphenyl boronic acid (27mg, 0.132mmol) was prepared the title compound, 75mg to give the desired compound; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.99 (s, 9H), 3.50 (s, 2H), 3.76 (s, 3H), 6.81 (d, J = 16.2 Hz, 1H), 6.88-6.94 (m, 1H), 6.99 (d, J = 4.2 Hz, 2H), 7.42-7.48 (m, 4H), 8.18 (d, J = 15.6 Hz, 1H), 8.26 (s, 1H); ESI-MS (m/z) ) 565.55,567 (M+H) ⁺ .

Example 79: 2-Chloro-6-[4-(dimethylamino)phenyl]-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3 -Methoxy-phenyl)vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 1, Pd[(C ₆ H ₅ ) ₃ P] ₄ (8 mg, 0.007 mmol) in toluene (5 ml) and ethanol (2 ml) was used, followed by water (2 ml). of sodium carbonate (119mg, 1.110mmol), from intermediate 19 (100mg, 0.181mmol) and 4- N, N - dimethylamino phenyl boronic acid (34mg, 0.210mmol) the title compound was prepared, to give 120mg of the desired ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.06 (s, 9H), 2.99 (s, 6H), 3.54 (s, 2H), 3.79 (s, 3H), 6.75 (d, J = 9.0 Hz, 2H), 6.88-6.96 (m, 3H), 7.15 (d, J = 8.1 Hz, 2H), 8.05 (s, 1H), 8.14 (s, 2H); ESI-MS (m/z) 524.49 , 526 (M+H) ⁺ .

Example 80: 4-{2-Chloro-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methoxyphenyl)vinyl]-5- Oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

According to the method described in Example 1, Pd[(C ₆ H ₅ ) ₃ P] ₄ (9 mg, 0.007 mmol) in toluene (5 ml) and ethanol (2 ml) was used, followed by water (2 ml) of sodium carbonate (119mg, 1.110mmol), from intermediate 19 (100mg, 0.181mmol) and 4-cyanophenyl boronic acid (30mg, 0.200mmol) the title compound was prepared, to give the desired compound 137mg; ¹ H NMR ( 300 MHz, DMSO- d ₆ ) δ 1.01 (s, 9H), 3.52 (s, 2H), 3.76 (s, 3H), 6.75 (d, J = 15.6 Hz, 1H), 6.96-7.02 (m, 3H) , 7.53 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 15.6 Hz, 1H), 8.28 (s, 1H); ESI-MS (m/) z) 506.55, 508 (M+H) ⁺ .

Example 81: 2-Chloro-6-[4-(dimethylamino)phenyl]-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)ethene ]]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one:

According to the method described in Example 1, in a mixture of toluene (10 ml), ethanol (3 ml) and water (3 ml), sodium carbonate (193 mg, 1.820 mmol), intermediate 20 (150 mg, 2.912 mmol), 4 - a coupling reaction of N,N -dimethylphenylaminoboronic acid (52 mg, 3.142 mmol) and Pd[(C ₆ H ₅ ) ₃ P] ₄ (13 mg, 0.001 mmol) afforded the title compound ¹ H NMR (300 MHz, DMSO- d ₆ ) δ].06 (d, J = 6.3 Hz, 6H), 2.06 (br s, 1H), 3.00 (s, 6H), 3.69 (d, J) = 6.9 Hz, 2H), 3.82 (s, 3H), 6.78-6.84 (m, 3H), 6.90-7.08 (m, 4H), 7.20-7.26 (m, 1H), 7.80 (s, 1H), 8.19 ( d, J = 16.2 Hz, 1H); ESI-MS (m/z) 510.76, 512 (M+H) ⁺ .

Example 82: 4-{7-[( E )-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-5-oxo-3-(trifluoromethyl) -5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile:

The title compound was prepared according to the method described in Example 1 using Pd[(C ₆ H ₅ ) ₃ P] ₄ (8 mg, 0.007 mmol) in toluene (10 ml), ethanol (5 ml) and water (4 ml) Sodium carbonate (112 mg, 1.053 mmol) from EtOAc (EtOAc (EtOAc,MeOHMeOHMeOH) the residue was purified by column chromatography to afford 70mg of the desired ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.03 (s, 9H), 3.53 (m, 2H), 3.77 (m, 2H), 6.72- 6.77 (m, 1H), 6.98-7.02 (m, 2H), 7.52-7.55 (m, 2H), 7.91-7.94 (m, 2H), 8.24 (s, 1H), 8.30 (s, 2H); MS (m/z) 540.53 (M+H) ⁺ .

Examples 83-90 described in Table 5 were prepared from Intermediate 22 with the appropriate aldehyde using a procedure analogous to Example 24.

Example 83: 4-(2-{( E )-2-[2-(3-Cyanopropoxy)-3-methoxyphenyl}-1-vinyl}-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

According to the method described in Example 24, intermediate 22 (350 mg, 1.102 mmol) and 4-(2-carbamido-6-methoxyphenoxy). Condensation of butyronitrile (338 mg, 1.543 mmol) in ethanol (15 ml) afforded the title compound to give 281 mg of desired desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.88 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.93 (t, J = 7.5 Hz, 2H), 6.84 (d, J = 15.3 Hz, 1H), 6.98 -7.06 (m, 3H), 7.55-7.61 (m, 4H), 7.96 (d, J = 8.4 Hz, 2H), 8.06-8.12 (m, 2H), 8.80-8.89 (m, 1H); ESI-MS (m/z) 519.24(M+H) ⁺ .

