# Patent

## Title
Azetidinyl diamides as monoacylglycerol lipase inhibitors

## Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows:




wherein Y, Z, R1, and s are defined herein.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. provisional patent application Nos. 61/171,658 and 61/171,649, each filed Apr. 22, 2009, which are hereby incorporated by reference in their entirety.


STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
The research and development of the invention described below was not federally sponsored.
BACKGROUND OF THE INVENTION
Cannabis sativa has been used for the treatment of pain for many years. Δ9-tetrahydrocannabinol is a major active ingredient from Cannabis sativa and an agonist of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two cannabinoid G protein-coupled receptors have been cloned, cannabinoid receptor type 1 (CB1 Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB2 Munro et al., Nature, 1993, 365, 61-5). CB1 is expressed centrally in brain areas, such as the hypothalamus and nucleus accumbens as well as peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB2 is predominantly expressed in immune cells, such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), and under certain conditions, also in the brain (Benito et al., Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110) and cardiac (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252) muscle. An abundance of pharmacological, anatomical and electrophysiological data, using synthetic agonists, indicate that increased cannabinoid signaling through CB1/CB2 promotes analgesia in tests of acute nociception and suppresses hyperalgesia in models of chronic neuropathic and inflammatory pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60; Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).
Efficacy of synthetic cannabinoid receptor agonists is well documented. Moreover, studies using cannabinoid receptor antagonists and knockout mice have also implicated the endocannabinoid system as an important modulator of nociception. Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and 2-arachidinoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97) are 2 major endocannabinoids. AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) and 2-AG is hydrolyzed by monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). Genetic ablation of FAAH elevates endogenous AEA and results in a CB1-dependent analgesia in models of acute and inflammatory pain (Lichtman et al., Pain, 2004, 109, 319-27), suggesting that the endocannabinoid system functions naturally to inhibit pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60). Unlike the constitutive increase in endocannabinoid levels using FAAH knockout mice, use of specific FAAH inhibitors transiently elevates AEA levels and results in antinociception in vivo (Kathuria et al., Nat Med, 2003, 9, 76-81). Further evidence for an endocannabinoid-mediated antinociceptive tone is demonstrated by the formation of AEA in the periaqueductal grey following noxious stimulation in the periphery (Walker et al., Proc Natl Acad Sci USA, 1999, 96, 12198-203) and, conversely, by the induction of hyperalgesia following antisense RNA-mediated inhibition of CB1 in the spinal cord (Dogrul et al., Pain, 2002, 100, 203-9).
With respect to 2-AG, intravenous delivery of 2-AG produces analgesia in the tail flick (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90) and hot plate (Lichtman et al., J Pharmacol Exp Ther, 2002, 302, 73-9) assays. In contrast, it was demonstrated that 2-AG given alone is not analgesic in the hot plate assay, but when combined with other 2-monoacylglycerols (i.e., 2-linoleoyl glycerol and 2-palmitoyl glycerol), significant analgesia is attained, a phenomenon termed the “entourage effect” (Ben-Shabat et al., Eur J Pharmacol, 1998, 353, 23-31). These “entourage” 2-monoacylglycerols are endogenous lipids that are co-released with 2-AG and potentiate endocannabinoid signaling, in part, by inhibiting 2-AG breakdown, most likely by competition for the active site on MGL. This suggests that synthetic MGL Inhibitors will have a similar effect. Indeed, URB602, a relatively weak synthetic MGL Inhibitor, showed an antinociceptive effect in a murine model of acute inflammation (Comelli et al., Brit J Pharmacol, 2007, 152, 787-794).
Although the use of synthetic cannabinoid agonists have conclusively demonstrated that increased cannabinoid signaling produces analgesic and anti-inflammatory effects, it has been difficult to separate these beneficial effects from the unwanted side effects of these compounds. An alternative approach is to enhance the signaling of the endocannabinoid system by elevating the level of 2-AG, the endocannabinoid of highest abundance in the central nervous system (CNS) and gastrointestinal tract, which may be achieved by inhibition of MGL. Therefore, MGL Inhibitors are potentially useful for the treatment of pain, inflammation, and CNS disorders (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80; Shaveri et al., Brit J Pharmacol, 2007, 152, 624-632; McCarberg Bill et al., Amer J Ther, 2007, 14, 475-83), as well as glaucoma and disease states arising from elevated intraocular pressure (Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp. Eye Res, 2008, 87(2):106-14).
SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula (I)




wherein

    
    
        Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
        Group a) is
        i) substituted C6-10 aryl,
        ii) C3-8 cycloalkyl,
        iii) trifluoromethyl, or
        iv) heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furazan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl, and [1,2,3]thiadiazolyl;
        
            wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        
        
    
    


Group b) is

    
    
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of thiazolyl, pyridinyl, indolyl, indazolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, imidazo[1,2-a]pyridin-2-yl, quinolinyl, thienyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, and benzimidazolyl;
        iii) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
        iv) 2-oxo-3,3-bis-(3-trifluoromethylphenylmethyl)-2,3-dihydro-1H-indol-5-yl;
        v) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        vi) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        vii) 2,3-dihydro-1H-indolyl;
        viii) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
        ix) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        x) 1,1,3-tris-(3-trifluoromethylphenylmethyl)indan-2-on-6-yl; or
        xi) 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;
    
    


wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4 alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

    
    
        i) C6-10aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) 3-trifluoromethyl-phenylaminocarbonylmethoxy;
        iv) C6-10aryl(C1-4)alkylthio;
        v) phenyl(C1-4)alkylsulfonyl;
        vi) phenylcarbonyl optionally substituted with chloro or fluoro;
        vii) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        viii) N-methyl-N-phenyl-aminocarbonyl-methyl;
        ix) pyrrolidin-1-ylcarbonylmethyl;
        x) phenyl(C2-6)alkynyl;
        xi) heteroaryl(C1-6)alkyl wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
        xii) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
        xiii) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent;
        xiv) heteroaryl-(Q)-C1-6alkyl wherein Q is O or S; wherein heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        xv) phenyl-(Q)-C1-6alkyl wherein Q is O, S, SO2, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
    
    


wherein phenyl of the C6-10aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkoxycarbonylamino; C1-4alkyl; cyanomethyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C1-4alkylcarbonyl; C1-4alkoxycarbonyl; cyano; carboxy; aminocarbonyl; C1-4alkylaminocarbonyl; di(C1-4alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy; aminosulfonyl; di(C1-4alkyl)aminosulfonyl; C1-4alkylsulfonyl; di(C1-4alkyl)aminosulfonyl; and NRcRd; wherein Rc is hydrogen or C1-6alkyl and wherein Rd is hydrogen, C1-6alkyl, cyano(C1-4)alkyl, C3-8cycloalkyl, C1-6alkylcarbonyl, C3-8cycloalkylcarbonyl, C3-8cycloalkyl(C1-4)alkyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C6-10arylcarbonyl; di(C1-4alkyl)aminosulfonyl, and C1-4alkylsulfonyl;
s is 0, 1 or 2; provided that when s is 2, R1 is independently selected from the group consisting of phenyl, C1-3alkyl, and C6-10aryl(C1-3)alkyl;
R1 is C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo, or aryl(C1-3)alkyl; or, when s is 2 and R1 is C1-3alkyl, the C1-3alkyl substituents are taken with the piperizinyl ring to form a 3,8-diaza-bicyclo[3.2.1]octanyl or 2,5-diaza-bicyclo[2.2.2]octanyl ring system;
provided that a compound of formula (I) is other than
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)phenyl, and s is 0; or
a compound wherein Y is thiazol-2-yl, Z is 4-(phenylmethyl)phenyl, s is 1, and R1 is 3-phenyl;
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
The present invention is further directed to a compound of Formula (I)




wherein

    
    
        Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
    
    


Group a) is

    
    
        i) substituted C6-10 aryl,
        ii) trifluoromethyl; or
        iii) heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, pyrrolyl, and pyridinyl;
        
            wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        
        
    
    


Group b) is

    
    
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
        iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        v) 2,3-dihydro-1H-indolyl;
        vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
        vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        viii) 1,1,3-tris-(3-trifluoromethylphenylmethyl)indan-2-on-6-yl; or
        ix) 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;
    
    


wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

    
    
        i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) C6-10aryl(C1-4)alkylthio;
        iv) phenyl(C1-4)alkylsulfonyl;
        v) phenylcarbonyl optionally substituted with chloro or fluoro;
        vi) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        vii) N-methyl-N-phenyl-aminocarbonyl-methyl;
        viii) phenyl(C2-6)alkynyl;
        ix) heteroaryl(C1-6)alkyl wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
        x) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
        xi) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        xii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, SO2, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
    
    


wherein phenyl of the C6-10aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkoxycarbonylamino; C1-4alkyl; cyanomethyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C1-4alkylcarbonyl; C1-4alkoxycarbonyl; cyano; carboxy; aminocarbonyl; C1-4alkylaminocarbonyl; di(C1-4alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxyl; di(C1-4alkyl)aminosulfonyl; and NRcRd; wherein Rc is hydrogen or C1-6alkyl and wherein Rd is hydrogen, C1-6alkyl, cyano(C1-4)alkyl, C3-8cycloalkyl, C1-6alkylcarbonyl, C3-8cycloalkylcarbonyl, C3-8cycloalkyl(C1-4)alkyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C6-10arylcarbonyl; di(C1-4alkyl)aminosulfonyl, and C1-4alkylsulfonyl;
s is 0 or 1;
R1 is phenyl or C1-3alkyl;
provided that a compound of formula (I) is other than
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)phenyl, and s is 0;
or
a compound wherein Y is thiazol-2-yl, Z is 4-(phenylmethyl)phenyl, s is 1, and R1 is 3-phenyl;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.
The present invention is also directed to a compound of Formula (I)




wherein

    
    
        Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
        Group a) is
        i) substituted C6-10 aryl,
        ii) trifluoromethyl; or
        iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
        wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        Group b) is
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
        iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        v) 2,3-dihydro-1H-indolyl;
        vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
        vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl; or
        viii) 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;
    
    


wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

    
    
        i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) C6-10aryl(C1-4)alkylthio;
        iv) phenylcarbonyl optionally substituted with chloro or fluoro;
        v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        vi) N-methyl-N-phenyl-aminocarbonyl-methyl;
        vii) phenyl(C2-6)alkynyl;
        viii) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
        ix) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        x) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4aryl, C1-4alkoxy, and trifluoromethyl;
    
    


wherein phenyl of the C6-10aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio;
s is 0 or 1;
R1 is phenyl or methyl;
provided that a compound of Formula (I) is other than
a compound wherein Y is thiazol-2-yl, Z is 4-(phenylmethyl)phenyl, s is 1, and R1 is 3-phenyl; a compound wherein Y is thiazol-2-yl, Z is 2-(pyridin-4-ylmethyl)-3H-benzimidazol-4-yl, and s is 0;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.
The present invention is directed to a compound of Formula (I)




wherein

    
    
        Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
        Group a) is
        i) substituted phenyl,
        ii) trifluoromethyl; or
        iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
        wherein phenyl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        Group b) is
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, and indazolyl;
        iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        v) 2,3-dihydro-1H-indolyl;
        vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
        vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
    
    


wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

    
    
        i) C6-10aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) C6-10aryl(C1-4)alkylthio;
        iv) phenylcarbonyl optionally substituted with chloro or fluoro;
        v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        vi) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
        vii) heteroaryl(C1-2)alkylthio, wherein heteroaryl is pyridinyl; wherein said pyridinyl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        viii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
    
    


wherein phenyl of the C6-10aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio;
s is 0 or 1;
R1 is methyl;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.
The present invention is directed to a compound of Formula (I)




selected from the group consisting of:

    a compound wherein Y is thiazol-2-yl, Z is 4-phenylmethyl-phenyl, s is 1, and R1 is 2-methyl;
    a compound wherein Y is thiazol-2-yl, Z is 4-phenylmethyl-phenyl, s is 1, and R1 is 3-methyl;
    a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(pyridin-4-ylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-fluoro-4-(3,4-dichlorophenylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(3-chlorophenylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(pyridin-3-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-pyridin-4-ylmethoxy-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(3,4-dichlorophenylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-fluoro-4-(2,3-dichlorophenylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(pyridin-2-ylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylmethylthio)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(2,3-dichlorophenylmethylthio)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3,4-dichlorophenylmethylthio)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(4-chlorophenylmethylthio)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(pyridin-3-ylmethylthio)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenoxymethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylthiomethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylaminomethyl)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(3-chlorophenylthiomethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenylthiomethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(3-chlorophenylmethoxy)-phenyl, and is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenoxymethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(5-chloro-thien-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(5-chloro-thien-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(5-chloro-thien-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(3-chlorophenylaminomethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(4-chlorophenoxymethyl)-4-methyl-thiazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 2-(4-chlorophenoxymethyl)-4-methyl-thiazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(quinolin-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(quinolin-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenylaminomethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(quinolin-2-ylmethoxy)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethylthio)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(3-trifluoromethylphenylmethylthio)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylthio)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylsulfonylmethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethyl-phenylsulfonylmethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(5-chloro-pyridin-3-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(5-chloro-pyridin-3-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(phenylmethyl)-1H-benzimidazol-4-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(5-chloro-pyridin-3-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(4-trifluoromethyl-phenyl-fluoromethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(6-bromo-pyridin-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-(6-bromo-pyridin-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(4-trifluoromethylphenylmethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(phenyl-difluoromethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(6-bromo-pyridin-2-ylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(2,3-dihydro-1H-indol-5-ylcarbonyl)-1H-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(2-fluoro-phenylmethyl)-3H-benzimidazol-4-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(3-fluoro-phenylmethyl)-3H-benzimidazol-4-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(4-chlorophenylmethyl)-3H-benzimidazol-4-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-oxo-3,3-bis-(3-trifluoromethylphenylmethyl)-2,3-dihydro-1H-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(phenylmethyl)-indol-3-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-phenylmethyl-2,3-dihydro-1H-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethyl)phenyl, and s is 0;
    a compound wherein Y is 4-(4-trifluoromethylphenylmethyl)phenyl, Z is thiazol-4-yl, and s is 0;
    a compound wherein Y is 4-(4-trifluoromethylphenylmethyl)phenyl, Z is thiazol-2-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethyl)phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 4-(4-trifluoromethyl-phenylmethyl)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(phenylethyl)-1H-benzimidazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(phenylmethyl)-3H-benzimidazol-5-yl, and s is 0;
    a compound wherein Y is 2-(phenylethyl)-3H-benzimidazol-5-yl, Z is thiazol-4-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 2-(phenylmethyl)-1H-benzimidazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(phenylmethyl)-1H-benzimidazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-(2-fluorophenylaminomethyl)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-(4-trifluoromethylphenyl-methyl)-4-fluoro-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-(4-trifluoromethylphenyl-methyl)-4-fluoro-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl, and s is 0;
    a compound wherein Y is 1H-pyrrol-2-yl, Z is 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl, and s is 0;
    a compound wherein Y is 1H-pyrrol-2-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
    a compound wherein Y is isothiazol-5-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)-phenyl, and s is 0;
    a compound wherein Y is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, Z is thiazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(phenylcarbonyl)phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
    a compound wherein Y is 1H-pyrrol-2-yl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl, and s is 0;
    a compound wherein Y is trifluoromethyl, Z is 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
    a compound wherein Y is 1H-pyrrol-2-yl, Z is 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 3-(4-fluorophenylcarbonyl)-indol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-methyl-3-(4-fluorophenylmethyl)-indol-6-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 1-methyl-3-(4-fluorophenylmethyl)-indol-6-yl, and s is 0;
    a compound wherein Y is 1H-pyrrol-2-yl, Z is 1-methyl-3-(4-fluorophenylmethyl)-indol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylmethyl)-1H-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(4-fluorophenylmethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(N-methyl-N-phenyl-aminocarbonyl-methyl)-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-4-yl, Z is 1-(N-methyl-N-phenyl-aminocarbonyl-methyl)-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-methyl-3-(3-fluorophenylmethyl)-indol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-methyl-3-(phenylmethyl)-indol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(pyrrolidin-1-ylcarbonylmethyl)-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-trifluoromethyl-phenylmethyl)-1H-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(4-trifluoromethylphenylmethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(3-trifluoromethyl-phenylmethyl)-1H-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(3-trifluoromethylphenylmethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is (1-phenyl-ethyl)-2H-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethyl-phenylaminocarbonylmethoxy)-phenyl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-aminosulfonyl-phenylmethyl)-2,5-dimethyl-pyrrol-3-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-aminocarbonyl-phenylmethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-cyano-phenylmethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(pyridin-4-ylmethyl)-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(pyridin-4-ylmethyl)-indol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(pyridin-3-ylmethyl)-indol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(4-fluoro-phenylethyl)-indazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylmethyl)-indazol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 2-(4-fluoro-phenylmethyl)-indazol-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1-(4-chloro-phenylmethyl)-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1,1,3-tris-(3-trifluoromethylphenylmethyl)indan-2-on-6-yl, and s is 0;
    a compound wherein Y is thiazol-2-yl, Z is 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;


or a solvate or a pharmaceutically acceptable salt form thereof.
The present invention also provides, inter alia, a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.
Also provided are processes for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.
The present invention further provides, inter alia, methods for treating or ameliorating a MGL-modulated disorder in a subject, including a human or other mammal in which the disease, syndrome, or condition is affected by the modulation of the MGL enzyme, such as pain and the diseases that lead to such pain, inflammation and CNS disorders, using a compound of Formula (I).
The present invention also provides, inter alia, methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.


DETAILED DESCRIPTION OF THE INVENTION
With reference to substituents, the term “independently” refers to the situation that when more than one substituent is possible, the substituents may be the same or different from each other.
The term “alkyl” whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, designated numbers of carbon atoms (e.g., C1-8) refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups, such as (C1-6alkyl)2amino, the C1-6alkyl groups of the dialkylamino may be the same or different.
The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl” is as defined above.
The terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 or more carbon atoms, wherein an alkenyl chain contains at least one double bond and an alkynyl chain contains at least one triple bond.
The term “cycloalkyl” refers to saturated or partially saturated, monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
The term “benzo-fused cycloalkyl” refers to a 5- to 8-membered monocyclic cycloalkyl ring fused to a benzene ring. The carbon atom ring members that form the cycloalkyl ring may be fully saturated or partially saturated.
The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclic ring system having 3 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heterocyclyl is a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are nitrogen, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1 or 2 members are nitrogen and up to 2 members are oxygen or sulfur and at least one member must be either nitrogen, oxygen or sulfur; wherein, optionally, the ring contains zero to one unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to 2 unsaturated bonds. The carbon atom ring members that form a heterocycle ring may be fully saturated or partially saturated. The term “heterocyclyl” also includes two 5 membered monocyclic heterocycloalkyl groups bridged to form a bicyclic ring. Such groups are not considered to be fully aromatic and are not referred to as heteroaryl groups. When a heterocycle is bicyclic, both rings of the heterocycle are non-aromatic and at least one of the rings contains a heteroatom ring member. Examples of heterocycle groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
The term “benzo-fused heterocyclyl” refers to a 5 to 7 membered monocyclic heterocycle ring fused to a benzene ring. The heterocycle ring contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. The carbon atom ring members that form the heterocycle ring may be fully saturated or partially saturated. Unless otherwise noted, benzo-fused heterocycle ring is attached to its pendant group at a carbon atom of the benzene ring.
The term “aryl” refers to an unsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of aryl rings include phenyl and naphthalenyl.
The term “heteroaryl” refers to an aromatic monocyclic or bicyclic aromatic ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6 membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For the case wherein the 6 membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. When a heteroaryl is bicyclic, at least one heteroatom is present in each ring. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Unless otherwise noted, the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
Unless otherwise noted, the term “benzo fused heteroaryl” refers to a 5 to 6 membered monocyclic heteroaryl ring fused to a benzene ring. The heteroaryl ring contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Examples of heteroaryl groups with the optionally fused benzene rings include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise noted, the benzo-fused heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “formyl” refers to the group —C(═O)H.
The term “oxo” refers to the group (═O).
Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C1-C6) refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and alkoxy substituents, the designated number of carbon atoms includes all of the independent members included within a given range specified. For example C1-6 alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g., C1-2, C1-3, C1-4, C1-5, C2-6, C3-6, C4-6, C5-6, C2-5, etc.).
In general, under standard nomenclature rules used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a “C1-C6 alkylcarbonyl” substituent refers to a group of the formula:




The numbering system shown below is used for describing the position of R1 substituents on the piperazinyl ring of Formula (I):




The term “R” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the S-configuration. As used herein, the terms “*R” or “*S” at a stereocenter are used to designate that the stereocenter is of pure but unknown configuration. As used herein, the term “RS” refers to a stereocenter that exists as a mixture of the R- and S-configurations. Similarly, the terms “*RS” or “*SR” refer to a stereocenter that exists as a mixture of the R- and S-configurations and is of unknown configuration relative to another stereocenter within the molecule.
Compounds containing one stereocenter drawn without a stereo bond designation are a mixture of 2 enantiomers. Compounds containing 2 stereocenters both drawn without stereo bond designations are a mixture of 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” and drawn with stereo bond designations are a 2-component mixture with relative stereochemistry as drawn. Compounds with 2 stereocenters both labeled “*RS” and drawn with stereo bond designations are a 2-component mixture with relative stereochemistry unknown. Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and S-configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.
Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of Formula (I) as herein defined can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The term “subject” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” refers to an amount of an active compound or pharmaceutical agent, including a compound of the present invention, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.
The term “composition” refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.
The term “MGL inhibitor” is intended to encompass a compound that interacts with MGL to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s). The term “MGL-modulated” is used to refer to the condition of being affected by the modulation of the MGL enzyme including the condition of being affected by the inhibition of the MGL enzyme, such as, for example, pain and the diseases that lead to such pain, inflammation and CNS disorders.
As used herein, unless otherwise noted, the term “affect” or “affected” (when referring to a disease, syndrome, condition or disorder that is affected by inhibition of MGL) shall include a reduction in the frequency and/or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and/or include the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.
The compounds of Formula (I) are useful in methods for treating, ameliorating and/or preventing a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MGL. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and/or prevention, a therapeutically effective amount of a compound of Formula (I) as herein defined, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof. In particular, the compounds of Formula (I) as herein defined are useful for treating, ameliorating and/or preventing pain; diseases, syndromes, conditions, or disorders causing such pain; inflammation and/or CNS disorders. More particularly, the compounds of Formula (I) as herein defined are useful for treating, ameliorating and/or preventing inflammatory pain, inflammatory hypersensitivity conditions and/or neuropathic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), as herein defined.
Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder, or a pain state including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.
One type of inflammatory pain is inflammatory hyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases including Crohn's Disease, ulcerative colitis, urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, nasal hypersensitivity, itch, contact dermintisi and/or dermal allergy and chronic obstructive pulmonary disease.
In an embodiment, the present invention is directed to a method for treating, ameliorating and/or preventing inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I), as herein defined. In a further embodiment, the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formule (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
A further embodiment of the present invention is directed to a method for treating, ameliorating and/or preventing neuropathic pain. Examples of a neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.
One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain (neuralgia), pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.
In a further embodiment, the present invention is directed to a method for treating, ameliorating and/or preventing neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I), as herein defined, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention is directed to a method for treating, ameliorating and/or preventing CNS disorders. Examples of CNS disorders include anxieties, such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress, disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, such as major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.
The present invention includes a pharmaceutical composition comprising a compound of Formula (I) wherein:




wherein

a) Group a) is

    
    
        i) substituted C6-10aryl,
        ii) trifluoromethyl; or
        iii) heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, pyrrolyl, and pyridinyl;
        
            wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        
        
    
    


b) Group a) is

    
    
        i) substituted C6-10 aryl,
        ii) trifluoromethyl; or
        iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
        
            wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        
        
    
    


c) Group a) is

    
    
        i) substituted phenyl,
        ii) trifluoromethyl; or
        iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
        
            wherein phenyl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
        
        
    
    


d) Group b) is

    
    
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
        iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        v) 2,3-dihydro-1H-indolyl;
        vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
        vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        
            wherein C6-10aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of
        
        
        i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) C6-10aryl(C1-4)alkylthio;
        iv) phenyl(C1-4)alkylsulfonyl;
        v) phenylcarbonyl optionally substituted with chloro or fluoro;
        vi) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        vii) N-methyl-N-phenyl-aminocarbonyl-methyl;
        viii) phenyl(C2-6)alkynyl;
        ix) heteroaryl(C1-6)alkyl wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
        x) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
        xi) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        xii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, SO2, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
        
            wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkoxycarbonylamino; C1-4alkyl; cyanomethyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C1-4alkylcarbonyl; C1-4alkoxycarbonyl; cyano; carboxy; aminocarbonyl; C1-4alkylaminocarbonyl; di(C1-4alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxyl; di(C1-4alkyl)aminosulfonyl; and NRcRd; wherein Rc is hydrogen or C1-6alkyl and wherein Rd is hydrogen, C1-6alkyl, cyano(C1-4)alkyl, C3-8cycloalkyl, C1-6alkylcarbonyl, C3-8cycloalkylcarbonyl, C3-8cycloalkyl(C1-4)alkyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C6-10arylcarbonyl; di(C1-4alkyl)aminosulfonyl, and C1-4alkylsulfonyl;
        
        
    
    


e) Group b) is

    
    
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
        iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        v) 2,3-dihydro-1H-indolyl;
        vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
        vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        
            wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of
        
        
        i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) C6-10aryl(C1-4)alkylthio;
        iv) phenylcarbonyl optionally substituted with chloro or fluoro;
        v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        vi) N-methyl-N-phenyl-aminocarbonyl-methyl;
        vii) phenyl(C2-6)alkynyl;
        viii) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
        ix) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        x) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
        
            wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio;
        
        
    
    


f) Group b) is

    
    
        i) C6-10 aryl;
        ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, and indazolyl;
        iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
        iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        v) 2,3-dihydro-1H-indolyl;
        vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
        vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
        
            wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of
        
        
        i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
        ii) C6-10aryl(C1-4)alkoxy;
        iii) C6-10aryl(C1-4)alkylthio;
        iv) phenylcarbonyl optionally substituted with chloro or fluoro;
        v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
        vi) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
        vii) heteroaryl(C1-2)alkylthio, wherein heteroaryl is pyridinyl; wherein said pyridinyl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
        viii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
        
            wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio;
        
        
    
    


g) s is 0 or 1;
h) R1 is phenyl or C1-3alkyl;
i) R1 is methyl;
and any combination of embodiments a) through i) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded;
provided that a compound of formula (I) is other than a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)phenyl, and s is 0;
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
For use in medicine, salts of compounds of Formula (I) as herein defined refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of Formula (I) as herein defined or of their pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (I) as herein defined include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) as herein defined carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids and bases that may be used in the preparation of pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholin, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
Embodiments of the present invention include prodrugs of compounds of Formula (I) as herein defined. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing embodiments of the present invention, the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula I.
Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
One embodiment of the present invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enantiomer of a compound of Formula (I) as herein defined wherein said composition is substantially free from the (−)-isomer of said compound. In the present context, substantially free means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (−)-isomer calculated as.




  
    
      %
      ⁢
      
        (
        +
        )
      
    
    -
    enantiomer
  
  =
  
    
      
        (
        
          
            mass
            ⁡
            
              (
              +
              )
            
          
          -
          enantiomer
        
        )
      
      
        
          (
          
            
              mass
              ⁡
              
                (
                +
                )
              
            
            -
            enantiomer
          
          )
        
        +
        
          (
          
            
              mass
              ⁡
              
                (
                -
                )
              
            
            -
            enantiomer
          
          )
        
      
    
    ×
    100
  




Another embodiment of the present invention is a composition, including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the (−)-enantiomer of a compound of Formula (I) as herein defined wherein said composition is substantially free from the (+)-isomer of said compound. In the present context, substantially free from means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (+)-isomer calculated as




  
    
      %
      ⁢
      
        (
        +
        )
      
    
    -
    enantiomer
  
  =
  
    
      
        (
        
          
            mass
            ⁡
            
              (
              +
              )
            
          
          -
          enantiomer
        
        )
      
      
        
          (
          
            
              mass
              ⁡
              
                (
                +
                )
              
            
            -
            enantiomer
          
          )
        
        +
        
          (
          
            
              mass
              ⁡
              
                (
                -
                )
              
            
            -
            enantiomer
          
          )
        
      
    
    ×
    100
  




During any of the processes for preparation of the compounds of the various embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) as herein defined and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent
By way of example, in the pharmaceutical compositions of embodiments of the present invention, the compounds of Formula (I) as herein defined may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.
Solid oral dosage forms, such as tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
Additional oral forms in which the present inventive compounds may be administered include exilirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
Alternatively, compounds of Formula (I) as herein defined can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between about 1% and about 10% by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a white wax or white soft paraffin base together with any stabilizers and preservatives as may be required. An alternative means of administration includes transdermal administration by using a skin or transdermal patch.
The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
For buccal or sublingual administration, the pharmaceutical compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
By way of further example, pharmaceutical compositions containing at least one of the compounds of Formula (I) as herein defined as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus for liquid oral preparations, such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be optionally coated with substances, such as, sugars, or be enterically-coated so as to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives, such as solubilizers and preservatives.
A therapeutically effective amount of a compound of Formula (I) as herein defined or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) as herein defined will vary as will the diseases, syndromes, conditions, and disorders being treated.
For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of a compound of Formula (I) as herein defined.
Advantageously, a compound of Formula (I) as herein defined may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.
Optimal dosages of a compound of Formula (I) as herein defined to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of Formula (I) as herein defined may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) as herein defined is required for a subject in need thereof.
As MGL Inhibitors, the compounds of Formula (I) as herein defined are useful in methods for treating and preventing a disease, a syndrome, a condition or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition or the disorder is affected by the modulation of the MGL enzyme. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I) as herein defined. In particular, the compounds of Formula (I) as herein defined are useful for preventing or treating pain, or diseases, syndromes, conditions, or disorders causing such pain, or for treating inflammation or CNS disorders.
Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder, or a pain state, including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pain, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.
Examples of CNS disorders include anxieties, such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress, disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, such as major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.
General Synthetic Methods
Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein.
Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:
















AcCl
acetyl chloride



AcOH
glacial acetic acid



aq.
aqueous



Bn or Bzl
benzyl



CAN
ceric ammonium nitrate



conc.
concentrated



DBU
1,8-diazabicyclo[5.4.0]undec-7-ene



DCC
N,N′-dicyclohexyl-carbodiimide



DCE
1,2-dichloroethane



DCM
dichloromethane



DIAD
diisopropyl azodicarboxylate



DIPEA
diisopropyl-ethyl amine



DMF
N,N-dimethylformamide



DMSO
dimethylsulfoxide



DPPA
diphenylphosphoryl azide



EDC
N-(3-dimethylaminopropyl)-N′-




ethylcarbodiimide hydrochloride



ESI
electrospray ionization



EtOAc
ethyl acetate



EtOH
ethanol



h
hour(s)



HATU
O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-




tetramethyluronium hexafluorophosphate



HBTU
O-(1H-benzotriazol-1-yl)-1,1,3,3-




tetramethyluronium hexafluorophosphate



HEK
human embryonic kidney



HPLC
high performance liquid chromatography



mCPBA
meta-chloroperoxybenzoic acid



MeCN
acetonitrile



MeOH
methanol



MeOTf
methyl triflate



MHz
megahertz



min
minute(s)



MS
mass spectrometry



NBS
N-bromosuccinimide



NMR
nuclear magnetic resonance



PyBrOP
bromo-tris-pyrrolidinophosphonium




hexafluorophosphate



RP
reverse-phase



Rt
retention time



TEA or Et3N
triethylamine



TFA
trifluoroacetic acid



THF
tetrahydrofuran



TLC
thin layer chromatography



TMS
tetramethylsilane










Scheme A illustrates a route for the synthesis compounds of Formula (I)-A, wherein R1, s, Y, and Z are as defined herein.




A compound of formula A1, wherein PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula A1 in the presence of a non-nucleophilic base, such as pyridine, may be treated with trifluoroacetic anhydride to afford a compound of formula A2. Removal of the protecting group (PG) by conventional methods affords a compound of formula A3. A compound of formula A3 may be treated with a compound of formula A4 in the presence of a hindered amine base, such as DIPEA, to afford a compound of formula A5. Treatment of a compound of formula A5 with 1-chloroethyl chloroformate followed by methanolysis affords the corresponding amine of formula A6. Similarly, when the R1 substituent of a compound of formula A5 is hydroxy(C1-3)alkyl, the benzhydryl group may be removed by hydrogenation in the presence of a palladium catalyst to afford the amine of formula A6. A compound of formula A6 may be coupled with a carboxylic acid of formula A7 wherein Q is hydroxy, in the presence of an appropriate coupling agent such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, to afford an amide of formula A8. Similarly, an acid chloride of formula A7 wherein Q is chloro may be used to effect the acylation of a compound of formula A6. In such case a non-nucleophilic base such as pyridine may be added to afford an amide of formula A8. Removal of the trifluoroacetyl group of a compound of formula A8 may be accomplished by the action of potassium carbonate or TEA in the presence of an alcoholic solvent such as methanol to afford a compound of formula A9. A compound of formula A9 may be acylated with a carboxylic acid or acid chloride of formula A10, wherein Q is hydroxy or chloride, respectively. Appropriate coupling conditions when using a compound of formula A10 (wherein Q is OH) include a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; and a base such as DIPEA to afford a compound of Formula (I)-A. When the acylation is effected by the addition of the corresponding acid chloride, the addition of a non-nucleophilic base such as pyridine affords a compound of Formula (I)-A.

Scheme B illustrates an alternate route for the synthesis compounds of Formula (I)-A, wherein R1, s, Y, and Z are as defined herein.




A compound of formula A1, wherein PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula A1 may be acylated with a compound of formula A10 using methods and reagents previously described in Scheme A to afford a compound of formula B1. Upon conventional removal of the protecting group PG, a compound of formula B2 may be treated with a compound of formula A4 in the presence of a hindered amine base such as DIPEA using the methods described in Scheme A to afford a compound of formula B3. Treatment of a compound of formula B3 with 1-chloroethyl chloroformate followed by methanolysis affords the corresponding amine of formula B4. Similarly, when the R1 substituent of a compound of formula B3 is hydroxy(C1-3)alkyl, the benzhydryl group may be removed by hydrogenation in the presence of a palladium catalyst to afford the amine of formula B4. An acylation reaction with a compound of formula A7 using the methods described in Scheme A affords the corresponding compound of Formula (I)-A.

Scheme C illustrates an alternate route for the synthesis compounds of Formula (I)-A, wherein R1, s, Y, and Z are as defined herein.




A compound of formula B2 may be treated with a ketone of formula C1 in the presence of decaborane or a reducing agent, such as sodium triacetoxyborohydride, to afford a compound of formula C2. Removal of the Boc-amino protecting group, using conventional reagents and methods, affords a compound of formula B4. Coupling with a compound of formula A7 as described herein provides a compound of Formula (I)-A.

Scheme D illustrates a route for the synthesis compounds of Formula (I)-A, wherein R1, s, Y, and Z are as defined herein.




A compound of formula A1, wherein PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula A1 may be treated with a compound of formula A4 to afford a compound of formula D1. Upon conventional removal of protecting group PG, a compound of formula D2 may be coupled with a compound of formula A10 (wherein Q is OH) in the presence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, to afford a compound of formula B3. When the acylation is effected by the addition of the corresponding acid chloride, the addition of a non nucleophilic base, such as pyridine, affords a compound of formula B3. Removal of the benzhydryl group as described herein, followed by acylation with a compound of formula A7 affords a compound of Formula (I)-A.

One skilled in the art will recognize that the synthetic sequences of Schemes A, B, C and D may be altered so that the acylation with a compound of formula A7 precedes removal of the benzhydryl group, which is then followed by acylation with a compound of formula A10, thus reversing the order for introduction of groups Y and Z.
Scheme E illustrates a route for the synthesis compounds of Formula (I)-E, wherein R1, s, and Y are as defined herein, and Z is a C6-10aryl ring or heteroaryl group, substituted with an optionally substituted C6-10aryl or heteroaryl group, as defined herein.




A compound of formula C1 may be deprotected using conventional methods to afford the corresponding free amine of formula E1. Coupling with a carboxylic acid of formula E2, (wherein ArE is a C6-10aryl or heteroaryl group, and said ArE is substituted with one bromo, chloro, or iodo substitutent), in the presence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, affords a compound of formula E3. A ketone of formula E3 may undergo a reductive amination with a compound of formula A1 in the presence of decaborane, sodium triacetoxyborohydride, and the like, to afford a compound of formula E4. Upon conventional removal of the protecting group PG, the free amine of formula E5 may be acylated with a compound of formula A10 as described herein to afford a compound of formula E6. The substituted ArE substituent of formula E6 may be treated with an appropriately substituted ArE1-boronic acid or ester (E7), or an appropriately substituted trialkyltin reagent, trialkylsilane, and the like (wherein ArE1 is an optionally substituted C6-10aryl or heteroaryl as defined herein), using one of a variety of coupling reactions (e.g., Suzuki, Stille, and Hiyama reactions) that are well known to those versed in the art; in the presence of a suitable catalyst; and in the presence of a base such as cesium carbonate, sodium bicarbonate, potassium fluoride, and the like; to afford a compound of the Formula (I)-E.

Scheme F illustrates a route for the synthesis of compounds of Formula (I)-F, wherein R1, s, and Y are as defined herein, and Z is an optionally substituted C6-10aryl(C1-6)alkyl or C6-10aryl(C2-6)alkenyl group, wherein L is (C1-6)alkyl or (C2-6)alkenyl, respectively.




A compound of formula B4 may be coupled with a commercially available compound of formula F2 (wherein ArF is an optionally substituted C6-10aryl substituent as defined herein) in the presence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base, such as DIPEA; to afford a compound of Formula (I)-F.

Scheme G illustrates a route for the synthesis of compounds of Formula (I)-G and Formula (I)-G1, wherein R1, s, and Y are as defined herein, and Z is either an optionally substituted C6-10aryl (ArG) substituted with phenyl(C2-6)alkynyl (Formula (I)-G) or an optionally substituted C6-10aryl substituted with phenyl(C1-6)alkyl.




A compound of Formula G1 may be prepared according to the methods described herein, wherein ArG is C6-10aryl and X is a substituent selected from bromo or iodo. An X-substituted ArG ring may be cross-coupled with a compound of formula G2 in the presence of a palladium catalyst, copper iodide, and a base such as triethylamine to afford a compound of Formula (I)-G. The alkynyl functionality of a compound of Formula (I)-G may be reduced to the corresponding alkyl group by transition metal catalyzed hydrogenation, using a transition metal such as palladium on carbon, palladium (II) hydroxide, or platinum, under a hydrogen gas atmosphere, to afford a compound of Formula (I)-G1.

Scheme H illustrates a route for the synthesis of compounds of Formula (I)-H, H1, H2, and H3, wherein R1, s, and Y are as defined herein, and Z is a benzofused heterocyclyl attached via the benzo ring, wherein the heterocyclyl portion contains a nitrogen atom, and wherein the nitrogen atom is optionally substituted. For illustrative purposes only, a 1,2,3,4-tetrahydroisoquinolinyl group has been selected to represent a nitrogen-containing benzofused heterocyclyl of the present invention.




A compound of formula B4 may be coupled with a carboxylic acid-substituted benzofused heterocyclyl of formula Formula H1 (wherein PG is a conventional amino protecting group) to afford a compound of formula H2. Deprotection of the amino functionality of a compound of formula H2 affords the corresponding amine of Formula (I)-H, which may be derivatized using a variety of synthetic methods to form additional compounds of the present invention. For example, a compound of Formula (I)-H may be treated with an appropriately substituted sulfonyl chloride of formula H3 in the presence of an organic base to afford a compound of Formula (I)-H1 (wherein RH2 is phenyl or C1-6alkyl. Additionally, a compound of the Formula (I)-H2 may be prepared by alkylation of the amino functionality of a compound of Formula (I)-H with an alkylating agent of formula H4 (wherein RH3 is phenyl or C1-6alkylcarbonyl) in the presence of a base. LG of a compound of formula H4 is a common leaving group, such as a bromide, iodide, tosylate, mesylate, and the like. A compound of Formula (I)-H2 may also be prepared by a reductive amination with a compound of formula H5 in the presence of a reducing agent, such as sodium triacetoxy borohydride. A compound of Formula (I)-H3 may be prepared via a peptide coupling reaction between a compound of Formula (I)-H and an appropriately substituted carboxylic acid of formula H6 (wherein RH is an optionally substituted cyclohexyl, C1-6alkyl, or phenyl as defined herein) in the presence of a suitable coupling agent. Finally, compounds of Formula (I)-H4 of the present invention, wherein ArH is pyrimidine or an appropriately substituted phenyl group, may be prepared by the treatment of a compound of Formula (I)-H with a compound of formula H7 (wherein XH is a group such as chloro, bromo, or iodo and ArH is as defined herein) in the presence of a transition metal catalyst, such as palladium acetate, a suitable phosphine ligand, such as BINAP, and a base, such as potassium t-butoxide.

Scheme I illustrates a route for the synthesis of compounds of Formula (I)-I, wherein R1, s, and Y are as defined herein and Z is a C6-10aryl substituted with C6-10aryl(C1-4)alkoxy as defined herein. For illustrative purposes only, the Z—C6-10aryl ring is depicted as a phenyl group.




A commercially available compound of formula I1 may be converted to a compound of formula I2 by the action of a chlorinating agent such as oxalyl chloride, thionyl chloride, and the like. A compound of formula B4 may be acylated with a compound of formula I2 to afford a compound of formula I3. Removal of the acetyl functionality of a compound of formula I3 by hydrolysis in the presence of a nucleophilic base like lithium hydroxide, affords the corresponding compound of formula I4. Alkylation with a compound of formula I5 (wherein Ar1 is an optionally substituted C6-10aryl group and XI is I, Br, Cl, or tosylate) affords a compound of Formula (I)-I. Similarly, Mitsunobu chemistry with a compound of formula I6 (wherein XI is hydroxy) may be used to prepare a compound of Formula (I)-I.

Scheme J illustrates a route for the synthesis of compounds of Formula (I)-J, wherein R1, s, and Y are as defined herein, and Z is a C6-10aryl substituted with C6-10aryl(C1-4)alkylthio as defined herein. For illustrative purposes only, the Z C6-10aryl ring is depicted as a phenyl group.




A compound of formula J1 is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula J1 may be alkylated with a compound of formula I5 (wherein XI is I, Br, Cl, or tosylate) to afford a compound of formula J2. Saponification of a compound of formula J2 affords a compound of formula J3 (wherein QJ is hydroxy), which may be coupled with a compound of formula B4; or the carboxylic acid may first be converted to its corresponding acid chloride of formula J3 (wherein QJ is chloro) followed by the acylation of a compound of formula B4; to afford a compound of Formula (I)-J.

Scheme K illustrates a route for the synthesis of compounds of Formula (I)-K, wherein R1, s, and Y are as defined herein, and Z is an optionally substituted C6-10aryl, further substituted with phenyloxy, and wherein phenyloxy is optionally substituted with C1-4alkyl, trifluoromethyl, or one to two chloro substituents as defined herein. For illustrative purposes only, the Z C6-10aryl ring is depicted as a phenyl group.




A compound of formula K1 is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula K1, or an optionally substituted derivative thereof, may be coupled with an aryl boronic acid of formula K2 (wherein ArK is phenyl optionally substituted with C1-4alkyl, trifluoromethyl, or one to two chloro substituents), in the presence of a copper catalyst, such as copper iodide or copper (II) acetate, appropriate ligands, such as pyridine, 1,10-phenanthroline, ethylene diamine and the like, and an organic base, such as triethylamine, to afford a compound of formula K3. Alternatively, compounds of formula K3 may be prepared by nucleophilic aromatic displacement of an appropriately substituted methyl halobenzoate derivative, wherein the preferred halogen substituent is fluoro, with ArK-OH, wherein ArK is as previously defined, in the presence of a base. Saponification followed by optional treatment with an appropriate chlorinating agent affords a compound of formula K4 wherein QK is hydroxy or chloro. Acylation of a compound of formula B4 with a compound of formula K4 affords a compound of Formula (I)-K.

Scheme L illustrates a route for the synthesis of compounds of Formula (I)-L, wherein R1, s, and Y are as defined herein, and Z is an optionally substituted C6-10aryl substituted with phenylthio, wherein phenylthio is optionally substituted with C1-4alkyl, trifluoromethyl, or one to two chloro substituents as defined herein. For illustrative purposes only, the Z C6-10aryl ring is depicted as a phenyl group.




A compound of formula L1 is either commercially available or may be prepared by known methods described in the scientific literature. An aryl bromide of formula L1, or an optionally substituted derivative thereof, may be cross coupled with a compound of formula L2 (wherein ArL is phenyl optionally substituted with C1-4alkyl, trifluoromethyl, or one to two chloro substituents), in the presence of a palladium catalyst, such as palladium tetrakis(triphenylphosphine), appropriate ligands, such as triphenylphosphine, and a base, such as potassium t-butoxide, to afford a compound of formula L3. Saponification of the methyl ester affords a compound of formula L4. A compound of formula B4 may be coupled with a compound of formula L4 in the presence of an appropriate peptide coupling agent such as DCC, EDC, HBTU, PyBrOP, and the like to afford a compound of Formula (I)-L.

Scheme M illustrates a route for the synthesis of compounds of Formula (I)-M, wherein R1, s, and Y are as defined herein, and Z is a C6-10aryl substituted with phenylsulfonyl. For illustrative purposes only, the Z C6-10aryl ring is depicted as a phenyl group.




A compound of formula M1 may be prepared according to the methods described in Scheme L. Oxidation of the thioether functionality may be accomplished by the action of an appropriate oxidizing agent, such as mCPBA, hydrogen peroxide, and the like, to afford a compound of formula M2. Upon saponification, and subsequent peptide coupling with a compound of formula B4, a compound of Formula (I)-M may be prepared.

Scheme N illustrates a route for the synthesis of compounds of Formula (I)-N, wherein R1, s, and Y are as defined herein and Z is C6-10aryl substituted with a 5 to 8 membered heterocyclyloxy optionally substituted at a nitrogen atom with phenylcarbonyl, C1-4alkylcarbonyl, or C1-4alkoxycarbonyl. For illustrative purposes only, the Z—C6-10aryl ring is depicted as a phenyl group.




A compound of formula I4 may be coupled with a compound of formula N1 (wherein RN is phenyl, C1-4alkyl, C1-4alkoxy, C1-4alkylamino, C1-4dialkylamino, or N-containing heterocyclyl attached via the nitrogen atom) under Mitsunobu conditions in an aprotic organic solvent, such as THF, to afford a compound of Formula (I)-N. Mitsunobu coupling may also be performed between I4 and a compound of formula N2, where PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like. Subsequent removal of the protecting group (PG) by conventional methods affords a compound of formula N3, which may be derivatized using a variety of synthetic methods to form additional compounds of the present invention. For example, a compound of formula N3 may be coupled with a carboxylic acid (Q is hydroxy, RN is phenyl or C1-4alkyl), acid chloride (Q is chloride, RN is phenyl or C1-4alkyl), chloroformate (Q is chloride, RN is C1-4alkoxy), or carbamoyl chloride (Q is chloride, RN is C1-4alkylamino, C1-4dialkylamino, or N-containing heterocyclyl attached via the nitrogen atom) of formula N4 as described herein to provide a compound of Formula (I)-N. Additionally, a compound of formula N3 may be reacted with a sulfamoyl chloride of formula N5, where RN2 is C1-4alkylamino, C1-4dialkylamino, or N-containing heterocyclyl attached via the nitrogen atom, to afford a compound of Formula (I)-N2.

Scheme O illustrates a route for the synthesis of compounds of Formula (I)-O, wherein R1, s, and Y are as defined herein, and Z is an optionally substituted C6-10aryl, further substituted with RO, wherein RO is (1-R2)-pyrrolidin-3-yloxy, C1-4alkyl, or C6-10aryl(C1-4)alkyl. For illustrative purposes only, the Z—C6-10aryl ring is depicted as a phenyl group.




A compound of formula O1 may be coupled with a compound of formula O2 (wherein XO is hydroxy) under Mitsunobu conditions to afford a compound of formula O3. Alkylation may also be achieved via a nucleophilic displacement reaction with a compound of formula O2 (wherein XO is I, Br, Cl, or tosylate) in the presence of a base to afford a compound of formula O3. Saponification of the methyl ester of a compound of formula O3 affords the corresponding carboxylic acid of formula O4. A compound of formula O4 may be coupled with a compound of formula B4 as described herein to afford a compound of Formula (I)-O. Furthermore, a compound of formula O3, where RO is (1-R2)-pyrrolidin-3-yloxy and R2 is a conventional amino protecting group, may be deprotected and additionally derivatized on the pyrrolidine nitrogen as described herein to afford, after conversion to a compound of formula O4 and subsequent coupling with a compound of formula B4, a compound of Formula (I)-O.

Scheme P illustrates a route for the synthesis of compounds of Formula (I)-P, wherein R1, s, and Y are as defined herein, and Z is C6-10aryl substituted with phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl of phenyl-(Q)-C1-6alkyl is optionally independently substituted with one to two substitutents selected from bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl.




A compound of formula P1 (wherein XP is hydroxy, chloro, or bromo) is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula P1 may undergo an alkylation via Mitsunobu reaction or nucleophilic displacement chemistry with a compound of formula P2 to afford a compound of formula P3. Saponification of the methyl ester of a compound of formula P3 affords the corresponding carboxylic acid of formula P4. A compound of formula P4 may be coupled with a compound of formula B4 as described herein to afford a compound of Formula (I)-P.

Scheme Q illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a heteroaryl substituted with an optionally substituted aryl group (ArQ). For illustrative purposes only, the heteroaryl ring is represented by an indole.




A compound of formula Q1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound Q1 may be treated with an aryl iodide of formula Q2 in the presence of copper iodide, trans-N,N′-dimethylcyclohexane-1,2-diamine, and potassium phosphate to afford a compound of formula Q3. Subsequent saponification affords useful carboxylic acid intermediates of formula Q4.

Scheme R illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a benzimidazolyl or benzoxazolyl, and Z is substituted with an optionally substituted aryl or heteroaryl group (ArR) or with ArR(C1-4)alkyl.




A compound of formula R1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound R1 may be treated with an aryl or heteroaryl substituted carboxylic acid of formula R2 in the presence of a coupling agent such as DCC, and a hindered base such as DMAP, in an aprotic organic solvent to afford a compound of formula R3. Acid catalyzed ring closure of a compound of formula R3 affords the substituted benzimidazole or benzoxazole of formula R4 or R6, respectively. Subsequent saponification affords useful carboxylic acid intermediates of formula R5 or R7.

Scheme S illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is an optionally substituted benzothienyl group, and RS represents appropriate substituents as defined in Formula (I).




A compound of formula S1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula S1 may be treated with thionyl chloride in an aprotic organic solvent, followed by treatment with methanol to afford a compound of formula S2. Subsequent saponification affords useful carboxylic acid intermediates of formula S3. One skilled in the art will recognize that asymmetrically substituted compounds of formula S1 could lead to mixtures of positional isomers upon cyclization with thionyl chloride. The isomers may then be separated and isolated using conventional chromatography known to those skilled in the art.

Scheme T illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a C6-10aryl (ArT) substituted by an optionally substituted C6-10arylmethyl group.




A compound of formula T1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula T1 may be treated with an appropriately substituted organometallic reagent, such as an ArT1-methylzinc chloride of formula T2, in the presence of a palladium catalyst to afford a compound of formula T3. Subsequent saponification affords useful carboxylic acid intermediates of formula T4.

Scheme U illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a benzothienyl group substituted with a fluoro substituent and an optionally substituted C6-10aryl or heteroaryl group (ArE1).




A compound of formula U1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula U1 may be cross-coupled with a boronic acid or ester (E7) in the presence of a palladium catalyst; and in the presence of a suitable base such as potassium carbonate to afford a compound of formula U2. Saponification affords the corresponding carboxylic acid U3, which may be treated with N-fluorobenzenesulfonimide in the presence of an organometallic base such as n-butyllithium, to afford the fluorinated compound of formula U4.

Scheme V illustrates the preparation of certain useful intermediates of formulae V6, V8, and V10 (Q is hydroxy) wherein Z is a benzimidazolyl group substituted with an ArV group (wherein ArV is an optionally substituted aryl or heteroaryl substituent as defined in Formula (I)) and optionally substituted in the 2-position with methyl or oxo.







A compound of formula V1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula V1 may be treated with a compound of formula V2 to afford a compound of formula V3. The amino group may be reduced by the action of tin chloride in an alcoholic solvent, or by palladium catalyzed hydrogenation to afford the diamine of formula V4. Treatment with trimethyl orthoformate affords a benzimidazole of formula V5, which may be saponified to afford a compound of formula V6.