Example 84: 4-(2-{( E )-2-[3-Methoxy-2-(methoxyethoxy)phenyl}-1-vinyl}-4-oxo-4 H -Benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

Intermediate 22 (340 mg, 1.072 mmol) and 3-methoxy-[2-(2-methoxyethoxy) in the presence of sodium ethoxide (146 mg, 2.147 mmol) according to the procedure described in Example 24 The title compound was synthesized from the condensation of benzaldehyde (315 mg, 1.501 mmol) in EtOAc (15 mL) to yield 261 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.37 (s, 3H), 3.51 (s, 2H), 3.78 (s, 3H), 4.04 (s, 2H), 6.78 (d, J = 15.6 Hz, 1H), 6.97-7.03 (m, 3H), 7.57-7.61 (m , 4H), 7.95 (d, J = 8.4 Hz, 2H), 8.02 - 8.08 (m, 1H), 8.27 (d, J = 15.6 Hz, 1H), 8.43 - 8.49 (m, 1H); ESI-MS ( m/z) 510.47 (M+H) ⁺ .

Example 85: 4-{2-[( E )-2-[2-(2-ethoxyethoxy)-3-methoxy]phenyl}-1-vinyl]-4-oxo -4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

According to the method described in Example 24, in the presence of sodium ethoxide (171 mg, 2.527 mmol), Intermediate 22 (400 mg, 1.262 mmol) and 2-(2-ethoxyethoxy)-3-methoxy benzaldehyde (395mg, 1.762mmol) the title compound was prepared in the condensation (15ml) in ethanol, 310mg generating a desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.20 (t, J = 6.9 Hz, 3H), 3.50-3.56 (m, 4H), 3.78 (s, 3H), 4.04-4.10 (m, 2H), 6.76 (d, J = 15.6 Hz, 1H), 6.95-7.01 (m, 3H) ), 7.54-7.61 (m, 4H), 7.95 (d, J = 8.4 Hz, 2H), 8.04-8.10 (m, 1H), 8.23 (d, J = 15.6 Hz, 1H), 8.80-8.90 (m, 1H); ESI-MS (m/z) 523.67 (M+H) ⁺ .

Example 86: 4-{2-[( E )-2-[2-cyclopropylmethoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H - Benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

Intermediate 22 (350 mg, 1.102 mmol) and 2-cyclopropylmethoxy-3-methoxybenzaldehyde (by a solution of EtOAc (150 mg, 2.. 341mg, 1.653mmol) in ethanol analogously title (15ml) of the compound, 251mg generate the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.25-0.33 (m, 2H), 0.50 -0.54 (m, 2H), 1.10 - 1.20 (m, 1H), 3.71 (d, J = 3.6 Hz, 2H), 3.77 (s, 3H), 6.83 (d, J = 15.6 Hz, 1H), 6.95- 7.09 (m, 3H), 7.53-7.60 (m, 4H), 7.90-7.99 (m, 2H), 8.02-8.08 (m, 1H), 8.22 (d, J = 15.6 Hz, 1H), 8.80-8.90 ( m, 1H); ESI-MS (m/z) 506.27 (M+H) ⁺ .

Example 87: 4-{2-[( E )-2-[2-Butoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[ 4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

According to the method described in Example 24, in the presence of sodium ethoxide (107 mg, 1.572 mmol), Intermediate 22 (250 mg, 0.783 mmol) and (2-butoxy-3-methoxy)benzaldehyde (229 mg) , 1.104 mmol) in ethanol analogously title (15ml) of the compound, to generate the desired product as a pale yellow solid ^{251mg; 1 H NMR (300 MHz} , DMSO- d 6) δ 0.98-1.04 (m, 3H), 1.53 ( s,4H),3.77(s,3H),3.85(s,2H),6.88(d,J=15.6 Hz,1H),6.95-7.09(m,2H),7.54-7.61(m,5H),7.96 (d, J = 8.4 Hz, 2H), 8.02 - 8.09 (m, 1H), 8.15 (d, J = 15.6 Hz, 1H), 8.82-8.88 (m, 1H); ESI-MS (m/z) 508.31 (M+H) ⁺ .

Example 88: 4-{2-[( E )-2-[2-(3-methylbutoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

According to the method described in Example 24, in the presence of sodium ethoxide (107 mg, 1.572 mmol), Intermediate 22 (250 mg, 0.781 mmol) and 2-(3-methylbutoxy-3-methoxy) benzaldehyde (215mg, 1.102mmol) in ethanol analogously title (15ml) of the compound, 212mg generate the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.98 (d, J = 6.9 Hz,6H), 1.46 (q, J = 6.3 Hz, 2H), 3.15 (d, J = 5.4 Hz, 1H), 3.78 (s, 3H), 3.88 (t, J = 6.3 Hz, 2H), 6.87 ( d, J = 15.6 Hz, 1H), 6.95-7.09 (m, 3H), 7.53-7.60 (m, 4H), 7.95 (d, J = 8.4 Hz, 2H), 8.04-8.10 (m, 1H), 8.14 (d, J = 15.6 Hz, 1H), 8.80-8.90 (m, 1H); ESI-MS (m/z) 522.29 (M+H) ⁺ .

Example 89: 4-{2-[( E )-2-[2-Cyclobutylmethoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo [4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

According to the method described in Example 24, in the presence of sodium ethoxide (107 mg, 1.571 mmol), Intermediate 22 (250 mg, 0.781 mmol) and 2-(cyclobutylmethoxy-3-methoxy)benzaldehyde ( 243mg, 1.101mmol) in ethanol analogously title (15ml) of the compound, 227mg generate the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.85-1.92 (m, 5H), 1.98 -2.11 (m, 2H), 3.78 (s, 3H), 3.85 (d, J = 6.0 Hz, 2H), 6.84 (d, J = 15.6 Hz, 1H), 6.98-7.05 (m, 3H), 7.56- 7.62 (m, 4H), 7.96 (d, J = 7.8 Hz, 2H), 8.03-8.09 (m, 1H), 8.20 (d, J = 15.6 Hz, 1H), 8.80-8.89 (m, 1H); - MS (m/z) 520.28 (M+H) ⁺ .

Example 90: 4-{2-[( E )-2-[3-methoxy-2-pyridin-2-ylmethoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile:

By intermediate 22 (350 mg, 1.102 mmol) and 3-methoxy-2-(pyridin-2-ylmethoxy) in the presence of sodium ethoxide (150 mg, 2.201 mmol) according to the procedure described in Example 24 ) benzaldehyde (376mg, 1.541mmol) the title compound is synthesized by condensation in ethanol (15ml) is generated 296mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.82 (s, 3H) , 5.01(s, 2H), 6.77 (d, J = 15.6 Hz, 1H), 6.98-7.06 (m, 3H), 7.36 (t, J = 5.4 Hz, 1H), 7.54 - 7.62 (m, 5H), 7.88 (d, J = 8.1 Hz, 3H), 8.00-8.08 (m, 1H), 8.13 (d, J = 15.6 Hz, 1H), 8.56 (d, J = 3.9 Hz, 1H), 8.80-8.86 (m , 1H); ESI-MS (m/z) 543.28 (M+H) ⁺ .

Examples 91-94 described in Table 6 were prepared from Intermediate 23 with the appropriate aldehyde using a procedure analogous to Example 24.

Example 91: 2-{( E )-2-[(2-cyclopropylmethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethyl- Phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one:

According to the method described in Example 24, in the presence of sodium ethoxide (94 mg, 1.380 mmol), intermediate 23 (250 mg, 0.690 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde ( 200mg, 0.970mmol) in ethanol analogously title (15ml) of the compound, 160mg generate the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.28-0.30 (m, 2H), 0.51 -0.53 (m, 2H), 0.90-1.01 (m, 1H), 3.69 (d, J = 7.5 Hz, 2H), 3.77 (s, 3H), 6.92 (d, J = 15.6 Hz, 2H), 6.98- 7.00(m,2H), 7.56-7.64(m,4H),7.84-7.86(m,2H),8.06-8.08(m,1H),8.22(d,J=15.6 Hz,1H),8.84-8.86( m, 1H); ESI-MS (m/z) 549.36 (M+H) ⁺ .

Example 92: 2-{( E )-2-[(2-methoxyethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethylbenzene yl) -4 H - benzo [4,5] [1,3] thiazolo - [3,2- a] pyrimidin-4-one:

By intermediate (23 mg, 0.690 mmol) with 2-(2-methoxyethoxy)-3-methoxy benzaldehyde (218mg, 0.970mmol) the title compound is synthesized by condensation in ethanol (15ml) is generated 178mg of the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.37 (s, 3H) , 3.50 (br s, 2H), 3.78 (s, 3H), 4.04 (br s, 2H), 6.82 (d, J = 15.6 Hz, 1H), 6.94 - 6.95 (m, 1H), 7.00 - 7.02 (m , 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 7.84-7.86 (m, 2H), 8.05-8.07 (m, 1H), 8.27 (d, J = 15.6 Hz, 1H ), 8.85-8.87 (m, 1H); ESI-MS (m/z) 553.81 (M+H) ⁺ .

Example 93: 2-{( E )-2-[(2-ethoxyethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethyl- Phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one:

According to the method described in Example 24, intermediate 23 (250 mg, 0.690 mmol) and 2-(2-ethoxyethoxy)-3-methoxy benzaldehyde (204mg, 0.970mmol) in ethanol analogously title (15ml) of the compound, 178mg generate the desired product as a pale yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.91 (t, J = 6.9 Hz, 3H), 3.48-3.55 (m, 4H), 3.78 (s, 3H), 4.06 (br s, 2H), 6.81 (d, J = 15.6 Hz, 1H), 6.92-6.94 (m, 1H) , 7.00-7.02 (m, 1H), 7.55-7.57 (m, 2H), 7.61-7.64 (m, 2H), 7.84-7.87 (m, 2H), 8.07-8.09 (m, 1H), 8.23 (d, J=15.6 Hz, 1H), 8.84-8.87 (m, 1H); ESI-MS (m/z) 567.21. (M+H) ⁺ .

Example 94: 2-{( E )-2-[(3-Cyanopropoxy-3-methoxy)phenyl]-1-vinyl}-3-(4-trifluoromethyl-benzene yl) -4 H - benzo [4,5] [1,3] thiazolo - [3,2- a] pyrimidin-4-one:

According to the method described in Example 24, in the presence of sodium ethoxide (94 mg, 1.380 mmol), Intermediate 23 (250 mg, 0.690 mmol) and 2-(3-cyanopropoxy)-3-methoxy The title compound was synthesized by condensation of benzaldehyde (213 mg, 0.970 mmol) in EtOAc (15 mL) to yield 168 mg of the desired pale yellow solid product: ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.81-1.85 (m, 2H) ), 2.65-2.70 (m, 2H), 3.79 (s, 3H), 3.89-3.90 (m, 2H), 6.90 (d, J = 16.2 Hz, 1H), 6.99-7.03 (m, 3H), 7.55- 7.64 (m, 4H), 7.85-7.88 (m, 2H), 8.04-8.09 (m, 2H), 8.84 - 8.86 (m, 1H); ESI-MS (m/z) 562.36 (M+H) ⁺ .