A compound of formula V4 may be treated with trimethyl orthoacetate followed by saponification to afford the corresponding 2-methyl substituted benzimidazole, V8. Similarly, a compound of formula V4 may be treated with 1,1′-carbonyldiimidazole in DMF, followed by saponification to afford the corresponding 2-oxo substituted benzimidazole, V10.
Example 1







A. 4-(2,2,2-Trifluoro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester, 1c. To a solution of piperazine-1-carboxylic acid tert-butyl ester (1a, 10 g, 53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH2Cl2 (100 mL) was added dropwise compound 1b (10.5 mL, 75.54 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. 2N HCl (60 mL) was added to the mixture. The organic layer was dried over MgSO4, filtered, and then concentrated. The crude compound 1c was used in the next reaction without further purification. MS m/z (MH+-Boc) 183.1, (MH+-C4H9) 227.1; 1H NMR (300 MHz, CDCl3): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).
B. 2,2,2-Trifluoro-1-piperazin-1-yl-ethanone, 1d. To a solution of compound 1c (15.15 g, 53.69 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with ether, and dried under vacuum. The crude compound 1d was used in the next reaction without further purification. MS m/z (M+H+) 183.1.
C. 1-[4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone, 1f. To a solution of compound 1d (6 g, 32.94 mmol) and compound 1e (12.5 g, 39.38 mmol) in CH3CN (60 mL) was added DIPEA (12 mL, 68.89 mmol) at room temperature. The mixture was refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aq NaHCO3. The organic layer was washed with aq NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then the pH adjusted with 1N NaOH until basic (pH=10). The mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. Compound 1f was purified by reverse phase chromatography. MS m/z (M+H+) 404.2.
D. 1-(4-Azetidin-3-yl-piperazin-1-yl)-2,2,2-trifluoro-ethanone, 1g. To a solution of compound 1f (2.11 g, 5.23 mmol) in CH2Cl2 (60 mL) was added 1-chloroethyl chloroformate (2.0 mL, 18.35 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for 90 min and then MeOH (4 mL) was added. The mixture was refluxed for 1 h. Upon cooling, Et2O (50 mL) was added to the mixture. The resulting solid was collected by filtration and dried. The crude compound 1g was used in the next reaction without further purification. MS m/z (M+H+) 238.1.
E. 1-{4-[1-(4-Cyclohexyl-benzoyl)-azetidin-3-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone, 1i. To a solution of compound 1g (2.5 g, 10.54 mmol) and HATU (4 g, 10.52 mmol) in DMF (25 mL) was added DIPEA (5 mL, 28.70 mmol). The mixture was stirred at room temperature for 30 min, and then compound 1h (2 g, 9.79 mmol) was added to the mixture. The reaction was stirred at room temperature for 18 h. Water (40 mL) was added to the reaction. The mixture was extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude compound 1i was purified by reverse phase chromatography. MS m/z (M+H+) 424.2.
F. (4-Cyclohexyl-phenyl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 1j. To a solution of compound 1i (0.95 g, 2.24 mmol) in CH3OH (16 mL) and H2O (4 mL) was added K2CO3 (0.8 g, 5.79 mmol). The mixture was stirred at room temperature for 1 h. After filtration, the solvent was removed by evaporation. The crude compound 1j was used in the next reaction without further purification. MS m/z (M+H+) 328.2.
G. 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)-piperazine, Cpd 1. To a solution of compound 1j (0.08 g, 0.24 mmol) and HATU (0.093 g, 0.24 mmol) in DMF (3 mL) was added DIPEA (0.1 mL). The mixture was stirred at room temperature for 30 min, and then compound 1k (0.03 g, 0.25 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 18 h. Water (6 mL) was added to the mixture. The mixture was extracted with EtOAc (2×6 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude compound 1 was purified by reverse phase chromatography. 1H NMR (300 MHz, CD3OD): δ 7.58 (d, 2H), 7.44-7.53 (m, 5H), 7.34 (d, 2H), 4.6 (m, 1H), 4.42 (m, 2H), 4.27 (m, 1H), 3.85 (m, 5H), 3.05 (m, 4H), 2.57 (m, 1H), 1.85 (m, 5H), 1.45 (m, 5H). MS m/z (M+H+) 432.3.
Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Characterization Data
















2
1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(furan-



2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.71 (d, 1H), 7.59 (d, 2H),



7.34 (d, 2H), 7.13 (d, 1H), 6.62 (dd, 1H), 4.62 (m, 1H),



4.52 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 4.05 (m, 4H), 3.98 (m,



1H), 3.18 (m, 4H), 2.58 (m, 1H), 1.84 (m, 5H), 1.24-1.52 (m,



5H)



MS m/z (M + H+) 422.2


3
1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-[(1-



methyl-1H-imidazol-2-yl)carbonyl]piperazine



MS m/z (M + H+) 436.2


4
1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-



(pyridin-2-ylcarbonyl)piperazine



MS m/z (M + H+) 433.2


5
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.65 (m, 4H), 7.56 (d, 2H),



7.25-7.46 (m, 8H), 4.58 (m, 1H), 4.49 (m, 1H), 4.35 (m, 1H),



4.26 (m, 1H), 3.92 (m, 1H), 3.78 (m, 4H), 3.09 (m, 4H)



MS m/z (M + H+) 426.1


6
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(furan-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.66 (m, 4H), 7.62 (d, 1H),



7.56 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 7.03 (d, 1H), 6.51 (dd,



1H), 4.56 (m, 1H), 4.44 (m, 1H), 4.33 (m, 1H), 4.22 (m, 1H),



3.95 (m, 4H), 3.81 (m, 1H), 3.01 (m, 4H)



MS m/z (M + H+) 416.2


7
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.97 (s, 1H), 8.14 (s, 1H),



7.66 (m, 4H), 7.56 (d, 2H), 7.37 (t, 2H), 7.30 (m, 1H), 4.60 (m,



1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 4.08 (m, 4H),



3.95 (m, 1H), 3.14 (m, 4H)



MS m/z (M + H+) 433.2


8
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-5-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.08 (s, 1H), 8.11 (s, 1H),



7.66 (m, 4H), 7.56 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 4.54 (m,



1H), 4.39 (m, 1H), 4.31 (m, 1H), 4.17 (m, 1H), 3.84 (m, 4H),



3.73 (m, 1H), 2.92 (m, 4H)



MS m/z (M + H+) 433.2


9
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.88 (d, 1H), 7.78 (d, 1H),



7.66 (m, 4H), 7.57 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 4.62 (m,



3H), 4.48 (m, 1H), 4.37 (m, 1H), 4.26 (m, 1H), 3.91 (m, 3H),



3.13 (m, 4H)



MS m/z (M + H+) 433.2


10
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2-methyl-1,3-



thiazol-4-yl)carbonyl]piperazine



MS m/z (M + H+) 447.1


11
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(1-methyl-1H-



pyrrol-2-yl)carbonyl]piperazine



MS m/z (M + H+) 429.3


12
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-bromofuran-



2-yl)carbonyl]piperazine



1H NMR (300 MHz, CD3OD): δ 7.76 (m, 4H), 7.66 (d, 2H),



7.47 (t, 2H), 7.39 (m, 1H), 7.11 (d, 1H), 6.64 (d, 1H), 4.66 (m,



1H), 4.57 (m, 1H), 4.44 (m, 1H), 4.34 (m, 1H), 3.91-4.10 (m,



5H), 3.17 (m, 4H)



MS m/z (M + H+) 494.1/496.0


13
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thiophen-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.75 (m, 4H), 7.61-7.72 (m,



3H), 7.34-7.52 (m, 4H), 7.14 (t, 1H), 4.65 (m, 1H), 4.52 (m,



1H), 4.42 (m, 1H), 4.29 (m, 1H), 3.96 (m, 4H), 3.90 (m, 1H),



3.07 (m, 4H)



MS m/z (M + H+) 432.1 (calculated for C25H25N3O2S, 431.56)


14
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-



methylthiophen-2-yl)carbonyl]piperazine



MS m/z (M + H+) 446.1


15
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-



bromothiophen-2-yl)carbonyl]piperazine



MS m/z (M + H+) 510.1/512.1


16
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-



chlorothiophen-2-yl)carbonyl]piperazine



MS m/z (M + H+) 466.1/467.1


17
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3-



bromothiophen-2-yl)carbonyl]piperazine



MS m/z (M + H+) 510.0/512.1


18
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(4-



bromothiophen-2-yl)carbonyl]piperazine



MS m/z (M + H+) 510.0/512.1


19
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thieno[3,2-



b]thiophen-2-ylcarbonyl)piperazine



MS m/z (M + H+) 488.1


20
1-(1-Benzothiophen-2-ylcarbonyl)-4-[1-(biphenyl-4-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 482.1


21
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3-



methoxythiophen-2-yl)carbonyl]piperazine



MS m/z (M + H+) 462.1


22
1-{1-[(4-Bromo-2-methylphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 442.22/444.19


23
1-{1-[(4-Bromo-3-methoxyphenyl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 465.0/467.1


24
1-{1-[(4-Bromo-3-methoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 458.1/460.0


25
1-{1-[(4-Bromo-2-chlorophenyl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 469.04/471.04


26
1-{1-[(4-Bromo-2-chlorophenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 462.11/464.11


581
1-(Phenylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2-



yl]phenyl}carbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 500


1382
2-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 474


1071
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[5-



(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 507


1361
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[5-



(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 507









Example 1a




H. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 1m. A mixture of methyl indole-5-carboxylate 1j (0.5 g, 2.85 mmol), 1-bromo-4-fluoro-benzene 1k (2 mL, 18.21 mmol), CuI (0.544 g, 2.85 mmol), and K2CO3 (0.591 g, 4.28 mmol) was heated under microwave at 220° C. for 2.5 hours. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give 1m (0.58 g).
I. 1-(4-fluorophenyl)-indole-5-carboxylic acid, 1n. A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 1m (0.58 g, 2.15 mmol) and LiOH H2O (0.36 g, 8.6 mmol) in THF (15 mL) and H2O (10 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3 ̃4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1n (0.5 g).
J. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 487. The title compound, Cpd 487, was prepared according to Example 1 using intermediate 1n from Example 1a and intermediate 1g in Example 1 as starting materials. 1H NMR (400 MHz, CD3OD): δ 8.00 (d, J=1.2 Hz, 1H), 7.88 (d, J=3 Hz, 1H), 7.55 (m, 2H), 7.46 (m, 3H), 7.34 (d, J=3 Hz, 1H), 7.27-7.21 (m, 2H), 6.74 (d, J=3 Hz, 1H), 4.52 (bs, 1H), 4.43-4.20 (m, 4H), 4.14 (m, 1H), 3.95-3.80 (m, 2H), 3.25 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H+) 490.
Following the procedure described above for Example 1a, steps H and I, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 1a, step J, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the invention were prepared:











Cpd
Cpd Name and Data
















567
1-(4-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (400 MHz, CD3OD): d 7.99 (s, 1H), 7.55-7.21 (m,



12H), 6.73 (s, 1H), 4.37 (bs, 1H), 4.25 (m, 2H), 4.10 (bs,



1H), 3.90 (bs, 1H), 3.75 (bs, 1H), 3.48 (bs, 2H), 3.24 (m,



1H), 2.50-2.20 (m, 4H).



MS m/z (M + H+) 483


587
1-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1H-indazole



MS m/z (M + H+) 466


579
1-(2,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 501


1356
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-indole.



MS m/z (M + H+) 540


1408
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 540


1357
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



1H NMR (400 MHz, CD3OD): d 8.00 (s, 1H), 7.88 (d, J = 3 Hz,



1H), 7.81 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H),



7.59 (s, 2H), 7.54 (d, J = 3 Hz, 1H), 7.41 (d, J = 3.5 Hz, 1H),



6.79 (d, J = 3.5 Hz, 1H), 4.53 (bs, 1H), 4.43 (m, 2H),



4.28 (m, 2H), 4.14 (bs, 1H), 3.86 (m, 2H), 3.26 (m, 1H), 2.50 (m,



4H).



MS m/z (M + H+) 540


1358
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 490


1359
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 540


1163
1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indazole



MS m/z (M + H+) 473


1360
1-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indazole



1H NMR (400 MHz, CD3OD): d 8.27 (s, 1H), 8.11 (s, 1H),



7.88 (d, J = 3 Hz, 1H), 7.77 (m, 2H), 7.72 (d, J = 8 Hz, 2H),



7.56 (m, 3H), 7.41 (t, J = 8 Hz, 1H), 4.53 (bs, 1H),



4.44-4.28 (m, 4H), 4.15 (m, 1H), 3.86 (m, 2H), 3.28 (m, 1H),



2.50 (m, 4H). MS m/z 490 (M + H+)



MS m/z (M + H+) 473


1364
1-(2,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 508


1139
1-(2,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (CDCl3, 400 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H),



7.93-8.09 (m, 2 H), 7.39-7.64 (m, 2 H), 7.18-7.34 (m, 2 H),



6.98-7.16 (m, 2 H), 6.76 (d, J = 3.1 Hz, 1 H), 4.20-4.51 (m, 3



H), 4.13 (d, J = 3.9 Hz, 1 H), 3.92 (br. s., 3 H), 3.67-3.84 (m,



1 H), 3.18-3.32 (m, 1 H), 2.49 (br. s., 4 H).



MS m/z (M + H+) 508


1061
1-(2,4-Difluorophenyl)-5-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 490









Following the procedure described above for Example 1a, steps H and I, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 1a, step J, with the exception of using dioxane as a solvent in step A, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















595
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-pyrimidin-2-yl-1H-indole



MS m/z (M + H+) 467


598
1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 485


1174
1-Pyrimidin-2-yl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (CDCl3, 400 MHz): d = 8.83 (d, J = 8.6 Hz, 1 H),



8.73 (d, J = 4.7 Hz, 2 H), 8.33 (d, J = 3.9 Hz, 1 H),



7.80-8.02 (m, 2 H), 7.64 (dd, J = 8.8, 1.8 Hz, 1 H), 7.54 (d, J =



3.1 Hz, 1 H), 7.10 (t, J = 4.9 Hz, 1 H), 6.75 (d, J = 3.5 Hz, 1 H),



4.03-4.72 (m, 6 H), 3.86 (m, 2 H), 3.08-3.37 (m, 1 H),



2.31-2.68 (m, 3 H).



MS m/z (M + H+) 474


1201
1-Pyrimidin-2-yl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 474


1248
1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 492


1147
1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 492









Example 1b




K. Methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate, 1p. A mixture of methyl indole-5-carboxylate 1j (2 g, 11.4 mmol), 1-iodo-3,4-difluoro-benzene 1o (1.5 mL, 12.5 mmol), CuI (0.22 g, 1.14 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.54 mL, 3.43 mmol), and K3PO4 (6.06 g, 28.5 mmol) in toluene (12 mL) was heated at 110° C. for 7 hours. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 1p (3.0 g).
L. 1-(3,4-Difluorophenyl)-indole-5-carboxylic acid, 1q. A mixture of methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate 1p (3.0 g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H2O (60 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3 ̃4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1q (2.85 g).
M. 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1362. The title compound, Cpd 1362, was prepared according to Example 1 using intermediate 1q from Example 1b and intermediate 1g in Example 1 as starting materials. 1H NMR (CDCl3, 400 MHz): d=7.99 (d, J=1.6 Hz, 1H), 7.88 (d, J=3.1 Hz, 1H), 7.44-7.64 (m, 3H), 7.18-7.44 (m, 4H), 6.75 (d, 1H), 4.47-4.63 (m, 1H), 4.19-4.47 (m, 4H), 4.07-4.19 (m, 1H), 3.89 (br. s, 2H), 3.18-3.33 (m, 1H), 2.50 (t, J=5.1 Hz, 4H). MS m/z (M+H+) 508.
Following the procedure described above for Example 1b, steps K and L, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:



















Following the procedure described above for Example 1b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1363
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3, 400 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H),



8.00 (dd, J = 11.5, 1.8 Hz, 2 H), 7.44-7.65 (m, 2 H),



7.18-7.42 (m, 4 H), 6.75 (d, J = 3.5 Hz, 1 H), 4.20-4.46 (m, 3 H),



4.13 (br. s., 1 H), 3.93 (br. s., 3 H), 3.67-3.85 (m, 1 H),



3.17-3.36 (m, 1 H), 2.49 (br. s., 4 H)



MS m/z 508 (M + H+)


1366
1-(3,4-Difluorophenyl)-5-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3, 400 MHz): d = 9.42-9.61 (m, 1 H),



7.99 (s, 1 H), 7.54-7.64 (m, 1 H), 7.45-7.54 (m, 1 H),



7.15-7.43 (m, 4 H), 6.93 (s, 1 H), 6.75 (d, J = 3.1 Hz, 1 H),



6.52 (br. s., 1 H), 6.18-6.31 (m, 1 H), 4.19-4.42 (m, 3 H),



4.08-4.19 (m, 1 H), 3.90 (br. s., 4 H), 3.24 (s, 1 H), 2.34-2.56



(m, 4 H)



MS m/z 490 (M + H+)


603
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-pyridin-4-yl-1H-indole



MS m/z (M + H+) 466.1


630
1-(2-Methylpyridin-4-yl)-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indole



MS m/z (M + H+) 480.1


1192
1-Pyridin-3-yl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 473.2


1247
1-Pyridin-3-yl-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 456.3


1127
1-Pyridin-4-yl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 473.0


1072
1-(6-Methoxypyridin-3-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 503.2


1176
1-(6-Methoxypyridin-3-yl)-5-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 485.4


1105
1-(6-Methylpyridin-3-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 487.3


1181
1-(6-Methylpyridin-3-yl)-5-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 469.3


1062
5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-



indole



MS m/z (M + H+) 523.2


1312
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-



indole



MS m/z (M + H+) 541.3


1107
1-(2-Methoxypyridin-4-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 503.0


1263
1-Pyrimidin-5-yl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 474.1


1410
1-(2-Methylpyridin-4-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 487.0


586
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-indole



MS m/z (M + H+) 534.1


596
1-(5-Fluoropyridin-2-yl)-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indole



MS m/z (M + H+) 484.0


1135
1-Pyridin-2-yl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 473.2


1189
1-Pyridin-2-yl-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 455.2


1073
1-(5-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 509.0


1126
1-(6-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 487.3


1128
1-(4-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 487.2


1216
1-(2-Methylpyrimidin-4-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 488.0


1314
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-



indole



MS m/z (M + H+) 541.0


1121
1-(5-Fluoropyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 491.0


1197
1-(4-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 487.1


1337
5-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



1H NMR (400 MHz, CDCl3): δ 9.06 (s, 1H); 8.4 (s, 1H);



7.9-7.68 (m, 8H); 7.4 (ar, 1H); 4.97 (m, 2H); 4.45 (m, 2H);



4.16 (bs, 1H);



MS m/z (M + H+) 508.0


1338
5-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



1H NMR (400 MHz, CDCl3): δ 7.91 (m, 1H); 7.81 (m, 4H);



7.70 (m, 2H); 7.60 (m, 2H); 7.30 (m, 1H); 6.75 (m, 1H);



5.01-4.84 (m, 2H); 4.37 (m, 2H); 4.09 (bm, 1H)



MS m/z (M + H+) 540.2


1339
5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 522.2


1097
5-({3-[4-(Isothiazol-5-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H); 7.94 (s, 1H);



7.80 (m, 2H); 7.69 (m, 2H); 7.59 (m, 2H); 7.49 (m, 2H);



6.77 (m, 1H); 4.65-4.15 (bm, 3H); 3.81 (bm, 4H); 3.0 (bm,



4H)



MS m/z (M + H+) 540.2


1230
1-(4-Fluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 504.1


1089
1-(4-Fluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-



indole



1H NMR (400 MHz, CDCl3): δ 7.92 (d, 1H); 7.78 (d, 1H);



7.69 (m, 1H); 7.42 (m, 3H); 7.21 (m, 6H); 4.94 (m, 1H);



4.40 (dd, 1H); 4.25 (dd, 1H); 4.0 (bm, 1H); 3.85 (bm, 3H);



3.15 (bm, 3H); 2.3 (s, 3H)



MS m/z (M + H+) 504.1


1120
5-({4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]piperazin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 522.1


1134
1-(3,4-Difluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-



indole



1H NMR (400 MHz, CDCl3): δ 8.0 (s, 1H); 7.86 (s, 1H);



7.80 (s, 1H); 7.62-7.42 (m, 3H); 7.36 (m, 3H); 5.05 (m,



1H); 4.5 (m, 1H); 4.35 (m, 1H); 4.08 (bm, 1H); 3.94 (bm,



4H); 3.24 (m, 3H)



MS m/z (M + H+) 522.2


1219
1-(3,4-Difluorophenyl)-3-methyl-5-({4-[1-(1H-pyrrol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 465.1









Example 1c




N. 1-(5-Methylpyridin-2-yl)-5-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole; Cpd 1184. The title compound, Cpd 1184, was prepared according to Example 1 using intermediate 1r from Example 1b and intermediate 1g in Example 1 as starting materials. MS m/z (M+H+) 472.1
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:














Salt


Cpd
Cpd Name and Data
Form

















1409
1-(5-Chloropyridin-2-yl)-5-({3-[4-
N-TFA



(trifluoroacetyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1H-indole



MS m/z (M + H+) 492.1


1199
1-(4-Methylpyridin-2-yl)-5-({3-[4-
N-TFA



(trifluoroacetyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1H-indole



MS m/z (M + H+) 472.1


656
1-(1-{[3-Chloro-6-(trifluoromethyl)-1-
N-TFA



benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-



(trifluoroacetyl)piperazine



MS m/z (M + H+) 500.1


1079
1-(4-Fluorophenyl)-5-({3-[4-
N-TFA



(trifluoroacetyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1H-indole



MS m/z (M + H+) 475.2









Example 1d




O. Methyl 2-phenyl-benzooxazole-6-carboxylate, 1u. A mixture of methyl 4-amino-3-hydroxy-benzoate is (0.3 g, 1.8 mmol) and benzoyl chloride 1t (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heated at 210° C. under microwave for 15 min. The reaction mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic solution was dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 1u (0.39 g).
P. 2-Phenyl-benzooxazole-6-carboxylic acid, 1v. A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1t (0.34 g).
Following the procedure described above for Example 1d and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1141
2-Phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 474


1151
6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3-



benzoxazole



MS m/z (M + H+) 542


1158
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3-



benzoxazole



MS m/z (M + H+) 542









Example 1e




Q. Ethyl 2-phenyl-benzothiazole-6-carboxylate, 1y. A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (300 mg, 1.05 mmol), phenylboronic acid 1×(192 mg, 1.57 mmol), K2CO3 (188 mg, 1.36 mmol) and Pd(dppf)Cl2.CH2Cl2 (43 mg, 0.05 mmol) in dioxane (2 mL) and H2O (0.4 ml) was heated at 120° C. for 25 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc/heptane) gave 1y (220 mg).
R. 2-Phenyl-benzothiazole-6-carboxylic acid, 1z. Ethyl 2-phenyl-benzothiazole-6-carboxylate 1y (220 mg, 0.78 mmol) was stirred with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H2O (4 mL) for 16 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1z (200 mg).
Following the procedure described above for Example 1e and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















592
2-Phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 483


1125
2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole



1H NMR (400 MHz, CD3OD): d 8.25 (s, 1H), 8.12-8.06 (m,



3H), 7.88 (d, J = 3 Hz, 1H), 7.74 (d, J = 8 Hz, 1H), 7.53 (m,



4H), 4.53 (bs, 1H), 4.4-4.26 (m, 4H), 4.15 (m, 1H), 3.86 (m,



2H), 3.27 (m, 1H), 2.50 (m, 4H)



MS m/z (M + H+) 490


1187
2-Phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z 490 (M + H+)









Example 1f




Q. Methyl 1-(5-chloropyridin-2-yl)-1H-indole-5-carboxylate, 1bb. A mixture of 1j (1.14 mmol, 200 mg), 1aa (1.14 mmol, 150 mg), K2CO3 (2.28 mmol, 315 mg) and NMP (1.5 mL) was heated at 200° C. in a microwave reactor for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuo. Purification was carried by flash column chromatography (silica gel, 15% EtOAc/heptane) to give 290 mg of 1bb (290 mg).
R. (5-Chloropyridin-2-yl)-1H-indole-5-carboxylic acid, 1cc. A mixture of 1bb (0.942 mmol, 270 mg), LiOH (3.77 mmol, 90 mg), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for overnight. The reaction mixture was acidified with 1N aqueous HCl to pH=5. The solid precipitate was filtered, washed with EtOAc, and dried under vacuo to give 202 mg of 1cc.
Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1313
1-(5-Chloropyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3) d: 8.52 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.6 Hz,



1H), 7.96 (s, 1H), 7.88 (d, J = 3.2 Hz, 1H),



7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 (d, J = 3.4 Hz, 1H),



7.60 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.9 Hz, 1H),



7.44 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 3.4 Hz, 1H), 4.51 (br. s.,



1H), 4.19-4.47 (m, 4H), 4.12 (q, J = 7.1 Hz, 2H),



3.74-3.95 (m, 2H), 3.25 (t, J = 5.6 Hz, 1H), 2.49 (br. s., 4H)



MS m/z (M + H+) 508.0


629
1-(5-Chloropyridin-2-yl)-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indole



MS m/z (M + H+) 501.0


1180
1-(5-Chloropyridin-2-yl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3) d: 8.79 (s, 1H), 8.49 (s, 1H), 8.21 (d,



J = 8.6 Hz, 1H), 7.95 (s, 1H), 8.00 (s, 1H), 7.78 (d, J = 8.6 Hz,



1H), 7.68 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.6 Hz,



1H), 7.42 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 2.9 Hz,



1H), 4.31-4.47 (m, 1H), 4.16-4.31 (m, 1H), 4.11 (q, J = 7.0 Hz,



1H), 3.84-4.04 (m, 3H), 3.80 (br. s., 1H),



3.18-3.31 (m, 1H), 2.47 (br. s., 3H), 2.40 (br. s., 1H)



MS m/z (M + H+) 507.0









Example 2




A. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-phenyl-methanone, 2b. The title compound 2b was prepared using the method described in Example 1, substituting compound 2a for compound 1d in Procedure C. The crude compound 2b was purified by flash column chromatography. MS m/z (M+H+) 412.2.
B. (4-Azetidin-3-yl-piperazin-1-yl)-phenyl-methanone, 2c. The title compound 2c was prepared using the method described in Example 1, substituting compound 2b for compound 1f in Procedure D. The crude compound 2c was used in the next reaction without further purification. MS m/z (M+H+) 246.1.
C. 1-{1-[(4-Bromophenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 27. The title compound 27 was prepared using the method described in Example 1, substituting compound 2c for compound 1g and substituting compound 2d for compound 1h in Procedure E. The crude compound 27 was purified by reverse phase chromatography. MS m/z (M+H+) 428.1/430.0.
Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















28
1-(Phenylcarbonyl)-4-(1-{[4-(1H-pyrrol-1-



yl)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 415.2


29
1-(Phenylcarbonyl)-4-{1-[(4-pyrrolidin-1-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 419.2


30
N,N-Diethyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



LC/MS m/z (M + H+) 421.2


31
N,N-Dimethyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)aniline



MS m/z (M + H+) 393.2


32
1-{1-[(4-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 442.2


33
1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 444.1


34
1-{1-[(4′-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 456.1


35
1-(1-{[4-(Benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



LC/MS (m/z) (M + H+) 456.1


36
1-{1-[(2′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 460.2


37
1-Cyclohexyl-2-methyl-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



LC/MS m/z (M + H+) 486.3


38
1-(1-Methylethyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H-benzimidazole



LC/MS m/z (M + H+) 500.3


39
1-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.73 (d, 1H), 7.65 (m, 4H),



7.50 (m, 2H), 7.35-7.46 (m, 5H), 4.55 (m, 2H), 4.35



(m, 2H), 4.01 (m, 1H), 3.80 (m, 4H), 3.17 (m, 4H); LC/MS



m/z (M+H+) 494.1 (calculated for C27H25Cl2N3O2, 494.43)


40
N-Methyl-N-phenyl-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



1H NMR (300 MHz, CD3OD): δ 7.45-7.56 (m, 7H), 7.41 (t, 2H),



7.22 (m, 3H), 6.80 (d, 2H), 4.27-4.75 (m, 4H), 4.07 (m, 1H),



3.88 (m, 4H), 3.34 (s, 3H), 3.25 (m, 4H); LC/MS m/z (M + H+)



455.3 (calculated for C28H30N4O2, 454.58)


41
1-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]azepane



1H NMR (300 MHz, CD3OD): δ 7.45-7.57 (m, 7H), 6.73 (d, 2H),



4.28-4.73 (m, 4H), 4.12 (m, 1H), 3.89 (m, 4H), 3.30 (m, 8H),



1.80 (m, 4H), 1.54 (m, 4H); LC/MS m/z (M + H+)



447.3 (calculated for C27H34N4O2, 446.6)


42
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-propyl-1H-indole



LC/MS m/z (M + H+) 431.1


43
1-(Biphenyl-4-ylcarbonyl)-2-phenyl-4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazine



1H NMR (400 MHz, MeOD): δ 7.86-7.95 (m, 1H), 7.73-7.79 (m,



1H), 7.62-7.68 (m, 2H), 7.53-7.59 (m, 2H), 7.47-7.52 (m, 2H),



7.41-7.47 (m, 2H), 7.33-7.41 (m, 4H), 7.21-7.33 (m, 2H),



5.67 (br. s., 1H), 4.51-4.62 (m, 2H), 4.19-4.38 (m, 1H),



4.01-4.12 (m, 1H), 3.71-3.81 (m, 1H), 3.54-3.67 (m, 1H), 3.32



(m, 1H), 2.98-3.12 (m, 2H), 2.79-2.90 (m, 1H), 2.44-2.56 (m, 1H);



MS m/z (M + H+) 509.2 (calculated for C30H28N4O2S, 508.65)


44
1-(Biphenyl-4-ylcarbonyl)-2-phenyl-4-[1-



(phenylcarbonyl)azetidin-3-yl]piperazine



1H NMR (400 MHz, MeOD): δ 7.67-7.75 (m, 2H), 7.59-7.67 (m,



4H), 7.53-7.58 (m, 2H), 7.40-7.53 (m, 9H), 7.31-7.40 (m, 2 H),



5.73 (br. s., 1 H), 4.34-4.57 (m, 1H), 4.23-4.34 (m, 1H),



4.02-4.18 (m, 2H), 3.69-3.88 (m, 1H), 3.55-3.68 (m, 1H),



3.35-3.46 (m, 2H), 3.07 (m, 1H), 2.81-2.93 (m, 1H), 2.43-



2.63 (m, 1H); MS m/z (M+) 502.2 (calculated for C33H31N3O2,



502.23)


45
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-methyl-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 447.29 (calculated for C25H26N4O2S, 446.58)


46
2-Methyl-1-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 463.2 (calculated for C25H26N4O3S, 462.57)


47
1-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-methyl-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 461.0 (calculated for C26H28N4O2S, 460.60)


48
1-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]-1H-benzimidazole



MS m/z (M + H+) 466.3 (calculated for C28H27N5O2, 465.56)


49
1-{1-[(4-Fluorophenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 368.2 (calculated for C21H22FN3O2, 367.43)


50
N-Benzyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1,3-thiazol-2-amine MS m/z (M + H+)



462.2 (calculated for C25H27N5O2S, 461.59)


51
9-Methyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-9H-carbazole



MS m/z (M + H+) 453.3 (calculated for C28H28N4O2, 452.56)


52
N-Benzyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



MS m/z (M + H+) 455.3 (calculated for C28H30N4O2, 454.58)


53
1-(Phenylcarbonyl)-4-{1-[(4-piperidin-1-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 433.3 (calculated for C26H32N4O2, 432.57)


54
N-Butyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



MS m/z (M + H+) 421.2 (calculated for C25H32N4O2, 420.56)


55
6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2,3,4,9-tetrahydro-1H-carbazole



MS (m/z) (M + H+) 443.3 (calculated for C27H30N4O2, 442.57)


56
2-[3-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]-2,3-dihydro-1H-isoindole



MS m/z (M + H+) 467.2 (calculated for C29H30N4O2, 466.59)


57
2-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-N-[3-(trifluoromethyl)phenyl]aniline



MS m/z (M + H+) 509.1 (calculated for C28H27F3N4O2, 508.55)


58
N-Phenyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



MS m/z (M + H+) 441.2 (calculated for C27H28N4O2, 440.55)


59
N-(3-Fluorophenyl)-2-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS m/z (M + H+) 459.2 (calculated for C27H27FN4O2, 458.54)


60
2,3-Dimethyl-N-[2-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]aniline



MS m/z (M + H+) 469.2 (calculated for C29H32N4O2, 468.60)


461
1-(1-{[2-(Benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 456.221


462
1-{1-[(3-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 442.3


463
1-{1-[(2-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 442.3


464
1-(Phenylcarbonyl)-4-(1-{[4-



(trifluoromethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 434.161


465
1-{1-[(3-Bromo-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 458.1


466
1-{1-[(3-Chloro-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 414.151


467
1-{1-[(4-Ethoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 394.205


468
1-{1-[(3-Iodo-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 506.086


469
1-(1-{[4-(1-Methylethoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 408.221


470
1-(1-{[4-(Methylsulfanyl)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 396.167


471
4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl acetate



MS m/z (M + H+) 415.136


472
1-(1-{[4-(Methylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 428.157


539
N-[3-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]cyclohexanecarboxamide



MS m/z (M + H+) 475.2


622
1-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H-pyrazol-1-



yl]phenyl}carbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 484.0


531
N-Benzyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



MS m/z (M + H+) 455.1


565
1-Benzyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)pyridin-2(1H)-one



MS m/z (M + H+) 457.1


562
1-(3-Chlorobenzyl)-3-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)pyridin-2(1H)-one



MS m/z (M + H+) 491.1


627
1-(Phenylcarbonyl)-4-(1-{[3-(1H-pyrrol-1-



yl)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 415.2


541
4-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]morpholine



MS m/z (M + H+) 435.1


1485
4-[5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)pyridin-2-yl]morpholine



MS m/z (M + H+) 436.0


559
4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-phenyl-1-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 516.1


628
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 502.0


1404
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 509.1


1464
4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-phenyl-1-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 523.1


1266
2-Benzyl-1-(biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 523.3


1284
2-Benzyl-1-(biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 523.2


954
(2R,6S)-2,6-Dimethyl-1-(1,3-thiazol-2-ylcarbonyl)-4-(1-{[6-



(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 509.0









Example 3




A. (4-Benzyl-phenyl)-piperazin-1-yl-methanone, 3b. To a solution of compound 1a (1 g, 5.36 mmol), compound 3a (1.14 g, 5.36 mmol), and DIPEA (1.38 g, 10.7 mmol) in acetonitrile (20 mL) was added HBTU (2.64 g, 7.0 mmol). The reaction was stirred for 18 h at which time the solvent was removed under reduced pressure and the crude product purified by reverse phase HPLC. Upon lyophilization, the remaining solid was dissolved in DCM (20 mL) and trifluoroacetic acid was slowly added (15 mL). After stirring at room temperature 2 h, the solvents were removed and the residue partitioned between aqueous 1N NaOH and CHCl3. The organic layer was separated, dried (MgSO4), filtered, and then concentrated to yield compound 3b (1.21 g).
B. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-4-benzyl-phenyl-methanone, 3c. The title compound 3c was prepared using the method described in Example 1, substituting compound 3b for compound 1d in Procedure C.
C. (4-Azetidin-3-yl-piperazin-1-yl)-4-benzyl-phenyl-methanone, 3d. The title compound 3d was prepared using the method described in Example 1, substituting compound 3c for compound 1f in Procedure D.
D. 1-[(4-Benzylphenyl)carbonyl]-4-[1-(phenylcarbonyl)azetidin-3-yl]piperazine, Cpd 61. Compound 3d was converted into title compound 61 using the method described in Example 2, substituting compound 3d for compound 2c, benzoic acid (compound 1k) for compound 2d, and HBTU for HATU in Procedure D. 1H NMR (400 MHz, MeOD): δ 7.64 (d, J=1.7 Hz, 2H), 7.51-7.58 (m, 1H), 7.48 (br. s, 2H), 7.38 (s, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.25 (br. s, 2H), 7.20 (d, J=7.3 Hz, 3H), 4.51-4.64 (m, 1H), 4.33-4.51 (m, 2H), 4.20-4.33 (m, 1H), 4.01 (s, 2H), 3.86-3.96 (m, 2H), 3.69-3.86 (m, 3H), 3.07 (br. s, 4H); MS m/z (M+H+) 440.2 (calculated for C28H29N3O2, 439.56)
Following the procedure described above for Example 3 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1246
1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 433.1


1235
1-(Biphenyl-4-ylcarbonyl)-4-[1-(isothiazol-5-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 433.2


1242
1-(Biphenyl-4-ylcarbonyl)-4-{1-[(3-



fluorophenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 444.1


1236
1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 433.2


1383
1-(Biphenyl-4-ylcarbonyl)-4-[1-(1H-pyrrol-2-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 414.0


1276
1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,2,3-thiadiazol-4-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 434.0


1292
1-(Biphenyl-4-ylcarbonyl)-4-[1-(1H-pyrrol-3-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 413.0


1400
2-({3-[4-(Biphenyl-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)pyrimidine



MS m/z (M + H+) 428.1


1283
1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-oxazol-2-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 417.0


676
1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 481.1


722
1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 462.1


741
1-[1-(1H-Pyrrol-3-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 461.0


716
1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 481.0


703
1-[1-(Isothiazol-5-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 481.0


921
1-[1-(1,2,5-Oxadiazol-3-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 466.1


753
1-[1-(1,2,3-Thiadiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[5-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}piperazine



MS m/z (M + H+) 482.2


1067
1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine



MS m/z (M + H+) 501.0


1243
1-[1-(1H-Pyrrol-3-ylcarbonyl)azetidin-3-yl]-4-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine



MS m/z (M + H+) 483.0


1166
1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine



MS m/z (M + H+) 483.0


1402
4-(Biphenyl-4-ylcarbonyl)-2-phenyl-1-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 509.0


1401
4-(Biphenyl-4-ylcarbonyl)-2-phenyl-1-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 509.0









Example 4




A. 3-(4-Benzoyl-piperazin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester, 4b. To a solution of 1-Boc-azetidin-3-one (compound 4a) and compound 2a in CH3OH was added decaborane at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude compound 4b was used in the subsequent reaction without further purification. MS m/z (M+H+) 346.2.
B. (4-Azetidin-3-yl-piperazin-1-yl)-phenyl-methanone, 2c. The title compound 2c was prepared using the method described in Example 1, substituting compound 4b for compound 1c in Procedure B. The crude compound 2c was used in the next reaction without further purification. MS m/z (M+H+) 246.1.
C. 1-{1-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 62. The title compound 62 was prepared using the method described in Example 1, substituting compound 2c for compound 1g and substituting compound 4c for compound 1h in Procedure E. The crude compound 62 was purified by reverse phase chromatography. MS m/z (M+H+) 447.1.
Following the procedure described above for Example 4 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















63
1-{1-[(4-Methyl-2-thiophen-2-yl-1,3-thiazol-5-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 453.1


64
1-(1-{[4-Methyl-2-(4-methylphenyl)-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 461.2


65
1-[1-({4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 515.1


66
1-(Phenylcarbonyl)-4-{1-[(3-thiophen-2-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 432.1


67
1-(Phenylcarbonyl)-4-{1-[(4-thiophen-2-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 432.1


68
1-(Phenylcarbonyl)-4-{1-[(3-pyridin-2-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 427.2


69
1-(Phenylcarbonyl)-4-{1-[(3-pyridin-3-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 427.2


70
1-(Phenylcarbonyl)-4-{1-[(3-pyridin-4-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 427.2


71
1-(Phenylcarbonyl)-4-{1-[(4-pyridin-3-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 427.2


72
1-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.81 (d, 1H), 7.64-7.77 (m,



3H), 7.59 (t, 1H), 7.42-7.54 (m, 7H), 7.36 (d, 1H), 4.70 (m,



1H), 4.58 (m, 1H), 4.47 (m, 1H), 4.35 (m, 1H), 4.04 (m, 1H),



3.86 (m, 4H), 3.19 (m, 4H); LC/MS m/z (M + H+)



494.2 (calculated for C28H26F3N3O2, 493.53)


73
1-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-3-



yl]carbonyl}azetidin-3-yl)piperazine



LC/MS m/z (M + H+) 494.2


74
1-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-3-



yl]carbonyl}azetidin-3-yl)piperazine



LC/MS m/z (M + H+) 494.2


75
1-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.74-7.89 (m, 8H),



7.46-7.54 (m, 5H), 4.68 (m, 1H), 4.61 (m, 1H), 4.47 (m, 1H),



4.38 (m, 1H), 4.07 (m, 1H), 3.88 (m, 4H), 3.23 (m, 4H)); LC/MS



m/z (M + H+) 494.2 (calculated for C28H26F3N3O2, 493.53)


76
4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-carbonitrile



LC/MS m/z (M + H+) 451.0


77
1-{1-[(3′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



1H NMR (300 MHz, DMSO-d6): δ 7.77-7.86 (m, 3H),



7.68-7.76 (m, 3H), 7.43-7.58 (m, 7H), 4.60 (m, 2H), 4.39 (m, 1H),



4.28 (m, 1H), 4.08 (m, 1H), 3.29-3.94 (m, 6H), 3.06 (m, 2H);



LC/MS m/z (M + H+) 460.0 (calculated for C27H26ClN3O2,



459.98)


78
1-{1-[(4′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 460.0


79
1-{1-[(3′,5′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



1H NMR (300 MHz, DMSO-d6): δ 7.87 (d, 2H), 7.81 (d,



2H), 7.73 (d, 2H), 7.67 (t, 1H), 7.48 (m, 5H), 4.67 (m, 1H),



4.58 (t, 1H), 4.43 (m, 1H), 4.29 (t, 1H), 4.10 (m, 1H),



3.25-3.93 (m, 6H), 3.06 (m, 2H); LC/MS m/z (M + H+)



494.1 (calculated for C27H25Cl2N3O2, 494.43)


80
1-(Phenylcarbonyl)-4-{1-[(5-phenylpyridin-3-



yl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 427.2


81
1-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 444.1


82
4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-4-carbonitrile



LC/MS m/z (M + H+) 451.2


83
1-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.25-7.74 (m, 13H),



4.08-4.59 (m, 4H), 3.43-3.97 (m, 5H), 2.92 (m, 4H); LC/MS m/z



(M + H+) 504.0/506.1 (calculated for C27H26BrN3O2, 504.43)


474
1-(1-{[2-(4-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-



3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 477.2


473
1-{1-[3-(4-Methylphenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 392.3


84
1-{1-[3-(4-Chlorophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 412.21 (calculated for C23H26ClN3O2,



411.92)


85
1-{1-[3-(4-Bromophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 456.15 (calculated for C23H26BrN3O2,



456.38)


86
1-(Phenylcarbonyl)-4-(1-{3-[4-



(trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)piperazine



LC/MS m/z (M + H+) 446.23 (calculated for C24H26F3N3O2,



445.48)


87
1-{1-[3-(3-Chlorophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 412.18 (calculated for C23H26ClN3O2,



411.92)


88
1-{1-[3-(2-Chlorophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 412.21 (calculated for C23H26ClN3O2,



411.92)


89
1-{1-[3-(2,6-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 446.16 (calculated for C23H25Cl2N3O2,



446.37)


90
1-{1-[3-(1,3-Benzodioxol-5-yl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 422.2 (calculated for C24H27N3O4,



421.49)


91
1-(Phenylcarbonyl)-4-{1-[(2E)-3-{4-



[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3-



yl}piperazine



LC/MS m/z (M + H+) 476.20 (calculated for C24H24F3N3O2S,



475.54


92
1-(1-{3-[3,5-Bis(trifluoromethyl)phenyl]propanoyl}azetidin-



3-yl)-4-(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 514.18 (calculated for C25H25F6N3O2,



514.18)


93
1-[1-(3-Naphthalen-1-ylpropanoyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 428.27 (calculated for C27H29N3O2,



427.54)


94
1-{1-[3-(3,4-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine. LC/MS m/z (M + H+)



448.16 (calculated for C23H25Cl2N3O2, 446.38)


95
1-{1-[3-(4-Phenoxyphenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 470.29 (calculated for C29H31N3O3,



469.59)


96
1-{1-[(4-Chlorophenoxy)acetyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 414.21 (calculated for C22H24ClN3O3,



413.91)


97
1-(Phenylcarbonyl)-4-{1-[3-(5,5,8,8-tetramethyl-5,6,7,8-



tetrahydronaphthalen-2-yl)propanoyl]azetidin-3-



yl}piperazine.



LC/MS m/z (M + H+) 488.32 (calculated for C31H41N3O2,



487.69)


98
1-{1-[3-(2-Bromophenyl)propanoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 458.18 (calculated for C23H26BrN3O2,



456.39


99
1-(Phenylcarbonyl)-4-(1-{[4-



(trifluoromethoxy)phenoxy]acetyl}azetidin-3-yl)piperazine.



LC/MS m/z (M + H+) 464.26 (calculated for C23H24F3N3O4,



475.54


100
N-Cyclopropyl-4-(3-oxo-3-{3-[4-(phenylcarbonyl)piperazin-



1-yl]azetidin-1-yl}propyl)benzenesulfonamide.



LC/MS m/z (M + H+) 497.23 (calculated for C26H32N4O4S,



496.21


101
N-(Cyclohexylmethyl)-N-methyl-4-(3-oxo-3-{3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)aniline.



LC/MS m/z (M + H+) 503.37 (calculated for C31H42N4O2,



502.71


102
1-[1-(1-Benzothiophen-2-ylcarbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 406.2 (calculated for C23H23N3O2S,



405.52


103
1-{1-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 410.29 (calculated for C23H24ClN3O2,



409.92


104
1-{1-[(2E)-3-(2-Bromophenyl)prop-2-enoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 456.16 (calculated for C23H24BrN3O2,



454.37


105
1-{1-[(2E)-3-Naphthalen-2-ylprop-2-enoyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine.



LC/MS m/z (M + H+) 426.32 (calculated for C27H27N3O2,



425.54


106
1-(Phenylcarbonyl)-4-{1-[(4-



phenylcyclohexyl)carbonyl]azetidin-3-yl}piperazine.



LC/MS m/z (M + H+) 432.38 (calculated for C27H33N3O2,



431.58


107
3-Methyl-2-phenyl-8-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-4H-chromen-4-one.



LC/MS m/z (M + H+) 508.31 (calculated for C31H29N3O4,



507.59


108
Phenyl[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)cyclohexyl]methanone.



LC/MS m/z (M + H+) 460.35 (calculated for C28H33N3O3,



459.59)


109
tert-Butyl 4-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-carboxylate.



1H NMR (300 MHz, MeOD): δ 7.55 (Ar, 2H), 7.4 (m, 5H).



7.25 (ar, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 4.1 (m, 3H), 3.7 (bm,



4H), 3.0 (bm, 4H), 2.7 (m, 4H), 1.7 (m, 2H), 1.5 (m, 2H),



1.4 (s, 9H).



LC/MS m/z (M + H+) 533.33 (calculated for C31H40N4O4,



532.69


110
1-{1-[(2-Phenoxypyridin-3-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine. LC/MS m/z (M + H+)



443.28 (calculated for C26H26N4O3, 442.52


111
tert-Butyl 3-[2-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]pyrrolidine-1-carboxylate.



LC/MS m/z (M + H+) 519.35 (calculated for C30H38N4O4,



518.66)


496
tert-Butyl [4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenyl]carbamate



1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.8 Hz, 2H),



7.44 (d, J = 8.8 Hz, 2H), 7.36-7.42 (m, 4H), 7.20 (s, 1H),



4.25-4.34 (m, 1H), 4.17-4.26 (m, 1H), 4.13 (s, 1H),



3.97-4.08 (m, 1H), 3.81-3.95 (m, 1H), 3.68-3.80 (m, 1H),



3.32-3.61 (m, 2H), 3.15-3.27 (m, 1H), 2.16-2.59 (m, 4H), 1.50 (s,



9H)



MS (m/z) (M + H+) 465.2


619
1-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 481.0


618
1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 515.1


620
1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 481.0


621
1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 465.1


625
1-(Phenylcarbonyl)-4-(1-{[2-phenyl-5-(trifluoromethyl)-1,3-



oxazol-4-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 485.1


623
1-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 430.2


624
1-(Phenylcarbonyl)-4-(1-{[5-phenyl-2-



(trifluoromethyl)furan-3-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 484.0


558
1-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 511.1


626
1-(Phenylcarbonyl)-4-(1-{[1-phenyl-5-(trifluoromethyl)-1H-



pyrazol-4-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 484.2









Example 5




A. 4-(1-Benzhydryl-azetidin-3-yl)-piperazine-1-carboxylic acid tent-butyl ester, 5a. The title compound 5a was prepared using the method described in Example 1, substituting compound 1a for compound 1d in Procedure C. The crude compound 5a was used in the next reaction without further purification. MS m/z (M+H+) 408.1.
B. 1-(1-Benzhydryl-azetidin-3-yl)-piperazine, 5b. The title compound 5b was prepared using the method described in Example 1, substituting compound 5a for compound 1c in Procedure B. The crude compound 5b was used in the next reaction without further purification. MS m/z (M+H+) 208.1.
C. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-thiazol-2-yl-methanone, 5d. The title compound 5d was prepared using the method described in Example 1, substituting compound 5b for compound 1g and substituting compound 5c for compound 1h in Procedure E. The crude compound 5d was purified by flash column chromatography. MS m/z (M+H+) 419.2.
D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e. The title compound 5e was prepared using the method described in Example 1, substituting compound 5d for compound 1f in Procedure D. The crude compound 5e was used in the next reaction without further purification. MS m/z (M+H+) 253.2.
E. 1-{1-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)-carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 133. The title compound 133 was prepared using the method described in Example 1, substituting compound 5e for compound 1g and substituting compound 4c for compound 1h in Procedure E. The crude compound 133 was purified by reverse phase chromatography. 1H NMR (300 MHz, CD3OD): δ 7.98 (m, 3H), 7.89 (d, 1H), 7.46-7.55 (m, 3H), 4.80 (m, 1H), 4.41-4.69 (m, 4H), 4.09 (m, 3H), 3.35 (m, 5H), 2.68 (s, 3H); LC/MS m/z (M+H+) 454.2 (calculated for C22H23N5O2S2, 453.59).
Following the procedure described above for Example 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















134
1-{1-[(4-Methyl-2-thiophen-2-yl-1,3-thiazol-5-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (s, 1H), 7.88 (s, 1H),



7.67 (m, 2H), 7.16 (m, 1H), 4.79 (m, 1H), 4.35-4.69 (m, 4H), 4.07 (m,



3H), 3.33 (m, 5H), 2.62 (s, 3H); LC/MS m/z (M + H+)



460.0 (calculated for C20H21N5O2S3, 459.61)


135
1-(1-{[4-Methyl-2-(4-methylphenyl)-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.82-7.91 (m,



3H), 7.32 (d, 2H), 4.80 (m, 1H), 4.40-4.66 (m, 4H), 4.08 (m,



3H), 3.34 (m, 5H), 2.66 (s, 3H), 2.46 (s, 3H); LC/MS m/z



(M + H+) 468.1 (calculated for C23H25N5O2S2, 467.62)


136
1-[1-({4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.19 (d, 2H), 7.97 (d, 1H),



7.86 (d, 1H), 7.82 (d, 2H), 4.25-4.76 (m, 5H), 3.95 (m, 2H), 3.76 (m,



1H), 3.33 (m, 2H), 2.99 (m, 3H), 2.69 (s, 3H); LC/MS m/z



(M + H+) 522.2 (calculated for C23H22F3N5O2S2, 521.59)


137
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(3-thiophen-2-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.91 (t, 1H),



7.88 (d, 1H), 7.83 (dt, 1H), 7.54 (m, 2H), 7.47 (dd, 2H), 7.13 (dd,



1H), 4.30-4.79 (m, 5H), 4.02 (m, 3H), 3.24 (m, 5H); LC/MS m/z



(M + H+) 439.0 (calculated for C22H22N4O2S2, 438.57)


138
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-thiophen-2-



ylphenyl)carbonyl]azetidin-3-yl}piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.89 (d, 1H),



7.75 (m, 4H), 7.51 (m, 2H), 7.14 (m, 1H), 4.28-4.82 (m, 5H), 4.02 (m,



3H), 3.25 (m, 5H); LC/MS m/z (M + H+) 439.1 (calculated for



C22H22N4O2S2, 438.57)


139
1-{1-[(3-Pyridin-2-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 434.0


140
1-{1-[(3-Pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 434.0


141
1-{1-[(3-Pyridin-4-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 434.0


142
1-{1-[(4-Pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 434.0


143
5-[3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]pyrimidine



LC/MS m/z (M + H+) 435.0


144
5-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]pyrimidine



LC/MS m/z (M + H+) 435.0


145
2-[3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]pyrimidine



LC/MS m/z (M + H+) 435.0


146
2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]pyrimidine



LC/MS m/z (M + H+) 435.0


147
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[2′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.88 (d, 1H),



7.81 (d, 1H), 7.74 (d, 2H), 7.68 (t, 1H), 7.59 (t, 1H), 7.45 (d, 2H),



7.37 (d, 1H), 4.33-4.82 (m, 5H), 4.04 (m, 3H), 3.27 (m, 5H);



LC/MS m/z (M + H+) 501.0 (calculated for C25H23F3N4O2S,



500.55)


148
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[2′-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.88 (d, 1H),



7.81 (d, 1H), 7.73 (dt, 1H), 7.67 (d, 1H), 7.49-7.64 (m, 4H), 7.39 (d,



1H), 4.30-4.81 (m, 5H), 4.03 (m, 3H), 3.25 (m, 5H); LC/MS m/z



(M + H+) 501.0 (calculated for C25H23F3N4O2S, 500.55)


149
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4′-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



LC/MS m/z (M + H+) 501.0


150
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.76-7.89 (m,



9H), 4.62-4.77 (m, 5H), 3.97 (m, 3H), 3.13 (m, 5H); LC/MS m/z



(M + H+) 501.0 (calculated for C25H23F3N4O2S, 500.55)


151
1-(1-{[3-(6-Bromopyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.34 (t, 1H), 8.21 (dt, 1H),



7.97 (d, 1H), 7.94 (dd, 1H), 7.87 (d, 1H), 7.72-7.82 (m, 2H),



7.54-7.67 (m, 2H), 4.26-4.68 (m, 6H), 3.84-4.06 (m, 3H), 3.13 (m,



4H); LC/MS m/z (M + H+) 512.0/513.9 (calculated for



C23H22BrN5O2S, 512.43)


152
1-(1-{[3-(5-Nitropyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 479.0


153
1-(1-{[4-(5-Nitropyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 479.0


154
1-(1-{[5-(4-Fluorophenyl)pyridin-2-yl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 452.0


155
1-(1-{[2-(4-Fluorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 458.0


156
1-(1-{[2-(3-Fluorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 458.0


157
1-(1-{[2-(2,4-Dichlorophenyl)-1,3-thiazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



LC/MS m/z (M + H+) 507.9


158
1-(1-{[2-(3,5-Dichlorophenyl)-1,3-thiazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.31 (s, 1H), 7.89 (m, 3H),



7.79 (d, 1H), 7.52 (t, 1H), 5.01 (m, 1H), 4.84 (m, 2H), 4.65 (m,



1H), 4.38 (dd, 1H), 4.26 (dd, 1H), 3.93 (m, 3H), 3.17 (m, 4H);



LC/MS m/z (M + H+) 507.9 (calculated for C21H19Cl2N5O2S2,



508.45)


159
1-(1-{[2-(4-Methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 470.0


160
1-{1-[(2-Phenyl-1,3-thiazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 440.0


161
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-carbonitrile



1H NMR (300 MHz, DMSO-d6): δ 8.10 (d, 1H), 8.06 (d, 1H),



7.78-7.86 (m, 3H), 7.68-7.77 (m, 3H), 7.46-7.58 (m, 2H),



4.62 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 4.27-3.87 (m,



6H), 3.12 (m, 2H); LC/MS m/z (M + H+) 458.1 (calculated for C25H23N5O2S,



457.56)


162
1-{1-[(3′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, DMSO-d6): δ 8.10 (d, 1H), 8.06 (d, 1H),



7.78-7.86 (m, 3H), 7.68-7.77 (m, 3H), 7.46-7.58 (m, 2H),



4.61 (m, 2H), 4.37 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 4.30-3.84 (m,



6H), 3.08 (m, 2H); LC/MS m/z (M + H+) 467.1 (calculated for



C24H23ClN4O2S, 466.99)


163
1-{1-[(4′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.88 (d, 1H),



7.76 (m, 4H), 7.66 (m, 2H), 7.48 (m, 2H), 4.71 (m, 3H), 4.58 (m, 1H),



4.47 (m, 1H), 4.36 (m, 1H), 4.02 (m, 3H), 3.23 (m, 4H); LC/MS



m/z (M + H+) 467.1 (calculated for C24H23ClN4O2S, 466.99)


164
1-{1-[(3′,5′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.88 (d, 1H), 7.78 (d, 1H),



7.68 (m, 4H), 7.55 (d, 2H), 7.39 (t, 1H), 4.57 (m, 3H), 4.45 (m, 1H),



4.35 (m, 1H), 4.23 (m, 1H), 3.91 (m, 2H), 3.81 (m, 1H), 3.03 (m,



4H); LC/MS m/z (M + H+) 501.0 (calculated for C24H22Cl2N4O2S,



501.44)


165
1-{1-[(5-Phenylpyridin-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 434.1


166
1-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.37-7.67 (m, 8H), 4.66 (m, 3H), 4.53 (m, 1H), 4.42 (m, 1H), 4.30 (m,



1H), 3.98 (m, 2H), 3.85 (m, 1H), 3.07 (m, 4H); LC/MS m/z



(M + H+) 451.0 (calculated for C24H23FN4O2S, 450.54)


167
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-4-carbonitrile



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.77-7.92 (m, 9



H), 4.63-4.79 (m, 3H), 4.57 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H),



3.90-4.13 (m, 3 H), 3.19 (m, 4 H); LC/MS m/z (M + H+)



458.1 (calculated for C25H23N5O2S, 457.56)


168
1-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.76 (m, 4H), 7.62 (dd, 4H), 4.67 (m, 3H), 4.51 (m, 1H), 4.44 (m,



1H), 4.30 (m, 1H), 3.98 (m, 2H), 3.88 (m, 1H), 3.10 (m, 4H);



LC/MS m/z (M + H+) 511.0/513.0 (calculated for C24H23BrN4O2S, 511.44)


169
1-{1-[(5-Phenylpyridin-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 434.1


170
1-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.37-7.67 (m, 8H), 4.70 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H),



4.34 (m, 1H), 4.11 (m, 4H), 3.99 (m, 1H), 3.17 (m, 4H); LC/MS



m/z (M + H+) 451.0 (calculated for C24H23FN4O2S, 450.54)


171
4′-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-4-carbonitrile



LC/MS m/z (M + H+) 458.1


172
1-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.76 (m, 4H), 7.61 (dd, 4H), 4.68 (m, 1H), 4.57 (m, 1H), 4.46 (m,



1H), 4.36 (m, 1H), 4.15 (m, 4H), 4.04 (m, 1H), 3.22 (m, 4H);



LC/MS m/z (M + H+) 511.0/513.0 (calculated for C24H23BrN4O2S, 511.44)


475
1-{1-[(4-Phenylcyclohexyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 439.2


476
3-Methyl-2-phenyl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-4H-chromen-4-one



MS m/z (M + H+) 515.2


477
1-[1-(3-Phenylprop-2-ynoyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 381.1