Example 95: 2-{( E )-2-[2-cyclopropylmethoxy-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethoxy-benzene yl) -4 H - benzo [4,5] [1,3] thiazolo - [3,2- a] pyrimidin-4-one:

According to the method described in Example 24, intermediate 24 (300 mg, 0.796 mmol) and (2-cyclopropylmethoxy-3-methoxy)benzene in the presence of sodium ethoxide (108 mg, 1.593 mmol) the title compound is synthesized by condensation carbaldehyde (230mg, 1.115mmol) generates 210mg of the desired ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.29-0.30 (m, 1H), 0.51-0.54 (m, 2H) , 1.50-1.51 (m, 1H), 3.15 (s, 3H), 3.70 (d, J = 6.9 Hz, 2H), 3.77 (s, 3H), 6.88-7.00 (m, 4H), 7.49-7.54 (m , 6H), 8.01 - 8.06 (m, 1H), 8.20 (d, J = 15.6 Hz, 1H), 8.83 - 8.85 (m, 1H); ESI-MS (m/z) 565.25 (M+H) ⁺ .

Example 96: 2-{( E )-2-[3-Methoxy-2-(2-methoxyethoxy)phenyl]-1-vinyl}-3-(4-trifluoromethyl) Oxy-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one:

According to the method described in Example 24, intermediate 24 (250 mg, 0.663 mmol) and 3-methoxy-2-(2-methoxy-ethoxy) in the presence of sodium ethoxide (90 mg, 1.327 mmol) yl) - benzaldehyde (195mg, 0.929mmol) condensation title compound was prepared in ethanol (10ml) is generated 167mg of the desired ^{product; 1 H NMR (300 MHz,} DMSO- d 6) δ 3.37 (s, 1H), 3.51 (br s, 2H), 3.78 (s, 3H), 4.03 (br s, 2H), 6.82 (d, J = 15.6 Hz, 1H), 6.91-6.93 (m, 1H), 7.00-7.02 (m, 2H), 7.49-7.54 (m, 6H), 8.05-8.06 (m, 1H), 8.25 (d, J = 15.9 Hz, 1H), 8.83 - 8.85 (m, 1H); ESI-MS (m/z) 569.14(M+H) ⁺ .

Example 97: 2-{( E )-2-[(2-ethoxyethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethoxy) -phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one:

According to the method described in Example 24, in the presence of sodium ethoxide (105 mg, 1.540 mmol), intermediate 24 (290 mg, 0.770 mmol) and 2-(2-ethoxyethoxy)-3-methoxy benzaldehyde (242mg, 1.07mmol) condensation title compound was prepared in ethanol (10ml) is generated 225mg of the desired product as a yellow ^{solid; 1 H NMR (300 MHz,} DMSO- d 6) δ 1.91 (t, J = 6.6 Hz, 3H), 3.48-3.54 (m, 4H), 3.78 (s, 3H), 4.01-4.06 (m, 2H), 6.80 (d, J = 15.6 Hz, 1H), 6.90-6.92 (m, 1H) , 7.00-7.01 (m, 2H), 7.4-7.55 (m, 6H), 8.05-8.06 (m, 1H), 8.20 (d, J = 15.6 Hz, 1H), 8.84 - 8.85 (m, 1H); - MS (m/z) 583.21 (M+H) ⁺ .

Example 98: 2-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-3-(4-trifluoromethoxyphenyl)-10 -Methylpyrimido[1,2- a ]benzimidazole-4(10 H )-one:

The title compound was synthesized according to the method described in Example 24: Intermediate 25 (300 mg, &lt;RTI ID=0.0&gt;&gt; benzaldehyde (215mg, 1.010mmol) obtained in the condensation (25 ml) in ethanol the crude product; the crude product was purified by column chromatography, 416mg of the desired compound ^{of; 1 H NMR (300 MHz,} DMSO- d 6) δ 0.23-0.32 (m, 2H), 0.49-0.56 (m, 2H), 1.12 (br s, 1H), 3.70-3.78 (m, 6H), 3.87 (s, 2H), 6.91-6.99 (m, 3H) ), 7.20-7.26 (m, 1H), 7.32-7.38 (m, 1H), 7.45-7.54 (m, 5H), 7.68 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 16.2 Hz, 1H), 8.37-8.43 (m, 1H); APCI-MS (m/z) 562.49 (M+H) ⁺ .

Pharmacological activity

According to T The improved process described by th, A., Kedei, N., Wang, Y. and Blumberg, PM, Life Sciences, (2003), 73, 487-498 screens for TRPV3 activity of exemplary embodiments of the invention. Screening of compounds can be carried out by other methods and procedures known to those skilled in the art. These screening methods can be found in (a) Hu, H.-Z. et al, J. Biol. Chem . (2004), 279, 35741-35747; (b) Smith, GD et al, Nature (2002), 418, 186-190; (c) Peier, AM et al, Science (2002), 296, 2046-2049.

Screening of TRPV3 antagonists using ⁴⁵ calcium absorption assay

Inhibition of TRPV3 receptor activation was examined by inhibition of cellular uptake induced by radioactive calcium 2-aminoethoxydiphenylborate (2-APB). The test compound was dissolved in dimethyl hydrazine (DMSO) to prepare a 20 mM stock solution, which was then diluted with DMEM/F-12 plain medium containing 1.8 mM CaCl ₂ to obtain the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v/v). Human TRPV3 expressing CHO cells was grown in DMEM/F-12 medium containing 10% FBS, 1% penicillin-streptomycin solution and 400 μg/ml G-418. At 24 h prior to analysis, cells were seeded in 96-well plates such that ~50,000 cells/well were obtained on the day of the experiment. The cells were treated with the test compound for 10 minutes and then added to a final concentration of 500 μM of 2-APB and 5 μCi/ml of ⁴⁵ Ca ⁺² over 4 minutes. The cells were washed and lysed using a buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. The radioactivity in the lysate was measured in a Packardt Top count after the addition of a liquid scintillant. The concentration response curve was plotted as the maximum response % obtained in the absence of the test antagonist. Using the GraphPad PRISM software, IC ₅₀ values can be calculated from the concentration response curve by nonlinear regression analysis.

Each of the prepared compounds was tested using the above analysis procedure, and the results obtained are shown in Table 6. For the selected examples, % inhibition at 1.0 μM and 10.0 μM along with IC ₅₀ (nM) values are shown in the table.

The IC ₅₀ (nM) values for these compounds are illustrated in Table 6, where "A" means an IC ₅₀ value of less than 250.0 nM, "B" means an IC ₅₀ value in the range of 250.1 - 500.0 nM, and "C" means IC _{The 50} value is in the range of 500.1-1000 nM, and "D" means the IC ₅₀ value is in the range of 1000.1-10,000 nM. IC ₅₀ less than 250 nM, less than 500nM group of compounds of less than 1000nM, in the structures disclosed herein, in consideration column separately.

Claims (9)