478
Phenyl-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)cyclohexyl]methanone



MS m/z (M + H+) 467.2


479
1-[1-({2-[(4-Methylphenyl)sulfanyl]pyridin-3-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 480.1


298
1-(1-{[5-(4-Methylphenyl)-1H-pyrrol-2-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 436.2


112
2-Methyl-4-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-1-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 463.2 (calculated for C25H26N4O3S, 462.57)


113
2-Methyl-4-{1-[(3-phenoxyphenyl)carbonyl]azetidin-3-yl}-1-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 463.2 (calculated for C25H26N4O3S, 462.57)


114
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 509.0 (calculated for C30H28N4O2S, 508.65)


115
4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-methyl-1-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 461.0 (calculated for C26H28N4O2S, 460.60)


116
4-[1-(Biphenyl-3-ylcarbonyl)azetidin-3-yl]-2-methyl-1-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 446.9 (calculated for C25H26N4O2S, 446.58)


117
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-methyl-1-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 447.3 (calculated for C25H26N4O2S, 446.58)


489
1-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.81-8.02 (m, 4H), 7.52 (d,



2H), 4.30-4.64 (m, 6H) 3.84-4.09 (m, 3H), 3.10-3.29 (m, 4H),



2.67 (s, 3H); LC/MS m/z (M + H+) 488.1 (calculated for



C22H22ClN5O2S2, 488.03)


490
1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.95-8.05 (m, 2H),



7.84-7.94 (m, 2H), 7.45-7.60 (m, 2H), 4.32-4.84 (m, 6H) 3.92-4.09 (m,



3H), 3.15-3.27 (m, 4H), 2.68 (s, 3H); LC/MS m/z (M + H+)



488.1 (calculated for C22H22ClN5O2S2, 488.03)


485
1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.16-8.36 (m,



3H), 7.79-7.89 (m, 1H), 7.66-7.78 (m, 1H), 4.23-4.76 (m, 4H)



3.84-4.22 (m, 5H), 3.04-3.22 (m, 4H), 2.70 (s, 3H); LC/MS m/z



(M + H+) 522.2 (calculated for C23H22F2N5O2S2, 521.59)


744
2,3-Dimethyl-N-[2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]aniline



MS m/z (M + H+) 476.1


1297
1-{1-[(1,5-Diphenyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 499.1


768
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-N-[3-(trifluoromethyl)phenyl]aniline



MS m/z (M + H+) 516.2


781
N-Phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS m/z (M + H+) 448.0


1460
N-(3-Bromophenyl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzamide



MS m/z (M + H+) 552.0/554.0


1214
1-(1-{[5-Methyl-2-(4-methylphenyl)-2H-1,2,3-triazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 452.1


754
N-(3-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline



MS m/z (M + H+) 466.0


1103
1-(1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-



pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 615.0


886
1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 479.1


1301
1-(1-{[1-(4-Fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 469.1


1164
1-{1-[(1,5-Diphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 499.1


1218
1-(1-{[2-(4-Chlorophenyl)-5-methyl-2H-1,2,3-triazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 472.1


843
4-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]thiomorpholine 1,1-dioxide



MS m/z (M + H+) 490.0


815
4-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]morpholine



MS m/z (M + H+) 442.0


1249
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H-



pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 491.1


1300
1-{1-[(2-Phenyl-2H-1,2,3-triazol-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 424.0


646
4-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)piperidin-1-yl]benzonitrile



MS m/z (M + H+) 465.1


763
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2,3,4,9-tetrahydro-1H-carbazole



MS m/z (M + H+) 450.1


750
9-Methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-9H-carbazole



MS m/z (M + H+) 460.2


795
N-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-thiazol-2-amine



MS m/z (M + H+) 469.0


1225
1-(1-{[1-(3,4-Dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 519.0


636
1-(1-Hexadecanoylazetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 491.4


687
1-Propyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 438.3


776
1-{1-[(3,5-Di-tert-butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 469.4


637
1-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 473.2


672
1-{1-[(4-tert-Butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 413.3


669
1-{1-[(4-Pyrrolidin-1-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 426.3


887
1-(1-{[4-(1,1-Dimethylpropyl)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 427.2


1434
1-[1-(4-Phenylbutanoyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 399.3


888
1-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]azepane



MS m/z (M + H+) 454.4


889
1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 439.2


890
1-{1-[(1-Chloronaphtho[2,1-b]thiophen-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 497.1


891
1-(1-{[4-(2-Methylpropyl)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 413.3


892
1-{1-[(4-Heptylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 455.3


893
1-{1-[(4-Pentylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 427.2


655
1-{1-[(4-Propylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 399.1


894
1-{1-[(4-Butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 413.3


849
1-{1-[(5-tert-Butyl-2-methoxyphenyl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 443.2


639
1-{1-[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyl]azetidin-3-



yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 539.4


641
1-{1-[(9Z)-Octadec-9-enoyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 517.3


638
1-{1-[(9Z,12Z)-Octadeca-9,12-dienoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 515.4


1017
Phenyl[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]methanone



MS m/z (M + H+) 461.1


1082
1-[1-({4-[4-(4-Fluorophenyl)-1,3-thiazol-2-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 534.2


1245
1-[1-({4-[5-(4-Methylphenyl)-1H-1,2,3-triazol-1-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 500.1


1326
1-(1-{[4-(4-Phenyl-1,3-thiazol-2-yl)phenyl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 516.2


1327
3-(4-Chlorophenyl)-2-[4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-



4,5,6,7-tetrahydro-2H-indazole



MS m/z (M + H+) 587.3


1179
1-(1-{[4-(4,5-Diphenyl-1H-imidazol-2-



yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 575.2


693
1-(1-{[3-Chloro-4-(trifluoromethoxy)phenyl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 475.0


667
4-(3-Chlorophenyl)-8-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3a,4,5,9b-



tetrahydro-3H-cyclopenta[c]quinoline



MS m/z (M + H+) 560.2


1328
1-[1-({4-[4-(2-Chlorophenyl)-1,3-thiazol-2-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 550.0


1329
1-[1-({4-[4-(2,4-Dichlorophenyl)-1,3-thiazol-2-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 584.1


640
1-(1-Icosanoylazetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 547.3


1156
1-[1-({4-[5-(4-Methylphenyl)-1,3,4-oxadiazol-2-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 515.2


1330
2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]-3-[3-(trifluoromethyl)phenyl]-2,4,5,6-



tetrahydrocyclopenta[c]pyrazole



MS m/z (M + H+) 607.3


826
7-Chloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 456.1


797
6-Chloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 442.2


787
7-Chloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 442.2


835
6-Chloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 456.1


743
6,7-Dichloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 476.1


1331
1-[1-({4-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 584.1


727
1-{1-[(4-Bromo-3-methylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 447.1/449.1


786
1-{1-[(4-Bromo-2-methylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 447.1/449.1


766
1-{1-[(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 427.2


658
N,N-Dipropyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzenesulfonamide



MS m/z (M + H+) 520.2


816
N-Ethyl-2-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenoxy]acetamide



MS m/z (M + H+) 458.3


874
Phenyl[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-pyrrol-3-yl]methanone



MS m/z (M + H+) 450.1


1332
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{4-[3-



(trifluoromethyl)phenyl]-1,3-thiazol-2-



yl}phenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 584.1


1333
2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 472.2


1083
1-(1-{[5-(4-Chlorophenyl)-1-(3,4-dichlorophenyl)-1H-pyrazol-



3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 601.0


788
1-(1-{[2,5-Dimethyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 456.1


702
2-Chloro-5-fluoro-N-[4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]benzamide



MS m/z (M + H+) 529.0


770
1-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)azetidin-



3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 429.1


783
2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 428.1


694
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[(2,2,2-



trifluoroethoxy)methyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 469.2


836
N-{2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenoxy]ethyl}acetamide



MS m/z (M + H+) 458.3


730
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(2,2,2-



trifluoroethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 455.1


1334
1-[1-({4-[4-(4-Chlorophenyl)-1H-pyrazol-1-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 533.1


1203
1-(4-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



pyrazolo[3,4-b]pyridine



MS m/z (M + H+) 506.2


1146
3-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-



thieno[2,3-c]pyrazole



MS m/z (M + H+) 561.0


1272
1-{1-[(4-Methyl-2-pyridin-4-yl-1,3-thiazol-5-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 455.1


1119
2,3-Diphenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 548.2


824
3-Methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-7,8-dihydropyrrolo[1,2-a]thieno[2,3-



d]pyrimidin-4(6H)-one



MS m/z (M + H+) 485.1


710
3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-9H-xanthen-9-one



MS m/z (M + H+) 475.1


823
5,7-Dichloro-2-methyl-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 490.0


782
1-(1-{[4-(2-Methoxyethoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 431.3


698
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-9H-fluoren-9-one



MS m/z (M + H+) 459.1


1123
1-[1-({4-[4-(3,5-Difluorophenyl)-1H-pyrazol-1-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 535.2


791
5-Chloro-2,8-dimethyl-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 470.1


845
7-Methoxy-2-methyl-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline



MS m/z (M + H+) 452.2


1412
1-[1-({4-[5-(4-Fluorophenyl)-1H-pyrazol-1-



yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 518.1


946
N-Methyl-N-phenyl-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)benzenesulfonamide



MS m/z (M + H+) 526.0


1041
2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenoxy]-N-[3-(trifluoromethyl)phenyl]acetamide



MS m/z (M + H+) 574.0


1042
4-{[2,5-Dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-pyrrol-1-



yl]methyl}benzenesulfonamide



MS m/z (M + H+) 544.0


947
1-(1-{[4-(Piperidin-1-ylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 504.1


1053
1-(4-Chlorobenzyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



thieno[2,3-c]pyrazole



MS m/z (M + H+) 542.2


952
1-{1-[(9,9-Dimethyl-9H-fluoren-2-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 473.0


1407
1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): d 8.28 (s, 1H), 8.23 (d, 1H),



7.98 (d, 1H), 7.88 (d, 1H), 7.82 (d, 1H), 7.72 (t, 1H), 4.35-4.81 (m,



6H), 3.92-4.13 (m, 3H), 3.19-3.27 (m, 4H), 2.71 (s, 3H)



MS m/z (M + H+) 522.2


1384
1-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 488.1


1381
1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 488.1


1150
1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 472.0


1386
1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 472.0


1385
1-(1-{[2-Phenyl-5-(trifluoromethyl)-1,3-oxazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 492.1


1378
1-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 437.1


1379
1-(1-{[5-Phenyl-2-(trifluoromethyl)furan-3-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 491.1


965
1-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 518.1


1392
1-(1-{[1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 491.1


1403
1-(1-{[2-Phenyl-5-(trifluoromethyl)-1,3-oxazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 492.1


1396
1-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 437.1


1397
1-(1-{[5-Phenyl-2-(trifluoromethyl)furan-3-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 491.1


966
1-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 518.1


1477
1-(1-{[1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 491.1


1395
1-(1-{[2-(3,5-Dichlorophenyl)-1,3-thiazol-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 507.9/508.8


923
1-(1-{[3-Bromo-5-(trifluoromethyl)phenyl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 503/505


910
1-(1-{[3-Bromo-5-(trifluoromethyl)phenyl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 503/505


915
1-{1-[(5-Bromo-2-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 453/455


912
1-{1-[(3-Bromo-5-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 453/455


925
1-{1-[(5-Bromo-2-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 453/455


926
1-{1-[(3-Bromo-5-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 453/455


1202
1-(1-{[2-(2-Fluorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 472.2


1287
1-(1-{[2-(2-Fluorophenyl)-4-methyl-1,3-thiazol-5-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 472.2


831
1-(1-Methylethyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H-



benzimidazole



MS m/z (M + H+) 507.1


740
1-(1-Methylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H-



benzimidazole



MS m/z (M + H+) 507.1


1432
2-(2-Oxo-2-{3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}ethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide



MS m/z (M + H+) 476.1


517
2-Phenyl-4-[1-(phenylcarbonyl)azetidin-3-yl]-1-{[5-



(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine



MS m/z (M + H+) 550.03


1489
3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(phenylcarbonyl)azetidin-



3-yl]piperazin-1-yl}carbonyl)-4H-chromen-4-one



MS m/z (M + H+) 584.34


1490
1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-



3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 422.06


526
7-Methoxy-3-methyl-2-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 433.2


610
1-[4-({4-[1-(Phenylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)phenyl]-1H-benzimidazole



MS m/z (M + H+) 466.2


523
1-Cyclohexyl-2-methyl-5-({4-[1-(phenylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 486.3


1491
1-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 424


611
2-Phenyl-5-({4-[1-(phenylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 466.2


524
1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-



(phenylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 432.9


502
1-(Phenylcarbonyl)-4-(1-{[4-



(trifluoromethyl)cyclohexyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 424


503
1-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 466


648
1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(2E)-3-{4-



[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 483.3


644
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-



(trifluoromethyl)cyclohexyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 431.29


643
1-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 473.27


1481
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 509.28


804
2-Phenyl-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]-1-{[5-



(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine



MS m/z (M + H+) 557.14


905
2-Phenyl-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]-1-{[5-



(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine



1H NMR (CDCl3): δ 9.02 (d, 1H); 8.31 (s, 1H); 8.22 (s, 1H);



8.12 (m, 1H); 7.77 (s, 1H); 7.69 (m, 1H); 7.50 (m, 5H); 7.35 (m,



1H); 5.91 (bm, 1H); 4.83 (m, 1H); 4.64 (m, 1H); 4.48-4.46 (m,



2H); 4.14 (m, 1H); 3.86 (m, 1H); 3.87 (m, 1H); 3.51 (m, 1H);



3.12 (t, 1H); 2.97 (m, 1H).



MS m/z (M + H+) 557.18


1436
3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen-4-one



MS m/z (M + H+) 591.26


854
3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen-



4-one



MS m/z (M + H+) 591.24


1307
1-(1-{[5-(4-Chlorophenyl)-1H-pyrrol-2-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 256


1122
1-{1-[(5-Phenylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.99 (d, 1H), 7.88 (d, 1H); 7.71 9m, 2H);



7.52-7.32 (m, 4H); 4.75 (b, 4H); 4.0 (bm, 3H); 3.22 (bm, 4H)



MS m/z (M + H+) 439.16


1473
1-(1-{[5-(4-Chlorophenyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 458.13


838
1-Methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 410.12


796
1,2-Dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 424.21


1475
1-{1-[(3-Phenyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 323.13


993
1-Benzyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 486


850
1-{1-[(6-Methoxy-3-methyl-1-benzofuran-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 441.1


721
1-{1-[(6-Methoxy-3-methyl-1-benzofuran-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 441.1


862
1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 429.1


751
1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 429.1


840
7-Methoxy-3-methyl-2-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 440.1


760
7-Methoxy-3-methyl-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 440.1


1442
6-Fluoro-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 415


846
7-Methoxy-3-methyl-2-({4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 439.7/440.3


871
1-{1-[(7-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 428.8


857
7-Methoxy-3-methyl-2-({4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 440.1


755
5-Chloro-3-methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 444.1


1443
5-Fluoro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 415.2


794
1-{1-[(7-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 428.8


688
5-Chloro-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (CDCl3): δ 7.88 (d, 1H); 7.78 (d, 1H); 7.5 (m, 1H);



7.27 (m, 1H); 7.12 (m, 1H); 4.16 (bm, 1H); 4.32 (bm, 2H);



3.16 (m, 3H); 2.36 (s, 3H)



MS m/z (M + H+) 443.1


1293
1-[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]-1H-benzimidazole



MS m/z (M + H+) 472.83


1223
1-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]-1H-benzimidazole



MS m/z (M + H+) 473.1


1305
1-[4-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)phenyl]-1H-benzimidazole



MS m/z (M + H+) 473.1


1298
1-[4-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)phenyl]-1H-benzimidazole



MS m/z (M + H+) 473.1


732
1-Cyclohexyl-2-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 493.2


793
1-Cyclohexyl-2-methyl-5-({4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 493.2


814
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}-4-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-



yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 563.1


800
2-Cyclohexyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 479.1


735
2-Cyclohexyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 479.1


827
2-Cyclohexyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 479.1


853
2-Cyclohexyl-5-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 479.1


1299
2-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 473.1


1194
2-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 473.1


1271
2-Phenyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 473.1


1444
1-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 431


818
1-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 431


785
1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 430.86


809
1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 430.93


1000
2-(2-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 501.1


1001
2-Benzyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 486.9


855
5-Chloro-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 447.6


1002
2-(2-Phenylethyl)-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 501.1


728
5-Chloro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 448


764
5-Chloro-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 448


1003
2-Benzyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 487


1004
2-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 487


821
5-Chloro-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 448.1


779
4-Chloro-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline



MS m/z (M + H+) 5.1


848
4-Chloro-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline



MS m/z (M + H+) 509.72


859
4-Chloro-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline



MS m/z (M + H+) 510


842
4-Chloro-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline



MS m/z (M + H+) 510


756
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)-1H-indole



MS m/z (M + H+) 463.81


828
2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)-1H-indole



MS m/z (M + H+) 463.81


1445
2-({3-[4-(Isothiazol-5-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)-1H-indole



MS m/z (M + H+) 463.81


747
2-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)-5-(trifluoromethyl)-1H-indole



MS m/z (M + H+) 464.1


772
2-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)-5-(trifluoromethyl)-1H-indole



MS m/z (M + H+) 464.1


726
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}-4-[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 494.97


731
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}-4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 477.02


748
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}-4-[1-(1H-pyrrol-3-ylcarbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 477.02


844
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine



MS m/z (M + H+) 466.1


808
2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine



MS m/z (M + H+) 465.98


1446
2-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine



MS m/z (M + H+) 448.2


860
2-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine



MS m/z (M + H+) 466


678
1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.38 (m, 2H); 7.19-6.84 (m, 5H); 6.88 (m,



1H); 6.56 (m, 1H); 6.13 (m, 1H); 4.67-4.21 (m, 3H);



4.12-3.90 (bd, 4H); 3.25 (bm, 3H)



MS m/z (M + H+) 461.2


799
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine



MS m/z (M + H+) 465.2


865
2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine



MS m/z (M + H+) 465.1


1447
2-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine



MS m/z (M + H+) 447.1


1448
5-Bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine



MS m/z (M + H+) 477.1


864
5-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine



MS m/z (M + H+) 477.1


1449
5-Bromo-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)furo[2,3-b]pyridine



MS m/z (M + H+) 477.1


696
5-Chloro-1,3-dimethyl-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 458.2


758
5-Chloro-1,3-dimethyl-2-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 458.1


762
5-Chloro-1,3-dimethyl-2-({4-[1-(1,3-thiazol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 485.1


839
5-Chloro-1,3-dimethyl-2-({4-[1-(1H-pyrrol-2-



ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 440.2


774
3-Bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-



b]pyridine



MS m/z (M + H+) 543.1


733
5-Chloro-1,3-dimethyl-2-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 440.2


675
3-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-



b]pyridine



MS m/z (M + H+) 543.1


739
3-Bromo-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-



b]pyridine



MS m/z (M + H+) 525.2


746
3-Bromo-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-



b]pyridine



MS m/z (M + H+) 543


863
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine



MS m/z (M + H+) 465.1


830
2-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine



MS m/z (M + H+) 465.1


1450
2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine



MS m/z (M + H+) 465.1


719
5-Fluoro-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 428.3


852
6-Bromo-7-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 495.1


1451
6-Bromo-7-methyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 472.8


1452
8-Bromo-6-chloro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 472.8


1453
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 465.1


682
5-Bromo-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 488.1


868
6-Bromo-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 490.1


873
6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 475


825
6-Bromo-3-methyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine



MS m/z (M + H+) 471.1


792
6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 476.1


953
(2R,6S)-2,6-Dimethyl-4-(1,3-thiazol-2-ylcarbonyl)-1-(1-{[6-



(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 509.0









Example 6




A. Azetidin-3-one, 6a. The title compound 6a was prepared using the method described in Example 1, substituting compound 4a for compound 1c in Procedure B. The crude compound 6a was used in the next reaction without further purification. MS m/z (M+H++CF3CO2H) 186.1.
B. 1-(4-Bromo-benzoyl)-azetidin-3-one, 6b. The title compound 6b was prepared using the method described in Example 1, substituting compound 6a for compound 1g and substituting compound 2d for compound 1h in Procedure E. The crude compound 6b was used in the next reaction without further purification. MS m/z (M+H+) 419.2.
C. 4-[1-(4-Bromo-benzoyl)-azetidin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester, 6c. The title compound 6c was prepared using the method described in Example 4, substituting compound 6b for compound 4a and substituting compound 1a for compound 2a in Procedure A. The crude product 6c was purified by flash column chromatography. MS m/z (M+H+) 424.0/426.1.
D. (4-Bromo-phenyl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 6d. The title compound 6d was prepared using the method described in Example 1, substituting compound 6c for compound 1c in Procedure B. The crude product 6d was used in the next reaction without further purification. MS m/z (M+H+) 324.09/326.08.
E. 1-{1-[(4-Bromophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 173 The title compound Cpd 173 was prepared using the method described in Example 1, substituting compound 6d for compound 1g and substituting compound 5c for compound 1h in Procedure E. The crude product Cpd 173 was used in the next reaction without further purification. MS m/z (M+H+) 435.0/437.0.
F. 1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 174. To a suspension of compound 173 (0.05 g, 0.115 mmol), compound 6e (0.0193 g, 0.14 mmol), and Cs2CO3 (0.094 g, 0.288 mmol) in dioxane (3 mL) and EtOH (1 mL) was added Pd(dppf)Cl2 (0.0084 g, 0.0115 mmol). The reaction mixture was stirred at 80° C. for 3 h. After cooling, the solid was removed by filtration and washed with CH3OH. The filtrate was concentrated. The crude compound 174 was purified by reverse phase chromatography. 1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.65-7.79 (m, 6H), 7.21 (t, 2H), 4.67 (m, 3H), 4.52 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.98 (m, 2H), 3.89 (m, 1H), 3.11 (m, 4H); MS m/z (M+H+) 451.2 (calculated for C24H23FN4O2S, 450.54).
Following the procedure described above for Example 6 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















175
1-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.88 (d, 1H),



7.85 (d, 1H), 7.77 (m, 4H), 7.62 (m, 2H), 4.54-4.81 (m, 4H)



4.46 (m, 1H), 4.38 (m, 1H), 4.04 (m, 3H), 3.25 (m, 4H);



LC/MS m/z (M + H+) 501.0/503.1 (calculated for



C24H22Cl2N4O2, 501.44)


176
1-{1-[(3′-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.74 (m, 4H), 7.45 (m, 2H), 7.35 (t, 1H), 7.22 (d, 1H), 4.68 (m,



3H), 4.53 (m, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.87-4.05 (m,



3H), 3.15 (m, 4H); LC/MS m/z (M + H+) 447.1 (calculated for



C25H26N4O2S, 446.58)


177
1-{1-[(5′-Fluoro-2′-methylbiphenyl-4-yl)carbonyl]azetidin-3-



yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.76 (d, 2H), 7.46 (d, 2H), 7.30 (dd, 1H), 7.02 (td, 1H),



6.94 (dd, 1H), 4.68 (m, 3H), 4.55 (m, 1H), 4.44 (m, 1H), 4.33 (m,



1H), 4.01 (m, 2H), 3.92 (m, 1H), 3.14 (m, 4H); LC/MS m/z



(M + H+) 465.1 (calculated for C25H25FN4O2S, 464.57)


178
1-{1-[(3′-Chloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-



yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.80 (dd, 1H), 7.76 (m, 4H), 7.64 (m, 1H), 7.36 (t, 1H),



4.68 (m, 3H), 4.52 (m, 1H), 4.45 (m, 1H), 4.32 (m, 1H),



3.89-4.06 (m, 3H), 3.16 (m, 4H); LC/MS m/z (M + H+)



485.1 (calculated for C24H22ClFN4O2S, 484.98)


179
1-{1-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.77 (d, 2H), 7.65 (d, 2H), 7.55 (m, 1H), 7.10 (m, 2H),



4.65 (m, 3H), 4.50 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 3.97 (m,



2H), 3.86 (m, 1H), 3.07 (m, 4H); LC/MS m/z (M + H+)



469.0 (calculated for C24H22F2N4O2S, 468.53)


180
1-{1-[(3′-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.75 (m, 4H), 7.39 (t, 1H), 7.22 (d, 1H), 7.18 (t, 1H), 6.97 (dd,



1H), 4.67 (m, 3H), 4.51 (m, 1H), 4.43 (m, 1H), 4.32 (m, 1H),



3.96 (m, 3H), 3.86 (s, 3H), 3.15 (m, 4H); LC/MS m/z (M + H+)



463.2 (calculated for C25H26N4O3S, 462.57)


181
1-(1-{[4-(1,3-Benzodioxol-5-yl)phenyl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.87 (d, 1H),



7.70 (m, 4H), 7.16 (m, 2H), 6.92 (d, 1H), 6.01 (s, 2H), 4.69 (m,



3H), 4.54 (m, 1H), 4.44 (m, 1H), 4.33 (m, 1H), 3.97 (m, 3H),



3.17 (m, 4H); LC/MS m/z (M + H+) 477.1 (calculated for



C25H24N4O4S, 476.56)


182
1-{1-[(4-Naphthalen-2-ylphenyl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.79-8.01 (m, 11H),



7.50-7.56 (m, 2H), 4.60 (m, 1H), 4.49 (m, 1H), 4.37 (m, 1H),



4.27 (m, 1H), 4.08 (m, 4H),



3.95 (m, 1H), 3.14 (m, 4H); LC/MS m/z



(M + H+) 483.1 (calculated for C28H26N4O2S, 482.61)


183
1-{1-[(3′-Nitrobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.53 (t, 1H), 8.29 (m, 1H),



8.10 (m, 1H), 7.97 (d, 1H), 7.82-7.90 (m, 5H), 7.75 (t, 1H),



4.69 (m, 3H), 4.55 (m, 1H), 4.46 (m, 1H), 4.34 (m, 1H),



3.88-4.07 (m, 3H), 3.15 (m, 4H); LC/MS m/z (M + H+)



478.2 (calculated for C24H23N5O4S, 477.55)


184
5-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenyl]quinoline



1H NMR (300 MHz, CD3OD): δ 9.14 (d, 1H), 8.80 (d, 1H),



8.24 (d, 1H), 8.13 (dd, 1H), 7.97 (d, 1H), 7.89 (m, 5H),



7.68 (m, 2H), 4.70 (m, 3H), 4.60 (m, 1H), 4.47 (m, 1H), 4.36 (m,



1H), 4.00 (m, 2H), 3.91 (m, 1H), 3.12 (m, 4H); LC/MS m/z



(M + H+) 484.2 (calculated for C27H25N5O2S, 483.6)


185
1-{1-[(2′,4′-Dimethoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-



4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 486.1


186
1-(Phenylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.94 (m, 2H), 7.80 (m, 4H),



7.70 (m, 2H), 7.45-7.53 (m, 5H), 4.66 (m, 1H), 4.52 (m, 1H),



4.44 (m, 1H), 4.31 (m, 1H), 3.95 (m, 1H), 3.84 (m, 4H),



3.10 (m, 4H); LC/MS m/z (M + H+) 494.1 (calculated for



C28H26F3N3O2, 493.53)


187
1-{1-[(2′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 444.1


188
1-(1-{[3′-(1-Methylethoxy)biphenyl-4-yl]carbonyl}azetidin-3-



yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.73 (m, 4H), 7.48 (m, 5H),



7.36 (t, 1H), 7.19 (d, 1H), 7.14 (t, 1H), 6.94 (dd, 1H),



4.19-4.82 (m, 5H), 3.83 (m, 5H), 2.98 (m, 4H), 1.34 (d, 6H);



LC/MS m/z (M + H+) 484.2 (calculated for C30H33N3O3, 483.62)


189
1-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethoxy)biphenyl-4-



yl]carbonyl}azetidin-3-yl)piperazine



LC/MS m/z (M + H+) 510.1


190
1-(1-{[4-(2-Fluoropyridin-4-yl)phenyl]carbonyl}azetidin-3-



yl)-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 445.2


191
1-{1-[(3′-Fluoro-4′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-



yl}-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 474.1


192
Methyl 4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-4-carboxylate



LC/MS m/z (M + H+) 484.2


193
1-(Phenylcarbonyl)-4-{1-[(3′,4′,5′-trifluorobiphenyl-4-



yl)carbonyl]azetidin-3-yl}piperazine



LC/MS m/z (M + H+) 480.1


194
N,N-Diethyl-4′-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-carboxamide



LC/MS m/z (M + H+) 525.3


195
1-{1-[(3′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.76 (m, 4H), 7.38-7.54 (m,



8H), 7.13 (m, 1H), 4.66 (m, 1H), 4.53 (m, 1H), 4.43 (m, 1H),



4.31 (m, 1H), 3.95 (m, 1H), 3.83 (m, 4H), 3.11 (m, 4H);



LC/MS m/z (M + H+) 444.1 (calculated for C27H26FN3O2,



443.53)


196
1-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethoxy)biphenyl-4-



yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.77 (d, 2H), 7.60 (d, 2H),



7.39-7.55 (m, 9H), 4.68 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H),



4.33 (m, 1H), 3.97 (m, 1H), 3.83 (m, 4H), 3.13 (m, 4H);



LC/MS m/z (M + H+) 510.1 (calculated for C28H26F3N3O3,



509.53)


197
1-{1-[(4′-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 440.2


198
1-(1-{[2′-(1-Methylethoxy)biphenyl-4-yl]carbonyl}azetidin-3-



yl)-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 484.2


199
Methyl 4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-2-carboxylate



LC/MS m/z (M + H+) 484.2


200
1-{1-[(4′-Fluoro-2′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-



yl}-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 474.3


201
1-{1-[(2′,3′-Dimethoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-



4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 486.3


202
1-{1-[(2′,5′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 462.1


203
1-{1-[(2′-Fluoro-6′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-



yl}-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 474.3


204
1-{1-[(2′,3′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 462.1


205
N,N-Dimethyl-N′-[4′-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]sulfamide



1H NMR (300 MHz, CD3OD): δ 7.73 (dd, 4H), 7.33-7.54 (m,



8H), 7.23 (dt, 1H), 4.18-4.72 (m, 4H), 3.83 (m, 5H), 3.01 (m,



4H), 2.80 (s, 6H); LC/MS m/z (M + H+) 548.3 (calculated for



C29H33N5O4S, 547.68)


206
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-carboxylic acid



LC/MS m/z (M + H+) 477.1


207
[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-yl]acetonitrile



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.78 (m, 4H), 7.65 (m, 2H), 7.51 (t, 1H), 7.42 (d, 1H),



4.25-4.76 (m, 6H), 4.00 (s, 2H), 3.86-4.03 (m, 3H), 3.13 (m, 4H);



LC/MS m/z (M + H+) 472.2 (calculated for C26H25N5O2S,



471.59)


208
1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.22 (m, 1H), 7.95-8.07 (m,



3H), 7.71-7.90 (m, 6H), 4.31-4.81 (m, 6H), 4.03 (m, 3H),



3.21-3.36 (m, 4H), 3.19 (s, 3H); LC/MS m/z (M + H+)



511.2 (calculated for C25H26N4O4S2, 510.64)


209
1-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)biphenyl-4-yl]ethanone



1H NMR (300 MHz, CD3OD): δ 8.11 (d, 2H), 7.97 (d, 1H),



7.76-7.91 (m, 7H), 4.70 (m, 3H), 4.55 (m, 1H), 4.45 (m, 1H),



4.34 (m, 1H), 3.98 (m, 3H), 3.16 (m, 4H), 2.65 (s, 3H); LC/MS



m/z (M + H+) 475.2 (calculated for C26H26N4O3S, 474.59)


210
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-carbaldehyde



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.76 (m, 4H), 7.72 (m, 1H), 7.65 (m, 1H), 7.49 (m, 2H),



4.69 (m, 3H), 4.53 (m, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.96 (m,



3H), 3.15 (m, 4H); LC/MS m/z (M + H+) 461.2 (calculated for



C25H24N4O3S, 460.56)


211
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-4-ol



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.86 (d, 1H),



7.69 (m, 4H), 7.52 (d, 2H), 6.88 (d, 2H), 4.66 (m, 3H),



4.51 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 3.98 (m, 2H), 3.86 (m,



1H), 3.09 (m, 4H); LC/MS m/z (M + H+) 449.2 (calculated for



C24H24N4O3S, 448.55)


212
1-(1-{[4′-Chloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.03 (d, 1H), 7.97 (d, 1H),



7.92 (dd, 1H), 7.86 (d, 1H), 7.80 (m, 4H), 7.73 (d, 1H),



4.62 (m, 3H), 4.45 (m, 2H), 4.28 (m, 1H), 3.96 (m, 2H), 3.82 (m,



1H), 3.03 (m, 4H); LC/MS m/z (M + H+) 535.0 (calculated for



C25H22ClF3N4O2S, 534.99)


213
N,N-Dimethyl-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-4-sulfonamide



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.78-7.95 (m,



9H), 4.70 (m, 3H), 4.55 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H),



3.97 (m, 3H), 3.17 (m, 4H), 2.72 (s, 6H); LC/MS m/z (M + H+)



540.2 (calculated for C26H29N5O4S2, 539.68)


214
1-{1-[(4′,5′-Difluoro-2′-methoxybiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.88 (d, 1H),



7.71 (d, 2H), 7.69 (d, 2H), 7.26 (dd, 1H), 7.08 (dd, 1H),



4.70 (m, 3H), 4.56 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 3.99 (m,



3H), 3.20 (m, 4H); LC/MS m/z (M + H+) 499.2 (calculated for



C25H24F2N4O3S, 498.56)


215
1-{1-[(4′-Nitrobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.36 (d, 2H), 7.78-7.99 (m,



8H), 4.67 (m, 3H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31 (m, 1H),



3.98 (m, 2H), 3.99 (m, 1H), 3.12 (m, 4H); LC/MS m/z (M + H+)



478.2 (calculated for C24H23N5O4S, 477.55)


216
4-Methoxy-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-carbaldehyde



1H NMR (300 MHz, CD3CN): δ 10.38 (s, 1H), 7.96 (d, 1H),



7.84-7.91 (m, 2H), 7.59-7.69 (m, 5H), 7.19 (d, 1H),



4.33-4.64 (m, 4H), 4.23 (m, 2H),



3.91 (s, 3H), 3.89 (m, 1H), 3.74 (m,



2H), 3.02 (m, 4H); LC/MS m/z (M + H+) 491.2 (calculated for



C26H26N4O4S, 490.59)


217
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-carboxamide



LC/MS m/z (M + H+) 476.1


218
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-ol



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.72 (m, 4H), 7.28 (t, 1H), 7.11 (d, 1H), 7.06 (t, 1H), 6.82 (dd,



1H), 4.64 (m, 3H), 4.49 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H),



3.96 (m, 2H), 3.81 (m, 1H), 3.03 (m, 4H); LC/MS m/z (M + H+)



449.2 (calculated for C24H24N4O3S, 448.55)


219
N-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]methanesulfonamide



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.88 (d, 1H),



7.76 (m, 4H), 7.55 (t, 1H), 7.45 (m, 2H), 7.28 (m, 1H),



4.73 (m, 3H), 4.60 (m, 1H), 4.47 (m, 1H), 4.38 (m, 1H), 4.03 (m,



3H), 3.26 (m, 4H), 3.00 (s, 1H); LC/MS m/z (M + H+)



526.2 (calculated for C25H27N5O4S2, 525.65)


220
tert-Butyl [4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]carbamate



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.80 (m, 1H), 7.75 (m, 4H), 7.37 (m, 2H), 7.30 (m, 1H),



4.69 (m, 3H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31 (m, 1H),



3.85-4.07 (m, 3H), 3.13 (m, 4H),



1.53 (s, 9H); LC/MS m/z (M + H+)



548.3 (calculated for C29H33N5O4S, 547.68)


221
1-(1-{[3′-(2-Methylpropoxy)biphenyl-4-yl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.75 (m, 4H), 7.37 (t, 1H), 7.21 (d, 1H), 7.17 (t, 1H), 6.96 (dd,



1H), 4.67 (m, 3H), 4.52 (m, 1H), 4.43 (m, 1H), 4.30 (m, 1H),



3.76-4.04 (m, 5H), 3.10 (m, 4H), 2.08 (m, 1H), 1.06 (d, 6H);



LC/MS m/z (M + H+) 505.2 (calculated for C28H32N4O3S,



504.66)


222
N-(2-Cyanoethyl)-4′-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-



carboxamide



LC/MS m/z (M + H+) 529.2


223
3-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)biphenyl-3-yl]prop-2-enenitrile



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 8.14 (s, 1H),



7.89 (m, 1H), 7.86 (d, 1H), 7.79 (m, 4H), 7.76 (m, 1H),



7.50-7.69 (m, 2H), 6.36 (d, 1H), 4.62 (m, 3H), 4.48 (m, 1H),



4.40 (m, 1H), 4.27 (m, 1H), 4.95 (m, 2H), 3.77 (m, 1H), 3.00 (m,



4H); LC/MS m/z (M + H+) 484.2 (calculated for C27H25N5O2S,



483.6)


224
Methyl 3-[4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-4-yl]prop-2-enoate



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.79 (m, 4H), 7.74 (m, 5H), 6.60 (d, 1H), 4.66 (m, 3H),



4.53 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.98 (m, 2H), 3.88 (m,



1H), 3.80 (s, 3H), 3.11 (m, 4H); LC/MS m/z (M + H+)



517.2 (calculated for C28H28N4O4S, 516.62)


225
1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.74 (m, 4H), 7.69 (dd, 2H), 7.21 (t, 2H), 4.67 (m, 1H),



4.56 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 3.94-4.22 (m, 5H),



3.18 (m, 4H); LC/MS m/z (M + H+) 451.2 (calculated for



C24H23FN4O2S, 450.54)


226
1-{1-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.77 (d, 2H), 7.65 (d, 2H), 7.55 (m, 1H), 7.12 (m, 1H), 7.08 (d,



1H), 4.69 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H),



3.94-4.22 (m, 5H), 3.20 (m, 4H); LC/MS m/z (M + H+)



469.1 (calculated for C24H22F2N4O2S, 468.53)


227
1-{1-[(3′-Chloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-



yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.79 (dd, 1H), 7.76 (m, 4H), 7.63 (m, 1H), 7.35 (t, 1H),



4.67 (m, 1H), 4.56 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H),



3.95-4.23 (m, 5H), 3.21 (m, 4H); LC/MS m/z (M + H+)



485.1 (calculated for C24H22ClFN4O2S, 484.98)


228
1-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.96 (s, 1H), 8.12 (s, 1H),



7.75 (d, 1H), 7.67 (m, 4H), 7.52 (m, 2H), 4.57 (m, 1H),



4.50 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 3.88-4.15 (m, 5H),



3.13 (m, 4H); LC/MS m/z (M + H+) 501.1 (calculated for



C24H22Cl2N4O2S, 501.44)


229
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.23 (s, 1H),



7.94 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 4.67 (m, 2H),



4.45 (m, 2H), 4.01-4.29 (m, 5H),



3.30 (m, 4H); LC/MS m/z (M + H+)



501.1 (calculated for C25H23F3N4O2S, 500.55)


230
4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-amine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.79 (m, 4H), 7.75 (d, 1H), 7.63 (m, 2H), 7.38 (d, 1H),



4.52-4.80 (m, 4H), 4.45 (m, 1H), 4.38 (m, 1H), 3.89-4.10 (m, 3H),



3.17 (m, 4H); LC/MS m/z (M + H+) 448.0 (calculated for



C24H25N5O2S, 447.56)


231
1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)-4-(phenylcarbonyl)piperazine



LC/MS m/z (M + H+) 504.0


232
1-(1-{[4′-Chloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, DMSO-d6): δ 8.21 (s, 1H), 8.10 (d, 1H),



7.97 (d, 1H), 7.89 (d, 2H), 7.79 (m, 3H), 7.48 (m, 4H),



4.62 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 4.10 (m, 1H), 3.86 (m,



4H), 3.55 (m, 2H), 3.06 (m, 2H); LC/MS m/z (M + H+)



528.0 (calculated for C28H25ClF3N3O2, 527.98)


233
N-[4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)biphenyl-3-yl]acetamide



LC/MS m/z (M + H+) 483.3


234
N-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide



1H NMR (300 MHz, DMSO-d6): δ 8.10 (d, 1H), 8.06 (d, 1H),



8.00 (m, 1H), 7.75 (d, 2H), 7.70 (d, 2H), 7.57 (dt, 1H),



7.34-7.46 (m, 2H), 4.61 (m, 2H), 4.37 (m, 1H), 4.29 (m, 1H),



4.05 (m, 1H), 3.35-3.82 (m, 6H), 3.09 (m, 2H), 2.07 (s, 3H);



LC/MS m/z (M + H+) 490.2 (calculated for C26H27N5O3S,



489.6)


235
N-[4′-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide



LC/MS m/z (MH+) 490.2


236
1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 511.2


237
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (300 MHz, DMSO-d6): δ 8.01-8.14 (m, 4H), 7.88 (d,



2H), 7.67-7.83 (m, 4H), 4.60 (m, 2H), 4.39 (m, 1H), 4.28 (m,



1H), 4.06 (m, 2H), 3.22-3.85 (m, 5H), 3.10 (m, 2H); LC/MS



m/z (M + H+) 501.1 (calculated for C25H23F3N4O2S, 500.55)


238
1-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.85-7.94 (m, 2H),



7.40-7.73 (m, 10H), 4.42 (m, 1H), 4.26 (m, 2H), 4.16 (m, 1H),



3.61-3.96 (m, 5H), 2.99 (m, 4H), 2.47 (s, 3H);



LC/MS m/z (M + H+)



508.2 (calculated for C29H28F3N3O2, 507.56)


239
1-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.85-8.01 (m, 4H),



7.54-7.72 (m, 4H), 7.45 (d, 1H), 4.69 (m,



2H), 4.44 (m, 1H), 4.29 (m, 2H),



4.20 (m, 1H), 3.99 (m, 2H), 3.90 (m, 1H), 3.10 (m, 4H), 2.49 (s,



3H); LC/MS m/z (M + H+) 515.1 (calculated for C26H25F3N4O2S,



514.57)


240
1-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.04 (s, 1H), 8.21 (s, 1H),



7.89 (m, 2H), 7.51-7.72 (m, 4H), 7.45 (d, 1H), 3.87-4.54 (m, 9H)



3.14 (m, 4H), 2.48 (s, 3H); LC/MS m/z (M + H+)



515.1 (calculated for C26H25F3N4O2S, 514.57)


241
1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.88 (d, 1H),



7.54-7.77 (m, 6H), 7.36 (d, 1H), 4.64-4.80 (m, 3H), 4.59 (m, H),



4.48 (m, 1H), 4.38 (m, 1H), 3.92-4.12 (m, 3H), 3.27 (m, 4H),



2.30 (s, 3H); LC/MS m/z (M + H+) 515.1 (calculated for



C26H25F3N4O2S, 514.57)


242
1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.07 (s, 1H), 8.22 (s, 1H),



7.49-7.78 (m, 6H), 7.34 (d, 1H), 4.66 (m, 1H), 4.39-4.58 (m,



2H), 4.33 (m, 1H), 3.87-4.20 (m, 5H), 3.14 (m, 4H), 2.31 (s,



3H); LC/MS m/z (M + H+) 515.1 (calculated for C26H25F3N4O2S,



514.57)


243
1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.44-7.75 (m, 11H), 7.34 (d,



1H), 4.64 (m, 1H), 4.34-4.55 (m, 2H), 4.29 (m, 1H),



3.66-3.97 (m, 5H), 3.03 (m, 4H), 2.30 (s, 3H);



LC/MS m/z (M + H+)



508.2 (calculated for C29H28F3N3O2, 507.56)


244
1-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.91-8.05 (m, 3H), 7.87 (d,



1H), 7.56-7.80 (m, 5H), 4.60-4.77 (m, 2H), 4.38-4.51 (m, 2H),



4.24-4.38 (m, 2H), 3.84-4.09 (m, 3H), 3.10 (m, 4H); LC/MS m/z



(M + H+) 519.2 (calculated for C25H22F4N4O2S, 518.54)


245
1-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.20 (s, 1H),



7.95 (m, 2H), 7.55-7.80 (m, 5H), 4.38-4.51 (m, 2H), 4.25-4.38 (m,



2H), 3.86-4.19 (m, 5H), 3.08 (m, 4H); LC/MS m/z (M + H+)



519.2 (calculated for C25H22F4N4O2S, 518.54)


246
1-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.90-8.01 (m, 2H),



7.56-7.80 (m, 5H), 7.42-7.56 (m, 5H),



4.35-4.50 (m, 2H), 4.20-4.35 (m,



2H), 3.66-3.98 (m, 5H), 3.00 (m, 4H); LC/MS m/z (M + H+)



512.1 (calculated for C28H25F4N3O2, 511.52)


247
1-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.79 (d, 1H), 7.88 (d, 1H),



7.71-7.82 (m, 2H), 7.56-7.69 (m, 2H), 7.45 (d, 1H), 7.39 (d,



1H), 7.34 (dd, 1H), 4.61-4.78 (m, 3H), 4.57 (m, 1H), 4.46 (m,



1H), 4.34 (m, 1H), 3.87-4.06 (m, 3H), 3.89 (s, 3H), 3.17 (m, 4



H); LC/MS m/z (M + H+) 531.2 (calculated for C26H25F3N4O3S,



530.57)


248
1-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.71-7.81 (m, 2H), 7.55-7.69 (m, 2H), 7.45 (d, 1H), 7.38 (s,



1H), 7.33 (dd, 3H), 4.70 (m, 1H), 4.58 (m, 1H), 4.47 (m, 1H),



4.36 (m, 1H), 3.94-4.25 (m, 5H), 3.89 (s, 3H), 3.21 (m, 4H);



LC/MS m/z (M + H+) 531.2 (calculated for C26H25F3N4O3S,



530.57)


249
1-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.72-7.84 (m, 2H),



7.56-7.71 (m, 2H), 7.27-7.56 (m, 8H),



4.66 (m, 1H), 4.37-4.59 (m, 2H),



4.32 (m, 1H), 3.66-4.03 (m, 8H), 3.08 (m, 4H); LC/MS m/z



(M + H+) 524.3 (calculated for C29H28F3N3O3, 523.56)


250
1-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.90-8.03 (m, 3H),



7.82-7.90 (m, 2H), 7.62-7.79 (m, 3H),



7.57 (d, 1H), 4.62-4.78 (m, 2H),



4.41-4.54 (m, 1H), 4.20-4.40 (m, 3H), 3.90-4.10 (m, 3H),



3.02-3.24 (m, 4H); LC/MS m/z (M + H+) 535.0 (calculated for



C25H22ClF3N4O2S, 534.99)


251
1-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.20 (s, 1H),



7.90-8.02 (m, 2H), 7.85 (s, 1H), 7.63-7.81 (m, 3H), 7.56 (d,



1H), 4.40-4.54 (m, 1H), 4.17-4.38 (m, 3H), 3.85-4.17 (m, 5H),



2.98-3.15 (m, 4H); LC/MS m/z (M + H+) 535.0 (calculated for



C25H22ClF3N4O2S, 534.99)


252
1-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.87-7.97 (m, 2H), 7.84 (d,



1H), 7.64-7.79 (m, 3H), 7.55 (d, 1H), 7.41-7.52 (m, 5H),



4.41 (dd, 1H), 4.21-4.34 (m, 2H),



4.17 (dd, 1H), 3.65-3.99 (m, 5H),



2.94 (m, 4H); LC/MS m/z (M + H+) 528.2 (calculated for



C28H25ClF3N3O2, 527.98)


253
1-{1-[(3′-Chloro-4′-fluoro-3-methylbiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.19 (d, 1H),



7.75 (dd, 1H), 7.55-7.66 (m, 2H), 7.51 (dd, 1 H), 7.27-7.45 (m,



2H), 4.42 (dd, 1H), 4.21-4.34 (m, 2H), 3.95-4.21 (m, 5H),



3.88 (m, 1H), 2.94-3.15 (m, 4H), 2.46 (s, 3H);



LC/MS m/z (M + H+)



499.0 (calculated for C25H24ClFN4O2S, 499.01)


254
1-(1-{[4′-Chloro-3-methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.19 (d, 1H),



7.98 (d, 1H), 7.88 (dd, 1H), 7.71 (d, 1H), 7.63 (m, 1H),



7.57 (dd, 1 H), 7.45 (d, 1H), 4.44 (dd, 1H), 4.23-4.35 (m, 2H),



3.85-4.23 (m, 6H), 2.96-3.19 (m,



4H), 2.48 (s, 3H); LC/MS m/z



(M + H+) 549.2 (calculated for C26H24ClF3N4O2S, 549.02)


255
1-{1-[(3′-Chloro-4′-fluoro-3-methylbiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.75 (dd, 1H), 7.28-7.65 (m,



10H), 4.38 (dd, 1H), 4.16-4.29 (m, 2H), 4.10 (m, 1H),



3.60-3.95 (m, 5H), 2.91 (m, 4H), 2.45 (s,



3 H); LC/MS m/z (M + H+)



492.1 (calculated for C28H27ClFN3O2, 492.00)


256
1-(1-{[4′-Chloro-3-methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (m, 1H), 7.87 (dd, 1H),



7.71 (d, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 7.38-7.52 (m, 6H),



4.39 (dd, 1H), 4.16-4.28 (m, 2H), 4.11 (m, 1H), 3.63-3.93 (m,



5H), 2.91 (m, 4H), 2.47 (s, 3H); LC/MS m/z (M + H+)



542.1 (calculated for C29H27ClF3N3O2, 542.01)


257
1-{1-[(3′-Chloro-4′-fluoro-2-methylbiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.20 (s, 1H),



7.49-7.67 (m, 2H), 7.44 (dd, 1H), 7.20-7.37 (m, 3H), 4.63 (m,



1H), 4.37-4.56 (m, 2H), 4.31 (m, 1H), 3.84-4.19 (m, 5H),



3.12 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H+)



499.0 (calculated for



C25H24ClFN4O2S, 499.01)


258
1-(1-{[4′-Chloro-2-methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.20 (s, 1H),



7.66-7.76 (m, 2H), 7.51-7.65 (m, 3H), 7.36 (d, 1H), 4.63 (m,



1H), 4.37-4.56 (m, 2H), 4.29 (m, 1H), 3.84-4.21 (m, 5H),



3.09 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H+) 549.2



(calculated for



C26H24ClF3N4O2S, 549.02)


259
1-{1-[(3′-Chloro-4′-fluoro-2-methylbiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.59 (m, 1H), 7.40-7.57 (m,



7H), 7.23-7.39 (m, 3H), 4.65 (m, 1H), 4.37-4.58 (m, 2H),



4.32 (m, 1H), 3.67-4.05 (m, 5H),



3.11 (m, 4H), 2.30 (s, 3H); LC/MS



m/z (M + H+) 492.1 (calculated for C28H27ClFN3O2, 492.00)


260
1-(1-{[4′-Chloro-2-methyl-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.70-7.80 (m, 3H),



7.42-7.68 (m, 7H), 7.35 (d, 1H),



4.63 (m, 1H), 4.34-4.55 (m, 2H), 4.28 (m,



1H), 3.67-3.98 (m, 5H), 3.02 (m, 4H), 2.30 (s, 3H); LC/MS m/z



(M + H+) 542.1 (calculated for C29H27ClF3N3O2, 542.01)


261
1-{1-[(3′-Chloro-4′-fluoro-2-methoxybiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.20 (s, 1H),



7.61 (d, 1H), 7.20-7.50 (m, 5H),



4.67 (m, 1H), 4.55 (m, 1H), 4.43 (m,



1H), 4.31 (m, 1H), 3.90-4.25 (m, 5H), 3.90 (s, 3H), 3.11 (m,



4H); LC/MS m/z (M + H+) 515.1 (calculated for



C25H24ClFN4O3S, 515.01)


262
1-(1-{[4′-Chloro-2-methoxy-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.17 (s, 1H),



7.88 (s, 1H), 7.74 (dd, 1H),



7.66 (d, 1H), 7.45 (d, 1H), 7.38 (m, 1H),



7.33 (dd, 1H), 4.65 (m, 1H), 4.33-4.56 (m, 2H), 4.26 (m, 1H),



3.89-4.12 (m, 5H), 3.89 (s, 3H), 2.97 (m, 4H); LC/MS m/z



(M + H+) 565.0 (calculated for C26H24ClF3N4O3S, 565.02)


263
1-{1-[(3′-Chloro-4′-fluoro-2-methoxybiphenyl-4-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.61 (dd, 1H), 7.38-7.57 (m,



7H), 7.35 (d, 1H), 7.23-7.33 (m, 2H), 4.65 (m, 1H)



4.36-4.57 (m, 2H), 4.30 (m, 1H),



3.88 (s, 3H), 3.67-3.97 (m, 5H), 3.05 (m,



4H); LC/MS m/z (M + H+) 508.0 (calculated for C28H27ClFN3O3,



508.00)


264
1-(1-{[4′-Chloro-2-methoxy-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.88 (d, 1H), 7.74 (dd, 1H),



7.66 (d, 1 H), 7.42-7.57 (m, 6H), 7.38 (m, 1H), 7.32 (dd, 1H),



4.58-4.69 (m, 1H), 4.36-4.58 (m, 2H), 4.20-4.33 (m, 1H),



3.89 (s, 3H), 3.60-4.04 (m, 5H),



3.03 (m, 4 H); LC/MS m/z (M + H+)



558.2 (calculated for C29H27ClF3N3O3, 558.01)


265
1-{1-[(3,3′-Dichloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.18 (s, 1H),



7.77-7.83 (m, 2H), 7.68 (dd, 1H), 7.58-7.67 (m, 1H), 7.53 (d,



1H), 7.36 (t, 1H), 4.42 (dd, 1H), 4.22-4.35 (m, 2H), 4.18 (dd,



1H), 3.80-4.13 (m, 5H), 2.90-3.11 (m, 4H); LC/MS m/z (M + H+)



519.0 (calculated for C24H21Cl2FN4O2S, 519.43)


266
1-(1-{[3,4′-Dichloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.18 (s, 1H),



8.01 (m, 1H), 7.81-7.98 (m, 2H), 7.74 (d, 2H), 7.56 (d, 1H),



4.36-4.49 (dd, 1H), 4.22-4.35 (m,



2H), 4.19 (dd, 1H), 3.80-4.13 (m,



5H), 2.90-3.11 (m, 4H); LC/MS m/z (M + H+) 569.0 (calculated



for C25H21Cl2F3N4O2S, 569.44)


267
1-{1-[(3,3′-Dichloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-



3-yl}-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.77-7.84 (m, 2H),



7.58-7.71 (m, 2H), 7.42-7.57 (m, 6H), 7.36 (t, 1H), 4.42 (dd, 1H)



4.13-4.34 (m, 3H), 3.62-4.01 (m, 5H), 2.98 (m, 4H); LC/MS m/z



(M + H+) 512.1 (calculated for C27H24Cl2FN3O2, 512.42)


268
1-(1-{[3,4′-Dichloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.01 (d, 1H), 7.90 (dd, 1H),



7.85 (d, 1H), 7.74 (d, 2H), 7.56 (d, 1H), 7.41-7.53 (m, 5H),



4.43 (dd, 1H), 4.14-4.35 (m, 3H),



3.63-4.04 (m, 5H), 2.99 (m, 4H);



LC/MS m/z (M + H+) 562.0 (calculated for C28H24Cl2F3N3O2,



562.42)


488
1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (s, 1H),



7.30-7.71 (m, 8H), 3.92-4.57 (m, 9H) 3.11-3.29 (m, 4H), 2.46 (s,



3H); LC/MS m/z (M + H+) 447.1 (calculated for C25H26N4O2S,



446.58)


1070
1-(1-{[2-Fluoro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 518.9


1102
1-(1-{[2-Chloro-3′-(trifluoromethyl)biphenyl-4-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 434.9









Example 7




A. 2,2,2-Trifluoro-1-[4-(thiazole-2-carbonyl)-piperazin-1-yl]-ethanone, 7a. To a solution of compound 1d (5 g, 0.027 mol) in DMF (50 mL) and DIPEA (19.5 mL, 0.11 mol) was added compound 5c (3.3 g, 0.0255 mol) and HATU (12.6 g, 0.033 mol). The reaction was stirred for 4 h then poured into water and extracted with EtOAc. The organic portions were washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo. The residue was passed through a silica gel column (30-10%: EtOAc-heptane) to give compound 7a (3.8 g). MS m/z (M+H+) 294.1.
B. piperazin-1-yl-thiazol-2-yl-methanone, 7b. A solution of compound 7a (3.8 g, 0.013 mol) and K2CO3 (3.5 g, 0.026 mol) in MeOH (40 mL) and water (10 mL), was stirred for 4 h. The solid was collected by filtration and the solvent evaporated in vacuo to give compound 7b (6.12 g). MS m/z (M+H+) 198.1.
C. 3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carboxylic acid tert-butyl ester, 7c. A solution of compound 7b (6.1 g, 0.031 mol) and (5.1 g, 0.03 mol) compound 4a in MeOH (30 mL) was stirred for 15 min. Decaborane (1 g, 0.008 mol) was added and the reaction was stirred for 18 h. The solvent was evaporated in vacuo. The residue was used without further purification for the next step. MS m/z (M+H+) 353.1.
D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e. To a solution of compound 7c in CH2Cl2 (100 mL) was added TFA (30 mL). The reaction was stirred for 3.5 h and the solvent was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC to give compound 5e (5.15 g). MS m/z (M+H+) 253.1.
E. 1-{1-[3-(4-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 269. To a solution of compound 5e (150 mg, 0.52 mmol) in DMF (5 mL) and DIPEA (0.40 mL, 2.2 mmol) was added compound 7d (125 mg, 0.067 mmol), and HATU (0.25 g, 0.067 mmol). The reaction was stirred for 4 h, then poured into water and extracted with EtOAc. The combined extracts were concentrated in vacuo. The resultant residue was purified by reverse phase HPLC to give compound 269 (20.2 mg). LC/MS m/z (M+H+) 419.15 (calculated for C20H23ClN4O2S, 418.95).
Following the procedure described above for Example 7 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data
















270
1-{1-[3-(4-Bromophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + 2H+) 465.05 (calculated for C20H23BrN4O2S,



463.40)


271
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{3-[4-



(trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)piperazine.