a compound of formula (I), Or a pharmaceutically acceptable salt thereof, wherein X is O, S or NR ^b ; Y is CR ³ or N; ring A is aryl, heterocyclic or heteroaryl; R may be the same or different and is selected from hydrogen , nitro, cyano, halogen, -OR ^a , substituted or unsubstituted alkyl, alkenyl, haloalkyl, cyanoalkyl, cyanoalkoxy, cycloalkyl, aryl, heteroaryl or hetero a cyclic group; R ¹ and R ³ may be the same or different and each independently selected from hydrogen, halogen, nitro, cyano, -COOH, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, ring. Alkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic group, -NR ⁴ R ⁵ , -S(O) _p NR ⁴ R ⁵ or -S(O) _p R ⁴ ; or R ¹ and R ³ together with the carbon atom to which it is attached may form a 5-7 membered cyclic ring which may be substituted or unsubstituted, saturated, unsaturated or partially saturated, said cyclic ring being optional Included as one or more heteroatoms selected from O, NR ^b or S; R ² is an aryl, heteroaryl or heterocyclic group, which may optionally be mono- or polysubstituted with a substituent The substituents are independently selected from the group consisting of: , Hydroxy, nitro, cyano, -COOH, -NR ⁴ R ^5, acyl, a substituted or unsubstituted alkyl, alkenyl, alkoxy, cyanoalkoxy, haloalkyl, haloalkoxy, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkylalkoxy group, an aryl group, a heterocyclic group and a heteroaryl group; R ^a may be the same or different and is selected from the group consisting of hydrogen, Substituted or unsubstituted alkyl, haloalkyl, cyanoalkyl, alkenyl, cycloalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkylalkyl, arylalkyl Or a heteroarylalkyl or heterocyclylalkyl group; R ^{b is} selected from hydrogen, substituted or unsubstituted alkyl or arylalkyl; R ⁴ and R ⁵ may be the same or different and are independently selected from hydrogen, substituted Or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclic Alkyl; 'n' is an integer from 0 to 5, inclusive; and 'p' is an integer from 0 to 2, inclusive; wherein: R ² is preferably a para-substituted phenyl group, The para substituents are cyano, methoxy, trifluoro Methyl, trifluoromethoxy, difluoromethoxy, tert-butyl or N,N -dimethylamino; or R ² is halophenyl or haloalkoxyphenyl; or R ² is two Fluoromethoxyphenyl or trifluoromethoxyphenyl; preferably R ^a is alkyl, more preferably methyl; or preferably ^Ra is cycloalkylalkyl, more preferably cyclopropyl Methyl; preferably R ³ is methyl or trifluoromethyl; preferably R ¹ is hydrogen, halogen or methyl. The compound of claim 1, wherein the compound has the formula (IIa): Or a pharmaceutically acceptable salt thereof, R ¹ and R ^{3 , which} may be the same or different, each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, -COOH, substituted or unsubstituted alkyl, alkenyl, alkynyl , haloalkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic group, -NR ⁴ R ⁵ , -S(O) _p NR ⁴ R ⁵ or -S(O) _p R ⁴ ; or R ¹ and R ³ together with the carbon atom to which they are attached may form a 5-7 membered cyclic ring which may be substituted or unsubstituted, saturated, unsaturated or partially saturated, The cyclic ring may optionally comprise one or more heteroatoms selected from O, NR ^b or S; each of R ^a1 and R ^a2 may be the same or different and is selected from hydrogen, substituted or unsubstituted alkyl, haloalkane Base, cyanoalkyl, alkenyl, cycloalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkylalkyl, arylalkyl, heteroarylalkyl or hetero Cycloalkyl; R ^{6 , which} may be the same or different, independently selected from halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , fluorenyl, substituted or unsubstituted alkyl, alkenyl, alkane Oxyl, cyanoalkoxy, haloalkyl Haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyl, alkoxy, aryl, heterocyclyl or heteroaryl group; R ⁴ and R ⁵ may be the same or different, are independently hydrogen, substituted or Unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocycloalkane R ^{b is} selected from hydrogen, substituted or unsubstituted alkyl or arylalkyl; 'm' is an integer from 0 to 3, inclusive; and 'p' is an integer from 0 to 2, both ends Preferably, wherein R ^a1 is cyclopropylmethyl; preferably R ^a2 is methyl; preferably R ⁶ is trifluoroalkoxy, more preferably trifluoromethoxy. A compound according to claim 2, wherein the compound has the formula (IIb): Or a pharmaceutically acceptable salt thereof, R ^{6 is} independently selected from the group consisting of halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , substituted or unsubstituted alkyl, alkoxy, haloalkyl or haloalkane Alkoxy; R ^{a1 is} selected from substituted or unsubstituted alkyl, alkoxy or cycloalkyl; R ^{a2 is} selected from substituted or unsubstituted alkyl or haloalkyl; and 'q' is an integer from 1 to 4, inclusive Both ends. The compound of claim 1, wherein the compound has the formula (III): Or a pharmaceutically acceptable salt thereof, R may be the same or different and is selected from the group consisting of hydrogen, nitro, cyano, halogen, -OR ^a , substituted or unsubstituted alkyl, alkenyl, haloalkyl, cyanoalkyl, a cyanoalkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group; wherein R ^6a may be the same or different and independently selected from halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , fluorenyl, substituted or unsubstituted alkyl, alkenyl, alkoxy, cyanoalkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy a radical, an aryl group, a heterocyclic group or a heteroaryl group; R ^{7 is} independently selected from the group consisting of halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetero An aryl group, a heterocyclic group, -NR ⁴ R ⁵ , -S(O) _p NR ⁴ R ⁵ or -S(O) _p R ⁴ ; R ⁴ and R ⁵ may be the same or different and are independently selected from hydrogen, Substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclic Alkyl; 'n' is an integer from 0 to 5, inclusive; 'p' An integer of 0-2, containing both ends; 'm' is an integer from 0-3, containing both ends; and 'r' is an integer from 0-4. The compound of claim 1, wherein the compound is selected from the group consisting of: 7-{( E )-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]vinyl}- 6-phenyl-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 6-[4-(t-butylphenyl)]-7-[( E )- 2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one ; 1-{4-{7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H - [1,3]thiazolo[3,2- a ]pyrimidin-6-yl}phenyl}-1-ethanone; 6-(4-dimethylaminophenyl)-7-[( E )- 2-(2-cyclopropylmethoxy-3-methoxyphenyl]-1-vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-hydroxyphenyl)-5 H -[1, 