LC/MS m/z (M + H+) 453.15 (calculated for C21H23F3N4O2S,



452.50)


272
1-{1-[3-(3-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 419.17 (calculated for C20H23ClN4O2S,



418.95)


273
1-{1-[3-(2-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



1H NMR (300 MHz, MeOD): δ 8.0 (d, 1H), 7.9 (d, 2H),



4.7 (bm, 2H), 4.4 (m, 2H), 4.3-4.1 (m, 2H), 4.0 (bm, 2H), 3.25 (m,



5H), 3.0 (m, 2H), 2.5 (m, 2H)



LC/MS m/z (M + H+) 419.16 (calculated for C20H23ClN4O2S,



418.95)


274
1-{1-[3-(2,6-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



1H NMR (300 MHz, MeOD): δ 8 (d, 1H), 7.9 (d, 1H), 7.4 (ar,



2H), 7.2 (m, 1H), 4.75 (m, 2H), 4.5-4.1 (m, 5H), 4.0 (m, 3H),



3.2 (m, 5H), 2.4 (m, 3H)



LC/MS m/z (M + 2H+) 455.10 (calculated for C20H22Cl2N4O2S,



453.39)


275
1-{1-[3-(3,4-Difluorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 421.19 (calculated for C20H22F2N4O2S,



420.48)


276
1-{1-[3-(4-Methylphenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 399.23 (calculated for C21H26N4O2S,



398.53)


277
1-{1-[3-(4-Methoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine3



LC/MS m/z (M + H+) 415.23 (calculated for C21H26N4O3S,



414.53)


278
1-(1-{3-[3,5-Bis(trifluoromethyl)phenyl]propanoyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 521.14 (calculated for C22H22F6N4O2S,



520.50)


279
1-[1-(3-Naphthalen-1-ylpropanoyl)azetidin-3-yl]-4-(1,3-thiazol-



2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 435.22 (calculated for C24H26N4O2S,



434.56)


280
1-{1-[3-(4-Phenoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 477.20 (calculated for C26H28N4O3S,



476.60)


281
1-{1-[3-(3,4-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



1H NMR (300 MHz, MeOD) d 8.0 (ar, 1H), 7.9 (ar, 1H), 7.4 (m,



2H), 7.2 (m, 1H), 4.4 (dd, 1H), 4.3-4.2 (m, 2H), 4.1 (m, 1H),



3.9 (m, 1H), 3.3 (m, 3H), 3.2 (m, 4H), 3.0 (bs, 1H), 2.9 (m, 2H),



2.5 (m, 2H)



LC/MS m/z (M + 2H+) 455.10 (calculated for C20H22Cl2N4O2S,



453.39)


282
1-{1-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-



yl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine.



1H NMR (300 MHz, MeOD): δ 7.9 (ar, 1H), 7.7 (ar, 1H),



7.13 (ar, 1H), 7.0 (ar, 1H), 6.9 (ar, 1H),



4.2-4.1 (m, 2H), 4.1-4.0 (m,



1H), 3.9, (bs, 1H), 3.8 (m, 1H), 3.2 (m, 2H), 3.11 (m, 4H),



2.7 (t, 2H), 2.3 (t, 2H), 1.5 (s, 4H), 1.1 (dd, 12H).



LC/MS m/z (M + H+) 495.24 (calculated for C28H38N4O2S,



494.70)


283
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(2E)-3-{4-



[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3-



yl}piperazine



LC/MS m/z (M + H+) 483.18 (calculated for C21H21F3N4O2S2,



482.55)


284
1-{1-[(3-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 421.12 (calculated for C19H21ClN4O3S,



420.92)


285
1-{1-[(2-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 421.12 (calculated for C19H21ClN4O3S,



420.92)


286
1-{1-[3-(2-Bromophenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + 2H+) 465.07 (calculated for C20H23BrN4O2S,



463.40)


287
1-(1-{3-[4-(3,4-Dimethyl-1H-pyrazol-1-



yl)phenyl]propanoyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 479.29 (calculated for C25H30N6O2S,



478.62)


288
1-{1-[(2,4-Dichlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + 2H+) 457.13 (calculated for C19H20Cl2N4O3S,



455.37)


289
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-



(trifluoromethoxy)phenoxy]acetyl}azetidin-3-yl)piperazine.



LC/MS m/z (M + H+) 471.16 (calculated for C20H21F3N4O4S,



470.47)


290
N-Cyclopropyl-4-(3-oxo-3-{3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}propyl)benzenesulfonamide.



1H NMR (300 MHz, MeOD) d 8.0 (d, 1H); 7.9 (d, 1H); 7.4 (m,



4H); 4.7 (bs, 2H), 4.4-4.1 (m, 3H), 4.1-3.9 (m, 3H), 3.8 (m, 1H),



3.1 (m, 3H), 3.0 (t, 2H), 2.5 (t, 2H), 2.1 m, 1H), 0.5 (m, 4H)



LC/MS m/z (M + H+) 504.20 (calculated for C23H29N5O4S2,



503.65)


291
N-(Cyclohexylmethyl)-N-methyl-4-(3-oxo-3-{3-[4-(1,3-thiazol-



2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)aniline.



1H NMR (300 MHz, MeOD): δ 8.0 (d, 1H), 7.9 (d, 1H), 7.5 (m,



4H), 4.4 (bm, 2H), 4.25-4.0 (m, 4H), 3.8 (m, 1H), 3.4 (d, 2H),



3.2 (s, m, 3H), 3.1 (bs, 3H), 3.0 (t, 2H), 2.5 (t, 2H), 1.7 (m, 5H),



1.1 (m, 5H)



LC/MS m/z (M + H+) 510.32 (calculated for C28H39N5O2S,



509.72)


292
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({[4-



(trifluoromethyl)phenyl]sulfanyl}acetyl)azetidin-3-



yl]piperazine



LC/MS m/z (M + H+) 471.18 (calculated for C20H21F3N4O2S2,



470.54)


293
1-[1-(1-Benzothiophen-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



LC/MS m/z (M + H+) 413.20 (calculated for C20H20N4O2S2,



412.54)


294
1-{1-[3-(4-Ethoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 429.27 (calculated for C22H28N4O3S,



428.56)


295
1-{1-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 417.0 (calculated for C20H21ClN4O2S,



416.93)


296
1-{1-[(2E)-3-(2-Bromophenyl)prop-2-enoyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine.



LC/MS m/z (M + H+) 462.9 (calculated for C20H21BrN4O2S,



461.38)


297
3-Naphthalen-2-yl-1-{3-[4-(thiazole-2-carbonyl)-piperazin-1-



yl]-azetidin-1-yl}-propenone



LC/MS m/z (M + H+) 433.29 (calculated for C24H24N4O2S,



432.55)









Example 8




A. 4-(1-Benzhydryl-azetidin-3-yl)-piperazine-1-carboxylic acid benzyl ester, 8b. To a solution of compound 8a (1.4 g, 6.3 mmol) and compound 1e (2 g, 6.3 mmol) in CH3CN (30 mL) was added DIPEA (1.5 mL, 8.1 mmol) at room temperature. The mixture was refluxed for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between CHCl3 and water. The organic layer was dried over K2CO3, filtered, and concentrated to give crude compound 8b (2.65 g). MS m/z (M+H+) 442.
B. 4-Azetidin-3-yl-piperazine-1-carboxylic acid benzyl ester, 8c. To a solution of compound 8b (3.4 g, 7.7 mmol) in CH2Cl2 was added 1-chloroethyl chloroformate (2.5 mL, 23.1 mmol) at 0° C. under a N2 atmosphere. The ice bath was removed and the reaction stirred for 2 h. The organic phase was concentrated under reduced pressure, and MeOH was added to the resultant residue. The reaction was refluxed for 2 h at which time the solvent was removed under reduced pressure. The residue was partitioned between chloroform and aqueous HCl (1N). The aqueous layer was separated, made basic with aqueous NaOH (3N), and extracted with chloroform. The organic layer was then dried (K2CO3), filtered and concentrated to afford compound 8c (2.65 g). MS m/z (M+H+) 276.
C. 4-[1-(Biphenyl-4-carbonyl)-azetidin-3-yl]-piperazine-1-carboxylic acid benzyl ester, 8e. To a solution of compound 8c (2.6 g, 9.4 mmol), compound 8d (1.87 g, 9.4 mmol), and DIPEA (2.43 g, 18.9 mmol) in acetonitrile was added HBTU (4.6 g, 12.3 mmol). The reaction was stirred for 18 h at which time the solvent was removed under reduced pressure and the crude product purified by reverse phase HPLC. Lyophilization provided compound 8e (1.74 g). MS m/z (M+H+) 456.2.
D. Biphenyl-4-yl-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 8f. A mixture of compound 8e (1.7 g, 2.9 mmol), and 10% Palladium on carbon (300 mg) was hydrogenated (50 psi hydrogen gas) using a Parr apparatus for 18 h. The catalyst was removed by filtration, and the solvent concentrated under reduced pressure to afford crude compound 8f (1.5 g). MS m/z (M+H+) 322.
E. 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(4-fluorophenyl)-carbonyl]piperazine, Cpd 299. To a solution of compound 8f (100 mg, 0.3 mmol), compound 8g (44 mg, 0.31 mmol), and DIPEA (80 mg, 0.6 mmol) in dimethylformamide was added HBTU (141 mg, 0.37 mmol). After stirring for 18 h, the reaction was purified by preparative reverse phase HPLC to yield compound 299. 1H NMR (400 MHz, MeOD): δ 7.93-8.03 (m, 1H), 7.61-7.71 (m, 4H), 7.54-7.61 (m, 2H), 7.43-7.50 (m, 2H), 7.35-7.43 (m, 2H), 7.27-7.35 (m, 1H), 7.07-7.20 (m, 2H), 4.55-4.67 (m, 1H), 4.43-4.53 (m, 1H), 4.32-4.43 (m, 1H), 4.19-4.32 (m, 1H), 3.89-4.00 (m, 1H), 3.66-3.89 (m, 4H), 3.08 (br. s, 4H); MS m/z (M+H+) 444.2 (calculated for C27H26FN3O2, 443.53).
Following the procedure described above for Example 8 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:













300
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2-



fluorophenyl)carbonyl]piperazine



MS m/z (M + H+) 444.2 (calculated for C27H26FN3O2, 443.53)


301
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thiophen-3-



ylcarbonyl)piperazine



MS m/z (M + H+) 432.1 (calculated for C25H25N3O2S, 431.56)


302
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-2-



ylcarbonyl)piperazine



MS m/z (M + 2H+) 416.2 (calculated for C25H26N4O2, 414.51)


303
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-



(cyclopropylcarbonyl)piperazine



MS m/z (M + H+) 390.23 (calculated for C24H27N3O2, 389.5)


304
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3-



fluorophenyl)carbonyl]piperazine



MS m/z (M + H+) 444.2 (calculated for C27H26FN3O2, 443.53)


305
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-oxazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 417.2 (calculated for C24H24N4O3, 416.48)


306
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,2,3-



thiadiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 434.1 (calculated for C23H23N5O2S, 433.54)


307
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isoxazol-5-



ylcarbonyl)piperazine



MS m/z (M + H+) 417.2 (calculated for C24H24N4O3, 416.48)


308
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,2,5-



oxadiazol-3-ylcarbonyl)piperazine



MS m/z (M + H+) 418.2 (calculated for C23H23N5O3, 417.47)


309
5-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)thiophene-3-carbonitrile



MS m/z (M + H+) 457.2 (calculated for C26H24N4O2S, 456.57)


310
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isothiazol-5-



ylcarbonyl)piperazine



1H NMR (400 MHz, MeOD): δ 8.44 (s, 1H), 7.65 (s, 4H),



7.53-7.58 (m, 2H), 7.47 (d, J = 1.71 Hz, 1H), 7.34-7.40 (m,



2H), 7.26-7.32 (m, 1H), 4.49-4.60 (m, 1H), 4.37-4.49 (m,



1H), 4.27-4.37 (m, 1H), 4.15-4.27 (m, 1H), 3.72-3.88 (m,



5H), 2.92-3.02 (m, 4H);



MS m/z (M + H+) 433.2 (calculated for C24H24N4O2S, 432.55)


311
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-3-



ylcarbonyl)piperazine



1H NMR (400 MHz, MeOD): δ 7.66 (s, 4H), 7.56-7.59 (m,



1H), 7.54-7.56 (m, 1H), 7.35-7.41 (m, 2H), 7.26-7.33 (m,



1H), 7.08-7.15 (m, 1H), 6.64-6.75 (m, 1H), 6.24-6.31 (m,



1H), 4.54-4.64 (m, 1H), 4.43-4.51 (m, 1H), 4.32-4.41 (m,



1H), 4.20-4.28 (m, 1H), 3.85-3.97 (m, 5H), 3.06 (br. s., 4H);



MS m/z (M + H+) 415.2 (calculated for C25H26N4O2, 414.51)


312
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-



chlorofuran-2-yl)carbonyl]piperazine



1H NMR (400 MHz, MeOD): δ 7.66 (s, 4H), 7.54-7.59 (m,



2H), 7.38 (d, J = 7.58 Hz, 2H),



7.26-7.33 (m, 1H), 7.05 (d, J = 3.67 Hz,



1H), 6.42 (d, J = 3.42 Hz, 1H), 4.50-4.63 (m, 1H),



4.40-4.48 (m, 1H), 4.28-4.39 (m, 1H), 4.17-4.28 (m, 1H),



3.87-3.97 (m, 4H), 3.78-3.87 (m, 1H), 2.97-3.07 (m, 4H);



MS m/z (M + H+) 450.1 (calculated for C25H24ClN3O3, 449.94)


480
N-[4-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-



1-yl}carbonyl)-1,3-thiazol-2-yl]acetamide



MS m/z (M + H+) 490.2


1478
2-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)pyrimidine



MS m/z (M + H+) 428.0


1398
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-



(cyclopentylcarbonyl)piperazine



MS m/z (M + H+) 418.2


1465
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-



methylisoxazol-3-yl)carbonyl]piperazine



MS m/z (M + H+) 431.3


1258
1-[1-(1,3-Oxazol-4-ylcarbonyl)azetidin-3-yl]-4-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine



MS m/z (M + H+) 485.0


1262
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isoxazol-3-



ylcarbonyl)piperazine



MS m/z (M + H+) 417.1


1222
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-oxazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 417.0


1269
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-1,2,3-



triazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 417.0


1256
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2,2-



difluorocyclopropyl)carbonyl]piperazine



MS m/z (M + H+) 426.0


1310
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 416.2


1140
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(furan-3-



ylcarbonyl)piperazine



MS m/z (M + H+) 416.2


1232
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-



(cyclobutylcarbonyl)piperazine



MS m/z (M + H+) 404.2


1308
3-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-



yl}carbonyl)-1H-indole



MS m/z (M + H+) 465.3


1324
1-(1H-Pyrrol-3-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 481.0


1325
1-(1H-Pyrrol-2-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 483.1


186-A
1-[(D5)Phenylcarbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-



4-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 499.4


1169
1-(1,3-Oxazol-5-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 485.0


1335
1-[(5-Bromofuran-2-yl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 560.0/562.0


1087
1-[(4-Bromothiophen-2-yl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 576.0/578.0


1078
1-[(5-Chlorofuran-2-yl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 518.2


1118
1-(Isoxazol-5-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 485.1


1336
1-[(5-Fluorothiophen-2-yl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 519.2


1145
1-(Isoxazol-3-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 485.2


1143
1-[(5-Chlorothiophen-2-yl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 535.2


1085
1-(1,3-Oxazol-2-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 485.1


1112
1-[(2,2-Difluorocyclopropyl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 494.2


1094
1-(1,3-Oxazol-4-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine MS m/z (M + H+) 485.2


1057
1-(Cyclopropylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-



4-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 458.3


1217
1-[(2-Methyl-1,3-thiazol-4-yl)carbonyl]-4-(1-{[3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 516.3


1423
5-[(3-{4-[(5-Chlorothiophen-2-yl)carbonyl]piperazin-1-



yl}azetidin-1-yl)carbonyl]-1-(4-fluorophenyl)-1H-indole



MS m/z (M + H+) 523.2


1424
1-(4-Fluorophenyl)-5-[(3-{4-[(3-



fluorophenyl)carbonyl]piperazin-1-yl}azetidin-1-



yl)carbonyl]-1H-indole



MS m/z (M + H+) 501.2


1425
5-[(3-{4-[(5-Chlorofuran-2-yl)carbonyl]piperazin-1-



yl}azetidin-1-yl)carbonyl]-1-(4-fluorophenyl)-1H-indole



MS m/z (M + H+) 507.1


1426
1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 474.1


567-A
1-(4-Fluorophenyl)-5-[(3-{4-



[(~2~H_5_)phenylcarbonyl]piperazin-1-yl}azetidin-1-



yl)carbonyl]-1H-indole



MS m/z (M + H+) 488.1


1427
1-(4-Fluorophenyl)-5-[(3-{4-[(5-fluorothiophen-2-



yl)carbonyl]piperazin-1-yl}azetidin-1-yl)carbonyl]-1H-indole



MS m/z (M + H+) 507.1


1428
1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 474.1


1429
1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-5-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 474.1









Example 9




A. 4-(Thiazole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester, 9a. To a solution of compound 5c (2.0 g, 15.50 mmol), compound 1a (3.2 g, 17.20 mmol), and Et3N (8.6 mL, 61.2 mmol) in CH2Cl2 (100 mL) was added HATU (6.5 g, 17.1 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was then diluted with CH2Cl2 and washed with aq. NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 30% EtOAc/heptane) gave compound 9a (4.0 g).
B. piperazin-1-yl-thiazol-2-yl-methanone trifluoroacetic acid salt, 9b. To a solution of compound 9a (3.5 g, 11.78 mmol) in CH2Cl2 (40 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h. It was then concentrated to give compound 9b, which was used in the next reaction without further purification.
C. 3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carboxylic acid tert-butyl ester, 7c. To a solution of compound 9b (11.78 mmol) and compound 4a (2.2 g, 12.87 mmol) in 1,2-DCE (35 mL) and acetic acid (2 mL) was added Na(OAc)3BH (2.75 g, 12.97 mmol). The reaction was stirred at room temperature for 5 h. To the reaction mixture was added aq. NaHCO3, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 80% EtOAc/heptane) gave compound 7c (3.78 g).
D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e. To a solution of compound 7c (1.2 g, 3.41 mmol) in CH2Cl2 (12 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 4.5 h, concentrated, and to the resulting residue was added aq. NaHCO3. The mixture was extracted with 2% MeOH/CH2Cl2 (3×). The organic solution was dried over Na2SO4 and concentrated to give compound 5e, which was used in the next reaction without further purification.
D. 1-{1-[(5-Bromonaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 313. To a solution of compound 5e (63 mg, 0.25 mmol), compound 9c (95 mg, 0.38 mmol), and Et3N (0.14 mL, 1.01 mmol) in CH2Cl2 (3 mL) was added HATU (143 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with diethyl ether and washed with aq. NaHCO3 and aq. NaCl. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 313. 1H NMR (400 MHz, CD3OD): δ 8.28 (d, J=9 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 7.88-7.85 (m, 3H), 7.81 (d, J=8.4 Hz, 1H), 7.54 (d, J=3 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 4.53 (bs, 1H), 4.45 (bs, 1H), 4.34 (m, 2H), 4.26 (m, 1H), 4.16 (m, 1H), 3.95-3.80 (m, 2H), 3.28 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H+) 485/487.
Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:













314
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)phenyl]-



1,3-benzoxazole



1H NMR (400 MHz, CD3OD): δ 8.40 (d, J = 7.8 Hz, 1H),



7.95 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.83-7.80 (m, 2H),



7.69 (d, J = 8 Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 4.53 (m,



1H), 4.45-4.25 (m, 4H), 4.16 (m, 1H), 3.95-3.80 (m, 2H),



3.27 (m, 1H), 2.60-2.40 (m, 4H).



MS m/z (M + H+) 542


315
6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 475/477


316
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.13 (s, 1H), 7.98 (d, J = 8.6 Hz,



1H), 7.89 (d, J = 3 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.6 Hz,



1H), 7.56 (d, J = 3 Hz, 1H), 4.62-4.40 (m, 4H),



4.31 (m, 1H), 4.16 (m, 1H), 3.35 (m, 1H), 2.60-2.40 (m,



4H).



MS m/z (M + H+) 481


317
2-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



1H NMR (400 MHz, CD3OD): δ 8.26 (m, 2H), 8.00 (s,



1H), 7.88 (d, J = 3 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H),



7.63 (d, J = 8.6 Hz, 1H), 7.60-7.52 (m, 4H), 4.60-4.40 (m, 2H),



4.38 (m, 1H), 4.28 (m, 2H), 4.15 (m, 1H), 3.86 (m, 2H),



3.27 (m, 1H), 2.50 (m, 4H).



MS m/z (M + H+) 474


318
2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



1H NMR (400 MHz, CD3OD): δ 8.28 (m, 2H), 7.92 (s,



1H), 7.88 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H),



7.66 (d, J = 8 Hz, 1H), 4.60-4.20 (m, 5H), 4.15 (m, 1H),



3.86 (m, 2H), 3.28 (m, 1H), 2.50 (m, 4H).



MS m/z (M + H+) 474


319
tert-Butyl 6-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-2(1H)-



carboxylate,



1H NMR (CDCl3): δ 7.44-7.39 (m, 7H), 7.13 (d, J = 0.02,



1H), 4.59 (s, 2H), 4.27 (m, 2H), 4.15 (m, 1H), 4.06 (m,



1H), 3.90 (m, 1H), 3.74 (m, 1H), 3.65 (m, 2H), 3.46 (m,



2H), 3.22 (m, 1H), 2.85 (m, 2H), 2.27-2.23 (m, 4H),



1.49 (s, 9H)



MS m/z 405.0 (M-Boc), 449.0 (M-Bu-t), 527 (M + Na),



1009.2 (2M + H)


320
1-{1-[(4,5-Dibromothiophen-2-yl)carbonyl]azetidin-3-yl}-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 511.8, 513.8, 514.8


321
1-{1-[(5-Benzylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine,



1H NMR (CDCl3): δ 7.42-7.38 (m, 5H), 7.33-7.29 (m,



3H), 7.26 (m, 3H), 6.78 (d, J = 0.01, 1H), 4.41 (m, 1H),



4.24 (m, 2H), 4.13 (s, 2H), 4.03 (m, 1H), 3.92-3.74 (m,



2H), 3.47 (m, 2H), 3.24 (m, 1H), 2.42-2.29 (m, 4H)



MS m/z (M + H+) 446.6


322
1-{1-[(5-Bromothiophen-2-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 432.4, 434.4


832
1-Cyclohexyl-2-methyl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 493.0


1198
1-(1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-



methyl-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 615.0


647
4-[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)piperidin-1-yl]benzonitrile



MS m/z (M + H+) 465.1


1302
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3-



(trifluoromethyl)-1H-pyrazol-1-



yl]phenyl}carbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 491.1


1261
1-{1-[(1,5-Diphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3-



yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 499.2


654
1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 479.1


767
9-Methyl-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-9H-carbazole



MS m/z (M + H+) 460.0


822
1-(1-{[4-(Phenylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 497.1


817
6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2,3,4,9-tetrahydro-1H-



carbazole



MS m/z (M + H+) 450.1


775
N-Benzyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS m/z (M + H+) 462.3


713
N-Benzyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS m/z (M + H+) 462.3


1413
3-Methyl-1-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)phenyl]-1H-indole



MS m/z (M + H+) 486.1


918
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-indol-2-one



MS m/z (M + H+) 412.1


829
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole



1H NMR (400 MHz, CD3OD): δ 7.99 (d, 1H), 7.89 (d,



1H), 7.57 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.1 Hz,



1H), 4.28-4.90 (m, 6H), 4.01-4.22 (m, 3H), 3.73 (t, J = 8.2 Hz,



2H), 3.37 (br. s., 4H), 3.19 (t, J = 8.2 Hz, 2H)



MS m/z (M + H+) 398.1


1320
1-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.2 Hz, 1H),



7.50-7.57 (m, 2H), 7.42-7.48 (m, 2H), 7.38 (d, J = 3.2 Hz,



1H), 7.33 (d, J = 7.3 Hz, 1H),



7.18-7.26 (m, 3H), 6.99 (d, J = 3.2 Hz,



1H), 4.05-4.63 (m, 6H), 3.75-3.99 (m, 2H),



3.22-3.32 (m, 1H), 2.37-2.62 (m, 4H)



MS m/z (M + H+) 490.1


806
1-{1-[(4-Bromothiophen-2-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M+) 440.0, (M + 2+) 442.0


718
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1,3-



benzothiazole



MS m/z 482 (M + H+)


1088
1-(4-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3, 400 MHz): δ 7.98 (s, 1 H), 7.88 (d, J = 3.1 Hz,



1 H), 7.47-7.58 (m, 2 H), 7.38-7.47 (m, 3 H),



7.16-7.26 (m, 2 H), 7.12 (s, 1 H), 4.47-4.64 (m, 1 H), 4.38 (br.



s., 4 H), 4.07-4.19 (m, 1 H), 3.74-3.97 (m, 2 H),



3.17-3.33 (m, 1 H), 2.50 (t, J = 4.9 Hz, 4 H), 2.39 (s, 3 H).



MS m/z 504 (M + H+)


1131
2-(3-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzothiazole



MS m/z 508 (M + H+)


1054
3-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 486 (M + H+)


1152
3-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 486 (M + H+)


1367
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H-



indole



MS m/z 526 (M + H+)


1106
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 1 H), 8.12 (s, 1 H),



7.88 (br. s., 1 H), 7.67-7.85 (m, 2 H), 7.42-7.67 (m, 3 H),



7.36 (q, J = 8.7 Hz, 1 H), 4.49-4.62 (m, 1 H),



4.20-4.48 (m, 4 H), 4.05-4.20 (m, 1 H), 3.84 (br. s., 2 H),



3.20-3.38 (m, 1 H), 2.51 (m, 4 H).



MS m/z 509 (M + H+)


1129
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



MS m/z 509 (M + H+)


1055
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H-



indole



MS m/z 526 (M + H+)


1077
2-(3,4-Difluorophenyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z 510 (M + H+)


1178
2-(3,4-Difluorophenyl)-6-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z 510 (M + H+)


1368
1-(3-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 504 (M + H+)


1369
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[4-



(trifluoromethoxy)phenyl]-1H-indole



MS m/z 556 (M + H+)


1370
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[4-



(trifluoromethoxy)phenyl]-1H-indole



MS m/z 556 (M + H+)


1371
1-(3,5-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 508 (M + H+)


1068
3-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[3-



(trifluoromethoxy)phenyl]-1H-indole



MS m/z 570 (M + H+)


1110
1-(3-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



MS m/z 491 (M + H+)


1372
1-(4-Chloro-3-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 523 (M + H+)


1373
1-(2,5-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 508 (M + H+)


1090
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



MS m/z 491 (M + H+)


1492
1-{1-[(5-Bromo-1-benzofuran-2-yl)carbonyl]azetidin-3-



yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 455, 457


812
1-{1-[(5-Bromo-1-benzofuran-2-yl)carbonyl]azetidin-3-



yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+)468, 470


681
7-Bromo-1-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 488, 490


723
1-{1-[(5-Bromo-4-methylthiophen-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 455, 457


745
1-{1-[(4-Bromo-5-methylthiophen-2-yl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 475, 477


1224
1-(4-Fluorophenyl)-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 490


1226
1-(3-Fluorophenyl)-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 490


1279
1-(3-Fluorophenyl)-3-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 490


1295
1-(4-Fluorophenyl)-3-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 490


1275
2-Phenyl-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 474.1


606
7-(Biphenyl-4-ylcarbonyl)-4-[1-(phenylcarbonyl)azetidin-



3-yl]-4,7-diazaspiro[2.5]octane



MS m/z (M + H+) 452.4


1286
7-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4-



ylcarbonyl)azetidin-3-yl]-4,7-diazaspiro[2.5]octane



MS m/z (M + H+) 459.3


1499
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-7-



(phenylcarbonyl)-4,7-diazaspiro[2.5]octane



MS m/z (M + H+) 272


820
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indazole



1H NMR (400 MHz, CDCl3): δ 3.34-3.48 (m, 1 H),



3.89 (br. s., 3 H), 4.08-4.66 (m, 8 H), 7.55 (d, J = 8.8 Hz, 1 H),



7.62 (d, J = 3.2 Hz, 1 H), 7.66 (dd, J = 8.8, 1.5 Hz, 1 H),



7.89 (d, J = 3.2 Hz, 1 H), 8.04 (s, 1 H), 8.09 (s, 2 H)



MS m/z (M + H+) 397.2


1277
1-(4-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



pyrrolo[3,2-b]pyridine



1H NMR (400 MHz, CDCl3): δ 2.92-3.16 (m, 4 H), 3.76 (t,



J = 5.3 Hz, 1 H), 4.06 (br. s., 2 H), 4.39 (br. s., 1 H),



4.49-4.93 (m, 5 H), 7.23 (d, J = 3.2 Hz, 1 H), 7.30-7.38 (m, 2



H), 7.44-7.54 (m, 2 H), 7.60 (d, J = 3.2 Hz,



1 H), 7.89 (d, J = 3.2 Hz,



1 H), 7.97 (d, J = 3.2 Hz, 1 H), 8.63 (s, 1 H),



9.12 (s, 1 H)



MS m/z (M + H+) 491.2


1056
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



pyrrolo[2,3-b]pyridine



1H NMR (400 MHz, CDCl3): δ 3.75 (s, 1 H), 4.11 (br. s., 2



H), 4.32-5.02 (m, 10 H), 6.75 (d, J = 3.6 Hz, 1 H), 7.23 (d,



J = 8.9 Hz, 2 H), 7.53 (d, J = 3.7 Hz, 1 H), 7.61 (d, J = 3.2 Hz,



1 H), 7.65 (m, J = 9.0, 4.7 Hz, 2 H), 7.89 (d, J = 3.2 Hz,



1 H), 8.33 (d, J = 2.0 Hz, 1 H), 8.60 (d, J = 1.7 Hz, 1



H)



MS m/z (M + H+) 491.2


1153
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



pyrrolo[3,2-b]pyridine



1H NMR (400 MHz, CDCl3): δ 3.83-4.34 (m, 9 H),



4.41-4.70 (m, 2 H), 5.14 (d, J = 5.8 Hz, 2 H), 6.90 (br. s., 1 H),



7.28 (d, J = 8.2 Hz, 2 H), 7.38-7.51 (m, 2 H), 7.62 (d, J = 3.2 Hz,



1 H), 7.65 (d, J = 2.9 Hz, 1 H), 7.85 (d, J = 8.6 Hz,



1 H), 7.90 (d, J = 3.2 Hz, 1 H), 7.99 (d, J = 8.6 Hz, 1 H)



MS m/z (M + H+) 491.2


1306
1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-



2-ylcarbonyl)-2-(trifluoromethyl)piperazine



1H NMR (400 MHz, CD3OD): δ 2.14 (dd, J = 22.7, 10.5 Hz,



1 H), 2.43 (dd, J = 41.6, 11.7 Hz, 1 H), 2.87-3.18 (m,



1 H), 3.18-3.44 (m, 1.5 H), 3.58-3.81 (m, 0.5 H),



3.95-4.17 (m, 1 H), 4.18-4.40 (m, 2 H), 4.49 (m, 1.5 H),



5.43 (d, J = 26.4 Hz, 1 H), 6.95 (br. s., 0.5 H), 7.33-7.43 (m, 1



H), 7.43-7.51 (m, 2 H), 7.66 (d, J = 7.6 Hz, 2 H),



7.70-7.80 (m, 4 H), 7.88 (br. s., 1 H), 7.93-8.03 (m, 1 H)



MS m/z (M + H+) 501.1


856
5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 378


1116
2:1 mixture of 2 components:



Major: 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-5-



({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1H-indole



MS m/z (M + H+) 575.1



Minor: 1-[2-Fluoro-5-(trifluoromethyl)pyridin-3-yl]-5-



({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1H-indole



MS m/z (M + H+) 559.0


1233
2-Phenyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+)) 474.1









Example 9b




1-{1-[(6-Bromonaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 118: The title compound was prepared in an analogous manner to the preparation of Cpd 313 of Example 9, except commercially available N-benzoylpiperazine was used as starting material, instead of intermediate 9b. MS 478/480 (M+H+).
Following the procedure described above for Example 9b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







119
7-Bromo-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)quinoline



MS m/z (M + H+) 479/481


120
1-{1-[(5-Chloro-3-methyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



1H NMR (400 MHz, CD3OD): δ 7.74 (d, J = 2 Hz, 1H),



7.71 (d, J = 8.6 Hz, 1H), 7.43-7.36 (m, 6H), 4.28 (m, 2H),



4.20-4.00 (m, 2H), 4.00-3.70 (m, 2H), 3.48 (m, 2H), 3.24 (m, 1H),



2.58 (s, 3H), 2.50-2.20 (m, 4H).



MS m/z (M + H+) 454


121
2-Phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 467


122
2-Methyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1,3-benzothiazole



MS m/z (M + H+) 421


123
2-(4-Methoxyphenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 497


124
1-(Phenylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 474


125
1-{1-[(6-Bromo-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 484/486


126
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole



1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.81 (d, J = 8.2 Hz,



2H), 7.63 (d, J = 8.6 Hz, 2H), 7.58 (s, 2H), 7.40 (m, 6H),



6.78 (d, J = 3.5 Hz, 1H), 4.37 (m, 1H), 4.30-4.20 (m, 2H),



4.11 (m, 1H), 3.60-3.40 (m, 2H), 3.24 (m, 1H), 2.50-2.20 (m, 4H).



MS m/z (M + H+) 533


127
2-(4-Chlorophenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 500


128
1-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1H-indole



1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 7.56-7.37 (m,



13H), 6.73 (d, J = 3.2 Hz, 1H), 4.37 (m, 1H), 4.29-4.20 (m,



2H), 4.10 (bs, 1H), 3.90 (bs, 1H), 3.74 (bs, 1H), 3.38 (m, 2H),



3.23 (m, 1H), 2.50-2.20 (m, 4H).



MS m/z (M + H+) 465


129
1-[3-(Trifluoromethyl)phenyl]-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.76 (s, 1H),



7.72-7.64 (m, 3H), 7.58-7.50 (m, 2H), 7.41 (m, 6 H), 6.78 (d,



J = 3 Hz, 1H), 4.37 (m, 1H), 4.30-4.20 (m, 2H), 4.11 (m, 1H),



3.91 (bs, 1H), 3.75 (bs, 1H), 3.48 (m, 2H), 3.25 (m, 1H),



2.55-2.20 (m, 4H).



MS m/z (M + H+) 533


130
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-(phenylsulfonyl)-1H-indole



MS m/z (M + H+) 529


131
6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3-benzoxazole



1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1H), 8.45 (d, J = 8.2 Hz,



1H), 7.94 (d, J = 1.2 Hz, 1H), 7.82 (m, 2H), 7.69 (m, 2H),



7.41 (m, 5H), 4.38 (m, 1H), 4.32-4.22 (m, 2H), 4.12 (m, 1H),



3.90 (bs, 1H), 3.76 (bs, 1H), 3.50 (bs, 2H), 3.27 (m, 1H),



2.50-2.20 (m, 4H).



MS m/z (M + H+) 535


132
2-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 467


617
1-(4-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indazole



MS m/z 484 (M + H+)


571
1-(3,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (CDCl3, 400 MHz): δ 7.99 (s, 1 H), 7.53-7.63 (m, 1



H), 7.45-7.53 (m, 1 H), 7.16-7.45 (m, 9 H), 6.74 (d, J = 3.1 Hz,



1 H), 4.37 (br. s., 1 H), 4.16-4.32 (m, 2 H), 4.11 (br. s., 1 H),



3.83-4.00 (m, 1 H), 3.65-3.83 (m, 1 H), 3.48 (br. s., 2 H),



3.17-3.31 (m, 1 H), 2.44 (br. s., 4 H)



MS m/z 501 (M + H+)


584
1-(4-Fluorophenyl)-3-methyl-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 497 (M + H+)


599
2-(3-Fluorophenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole



MS m/z 501 (M + H+)


583
1-(3-Fluorophenyl)-3-methyl-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 497 (M + H+)


577
3-Methyl-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z 479 (M + H+)


569
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H-indole



MS m/z 519 (M + H+)


573
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[4-(trifluoromethoxy)phenyl]-1H-indole



MS m/z 549 (M + H+)


580
1-(3,5-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z 501 (M + H+)


568
1-(4-Chloro-3-fluorophenyl)-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z 517 (M + H+)


578
1-(2,5-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z 501 (M + H+)


590
1-(3,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indazole



MS m/z 502 (M + H+)









Example 9c
Following the procedure described above for Example 1b, with the exception of using 1,10-phenanthroline instead of trans-N,N′-dimethylcyclohexane-1,2-diamine as a ligand in step K, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound:




Following the procedure described above for Example 9, step D, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1375
2-Methyl-4-[5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 511


1421
2-Methyl-4-[5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 511


566
2-Methyl-4-[5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-



yl]benzonitrile



MS m/z (M + H+) 504









Example 9d




E. Methyl 1-(4-cyanophenyl)-indole-5-carboxylate, 9d was prepared according to Example 1a step H.
F. 1-(4-cyanophenyl)-indole-5-carboxylic acid, 9e and 1-(4-carbamoyl-phenyl)-indole-5-carboxylic acid, 9f. A mixture of methyl 1-(4-cyanophenyl)-indole-5-carboxylate, 9d (156 mg, 0.57 mmol) and LiOH (54 mg, 2.26 mmol) in THF (4 mL) and H2O (2 mL) was stirred at room temperature for 4 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3 ̃4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 4-8% MeOH/CH2Cl2) gave 9e (75 mg), followed by 9f (27 mg).
Following the procedure described above for Example 9d and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1159
4-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 497


1171
4-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide



MS m/z (M + H+) 515


1133
4-[5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 497


1109
2-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 497


1182
2-[5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 497


1113
3-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 497


1177
3-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide



MS m/z (M + H+) 515









Following the procedure described above for Example 9b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







582
4-[5-({3-[4-(Phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-



yl]benzonitrile



MS m/z (M + H+) 490


588
2-[5-({3-[4-(Phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-



yl]benzonitrile



MS m/z (M + H+) 490


594
3-[5-({3-[4-(Phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide



MS m/z (M + H+) 508









Example 9e




G. Ethyl 1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 91 and Ethyl 1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 9j. A mixture of ethyl 1H-Indazole-5-carboxylate 9g (150 mg, 0.79 mmol), 1-bromo-3-trifluoromethylbenzene 9h (0.13 mL, 0.95 mmol), CuI (22.5 mg, 0.12 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.056 mL, 0.36 mmol), and K3PO4 (0.37 g, 1.74 mmol) in toluene (1.5 mL) was heated at 110° C. for 16 hours. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 10% EtOAc/heptane) to give 9i (190 mg), followed by 9j (37 mg).
H. 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid, 9k and 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid, 9l. 9k and 9l were prepared according to Example 1b Step L from 9i and 9j respectively.
Following the procedure described above for Example 9e, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1080
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-



1H-indazole



MS m/z (M + H+) 541


1374
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[3-



(trifluoromethoxy)phenyl]-1H-indazole



MS m/z (M + H+) 557


1376
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-[3-



(trifluoromethoxy)phenyl]-2H-indazole



MS m/z (M + H+) 557


1419
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-



1H-indazole



MS m/z (M + H+) 541


1420
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-



2H-indazole



MS m/z (M + H+) 541


1422
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-[3-



(trifluoromethoxy)phenyl]-2H-indazole



MS m/z (M + H+) 557









Following the procedure described above for Example 9b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







575
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-



indazole



MS m/z (M + H+) 534


576
5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[3-(trifluoromethoxy)phenyl]-1H-



indazole



MS m/z (M + H+) 550









Example 9f




I. Methyl 1-(4-cyano-3-fluorophenyl)-indole-5-carboxylate, 9m was prepared according to Example 9e step H.
J. Methyl 1-(4-cyano-3-methoxyphenyl)-indole-5-carboxylate, 9n. A solution of 95 mg (0.32 mmol) of compound 9m was combined with 120 mg (0.87 mmol) of K2CO3 in 8 mL of MeOH and heated at 75° C. for 5 h. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic solution was concentrated to give 100 mg (100%) of 9n as a white solid.
K. 1-(4-cyano-3-methoxyphenyl)-indole-5-carboxylic acid, 93 and 1-(4-carbamoyl-phenyl)-indole-5-carboxylic acid, 9o. A mixture of 100 mg (0.33 mmol) of compound 9m and LiOH (31 mg, 1.3 mmol) in THF (4 mL) and H2O (2 mL) was stirred at room temperature for 3 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3 ̃4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 90 mg (94%) of compound 90 as a white solid.
Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1115
2-Methoxy-4-[5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indol-1-yl]benzonitrile



MS m/z (M + H+) 527


633
2-Methoxy-4-[5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile



MS m/z (M + H+) 520









Example 9g




L. Ethyl 2-(thiazol-2-yl)benzo[d]thiazole-6-carboxylate, 9q. A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (150 mg, 0.53 mmol), 2-tributylstannylthiazole 9p (0.25 mL, 0.79 mmol), and Pd(PPh3)4 (30 mg, 0.03 mmol) in dioxane (2 mL) was heated at 130° C. for 30 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with aq. NaHCO3, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 10% EtOAc/heptane) gave 9q (130 mg).
M. 2-(Thiazol-2-yl)benzo[d]thiazole-6-carboxylic acid, 9r. Ethyl 2-phenyl-benzothiazole-6-carboxylate 9q (130 mg, 0.45 mmol) was stirred with LiOH (43 mg, 1.8 mmol) in THF (4 mL) and H2O (2 mL) for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 9r (110 mg).
Following the procedure described above for Example 9g and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1210
2-(1,3-Thiazol-2-yl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzothiazole



MS m/z (M + H+) 497


1165
2-Pyridin-2-yl-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzothiazole



MS m/z (M + H+) 491









Example 9h




N. Methyl 2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate, 9u. A mixture of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate 9s (100 mg, 0.44 mmol), 2-bromopyrimidine 9t (77 nm, 0.48 mmol), and Et3N (0.13 mL, 0.92 mmol) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was worked up to give crude 9v (187 mg).
M. 2-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid, 9v. Compound 9u (187 mg, 0.44 mmol) was refluxed with 3N aqueous NaOH (0.25 mL mg, 0.75 mmol) in THF (6 mL) overnight. Concentrated HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was concentrated to give 9v (350 mg) as the tris-HCl salt.
Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compound of the present invention was prepared:











Cpd
Cpd Name and Data

















2-Pyrimidin-2-yl-8-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 490.1










Example 9i




N. Methyl 3-Amino-2-benzoylamino-benzoate, 9y: To a solution of 500 mg (3.0 mmol) of methyl 2,3-diaminobenzoate 9w and 730 mg (6.0 mmol) of benzoic acid 9x in 8 mL of CH2Cl2 was added 620 mg (3.0 mmol) of dicyclohexylcarbodiimide (DCC) and 4 mg (0.033 mmol) of DMAP. The reaction was stirred overnight and the solid was filtered off. The solid was purified by flash column chromatography (silica gel, 10-30% gradient of EtOAc in heptanes) to give 220 mg (27%) of methyl 3-Amino-2-benzoylamino-benzoate, 9y. MS m/z (M+H+) 271.2
O. Methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z. A solution of 810 mg (3.0 mmol) of methyl 3-amino-2-benzoylamino-benzoate 9y in 15 ml acetic acid was heated to 125° C. for 1.5 h. The reaction was cooled and poured into ice/water. The aqueous layer was made basic with NaHCO3 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and evaporated to give 540 mg (71%) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z. MS m/z (M+H+) 253.2
P. Phenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa. A mixture of 540 mg (2.1 mmol) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate 9z and 3 mL (9 mmol) of 3N aqueous NaOH was refluxed in 8 mL of THF overnight. After cooling, the mixture was poured into ice water and acidified with conc. HCl. The resulting solid was filtered and dried to give 440 mg (86%) of phenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa. MS m/z (M+H+) 238.9.
Following the procedure described above for Example 9i, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:







Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















608
2-(2-Chlorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 500.3


609
2-(3-Fluorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 484.3


602
2-(4-Fluorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 484.3


607
2-(4-Chlorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 500.3


601
2-Phenyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 466.3


1389
2-(3-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 507.2


1399
2-Furan-2-yl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 463.2


1390
2-Phenyl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 473.2


1387
2-Pyridin-4-yl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 474.3


1252
2-Furan-2-yl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 463.3


1255
2-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 463.3


1388
2-(2-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 491.2


1391
2-(3-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 491.2


1393
2-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 491.2


1394
2-(2-Chlorophenyl)-4-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 507.2


1290
2-(4-Chlorophenyl)-4-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 507.2


980
2-Benzyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 487


989
2-(2-Fluorobenzyl)-7-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 505.2


990
2-(3-Fluorobenzyl)-7-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 505.2


991
2-(4-Chlorobenzyl)-7-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 521.2


1461
2-(Pyridin-4-ylmethyl)-7-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 488.2









Example 9j




Q. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd. A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9bb, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9 cc, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd, which was used without purification. MS m/z (M+H+) 290.1.
R. Methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate 9dd (7.4 mmol, 1.2 g crude) and 1.3 g (7.5 mmol) of p-toluenesulfonic acid was refluxed in 10 mL of xylene overnight. After cooling saturated NaHCO3 was added and the resulting mixture was extracted with EtOAc. The organic solvent was evaporated to give 1.1 g (55%) of methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee. MS m/z (M+H+) 272.0.
S. 2-(4-Fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff. A mixture of 1.1 g (4.0 mmol) methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9ee and 3.7 mL of 3N aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling the reaction mixture was poured into water and acidified with conc. HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff. MS m/z (M+H+) 258.1.
Following the procedure described above for Example 9j, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:







Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1154
2-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



1H NMR (400 MHz, CDCl3): δ 8.32 (m, 2H); 7.95 (m, 2H);



7.85 (m, 1H); 7.71-7.49 (m, 5H); 4.85-4.44 (bm, 3H);



4.15-3.91 (bm, 3H); 3.23 (bm, 3H)



MS m/z (M + H+) 474.2


1254
2-(3-Fluorophenyl)-7-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 492.1


1282
2-(4-Fluorophenyl)-7-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 492.1


1238
2-(3-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 507.9


1380
2-(4-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



1H NMR (400 MHz, CDCl3): δ 9.05 (bs, 1H); 8.3 (d, 2H);



8.2 (m, 1H); 7.95 (d, 1H); 7.66 (t, 3H); 7.44 (t, 1H);



4.69-4.52 (m, 1H); 4.44 (m, 2H); 4.10 (bm, 2H); 3.20 (m, 4H).



MS m/z (M + H+) 507.9


1190
2-Phenyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 474


1193
2-(2-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 492.2


1257
2-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 492.2


1173
2-(2-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 508.2


1191
2-(3-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 508.2


1220
2-(4-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzoxazole



MS m/z (M + H+) 508.9


1237
2-Phenyl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 474.2


1251
2-Pyridin-3-yl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole



MS m/z (M + H+) 475.1









Example 10




A. 6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 10b. To compound 10a (0.13 g, 0.53 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 10b, which was used in the next reaction without further purification.
B. 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine. To a solution of compound 5e (60 mg, 0.24 mmol) and Et3N (0.08 mL, 0.58 mmol) in CH2Cl2 (3 mL) at 0° C. was added a solution of compound 10b (0.53 mmol) in CH2Cl2 (1 mL). The reaction was slowly warmed up to room temperature over 4.5 h, diluted with CH2Cl2, and washed with aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) afforded compound 323. 1H NMR (400 MHz, CD3OD): δ 8.15 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.89 (d, J=3 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.56 (d, J=3 Hz, 1H), 4.60 (m, 2H), 4.45 (m, 2H), 4.30 (m, 1H), 4.16 (m, 1H), 3.95-3.89 (m, 2H), 3.35 (m, 1H), 2.55 (bs, 4H). MS m/z (M+H+) 481.
Following the procedure described above for Example 10 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







324
1-(1-{[-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.13 (s, 1H), 8.01 (d, J = 8



Hz, 1H), 7.88 (d, J = 3 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.55



(d, J = 3 Hz, 1H), 4.53 (bs, 1H), 4.46 (bs, 1H), 4.31 (m, 2H),



4.22 (m, 1H), 4.16 (m, 1H), 3.33 (m, 1H), 2.60-2.40 (m, 4H).



MS m/z (M + H+) 515


325
1-(Phenylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.15 (s, 1H), 7.94 (d, J = 8.6



Hz, 1H), 7.73 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.42 (m, 5H),



4.58 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.12 (m, 1H), 3.93



(bs, 1H), 3.77 (bs, 1H), 3.51 (bs, 2H), 3.34 (m, 1H), 2.60-2.30



(m, 4H).



MS m/z (M + H+) 474


686
3-Methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)thieno[2,3- 



b]pyridine



MS m/z (M + H+) 496


749
3-Methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)thieno[2,3-



b]pyridine



MS m/z (M + H+) 496


801
1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbony1)-2-



(trifluoromethyl)piperazine



MS m/z (M + H+) 583.0


833
4-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-1-(1,3-thiazol-4-ylcarbony1)-2-



(trifluoromethyl)piperazine



MS m/z (M + H+) 583.0


778
1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbony1)-2-



(trifluoromethyl)piperazine



1H NMR (400 MHz, CD3OD): δ 2.13 (d, J = 13.2 Hz, 1 H),



2.41 (d, J = 47.2 Hz, 1 H), 2.8-3.3 (m, 2.5 H), 3.69 (d, J = 13.7



Hz, 0.5 H), 3.98-4.42 (m, 4 H), 4.51 (t, J = 13.4 Hz, 0.5 H),



5.27-5.54 (m, 1 H), 6.93 (br. s., 0.5 H), 7.83 (d, J = 8.6 Hz, 1



H), 7.88 (br. s., 1 H), 7.97 (t, J = 6.8 Hz, 1 H), 8.11 (d, J = 8.8



Hz, 1 H), 8.42 (s, 1 H)



MS m/z (M + H+) 583.0









Example 10a




C. Methyl 3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate, 10d and methyl 3-chloro-6-trifluoromethyl-7-fluoro-benzo[b]thiophene-2-carboxylate, 10e. A mixture of 3-fluoro-4-(trifluoromethyl)-cinnamic acid 10c (1.5 g, 6.4 mmol), SOCl2 (2.33 mL, 32 mmol), DMF (0.05 mL, 0.64 mmol), and pyridine (0.05 mL, 0.64 mmol) in chlorobenzene (5 mL) was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in MeOH (50 mL) and stirred at room temperature for 16 h. The solution was concentrated, diluted with CH2Cl2 and washed with H2O. The organic solution was dried over Na2SO4 and concentrated. Recrystallization with heptanes, followed by flash column chromatography (silica gel, 2% EtOAc/heptane) gave 10d (580 mg) and 10e (380 mg).
D. 3-Chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 10f. Methyl 3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate 10d (180 mg, 0.58 mmol) was stirred with LiOH (55 mg, 2.3 mmol) in THF (5 mL) and H2O (2.5 mL) for 4 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3 ̃4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 10f (150 mg).
E. 3-Chloro-6-trifluoromethyl-7-fluoro-benzo[b]thiophene-2-carboxylic acid, 10g. Compound 10g was prepared from 10e following the procedure described in above step D.
Following the procedure described above for Example 10, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:













Cpd
Cpd Name and Data








666
1-(1-{[3-Chloro-5-fluoro-6-(trifluoromethyl)-1-




benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-




thiazol-4-ylcarbonyl)piperazine




MS m/z (M + H+) 533



900
1-(1-{[3-Chloro-5-fluoro-6-(trifluoromethyl)-1-




benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-




thiazol-2-ylcarbonyl)piperazine




MS m/z (M + H+) 533



670
1-(1-{[3-Chloro-7-fluoro-6-(trifluoromethyl)-1-




benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-




thiazol-4-ylcarbonyl)piperazine




MS m/z (M + H+) 533



650
1-(1-{[3-Chloro-7-fluoro-6-(trifluoromethyl)-1-




benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-




thiazol-2-ylcarbonyl)piperazine




MS m/z (M + H+) 533









Example 10b




F. 3-Chloro-5-trifluoromethyl-6-fluoro-benzo[b]thiophene-2-carboxylic acid, 10h and 3-chloro-6-fluoro-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 10i. Compounds 10h and 10i were prepared according to Example 10a, using 4-fluoro-3-(trifluoromethyl)-cinnamic acid in place of 10c, and were obtained as a  ̃2:1 mixture.
G. 3-Chloro-5-trifluoromethyl-6-fluoro-benzo[b]thiophene-2-carbonyl chloride, 10j and 3-chloro-6-fluoro-7-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 10k. Compounds 10j and 10k were prepared according to Example 10a from 10h and 10i, and were obtained as a  ̃2:1 mixture.
H. 1-(1-{[3-Chloro-6-fluoro-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 901, and 1-(1-{[3-chloro-6-fluoro-7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 902. Cpd 901 and Cpd 902 were prepared according to Example 10 from 5e bis HCl salt (0.31 mmol, 150 mg), the mixture of 10j and 10k (0.24 mmol, 76 mg), and Et3N (1.44 mol, 0.2 mL) in 7 mL of CH2Cl2. Workup and purification by flash column chromatography (silica gel, 2% MeOH/CH2Cl2) gave 50 mg (39%) of Cpd 901 followed by 18 mg (14%) of Cpd 902. Cpd 901: MS m/z (M+H+) 533. Cpd 902: MS m/z (M+H+) 533.
Following the procedure described above for Example 10b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







659
1-(1-{[3-Chloro-6-fluoro-5-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-



4-ylcarbonyl)piperazine



MS m/z (M + H+) 533


697
1-(1-{[3-Chloro-6-fluoro-7-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-



4-ylcarbonyl)piperazine



MS m/z (M + H+) 533









Example 11




A. 1-{4-[1-(6-Bromo-3-chloro-benzo[b]thiophene-2-carbonyl)-azetidin-3-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone, 11b. To a solution of compound 1g (0.19 g, 0.61 mmol) and Et3N (0.51 mL, 3.67 mmol) in CH2Cl2 (4 mL) at 0° C. was added a solution of compound 11a (prepared in an analogous manner to that of compound 10b of Example 10) (0.69 mmol) in CH2Cl2 (2 mL). The reaction mixture was slowly warmed up to room temperature over 18 h. The reaction mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 11b (0.3 g).
B. (6-Bromo-3-chloro-benzo[b]thiophen-2-yl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 11c. A solution of compound 11b (0.3 g, 0.59 mmol) in Et3N (1 mL) and MeOH (9 mL) was stirred at room temperature for 3 days. It was then concentrated to give compound 11c, which was used in the next reaction without further purification.
C. 1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 326. To a mixture of compound 11c (0.2 mmol), compound 5c (31 mg, 0.24 mmol), and Et3N (0.08 mL, 0.58 mmol) in CH2Cl2 (3 mL) at room temperature was added HATU (91 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with diethyl ether, washed with aq. NaHCO3 and aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 326 (57 mg). 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 7.88 (d, J=3 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.55 (d, J=3 Hz, 1H), 4.53 (bs, 1H), 4.44 (bs, 1H), 4.30 (bs, 2H), 4.21 (bs, 1H), 4.13 (bs, 1H), 3.89 (bs, 1H), 3.84 (bs, 1H), 3.31 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H+) 525/527/529.
Following the procedure described above for Example 11 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







327
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.05 (d, J = 8.2 Hz, 1H),



7.89 (d, J = 3 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H),



7.55 (d, J = 3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.60 (m, 2H),



4.45 (m, 2H), 4.31 (m, 1H), 4.17 (m, 1H), 3.95-3.80 (m, 2H),



3.35 (m, 1H), 2.56 (bs, 4H).