3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl -6-(3,5-difluorophenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2- (2-Butoxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl} Benzonitrile; 4-{7-[( E )-2-(3-methoxy Benzyl-2-pentyloxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4- {7-[( E )-2-(3-methoxy-2-(2-methoxyethoxy)phenyl]-1-vinyl}-5-oxo-5 H- [1, 3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-(2-ethoxyethoxy-3-methoxyphenyl) ]-1-vinyl}-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2 -[2-(cyclopropylmethoxy)-3-methoxyphenyl]-1-vinyl}-5-oxo-5 H -[1,3]thiazolo[3,2- a ] Pyrimidine-6-yl}benzonitrile; 4-{7-[( E )-2-(2-cyclohexylmethoxy-3-methoxy)phenyl-1-vinyl]-5-oxo- 5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-[2-(3-fluorobenzyloxy) )-3-methoxyphenyl-1-vinyl]-5-oxo-5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4- {7-[( E )-2-{3-Methoxy-2-(2-pyridylmethoxy)phenyl]-1-vinyl]}-5-oxo-5 H -[1, 3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-{2-(3-cyanopropoxy)-3-(A) Oxyphenyl]-1-vinyl]}-5-oxo-5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile ;7-[( E )-2-(3-methoxy-2-propoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H - [1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-butoxy-3-methoxyphenyl)-1-vinyl] -6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2 -isobutoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2 - a ] pyrimidin-5-one; 7-[( E )-2-(2-isopentyloxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl) yl) phenyl] -5 H - [1,3] thiazolo [3,2- a] pyrimidin-5-one; 3- {2-methoxy -6 - {[(E) -2- {5 -oxo-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-7-yl}-1-vinyl]phenoxy Propyl cyanide; {7-[( E )-2-(2-methoxyethoxy-3-methoxy)phenyl}vinyl]-6-[4-(trifluoromethyl) Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; {7-[( E )-2-(2-ethoxyethoxy)-3- Methoxy)phenyl-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one ; 7 - [(E) -2- {3- methoxy-2-neopentyl-phenyl} -1-ethenyl] -6- [4- (trifluoromethyl Yl) - phenyl] -5 H - [1,3] thiazolo [3,2- a] pyrimidin-5-one; 7 - [(E) -2- (3- methoxy-2-neopentyl Oxy)phenyl-1-vinyl]-6-(4-(trifluoromethyl)phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-{3-methoxy-2-(2-trifluoromethylethoxy)phenyl}-1-vinyl]-6-[4-(trifluoro Methoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy) )-3-methoxyphenyl}-1-vinyl]-6-(4-trifluoromethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidine- 5-ketone; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-difluoromethoxyphenyl]-1-vinyl}-6-(4-trifluoromethyl) Oxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-{2-isopentyloxy-3-methoxy Phenyl}-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3]thiazolidine [3,2- a ]pyrimidin-6-yl}benzonitrile; 7-[( E )-2-(3-methoxy-2-pentyloxyphenyl)-1-vinyl]-6-[ 4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7- [( E )-2-(2-Isobutoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[ 1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-ethene 2-methyl-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[ ( E )-2-{2-cyclobutylmethoxy-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[ 1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-ethene 6-(4-difluoromethoxyphenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-( 3-methoxy-2-propoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3, 2- a ] pyrimidin-5-one; 7-[( E )-2-(2-butoxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl) Oxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; {7-[( E )-2-(2-cyclopropylmethoxy) 3-methoxyphenyl]-1-vinyl]-6-[4-(trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine 5-one; 4- {7 - [(E ) -2- (2- isopentyl-3-methoxy-phenyl) -1- Enyl] -5-oxo -5 H - [1,3] thiazolo [3,2- a] pyrimidin-6-yl} benzonitrile; 4- {7 - [(E ) -2- (2- Isobutoxy-3-methoxyphenyl)-1-vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]-pyrimidin-6-yl}benzyl Nitrile; 4-{7-[( E )-2-(2-cyclopentyloxy-3-methoxy)phenyl-1-vinyl]-5-oxo-5 H -[1,3] Thiazolo-[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-{7-[( E )-2-(2-cyclobutylmethoxy-3-methoxy)phenyl-1- Vinyl]-5-oxo-5 H -[1,3]-thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 7-[( E )-2-{2-(2 -ethoxyethoxy)-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazole And [3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclobutylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[4 -(trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopentyloxy) 3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ] Pyrimidin-5-one; 7-[( E )-2-{3-methoxy-2-(pyridin-2-ylmethoxy)phenylvinyl]-6-[4-(trifluoromethyl) Phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2- Cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-[3-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3, 2- a ] pyrimidin-5-one; 6-(4-dimethylaminophenyl)-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)- 1-vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 6-(4-dimethylaminophenyl)-7-[( E )- 2-(3-methoxy-2-pivaloxy)phenyl-1-vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7- [( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-6-(4-methoxyphenyl)-5 H -[1, 3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl] -6-(4-ethoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropane Methoxy-3-methoxyphenyl)-1-vinyl]-6-(4-(2,2,2-trifluoroethoxy)phenyl]-5 H -[1,3] Thiazolo[3,2- a ]pyrimidin-5-one; 3-4-{7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1- Vinyl]-5 H -[1,3]thiazolo-[3,2- a ]pyrimidin-6-yl}phenoxy)propyl cyanide; 7-[( E )-2-(2-cyclopropane Methoxy-3-methoxyphenyl)-1-vinyl]-6-(4-cyclopropyl- Methoxyphenyl] -5 H - [1,3] thiazolo [3,2- a] pyrimidin-5-one; 4- {7 - [(E ) -2- {2- (4- fluoro-butoxy 3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ] pyrimidin-5-one; 7-{( E )-(2,3-dihydroxy)phenyl}-1-vinyl]-6-(4-trifluoromethoxy-phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-(2-cyclopropylmethoxy-3-hydroxy)phenyl]-1-vinyl }-6-(4-Trifluoro-methoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[ 2-(cyclopropylmethoxy)-3-ethoxyphenyl}-1-vinyl]-6-(4-trifluoromethoxy-phenyl)-5 H -[1,3]thiazole And [3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-(2-ethoxyethoxy)phenyl] 1-vinyl}-6-(4-trifluoro-methoxyphenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-(cyclopropylmethoxy)phenyl]-1-vinyl}-6-(4-trifluoromethoxyphenyl)- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-(3-cyanide Propyloxy)phenyl]-1-vinyl}-6-(4-trifluoromethoxyphenyl)-5 H -[ 1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-{( E )-2-[2-(cyclopropylmethoxy)-3-propoxyphenyl}-1 -vinyl]-6-(4-trifluoromethoxy-phenyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )- 