MS m/z (M + H+) 481


328
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 481


329
1-(Phenylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.02 (d, J = 8.2 Hz, 1H),



7.80 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H),



7.42 (m, 5H), 4.60 (m, 1H), 4.43 (m, 1H), 4.28 (m, 1H), 4.12 (m,



1H), 3.94 (bs, 1H), 3.76 (bs, 1H), 3.51 (bs, 2H), 3.33 (m, 1H),



2.60-2.30 (m, 4H).



MS m/z (M + H+) 474


330
1-(Phenylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.05 (d, J = 8 Hz, 1H), 7.84 (s,



1S), 7.71 (d, J = 8 Hz, 1H), 7.50 (t, J = 8 Hz, 1H), 7.42 (m,



5H), 4.59 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 4.13 (m, 1H),



3.92 (bs, 1H), 3.79 (bs, 1H), 3.51 (bs, 1H), 3.34 (m, 1H),



2.60-2.30 (m, 4H).



MS m/z (M + H+) 474


331
1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 518/520/522


332
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 8.04 (s, 1H),



8.02 (d, J = 8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H),



7.51 (t, J = 7.6 Hz, 1H), 4.60 (m, 1H), 4.45 (m, 1H), 4.30 (m,



1H), 4.15 (m, 1H), 4.02 (bs, 1H), 3.95 (m, 2H), 3.82 (bs, 1H),



3.35 (m, 1H), 2.60-2.40 (m, 4H).



MS m/z (M + H+) 481


333
1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 8.02 (s, 1H),



7.97 (s, 1H), 7.74 (m, 1H), 7.60 (m, 1H), 4.30 (m, 2H),



4.21 (bs, 1H), 4.12 (bs, 1H), 4.00 (bs, 1H), 3.92 (m, 2H), 3.81 (bs,



1H), 3.31 (m, 1H), 2.50-2.30 (m, 4H).



MS m/z (M + H+) 525/527/529


334
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 8.05 (d, J = 8 Hz,



1H), 8.04 (s, 1H), 7.85 (m, 1H), 7.72 (d, J = 8 Hz, 1H), 7.51 (t,



J = 7.6 Hz, 1H), 4.60 (m, 1H), 4.44 (m, 1H), 4.30 (m, 1H),



4.16 (m, 1H), 4.10-3.80 (m, 4H), 3.36 (m, 1H), 2.60-2.40 (m,



4H).



MS m/z (M + H+) 481


335
1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.80 (d, J = 2 Hz, 1H), 8.13 (t,



J = 0.8 Hz, 1H), 8.03 (d, J = 2 Hz, 1H), 8.01 (d, J = 8.6 Hz,



1H), 7.73 (dd, J = 1.2 Hz, 8.6 Hz, 1H), 4.31 (m, 2H), 4.21 (m,



1H), 4.15 (m, 1H), 4.01 (m, 1H), 3.93 (m, 2H), 3.81 (m, 1H),



3.33 (m, 1J), 2.55-2.40 (m, 4H).



MS m/z (M + H+) 515


336
1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 508


337
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 481


504
1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 488


543
1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 458


516
1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 438


908
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 481


897
1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 495


898
1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 495


929
1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 465


930
1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 465


810
1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(pyridin-2-ylcarbonyl)piperazine



MS m/z (M + H+) 459


742
1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 445


684
1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 445









Example 12




1-{1-[(5-Phenylnaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 338. A mixture of compound 313 (48 mg, 0.1 mmol), compound 12a (24 mg, 0.2 mmol), K2CO3 (27 mg, 0.2 mmol) and Pd(dppf)C2.CH2Cl2 (4 mg, 0.005 mmol) in EtOH (1 mL) and H2O (0.2 mL) was heated in a microwave reactor at 130° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with CH2Cl2, and washed with H2O. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 338 (28 mg). 1H NMR (400 MHz, CD3OD): δ 8.20 (d, J=1.6 Hz, 1H), 7.93 (t, J=9.6 Hz, 2H), 7.88 (d, J=3 Hz, 1H), 7.66-7.43 (m, 9H), 4.52 (bs, 1H), 4.50-4.20 (m, 4H), 4.16 (m, 1H), 3.88 (bs, 1H), 3.83 (bs, 1H), 3.28 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H+) 483.
Following the procedure described above for Example 12 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







339
1-(Phenylcarbonyl)-4-{1-[(6-phenylnaphthalen-2-



yl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 476


340
7-Phenyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)quinoline



MS m/z (M + H+) 477


341
1-(Phenylcarbonyl)-4-[1-({6-[4-(trifluoromethyl)phenyl]-1-



benzothiophen-2-yl}carbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 550


342
1-{1-[(6-Phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-



yl}-4-(phenylcarbonyl)piperazine



1H NMR (400 MHz, CD3OD): δ 8.05 (s, 1H), 7.88 (d, J = 8.6 Hz,



1H), 7.70 (s, 1H), 7.66-7.62 (m, 3H), 7.49-7.36 (m, 8H),



4.58 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.11 (m, 1H),



3.92 (bs, 1H), 3.76 (bs, 1H), 3.49 (bs, 2H), 3.31 (m, 1H),



2.60-2.25 (m, 4H).



MS m/z (M + H+) 482









Example 13




1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 343. The title compound was prepared in an analogous manner to that of compound 338 of Example 12, using 1 equivalent of compound 12a, and substituting compound 326 for compound 313. The reaction was heated in a microwave reactor at 120° C. for 20 min. 1H NMR (400 MHz, CD3OD): δ 8.01 (d, J=1.2 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.88 (d, J=3 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.55 (d, J=3 Hz, 1H), 7.49 (m, 2H), 7.41 (m, 1H), 4.54 (bs, 1H), 4.46 (bs, 1H), 4.33 (m, 2H), 4.25 (m, 1H), 4.14 (m, 1H), 3.89 (bs, 1H), 3.84 (bs, 1H), 3.32 (m, 1H), 2.50 (m, 4H). MS m/z (M+H+) 523.
Following the procedure described above for Example 13 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







344
1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 516 (M + H+).


345
1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 523


591
1-(Phenylcarbonyl)-4-(1-{[3-phenyl-6-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 550


515
1-(1-{[3-Cyclopropyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 514


511
1-(1-{[3-(2-Methylprop-1-en-1-yl)-6-(trifluoromethyl)-1-



benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 528









Example 14




1-(Phenylcarbonyl)-4-{1-[(5-phenylthiophen-2-yl)carbonyl]azetidin-3-yl}piperazine, Cpd 346. A mixture of compound 322 (40 mg), compound 12a (16 mg), Pd(dppf)Cl2.CH2Cl2 (8 mg), and Na2CO3 (19 mg), in a dioxane (0.8 mL)/water (0.2 mL) mixture, was placed in a capped vial and heated at 80° C. for 4 h. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to give compound 346 (17 mg). MS m/z (M+H+) 432.6.
Following the procedure described above for Example 14 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















347
1-(Phenylcarbonyl)-4-[1-({5-[4-



(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 500.0


924
1-Acetyl-6-phenyl-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



MS m/z (M + H+) 530.0


917
1-Acetyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-[3-(trifluoromethyl)phenyl]-



1,2,3,4-tetrahydroquinoline



MS m/z (M + H+) 598.0


919
1-Acetyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-6-[4-(trifluoromethyl)phenyl]-



1,2,3,4-tetrahydroquinoline



MS m/z (M + H+) 598.0


920
1-Acetyl-6-(5-chlorothiophen-2-yl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



MS m/z (M + H+) 570.1


1157
1-(1-{[4-(4-Fluorophenyl)thiophen-2-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 457.0


1160
1-(1-{[4-(3-Fluorophenyl)thiophen-2-yl]carbonyl}azetidin-3-



yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 457.0


1321
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-



(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 507.0


605
1-{1-[(5-Phenyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 466


600
7-(3-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 483


1342
1-{1-[(5-Phenyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 473


1343
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({5-[3-



(trifluoromethyl)phenyl]-1-benzofuran-2-yl}carbonyl)azetidin-



3-yl]piperazine



MS m/z (M + H+) 541


1059
1-(1-{[4-(3-Fluorophenyl)-5-methylthiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 471


1351
1-[1-({5-Methyl-4-[3-(trifluoromethyl)phenyl]thiophen-2-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 521


1066
7-(3-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 504


1101
7-(4-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 504


1060
1-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-7-[3-(trifluoromethyl)phenyl]-1H-



indole



MS m/z (M + H+) 554


1352
1-[1-({4-Methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 521


1353
1-(1-{[5-(4-Fluorophenyl)-4-methylthiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine


1065
1-(1-{[5-(3-Fluorophenyl)-4-methylthiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 471


1354
1-[1-({4-Methyl-5-[3-(trifluoromethyl)phenyl]thiophen-2-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 521


1183
7-(3-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 490


1096
1-(1-{[4-(4-Fluorophenyl)-5-methylthiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 471









Example 14a
Following the procedure described above for Example 14, substituting Cpd 682 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1075
5-(4-Fluorophenyl)-3-methyl-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (400 MHz, CDCl3): δ 7.93 (ar, 1H); 7.82 (ar, 1H);



7.76 (ar, 1H); 7.64 (m, 2H); 7.46 (m, 2H); 7.15 (m, 2H);



4.47-4.0 (bm, 6H); 3.82 (b, 2H); 2.5 (s, 3H)



MS m/z (M + H+) 504.1


1149
5-(2-Fluoropyridin-3-yl)-3-methyl-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (400 MHz, CDCl3): δ 8.09-7.97 9m, 2H); 7.88 (ar,



1H); 7.82-7.72 (m, 2H); 7.42 (ar, 2H); 7.31 (m, 1H);



7.62 (bm, 1H); 4.48 (bm, 1H); 4.35 (bm, 2H); 3.96 (bm, 2H);



3.14 (m, 4H); 2.44 (s, 3H)



MS m/z (M + H+) 505.2


1175
5-(5-Methoxypyridin-3-yl)-3-methyl-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 517.2


1205
3-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-({3-[4-(1,3-



thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indole



MS m/z (M + H+) 490.2









Example 14b
Following the procedure described above for Example 14, substituting Cpd 792 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1204
6-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 491.1


1241
6-(1-Methyl-1H-pyrazol-5-yl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 477.3


1244
6-(2-Fluoropyridin-3-yl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 491.2


1211
6-(3,5-Dimethylisoxazol-4-yl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 491.1


1196
6-(5-Methoxypyridin-3-yl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 503.1









Example 14c
Following the procedure described above for Example 14, substituting Cpd 864 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1213
5-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)furo[2,3-



b]pyridine



MS m/z (M + H+) 492.1


1209
5-Phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine



MS m/z (M + H+) 474.1









Example 14d
Following the procedure described above for Example 14, substituting Cpd 315 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1443
5-Fluoro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 415.2


1476
5-(2-Fluoropyridin-3-yl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 492.1


1303
2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-5-[4-(trifluoromethoxy)phenyl]-1H-



benzimidazole



MS m/z (M + H+) 494.97


1294
5-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole;



MS m/z (M + H+) 491.1









Example 15




1-(Phenylcarbonyl)-4-(1-{[5-(phenylethynyl)thiophen-2-yl]carbonyl}azetidin-3-yl)piperazine, Cpd 348. To a solution of compound 322 (100 mg), compound 15a (0.46 mmol, 0.05 mL), CuI (4.4 mg), and Pd(PPh3)2Cl2 (16 mg) in THF (1 mL) was added TEA (0.25 mL) and the mixture was heated at 40° C. for 1 h. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to yield compound 348 (75 mg). MS m/z (M+H+) 456.6.
Example 16




1-(Phenylcarbonyl)-4-(1-{[5-(2-phenylethyl)thiophen-2-yl]carbonyl}azetidin-3-yl)piperazine, Cpd 349. To a solution of compound 348 (30 mg) in EtOH (20 mL) was added 10% Pd/C (10 mg) and the mixture was subjected to hydrogenation (45 psi H2) for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 349 (30 mg). MS m/z (M+H+) 460.6.
Example 17




A. 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, 17a. To a solution of compound 319 (500 mg) in CH2Cl2 (6 mL) was added TFA (4 mL) at room temperature. The mixture was stirred for 1.5 h and was then concentrated under reduced pressure. The residue was diluted with CH2Cl2 and made basic with aqueous 2N NaOH solution. The organic layer was washed with water and brine, dried over anhydrous K2CO3, filtered, and concentrated to give compound 17a, which was used without further purification.
B. 2-(Cyclohexylcarbonyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 350. A mixture of compound 17a (31 mg, 0.03 mL), HATU (100 mg), and TEA (0.11 mL) in DCM (1 mL) was stirred at room temperature for 5 h. The reaction was diluted with DCM and water. The organics were concentrated and purified by flash column chromatography (silica gel, 8% MeOH/EtOAc) to give compound 350 (65 mg). 1H NMR (CDCl3): δ 7.47-7.39 (m, 7H), 7.17 (d, J=0.02, 1H), 4.74 (s, 1.2H), 4.48 (s, 0.8H), 4.25 (m, 2H), 4.10 (m, 2H), 3.92-3.71 (m, 4H), 3.43 (m, 2H), 3.19 (m, 1H), 2.93 (m, 1.2H), 2.86 (m, 0.8H), 2.55 (m, 1H), 2.42-2.24 (m, 4H), 1.83-1.57 (m, 8H), 1.26 (m, 2H). MS m/z (M+H+) 515.7.
Following the procedure described above for Example 17 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















351
2-(3,3-Dimethylbutanoyl)-6-({3-[4-(phenylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 503.7


352
2-(3,3-Dimethylbutanoyl)-6-({3-[4-(phenylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 509.6


353
2-[(4,4-Difluorocyclohexyl)carbonyl]-6-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 463.6


354
6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-{[4-(trifluoromethyl)cyclohexyl]carbonyl}-



1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 583.7


546
1-(1-{[4-(1-Acetylpiperidin-4-yl)phenyl]carbonyl}azetidin-3-



yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 475.2


1486
1-[1-({2-[(3S)-1-Acetylpyrrolidin-3-



yl]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 461.2


1437
2-(Phenylcarbonyl)-8-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 516.2









Example 17a




D. 6-{3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 17c. To a solution of compound 5e (651 mg, 2 mmol), 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 17b (555 mg, 2 mmol), and EDC (466 mg, 3 mmol) in CH2Cl2 (20 mL) was added Et3N (0.84 mL, 6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted with CH2Cl2, and H2O after acidifying the water layer to pH ̃6 with 1N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave 17c (826 mg). MS m/z (M+H+) 512.1.
Following the procedure described above for Example 17a, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 17a, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







538
tert-Butyl 4-[3-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-carboxylate



MS m/z (M + H+) 533.4


903
tert-Butyl 4-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-



carboxylate



MS m/z (M + H+) 540.1


861
tert-Butyl 8-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-



2(1H)-carboxylate



MS m/z (M + H+) 512.2









Example 17b




E. 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 916. To a solution of compound 17c (826 mg, 1.61 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was extracted with CH2Cl2, and H2O after basifying the water layer to pH ̃8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 916 (675 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.54 (br. s, 1H), 4.44 (br. s, 1H), 4.01-4.35 (m, 6H), 3.75-3.95 (m, 2H), 3.12-3.31 (m, 2H), 2.85 (t, J=5.8 Hz, 1H), 2.49 (br. s, 4H). MS m/z (M+H+) 412.0.
Following the procedure described above for Example 17b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Example 18




2-Benzyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 355. To a suspension of compound 17a (100 mg) and K2CO3 (69 mg) in MeCN was added compound 18a (0.0353 mL) and the mixture was stirred at room temperature for 30 min. The reaction was concentrated and the residue was diluted with EtOAc and water. The organics were concentrated and purified by flash column chromatography (silica gel, 8% MeOH/EtOAc) to afford compound 355 (85 mg). MS m/z (M+H+) 495.6.
Example 19




N-tert-Butyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide, Cpd 356. To a solution of compound 17a (75 mg) in DCM (1 mL) was dropwise added compound 19a (0.026 mL) at 0° C. After 30 min, the reaction mixture was quenched with DCM and water at 0° C. The organics were concentrated and purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to give compound 356 (60 mg). MS m/z (M+H+) 504.7.
Example 20




A. 6-({3-[4-(Trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, 20b. To a solution of compound 1g (308 mg, 1 mmol), compound 20a (177 mg, 1 mmol), and Et3N (0.42 mL, 3 mmol) in CH2Cl2 (10 mL) was added HATU (570 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 20b (279 mg). LC/MS m/z (M+H+) 397.0.
B. 6-([3-piperazin-1-yl]-azetidin-1-yl)carbonyl-1,2,3,4-tetrahydroquinoline, 20c. To a solution of compound 20b (529 mg, 1.33 mmol) in MeOH (10 mL) was added K2CO3 (368 mg, 2.66 mmol). The reaction mixture was stirred at room temperature for 30 min. The resultant mixture was filtered, concentrated under reduced pressure, and the resultant residue was partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 20c (370 mg). LC/MS m/z (M+H+) 301.0.
C. 6-(3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]-azetidin-1-yl)carbonyl-1,2,3,4-tetrahydroquinoline, Cpd 357. To a solution of compound 20c (370 mg, 1.23 mmol), compound 5c (160 mg, 1.24 mmol), and Et3N (0.51 mL, 3.69 mmol) in CH2Cl2 (10 mL) was added HATU (703 mg, 1.85 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 357 (483 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.0 Hz, 1H), 7.53-7.58 (m, 1H), 7.33 (s, 1H), 7.24-7.30 (m, 1H), 6.39 (d, J=8.1 Hz, 1H), 3.97-4.66 (m, 6H), 3.86 (d, J=18.4 Hz, 2H), 3.35 (t, J=5.4 Hz, 2H), 3.16-3.26 (m, 1H), 2.77 (t, J=6.2 Hz, 2H), 2.39-2.59 (m, 4H), 1.94 (dt, J=11.8, 6.1 Hz, 2H); LC/MS m/z (M+H+) 412.0.
Example 21




6-(3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]-azetidin-1-yl)-carbonyl 1-[3-(trifluoromethyl)phenyl]carbonyl-1,2,3,4-tetrahydroquinoline, Cpd 358. To a solution of compound 357 (30 mg, 0.073 mmol) in CH2Cl2 (1 mL), at 0° C., was added compound 1f (0.013 mL, 0.088 mmol), then Et3N (0.03 mL, 0.22 mmol). The reaction mixture was stirred at 0° C. for 2 h. The resultant mixture was partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 358 (42 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.52-7.59 (m, 3H), 7.41-7.49 (m, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 4.35-4.59 (m, 2H), 4.18-4.26 (m, 2H), 4.01-4.16 (m, 2H), 3.75-3.95 (m, 4H), 3.17-3.26 (m, 1H), 2.90 (t, J=6.6 Hz, 2H), 2.37-2.57 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M+H+) 584.0.
Following the procedure described above for Example 21 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







359
1-(Cyclopropylcarbonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H),



7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.43-7.47 (m, 2H),



4.05-4.62 (m, 6H), 3.75-3.97 (m, 4H), 3.21-3.31 (m, 1H), 2.78 (t, J = 6.6 Hz,



2H), 2.38-2.59 (m, 4H), 1.90-2.03 (m, 3H),



1.13-1.21 (m, 2H), 0.80-0.86 (m, 2H); LC/MS m/z (M + H+) 480.0.


360
1-(Cyclohexylcarbonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 3.0 Hz, 1H),



7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.44 (dd, J = 8.2, 1.6 Hz, 1H),



7.28-7.33 (m, 1H), 4.04-4.62 (m, 6H), 3.73-3.96 (m, 4H),



3.21-3.30 (m, 1H), 2.72-2.82 (m, 3H), 2.40-2.59 (m, 4H), 1.98 (quin,



J = 6.6 Hz, 2H), 1.71-1.83 (m, 4H), 1.49-1.70 (m, 2H),



1.10-1.36 (m, 4H); LC/MS m/z (M + H+) 522.2.


361
1-(Methylsulfonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 3.0 Hz, 1H),



7.74 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 1.8 Hz,



1H), 7.40 (dd, J = 8.6, 2.3 Hz, 1H), 4.03-4.61 (m, 6H),



3.78-3.96 (m, 4H), 3.21-3.29 (m, 1H), 2.95 (s, 3H), 2.89 (t, J = 6.6 Hz,



2H), 2.40-2.59 (m, 4H), 1.97-2.08 (m, 2H); LC/MS m/z



(M + H+) 490.0.


362
1-(Methylsulfonyl)-6-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 8.79 (d, J = 2.0 Hz, 1H),



8.02 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H),



7.39 (dd, J = 8.7, 2.1 Hz, 1H), 3.72-4.37 (m, 10H), 3.19-3.30 (m,



1H), 2.94 (s, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.33-2.56 (m, 4H),



1.96-2.04 (m, 2H); LC/MS m/z (M + H+) 490.0.


363
1-(Methylsulfonyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.6 Hz, 1H),



7.49 (s, 1H), 7.35-7.44 (m, 6H), 4.00-4.36 (m, 4H), 3.64-3.97 (m,



4H), 3.48 (br. s., 2H), 3.18-3.27 (m, 1H), 2.91-2.97 (m, 3H),



2.87 (t, J = 6.6 Hz, 2H), 2.19-2.56 (m, 4H), 1.97-2.04 (m, 2H);



LC/MS m/z (M + H+) 483.0.


364
1-(Cyclobutylcarbonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H),



7.55 (d, J = 3.3 Hz, 1H), 7.48 (s, 1H), 7.39-7.44 (m, 1H),



7.24-7.28 (m, 1H), 4.01-4.63 (m, 6H), 3.78-3.97 (m, 2H), 3.67-3.76 (m,



2H), 3.48 (quin, J = 8.4 Hz, 1H), 3.20-3.30 (m, 1H), 2.76 (t, J = 6.3 Hz, 2H),



2.34-2.60 (m, 6H), 2.08 (m, 2H), 1.83-2.02 (m,



4H); LC/MS m/z (M + H+) 494.0.


365
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-(4-trifluoromethylbenzoyl)-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H),



7.52-7.61 (m, 4H), 7.49 (d, J = 8.1 Hz, 2H), 7.12-7.18 (m, 1H),



6.75-6.85 (m, 1H), 4.00-4.60 (m, 6H), 3.76-3.95 (m, 4H),



3.18-3.27 (m, 1H), 2.90 (t, J = 6.6 Hz, 2H), 2.37-2.57 (m, 4H),



2.02-2.12 (m, 2H); LC/MS m/z (M + H+) 584.0.


729
2-[(4,4-Difluorocyclohexyl)carbonyl]-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 558.0


679
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-{[3-(trifluoromethyl)phenyl]carbonyl}-1,2,3,4-



tetrahydroisoquinoline



1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 3.3 Hz, 1H),



7.70-7.79 (m, 2H), 7.63-7.68 (m, 1H), 7.57-7.62 (m, 1H), 7.55 (d, J = 3.3 Hz,



1H), 7.50 (s, 1H), 7.45 (br. s., 1H), 7.26 (s, 1H),



4.94 (br. s., 1H), 4.48-4.66 (m, 2H), 4.44 (br. s., 1H), 3.97-4.36 (m,



5H), 3.75-3.96 (m, 2H), 3.65 (br. s., 1H), 3.19-3.33 (m, 1H),



2.85-3.12 (m, 2H), 2.37-2.62 (m, 4H)



MS m/z (M + H+) 584.0


907
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-{[4-(trifluoromethyl)phenyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H),



7.72 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 3.3 Hz,



1H), 7.38-7.52 (m, 2H), 7.21-7.27 (m, 1H), 4.94 (br. s.,



1H), 4.48-4.65 (m, 2H), 4.43 (br. s., 1H), 3.95-4.36 (m, 5H),



3.73-3.95 (m, 2H), 3.62 (br. s., 1H), 3.19-3.32 (m, 1H),



2.85-3.10 (m, 2H), 2.38-2.59 (m, 4H)



MS m/z (M + H+) 584.0


685
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-{[4-(trifluoromethyl)cyclohexyl]carbonyl}-



1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 590.0


736
2-(Phenylcarbonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 516.0


665
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-(thiophen-2-ylcarbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 522.0


690
2-(1H-Pyrrol-2-ylcarbonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 505









Example 22




1-(Phenylsulfonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 366. To a solution of compound 357 (60 mg, 0.015 mmol) in pyridine (1 mL) was added compound 22a (0.023 mL, 0.017 mmol). The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) to give compound 366 (66 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.3 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.61-7.67 (m, 2H), 7.52-7.59 (m, 2H), 7.36-7.47 (m, 4H), 4.03-4.61 (m, 6H), 3.78-3.93 (m, 4H), 3.20-3.30 (m, 1H), 2.41-2.58 (m, 6H), 1.63-1.71 (m, 2H); LC/MS m/z (M+H+) 552.0.
Following the procedure described above for Example 22 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







367
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4-tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.87-7.91 (m, 2H),



7.78-7.86 (m, 3H), 7.57-7.63 (m, 1H), 7.54-7.57 (m, 1H), 7.39-7.45 (m,



2H), 4.07-4.61 (m, 6H), 3.77-3.95 (m, 4H), 3.20-3.30 (m, 1H),



2.41-2.59 (m, 6H), 1.70 (quin, J = 6.3 Hz, 2H); LC/MS m/z (M + H+) 620.0.


368
1-[(3-Fluorophenyl)sulfonyl]-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H),



7.81 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 3.0 Hz, 1H), 7.38-7.47 (m, 4H),



7.32-7.37 (m, 1H), 7.22-7.29 (m, 1H), 4.02-4.61 (m, 6H),



3.77-3.96 (m, 4H), 3.20-3.30 (m, 1H), 2.40-2.60 (m, 6H),



1.65-1.77 (m, 2H); LC/MS m/z (M + H+) 570.0.


369
6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H),



7.80-7.85 (m, 1H), 7.73-7.79 (m, 2H), 7.68-7.73 (m, 2H), 7.55 (d, J = 3.3 Hz,



1H), 7.39-7.44 (m, 2H), 4.02-4.61 (m, 6H),



3.77-3.95 (m, 4H), 3.21-3.29 (m, 1H), 2.39-2.59 (m, 6H), 1.65-1.73 (m,



2H); LC/MS m/z (M + H+) 620.0


927
2-(Phenylsulfonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 552.0


928
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 619.8


906
2-(Cyclohexylsulfonyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 558.0









Example 23




1-Benzyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 370. To a solution of compound 357 (30 mg, 0.0073 mmol) in CH3CN (1 mL) was added compound 18a (0.01 mL, 0.0088 mmol), followed by the addition of K2CO3 (20 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was partitioned between CH2Cl2 and H2O. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 1% MeOH/EtOAc+0.5% Et3N) gave compound 370 (14 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.19-7.30 (m, 4H), 6.44 (d, J=8.6 Hz, 1H), 4.54 (s, 2H), 3.97-4.52 (m, 6H), 3.77-3.96 (m, 2H), 3.40-3.47 (m, 2H), 3.15-3.24 (m, 1H), 2.83 (t, J=6.2 Hz, 2H), 2.38-2.59 (m, 4H), 1.98-2.05 (m, 2H); LC/MS m/z (M+H+) 502.2.
Following the procedure described above for Example 23 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







371
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-(4-trifluoromethylbenzyl)-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H),



7.59 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 3.0 Hz, 1H), 7.39 (s, 1H),



7.34 (d, J = 8.1 Hz, 2H), 7.23-7.29 (m, 1H), 6.35 (d, J = 8.6 Hz,



1H), 4.58 (s, 2H), 3.97-4.54 (m, 6H), 3.74-3.97 (m, 2H),



3.39-3.49 (m, 2H), 3.15-3.26 (m, 1H), 2.85 (t, J = 6.1 Hz, 2H),



2.38-2.59 (m, 4H), 1.99-2.10 (m, 2H); LC/MS m/z



(M + H+) 570.0.


879
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-[3-(trifluoromethyl)benzyl]-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 570.0.


880
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-



tetrahydroisoquinoline



MS m/z (M + H+) 570.0.









Example 23a




2-Benzyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 680. A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014 mL, 0.134 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and the mixture was stirred overnight. The resulting mixture was combined with CH2Cl2 and H2O, and pH of the water layer was adjusted to pH ̃8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H), 3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.37-2.60 (m, 4H). MS m/z (M+H+) 502.0.
Following the procedure described above for Example 23a, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1458
2-Benzyl-8-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 502.3









Example 24




1-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 372. To a dry Schlenk tube was added a mixture of compound l1 (30 mg; 0.0073 mmol), palladium (II) acetate (1 mg; 0.00037 mmol), BINAP (3 mg; 0.00044 mmol), and KOtBu (12 mg; 0.01 mmol). The tube, equipped with a teflon-lined septum, was evacuated, and filled with argon. Bromobenzene (14 mg; 0.0088 mmol), and toluene (0.8 mL) were added to the reaction mixture via syringe. The reaction mixture was heated at 110° C. for 21 h. The resultant mixture was diluted with CH2Cl2, and washed sequentially with saturated NH4Cl(aq) and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated. Purification of the residue by preparative TLC (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 372 (1.3 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.0 Hz, 1H), 7.36-7.45 (m, 3H), 7.14-7.26 (m, 4H), 6.55 (d, J=8.6 Hz, 1H), 3.98-4.64 (m, 6H), 3.74-3.96 (m, 2H), 3.61-3.72 (m, 2H), 3.16-3.27 (m, 1H), 2.88 (t, J=6.3 Hz, 2H), 2.37-2.61 (m, 4H), 2.05-2.13 (m, 2H); LC/MS m/z (M+H+) 488.0.
Following the procedure described above for Example 24 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:













373
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 3.3 Hz, 1H),



7.60 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.46 (s, 1H),



7.33 (d, J = 8.3 Hz, 2H), 7.24 (dd, J = 8.7, 2.1 Hz, 1H), 6.84 (d, J = 8.6 Hz,



1H), 4.01-4.62 (m, 6H), 3.75-3.98 (m, 2H),



3.64-3.73 (m, 2H), 3.18-3.30 (m, 1H), 2.87 (t, J = 6.3 Hz, 2H),



2.36-2.62 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M + H+) 556.0.


374
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-



tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H),



7.55 (d, J = 3.0 Hz, 1H), 7.37-7.52 (m, 5H), 7.22 (dd, J = 8.6, 2.0 Hz,



1H), 6.66 (d, J = 8.6 Hz, 1H), 4.03-4.59 (m, 6H),



3.74-3.96 (m, 2H), 3.61-3.72 (m, 2H), 3.18-3.27 (m, 1H), 2.89 (t, J = 6.3 Hz,



2H), 2.37-2.60 (m, 4H), 2.03-2.14 (m, 2H); LC/MS m/z



(M + H+) 556.0.


375
1-Pyrimidin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline



1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 4.8 Hz, 2H),



7.89 (d, J = 3.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.3 Hz,



1H), 7.50 (s, 1H), 7.41 (dd, J = 8.6, 2.0 Hz, 1H), 6.75 (t, J = 4.8 Hz,



1H), 4.06-4.61 (m, 6H), 3.99-4.06 (m, 2H),



3.77-3.96 (m, 2H), 3.18-3.29 (m, 1H), 2.83 (t, J = 6.4 Hz, 2H),



2.39-2.59 (m, 4H), 1.99-2.07 (m, 2H); LC/MS m/z (M + H+) 490.0.


883
2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 488.1


668
2-Pyrimidin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 490.0


661
2-Pyridin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 489.0


805
2-Phenyl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline



MS m/z (M + H+) 490.1









Example 25




A. 1-Acetyl-6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid methyl ester, 25b. To a solution of compound 25a (100 mg, 0.37 mmol) in CH2Cl2 (5 mL) was added acetyl chloride (0.1 mL), and pyridine (0.1 mL). The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated to give the crude compound 25b (116 mg), which was used in the next step without further purification. LC/MS m/z 312.0 (M+H+), 314.0 (M+2H+).
B. 1-Acetyl-6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, 25c. To a solution of compound 25b (116 mg, 0.37 mmol) in THF/MeOH/H2O (2/2/2 mL) was added LiOH (62 mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 3 h. The resultant mixture was concentrated under reduced pressure, partitioned between CH2Cl2 and H2O, and the aqueous phase was brought to pH 5 by the addition of 2N HCl (aq). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound 25c, which was used in the next step without further purification. LC/MS m/z 298.0 (M+H+), 300.0 (M+2H+).
C. 1-Acetyl-6-bromo-2-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, 25d. To a solution of compound 1g (228 mg, 0.74 mmol), compound 25c (22 mg, 0.74 mmol), and Et3N (0.3 mL, 2.22 mmol) in CH2Cl2 (7 mL) was added HATU (338 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 25d (265 mg). LC/MS m/z (M+H+), 517.0 (M+2H+), 519.0.
D. 1-Acetyl-6-bromo-2-({3-[piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, 25e. To a solution of compound 25d (261 mg, 0.505 mmol) in MeOH (3 mL) was added K2CO3 (140 mg, 1.01 mmol). The reaction mixture was stirred at room temperature for 30 min. The resultant mixture was filtered, the filtrate concentrated under reduced pressure, and the resultant residue partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 25e (158 mg). LC/MS m/z (M+H+) 421.0, (M+2H+) 423.0.
E. 1-Acetyl-6-bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 376. The title compound was prepared in an analogous manner to that of compound 357 substituting compound 25e for compound 20c. LC/MS m/z (M+H+) 532.0, (M+2H+) 534.0.
Following the procedure described above for Example 25 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







377
1-Acetyl-6-bromo-2-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-



tetrahydroquinoline



LC/MS m/z (M + H+) 532.0, (M + 2H+) 534.0.


378
1-Acetyl-6-bromo-2-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline



LC/MS m/z (M + H+) 525.0, (M + 2H+) 527.0.









Example 26




A. tert-Butyl 3-(4-Benzoyl-piperazin-1-yl)-azetidine-1-carboxylate, 4b. To a solution of compound 2a (5g) and compound 4a (6.75 g) in 1,2 dichloroethane (50 mL) was added AcOH (1.0 mL) and 4 Å molecular sieves. The resultant mixture was stirred for 2 h, at which time NaBH(OAc)3 (11 g) was added in three portions. The mixture was stirred for 18 h, poured into 2N KOH (aq., 50 mL), and then extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure reduced pressure. The residue was purified by flash column chromatography (5% MeOH/CH2Cl2) to give compound 4b (11.6 g).
B. 3-(4-Benzoyl-piperazin-1-yl)-azetidine, HCl salt 2c. To a solution of compound 4b (5.1 g) in CH2Cl2 (20 mL) was added TFA (10 mL). The resultant mixture was stirred at room temperature for 4 h. The solvents were removed under reduced pressure. The resultant residue was dissolved in CH2Cl2 (5 mL), to which was added 4M HCl in dioxane (3.67 mL). The resulting solid was collected by filtration, washed with ether, and dried under reduced pressure to give compound 2c as its hydrochloride salt (4.0 g).
C. 4-Acetoxy benzoyl chloride, 26b. To a solution of compound 26a (200 mg, 1.11 mmol) in THF (5 mL) was added oxalyl dichloride (97 μL, 1.11 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then warmed to room temperature for 18 h. The solvents were removed under reduced pressure and the crude residue, compound 26b, was dried under reduced pressure for 2 h, and used in the next step without further purification.
D. 4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl acetate (26c). To a mixture of the HCl salt of compound 2c (373 mg, 1.33 mmol), Et3N (0.5 mL) and CH2Cl2 (5 mL) was added a solution of compound 26b in CH2Cl2 (1 mL). The resultant mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, the residue dissolved in CH2Cl2 (1 mL), and then purified by flash column chromatography (silica gel, 5% MeOH/CH2Cl2) to give compound 26c (442 mg).
E. 4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenol, 26d. A mixture of compound 26c (420 mg, 1.03 mmol) and LiOH (100 mg, 4.0 mmol) in a solvent mixture of THF/MeOH/H2O (2/2/2 mL) was stirred at room temperature for 4 h, at which time it was brought to pH 5 by the addition of 2N HCl (aq). The mixture was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue (crude compound 26d) was dried under reduced pressure for 18 h, and used in the following step without further purification.
F. 1-[1-({4-[(3,4-dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 379. A mixture of compound 26d (70 mg, 0.191 mmol), K2CO3 (53 mg, 0.382 mmol), compound 26e (68 mg, 0.287 mmol) and DMF (3 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 379 (83 mg). 1H NMR (CDCl3): δ 7.59-7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=2.0 Hz, 1H), 7.455 (d, J=8.0 Hz, 1H), 7.37-7.44 (m, 5H), 7.23-7.28 (m, 2H), 6.955 (d, J=8.84 Hz, 2H), 5.05 (s, 2H), 4.31 (br. s, 1H), 4.11-4.27 (m, 2H), 4.00-4.10 (m, 1H), 3.91 (br. s, 1H), 3.64-3.82 (m, 1H), 3.48 (br. s, 2H), 3.18-3.27 (m, 1H), 2.42 (br. s, 4H). MS m/z (M+H+) 524.0.
Following the procedure described above for Example 26 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







380
1-(1-{[4-(Naphthalen-2-ylmethoxy)phenyl]carbonyl}azetidin-3-



yl)-4-(phenylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.80-7.88 (m, 4H), 7.59-7.64 (m, J = 8.8 Hz,



2H), 7.45-7.53 (m, 3H), 7.36-7.43 (m, 5H), 7.00 (d, J = 8.8 Hz,



2H), 5.22 (s, 2H), 4.24-4.32 (m, 1H), 4.08-4.24 (m, 2H),



4.03 (br. s., 1H), 3.60-3.79 (m, 1H), 3.31-3.52 (m, 2H),



3.10-3.22 (m, 1H), 2.38 (br. s., 4H).



MS m/z (M + H+) 506.2


381
1-[1-({4-[(2,3-Dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-



yl]-4-(phenylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.625 (d, J = 8.4 Hz, 2H), 7.44 (dd, J = 8.0,



2.1 Hz, 2H), 7.37-7.41 (m, 5H), 7.23 (t, J = 8.1, 1H), 6.97 (d, 



J = 8.8 Hz, 2H), 5.18 (s, 2H), 4.26-4.36 (m, 1H), 4.12-4.26 (m,



2H), 4.07 (br. s, 1H), 3.88 (br. s., 1H), 3.74 (br. s., 1H), 3.47 (br.



s., 2H), 3.14-3.27 (m, 1H), 2.41 (br. s., 3H), 2.22 (s, 1H).



MS m/z (M + H+) 524.0


382
1-[1-({4-[(4-Fluorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 474.2


383
1-(Phenylcarbonyl)-4-{1-[(4-{[4-



(trifluoromethyl)benzyl]oxy}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 524.2


384
1-[1-({4-[(4-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 490.2


385
1-[1-({4-[(2,4-Dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-



yl]-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 524.1


386
4-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenoxy]methyl}benzonitrile



MS m/z (M + H+) 481.2


387
1-[1-({4-[2-(4-Chlorophenyl)ethoxy]phenyl}carbonyl)azetidin-



3-yl]-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 504.2


388
1-[1-({4-[2-(4-Fluorophenyl)ethoxy]phenyl}carbonyl)azetidin-



3-yl]-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 488.2


389
1-(Phenylcarbonyl)-4-(1-{[4-({4-



[(trifluoromethyl)sulfanyl]benzyl}oxy)phenyl]carbonyl}azetidin-



3-yl)piperazine



MS m/z (M + H+) 556.2


390
1-(Phenylcarbonyl)-4-{1-[(4-{[4-



(trifluoromethoxy)benzyl]oxy}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 540.2


391
1-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 490.2


392
1-[1-({4-[(3-Chloro-4-



fluorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 508.2


393
1-(Phenylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethoxy)benzyl]oxy}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 540.2


394
4-[(4-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenoxy]methyl}phenyl)sulfonyl]morpholine



MS m/z (M + H+) 605.2


395
1-{1-[(4-{[3-Fluoro-4-



(trifluoromethyl)benzyl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 542.2


396
1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-4-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 457.2









Example 27




A. Methyl 4-(3-chlorobenzyloxy)-3-chlorobenzoate, 27c. A mixture of compound 27a (500 mg, 2.7 mmol), compound 27b (0.53 mL, 4.03 mmol), and K2CO3 (745 mg, 5.4 mmol) in DMF was stirred at room temperature for 18 h. Water was added to the reaction mixture and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash column chromatography, eluting with 30% EtOAc/hexanes to give compound 27c (662 mg).
B. 4-(3-Chlorobenzyloxy)-3-chlorobenzoic acid, 27d. A mixture of compound 27c (662 mg, 2.0 mmol) and LiOH (192 mg, 8 mmol) in a solvent mixture of THF/MeOH/H2O (3/3/3 mL) was stirred at room temperature for 4 h, then acidified with 15% citric acid in H2O. The mixture was extracted with EtOAc (3×), and the combined extracts washed sequentially with water and brine. The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant crude compound 3b was dried under reduced pressure for 18 h and used in the following reaction without further purification.
C. 4-(3-Chlorobenzyloxy)-3-chlorobenzoyl chloride, 27e. To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then was warmed up to room temperature over 18 h. The solvents were removed under reduced pressure. The resultant residue, crude compound 27e, was dried under reduced pressure for 2 h and used in the following step without further purification.
D. 1-[1-({3-Chloro-4-[(3-chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 397. To a mixture of compound 2c (84 mg, 0.30 mmol), Et3N (0.5 mL), and CH2Cl2 (2.5 mL) was added a solution of compound 27e in CH2Cl2 (1 mL). The resultant mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The resultant residue was dissolved in CH2Cl2 (1 mL), loaded on a silica gel column, and purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 397 (32 mg). 1H NMR (CDCl3): δ 7.695 (d, 1H, J=2.0 Hz), 7.515 (dd, 1H, J1=2.0 Hz, J2=8.6 Hz), 7.44 (s, 1H), 7.38-7.43 (m, 5H), 7.30-7.35 (m, 3H), 6.91-6.97 (d, 1H, J=8.6 Hz), 5.15 (s, 2H), 4.26-4.37 (m, 1H), 4.15-4.26 (m, 2H), 3.84-3.98 (m, 1H), 3.68-3.82 (m, 1H), 3.48 (br. s, 2H), 3.18-3.29 (m, 1H), 2.56-2.16 (m, 4H). MS m/z (M+H+) 524.0.
Following the procedure described above for Example 27 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







398
1-(1-{[3-Chloro-4-(pyridin-4-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3): δ 8.64 (d, J = 5.8 Hz, 2H), 7.2 (d, J = 2.0 Hz,



1H), 7.53 (dd, J1 = 2.1, 8.4 Hz, 1H), 7.36-7.45 (m, 7H),



6.88-6.95 (d, J = 8.6 Hz, 1H), 5.19 (s, 2H), 4.27-4.37 (m, 1H),



4.11-4.27 (m, 2H), 3.99-4.08 (m, 1H), 3.81-3.96 (m, 1H), 3.73 (br. s,



1H), 3.48 (br. s., 2H), 3.17-3.30 (m, 1H), 2.41 (br. s., 4H). MS



m/z (M + H+) 498.0


399
1-[1-({3-Chloro-4-[(3,4-



dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.70 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H),



7.53 (dd, J = 8.6, 2.0 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H),



7.37-7.44 (m, 5H), 7.28-7.32 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.14 (s,



2H), 4.28-4.37 (m, 1H), 4.12-4.27 (m, 2H), 4.05 (br. s., 1H),



3.91 (br. s., 1H), 3.74 (br. s., 1H), 3.49 (br. s., 2H),



3.16-3.27 (m, 1H), 2.42 (br. s., 4H).



MS m/z (M + H+) 558.0


400
1-[1-({4-[(3,4-Dichlorobenzyl)oxy]-3



fluorophenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.53-7.57 (m,



2H), 7.41-7.48 (m, 2H), 7.39 (dd, J = 8.5, 1.1 Hz, 1H),



7.25-7.30 (m, 1H), 6.97 (t, J = 8.3 Hz, 1H), 5.12 (s, 2H), 4.52 (br. d.,



J = 33.8 Hz, 1H), 4.37-4.47 (m, 1H), 4.32 (d, J = 6.8 Hz, 1H),



4.15-4.28 (m, 2H), 4.07 (d, J = 8.3 Hz, 1H), 3.85 (d, J = 17.4 Hz,



2H), 3.20-3.28 (m, 1H), 2.48 (t, J = 4.8 Hz, 4H).



MS m/z (M + H+) 549.0.


401
1-[1-({3-Chloro-4-[(3-



chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.71 (d, J = 2.0 Hz,



1H), 7.50-7.57 (m, 2H), 7.45 (s, 1H), 7.30-7.35 (m, 3H),



6.95 (d, J = 8.6 Hz, 1H), 5.17 (s, 2H), 4.43 (br. s., 1H),



4.28-4.38 (m, 1H), 4.17-4.28 (m, 1H), 4.03-4.15 (m, 2H), 3.85 (d, J = 19.5 Hz,



2H), 3.19-3.29 (m, 1H), 2.48 (m, 4H).



MS m/z (M + H+) 531.0


402
1-(1-{[3-Chloro-4-(pyridin-3-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3): δ 8.71 (s, 1H), 8.61 (d, J = 3.5 Hz, 1H),



7.88 (d, J = 3.0 Hz), 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 2.3 Hz,



1H), 7.56 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H),



7.36 (dd, J = 7.8, 4.8 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.21 (s, 2H),



4.52 (br. S, 1H), 4.43 (br. S, 1H), 4.32 (m, 1H), 4.16-4.29 (m,



2H), 4.03-4.16 (m, 1H), 3.76-3.95 (m, 2H), 3.20-3.30 (m, 1H),



2.57-2.36 (m, 4H).



MS m/z (M + H+) 498.0.


403
1-(1-{[4-(Pyridin-4-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 8.63 (d, J = 5.8 Hz, 2H), 7.88 (d, J = 3.0 Hz,



1H), 7.63 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 3.3 Hz, 1H),



7.36 (d, J = 6.1 Hz, 2H), 6.96 (d, J = 8.84 Hz, 2H), 5.14 (s, 2H),



4.52 (br. s, 1H), 4.43 (br. s, 1H), 4.36-4.29 (m, 1H), 4.16-4.29 (m,



2H), 4.04-4.16 (m, 1H), 3.75-3.93 (m, 2H), 3.18-3.28 (m, 1H),



2.37-2.58 (m, 4H).



MS m/z (M + H+) 464.0


404
1-[1-({3-Chloro-4-[(3,4-



dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H), 7.71 (d, J = 2.0 Hz,



1H), 7.51-7.58 (m, 3H), 7.47 (dd, J = 8.3, 4.0 Hz, 1H),



7.30 (dd, J = 8.1, 2.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.14 (s, 2H),



4.52 (br. s., 1H), 4.37 (br. s., 1H), 4.29-4.37 (m, 1H), 4.22 (br.



s., 2H), 4.01-4.14 (m, 1H), 3.88 (br. s., 2H), 3.19-3.32 (m, 1H),



2.40-2.55 (m, 4H)



MS m/z (M + H+) 564.6, 566.8


405
1-[1-({4-[(2,3-Dichlorobenzyl)oxy]-3-



fluorophenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 3.3 Hz,



1H), 7.50 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.43-7.46 (m,



1H), 7.40 (dd, J = 8.6, 1.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H),



7.25 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 8.3 Hz, 1H), 5.28 (s, 2H),



4.49 (d, J = 33.2 Hz, 2H), 4.31-4.39 (m, 1H), 4.22 (br. s., 2H),



4.03-4.16 (m, 1H), 3.88 (br. s., 2H), 3.19-3.31 (m, 1H),



2.40-2.58 (m, 4H).



MS m/z (M + H+) 549.0


406
1-(1-{[3-Chloro-4-(pyridin-2-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



1H NMR (CDCl3): δ 8.59 (d, J = 4.5 Hz, 1H), 7.76 (dd, J = 1.5,



7.6 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H),



7.50 (dd, J = 8.6, 2.0 Hz, 1H), 7.37-7.44 (m, 5H), 7.25 (dd, J = 6.9,



5.2 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.28-5.35 (m, 2H),



4.27-4.37 (m, 1H), 4.12-4.27 (m, 2H), 3.99-4.12 (m, 1H),



3.89 (br. s., 1H), 3.74 (br. s., 1H), 3.47 (br. s., 2H), 3.17-3.27 (m,



1H), 2.42 (br. s., 3H), 2.27 (br. s., 1H).


407
1-(1-{[3-Chloro-4-(pyridine-2-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3): δ 8.54 (br. s, 1H), 8.49 (br. s, 1H),



7.62-7.68 (m, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.29 (d, J = 9.1 Hz,



2H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 4.17-4.32 (m,



2H), 4.09-4.17 (m, 3H), 4.00-4.08 (m, 1H), 3.89 (br. s., 1H),



3.74 (br. s, 1H), 3.47 (br. s, 2H), 3.15-3.28 (m, 1H), 2.41 (br. s.,



3H), 2.17 (br. s, 1H)



MS m/z (M + H+) 498.0


408
1-(1-{[3-Chloro-4-(pyridin-4-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 491.2


409
1-(1-{[3-Chloro-4-(pyridin-3-



ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 491.2


481
1-[1-({4-[(4-Chlorobenzyl)oxy]-3-



fluorophenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 508.2


482
1-[1-({4-[(3,4-Dichlorobenzyl)oxy]-3-



fluorophenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 542.1


483
1-[1-({4-[(2,3-Dichlorobenzyl)oxy]-3-



fluorophenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 542.1


484
1-[1-({4-[(4-Chlorobenzyl)oxy]-3-



iodophenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 616.1


972
1-[1-({4-[(5-Chlorothiophen-2-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 496.0


560
2-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenoxy]methyl}quinoline



MS m/z (M + H+) 507.0


552
1-[1-({4-[(6-Bromopyridin-2-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 535.0


957
1-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 497.0


962
1-[1-({4-[(5-Chlorothiophen-2-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 503.0


967
2-{[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenoxy]methyl}quinoline



MS m/z (M + H+) 514.0


983
1-[1-({4-[(6-Bromopyridin-2-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 543.8


960
1-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-



4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 497.0


963
1-[1-({4-[(5-Chlorothiophen-2-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 503.0


970
2-{[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenoxy]methyl}quinoline



MS m/z (M + H+) 514.0


987
1-[1-({4-[(6-Bromopyridin-2-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 542.0









Example 27a




E. Methyl 4-((5-chloropyridin-3-yl)methoxy)benzoate, 27b. DIAD (2.35 mmol, 0.45 mL) was added to an ice-cold solution of methyl 4-hydroxybenzoate 29a (2.35 mmol, 358 mg), (5-chloropyridin-3-yl)methanol 27a (1.57 mmol, 225 mg), and Ph3P (2.35 mmol, 616 mg) in 8 mL of THF. The mixture was stirred at 0° C. for 1 h at room temperature overnight. Water was added and the crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford 300 mg (68%) of 27b.
F. 4-((5-Chloropyridin-3-yl)methoxy)benzoic acid, 27c. Compound 27b (1.22 mmol, 340 mg) was combined with LiOH (4.9 mmol, 118 mg) in 3 mL of THF, 3 mL of MeOH, and 3 mL of water. The mixture was stirred at room temperature for 4 h and was then combined with 15% aqueous citric acid and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2SO4, and concentrated under vacuum to give 288 mg of 27c.
Following the procedure described above for Example 1 or Example 27, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







554
1-[1-({4-[(5-Chloropyridin-3-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 491.0


978
1-[1-({4-[(5-Chloropyridin-3-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-



2-ylcarbonyl)piperazine



MS m/z (M + H+) 498.0


981
1-[1-({4-[(5-Chloropyridin-3-



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-



4-ylcarbonyl)piperazine



MS m/z (M + H+) 498.0









Example 27b
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:














Salt


Cpd
Cpd Name and Data
Form







958
1-[1-({4-[(3-
N-TFA



Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-




4-(trifluoroacetyl)piperazine




MS m/z (M + H+) 482.0



961
1-[1-({4-[(5-Chlorothiophen-2-
N-TFA



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-




(trifluoroacetyl)piperazine




MS m/z (M + H+) 488.0



968
2-{[4-({3-[4-(Trifluoroacetyl)piperazin-1-
N-TFA



yl]azetidin-1-




yl}carbonyl)phenoxy]methyl}quinoline




MS m/z (M + H+) 499.0



979
1-[1-({4-[(5-Chloropyridin-3-
N-TFA



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-




(trifluoroacetyl)piperazine



984
1-[1-({4-[(6-Bromopyridin-2-
N-TFA



yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-




(trifluoroacetyl)piperazine




MS m/z (M + H+) 535.0









Example 28




A. Methyl 4-(3-chlorobenzylsulfanyl)benzoate, 28b. The title compound 28c was prepared using the method described in Example 27, substituting compound 28a for compound 27a in Procedure A.
B. 4-(3-Chlorobenzylsulfanyl)benzoic acid, 28c. The title compound 28c was prepared using the method described in Example 27, substituting compound 28b for compound 27c in Procedure B.
C. 4-(3-Chlorobenzylsulfanyl)benzoyl chloride, 28d. The title compound 28d was prepared using the method described in Example 27, substituting compound 28c for compound 27d in Procedure C.
D. 1-[1-({4-[(3-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidi-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 410. The title compound 410 was prepared using the method described in Example 27, substituting compound 28d for compound 27e in Procedure D. 1H NMR (CDCl3): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s, 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H+) 506.0.
Following the procedure described above for Example 28 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







411
1-[1-({4-[(2,3-



Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.52 (d, J = 8.3 Hz, 2H), 7.38-7.43 (m,



5H), 7.29 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H), 7.2 (d, J = 7.4 Hz,



1H), 7.11 (q, J = 7.8 Hz, 1H), 4.24-4.38 (m, 4H),



4.22 (br. s., 1H), 4.12-4.21 (m, 1H), 4.02-4.12 (m, 1H), 3.91 (br. s.,



1H), 3.77 (br. s., 1H), 3.47 (s, 2H), 3.15-3.29 (m, 1H), 2.44 (br.



s., 4H).



MS m/z (M + H+) 540.0


412
1-[1-({4-[(3-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-



3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.49-7.57 (m,



3H), 7.25-7.30 (m, 3H), 7.18-7.25 (m, 3H), 4.51 (br. s., 2H),



4.21-4.34 (m, 2H), 4.03-4.21 (m, 4H), 3.72-3.94 (m, 2H),



3.18-3.29 (m, 1H), 2.35-2.59 (m, 4H).



MS m/z (M + H+) 513.0


413
1-[1-({4-[(2,3-



Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H), 7.50-7.57 (m,



3H), 7.38 (dd, J = 7.8, 1.5 Hz, 1H), 7.26-7.33 (m, 3H),



7.22 (dd, J = 7.7, 1.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.44 (br. d., J = 32.6 Hz,



2H), 4.22-4.35 (m, 4H), 4.15-4.22 (m, 1H),



4.04-4.15 (m, 1H), 3.85 (d, J = 17.4 Hz, 2H), 3.19-3.29 (m, 1H),



2.37-2.56 (m, 4H).



MS m/z (M + H+) 547.0.


414
1-[1-({4-[(3,4-



Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 3.3 Hz,



2H), 7.51-7.53 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.3 Hz,



1H), 7.24-7.29 (m, 3H), 7.13-7.17 (m, 1H),



4.48-4.59 (m, 1H), 4.35-4.48 (m, 1H), 4.20-4.34 (m, 2H), 4.13-4.20 (m,



1H), 4.01-4.13 (m, 4H), 3.79-3.94 (m, 2H), 3.19-3.29 (m, 1H),



2.37-2.57 (m, 4H).



MS m/z (M + H+) 547.0.


415
1-[1-({4-[(4-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-



3-yl]-4-(1,3-thiazol-2-ylcarboyl)piperazine



1H NMR (CDCl3): δ 7.87 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 3.3 Hz,



1H), 7.53 (d, J = 8.6 Hz, 2H), 7.27-7.29 (m, 2H),



7.24-7.27 (m, 4H), 4.51 (br. s., 1H), 4.35-4.47 (m, 1H), 4.20-4.33 (m,



2H), 4.02-4.20 (m, 4H), 3.76-3.93 (m, 2H), 3.18-3.28 (m, 1H),



2.38-2.54 (m, 4H).



MS m/z (M + H+) 513.0


416
1-[1-({4-[(Pyridin-3-



ylmethyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 8.55 (s, 1H), 8.48 (s, 1H), 7.82-7.93 (m,



1H), 7.65 (br. s., 1H), 7.47-7.60 (m, 3H), 7.18-7.36 (m, 3H),



4.44 (d, J = 33.9 Hz, 2H), 4.03-4.32 (m, 5H), 3.86 (br. s., 2H),



3.23 (br. s., 1H), 2.47 (br. s., 4H)


417
1-[1-({4-[(3,4-



Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 540.1


418
1-[1-({4-[(4-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-



3-yl]-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 506.2


555
1-(Phenylcarbonyl)-4-[1-({4-[(pyridin-3-



ylmethyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 473.0


550
1-(Phenylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 540.0


973
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 547.0


975
1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 531.8









Example 28a
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:














Salt


Cpd
Cpd Name and Data
Form







974
1-(Trifluoroacetyl)-4-{1-[(4-{[3-
N-TFA



(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]-




azetidin-3-yl}piperazine




MS m/z (M + H+) 532.0









Example 29




A. Methyl 4-(3-trifluoromethyl-phenoxy)-benzoate, 29c. To a solution of compound 29a (400 mg, 2.63 mmol) and compound 29b (1.0 g, 5.26 mmol) in CH2Cl2 (24 mL) was added Cu(OAc)2 (714 mg, 3.94 mmol), 4A sieves (400 mg, powder, activated), pyridine (2 mL), and Et3N (2 mL). The resultant reaction mixture was stirred at room temperature for 2 days. Water was added to the mixture, and the mixture was filtered. The filtrate was extracted with EtOAc (3×), the combined organic extracts dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 20% EtOAc/hexanes to give compound 29c (470 mg).
B. 4-(3-Trifluoromethyl-phenoxy)-benzoic acid (29d). A mixture of compound 29c (577 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue, compound 29d, was dried under reduced pressure for 18 h and was used without purification.
C. 4-(3-Trifluoromethyl-phenoxy)-benzoyl chloride, 29e. To a solution of compound 29d (100 mg, 0.35 mmol) in THF (2 mL) was added oxalyl dichloride (46 μL, 0.53 mmol) dropwise at 0° C., followed by addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, and was then warmed up to room temperature overnight. The solvents were removed under reduced pressure, and the residue, compound 29e, was dried under reduced pressure for 2 h and then used in the next step without further purification.
D. 1-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)phenoxy]phenyl}carbonyl)azetidin-3-yl]piperazine, Cpd 419. To a mixture of compound 2c (80 mg, 0.32 mmol), Et3N (0.5 mL), and CH2Cl2 (2.5 mL) was added a solution of compound 29e in CH2Cl2 (1 mL). The resultant mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the resultant residue was dissolved in CH2Cl2 (1 mL), directly loaded onto a silica gel column, and purified by silica gel flash column chromatography with 5% MeOH/CH2Cl2 to give compound 419 (53 mg). 1H NMR (CDCl3): δ 7.65 (d, J=8.6 Hz, 2H), 7.45-7.53 (m, 1H), 7.41 (br. s, 6H), 7.25-7.34 (m, 1H), 7.17-7.25 (m, 1H), 7.01 (d, J=7.3 Hz, 2H), 4.17-4.38 (m, 3H), 4.11 (br. s, 1H), 3.92 (br. s, 1H), 3.78 (br. s, 1H), 3.49 (br. s, 2H), 3.19-3.32 (m, 1H), 2.45 (br. s, 4H). MS m/z (M+H+) 510.0.
Following the procedure described above for Example 29 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







420
1-(1-{[4-(4-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.0 Hz, 1H), 7.64 (d, J = 8.6 Hz,



2H), 7.55 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H),



6.98 (d, J = 8.8 Hz, 4H), 4.52 (br. s., 1H), 4.38-4.48 (br. S, 1H),



4.15-4.37 (m, 3H), 4.10 (br. s., 1H), 3.88 (br. s., 1H), 3.82 (br.



s., 1H), 3.19-3.31 (m, 1H), 2.35-2.60 (m, 4H).



MS m/z (M + H+) 483.1


421
1-(1-{[4-(3-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.65 (tt, J1 = 2 Hz,



J2 = 8.8 Hz, 2H), 7.545 (d, J = 3.3 Hz, 1H), 7.26-7.30 (m, 1H),



7.14 (dt, J = 8.1, 1.0 Hz, 1H), 6.98-7.06 (m, 3H), 6.93-6.95 (m,



1H), 6.91-6.95 (m, 1H), 4.56 (br.s, 1H), 4.43 (br. s., 1H),



4.17-4.38 (m, 3H), 4.04-4.16 (m, 1H), 3.75-3.96 (m, 2H),



3.20-3.31 (m, 1H), 2.39-2.60 (m, 4H).



MS m/z (M + H+) 483.0


422
1-(1-{[4-(3,4-Dichlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-



4-(phenylcarbonyl)piperazine.



1H NMR (CDCl3): δ 7.65 (d, J = 8.6 Hz, 2H), 7.37-7.46 (m,



6H), 7.12 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.89 (dd,



J = 8.8, 2.8 Hz, 1H), 4.16-4.37 (m, 3H), 4.10 (br. s.,



1H), 3.92 (br. s., 1H), 3.68-3.84 (m, 1H), 3.46 (s, 2H), 3.19-3.30



(m, 1H), 2.44 (br. s., 4H).



MS m/z (M + H+) 510.0


423
1-(1-{[4-(3,4-Dichlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 8.8 Hz,



2H), 7.55 (d, J = 3.3 Hz, 1H), 7.42 (d J = 8.8 Hz, 1H),



7.13 (d, J = 2.8 Hz, 1H), 7.0 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 8.8,



2.8 Hz, 1H), 4.53 (br. s., 1H), 4.44 (br. S, 1H),



4.17-4.38 (m, 3H), 4.11 (dd, J = 9.0, 4.7 Hz, 1H), 3.88 (br. s.,



1H), 3.83 (br. s., 1H), 3.20-3.32 (m, 1H), 2.50 (t, J = 4.7 Hz, 4H).



MS m/z (M + H+) 517.0


424
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-



(trifluoromethyl)phenoxy]phenyl}carbonyl)azetidin-3-



yl]piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 8.6



Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H),



7.41 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.6



Hz, 2H), 4.53 (br. s., 1H), 4.44 (br. s, 1H), 4.17-4.38 (m, 3H),



4.16-4.05 (m, 1H), 3.86 (d, J = 19.2 Hz, 2H), 3.20-3.33 (m, 1H),



2.37-2.60 (m, 4H).



MS m/z (M + H+) 517.0


425
1-(1-{[4-(4-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 476.2


426
1-(1-{[4-(3-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 476.2


662
1-(1-{[4-(3-Chlorophenoxy)-3-fluorophenyl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 500.8









Example 29a
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:












Cpd
Cpd Name and Data
Salt Form







931
1-(1-{[4-(3-Chlorophenoxy)-3-
N-TFA



fluorophenyl]carbonyl}azetidin-3-yl)-4-




(trifluoroacetyl)piperazine




MS m/z (M + H+) 485.8









Example 30




A. Methyl 4-(3-chloro-phenylsulfanyl)-benzoate (30c). A mixture of compound 30a (400 mg, 1.86 mmol), compound 30b (321 mg, 2.23 mmol), Pd(PPh3)4 (215 mg, 0.186 mmol), KOtBu (2.23 mL, 2.23 mmol, 1M solution in THF), and THF (3.5 mL) were heated in a microwave reactor at 130° C. for 2 h, then poured into water (50 mL). The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 5% EtOAc/hexanes to give compound 30c (220 mg).
B. 4-(3-Chloro-phenylsulfanyl)benzoic acid (30d). A mixture of compound 30c (320 mg, 1.15 mmol), LiOH (110 mg, 4.59 mmol) in THF/MeOH/H2O (3/3/3 mL) was stirred for 4 h. A 15% aqueous citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, filtered, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue (compound 30d, 290 mg) was dried under reduced pressure for 18 h and was used without further purification.
C. 4-(1-{[4-(3-Chloro-phenylsulfanyl)phenyl]carbonyl}azetidin-3-yl)-1-(phenylcarbonyl)-piperazine, Cpd 427. A mixture of compound 30d (60 mg, 0.23 mmol), compound 2c (83 mg, 0.29 mmol), and HATU (129 mg, 0.34 mmol) in Et3N and DMF (1 mL/3 mL) was stirred for 18 h, and then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified on silica gel, eluting with 5% MeOH/CH2Cl2 to give compound 427 (33 mg). MS m/z (M+H+) 492.1.
Following the procedure described above for Example 30 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







428
1-[1-({4-[(3-Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-



3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 499.1


429
1-[1-({4-[(3-Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-



3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 499.1


430
1-(Phenylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 526.2


431
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 533.1


432
1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 533.1









Example 30a
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:














Salt


Cpd
Cpd Name and Data
Form







677
1-[1-({4-[(3-
N-TFA



Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-3-




yl]-4-(trifluoroacetyl)piperazine




MS m/z (M + H+) 483.8



790
1-(Trifluoroacetyl)-4-{1-[(4-{[3-
N-TFA



(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]-




azetidin-3-yl}piperazine




MS m/z (M + H+) 517.9









Example 31




A. 4-(3-Chloro-benzensulfonyl)-benzoic acid methyl ester (31a).
To a solution of compound 30c (200 mg, 0.72 mmol) in CH2Cl2 (5 mL) was added mCPBA (320 mg, 1.43 mmol) at 0° C. After 2 h, the mixture was poured into 2N KOH solution (20 mL) and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 5% EtOAc/hexanes to give compound 31a (138 mg).
B. 4-(3-Chloro-benzensulfonyl)-benzoic acid (31b). A mixture of compound 31a (138 mg, 0.44 mmol) and LiOH (42 mg, 1.77 mmol) in THF/MeOH/H2O (2/2/2 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue, compound 31b (130 mg) was dried under reduced pressure for 18 h and used without further purification.
C. 1-[1-({4-[(3-Chlorophenyl)sulfonyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 433. A mixture of compound 31b (40 mg, 0.14 mmol), compound 2c (49 mg, 0.18 mmol), and HATU (80 mg, 0.20 mmol) in Et3N (1 mL) and DMF (2 mL) was stirred for 18 h, and was then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 5% MeOH/CH2Cl2 to give compound 428 (29 mg). MS m/z (M+H+) 524.1.
Following the procedure described above for Example 31, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















508
1-(Phenylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 558.0


876
1-[1-({4-[(3-



Chlorophenyl)sulfonyl]phenyl}carbonyl)azetidin-3-yl]-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 530.8


651
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 564.8


1507
1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)benzyl]sulfonyl}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 578.8


738
1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 564.6









Example 31a
Following the procedure described above for Example 31 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 31 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







976
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-({[3-



(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin-



3-yl)piperazine



1H NMR (CDCl3): δ 7.80-7.97 (m, 4H), 7.63-7.73 (m, 1H),



7.56 (dd, J = 5.7, 2.4 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H),



4.34-4.60 (m, 3H), 4.20-4.33 (m, 2H), 4.03-4.20 (m, 2H),



3.86 (br. s., 2H), 3.15-3.32 (m, 1H), 2.37-2.60 (m, 4H),



MS m/z (M + H+) 578.8


564
1-(Phenylcarbonyl)-4-(1-{[4-({[3-



(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin-



3-yl)piperazine



MS m/z (M + H+) 572.0


971
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-



(trifluoromethyl)benzyl]sulfonyl}phenyl)carbonyl]azetidin-



3-yl}piperazine



1H NMR (CDCl3): δ 7.88 (d, J = 3.3 Hz, 1H), 7.65-7.77 (m,



4H), 7.52-7.65 (m, 2H), 7.35-7.52 (m, 2H), 7.24 (s, 1H),



4.39 (s, 4H), 4.17-4.33 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H),



3.86 (br. s., 2H), 3.19-3.34 (m, 1H), 2.38-2.59 (m, 4H).



MS m/z (M + H+) 578.8


977
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-({[3-



(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin-



3-yl)piperazine



MS m/z (M + H+) 578.6









Example 31b




D. 10-Oxidophenoxathiine-2-carboxylic acid, 31d. A mixture of phenoxathiine-2-carboxylic acid 31c (0.41 mmol, 100 mg) and sodium perborate tetrahydrate (0.82 mmol, 126 mg) in 3 mL of HOAc was stirred for 6 days at room temperature. TLC indicated 90% conversion to 31d. Water was added and the resulting precipitate was filtered and dried to give 65 mg of 31d, 90% pure.
Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







807
1-{1-[(10-Oxidophenoxathiin-2-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 495.1









Example 31c
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared:














Salt


Cpd
Cpd Name and Data
Form

















914
1-[1-({4-[(3-Chlorophenyl)sulfonyl]-
N-TFA



phenyl}carbonyl)azetidin-




3-yl]-4-(trifluoroacetyl)piperazine




MS m/z (M + H+) 516.8



1493
1-(Trifluoroacetyl)-4-{1-[(4-{[3-
N-TFA



(trifluoromethyl)phenyl]sulfonyl}-




phenyl)carbonyl]azetidin-3-




yl}piperazine




MS m/z (M + H+) 550.5



1498
1-(Trifluoroacetyl)-4-(1-{[4-({[3-
N-TFA



(trifluoromethyl)phenyl]sulfonyl}methyl)-




phenyl]carbonyl}azetidin-




3-yl)piperazine




MS m/z (M + H+) 563.8













tert-Butyl (3S)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-carboxylate, Cpd 434. To a solution of compound 26d (100 mg, 0.273 mmol) and (R)—N-Boc-3-hydroxyproline in THF was added DIAD at 0° C. The resulting reaction mixture was stirred for 18 h. After dilution with water and extraction with EtOAc (3×), the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel using 5% MeOH/CH2Cl2 to give compound 434 (95 mg). 1H NMR (CDCl3): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s, 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H+) 506.0.
Following the procedure described above for Example 32 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







435
1-(1-{[4-(Cyclohexyloxy)phenyl]carbonyl}azetidin-3-yl)-



4-(phenylcarbonyl)piperazine



1H NMR (CDCl3): δ 7.58 (d, J = 8.8 Hz, 2H),



7.36-7.44 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 4.26-4.38 (m, 2H),



4.25-4.12 (m, 2H), 4.07 (br. s, 1H), 3.82-3.99 (m, 1H), 3.48 (br.



s., 2H), 3.15-3.26 (m, 1H), 2.17-2.54 (m, 4H),



1.93-2.03 (m, 1H), 1.75-1.89 (m, 2H), 1.46-1.63 (m, 2H),



1.31-1.46 (m, 3H), 1.21-1.31 (m, 2H).



MS m/z (M + H+) 448.0


436
1-(1-{[4-(Cyclopentyloxy)phenyl]carbonyl}azetidin-3-yl)-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 434.2


437
tert-Butyl 4-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenoxy]piperidine-1-



carboxylate



MS m/z (M + H+) 549.3


438
tert-Butyl (3R)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-



carboxylate



MS m/z (M + H+) 535.3









Example 33




A. (3S)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine, 33a. To a solution of compound 434 (87.7 mg, 0.164 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give compound 33a, which was used without further purification.
B. (3S)—N,N-Dimethyl-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-sulfonamide, Cpd 439. A solution of compound 33a (0.164 mmol) and Et3N (0.5 mL) in CH2Cl2 (2 mL) was treated with N,N-dimethylsulfamoyl chloride (26 uL, 0.246 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the solvent was then removed under reduced pressure. The resultant residue was directly loaded onto a silica gel column and was purified by silica gel flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 439 (51.5 mg). 1H NMR (CDCl3): δ 7.61 (d, J=8.21 Hz, 2H), 7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s, 1H), 4.11-4.26 (m, 2H), 4.05 (br. s, 1H), 3.87-3.96 (m, 1H), 3.84 (m, 1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m, 4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s, 4H), 2.19-2.29 (m, 2H); MS m/z (M+H+) 542.0.
Following the procedure described above for Example 33 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







440
1-(Phenylcarbonyl)-4-{1-[(4-{[1-(phenylcarbonyl)piperidin-4-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 553.3


441
1-[1-({4-[(1-Acetylpiperidin-4-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 491.3


442
1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-



(phenylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 539.3


443
1-{1-[(4-{[(3R)-1-(Cyclohexylcarbonyl)pyrrolidin-3-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 545.3


444
1-(Phenylcarbonyl)-4-{1-[(4-{[(3R)-1-



(phenylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 539.3


445
1-{1-[(4-{[(3R)-1-(2,2-Dimethylpropanoyl)pyrrolidin-3-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 519.3


446
(3S)—N,N-Dimethyl-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-carboxamide



MS m/z (M + H+) 506.3


447
1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(pyrrolidin-1-



ylsulfonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 568.3


448
1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(pyrrolidin-1-



ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 532.3


449
4-({(3S)-3-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenoxy]pyrrolidin-1-yl}carbonyl)morpholine



MS m/z (M + H+) 548.3









Example 34




A. tert-Butyl 3-(2-iodo-4-methoxycarbonyl-phenoxy)-pyrrolidine-1-carboxylate, 34b. To a solution of compound 34a (500 mg, 1.8 mmol), compound 32a (504 mg, 2.7 mmol) and PPh3 (707 mg, 2.7 mmol) in THF (10 mL) was added DIAD (0.52 mL, 2.7 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h, then warmed up to room temperature and stirred for 18 h. The mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 50% EtOAc/hexanes to give compound 34b (704 mg).
B. Methyl 3-iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoate, 34d. To a solution of compound 34b (210 mg, 0.47 mmol) in CH2Cl2 (3 mL) was added TFA (1.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The resultant residue was dried under reduced pressure for 2 h. To the residue was added CH2Cl2 (3 mL) and Et3N (1 mL), followed by the addition of compound 34c (77 μL, 0.7 mmol). The resulting mixture was stirred for 2 h, then poured into water (50 mL) and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 80% EtOAc/hexanes to give compound 34d (180 mg).
C. 3-Iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoic acid, 34e. A mixture of compound 34d (180 mg, 0.41 mmol), LiOH (39 mg, 1.62 mmol), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for 4 h. The mixture was acidified with 15% aqueous citric acid and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was dried under reduced pressure for 2 h to give compound 34e (166 mg).
D. 3-Iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoyl chloride, 34f. To a solution of compound 34e (166 mg, 0.39 mmol) in THF (4 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, warmed to room temperature, and stirred for 18 h. The solvents were removed under reduced pressure. The resultant residue, compound 34f, was dried under reduced pressure for 2 h and used in the following step without further purification.
E. 1-{1-[(3-Iodo-4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 450. To a mixture of compound 2c (61 mg, 0.25 mmol), Et3N (0.5 mL), and CH2Cl2 (2.5 mL) was added a solution of compound 34f in CH2Cl2 (1 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (1 mL), directly loaded onto a silica gel column, and purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 451 (56 mg). 1H NMR (CDCl3): δ 8.06 (d, J=2.3 Hz, 1H), 7.60 (dd, J=8.5, 2.1 Hz, 1H), 7.34-7.48 (m, 5H), 6.80 (d, J=8.6 Hz, 1H), 5.01 (br. s, 1H), 3.66-4.36 (m, 8H), 3.28-3.64 (m, 8H), 3.12-3.27 (m, 1H), 2.05-2.56 (m, 6H), 1.55-1.97 (m, 4H).
Following the procedure described above for Example 34 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







451
(3S)-3-[2-Iodo-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenoxy]-N,N-dimethylpyrrolidine-



1-carboxamide



MS m/z (M + H+) 632.2


452
1-{1-[(3-Iodo-4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-



3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 665.2









Example 35




A. Methyl 4-[(3-Chlorophenoxy)methyl]benzoate, 35c. To a mixture of compound 35a (300 mg, 1.31 mmol) and K2CO3 (400 mg, 2.88 mmol) in DMF (1 mL) was added compound 35b (251 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 6 h. The mixture was poured into water (50 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over NaSO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash column chromatography, eluting with 20% EtOAc/hexanes to yield compound 35c (340 mg).
B. 4-[(3-Chlorophenoxy)methyl]benzoic acid, 35d. A mixture of compound 35c (340 mg, 1.18 mmol) and LiOH (114 mg, 4.74 mmol) in THF/MeOH/H2O (3/3/3 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue, compound 35d (230 mg) was dried under reduced pressure for 18 h and used without further purification.
C. 1-[1-({4-[(3-Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 453. A mixture of compound 35d (77 mg, 0.29 mmol), compound 5e (108 mg, 0.38 mmol) and HATU (165 mg, 0.44 mmol) in Et3N (1 mL) and DMF (3 mL) was stirred for 18 h, and then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2, to give compound 453 (67 mg). MS m/z (M+H+) 497.1. 1H NMR (CD3OD): δ 7.95 (d, J=2.0 Hz, 1H), 7.8 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.90-6.98 (m, 2H), 5.15 (s, 2H), 4.32-4.45 (m, 2H), 4.15-4.25 (m, 2H), 4.00-4.10 (m, 1H), 3.70-3.82 (br. s, 2H), 2.47 (br. s, 4H).
Following the procedure described above for Example 35 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







454
1-{1-[(4-{[(3-



Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-3-



yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 513.1


455
3-Chloro-N-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 496.1


548
1-[1-({4-[(3-



Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 490.0


959
1-[1-({4-[(3-



Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 497.0









Example 35a
Following the procedure described above for Example 35 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 35 or Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







551
1-{1-[(4-{[(3-



Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-



3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 506.0


549
3-Chloro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 489.0


956
1-{1-[(4-{[(3-



Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-



3-yl}-4-(1,3-thiazol-4-ylcarbonyl) piperazine



MS m/z (M + H+) 513.0


969
3-Chloro-N-[4-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 496.0









Example 35b
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:














Salt


Cpd
Cpd Name and Data
Form







955
1-{1-[(4-{[(3-
N-TFA



Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-



3-yl}-4-(trifluoroacetyl)piperazine



MS m/z (M + H+) 498.0


964
3-Chloro-N-[4-({3-[4-(trifluoroacetyl)piperazin-1-
N-TFA



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 481.0









Example 36




1-(Phenylcarbonyl)-4-{1-[(2-pyrrolidin-3-ylphenyl)carbonyl]azetidin-3-yl}piperazine, Cpd 456. To a solution of compound III (300 mg, 0.58 mmol) in 1,4-dioxane (10 mL) was added 6N HCl (3 mL). After stirring for 4 h, the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and 3N NaOH, and the organic phase was isolated and dried over MgSO4. The mixture was filtered, the filtrate concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give compound 456 (52.3 mg). LC/MS m/z (M+H+) 419.36 (calculated for C25H30N4O4, 418.54).
Example 37




A. tert-Butyl 4-[1-(diphenylmethyl)azetidin-3-yl]-3-(hydroxymethyl)piperazine-1-carboxylate, 37b. Compound 37a (811 mg, 3.21 mmol) was added in one portion to a stirring suspension of anhydrous K2CO3 (1.07 g, 7.9 mmol) in MeOH (4 mL). The mixture was stirred for 1.5 h at room temperature, and the MeOH was then removed under reduced pressure to near-dryness. The resulting white slurry was triturated with CH2Cl2 (40 mL) and filtered through a medium-porosity glass fritted funnel. The solids were washed with additional CH2Cl2 and the combined filtrates were concentrated and dried under reduced pressure to give compound 37a (733 mg) as a white solid, the free base of the HCl salt of 37a.
The material was suspended in CH3CN (8 mL) with compound 1e (1.07 g, 3.37 mmol). Diisopropylethylamine (1.23 mL, 7.06 mmol) was added and the mixture was heated at 60° C. for 14 h. EtOAc (100 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue (1.42 g) as a pale orange foam. The material was purified by medium pressure liquid chromatography (MPLC) using an ISCO CombiFlash system (silica gel, 10-50% EtOAc/hexanes) to give compound 37b (979 mg) as a white foam. 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J=8.1 Hz, 4H), 7.23-7.33 (m, 4H), 7.14-7.23 (m, 2H), 4.34 (s, 1H), 3.28-3.58 (m, 8H), 2.76-2.95 (m, 2H), 2.26-2.75 (m, 4H), 2.20 (dt, J=12.3, 4.9 Hz, 1H), 1.44 (s, 9H); LCMS m/z (M+H+) 438.5, (M+Na+) 460.5.
B. {1-[1-(Diphenylmethyl)azetidin-3-yl]-piperazin-2-yl}methanol, 37c. Compound 37b (450 mg, 1.03 mmol) was dissolved in CH2Cl2 (6 mL) and TFA (3 mL) and was stirred at 20° C. for 2.5 h. The reaction mixture was concentrated to dryness under reduced pressure to give the TFA salt of compound 37c as an orange foam. Compound 37c was used in the following step without further purification. MS m/z (M+H+) 338.2.
C. {1-[1-(Diphenylmethyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazin-2-yl}methanol, 37e. Compound 37c (1.03 mmol) was dissolved in CH2Cl2 (5 mL) and cooled in an ice water bath to 0° C. A 10% aqueous Na2CO3 solution (5 mL) was added and a solution of compound 37d (143 μL, 1.23 mmol) dissolved in CH2Cl2 (1 mL) was added dropwise. The resultant mixture was allowed to warm to 20° C. and then stirred rapidly for 62 h. CH2Cl2 (10 mL) was added to the reaction mixture and the aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 37e (465 mg) as an off white foam. Compound 37e was used in the following step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.39 (m, 9H), 7.22-7.32 (m, 4H), 7.14-7.23 (m, 2H), 4.35 (s, 1H), 4.07 (br. s, 1H), 3.30-3.71 (complex, 8H), 2.2-3.0 (complex, 6H); LCMS m/z (M+H+) 442.2.
D. [1-Azetidin-3-yl-4-(phenylcarbonyl)piperazin-2-yl]methanol, 37f. Compound 37e (450 mg, 1.02 mmol) was added to a 500 mL-Parr hydrogenation bottle and dissolved in absolute EtOH (6 mL). A 12N conc. HCl solution (95 μL, 1.14 mmol) was added and the bottle was purged with N2. 10% Pd/C (264 mg) was added and the mixture was shaken under 60 psi of H2 for 14 h. An additional amount of 10% Pd/C (430 mg) was added and the mixture was returned to 60 psi of H2 and shaken 5 h more. The mixture was filtered through a pad of diatomaceous earth, and the solids were rinsed thoroughly with MeOH. The fitrate was concentrated to dryness under reduced pressure to afford crude compound 37f as a sticky oil (428 mg) which was used in the following step without further purification. LC/MS m/z (M+H+) 276.3.
E. [1-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazin-2-yl]methanol, Cpd 457. Compound 3a (142 mg, 0.67 mmol) and HATU (256 mg, 0.67 mmol) were suspended in CH2Cl2 (1 mL) and DMF (0.2 mL). Et3N (195 μL, 1.4 mmol) was added and the solution was stirred for 15 min at 20° C. Crude compound 37f (214 mg, approximately 0.56 mmol) was dissolved in 1:1 CH2Cl2/DMF (3 mL) and was added in portions to the solution of compound 3a and the mixture was stirred for 64 h. The organic solution was diluted with EtOAc (50 mL), and washed sequentially with water (3×10 mL), and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a yellow oil (310 mg). The crude oil was purified by MPLC (4 g Silicycle SiO2 cartridge, 15-80% acetone/hexanes) to give compound 457 as a white foam (104 mg). 1H NMR (400 MHz, CDCl3) δ: 7.53 (d, J=7.8 Hz, 2H), 7.42 (br. s, 5H), 7.11-7.37 (m, 7H), 4.26 (m, 5H), 4.00 (s, 2H), 3.71-3.89 (m, 1H), 3.54-3.71 (m, 3H), 3.25-3.54 (m, 3H), 2.92 (br. s, 1H), 2.64 (br. s, 1H), 2.41 (br. s, 1H); LCMS m/z (M+H+) 470.5.
Following the procedure described above for Example 37 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







458
{1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazin-2-yl}methanol



1H NMR (400 MHz, CDCl3): δ 7.65-7.73 (m, 2H), 7.61 (dd,



J = 11.6, 8.1 Hz, 4H), 7.33-7.50 (m, 10H), 3.96-4.49 (m, 5H),



3.76-3.91 (m, 1H), 3.63 (m, 3H), 3.32-3.53 (m, 1H), 2.95 (br.



s., 1H), 2.64 (br. s., 1H), 2.45 (br. s., 1H)



LCMS m/z (M + H+) 456.5


459
[4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-1-



(phenylcarbonyl)piperazin-2-yl]methanol



1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.1 Hz, 2H),



7.35-7.46 (m, 5H), 7.10-7.34 (m, 7H), 4.82 (br. s., 1H), 4.01 (s,



2H), 3.72-4.40 (m, 5H), 3.52 (br. s., 1H), 3.16 (br. s., 1H),



2.54-3.04 (m, 2H), 1.93-2.30 (m, 4H)



LCMS m/z (M + H+) 470.5


460
{4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-



(phenylcarbonyl)piperazin-2-yl}methanol



1H NMR (400 MHz, CDCl3): δ 7.67-7.75 (d, J = 8.3 Hz, 2H),



7.55-7.67 (m, 4H), 7.34-7.52 (m, 8H), 3.39-4.96 (m, 9H),



3.20 (quin, 1H), 2.51-3.05 (m, 3H), 2.22 (br. s., 1H), 2.04 (br. s.,



1H)



LCMS m/z (M + H+) 456.5









Example 38




4,4,4-Trifluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]butanamide, Cpd 497. A mixture of Cpd 495 (65 mg, prepared according to Example 9), 4,4,4-trifluorobutanoic acid (30 mg), HATU (116 mg), and TEA (0.12 mL) in DCM 1.5 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and water. The normal work-up followed by chromatography gave Cpd 497 (71 mg). MS m/z (M+H+) 489.5.
Following the procedure described above for Example 38 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







498
2-Phenyl-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenyl]acetamide



MS m/z (M + H+) 483.6


499
N-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]cyclohexanecarboxamide



MS m/z (M + H+) 475.6


500
2-Ethyl-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)phenyl]butanamide



MS m/z (M + H+) 463.6+


501
N-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)phenyl]benzamide



MSm/z (M + H+) 469.2









Example 39




A. N-(Naphthalen-2-ylmethyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline, Cpd 495. Cpd 496 was dissolved in CH2Cl2 and TFA and was stirred at 20° C. The reaction mixture was concentrated to dryness under reduced pressure to give Cpd 495, which was used in the following step without further purification. MS m/z (M+H+) 365.
B. N-(Naphthalen-2-ylmethyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline, Cpd 491. A mixture of Cpd 495 (100 mg, 0.27 mmol), compound 39a (75 mg, 0.48 mmol) and AcOH (0.5 mL) in 1,2 dichloroethane (3 mL) was stirred for 1 h, then NaBH(OAc)3 (136 mg, 0.64 mmol) was added. The resulting mixture was stirred overnight, then was poured into 2N aqueous KOH solution (20 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give 33.2 mg of Cpd 491. 1H NMR (400 MHz, CDCl3): δ 7.75-7.85 (m, 4H), 7.43-7.53 (m, 5H), 7.35-7.42 (m, 5H), 6.61 (d, J=8.8 Hz, 2H), 4.64 (br. s, 1H), 4.51 (s, 2H), 4.27 (br. s, 1H), 4.08-4.35 (m, 3H), 4.02 (s, 1H), 3.89 (s, 1H), 3.71 (br. s, 1H), 3.34-3.55 (m, 2H), 3.10-3.22 (m, 1H), 2.13-2.49 (m, 3H); MS m/z (M+H+) 505.3.
Following the procedure described above for Example 39 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







492
N-(2-Chlorobenzyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS (m/z) (M + H+) 489.2


493
N-(3,4-Dichlorobenzyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS (m/z) (M + H+) 523.2


494
N-[4-Fluoro-3-(trifluoromethyl)benzyl]-4-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline



MS (m/z) (M + H+) 541.2









Example 40




1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[(1RS,2RS)-2-{4-[(trifluoromethyl)sulfanyl)phenyl}cyclopropyl]carbonyl}azetidin-3-yl)piperazine, Cpd 645 (racemic, trans). Trimethylsulfoxonium iodide 40a (1.15 mmol, 253 mg) and sodium hydride (60% dispersion in mineral oil, 1.1 mmol, 44 mg) were combined in 3 mL of dry DMSO and stirred 20 min at room temperature. Cpd 648, prepared in Example 5, was added and the mixture was stirred 15 min at room temperature, then heated at 50° C. overnight. After cooling, the mixture was partitioned between EtOAc and water, The organic layer was separated and concentrated to give crude product that was purified by preparative reverse-phase chromatography to afford 9.1 mg (2%) of Cpd 645 as the mono-TFA salt. MS m/z (M+H+) 497.2.
Following the procedure described above for Example 40, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compound of the present invention was prepared:











Cpd
Cpd Name and Data







642
1-(1-{[(1RS,2RS)-2-(2-



Chlorophenyl)cyclopropyl]carbonyl}azetidin-3-yl)-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 431.1









Example 41
Intentionally Left Blank
Example 42




A. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b. Argon was bubbled through a mixture of methyl 4-bromobenzoate 42a (9.3 mmol, 2.0 g), 2 mL of THF, and 4-trifluoromethylbenzylzinc chloride (0.5 M in THF, 46.5 mmol, 93 mL) for 5 min. Pd(dffp)Cl2.CH2Cl2(0.5 mol, 409 mg) was added and the reaction tube was capped and heated at 70° C. for 16 h. The mixture was cooled and filtered through Celite. Water was added to the filtrate and the resulting solid was filtered off. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (silica gel, 0-10% EtOAc in heptane) to give 1.5 g (55%) of methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.
B. 4-(4-(Trifluoromethyl)benzyl)benzoic acid, 42c. Following the procedure described in Example 91, Step P, methyl 4-(4-(trifluoromethyl)benzyl)benzoate 42b (1.5 g, 5.1 mmol) was converted to methyl 1.31 g (92%) of 4-(4-(trifluoromethyl)benzyl)benzoic acid, 42c. MS m/z (M+H+) 279.1.
Following the procedure described above for Example 42 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Intermediate compounds were optionally prepared by an alternative procedure:




C. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b. A mixture of 4-bromomethyl-benzoic acid methyl ester 42d (1.0 g, 4.37 mmol), 4-trifluorophenyl boronic acid 42e (0.995 g, 5.24 mmol), and Pd(PPh3)4 (50 mg, 0.044 mmol) in dioxane (15 mL) was stirred at room temperature for 1 min. Next, 4 mL of 2 M aqueous Na2CO3 solution was added. The resulting solution was heated at 90° C. for 5 h and was then cooled to rt. EtOAc and water were added to the reaction mixture. The organics were concentrated and purified by flash chromatography (silica gel, 5% EtOAc/hexanes) to give methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.
Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







 96
1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-({4-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)piperazine



1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H); 8.44 (s, 1H);



8.0-7.8 (m, 2H); 7.76-7.63 (m, 2H); 7.5 (d, 1H);



7.44-7.32 (m, 3H); 4.9-4.7 (m, 3H); 4.3-4.2 (m, 2H); 4.19-4.04 (m,



3H)



MS m/z (M + H+) 515.1


 97
1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)piperazine



1H NMR (400 MHz, CDCl3): δ 8.12 (m, 2H); 7.68 (m, 2H);



7.5 (m, 2H); 7.4 (m, 4H); 4.85 (bs, 2H); 4.47-4.26 (bm, 3H);



3.52 (bs, 4H); 3.02 (bs, 2H).



MS m/z (M + H+) 495.1


006
1-({4-Fluoro-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)-4-[1-(1,3-thiazol-



2-ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 533.1


016
1-({2-Methyl-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)-4-[1-(1,3-thiazol-



5-ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 529.2









Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















563
1-[1-({4-Fluoro-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-



4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 526.1


1007
1-[1-({4-Fluoro-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H); 7.78 (s,



1H); 7.50 (m, 5H); 7.82 (m, 2H); 7.12 (t, 1H); 4.69 (bm,



2H); 4.48 (bm, 2H); 4.32 (bm, 2H); 4.0 (s, bm, 5H);



3.5 (bm, s 2H)



MS m/z (M + H+) 533.1


1008
1-[1-({2-Methyl-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 529.2


1009
1-[1-({2-Methyl-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-



4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 529.2


1013
1-[1-({2-Methyl-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-



4-(1H-pyrrol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 511.2


1014
1-(Isothiazol-5-ylcarbonyl)-4-[1-({2-methyl-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 529.2


1015
1-[1-({2-Methyl-3-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-



4-(1,3-thiazol-5-ylcarbonyl)piperazine



MS m/z (M + H+) 529.2


995
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z 515 (M + H+)


985
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 515


998
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 515


999
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 515


771
1-(Phenylcarbonyl)-4-[1-({4-[4-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 508


547
1-(Phenylcarbonyl)-4-[1-({4-[3-



(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 508









Example 43




A. Methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate, 43c. A solution of 4-fluorobenzoyl chloride 43b (2 mmol, 0.24 mL) in 8 mL of DCE was added dropwise to an ice-cold solution of methyl 1H-indole-6-carboxylate 43a (1.43 mmol, 250 mg) and diethylaluminum chloride (1 M in hexanes, 1.86 mmol, 1.86 mL) in 8 mL of DCE. After 2 h at 0° C., the mixture was warmed to room temperature and was stirred overnight. To the mixture was added pH 7 buffer; the resulting solid was filtered and washed with CH2Cl2 to give 162 mg (38%) of methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate 43c. MS m/z (M+H+) 298.0.
B. 3-(4-Fluorobenzoyl)-1H-indole-6-carboxylic acid, 43d. Following the procedure described in Example 91, Step P, 110 mg (72%) of 3-(4-fluorobenzoyl)-1H-indole-6-carboxylic acid was obtained.
Following the procedure described above for Example 43 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1025
(4-Fluorophenyl)[6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indol-3-yl]methanone



MS m/z (M + H+) 518.2


802
((4,4-Difluorocyclohexyl)[6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indol-3-yl]methanone



MS m/z (M + H+) 542.1


949
(6-Chloropyridin-3-yl)[6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indol-3-yl]methanone



MS m/z (M + H+) 535.0


950
Pyridin-3-yl[6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-



1-yl]azetidin-1-yl}carbonyl)-1H-indol-3-yl]methanone



MS m/z (M + H+) 501.0









Example 44




A. Methyl 4-(pyridin-2-yloxy)-benzoate, 44b. A mixture of 29a (433 mg, 2.85 mmol), 44a (300 mg, 1.90 mmol), Cu(biPy)2BF4 (88 mg, 0.19 mmol), K3PO4 (805 mg, 3.80 mmol), and DMF (1.5 mL) was heated at 140° C. for 1 h. After 0.5 h, the mixture was poured into water (60 mL) and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give 298 mg of 44b.
B. 4-(Pyridin-2-yloxy)-benzoic acid, 44c. A mixture of 44b (430 mg, 1.87 mmol), LiOH (180 mg, 7.5 mmol), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for 4 h. Then the reaction mixture was acidified with 15% citric acid (10 mL). The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 44c (350 mg).
C. 1-(1-{[4-(Pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 913. A mixture of 44c (60 mg, 0.28 mmol), 5e (105 mg, 0.36 mmol), HATU (159 mg, 0.42 mmol), Et3N (1 mL), and DMF (3 mL) was stirred at room temperature overnight, and then poured into water (10 mL). The mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 7% MeOH/CH2Cl2) to give 98 mg of Cpd 913. MS m/z (M+H+) 450.0.
Following the procedure described above for Example 44, Steps A and B, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 44, Step C, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data
















527
1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-3-



yloxy)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 443.0


507
1-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 545.0


533
1-[1-({4-[(5-Methoxypyridin-3-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 497.0


1484
1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-2-



yloxy)phenyl]carbonyl}azetidin-3-yl)piperazine



MS m/z (M + H+) 443.0


875
1-(1-{[4-(3-Chlorophenoxy)-3-



fluorophenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 500.8


663
1-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 551.8


734
1-(1-{[4-(Pyridin-3-yloxy)phenyl]carbonyl}azetidin-3-yl)-



4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 450.0


904
1-[1-({4-[(5-Methoxypyridin-3-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 480.0


532
1-[1-({4-[(5-Bromopyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 522.8


537
1-(1-{[3-Fluoro-4-(pyridin-2-



yloxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 461.0


520
1-[1-({4-[(5-Chloropyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 477.0


525
1-(1-{[3-Chloro-4-(pyridin-2-



yloxy)phenyl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 477.0


522
1-[1-({4-[(6-Fluoropyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 504.0


518
1-(Phenylcarbonyl)-4-{1-[(4-{[4-(trifluoromethyl)pyridin-



2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 511.0


877
1-[1-({4-[(5-Bromopyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 529.8


765
1-[1-({4-[(5-Bromopyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 529.8


909
1-(1-{[3-Fluoro-4-(pyridin-2-



yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 468.0


717
1-[1-({4-[(5-Chloropyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 484.0


752
1-(1-{[3-Chloro-4-(pyridin-2-



yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 484.0


715
1-[1-({4-[(6-Fluoropyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 468.0


652
1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[4-



(trifluoromethyl)pyridin-2-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine



MS m/z (M + H+) 518.0









Example 44a
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:












Cpd
Cpd Name and Data
Salt Form







837
1-(Trifluoroacetyl)-4-{1-[(4-{[4-
N-TFA



(trifluoromethyl)pyridin-2-



yl]oxy}phenyl)carbonyl]azetidin-3-



yl}piperazine



MS m/z (M + H+) 503.0


869
1-(1-{[4-(Pyridin-2-
N-TFA



yloxy)phenyl]carbonyl}azetidin-3-yl)-4-



(trifluoroacetyl)piperazine



MS m/z (M + H+) 435.0


872
1-[1-({4-[(5-Bromopyridin-2-
N-TFA



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-



(trifluoroacetyl)piperazine



MS m/z (M + H+) 512.8


802
1-{1-[(4-{[3-Chloro-5-
N-TFA



(trifluoromethyl)pyridin-2-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-



(trifluoroacetyl)piperazine



MS m/z (M + H+) 536.8









Example 44b
Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data







922
1-(1-{[4-(Pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 450.0


757
1-[1-({4-[(5-Chloropyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 484.0


784
1-[1-({4-[(6-Fluoropyridin-2-



yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 468.0


769
1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[4-



(trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-



3-yl}piperazine



MS m/z (M + H+) 518.0


720
1-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2-



yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 551.8









Example 45




A. Methyl 6-(3-chloro-phenoxy)-nicotinate, 5c. A mixture of 45a (200 mg, 0.926 mmol), 45b (178 mg, 1.39 mmol), Cu(biPy)2BF4 (43 mg, 0.09 mmol), K3PO4 (392 mg, 1.85 mmol), and DMF (1.0 mL) was heated at 140° C. for 1 h. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give 202 mg of 45c.
B. 6-(3-Chloro-phenoxy)-nicotinic acid, 5d. A mixture of 45c (202 mg, 0.766 mmol), LiOH (74 mg, 3.06 mmol), THF (2 mL), MeOH (2 mL) and H2O (2 mL) was stirred at room temperature for 4 h. The reaction mixture was acidified with 15% citric acid (10 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, and concentrated to give 177 mg of 45d.
C. 1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine, Cpd 519. A mixture of 45d (60 mg, 0.24 mmol), 2c (101 mg, 0.36 mmol), HATU (137 mg, 0.36 mmol), Et3N (0.5 mL), and DMF (3 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (silica gel, 5% MeOH/CH2Cl2) to give 50 mg of Cpd 519. 1H NMR (CDCl3): δ 8.35-8.49 (m, 1H), 8.06 (dd, J=8.5, 2.1 Hz, 1H), 7.32-7.49 (m, 6H), 7.14-7.27 (m, 2H), 6.94-7.11 (m, 2H), 4.24 (br. s, 1H), 4.15 (br. s, 2H), 4.00-4.14 (m, 2H), 3.65-3.94 (m, 2H), 3.37-3.60 (m, 2H), 3.16-3.33 (m, 1H), 2.44 (br. s, 4H). MS m/z (M+H+) 477.0.
Following the procedure described above for Example 45, Steps A and B, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 45, Step C, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data







514
1-(Phenylcarbonyl)-4-[1-({6-[3-



(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 511.0


521
1-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-



3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 477.0


683
1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 484.0


660
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({6-[3-



(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 518.0


708
1-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 484.0


878
1-[1-({6-[2-Fluoro-5-(trifluoromethyl)phenoxy]pyridin-3-



yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 536.0









Example 45a
Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data







803
1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 504.0


689
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({6-[3-



(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 518.0


811
1-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-



3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 484.0









Example 46




A. 1-(4-Chloro-phenyl)-2-methyl-pent-1-en-3-one, 46b. To 4-chlorobenzaldehyde 46a (99.6 mmol, 14 g) in water (44 mL) was added KOH (44.6 mmol, 2.5 g). The mixture was heated at 65° C. and 3-pentanone (99.6 mmol, 8.58 g) was added dropwise over 10 min. After refluxing for 8 h, the reaction mixture was cooled to room temperature and stirred overnight. Following addition of 260 mL 1N aqueous HCl, the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/heptane) to give 8.59 g of 46b.
B. Ethyl 6-(4-chloro-phenyl)-3,5-dimethyl-2,4-dioxo-hex-5-enoate, 46c. To a solution of LiHMDS (1N solution in THF, 5.48 mmol, 5.17 mL) in THF (16 mL) at −78° C. was added a solution of 46b (4.98 mmol, 1.04 g) in THF (2.5 mL) drop wise. After stirring at −78° C. for 1 h, the mixture was treated with a solution of diethyl oxalate (4.98 mmol, 0.73 g) in THF (2.5 mL). After stirring at −78° C. for 1 h, then the mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the crude product was taken up in EtOAc, and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give 1.5 g of 46c.
C. 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylate, 46e. A mixture of 46c (15.6 mmol, 4.82 g), 2,4-dichlorophenylhydrazine 46d (17.2 mmol, 3.67 g), K2CO3 (17.2 mmol, 2.37 g) and EtOH (137 mL) was stirred at 70° C. overnight. The solid was filtered off and washed with EtOH. The filtrates were concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/heptane) to give 2.25 g of 46e.
D. 5-[2-(4-Chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, 46f. The mixture of 46e (3.34 mmol, 1.5 g), LiOH (13.3 mmol, 319 mg), THF (7 mL), MeOH (7 mL), and H2O (37 mL) was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl to pH=5 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give 46f (202 mg).
E. 5-[2-(4-Chlorophenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, Cpd 1010. To a solution of 46f (0.138 mmol, 60 mg) in CH2Cl2 and THF was added SOCl2 (2 N solution in THF, 0.414 mmol, 0.212 mL). After refluxing for 4 h, the mixture was concentrated and dried under vacuum for 1 h. In another flask was added 5e (0.18 mmol, 52 mg), CH2Cl2 (3 mL), and DIPEA (0.69 mmol, 0.12 mL). To this solution was added the crude product from the SOCl2 reaction dissolved in CH2Cl2 (1 mL). After stirring at room temperature for 1 h, the mixture was diluted with CH2Cl2 (15 mL), washed with 3N NaOH aqueous solution (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (silica gel, 4% MeOH/CH2Cl2) to give 74 mg of Cpd 1010. 1H NMR (CDCl3): δ 7.87 (d, J=3.5 Hz, 1H), 7.55 (t, J=2.3 Hz, 2H), 7.33-7.36 (m, 2H), 7.30 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 4.49-4.62 (m, 2H), 4.41 (dd, J=10.4, 5.3 Hz, 2H), 4.22 (dd, J=10.0, 7.2 Hz, 1H), 4.04-4.10 (m, 1H), 3.87 (br. s, 1H), 3.82 (br. s, 1H), 3.18-3.26 (m, 1H), 2.41-2.58 (m, 4H), 2.39 (s, 3H), 1.88 (s, 3H). MS m/z (M+H+) 657.0.
Following the procedure described above for Example 46, Steps A-D or B-D, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 46, Step E, or Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data







1011
1-[1-({5-[(E)-2-(4-Chlorophenyl)-1-methylethenyl]-1-(2,4-



dichlorophenyl)-4-methyl-1H-pyrazol-3-



yl}carbonyl)azetidin-3-yl]-4-(1H-pyrrol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 639.2


1018
(7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-



dichlorophenyl)-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-



tetrahydro-1H-indazole



MS m/z (M + H+) 669.0


1019
(7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-



dichlorophenyl)-3-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-



tetrahydro-1H-indazole



MS m/z (M + H+) 651.2


1021
(7Z)-1-(2,4-Dichlorophenyl)-7-[(4-



fluorophenyl)methylidene]-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7-



tetrahydrothiino[4,3-c]pyrazole



MS m/z (M + H+) 671.0


1024
(7Z)-1-(2,4-Dichlorophenyl)-7-[(4-



fluorophenyl)methylidene]-3-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7-



tetrahydrothiino[4,3-c]pyrazole



MS m/z (M + H+) 651.2


1267
1-(2,4-Dichlorophenyl)-3-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-



tetrahydro-1H-indazole



MS m/z (M + H+) 645.2


1309
1-(2,4-Dichlorophenyl)-3-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-



tetrahydro-1H-indazole



MS m/z (M + H+) 627.2


1023
(7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-



dichlorophenyl)-3-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-



tetrahydro-1H-indazole



MS m/z (M + H+) 669.1


1304
1-(2,4-Dichlorophenyl)-3-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-



tetrahydro-1H-indazole



MS m/z (M + H+) 545.2









Example 46a
Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:














Salt


Cpd
Cpd Name and Data
Form







1012
1-[1-({5-[(E)-2-(4-Chlorophenyl)-1-
N-TFA



methylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-



1H-pyrazol-3-yl}carbonyl)azetidin-3-yl]-4-



(trifluoroacetyl)piperazine



MS m/z (M + H+) 642.9


1020
(7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-
N-TFA



dichlorophenyl)-3-({3-[4-



(trifluoroacetyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole



MS m/z (M + H+) 654.0


1022
(7Z)-1-(2,4-Dichlorophenyl)-7-[(4-
N-TFA



fluorophenyl)methylidene]-3-({3-[4-



(trifluoroacetyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-1,4,6,7-tetrahydrothiino[4,3-



c]pyrazole



MS m/z (M + H+) 654.1


1311
1-(2,4-Dichlorophenyl)-3-({3-[4-
N-TFA



(trifluoroacetyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole



MS m/z (M + H+) 530.2









Example 47




4-(((2-fluorophenyl)amino)methyl)benzoic acid, 47c. A mixture of 4-formylbenzoic acid 47a (3.33 mmol, 500 mg), 2-fluoroaniline 47b (3.33 mmol, 370 mg), and decaborane (1 mmol, 122 mg) in 8 mL of MeOH was stirred at room temperature for 15 min. The mixture was concentrated and purified by preparative reverse-phase chromatography to afford 0.81 g (99%) of 47c.
Following the procedure described above for Example 47, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 1 or Example 9, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data
















553
2-Fluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 473.1


529
N-Benzyl-2-chloro-5-methoxy-4-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



MS m/z (M + H+) 520.2


530
N-(4,4-Difluorocyclohexyl)-4-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)aniline



MS m/z (M + H+) 483.2


561
2-Fluoro-N-[3-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 473.1


556
2,6-Difluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 491.0


542
N-Benzyl-2-iodo-4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)aniline



MS m/z (M + H+) 581.0


557
2,3,4-Trifluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 509.2


1005
2-Fluoro-N-[3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)benzyl]aniline



MS m/z (M + H+) 480.3









Example 48




4-(Cyclohexanecarboxamido)benzoic acid, 48d. A mixture of 4-aminobenzoic acid 48a (1.98 mmol, 300 mg), cyclohexanecarbonyl chloride 48b (1.98 mmol, 291 mg), and Et3N (2.52 mmol, 0.43 mL) in 6 mL of THF was stirred at room temperature overnight. 1N aqueous NaOH (7.9 mmol, 7.9 mL) was added to the mixture (containing methyl 4-(cyclohexanecarboxamido)benzoate 48c) and the reaction mixture was stirred for 5 h at room temperature. The THF was removed by rotary evaporation and 1N aqueous HCl was added to precipitate the product, which was filtered to give 480 mg (92%) of 48d.
Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared.











Cpd
Cpd Name and Data







709
N-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)phenyl]cyclohexanecarboxamide



MS m/z (M + H+) 482.1









Example 49




2-(4,4-Difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylic acid, 49d. A mixture of ethyl 2-bromo-benzo[d]thiazole-6-carboxylate 49a (1.75 mmol, 500 mg), 4,4-difluoropiperidine 49b (1.92 mmol, 303 mg), and Cs2CO3 (5.24 mmol, 1.71 g) in 15 mL of CH3CN was refluxed overnight. The suspension was cooled to room temperature and 15 mL of water was added to the mixture (containing ethyl 2-(4,4-difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylate 49c). The reaction mixture was heated at 60° C. for 18 h. After cooling, the mixture was acidified using 3N aqueous HCl and the resulting precipitate was filtered to give 575 mg (99%) of 49d. MS m/z (M+H+) 299.1.
Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared.











Cpd
Cpd Name and Data







671
2-(4,4-Difluoropiperidin-1-yl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



benzothiazole



MS m/z (M + H+) 533.2









Example 50




3-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1365. To a solution of Cpd 487 (0.2 mmol, 100 mg) in CCl4 (4 mL) and CH2Cl2 (4 mL) was added NCS (0.25 mmol, 33 mg). The reaction mixture was stirred at room temperature for 4 h. It was then diluted with CH2Cl2 and washed with 1N aqueous NaOH and H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave 51 mg of Cpd 1365. MS m/z (M+H+) 524.
Example 51




A. 1-(3-cyano-4-fluoro-phenyl)-indole-5-carboxylic acid, 51a and 1-(3-carbamoyl-4-fluoro-phenyl)-indole-5-carboxylic acid, 51b. Intermediates 51a and 51b were prepared according to Example 9e, and were obtained as a  ̃1:1 mixture.
B. 2-Fluoro-5-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile, Cpd 1417 and 2-fluoro-5-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide, Cpd 1418. Cpd 1417 and Cpd 1418 were prepared according to Example 9 from 5a bis HCl salt (0.22 mmol, 72 mg), the  ̃1:1 mixture of 51a and 51b (0.19 mmol, 54 mg), HATU (0.22 mmol, 85 mg), and Et3N (1.11 mmol, 0.15 mL) in 4 mL of CH2Cl2. After workup, purification by flash column chromatography (silica gel, 3-4% MeOH/CH2Cl2) gave 28 mg (59%) of Cpd 1417 followed by 15 mg (31%) of Cpd 1418. Cpd 1417: MS m/z (M+H+) 515. Cpd 1418: MS m/z (M+H+) 533.
Example 52




A. Methyl 5-Phenyl-benzo[b]thiophene-2-carboxylate, 52b. A mixture of compound 52a (542.3 mg, 2 mmol), phenyl boronic acid 1x (268.2 mg, 2.2 mmol), Pd(dppf)Cl2.CH2Cl2 (98 mg, 0.12 mmol), and K2CO3 (414.6 mg, 3 mmol), in a dioxane (4 mL)/water (1 mL) mixture, was placed in a capped vial and heated at 80° C. overnight. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2-10% EtOAc/heptane) to give compound 52b (510 mg). MS m/z (M+H+) 269.1.
B. 5-Phenyl-benzo[b]thiophene-2-carboxylic acid, 52c. A solution of compound 52b (510 mg, 1.9 mmol) and LiOH.H2O (319 mg, 7.6 mmol) in THF/H2O (10/10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ̃4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 52c (479 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 255.0.
C. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carboxylic acid, 52d. To a solution of compound 52c (507 mg, 1.99 mmol) in THF (8 mL) at −70° C. was added n-BuLi (1.6 M in hexane, 2.62 mL, 4.19 mmol). The mixture was stirred at −70° C. for 1 h; then a solution of N-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in THF (2 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was partitioned between dilute aqueous HCl and EtOAc. The organic solution was washed with water and brine, dried over Na2SO4, and concentrated. The residue was tritrated from CH2Cl2, filtered and dried the solid to give compound 52d (391.9 mg). MS m/z (M+H+) 273.0.
D. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carbonyl chloride, 52e. To a solution of compound 52d (136.2 mg, 0.5 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 52e (light pink powder), which was used in the next reaction without further purification.
E. 1-{1-[(3-Fluoro-5-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 1315. To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et3N (0.07 mL, 0.5 mmol) in CH2Cl2 (2 mL) at 0° C. was slowly added a solution of compound 52e (36.3 mg, 0.125 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 1315 (16.7 mg). 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J=1.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.80-7.86 (m, 1H), 7.73 (dd, J=8.6, 1.7 Hz, 1H), 7.62-7.68 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46-7.53 (m, 2H), 7.37-7.44 (m, 1H), 4.22-4.67 (m, 5H), 4.05-4.20 (m, 1H), 3.77-4.01 (m, 2H), 3.25-3.37 (m, 1H), 2.42-2.68 (m, 4H). MS m/z (M+H+) 507.0.
Following the procedure described above for Example 52, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1092
1-[1-({3-Fluoro-5-[4-(trifluoromethyl)phenyl]-1-



benzothiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 575.1.