2-{2-(cyclopentyloxy-3-methoxyphenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3 Thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-hydroxy-3-methoxyphenyl)-1-vinyl]-6-[4- (trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclohexylmethoxy) 3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a Pyrimidine-5-one; 7-[( E )-2-(2-cyclohexyloxy-3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy) )-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-{3-methoxy-2-(2- Methoxyethoxy)phenyl}-1-vinyl]-6-[4-(trifluoromethoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a Pyrimidine-5-one; 4-{7-[( E )-2-{(3-cyanopropoxy)-3-methoxy}phenylvinyl]-6-[4-(trifluoro Methoxy)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E ) -2-(2-cyclopropylmethoxy-3-methoxyphenyl)-1-vinyl]-3-methyl-6-[4-(trifluoro-methoxy)phenyl]- 5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy-3-methoxyphenyl) 1-vinyl]-2,3-dimethyl-6-[4-(trifluoromethoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine- 5-ketone; 2-chloro-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methoxyphenyl)vinyl]-6-[4- (trifluoro-methoxy)phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 2-chloro-6-[4-(dimethylamino) Phenyl]-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3-methoxy-phenyl)vinyl]-5 H -[1,3 Thiazolo[3,2- a ]pyrimidin-5-one; 4-{2-chloro-7-[( E )-2-(2-(2,2-dimethylpropoxy)-3- Methoxyphenyl)vinyl]-5-oxo-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 2-chloro-6-[4- (Dimethylamino)phenyl]-7-[( E )-2-(2-isobutoxy-3-methoxyphenyl)vinyl]-5 H -[1,3]thiazolidine [3,2- a ]pyrimidin-5-one; 4-{7-[( E )-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-5- Oxo-3-(trifluoromethyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}benzonitrile; 4-( 2-{( E )-2-[2-(3-Cyanopropoxy)-3-methoxyphenyl}-1-vinyl}-4-oxo-4 H -benzo[4, 5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-(2-{( E )-2-[3-methoxy-2-(methoxy) Ethoxy)phenyl}-1-vinyl}-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzyl Nitrile; 4-{2-[( E )-2-[2-(2-ethoxyethoxy)-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[2-cyclopropyl Methoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidine 3-yl)benzonitrile; 4-{2-[( E )-2-[2-butoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -Benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[2-(3-A Butyoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo-4 H -benzo[4,5]-[1,3]thiazolo-[3,2] Pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[2-cyclobutylmethoxy-3-methoxy]phenyl}-1-vinyl]-4-oxo- 4 H -benzo[4,5]-[1,3]thiazolo-[3,2]pyrimidin-3-yl)benzonitrile; 4-{2-[( E )-2-[3-methoxy G-pyridin-2-ylmethoxy ] Phenyl} -1-ethenyl] -4-oxo -4 H - benzo [4,5] - [1,3] thiazolo - [3,2] pyrimidin-3-yl) benzonitrile; 2 -{( E )-2-[(2-cyclopropylmethoxy)-3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethyl-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2-[(2-methoxyethoxy) 3-methoxyphenyl]-1-vinyl}-3-(4-trifluoromethyl-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3 , 2- a ] pyrimidin-4-one; 2-{( E )-2-[(2-ethoxyethoxy)-3-methoxyphenyl]-1-vinyl}-3-( 4-trifluoromethyl-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2 -[(3-cyanopropoxy-3-methoxy)phenyl]-1-vinyl}-3-(4-trifluoromethyl-phenyl)-4 H -benzo[4,5 ][1,3]thiazolo-[3,2- a ]pyrimidin-4-one; 2-{( E )-2-[2-cyclopropylmethoxy-3-methoxyphenyl]- 1-vinyl}-3-(4-trifluoromethoxy-phenyl)-4 H -benzo[4,5][1,3]thiazolo-[3,2- a ]pyrimidine-4- Ketone; 2-{( E )-2-[3-methoxy-2-(2-methoxyethoxy)phenyl]-1-vinyl}-3-(4-trifluoromethoxy - phenyl) -4 H - benzo [4,5] [1,3] thiazolo - [3,2- a] pyrimidin-4-one; 2 - {(E) -2 - [(2- Methoxyethoxy) -3-methoxyphenyl] -l-ethenyl} -3- (4-trifluoromethoxy - phenyl) -4 H - benzo [4,5] [1, 3]thiazolo-[3,2- a ]pyrimidin-4-one; 7-[( E )-2-(4-chlorophenyl)vinyl]-6-phenyl-5 H -[1,3 Thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(2-cyclopropylmethoxy)-3-methoxyphenyl)-1-vinyl] -6-(6-fluoro-3-pyridyl)-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 4-{5-oxo-7-[( E )-2-(3-pyridyl)-1-vinyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-6-yl}-benzonitrile; 7-[( E ) -2-(2-cyclopropylmethoxy)-1-vinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]-thiazolo[3,2 - a ] pyrimidin-5-one; 7-[( E )-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-vinyl]-6-[4-(three Fluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidin-5-one; 7-[( E )-2-(4-cyclopropylmethoxy) 3-methoxyphenyl)-1-vinyl]-6-[4-(trifluoromethyl)-phenyl]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine -5-keto; 7-[( E )-2-pyridin-3-ylvinyl]-6-[4-(trifluoromethyl)phenyl]-5 H -[1,3]thiazolo[3 , 2- a] pyrimidin-5-one; 7 - [(E) -2- (2- cyclopropyl-methoxy-3-fluorophenyl) -1-ethanone Yl] -6- [4- (trifluoromethoxy) - phenyl] -5 H - [1,3] thiazolo [3,2- a] pyrimidin-5-one; and 2 - [(E) -2-(2-cyclopropylmethoxy-3-methoxyphenyl)vinyl]-3-(4-trifluoromethoxyphenyl)-10-methylpyrimido[1,2- a ] benzimidazole-4(10 H )-one; or a pharmaceutically acceptable salt of the above compound. A method of preventing, ameliorating or treating a disease, disorder or syndrome mediated by a vanilloid receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount as claimed in claim 1 a compound of any of the five items. The method of claim 6, wherein the symptoms of the disease, disorder, syndrome or condition associated with TRPV3 function are selected from the group consisting of: pain; acute pain; chronic pain; nociceptive pain; Sexual pain; postoperative pain; toothache; cancer pain; heartache caused by ischemic myocardium; pain caused by migraine; joint pain; neuropathy; neuralgia; trigeminal neuralgia; nerve injury; diabetic neuropathy; neurodegenerative disease Retinopathy; neuropathic skin disorder; stroke; bladder allergy; urinary incontinence; vulvar pain; gastrointestinal disorders such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflamed bowel Disease, Crohn's disease, celiac disease; inflammatory diseases such as pancreatitis; respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; skin, eye or mucous membrane irritation; dermatitis; pruritus, Such as uremia pruritus; fever; muscle spasm; vomiting; dyskinesia; depression; Huntington's disease; memory loss; brain function Limit; amyotrophic lateral sclerosis (ALS); dementia; arthritis; osteoarthritis; diabetes; obesity; urticaria; actinic keratosis; keratoacanthoma; alopecia; Tinnitus; hypersensitivity; anxiety; and benign prostatic hyperplasia. A method of treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 5, wherein preferably the pain is Acute pain, chronic pain, or postoperative pain. A method of treating neuropathic pain or inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 5.