1063
1-[1-({3-Fluoro-6-[4-(trifluoromethyl)phenyl]-1-



benzothiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 575.1.









Example 53







A. 1-tert-Butyl 6-methyl 3-(4-fluorophenyl)-1H-indole-1,6-dicarboxylate, 53c. A mixture of compound 53a (1.00 g, 2.49 mmol), 4-fluorophenyl boronic acid 53b (523 mg, 3.74 mmol), Pd(OAc)2 (44.8 mg, 0.2 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 204.7 mg, 0.5 mmol), and K3PO4 (1.06 g, 4.99 mmol), in toluene (5 mL) was placed in a capped vial and heated at 90° C. under N2 for 3 h. The reaction mixture was then diluted with EtOAc and water. The organic layer was washed with brine, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, 2-10% EtOAc/heptane) to give compound 53c as a light yellow solid, which was further recrystallized from heptane to obtain white solid (707 mg). MS m/z (M+H+) 370.2.
B. Methyl 3-(4-fluorophenyl)-1H-indole-6-carboxylate, 53d. To a solution of compound 53c (705 mg, 1.91 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to give compound 53d (603.3 mg) as a white solid. MS m/z (M+H+) 270.1.
C. 3-(4-Fluoro-phenyl)-1H-indole-6-carboxylic acid, 53e. A solution of compound 53d (303 mg, 0.79 mmol), and LiOH.H2O (132.7 mg, 3.16 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ̃4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 53e (249 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 256.0.
D. 3-(4-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1317. To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 53e (30.6 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1317 (45.4 mg). 1H NMR (400 MHz, CDCl3): δ 8.56 (br. s, 1H), 7.83-7.94 (m, 3H), 7.57-7.65 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.40-7.45 (m, 1H), 7.13-7.20 (m, 2H), 4.07-4.66 (m, 6H), 3.76-4.01 (m, 2H), 3.21-3.36 (m, 1H), 2.38-2.64 (m, 4H). MS m/z (M+H+) 490.2.
Following the procedure described above for Example 53, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 53, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1316
3-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 472.2.


1319
3-(3-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 490.2.









Example 53a




E. Methyl 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylate, 53f. To a solution of compound 53d (300 mg, 0.78 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then CH3I (0.053 mL, 0.86 mmol) was added and stirring continued at 0° C. for another 1 h. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and dried the solid to give compound 53f (265 mg) as a light yellow solid. MS m/z (M+H+) 284.1.
F. 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylic acid, 53g. To a solution compound 53f (264 mg, 0.93 mmol), and LiOH.H2O (156.4 mg, 3.73 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ̃4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 53g (252 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 270.1.
Following the procedure described above for Example 53a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 53 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1318
3-(4-Fluorophenyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 2.9 Hz, 1H),



7.79-7.87 (m, 2H), 7.51-7.63 (m, 3H), 7.39 (d, J = 8.3 Hz,



1H), 7.31 (s, 1H), 7.15 (t, J = 8.7 Hz, 2H), 4.21-4.67 (m, 5H),



4.08-4.21 (m, 1H), 3.89 (s, 3H), 3.77-3.98 (m, 2H),



3.19-3.35 (m, 1H), 2.36-2.65 (m, 4H)



MS m/z (M + H+) 504.1


1142
3-(3-Fluorophenyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 504.1









Example 54




A. Ethyl 1-Methyl-3-phenyl-1H-indazole-5-carboxylate, 54b. A mixture of compound 54a (300 mg, 0.91 mmol), phenyl boronic acid 1x (133 mg, 1.09 mmol), Pd(dppf)Cl2.CH2Cl2 (40 mg, 0.055 mmol), and K2CO3 (251.2 mg, 1.82 mmol), in a toluene (2 mL)/water (0.4 mL) mixture, was placed in a capped vial and heated at 90° C. overnight. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2-10% EtOAc/Heptanes) to give compound 54b (231 mg). MS m/z (M+H+) 281.1.
B. 1-Methyl-3-phenyl-1H-indazole-5-carboxylic acid, 54c. A solution compound 54b (230 mg, 0.58 mmol), and LiOH.H2O (98 mg, 2.33 mmol) in THF/H2O (10/10 mL) was stirred at 45° C. for 8 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ̃4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 54c (206 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 253.1.
C. 1-Methyl-3-phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole, Cpd 1137. To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 54c (30.3 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1137 (48.1 mg). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.88 (d, J=3.2 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 7.49-7.58 (m, 3H), 7.39-7.48 (m, 2H), 4.16 (s, 3H), 4.09-4.62 (m, 6H), 3.86 (m, 2H), 3.21-3.33 (m, 1H), 2.39-2.63 (m, 4H). MS m/z (M+H+) 487.2.
Following the procedure described above for Example 54 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 54 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1170
3-(3-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



MS m/z (M + H+) 505.2


1195
3-(4-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



MS m/z (M + H+) 505.2


1130
4-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)quinazoline



MS m/z (M + H+) 485


1086
7-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-4-[4-(trifluoromethyl)phenyl]quinazoline



MS m/z (M + H+) 553


604
4-Phenyl-7-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)quinazoline



MS m/z (M + H+) 478


597
7-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-4-[4-(trifluoromethyl)phenyl]quinazoline



MS m/z (M + H+) 546









Example 55







A. Methyl 2,3-dihydro-1H-indole-5-carboxylate, 55a. To a solution of methyl 1H-indole-5-carboxylate 1j (2 g, 11.4 mmol) in glacial acetic acid (15 mL) at 0° C. was added sodium cyanoborohydride (1.08 g, 17.2 mmol) slowly. The mixture was allowed to warm up and stirred at room temperature for 2 h. Water was added to the resulting mixture at 0° C., and pH of the solution was adjusted to  ̃12 with 1N aqueous NaOH. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give compound 55a (1.79 g). MS m/z (M+H+) 178.1.
B. Methyl 1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylate, 55b, and 1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylic acid, 55c. A mixture of compound 55a (500 mg, 2.82 mmol), 1-bromo-4-fluoro-benzene 1k (0.31 mL, 2.82 mmol), Pd2(dba)3 (129 mg, 0.14 mmol), BINAP (132 mg, 0.21 mmol), and sodium t-butoxide (325 mg, 3.39 mmol) in toluene (25 mL) was placed in a capped vial and heated at 80° C. overnight. The reaction mixture was then diluted with EtOAc and water, and the water layer was basified to pH ̃8 with 1N aqueous NaOH. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 5-30% EtOAc/heptane) to give compound 55b (145 mg), MS m/z (M+H+) 272.1, and compound 55c (232 mg), MS m/z (M+H+) 258.0.
C. 1-(4-Fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylic acid, 55d. A solution of compound 55b (144 mg, 0.53 mmol) and LiOH.H2O (89.1 mg, 2.12 mmol) in THF/H2O (5 mL/5 mL) was stirred at 45° C. overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ̃4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55d (138 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 258.0.
D. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole, Cpd 885. To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 55d (30.9 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with H2O, aqueous NaHCO3 and brine, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give compound Cpd 885 (44.4 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.25 (m, 2H), 7.03-7.12 (m, 2H), 6.88 (d, J=8.3 Hz, 1H), 4.05-4.67 (m, 6H), 3.99 (t, J=8.6 Hz, 2H), 3.76-3.94 (m, 2H), 3.20-3.30 (m, 1H), 3.16 (t, J=8.6 Hz, 2H), 2.37-2.64 (m, 4H); MS m/z (M+H+) 492.1.
Following the procedure described above for Example 55 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 55 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















884
1-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-



dihydro-1H-indole



MS m/z (M + H+) 492.1


1081
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-



dihydro-1H-indole



MS m/z (M + H+) 492.1


1099
1-(4-Fluorophenyl)-5-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-



dihydro-1H-indole



MS m/z (M + H+) 474.1









Example 55a




E. Methyl 1-benzyl-2,3-dihydro-1H-indole-5-carboxylate, 55e. A solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (88.6 mg, 0.42 mmol), and benzaldehyde 23a (0.060 mL, 0.55 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the mixture and stirring was continued for 2 h. Water was added to the resulting mixture at 0° C., and pH of the solution was adjusted to  ̃8 with 1N aqueous NaOH. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (silica gel, 10-25% EtOAc/Heptanes) to give 55e (81.3 mg). MS m/z (M+H+) 268.0.
F. 1-Benzyl-2,3-dihydro-1H-indole-5-carboxylic acid, 55f. A solution of compound 55e (80.2 mg, 0.3 mmol), and LiOH.H2O (50.4 mg, 1.2 mmol) in THF/H2O (1.2/1.2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH  ̃4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55f (60 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 254.1.
G. 1-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole, Cpd 994. To a solution of compound 5e (89.5 mg, 0.261 mmol), compound 55f (60 mg, 0.237 mmol), and EDC (68.1 mg, 0.356 mmol) in CH2Cl2 (5 mL) was added Et3N (0.1 mL, 0.711 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O and the water layer was acidified to pH  ̃6 with 1 N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography to give Cpd 994 as a TFA salt (40.4 mg). 1H NMR (400 MHz, CD3OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.36-7.44 (m, 2H), 7.29-7.36 (m, 4H), 7.22-7.29 (m, 1H), 6.52 (d, J=8.3 Hz, 1H), 4.39-4.91 (m, 6H), 4.38 (s, 2H), 3.99-4.23 (m, 3H), 3.48 (t, J=8.6 Hz, 2H), 3.42 (br. s, 4H), 3.01 (t, J=8.6 Hz, 2H). MS m/z (M+H+) 488.1.
Following the procedure described above for Example 55a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 55a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







881
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[3-(trifluoromethyl)benzyl]-2,3-dihydro-



1H-indole



MS m/z (M + H+) 556.0


882
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)benzyl]-2,3-dihydro-



1H-indole



MS m/z (M + H+) 556.0









Example 55b




H. 1-Benzoyl-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester, 55g. To a solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (64.1 mg, 0.3 mmol), and benzoyl chloride 1t (0.042 mL, 0.36 mmol) in CH2Cl2 (1 mL) was added Et3N (0.13 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was partitioned between CH2Cl2 and H2O. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-20% EtOAc/Heptanes) gave 55g (88 mg). MS m/z (M+H+) 282.0.
I. 1-Benzoyl-2,3-dihydro-1H-indole-5-carboxylic acid, 55h. A solution of compound 55g (87 mg, 0.31 mmol), and LiOH.H2O (52 mg, 1.24 mmol) in THF/H2O (2/2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH  ̃6 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55h (82 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 268.0.
J. 1-(Phenylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole, Cpd 724. To a solution of compound 5e (115.9 mg, 0.34 mmol), compound 55h (82 mg, 0.31 mmol) and EDC (87.9 mg, 0.46 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O and the water layer was acidified to pH  ̃6 with 1 N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 724 (64.4 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.31-7.63 (m, 9H), 4.38-4.63 (m, 2H), 4.03-4.37 (m, 6H), 3.74-3.96 (m, 2H), 3.20-3.29 (m, 1H), 3.16 (t, J=8.3 Hz, 2H), 2.38-2.61 (m, 4H). MS m/z (M+H+) 502.0.
Following the procedure described above for Example 55b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 55b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared:











Cpd
Cpd Name and Data







773
1-(Cyclopropylcarbonyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-



dihydro-1H-indole



MS m/z (M + H+) 466.0









Example 56




A. Methyl 3-Benzyl-1-methyl-1H-indole-6-carboxylate, 56c. To a solution of compound 56a (500 mg, 2.64 mmol) and benzyl chloride 56b (0.33 mL, 2.91 mmol) in dioxane (5 mL) was added silver oxide (673.6 mg, 2.91 mmol). The mixture was stirred at 80° C. overnight. The resulted mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography (silica gel, 20-60% CH2Cl2/Heptanes) to give compound 56c (168 mg). MS m/z (M+H+) 280.2.
B. 3-Benzyl-1-methyl-1H-indole-6-carboxylic acid, 56d. To a solution compound 56c (168 mg, 0.60 mmol), and LiOH.H2O (101 mg, 2.41 mmol) in THF/H2O (3/3 mL) was stirred at room temperature for 6 h. Concentrated the resulted mixture, extracted the residue with CH2Cl2, H2O, acidified the water layer with 1N HCl(aq) to pH ̃4. The organic solution was dried over Na2SO4 and concentrated to give 56d (172.2 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 266.2.
C. 3-Benzyl-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 753. To a mixture of compound 5e (71.6 mg, 0.22 mmol), compound 56d (53.1 mg, 0.2 mmol), and Et3N (0.14 mL, 1.0 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (106.5 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) gave compound Cpd 753 (20.8 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=2.4 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.15-7.35 (m, 6H), 6.89 (s, 1H), 4.06-4.60 (m, 8H), 3.79-3.98 (m, 2H), 3.78 (s, 3H), 3.17-3.31 (m, 1H), 2.35-2.64 (m, 4H). MS m/z (M+H+) 500.3.
Following the procedure described above for Example 56 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 56 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1026
3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 518.1


1027
3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 518.1


1028
3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1H-pyrrol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 500.1


1033
3-(3-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



m/z (M + H+) 518.2









Example 57




5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3,3-tris[3-(trifluoromethyl)benzyl]-1,3-dihydro-2H-indol-2-one, Cpd 1430. To a solution of Cpd 918 from Example 9) (25 mg, 0.061 mmol) and K2CO3 (16.9 mg, 0.122 mmol) in DMF (0.8 mL) was added 3-trifluoromethyl-benzyl bromide (20.4 mg, 0.085 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc and H2O. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography to give Cpd 1430 as a TFA salt (3.6 mg), MS m/z (M+H+) 885.9.
Following the procedure described above for Example 57 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1431
1,3,3-Tribenzyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



dihydro-2H-indol-2-one



MS m/z (M + H+) 682.0


992
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-3,3-bis[3-(trifluoromethyl)benzyl]-1,3-



dihydro-2H-indol-2-one



MS m/z (M + H+) 728.0









Example 58




5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 911, and 1-(2,3-Dihydro-1H-indol-5-ylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 988. To a solution of compound 5e (300 mg, 0.92 mmol), a mixture of 2,3-dihydro-1H-indole-5-carboxylic acid HCl salt 58a (101 mg, 0.51 mmol) and 1H-indole-5-carboxylic acid HCl salt 58b (100 mg, 0.51 mmol), and EDC (265 mg, 1.38 mmol) in CH2Cl2 (10 mL) was added Et3N (0.39 mL, 2.77 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was extracted with CH2Cl2 and washed with H2O. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography to give Cpd 911 as a TFA salt (89.4 mg) and Cpd 988 as a TFA salt (13.8 mg).
Cpd 911: 1H NMR (400 MHz, CD3OD): δ 10.93 (br. s, 1H), 7.98 (d, J=3.2 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.47 (s, 2H), 7.36 (d, J=3.2 Hz, 1H), 6.57 (d, J=2.9 Hz, 1H), 4.25-4.84 (m, 6H), 3.91-4.15 (m, 4H), 2.80 (br. s, 4H). MS m/z (M+H+) 396.0. Cpd 988: 1H NMR (400 MHz, CD3OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.85 (d, J=1.0 Hz, 1H), 7.58 (s, 1H), 7.27-7.56 (m, 5H), 6.56 (d, J=3.2 Hz, 1H), 4.29-4.89 (m, 6H), 4.20 (t, J=8.3 Hz, 2H), 3.96-4.15 (m, 3H), 3.32-3.43 (m, 4H), 3.17 (t, J=8.3 Hz, 2H). MS m/z (M+H+) 541.0.
Example 59




A. 3-Methyl-[1,1′-biphenyl]-4-carboxylic acid, 59b. The title compound 59b was prepared using the method described in Example 6, Step F, substituting 4-bromo-2-methylbenzoic acid 59a for Cpd 173 and substituting phenylboronic acid 1x for compound 6e. The crude product 59b was purified by reverse phase chromatography. MS m/z (M+H+) 213.1.
B. 1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 619. The title compound Cpd 619 was prepared using the method described in Example 9, substituting compound 59b for compound 9c and substituting compound 2c for compound 5e. The crude compound Cpd 619 was purified by reverse phase chromatography. MS m/z (M+H+) 440.1.
Following the procedure described above for Example 59 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:







Following the procedure described above for Example 59 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















613
1-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 440.2


614
1-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 444.1


615
1-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 456.1


612
1-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 460.2


706
1-(1-{[4-(2,2,6,6-Tetramethyl-3,6-dihydro-2H-pyran-4-



yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 495.3


1074
1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.33-7.66 (m, 8H), 4.62-4.76 (m, 2H), 4.38-4.51 (m, 1H),



4.13-4.35 (m, 3H), 3.84-4.07 (m, 3H), 3.02-3.19 (m, 4H),



2.47 (s, 1H)



MS m/z (M + H+) 447.1


1322
1-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.98 (d, 1H), 7.88 (d, 1H),



7.59 (s, 1H), 7.54 (dd, 1H), 7.27-7.49 (m, 6H), 4.61-4.78 (m,



3H), 4.39-4.61 (m, 2H), 4.33 (M, 1H), 3.88-4.11 (m, 3H),



3.10-3.26 (m, 4H), 2.30 (s, 3H)



MS m/z (M + H+) 447.1


1405
1-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.36-7.73 (m, 8H), 4.23-4.76 (m, 6H), 3.85-4.07 (m, 3H),



3.04-3.20 (m, 4H)



MS m/z (M + H+) 451.2


1377
1-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 463.2


1323
1-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 467.1


1406
1-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 447.1


1108
1-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 9.06 (s, 1H), 8.22 (d, 1H),



7.38-7.71 (m, 8H), 4.28-4.53 (m, 4H), 3.94-4.25 (m, 5H),



3.16-3.27 (m, 4H)



MS m/z (M + H+) 451.1


1253
1-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 463.2


1221
1-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 467.1


1185
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[2′-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 501.0


1278
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4′-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 501.0


1250
1-{1-[(4′-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 563.0


1091
1-{1-[(4′-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 463.0


1093
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 501.0


1124
1-{1-[(3′-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1117
1-{1-[(2′,4′-Difluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.87 (d, 1H),



7.80 (d, 1H), 7.66-7.75 (m, 2H), 7.50-7.64 (m, 2H),



7.05-7.16 (d, 1H), 4.24-4.75 (m, 6H), 3.83-4.06 (m, 3H),



3.02-3.18 (m, 4H)



MS m/z (M + H+) 469.0


1188
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3′-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 501.0


1228
1-{1-[(3′-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1239
1-{1-[(2′,4′-Difluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 469.0


1172
1-{1-[(2-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1200
1-{1-[(4-Chlorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 467.0


1168
1-{1-[(6-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 463.0


1234
1-{1-[(2-Methylbiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 447.0


1240
1-{1-[(2-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1288
1-{1-[(4-Chlorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 467.0


1265
1-{1-[(6-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 463.0


1285
1-{1-[(2-Methylbiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-



(1,3-thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 447.0


1208
1-{1-[(4-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1280
1-{1-[(4-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1144
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[5-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (300 MHz, CD3OD): δ 8.12 (s, 1H), 8.07 (s, 1H),



7.96 (d, 1H), 7.92 (s, 1H), 7.86 (d, 1H), 7.67-7.74 (m, 2H),



7.42-7.57 (m, 3H), 4.57-4.74 (m, 3H), 4.38-4.55 (m, 2H),



4.33 (m, 1H), 3.91-4.02 (m, 2H), 3.85 (m, 1H), 3.01-3.13 (m,



4H)



MS m/z (M + H+) 501.0


1104
1-{1-[(5-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-2-ylcarbonyl)piperazine



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.88 (d, 1H),



7.64-7.74 (m, 3H), 7.56-7.63 (dt, 1H), 7.35-7.53 (m, 4H),



4.31-4.83 (m, 6H), 3.94-4.10 (m, 3H), 3.19-3.27 (m, 4H)



MS m/z (M + H+) 451.0


1259
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[5-



(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-



yl)piperazine



MS m/z (M + H+) 501.0


1273
1-{1-[(5-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-



thiazol-4-ylcarbonyl)piperazine



MS m/z (M + H+) 451.0


1114
1-(Isothiazol-5-ylcarbonyl)-4-(1-{[2-methyl-3′-



(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-



yl)piperazine



1H NMR (400 MHz, CDCl3): δ 8.56 (d, 1H); 7.92 (d, 1H);



7.78-7.56 (m, 5H); 7.46 (m, 1H); 4.45 (m, 1H);



4.41-4.19 (m, 3H); 3.94 (bs, 5H); 3.12 (bs, 4H); 2.5 (s, 3H)



MS m/z (M + H+) 515.2


1138
1-(1H-Pyrrol-2-ylcarbonyl)-4-[1-({4-[5-



(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 489


1268
1-(1,3-Thiazol-5-ylcarbonyl)-4-[1-({4-[5-



(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 507.1









Example 59a
Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1212
1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-



4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 515.12


1136
1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-({4-[5-



(trifluoromethyl)thiophen-2-



yl]phenyl}carbonyl)piperazine



MS m/z (M + H+) 507.05


1260
1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-



4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine



MS m/z (M + H+) 515.2


1161
1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[5-



(trifluoromethyl)thiophen-2-



yl]phenyl}carbonyl)piperazine



MS m/z (M + H+) 507.1


1162
1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[5-



(trifluoromethyl)thiophen-2-



yl]phenyl}carbonyl)piperazine



MS m/z (M + H+) 489.2









Example 60







A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 60c. A mixture of methyl 4-fluoro-3-nitrobenzoate 60a (1 g, 5.02 mmol), 4-fluoroaniline 60b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL, 6.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water was added to the mixture; the resulting solid was filtered, washed with water, and dried. The crude product 60c was used in the next reaction without purification.
B. Methyl 3-amino-4-((4-fluorophenyl)amino)benzoate, 60d. A mixture of 60c (1.4 g, 4.8 mmol) and SnCl2.2H2O (4.9 g, 21.7 mmol) in EtOH (50 mL) was stirred at 80° C. After 4 h, the mixture was cooled to room temperature and was slowly added to saturated aqueous NaHCO3. The solid was filtered and washed with H2O. The solid was triturated with EtOAc and the filtrate was concentrated. The crude product 60d was used in the next reaction without purification. MS m/z (M+H+) 261.1.
C. Methyl 1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60e. A mixture of 60d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled to room temperature. Water was added to the mixture. The resulting solid was filtered, washed, with water, and dried. The crude product 60e was used in the next reaction without purification. MS m/z (M+H+) 271.1.
D. 1-(4-Fluorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid, 60f. To a solution of 60e (0.18 g, 0.666 mmol) in EtOH (10 mL) was added 1N aqueous NaOH (2.5 mL, 2.5 mmol). The mixture was stirred at room temperature for 4 d. The solvent was evaporated and 1N aqueous HCl was added, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product 60f was purified by preparative reverse phase chromatography. MS m/z (M+H+) 257.1.
E. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole, Cpd 1167. To a solution of 5e (0.058 g, 0.178 mmol) and HATU (0.081 g, 0.214 mmol) in CH2Cl2 (3 mL) was added Et3N (0.099 mL, 0.713 mmol). The mixture was stirred at room temperature for 30 min, and then 60f (0.050 g, 0.196 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (6 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product Cpd 1167 was purified by preparative reverse phase chromatography. MS m/z (M+H+) 491.2.
Following the procedure described above for Example 60 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 60 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.













1186
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 509.2


1064
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-



benzimidazole



1H NMR (300 MHz, CD3OD): d 8.82 (s, 1H), 8.14 (s, 1H),



7.96-8.03 (m, 3H), 7.86-7.95 (m, 3H), 7.76-7.85 (m, 2H),



7.08 (d, 1H), 4.36-4.86 (m, 6H), 3.97-4.16 (m, 3H),



3.32-3.42 (m, 4H)



MS m/z (M + H+) 541.2


761
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole



MS m/z (M + H+) 479.1


780
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole



MS m/z (M + H+) 493.2


759
1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 515.2


1281
1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 473.2


1274
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 491.2


1270
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 509.1


1231
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-



benzimidazole



MS m/z (M + H+) 541.2


841
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole



MS m/z (M + H+) 479.1


851
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole



MS m/z (M + H+) 493.2


834
1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 515.2


1207
1-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 473









Example 60a




F. Methyl 2-methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60g. The title compound 60g was prepared using the method described in Example 60, substituting trimethyl orthoacetate for trimethyl orthoformate in Step C. The crude product 60g was used in the next reaction without purification. MS m/z (M+H+) 285.1.
G. 2-Methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60h. The title compound 60h was prepared using the method described in Example 60, substituting 60g for 60e in Step D. The crude product 60h was used in the next reaction without purification. MS m/z (M+H+) 271.2.
H. Cpd 1227. The title compound Cpd 1227 was prepared using the method described in Example 60, substituting 60h for 60f in Step E. The crude product Cpd 1227 was purified by preparative reverse phase chromatography. MS m/z (M+H+) 505.2.
Following the procedure described above for Example 60a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 60a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data
















1229
2-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 487.2


1206
1-(3,4-Difluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 523.2


1215
2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-



1H-benzimidazole



MS m/z (M + H+) 555.2


789
2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-



benzimidazole



MS m/z (M + H+) 493.2


777
2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-



benzimidazole



MS m/z (M + H+) 507.2


798
1-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[4-(1,3-thiazol-



2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 529.2


1291
1-(4-Fluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 505.2


1296
2-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 487.2


1264
1-(3,4-Difluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 523.2


1289
2-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-



1H-benzimidazole



MS m/z (M + H+) 555.2


858
2-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-



benzimidazole



MS m/z (M + H+) 493.2


866
2-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-



benzimidazole



MS m/z (M + H+) 507.1


1506
1-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[4-(1,3-thiazol-



4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



benzimidazole



MS m/z (M + H+) 529.2


635
2-Methyl-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-benzimidazole



MS m/z (M + H+) 480









Example 60b




I. Methyl 1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate, 60i. A mixture of 60d (0.20 g, 0.826 mmol) and 1,1′-carbonyldiimidazole (0.535 g, 3.3 mmol) in DMF (8 mL) was heated at 90° C. for 2 h. The solvent was removed and the residue was triturated with water (15 mL). The resulting precipitate was collected by filtration and washed several times with water. The crude product 60i was used in the next reaction without further purification. MS m/z (M+H+) 287.1.
J. 1-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate, 60j. The title compound 60j was prepared using the method described in Example 60, substituting 60i for 60e in Step D. The crude product 60j was used in the next reaction without purification. MS m/z (M+H+) 273.1.
K. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one, Cpd 934. The title compound Cpd 934 was prepared using the method described in Example 60, substituting 60j for 60f in Step E. The crude product Cpd 934 was purified by preparative reverse phase chromatography. MS m/z (M+H+) 507.1.
Following the procedure described above for Example 60b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.




Following the procedure described above for Example 60b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.











Cpd
Cpd Name and Data
















933
1-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-



one



1H NMR (300 MHz, CD3OD): δ 7.97 (d, 1H), 7.88 (d, 1H),



7.56-7.66 (m, 2H), 7.46-7.55 (m, 4H), 7.42 (dd, 1H), 7.08 (d,



1H), 4.26-4.81 (m, 6H), 3.93-4.10 (m, 3H), 3.18-3.27 (m,



4H)



MS m/z (M + H+) 489.1


932
1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



dihydro-2H-benzimidazol-2-one



MS m/z (M + H+) 531.0


935
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



dihydro-2H-benzimidazol-2-one



MS m/z (M + H+) 525.1


936
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro-



2H-benzimidazol-2-one



MS m/z (M + H+) 557.0


937
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-



benzimidazol-2-one



MS m/z (M + H+) 495.1


938
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H-



benzimidazol-2-one



MS m/z (M + H+) 509.1


939
1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-



one



MS m/z (M + H+) 489.1


940
1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



dihydro-2H-benzimidazol-2-one



MS m/z (M + H+) 507.1


941
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



dihydro-2H-benzimidazol-2-one



MS m/z (M + H+) 525.2


942
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro-



2H-benzimidazol-2-one



MS m/z (M + H+) 557.2


943
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-



benzimidazol-2-one



MS m/z (M + H+) 495.2


944
5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H-



benzimidazol-2-one



MS m/z (M + H+) 509.2


945
1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-



dihydro-2H-benzimidazol-2-one



MS m/z (M + H+) 531.2









Example 61




A. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 61a. A solution of 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 10a (2.031 mmol, 0.50 g) in THF (8 mL) at −70° C. was treated with a 1.6 M solution of n-BuLi in hexanes (4.26 mmol, 2.66 mL). After 1 h at −70° C., N-fluorobenzenesulfonimide (2.64 mmol, 0.833 g) in THF (2 mL) was slowly added and the reaction was warmed to room temperature. After 1 h the mixture was partitioned between dilute aqueous HCl and EtOAc. The organic layer was washed with water and brine, and then concentrated. The residue was triturated with CH2Cl2. The off-white precipitate was filtered and collected to provide 61a.
B. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 61b. The title compound 61b was prepared using the method described in Example 10, substituting 61a for 10a in Step A.
C. 1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 895. The title compound Cpd 895 was prepared using the method described in Example 10, substituting 61b for 10b in Step B. MS m/z (M+H+) 499.
Following the procedure described above for Example 61 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







653
1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 499


509
1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 492









Example 62




A. 1-tert-Butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate, 62b. A mixture of 1-tert-butyl 6-methyl 3-iodo-1H-indole-1,6-dicarboxylate 62a (5.02 mmol, 2.016 g), phenylboronic acid 1x (7.53 mmol, 0.92 g), Pd(OAc)2 (0.402 mmol, 90 mg), Sphos 0.904 mmol, (0.37 g), and K3PO4 (10.1 mmol, 2.13 g) in toluene (10 mL) in sealed reaction vial was stirred at room temperature for 2 min and then heated at 90° C. under N2 for 4 h. The reaction mixture was quenched with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 8% EtOAc/hexanes). The desired product was collected as a light yellow solid that was washed with small amount of hexanes to obtain 62b as a white solid.
B. Methyl 3-phenyl-1H-indole-6-carboxylate TFA salt, 62c. To a solution of 1-tert-butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate 62b (4.04 mmol, 1.42 g) in CH2Cl2 (8 mL) was added 6 mL of TFA. The resulting solution was stirred for 3 h. The mixture was then concentrated and washed with hexanes to afford 62c.
C. Methyl 1-methyl-3-phenyl-1H-indole-6-carboxylate, 62d. NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate TFA salt 62c (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 62d.
D. 1-Methyl-3-phenyl-1H-indole-6-carboxylic acid, 62e. The title compound 62e was prepared using the method described in Example 29, substituting 62d for 29c in Step B.
E. 1-Methyl-3-phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1132. The title compound Cpd 1132 was prepared using the method described in Example 9, substituting 62d for 9c in Step D. MS m/z (M+H+) 486.
Following the procedure described above for Example 62 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 62 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















701
3-Iodo-1-methyl-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 536


1084
1-Methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-



1H-indole



MS m/z (M + H+) 554


1148
1-Methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-



1H-indole



MS m/z (M + H+) 554


1100
1-Methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-



1H-indole



MS m/z (M + H+) 554


1347
1-Methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-



1H-indole



MS m/z (M + H+) 554


1155
1-Methyl-3-phenyl-6-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 486


593
1-Methyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 547


585
1-Methyl-3-phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 479









Example 62a




F. 1-tert-Butyl 6-methyl 3-(3-(trifluoromethyl)phenyl)-1H-indole-1,6-dicarboxylate, 62g. The title compound 62g was prepared using the method described in Example 62, substituting 62f for 1x in Step A.
G. Methyl 3-(3-(trifluoromethyl)phenyl)-1H-indole-6-carboxylate TFA salt, 62h. The title compound 62h was prepared using the method described in Example 62, substituting 62g for 62b in Step B.
H. 3-(3-(Trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid, 62i. The title compound was prepared using the method described in Example 62, substituting 62h for 62e in Step D.
E. 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole, Cpd 1341. The title compound Cpd 1341 was prepared using the method described in Example 9, substituting 62i for 9c in Step D. MS m/z (M+H+) 540.
Following the procedure described above for Example 62a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 62a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















572
6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 533


634
6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-



yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 533


1340
6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 540


1344
6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 540


1345
6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-



1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole



MS m/z (M + H+) 540









Example 63




A. Methyl 4-(hydroxy(4-(trifluoromethyl)phenyl)methyl)benzoate, 63c. To a solution of methyl 4-iodobenzoate 63a (8 mmol, 2.1 g) in 10 mL of dry THF was added i-propyl magnesium chloride (2M in THF, 8.4 mmol, 4.2 mL) dropwise under N2 at −20° C. The solution was stirred for 30 min. The formed Grignard reagent in THF was then added slowly to a solution of 4-trifluoromethylbenzaldehyde (8 mmol, 1.1 mL) in THF (20 mL) at −40° C. After 20 min, the reaction mixture was allowed to warm up slowly to room temperature. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give the 63c as white solid.
B. 4 Methyl 4-(fluoro(4-(trifluoromethyl)phenyl)methyl)benzoate, 63d. To a solution of 63c (0.97 mmol, 300 mg) in CH2Cl2 was added DAST (1.015 mmol, 0.133 mL) dropwise at −78° C. under N2. The reaction was kept at −78° C. for 30 min and then quenched with aqueous NaHCO3 solution at low temperature. Additional CH2Cl2 was added to the reaction and the organic solution was concentrated. The crude material was purified flash column chromatography (silica gel, 10% EtOAc/hexanes) to give 63d.
C. 4-(Fluoro(4-(trifluoromethyl)phenyl)methyl)benzoic acid, 63e. The title compound was prepared using the method described in Example 29, substituting 63d for 29c in Step B.
D. 1-{1-[(4-{Fluoro[4-(trifluoromethyl)phenyl]methyl}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 982. The title compound Cpd 982 was prepared using the method described in Example 9, substituting 63e for 9c in Step D. MS m/z (M+H+) 533.
Example 64




A. Methyl 4-(2-phenyl-1,3-dithiolan-2-yl)benzoate, 64b. Methyl 4-benzoylbenzoate 64a (2.08 mmol, 0.50 g) and BF3.(OAc)2 (5.2 mmol, 0.73 mL) were dissolved in dry CH2Cl2 under N2. Ethane-1,2-dithiol (3.95 mmol, 0.333 mL) was added and the solution was stirred overnight. The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to afford compound 64b.
B. Methyl 4-(difluoro(phenyl)methyl)benzoate, 64c. Selectfluor (1.07 mmol, 381 mg) and HF-pyridine reagent (1.5 mL, HF: Pyridine=70:30 wt %) were dissolved in CH2Cl2 (4 mL) in a polyethylene bottle and cooled to 0° C. A solution of 64b (0.512 mmol, 162 mg) in CH2Cl2 (2 mL) was slowly added and the mixture was stirred for 45 min at room temperature. When TLC indicated the consumption of all 64b, the reaction was diluted with CH2Cl2. The combined organics were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to afford compound 64c as a clear oil.
C. 4-(Difluoro(phenyl)methyl)benzoic acid, 64d. The title compound 64d was prepared using the method described in Example 29, substituting 64c for 29c in Step B.
D. 1-[1-({4-[Difluoro(phenyl)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 986. The title compound Cpd 986 was prepared using the method described in Example 9, substituting 64d for 9c in Step D. MS m/z (M+H+) 483.
Example 65




A. Methyl 3-cyclopropyl-6-fluorobenzo[b]thiophene-2-carboxylate, 65c. A mixture of methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate 65a (0.613 mmol, 150 mg), cyclopropylboronic acid 65b (0.92 mmol, 79 mg), Pd(OAc)2 (0.09 mmol, 20 mg), SPhos (0.215 mmol, 88 mg), and K3PO4 (1.23 mmol, 0.26 g) in toluene (2 mL) was heated to 100° C. for 3 h in a sealed reaction vessel. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 65c.
B. 3-Cyclopropyl-6-fluoro-benzo[b]thiophene-2-carboxylic acid, 65d. The title compound 65d was prepared using the method described in Example 29, substituting 65c for 29c in Step B.
C. 3-Cyclopropyl-6-fluoro-benzo[b]thiophene-2-carbonyl chloride, 65e. The title compound 65e was prepared using the method described in Example 10, substituting 65d for 10a in Step A.
D. 1-{1-[(3-Cyclopropyl-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 714. The title compound Cpd 714 was prepared using the method described in Example 10, substituting 65e for 10b in Step B. MS m/z (M+H+) 471.
Following the procedure described above for Example 65 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 65 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















695
1-{1-[(3-Cyclobutyl-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 485


528
1-{1-[(3-Cyclopropyl-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 464


513
1-{1-[(3-Cyclobutyl-6-fluoro-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 478


1346
1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



NMR (CDCl3) δ: 7.96 (d, J = 1.2 Hz, 1H), 7.84-7.93 (m, 2H),



7.62-7.74 (m, 3H), 7.55 (d, J = 3.2 Hz, 1H), 7.49 (m, 2H),



7.34-7.44 (m, 1H), 4.12-4.47 (m, 6H), 3.87 (m, 2H),



3.19-3.35 (m, 1H), 2.69 (s, 3H), 2.50 (m, 4H)



MS m/z (M + H+) 503


1058
1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-



ylcarbonyl)piperazine; MS m/z (M + H+) 503


691
1-(1-{[5-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine; MS m/z (M + H+) 495


737
1-(1-{[5-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine; MS m/z (M + H+) 495


707
1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine; MS m/z (M + H+) 495


712
1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine; MS m/z (M + H+) 495


1098
1-(1-{[6-Phenyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine; MS m/z (M + H+) 557


1095
1-(1-{[6-Phenyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine; MS m/z (M + H+) 557


570
1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2-



yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine; MS



m/z (M + H+) 496


510
1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine; MS



m/z (M + H+) 488









Example 66




A. Methyl 4-thiomorpholinoquinazoline-7-carboxylate, 66c. A solution of methyl 4-chloroquinazoline-7-carboxylate 66a (1.01 mmol, 225 mg) and thiomorpholine 66b (2.02 mmol, 208 mg) in MeOH (1.6 mL) was refluxed overnight. Compound 66c (30 mg) was isolated after purification.
B. 4-Thiomorpholinoquinazoline-7-carboxylic acid, 66d. The title compound 66d was prepared using the method described in Example 29, substituting 66c for 29c in Step B.
C. 7-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4-thiomorpholin-4-ylquinazoline, Cpd 951. The title compound Cpd 951 was prepared using the method described in Example 9, substituting 66d for 9c in Step D. MS m/z (M+H+) 510.
Example 67




A. 1-(5-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 67c. To a solution of LDA (2.0 M in THF/heptane/ethylbenzene, 25.3 mmol, 12.6 mL) in dry THF was slowly added 1-fluoro-4-chloro-benzene 67a (23.0 mmol, 2.45 mL) at −78° C. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (25.3 mmol, 3.02 mL) was added. The reaction mixture was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give a mixture of the compound 67c along with a regio-isomeric by-product, 1-(5-fluoro-2-chloro-phenyl)-2,2,2-trifluoro-ethanone, in a ratio of 5:1 (67c is the major product).
B. Methyl 5-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 67e. A solution of compound 67c (6.62 mmol, 1.5 g), methyl 2-mercaptoacetate 67d (6.62 mmol, 0.6 mL), and Et3N (8.6 mmol, 1.2 mL) in acetonitrile (12 mL) was heated at 75° C. for 4 h. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to provide the compound 67e.
C. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 67f. The title compound 67f was prepared using the method described in Example 29, substituting 67e for 29c in Step B.
D. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 67g. The title compound 65e was prepared using the method described in Example 10, substituting 67f for 10a in Step A.
E. 1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine. The title compound Cpd 896 was prepared using the method described in Example 10, substituting 67g for 10b in Step B. MS m/z (M+H+) 515.
Following the procedure described above for Example 67 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







673
1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 515


506
1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 508









Example 67a




F. 1-(4-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 67i. To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i.
G. Methyl 6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 67j. The title compound 67j was prepared using a similar method described in Example 67, substituting 67i for 67c in Step B.
Following the procedure described above for Example 67, Steps C-E, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







664
1-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



MS m/z (M + H+) 515


699
1-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 515


512
1-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-



(phenylcarbonyl)piperazine



MS m/z (M + H+) 508









Example 67b




H. Methyl 6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 67l. The title compound 67l was prepared using a similar method described in Example 67, substituting 67k for 67c, substituting NaH for Et3N, and substituting THF and DMSO for CH3CN in Step B.
Following the procedure described above for Example 67, Steps C-E, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







692
1-(Isothiazol-5-ylcarbonyl)-4-(1-{[3-methyl-6-



(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)piperazine



1H NMR (CDCl3): δ 8.41 (ar, 1H); 8.22 (ar, 1H);



7.98 (m, 1H); 7.65 (m, 1H); 7.48, (m, 1H); 3.83 (bm, 5H);



3.01 (bm, 4H); 2.5 (s, 3H)



MS m/z (M + H+) 477.0


505
1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine



MS m/z (M + H+) 488


899
1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-



ylcarbonyl)piperazine



1H NMR (CDCl3, 400 MHz): δ 8.11 (s, 1 H),



7.83-7.95 (m, 2 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.55 (d, J = 3.1 Hz,



1 H), 3.99-4.67 (m, 6 H), 3.87 (br. s., 2 H), 3.16-3.41 (m, 1



H), 2.66 (s, 3 H), 2.50 (br. s., 4 H).



MS m/z (M + H+) 495


674
1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



1H NMR (CDCl3, 400 MHz): δ 8.79 (s, 1 H), 8.10 (s, 1



H), 8.03 (s, 1 H), 7.89 (d, J = 8 Hz, 1 H), 7.65 (d, J = 8 Hz,



1 H), 3.80-4.40 (m, 8 H), 3.28 (m, 1 H), 2.66 (s, 3



H), 2.49 (br. s., 4 H).



MS m/z (M + H+) 495


657
1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}azetidin-3-yl)-4-(1H-pyrrol-2-



ylcarbonyl)piperazine



1H NMR (400 MHz, CDCl3): δ 8.33 (d, 1H); 8.09 (d,



1H); 7.72 (d, 1H); 6.95 (s, 1H); 6.67 (s, 1H); 6.23 (dd,



1H); 4.59 (bm, 3H); 4.26 (m, 1H); 3.40 (m, 3H); 2.68 (s,



3H)



MS m/z (M + H+) 477.1









Example 68




A. Methyl 3-Hydroxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylate, 68b. LiOH (4.5 mmol, 0.11 g) was added to a solution of methyl 2-fluoro-4-trifluoromethylbenzoate 68a (2.25 mmol, 0.50 g) and methyl 2-mercaptoacetate 67d (2.25 mmol, 0.21 mL) in DMF (3 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for 1 h. Water was added and the resulting solution was acidified with 1N aqueous HCl. The precipitates were filtered, washed with water, and dried to give compound 68b.
B. Methyl 3-methoxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylate, 68c. A mixture of compound 68b (0.543 mmol, 150 mg), dimethyl sulfate (0.608 mmol, 0.058 mL), and sodium bicarbonate (0.57 mmol, 48 mg) in acetone was heated at reflux overnight. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was partitioned between EtOAc and water. The organic solution was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 68c.
C. 3-Methoxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 68d. The title compound 68d was prepared using the method described in Example 29, substituting 68c for—29c in Step B.
D. 3-Methoxy-6-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride, 68e. The title compound 68e was prepared using the method described in Example 10, substituting 68d for 10a in Step A.
E. 1-(1-{[3-Methoxy-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 649. The title compound Cpd 649 was prepared using the method described in Example 10, substituting 68e for 10b in Step B. 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.83-7.96 (m, 2H), 7.62 (dd, J=8.4, 1.1 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 4.55-4.45 (m, 2H), 4.24-4.37 (m, 2H), 4.11-4.24 (m, 2H), 4.07 (s, 3H), 3.88 (m, 2H), 3.29 (m, 1H), 2.50 (m, 4H). MS m/z (M+H+) 511.
Following the procedure described above for Example 68 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







700
1-(1-{[3-Methoxy-6-(trifluoromethyl)-1-benzothiophen-



2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-



ylcarbonyl)piperazine



MS m/z (M + H+) 511









Example 68a
Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







705
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 495.1


704
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-



yl]carbonyl}-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-



yl]piperazine



MS m/z (M + H+) 495.1









Example 69




A. Methyl 3-fluoro-1H-indole-6-carboxylate, 69a. A solution of methyl 1H-indole-6-carboxylate 1j (11.4 mmol, 2.0 g) and N-fluoro-2,4,6-trimethylpyridinium triflate (14.8 mmol, 4.3 g) in MeOH (100 mL) was heated at reflux for 18 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 15-20% EtOAc/hexanes) to give compound 69a as an off-white solid.
B. Methyl 3-fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylate, 69c. Compound 69a (0.264 mmol, 51 mg), Cut (0.0264 mmol, 5 mg) and K3PO4 (0.66 mmol, 40 mg) were combined in a sealed reaction tube and the vial was back-flushed with N2. 4-fluoro-iodobenzene 69b (0.264 mmol, 0.0394 mL) and N,N′-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) were added via sringe, followed by toluene. The reaction mixture was heated at 95° C. for 6 h. The reaction was diluted with EtOAc and water. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give compound 69c.
C. 3-Fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylic acid, 69d. The title compound 69d was prepared using the method described in Example 29, substituting 69c for 29c in Step B.
D. 3-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 574. The title compound Cpd 574 was prepared using the method described in Example 9, substituting 69d for 9c and substituting 2c for 5e in Step D. MS m/z (M+H+) 501.
Following the procedure described above for Example 69, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







589
3-Fluoro-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 490









Example 70







A. Methyl 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylate, 70b. To a solution of 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylic acid 70a (prepared using a procedure described in Eur. J. Org. Chem. 2006, 2956) (8.08 mmol, 2.71 g) in dry CH2Cl2 (20 mL) was added oxalyl chloride (9.69 mmol, 0.82 mL) followed by DMF (0.81 mmol, 0.063 mL). The reaction was stirred at rt for 30 min and then concentrated. The residue was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. Et3N (40.4 mmol, 5.6 mL) was added, followed by slow addition of MeOH. The reaction mixture was stirred at 0° C. for 30 min and concentrated. The residue was partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to give compound 70b.
B. Methyl 4-fluoro-1H-indole-5-carboxylate, 70c. TBAF (1M solution in THF, 15.8 mmol, 15.8 mL) was added to a solution of compound 70b (7.9 mmol, 2.76 g) in THF at 0° C. After 10 min at room temperature, the reaction was diluted with EtOAc and washed with brine, saturated NaHCO3, and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to afford compound 70c.
C. Methyl 4-fluoro-1-(4-fluorophenyl)-1H-indole-5-carboxylate, 70d. The title compound 70d was prepared using the method described in Example 69, substituting 70c for 69a in Step B.
D. 4-Fluoro-1-(4-fluoro-phenyl)-1H-indole-5-carboxylic acid, 70e. The title compound 70e was prepared using the method described in Example 29, substituting 70d for 29c in Step B.
E. 4-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1348. The title compound Cpd 1348 was prepared using the method described in Example 9, substituting 70e for 9c in Step D. 1H NMR (CDCl3): δ 7.87 (d, J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.36-7.47 (m, 3H), 7.30 (d, J=3.2 Hz, 1H), 7.19-7.27 (m, 3H), 6.81 (d, J=3.2 Hz, 1H), 4.52-4.43 (m, 2H), 4.28 (dd, J=9.9, 7.7 Hz, 1H), 4.16-4.24 (m, 1H), 4.05-4.16 (m, 2H), 3.75-3.95 (m, 2H), 3.27 (m, 1H), 2.38-2.58 (m, 4H). MS m/z (M+H+) 508.
Following the procedure described above for Example 70, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















1069
6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 508


1349
6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 508


631
6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-



(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-



1H-indole



MS m/z (M + H+) 501


632
4-Fluoro-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 501









Example 70a




F. 7-Fluoro-1H-indole-5-carboxylic acid, 70h. To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THF at −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at −60° C. for 4 h and was then poured onto an excess of freshly crushed dry ice. Water was added and the mixture was acidified to pH=4. The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 70h.
Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1350
7-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3): δ 7.88 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 1.2 Hz,



1H), 7.55 (d, J = 3.2 Hz, 1H), 7.42 (m, 2H),



7.22-7.31 (m, 2H), 7.12-7.22 (m, 2H), 6.69-6.81 (m, 1H),



4.53-4.27 (m, 5H), 4.12 (m, 1H), 3.89-3.83 (m, 2H), 3.26 (m,



1H), 2.50 (m, 4H)



MS m/z (M + H+) 508


1111
7-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 508









Example 70b




G. Methyl 7-methyl-1H-indole-5-carboxylate, 70k. The titled compound was prepared using the method described in Example 65, substituting 70i for 65a and substituting 70j for 65b in Step A.
Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:




Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1355
1-(4-Fluorophenyl)-7-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3): δ 7.88 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H),



7.54 (d, J = 2.4 Hz, 1H), 7.36 (m, 2H), 7.28 (S, 1H),



7.10-7.21 (m, 3H), 6.67 (d, J = 2.4 Hz, 1H), 4.55-4.26 (m, 5H),



4.12 (m, 1H), 3.89 (m, 2H), 3.25 (m, 1H), 2.50 (m, 4H),



2.02 (s, 3H)



MS m/z (M + H+) 504


1076
1-(4-Fluorophenyl)-7-methyl-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 504









Example 70c




H. Methyl 4-amino-2-chloro-benzoate, 70m. Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 70l (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under vacuum. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 70m.
I. Methyl 4-amino-2-chloro-5-iodo-benzoate, 70n. To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monochloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.
J. Methyl 4-amino-2-chloro-5-((trimethylsilyl)ethynyl)benzoate, 70p. To a mixture of compound 70n (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.
K. Methyl 6-chloro-1H-indole-5-carboxylate, 70q. A mixture of compound 70p (0.532 mmol, 150 mg) and CuI (0.32 mmol, 60 mg) in DMF (1.5 mL) was heated at 110° C. for 5 h and them cooled to room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70q.
Following the procedure described above for Example 70c and Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data







1416
6-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 525


1415
1-(4-Fluorophenyl)-6-methyl-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



MS m/z (M + H+) 504


1414
4-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indole



1H NMR (CDCl3): δ 7.87 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz,



1H), 7.40-7.46 (m, 2H), 7.34-7.39 (m, 2H),



7.19-7.29 (m, 3H), 6.83 (d, J = 3.2 Hz, 1H), 4.52 (m, 1H),



4.35-4.48 (m, 1H), 4.30 (dd, J = 9.9, 7.5 Hz, 1H), 4.08-4.18 (m,



1H), 3.75-4.05 (m, 4H), 3.23-3.33 (m, 1H), 2.37-2.57 (m,



4H)



MS m/z (M + H+) 525.









Example 71




A. Methyl 1-(2,2-difluoroethyl)-1H-indole-5-carboxylate, 71b. To a suspension of NaH (60% dispersion in mineral oil, 1.48 mmol, 59 mg) in DMF (2 mL) was slowly added a solution of 1H-indole-5-carboxylic acid methyl ester 1j (1.14 mmol, 200 mg) in DMF (1 mL)at 0° C. The resulting solution was stirred at 0° C. for 20 min and 1,1-difluoro-2-iodoethane 71a (1.37 mmol, 263 mg) was added. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford compound 71b.
B. 1-(2,2-Difluoroethyl)-1H-indole-5-carboxylic acid, 71c. The title compound 71c was prepared using the method described in Example 29, substituting 71b for 29c in Step B.
C. 1-(2,2-Difluoroethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 711. The title compound Cpd 711 was prepared using the method described in Example 9, substituting 71c for 9c in Step D. 1H NMR (CDCl3): δ 7.94 (s, 1H), 7.88 (d, J=2.9 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.54 (d, J=2.9 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.17 (d, J=2.9 Hz, 1H), 6.63 (d, J=2.9 Hz, 1H), 6.01 (m, 1H), 4.51-4.24 (m, 7H), 4.12 (m, 1H), 3.85 (m, 2H), 3.24 (m, 1H), 2.49 (m, 4H). MS m/z (M+H+) 460.
Following the procedure described above for Example 71, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 71, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd
Cpd Name and Data
















813
1-(2,2-Difluoroethyl)-5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 460


1031
N-Methyl-N-phenyl-2-[5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-



1-yl]acetamide



MS m/z (M + H+) 543


1032
N-Methyl-N-phenyl-2-[5-({3-[4-(1,3-thiazol-4-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-



1-yl]acetamide



MS m/z (M + H+) 543


1035
1-(2-Oxo-2-pyrrolidin-1-ylethyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 507


1046
1-(Pyridin-4-ylmethyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 487


1047
1-(Pyridin-4-ylmethyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 487


1048
1-(Pyridin-3-ylmethyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole



MS m/z (M + H+) 487









Example 72




A. Ethyl 1-(4-fluorobenzyl)-1H-indazole-5-carboxylate, 72c, and ethyl 2-(4-fluorobenzyl)-2H-indazole-5-carboxylate, 72d. Ethyl 1H-indazole-5-carboxylate 72a (0.79 mmol, 150 mg) and Cs2CO3 (0.96 mmol, 312 mg) were combined in 2 mL of DMF, producing a clear, red-brown solution. Neat 1-(bromomethyl)-4-fluorobenzene 72b (0.87 mmol, 0.11 mL) was added dropwise and the mixture was stirred at room temperature overnight. EtOAc was added and the organic layer was washed with water and brine. The organic solution was dried over Na2SO4 and concentrated to give 260 mg of orange solid. The crude product was purified by flash column chromatography (silica gel, 15-50% EtOAc/heptanes) to give 133 mg (57%) of compound 72c as an orange solid and 67 mg (28%) of compound 72d as a white solid.
Compound 72c: 1H NMR (400 MHz, CDCl3): δ 1.41 (t, J=7.1 Hz, 3H), 4.40 (q, J=7.1 Hz, 2H), 5.58 (s, 2H), 6.99 (t, J=8.7 Hz, 2H), 7.19 (dd, J=8.8, 5.3 Hz, 2H), 7.36 (dt, J=8.9, 0.8 Hz, 1H), 8.04 (dd, J=8.9, 1.5 Hz, 1H), 8.15 (d, J=0.9 Hz, 1H), 8.53 (dd, J=1.5, 0.8 Hz, 1H). MS m/z (M+H+) 299.1.
Compound 72d: 1H NMR (400 MHz, CDCl3): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H+) 299.1.
B. 1-(4-Fluorobenzyl)-1H-indazole-5-carboxylate, 72e. To a stirring solution of compound 72c (0.43 mmol, 128 mg) in 2.5 mL of THF and 0.5 mL of MeOH was added 3N aqueous NaOH (2.62 mmol, 0.87 mL) and 0.5 mL of water. After stirring at room temperature overnight, the mixture was concentrated under vacuum. The yellow residue was dissolved in 10 mL of water and acidified to pH 2-3 with aqueous HCl. The resulting precipitate was vacuum-filtered through a paper disc and washed with water. The remaining material was pumped at high vacuum to give 108 mg (93%) of compound 72e as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H+) 271.2.
C. 1-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole, Cpd 1029. The title compound Cpd 1029 was prepared using the method described in Example 9, substituting 72e for 9c and substituting HBTU for HATU in Step D. 1H NMR (400 MHz, CDCl3): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H+) 505.2.
Following the procedure described above for Example 72, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:




Following the procedure described above for Example 72, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:











Cpd 
Cpd Name and Data







1030
2-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H-



indazole



1H NMR (400 MHz, CD3OD): δ 3.19-3.30 (m, 4 H), 4.05



(d, J = 5.6 Hz, 3 H), 4.25-4.88 (m, 6 H), 5.66 (s, 2 H),



7.09 (t, J = 8.4 Hz, 2 H), 7.33-7.43 (m, 2 H), 7.57 (d, J =



9.0 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.88 (m, J = 2.9



Hz, 1 H), 7.97 (d, J = 2.7 Hz, 1 H), 8.12 (s, 1 H), 8.49 (s,



1 H)



MS m/z (M + H+) 505.2


1036
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)benzyl]-



1H-indazole



1H NMR (400 MHz, CD3OD): δ 3.24 (br. s., 4 H), 3.89-



4.12 (m, 3 H), 4.25-4.85 (m, 6 H), 5.78 (s, 2 H), 7.37 (m,



J = 8.1 Hz, 2 H), 7.60 (m, J = 8.1 Hz, 2 H), 7.66 (d, J =



8.8 Hz, 1 H), 7.72 (dd, J = 8.8, 1.5 Hz, 1 H), 7.88 (d, J =



3.0 Hz, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 8.18 (s, 1 H), 8.23



(s, 1 H)



MS m/z (M + H+) 555.2


1037
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)benzyl]-



2H-indazole



1H NMR (400 MHz, CD3OD): δ 3.18-3.41 (m, 4 H),



3.92-4.18 (m, 3 H), 4.27-4.86 (m, 6 H), 5.79 (s, 2 H),



7.47 (d, J = 8.1 Hz, 2 H), 7.58 (dd, J = 9.1, 1.5 Hz, 1 H),



7.66 (d, J = 8.1 Hz, 2 H), 7.70 (d, 1 H), 7.88 (d, J = 3.0



Hz, 1 H), 7.97 (d, J = 3.0 Hz, 1 H), 8.14 (s, 1 H), 8.56 (s,



1 H)



MS m/z (M + H+) 555.2


1038
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)benzyl]-



1H-indazole



1H NMR (400 MHz, CD3OD): δ 3.25 (br. s., 4 H), 3.89-



4.13 (m, 3 H), 4.22-4.82 (m, 6 H), 5.78 (s, 2 H), 7.40-



7.54 (m, 3 H), 7.58 (m, J = 7.3 Hz, 1 H), 7.69 (m, J = 8.6



Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.88 (d, J = 3.3 Hz, 1



H), 7.97 (d, J = 3.3 Hz, 1 H), 8.18 (s, 1 H), 8.24 (s, 1 H)



MS m/z (M + H+) 555.2


1039
5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-



yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)benzyl]-



2H-indazole



1H NMR (400 MHz, CD3OD): δ 3.30 (br. s., 4 H), 4.04



(d, J = 6.8 Hz, 3 H), 4.29-4.84 (m, 6 H), 5.78 (s, 2 H),



7.58 (t, J = 7.1 Hz, 3 H), 7.64 (br. s., 2 H), 7.70 (d, J =



9.1 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.0



Hz, 1 H), 8.14 (s, 1 H), 8.56 (s, 1 H)



MS m/z (M + H+) 555.2


1411
1-(1-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



1H NMR (400 MHz, acetone-d6): δ 2.01 (d, J = 7.1 Hz, 3



H), 3.35 (br. s., 4 H), 4.07 (br. s., 2 H), 4.11-4.19 (m, 1



H), 4.25-4.53 (m, 2 H), 6 4.60 (br. s., 1 H), 4.68-4.96 (m,



3 H), 6.07 (q, J = 7.1 Hz, 1 H), 7.24 (d, J = 7.1 Hz, 1 H),



7.30 (t, J = 7.3 Hz, 2 H), 7.33-7.39 (m, 2 H), 7.58-7.68



(m, 2 H), 7.92 (d, J = 3.3 Hz, 1 H), 7.98 (d, J = 3.0 Hz, 1



H), 8.12 (s, 1 H), 8.18 (s, 1 H)



MS m/z (M + H+) 501.1


1040
2-(1-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H-



indazole



1H NMR (400 MHz, CD3OD): δ 2.04 (d, J = 7.1 Hz, 3



H), 3.20 (br. s., 4 H), 3.91-4.05 (m, 3 H), 4.25-4.63 (m, 4



H), 4.72 (br. s., 2 4 H), 5.94 (q, J = 6.9 Hz, 1 H), 7.25-



7.39 (m, 5 H), 7.57 (dd, J = 9.0, 1.4 Hz, 1 H), 7.69 (d, J = 



9.1 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.3



Hz, 1 H), 8.12 (s, 1 H), 8.51 (s, 1 H)



MS m/z (M + H+) 501.3


1043
1-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



pyrrolo[2,3-b]pyridine



1H NMR (400 MHz, CDCl3): δ 3.49 (br. s., 4 H), 4.12



(br. s., 2 H), 4.23-4.33 (m, 1 H), 4.34-5.17 (m, 6 H), 5.56



(s, 2 H), 6.61 (d, J = 3.5 Hz, 1 H), 7.08 (t, J = 8.7 Hz, 2



H), 7.38 (dd, J = 8.6, 5.6 Hz, 2 H), 7.63 (d, J = 3.5 Hz, 1



H), 7.93 (d, J = 3.3 Hz, 1 H), 7.99 (d, J = 3.3 Hz, 1 H),



8.27 (d, J = 1.8 Hz, 1 H), 8.61 (d, J = 1.8 Hz, 1 H)



MS m/z (M + H+) 505.2


1049
1-[2-(4-Fluorophenyl)ethyl]-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-



indazole



1H NMR (400 MHz, acetone-d6): δ 3.24 (t, J = 7.2 Hz, 2



H), 3.40 (br. s., 4 H), 4.09 (br. s., 2 H), 4.16-4.23 (m, 1



H), 4.31-4.65 (m, 4 H), 6 4.69 (t, J = 7.2 Hz, 2 H), 4.85



(br. s., 2 H), 6.96 (t, J = 8.8 Hz, 2 H), 7.19 (dd, J = 8.3,



5.6 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.62 (dd, J = 8.8,



1.3 Hz, 1 H), 7.93 (d, J= 3.0 Hz, 1 H), 8.00 (d, J = 3.0



Hz, 1 H), 8.09 (s, 1 H), 8.12 (s, 1 H)



MS m/z (M + H+) 519.2


1050
2-[2-(4-Fluorophenyl)ethyl]-5-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H-



indazole



1H NMR (400 MHz, acetone-d6): δ 3.35 (t, J = 7.1 Hz, 2



H), 3.38-3.43 (m, 4 H), 4.09 (br. s., 2 H), 4.12-4.20 (m, 1



H), 4.31-4.69 (m, 4 6 H), 4.74 (t, J = 7 .2 Hz, 2 H), 4.84



(br. s., 2 H), 7.01 (t, J = 8.7 Hz, 2 H), 7.21 (dd, J = 8.3,



5.6 Hz, 2 H), 7.55 (dd, J = 9.1, 1.5 Hz, 1 H), 7.66 (d, J =



9.1 Hz, 1 H), 7.93 (d, J = 3.0 Hz, 1 H), 8.00 (d, J = 3.3



Hz, 1 H), 8.03 (s, 1 H), 8.23 (s, 1 H)



MS m/z (M + H+) 519.2


1051
1-(4-Fluorobenzyl)-6-({3-[4-(1,3-thiazol-2- 



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbony1)-1H-



indazole



1H NMR (400 MHz, acetone-d6): δ 3.14-3.23 (m, 4 H),



3.91-4.00 (m, 1 H), 4.01-4.12 (m, 2 H), 4.26-4.56 (m, 3



H), 4.57-4.92 (m, 3 6 H), 5.74 (s, 2 H), 7.09 (t, J = 8.8



Hz, 2 H), 7.37-7.46 (m, 3 H), 7.84 (d, J = 8.3 Hz, 1 H),



7.89-7.95 (m, 2 H), 7.99 (d, J = 3.0 Hz, 1 H), 8.12 (s, 1



H)



MS m/z (M + H+) 505.2


1052
2-(4-Fluorobenzyl)-6-({3-[4-(1,3-thiazol-2-



ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H-



indazole



1H NMR (400 MHz, acetone-d6): δ 3.21-3.30 (m, 4 H),



3.94-4.15 (m, 3 H), 4.28-4.52 (m, 2 H), 4.52-4.68 (m, 1



H), 4.68-4.93 (m, 3 6 H), 5.72 (s, 2 H), 7.15 (t, J = 8.8



Hz, 2 H), 7.34 (dd, J = 8.6, 1.3 Hz, 1 H), 7.45-7.52 (m, 2



H), 7.75 (d, J = 8.6 Hz, 1 H), 7.91 (s, 1 H), 7.92 (d, J =



3.3 Hz, 1 H), 7.99 (d, J = 3.3 Hz, 1 H), 8.42 (s, 1 H)



MS m/z (M + H+) 505.2









Example 72a




D. Methyl 1-(4-cyanobenzyl)-1H-indazole-5-carboxylate, 72f. The title compound 72f was prepared using the procedure described in Example 72, substituting methyl 1H-indazole-5-carboxylate for 72a and substituting 4-(bromomethyl)benzonitrile for 72b. 1H NMR (400 MHz, CDCl3): δ 3.95 (s, 3H), 5.67 (s, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 8.06 (dd, J=8.9, 1.4 Hz, 1H), 8.18 (s, 1H), 8.55 (s, 1H). (M+H+) 292.2
E. 1-(4-cyanobenzyl)-1H-indazole-5-carboxylic acid, 72g, and 1-(4-carbamoylbenzyl)-1H-indazole-5-carboxylic acid, 72h. To a stirring solution of compound 72f (0.35 mmol, 102 mg) in 2 mL of THF and 0.5 mL of MeOH was added 3N aqueous NaOH (2.45 mmol, 0.82 mL). After stirring at room temperature overnight, the mixture was concentrated under vacuum. The yellow residue was dissolved in 15 mL of water and acidified to pH 1-2 with aqueous HCl. The resulting precipitate was vacuum-filtered through a paper disc and washed with water. The remaining material was pumped at high vacuum to give 87 mg of a 3:1 mixture (as shown by LC/MS) of compound 72g and compound 72h as an off-white solid. Compound 72g (less polar): MS m/z (M+H+) 278.1. Compound 72h (more polar): MS m/z (M+H+) 296.
F. 4-{[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl]carbonyl)-1H-indazol-1-yl}methyl}benzonitrile, Cpd 1045, and 4-{[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl]carbonyl)-1H-indazol-1-yl}methyl}benzamide, Cpd 1044. The title compounds Cpd 1045 and Cpd 1044 were prepared using the method described in Example 9, substituting the mixture of 72g and 72h prepared in Step E above for 9c and substituting HBTU for HATU in Step D. The products were separated by preparative reverse phase chromatography to give 64 mg of Cpd 1045 (less polar) and 6.4 mg of Cpd 1044 (more polar).
Cpd 1045: 1H NMR (400 MHz, acetone-d6): δ 3.24-3.49 (m, 4H), 4.00-4.11 (m, 2H), 4.11-4.20 (m, 1H), 4.26-4.96 (m, 6H), 5.85 (s, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.66-7.72 (m, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.92 (d, J=3.3 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 8.16 (s, 1H), 8.20 (s, 1H)
Cpd 1044: 1H NMR (400 MHz, acetone-d6): δ 3.14 (br. s, 4H), 3.87-3.96 (m, 1H), 3.96-4.08 (m, 2H), 4.35 (br. s, 2H), 4.47-4.85 (m, 4H), 5.78 (s, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.66 (s, J=8.8 Hz, 1H), 7.70 (d, J=8.6, 1.5 Hz, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.91 (d, J=3.3 Hz, 1H), 7.98 (d, J=3.3 Hz, 1H), 8.16 (s, 1H), 8.18 (s, 1H)
Biological Examples
In Vitro Methods
Example 1
MGL Enzyme Activity Assay
All rate-based assays were performed in black 384-well polypropylene polymerase chain reaction (“PCR”) microplates (Abgene) in a total volume of 30 μL. Substrate 4-methylumbelliferyl butyrate (4MU-B; Sigma) and either purified mutant MGL (mut-MGLL 11-313 L179S L186S) or purified wild type MGL (wt-MGLL 6H-11-313) were diluted separately into 20 mM 1,4-piperazinediethanesulfonic acid (“PIPES”) buffer (pH=7.0), containing 150 mM NaCl and 0.001% Tween 20. Compounds of Formula (I) were pre-dispensed (50 mL) into the assay plate using a Cartesian Hummingbird prior to adding 4MU-B (25 μL of 1.2× solution to a final concentration of 10 μM) followed by enzyme (5 μL of a 6× solution to a final concentration of 5 nM) to initiate the reaction. Final compound concentrations ranged from 17 to 0.0003 μM. The fluorescence change due to 4MU-B cleavage was monitored with excitation and emission wavelengths of 335 and 440 nm, respectively, and a bandwidth of 10 nm (Safire2, Tecan) at 37° C. for 5 min.
The IC50 values for compounds of Formula (I) were determined using Excel from a fit of the equation to the concentration-response plot of the fractional activity as a function of inhibitor concentration.










BIOLOGICAL DATA TABLE 1






Chemistry
MGL mutant
MGL wild type


Cpd
Example
inh IC50 (μM)
inh IC50 (μM)


















1
 1
0.0283



2
 1
0.0081


3
 1
5.20


4
 1
0.731


5
 1
0.0657
0.523


6
 1
0.0080


7
 1
0.0346
0.131


8
 1
0.101


9
 1
0.0087
0.0174


10
 1
0.329


11
 1
2.86


12
 1
0.0470


13
 1
0.0200
0.0192


14
 1
1.22


15
 1
2.18


16
 1
0.828


17
 1
14.3


18
 1
0.124


19
 1
0.979


20
 1
1.89


21
 1
2.35


22
 1
4.81


23
 1
2.78


24
 1
2.45


25
 1
2.29


26
 1
15.4


567
 1
0.018
0.015


579
 1

0.065


581
 1

0.080


587
 1
0.014
0.119


595
 1
0.098
0.500


598
 1

0.979


1061
 1

0.006


1071
 1

0.008


1139
 1

0.027


1147
 1

0.032


1163
 1
0.009
0.048


1174
 1
<0.005
0.066


1201
 1
0.007
0.151


1248
 1

0.559


1356
 1
<0.005
<0.005


1357
 1
<0.005
<0.005


1358
 1
<0.005
<0.005


1359
 1
<0.005
<0.005


1360
 1
<0.005
<0.005


1361
 1

<0.005


1362
 1

<0.005


1363
 1

<0.005


1364
 1

<0.005


1366
 1

<0.005


1382
 1
0.069


1408
 1
<0.005


586
 1b

0.112


596
 1b

0.543


603
 1b

1.722


630
 1b

0.714


1062
 1b

0.007


1072
 1b

0.008


1073
 1b

0.034


1089
 1b

0.010


1097
 1b

0.012


1105
 1b

0.013


1107
 1b

0.014


1120
 1b

0.018


1121
 1b

0.018


1126
 1b

0.019


1127
 1b

0.020


1128
 1b

0.021


1134
 1b

0.025


1135
 1b

0.025


1176
 1b

0.070


1181
 1b

0.077


1189
 1b

0.097


1192
 1b

0.109


1197
 1b

0.133


1216
 1b

0.216


1219
 1b

0.235


1230
 1b

0.307


1247
 1b

0.539


1263
 1b

0.968


1312
 1b

<0.00500035


1314
 1b

<0.00500035


1337
 1b

<0.00500035


1338
 1b

<0.00500035


1339
 1b

<0.00500035


1410
 1b

0.089


656
 1c

0.008


1079
 1c

0.009


1184
 1c

0.086


1199
 1c

0.146


1141
 1d
0.010
0.028


1151
 1d

0.037


1158
 1d

0.042


592
 1e
0.078
0.253


1125
 1e
<0.00500035
0.019


1187
 1e
<0.00500035
0.092


629
 1f

0.053


1180
 1f

0.075


1313
 1f

<0.00500035


1409
 1g


27
 2
14.5


487
 1a
<0.005
0.0104


28
 2
1.63


29
 2
0.363


30
 2
0.670


31
 2
5.07


32
 2
0.761


33
 2
0.633


34
 2
1.38


35
 2
0.459


36
 2
0.115


37
 2
0.117
5.99


38
 2
0.666


39
 2
0.0317
0.0147


40
 2
0.0491


41
 2
0.0322


42
 2
0.354


43
 2
0.0310
1.26


44
 2
0.0700


45
 2
3.42


46
 2
3.43


47
 2
0.129
0.129


48
 2
0.551


49
 2
5.78


50
 2
8.71


51
 2
0.227


52
 2
1.94


53
 2
0.988


54
 2
0.223


55
 2
0.307


56
 2
13.8


57
 2
5.24


58
 2
2.63


59
 2
3.38


60
 2
2.66


461
 2
5.28


462
 2
5.05


463
 2
9.63


464
 2
5.82


465
 2
8.27


466
 2
10.9


467
 2
9.82


468
 2
2.70


469
 2
2.25


470
 2
7.06


471
 2
3.38


472
 2
9.73


531
 2
0.766


539
 2
11.476


541
 2
13.059


559
 2
1.287


562
 2
13.474


565
 2
11.392


622
 2
1.360


627
 2
13.225


628
 2
13.502


954
 2

2.743


1266
 2

1.083


1284
 2

2.292


1404
 2
13.286


1482
 2
>16.9981


1483
 2
>16.6686


1485
 2

>16.6686


1464
 2
>16.6686


61
 3
0.0385


676
 3
<0.005
0.021


703
 3
0.014
0.088


716
 3
0.023
0.140


722
 3
0.051
0.180


741
 3
0.038
0.298


753
 3
0.075
0.434


921
 3
6.331


1067
 3
<0.005
0.007


1166
 3

0.052


1235
 3
0.030
0.360


1236
 3
0.042
0.390


1242
 3
0.146
0.461


1243
 3

0.463


1246
 3
0.207
0.506


1276
 3
0.650
1.764


1283
 3
0.063
2.171


1292
 3
0.244
3.070


1383
 3
0.081


1400
 3
5.929


1401
 3
8.843


1402
 3
9.972


62
 4
2.95


63
 4
4.84


64
 4
2.29


65
 4
0.893


66
 4
1.40


67
 4
0.134


68
 4
12.7


69
 4
4.31


70
 4
4.83


71
 4
7.58


72
 4
0.0270
0.326


73
 4
1.54


74
 4
3.34


75
 4
0.0939


76
 4
2.43


77
 4
0.0478


78
 4
0.607


79
 4
0.125


80
 4
4.85


81
 4
0.227


82
 4
0.466


83
 4
0.0989


474
 4
4.68


473
 4
9.79


84
 4
4.67


85
 4
4.17


86
 4
3.92


87
 4
4.81


88
 4
1.95


89
 4
1.76


90
 4
14.7


91
 4
1.87


92
 4
13.6


93
 4
3.93


94
 4
1.88


95
 4
0.669


96
 4
14.0


97
 4
0.920


98
 4
4.58


99
 4
6.36


100
 4
3.50


101
 4
0.299


102
 4
3.04


103
 4
8.93


104
 4
3.90


105
 4
2.97


106
 4
0.539


107
 4
1.12


108
 4
8.63


109
 4
0.0385


110
 4
1.22


111
 4
14.0


496
 4
1.30


558
 4
0.410


618
 4
0.140


619
 4
0.142


620
 4
0.153


621
 4
0.271


623
 4
2.423


624
 4
4.687


625
 4
9.761


626
 4
12.74


133
 5
<0.005
0.0673


134
 5
0.0114


135
 5
<0.005


136
 5
<0.005


137
 5
0.0073


138
 5
<0.005


139
 5
0.968


140
 5
0.653


141
 5
0.412


142
 5
1.55


143
 5
7.14


144
 5
4.68


145
 5
2.69


146
 5
0.518


147
 5
<0.005


148
 5
<0.005
<0.005


149
 5
0.249
0.0769


150
 5
0.0058
<0.005


151
 5
0.114


152
 5
3.51


153
 5
0.355


154
 5
0.127


155
 5
3.75


156
 5
1.54


157
 5
0.853


158
 5
0.0339
0.657


159
 5
0.682


160
 5
2.54


161
 5
0.0050
0.0117


162
 5
<0.005


163
 5
0.0239


164
 5
0.0100


165
 5
0.451


166
 5
<0.005
<0.005


167
 5
0.0500
0.0152


168
 5
0.0059
<0.005


169
 5
5.55


170
 5
0.0679


171
 5
0.380


172
 5
0.0088
0.0073


475
 5
0.234


476
 5
0.0443
0.338


477
 5
1.38


478
 5
3.12


479
 5
2.82


298
 5
1.16


112
 5
1.08


113
 5
0.587


114
 5
0.840


115
 5
0.0180
0.0117


116
 5
1.49


117
 5
0.396
4.23


489
 5
<0.005
0.0090


490
 5
<0.005
0.0223


485
 5
<0.005
0.102


502
 5
6.091


503
 5
0.152


517
 5
0.073
1.340


523
 5

3.135


524
 5

4.368


526
 5

8.102


610
 5

10.347


611
 5

13.253


636
 5

0.021


637
 5

0.041


638
 5

0.189


639
 5

0.419


640
 5

15.944


641
 5

<0.005


643
 5
0.411


644
 5
3.086


646
 5

7.158


648
 5
0.018


655
 5

0.008


658
 5

0.009


667
 5

0.014


669
 5

0.015


672
 5

0.017


675
 5

0.019


678
 5

0.022


682
 5

0.030


687
 5

0.044


688
 5

0.044


693
 5

0.047


694
 5

0.047


696
 5

0.059


698
 5

0.065


702
 5

0.303


710
 5

0.123


719
 5

0.154


721
 5

0.173


726
 5

0.218


727
 5

0.219


728
 5

0.231


730
 5

0.238


731
 5

0.238


732
 5

0.239


733
 5

0.240


735
 5

0.268


739
 5

0.290


740
 5

0.294


743
 5

0.324


744
 5

0.335


746
 5

0.373


747
 5

0.377


748
 5

0.384


750
 5

0.395


751
 5

0.402


754
 5

0.447


755
 5

0.468


756
 5

0.519


758
 5

0.535


760
 5

0.581


762
 5

0.632


763
 5

0.635


764
 5

0.636


766
 5

0.680


768
 5

0.697


770
 5

0.740


772
 5

0.799


774
 5

0.848


776
 5

0.902


779
 5

0.944


781
 5

1.042


782
 5

1.066


783
 5

1.086


785
 5

1.190


786
 5

1.203


787
 5

1.209


788
 5

1.227


791
 5

1.448


792
 5

1.458


793
 5

1.460


794
 5

1.469


795
 5

1.502


796
 5

1.529


797
 5

1.596


799
 5

1.667


800
 5

1.696


804
 5
0.058
1.993


808
 5

2.076


809
 5

2.104


814
 5

2.434


815
 5

2.492


816
 5

2.636


818
 5

2.702


821
 5

2.847


823
 5

2.970


824
 5

3.120


825
 5

3.148


826
 5

3.287


827
 5

3.308


828
 5

3.733


830
 5

3.942


831
 5

4.097


835
 5

4.705


836
 5

4.756


838
 5

5.113


839
 5

5.135


840
 5

5.155


842
 5

5.526


843
 5

5.531


844
 5

6.104


845
 5

6.421


846
 5

6.448


848
 5

6.902


849
 5

7.011


850
 5

7.278


852
 5

8.078


853
 5

8.344


854
 5
>16.6686
8.414


855
 5

8.435


857
 5

8.724


859
 5

8.815


860
 5

8.819


862
 5

9.510


863
 5

10.158


864
 5

10.221


865
 5

10.287


868
 5

12.112


871
 5

13.323


873
 5

14.703


874
 5

15.209


886
 5

<0.005


887
 5

<0.005


888
 5

<0.005


889
 5

<0.005


890
 5

<0.005


891
 5

<0.005


892
 5

<0.005


893
 5

<0.005


894
 5

<0.005


905
 5
0.015


910
 5
0.194


912
 5
0.472


915
 5
0.944


923
 5
8.756


925
 5
9.968


926
 5
10.457


946
 5

1.001


947
 5

1.065


952
 5

0.012


953
 5

>16.6686


965
 5
0.037


966
 5
0.222


993
 5

1.514


1000
 5

0.111


1001
 5

1.403


1002
 5

5.292


1003
 5

1.613


1004
 5

0.167


1017
 5

0.035


1041
 5

0.019


1042
 5

5.274


1053
 5

0.018


1082
 5

0.009


1083
 5

0.009


1103
 5

0.013


1119
 5

0.017


1122
 5

0.018


1123
 5

0.019


1146
 5

0.032


1150
 5
<0.005
0.036


1156
 5

0.041


1164
 5

0.048


1179
 5

0.073


1194
 5

0.118


1202
 5

0.152


1203
 5

0.153


1214
 5

0.209


1218
 5

0.222


1223
 5

0.267


1225
 5

0.273


1245
 5

0.500


1249
 5

0.605


1271
 5

1.568


1272
 5

1.608


1287
 5

2.450


1293
 5

3.172


1297
 5

3.311


1298
 5

3.850


1299
 5

3.856


1300
 5

4.135


1301
 5

4.608


1305
 5

6.676


1307
 5

8.776


1326
 5

<0.005


1327
 5

<0.005


1328
 5

<0.005


1329
 5

<0.005


1330
 5

<0.005


1331
 5

<0.005


1332
 5

<0.005


1333
 5

<0.005


1334
 5

<0.005


1378
 5
0.009


1379
 5
0.022


1381
 5
0.065


1384
 5
0.092


1385
 5
0.152


1386
 5
0.180


1392
 5
0.693


1395
 5
0.866


1396
 5
1.159


1397
 5
1.165


1403
 5
12.331


1407
 5
<0.005


1412
 5

0.087


1442
 5

>16.6686


1444
 5

>16.6686


1445
 5

>16.6686


1491
 5

>16.6686


1460
 5

>16.6686


1434
 5

>16.6686


1477
 5
>16.6686


1432
 5

>16.6686


1489
 5
>16.6686
>16.6686


1490
 5

>16.6686


1481
 5
>16.6686


1436
 5
>16.6686
>16.6686


1473
 5

>16.6686


1475
 5

>16.6686


1446
 5

>16.6686


1447
 5

>16.6686


1448
 5

>16.6686


1449
 5

>16.6686


1450
 5

>16.6686


1451
 5

>16.6686


1452
 5

>16.6686


1453
 5

>16.6686


173
 6
0.532


174
 6
0.0062


175
 6
<0.005
<0.005


176
 6
<0.005


177
 6
0.0088


178
 6
<0.005


179
 6
0.0069


180
 6
<0.005


181
 6
<0.005


182
 6
<0.005


183
 6
<0.005


184
 6
0.0385


185
 6
2.63


186
 6
0.0068
0.0184


187
 6
0.546


188
 6
0.0409


189
 6
0.651


190
 6
2.51


191
 6
1.46


192
 6
2.36


193
 6
0.460


194
 6
0.553


195
 6
0.0824


196
 6
0.0159
0.216


197
 6
0.931


198
 6
0.211


199
 6
5.46


200
 6
0.168


201
 6
1.57


202
 6
0.477


203
 6
1.05


204
 6
0.371


205
 6
0.0189


206
 6
1.36


207
 6
0.0098


208
 6
0.0190
0.0920


209
 6
0.0170


210
 6
0.0101


211
 6
0.0143


212
 6
<0.005
<0.005


213
 6
<0.005


214
 6
<0.005


215
 6
0.0540


216
 6
0.0113


217
 6
0.561


218
 6
0.0200


219
 6
0.0145
0.0320


220
 6
<0.005


221
 6
<0.005


222
 6
0.242


223
 6
0.0164


224
 6
<0.005


225
 6
0.0523
0.0547


226
 6
0.0696


227
 6
<0.005
0.0070


228
 6
0.0204
<0.005


229
 6
<0.005
<0.005


230
 6
0.0116


231
 6
0.516


232
 6
<0.005
0.0829


233
 6
1.78


234
 6
0.157


235
 6
1.70


236
 6
0.499


237
 6
<0.005
<0.005


238
 6
0.0516


239
 6
<0.005
0.0100


240
 6
<0.005
0.0508


241
 6
0.0070


242
 6
<0.005


243
 6
0.0057


244
 6
<0.005


245
 6
<0.005
0.0164


246
 6
0.0200


247
 6
<0.005


248
 6
<0.005
0.0070


249
 6
0.0120


250
 6
<0.005
<0.005


251
 6
<0.005
0.0170


252
 6
0.0125
0.0808


253
 6
<0.005
0.0494


254
 6
<0.005
<0.005


255
 6
0.0102


256
 6
0.0110
0.0134


257
 6
<0.005
<0.005


258
 6
<0.005


259
 6
0.0060


260
 6
0.0089


261
 6
<0.005
0.0084


262
 6
<0.005
<0.005


263
 6
<0.005
0.0285


264
 6
0.0050


265
 6
<0.005
0.0190


266
 6
<0.005
0.0498


267
 6
<0.005


268
 6
0.0544


488
 6
0.0173
0.382


1070
 6
<0.005
0.008


1102
 6
<0.005
0.013


269
 7
0.215


270
 7
0.289


271
 7
0.210


272
 7
2.71


273
 7
0.0872


274
 7
0.0705


275
 7
1.07


276
 7
0.341


277
 7
4.70


278
 7
4.18


279
 7
0.640


280
 7
0.141


281
 7
0.0930


282
 7
<0.005


283
 7
0.0222


284
 7
4.88


285
 7
13.2


286
 7
0.150


287
 7
6.81


288
 7
3.54


289
 7
6.56


290
 7
0.0600


291
 7
0.0071


292
 7
2.59


293
 7
0.380


294
 7
0.638


295
 7
2.13


296
 7
1.04


297
 7
0.358


299
 8
0.683


300
 8
6.99


301
 8
0.326


302
 8
0.143


303
 8
0.314
0.173


304
 8
0.358


305
 8
0.132


306
 8
0.666


307
 8
0.408


308
 8
6.07


309
 8
1.17


310
 8
0.0842


311
 8
0.0640


312
 8
0.0065


480
 8
3.38


1057
 8

0.006


1078
 8

0.009


1085
 8

0.009


1087
 8

0.009


1094
 8

0.011


1112
 8

0.016


1118
 8

0.016


1140
 8

0.027


1143
 8

0.030


1145
 8

0.031


1169
 8

0.055


1217
 8

0.220


1222
 8

0.266


1232
 8

0.326


1256
 8

0.808


1258
 8

0.829


1262
 8

0.950


1269
 8

1.264


1308
 8

9.277


1310
 8

11.649


1324
 8

<0.005


1325
 8

<0.005


1335
 8

<0.005


1336
 8

<0.005


1398
 8
1.222


1423
 8

0.278


1424
 8

0.075


1425
 8

0.009


1426
 8

<0.005


1427
 8

0.006


1428
 8

0.014


1429
 8

0.036


186-A
 8

0.010


567-A
 8

0.028


1478
 8
>16.6686


1465
 8

>16.6686


313
 9
<0.005


314
 9
0.0100
<0.005


315
 9
5.00


316
 9
<0.005
<0.005


317
 9
0.0050
<0.005


318
 9
<0.005
0.0139


319
 9
0.0088


320
 9
8.53


321
 9
0.0378


322
 9
13.7


606
 9

2.038


647
 9

12.723


654
 9

0.007


681
 9

0.027


713
 9

0.135


718
 9

0.148


723
 9

0.181


745
 9

0.342


767
 9

0.691


775
 9

0.862


806
 9

2.052


812
 9

2.192


817
 9

2.700


820
 9

2.815


822
 9

2.856


829
 9

3.905


832
 9

4.239


856
 9

8.486


918
 9
2.891


1054
 9

0.005


1055
 9

0.005


1056
 9

0.006


1068
 9

0.007


1077
 9

0.008


1088
 9

0.010


1090
 9

0.010


1106
 9

0.014


1110
 9

0.015


1116
 9

0.016


1129
 9

0.021


1131
 9

0.022


1152
 9

0.038


1153
 9

0.039


1178
 9

0.071


1198
 9

0.143


1224
 9

0.270


1226
 9

0.282


1233
 9

0.343


1261
 9

0.932


1275
 9

1.722


1277
 9

1.834


1279
 9

1.902


1286
 9

2.417


1295
 9

3.278


1302
 9

4.948


1306
 9

8.151


1320
 9

<0.005


1367
 9

<0.005


1368
 9

<0.005


1369
 9

<0.005


1370
 9

<0.005


1371
 9

<0.005


1372
 9

<0.005


1373
 9

<0.005


1413
 9

0.015


1492
 9

>16.6686


1499
 9

>16.6686


118
 9b
0.664


119
 9b
3.17


120
 9b
0.0783


121
 9b
1.91


122
 9b
5.97


123
 9b
0.591


124
 9b
0.118
0.321


125
 9b
0.322


126
 9b
0.0510
0.0200


127
 9b
0.499


128
 9b
0.0045


129
 9b
0.281


130
 9b
0.823


131
 9b
0.0767


132
 9b
0.880


568
 9b

0.072


569
 9b

0.021


571
 9b

0.028


573
 9b

0.046


577
 9b

0.052


578
 9b

0.063


580
 9b

0.069


583
 9b

0.104


584
 9b

0.105


590
 9b

0.186


599
 9b

1.031


617
 9b
0.102


566
 9c

0.014


1375
 9c

<0.005


1421
 9c

<0.005


582
 9d

0.097


588
 9d

0.142


594
 9d

0.449


1109
 9d

0.015


1113
 9d

0.016


1133
 9d

0.024


1159
 9d

0.045


1171
 9d

0.063


1177
 9d

0.063


1182
 9d

0.079


633
 9e

0.062


1115
 9e

0.016


575
 9f

0.051


576
 9f

0.051


1080
 9f

0.009


1374
 9f

<0.005


1376
 9f

<0.005


1419
 9f

<0.005


1420
 9f

0.005


1422
 9f

0.014


1165
 9g

0.051


1210
 9g

0.195


819
 9h

2.790


601
 9i
0.490
1.552


602
 9i
0.302
1.717


607
 9i
0.894
2.905


608
 9i
0.766
4.166


609
 9i
0.735
4.332


980
 9i
2.442
6.792


989
 9i
1.566


990
 9i
3.870


991
 9i
0.564


1252
 9i
0.136
0.706


1255
 9i
<0.005
0.769


1290
 9i
0.187
2.700


1387
 9i
0.300


1388
 9i
0.351


1389
 9i
0.379


1390
 9i
0.461


1391
 9i
0.505


1393
 9i
0.726


1394
 9i
0.756


1399
 9i
2.373


1154
 9j
<0.005
0.040


1173
 9j

0.065


1190
 9j

0.099


1191
 9j

0.105


1193
 9j

0.116


1220
 9j

0.255


1237
 9j

0.393


1238
 9j
<0.005
0.437


1251
 9j

0.684


1254
 9j
0.023
0.765


1257
 9j

0.827


1282
 9j
0.019
2.072


323
10
0.0110


324
10
<0.005
<0.005


325
10
0.0150
0.0695


686
10

0.039


749
10

0.387


778
10

0.933


801
10

1.712


833
10

4.562


650
10a

0.006


666
10a

0.013


670
10a

0.015


900
10a

<0.005


659
10b

0.009


697
10b

0.062


901
10b

<0.005


902
10b

<0.005


326
11
<0.005
<0.005


327
11
0.0089


328
11
0.0540


329
11
0.0358
1.22


330
11
0.0440
0.308


331
11
<0.005
0.0457


332
11
0.0117


333
11
<0.005
0.0162


334
11
0.0143
0.363


335
11
0.0060
0.0121


336
11
<0.005
<0.005


337
11
<0.005
0.0130


504
11
<0.005
0.010


516
11

0.465


543
11
<0.005


684
11

0.031


742
11

0.306


810
11

2.143


897
11
<0.005
<0.005


898
11
<0.005
<0.005


908
11
0.031


929
11
<0.005


930
11
<0.005


338
12
<0.005
<0.005


339
12
0.113


340
12
0.843


341
12
3.63


342
12
0.0440


343
13
0.0059


344
13
0.0270


345
13
<0.005
<0.005


511
13

0.240


515
13

0.455


591
13

0.212


346
14
2.83


347
14
0.0877


600
14

1.154


605
14

1.861


917
14
2.107


919
14
4.004


920
14
4.427


924
14
9.685


1059
14

0.006


1060
14

0.006


1065
14

0.007


1066
14

0.007


1096
14

0.011


1101
14

0.012


1157
14

0.041


1160
14

0.045


1183
14

0.085


1321
14

<0.005


1342
14

<0.005


1343
14

<0.005


1351
14

<0.005


1352
14

<0.005


1353
14

<0.005


1354
14

<0.005


1075
14a

0.008


1149
14a

0.035


1175
14a

0.066


1205
14a

0.168


1196
14b

0.123


1204
14b

0.166


1211
14b

0.200


1241
14b

0.460


1244
14b

0.463


1209
14c

0.193


1213
14c

0.206


1294
14d

3.229


1303
14d

5.112


1443
14d

>16.6686


1476
14d

>16.6686


348
15
1.16


349
16
1.03


350
17
0.0991


351
17
1.97


352
17
1.67


353
17
3.97


354
17
1.56


546
17


1437
17

>16.6686


1486
17
>16.6686
>16.6686


538
17a
8.813


861
17a

9.221


903
17a
0.009


690
17b

0.046


916
17b
1.683


355
18
2.05


356
19
1.62


357
20
0.0385
3.75


358
21
0.0670


359
21
0.0094


360
21
0.0060


361
21
0.0355


362
21
0.542


363
21
3.12


364
21
0.0085
0.210


365
21
0.0332


665
21

0.013


679
21
0.010
0.024


685
21
0.029
0.033


729
21

0.236


736
21
<0.005
0.273


907
21
0.029


366
22
<0.005


367
22
0.0080


368
22
0.0050


369
22
0.165


370
23
<0.005


371
23
<0.005


879
23
0.006
<0.005


880
23
0.025
<0.005


680
23a

0.025


1458
23a
>16.6686


372
24
<0.005


373
24
<0.005


374
24
<0.005


375
24
0.0414


661
24

0.010


668
24

0.015


805
24

1.995


883
24

<0.005


376
25
1.08


377
25
3.35


378
25
5.06


379
26
0.0367


380
26
0.0542


381
26
0.0099
<0.005


382
26
0.913


383
26
0.476


384
26
0.349


385
26
0.110


386
26
1.25


387
26
0.348


388
26
0.429


389
26
9.27


390
26
2.43


391
26
0.227


392
26
0.558


393
26
0.141


394
26
0.434


395
26
0.437


396
26
0.790


397
27
0.0180


398
27
0.0254


399
27
0.0312


400
27
<0.005


401
27
<0.005


402
27
0.0476


403
27
0.0958


404
27
0.0418


405
27
0.0067


406
27
0.0831


407
27
<0.005
0.0506


408
27
0.239


409
27
1.39


481
27
0.244


482
27
0.236


483
27
0.338


484
27
0.696


552
27
0.147


560
27
1.978


957
27
<0.005
<0.005


960
27
0.007


962
27
<0.00500035


963
27
0.190


967
27
0.020
0.009


970
27
0.805


972
27
0.013
0.023


983
27
0.006


987
27
0.071


554
27a
0.179


978
27a
<0.00500035
0.007


981
27a
0.186


958
27b
0.313


961
27b
1.122


968
27b

0.019


979
27b

0.648


984
27b

2.497


410
28
0.0253


411
28
0.0478


412
28
0.0249


413
28
0.0406


414
28
0.0144


415
28
0.0110


416
28
0.0129


417
28
0.197


418
28
0.315


550
28
0.114


555
28
0.196


973
28
<0.005


975
28
1.174
0.162


974
28a

0.177


419
29
0.0070
0.170


420
29
0.0112


421
29
0.0060


422
29
0.0568


423
29
0.0050


424
29
<0.005
<0.005


425
29
0.160


426
29
0.278


662
29
0.021
0.011


931
29a


427
30
0.0334


428
30
<0.005


429
30
<0.005


430
30
0.0180
0.0236


431
30
<0.005


432
30
<0.005
<0.005


677
30a

0.021


790
30a

1.417


433
31
0.0249


508
31
0.006
0.107


651
31
<0.005
0.007


738
31
0.065
0.289


876
31
<0.005
<0.005


1507
31
>16.6686


564
31a
4.633
5.400


971
31a
1.536


976
31a
0.566
0.574


977
31a
5.563


807
31b

2.075


914
31c
0.760


1493
31c

>16.6686


1498
31c

>16.6686


434
32
0.0647


435
32
0.0267


436
32
0.331


437
32
1.52


438
32
0.977


439
33
0.672


440
33
4.07


441
33
10.3


442
33
3.78


443
33
3.35


444
33
3.22


445
33
2.28


446
33
2.36


447
33
0.667


448
33
1.90


449
33
8.12


450
34
0.0088


451
34
0.652


452
34
0.288


453
35
<0.005


454
35
0.0060


455
35
<0.005


548
35
0.027


959
35
0.005
<0.005


549
35a
0.104


551
35a
0.125


956
35a
0.048


969
35a
0.077


955
35b
0.713


964
35b

1.701


456
36
1.98


457
37
0.876


458
37
3.72


459
37
0.950


460
37
0.548


497
38
2.36


498
38
0.679


499
38
0.418


500
38
1.18


501
38
>16.7


495
39
>16.7


491
39
0.254


492
39
0.0788


493
39
0.169


494
39
0.0771


642
40
0.069


645
40
5.207


1488
41
>16.6686


1457
41
>16.6686


996
42

<0.005


997
42

<0.005


1006
42

0.374


1016
42

0.085


547
42

<0.005


563
42

2.493


985
42
0.008


995
42

<0.005


998
42

<0.005


999
42

0.008


1007
42

0.027


1008
42

<0.005


1009
42

0.065


1013
42

0.161


1014
42

0.257


1015
42

0.777


771
42

0.007


948
43

0.011


949
43

0.163


950
43

1.501


1025
43

0.019


507
44
0.013
0.052


518
44

1.605


520
44

2.027


522
44

2.680


525
44

6.995


527
44
3.512
8.566


532
44
1.419


533
44
1.804


537
44
7.588


652
44

0.007


663
44
<0.005
0.011


715
44

0.135


717
44

0.147


734
44
0.163
0.256


752
44

0.421


765
44
0.236
0.667


875
44
<0.005
<0.005


877
44
0.012
<0.005


904
44
0.011


909
44
0.074


913
44
0.516


1484
44
>16.6686


802
44a

1.721


837
44a

5.036


869
44a

12.871


872
44a

13.954


720
44b

0.173


757
44b

0.530


769
44b

0.725


784
44b

1.125


922
44b
6.494


514
45

0.454


519
45

1.620


521
45

2.190


660
45

0.010


683
45

0.031


708
45

0.106


878
45

<0.005


1494
45a

>16.6686


689
45b

0.045


803
45b

1.868


811
45b

2.151


1010
46

<0.005


1011
46

<0.005


1018
46

0.101


1019
46

0.006


1021
46

0.015


1023
46

0.041


1024
46

0.069


1267
46

1.125


1304
46

6.035


1309
46

9.363


1012
46a

0.013


1020
46a

0.063


1022
46a

0.067


1311
46a

14.615


529
47
0.147


530
47
0.165


542
47
<0.005


553
47
0.176


556
47
0.293


557
47
0.340


561
47
2.745


1005
47

0.237


709
48

0.118


671
49

0.016


1365
50

<0.005


1417
51

<0.005


1418
51

0.016


1063
52

0.007


1092
52

0.011


1315
52

<0.005


1316
53

<0.005


1317
53

<0.005


1319
53

<0.005


1142
53a

0.029


1318
53a

<0.005


597
54

0.600


604
54

1.841


1086
54

0.009


1130
54

0.022


1137
54

0.026


1170
54

0.059


1195
54

0.120


884
55

<0.005


885
55

<0.005


1081
55

0.009


1099
55

0.012


881
55a

<0.005


882
55a

<0.005


994
55a

0.013


724
55b

0.206


773
55b

0.845


1026
56

0.016


1027
56

0.014


1028
56

0.016


1033
56

<0.005


1034
56

<0.005


992
57

7.761


1430
57

9.892


1431
57
0.589


911
58
0.272


988
58
0.036


612
59
0.016


613
59
0.019


614
59
0.025


615
59
0.026


616
59
0.076


706
59

0.103


1074
59
0.014
0.008


1091
59
0.011
0.011


1093
59
<0.005
0.011


1104
59
<0.005
0.013


1108
59
0.019
0.014


1114
59

0.016


1117
59
<0.005
0.016


1124
59
<0.005
0.019


1138
59

0.026


1144
59
0.006
0.031


1168
59
<0.005
0.053


1172
59
0.010
0.063


1185
59
0.007
0.088


1188
59
0.027
0.094


1200
59
0.020
0.151


1208
59
<0.005
0.190


1221
59
0.008
0.258


1228
59
0.249
0.295


1234
59
0.024
0.356


1239
59
0.338
0.449


1240
59
0.139
0.459


1250
59
0.174
0.638


1253
59
0.031
0.725


1259
59
0.062
0.847


1265
59
0.072
1.050


1268
59

1.220


1273
59
0.234
1.609


1278
59
1.392
1.863


1280
59
0.239
1.978


1285
59
1.041
2.317


1288
59
1.123
2.511


1322
59
<0.005
<0.005


1323
59
0.012
<0.005


1377
59
0.004


1405
59
<0.005


1406
59
<0.005


1136
59a

0.025


1161
59a

0.046


1162
59a

0.047


1212
59a

0.204


1260
59a

0.862


759
60

0.579


761
60

0.583


780
60

0.978


834
60

4.595


841
60

5.257


851
60

7.870


1064
60

0.007


1167
60

0.053


1186
60

0.088


1207
60

0.179


1231
60

0.316


1270
60

1.429


1274
60

1.660


1281
60

2.023


635
60a

0.838


777
60a

0.913


789
60a

1.366


798
60a

1.630


858
60a

8.772


866
60a

10.325


1206
60a

0.171


1215
60a

0.216


1227
60a

0.287


1229
60a

0.306


1264
60a

0.986


1289
60a

2.603


1291
60a

2.785


1296
60a

3.299


1506
60a

>16.6686


932
60b

0.104


933
60b

0.191


934
60b

0.174


935
60b

0.100


936
60b

0.013


937
60b

0.250


938
60b

0.698


939
60b

2.357


940
60b

2.237


941
60b

1.372


942
60b

0.216


943
60b

10.387


944
60b

7.322


945
60b

1.476


509
61

0.136


653
61

0.007


895
61

<0.005


585
62

0.107


593
62

0.311


701
62

0.077


1084
62

0.009


1100
62

0.012


1132
62
<0.005
0.023


1148
62

0.033


1155
62

0.041


1347
62

<0.005


572
62a

0.031


634
62a

0.057


1340
62a

<0.005


1341
62a

<0.005


1344
62a

<0.005


1345
62a

<0.005


982
63
0.010
<0.005


986
64
0.005


510
65

0.181


513
65

0.371


528
65
0.125


570
65

0.022


691
65

0.046


695
65

0.057


707
65

0.105


712
65

0.127


714
65

0.135


737
65

0.285


1058
65

0.006


1095
65

0.011


1098
65

0.012


1346
65

<0.005


951
66

0.540


506
67

0.048


673
67

0.017


896
67

<0.005


512
67a

0.260


664
67a

0.011


699
67a

0.069


505
67b
<0.005
0.039


657
67b

0.009


674
67b
<0.005
0.019


692
67b

0.047


899
67b
<0.005
<0.005


649
68

0.006


700
68

0.072


704
68a

0.096


705
68a

0.099


574
69

0.049


589
69

0.146


631
70

0.040


632
70

0.281


1069
70

0.007


1348
70

<0.005


1349
70

<0.005


1111
70a

0.016


1350
70a

<0.005


1076
70b

0.008


1355
70b

<0.005


1414
70c

0.011


1415
70c

0.115


1416
70c

0.039


711
71

0.127


813
71

2.422


1031
71

0.111


1032
71

3.020


1035
71

4.622


1046
71

0.288


1047
71

4.628


1048
71

0.695


1029
72

<0.005


1030
72

0.013


1036
72

<0.005


1037
72

0.005


1038
72

<0.005


1039
72

0.005


1040
72

0.025


1043
72

0.016


1049
72

0.010


1050
72

0.024


1051
72

0.128


1052
72

0.028


1411
72

0.012


1044
72a

0.718


1045
72a

0.021


1508

0.046









Example 2
2-AG Accumulation Assay
To measure the accumulation of 2-AG due to inhibition of MGL, one g rat brain was homogenized using a Polytron homogenizer (Brinkmann, PT300) in 10 mL of 20 mM HEPES buffer (pH=7.4), containing 125 mM NaCl, 1 mM EDTA, 5 mM KCl and 20 mM glucose. Compounds of Formula (I) (10 μM) were pre-incubated with rat brain homogenate (50 mg). After a 15-min incubation time at 37° C., CaCl2 (final concentration=10 mM) was added and then incubated for 15 min at 37° C. in a total volume of 5 mL. The reactions were stopped with 6 mL organic solvent extraction solution of 2:1 chloroform/methanol. Accumulated 2-AG in the organic phase was measured by a HPLC/MS method, according to the following equation:

percent vehicle=(2-AG accumulation in the presence of compound/2-AG accumulation in vehicle)×100.










BIOLOGICAL DATA TABLE 2









Rat Brain 2AG % VehCntrl













Chemistry

(%)
(%)
(%)


Cpd
Example
(%) @0.01 μM
@0.1 μM
@1 μM
@10 μM















2
 1



911


5
 1
122
123
156
279


6
 1
75
238
554
623


7
 1

216
238
568


9
 1
99
184
529
1026


12
 1



448


13
 1



730


567
 1


455


579
 1


265


581
 1


140


587
 1


148


595
 1


128


1061
 1


618


1071
 1


552


1139
 1


654


1147
 1


892


1163
 1


244


1174
 1


1021


1201
 1


475


1356
 1


1420


1357
 1


2570


1358
 1


1183


1359
 1


1016


1360
 1


576


1361
 1


994


1362
 1


635


1363
 1


628


1364
 1


944


1366
 1


586


1382
 1



293


1408
 1


1475


487
 1a

463
2081
2182


1062
 1b


451


1072
 1b


839


1073
 1b


749


1089
 1b


545


1097
 1b


422


1105
 1b


734


1107
 1b


838


1120
 1b


867


1126
 1b


850


1134
 1b


774


1135
 1b


884


1176
 1b


378


1181
 1b


288


1312
 1b


963


1337
 1b


979


1338
 1b


877


1339
 1b


574


1184
 1c


401


1141
 1d

148
442
996


1151
 1d


482


1158
 1d


1623


1125
 1e


1228


1187
 1e


319


1313
 1f


851


39
 2

173
168
277


40
 2



490


41
 2



544


43
 2



215


44
 2



238


61
 3



604


676
 3


437


703
 3


346


716
 3


326


722
 3


240


741
 3


182


753
 3


173


1067
 3


408


1166
 3


176


1235
 3


100


1236
 3


167


1283
 3


62


72
 4



334


75
 4



193


77
 4



231


83
 4


105


133
 5



623


134
 5



582


135
 5



592


136
 5



612


137
 5



441


138
 5



661


147
 5



676


148
 5



744


150
 5



1104


158
 5


126
213


161
 5


335
1280


162
 5



1099


163
 5



923


164
 5



969


166
 5


509


167
 5


481


168
 5


813


170
 5


205


172
 5


217


476
 5



272


115
 5



579


485
 5

208
396
818


489
 5
119
235
790
950


490
 5
208
343
756
886


636
 5


296


637
 5


272


641
 5


397


648
 5


126


655
 5


359


658
 5


351


667
 5


856


669
 5


583


672
 5


268


675
 5


330


678
 5


234


682
 5


390


687
 5


698


688
 5


373


693
 5


299


696
 5


444


702
 5


848


886
 5


823


887
 5


270


888
 5


940


889
 5


683


890
 5


823


891
 5


422


892
 5


948


893
 5


626


894
 5


534


905
 5


119


965
 5


591


1017
 5


307


1082
 5


742


1083
 5


299


1103
 5


698


1122
 5


143


1150
 5

139
459
715


1156
 5


681


1164
 5


250


1179
 5


996


1326
 5


944


1327
 5


966


1328
 5


1086


1329
 5


834


1330
 5


589


1331
 5


803


1332
 5


1168


1333
 5


824


1378
 5


493


1379
 5


282


1381
 5


604


1384
 5


313


1407
 5


1287


174
 6



1258


175
 6

330
706
1180


176
 6



1124


177
 6



768


178
 6



1192


179
 6



910


180
 6



703


181
 6



1236


182
 6



1500


183
 6



1090


184
 6



956


186
 6
123
199
260
521


188
 6



506


195
 6



365


196
 6



516


205
 6



1172


207
 6



402


208
 6


480
324


209
 6



1681


210
 6



122


211
 6



725


212
 6



831


213
 6



104


214
 6



769


215
 6



1091


216
 6



625


218
 6



764


219
 6



851


220
 6



993


221
 6



945


223
 6



1261


224
 6



906


225
 6



656


226
 6



652


227
 6



938


228
 6



710


229
 6

276
552
1304


230
 6



567


232
 6


152
427


237
 6


1044
1182


239
 6
153
290
1097
1353


240
 6

184
538
639


243
 6


120


245
 6

224
518
829


248
 6


312


250
 6
180
472
1011
1327


251
 6

144
586
791


253
 6

107
319
624


254
 6


544


255
 6


115


256
 6


157


257
 6


285


259
 6


156


260
 6


140


261
 6

148
525
856


262
 6


386


263
 6


199


264
 6


172


265
 6

126
162
643


266
 6


395


267
 6


130


268
 6


110


488
 6

219
247.5
681


1070
 6


551


1102
 6


878


273
 7



623


274
 7



876


281
 7



201


282
 7



1775


283
 7



605


291
 7



1019


310
 8


141


311
 8


125


312
 8


198


1140
 8


200


1325
 8


575


186-A
 8


149


1465
 8


110


313
 9



814


314
 9
175
237
512
553


316
 9
243
265
760
694


317
 9


417


318
 9


537


319
 9



396


321
 9



230


654
 9


389


681
 9


406


713
 9


718
 9


723
 9


745
 9


767
 9


775
 9


806
 9


812
 9


817
 9


820
 9


822
 9


829
 9


832
 9


856
 9


918
 9


1054
 9


1008


1055
 9


701


1056
 9


498


1068
 9


849


1077
 9


667


1088
 9


760


1090
 9


1106
 9


784


1110
 9


807


1116
 9


828


1129
 9


437


1131
 9


563


1152
 9


394


1153
 9


404


1178
 9


292


1198
 9


1224
 9


1226
 9


1233
 9


1261
 9


1275
 9


1277
 9


1279
 9


1286
 9


1295
 9


1302
 9


1306
 9


1320
 9


823


1367
 9


798


1368
 9


859


1369
 9


874


1370
 9


773


1371
 9


827


120
 9b



483


126
 9b
128
138
328
715


128
 9b



688


129
 9b


499


131
 9b



1406


569
 9b


198


571
 9b


307


573
 9b


277


577
 9b


207


580
 9b


179


582
 9d


169


1109
 9d


680


1113
 9d


819


1133
 9d


296


1159
 9d


654


1171
 9d


839


1177
 9d


895


1182
 9d


547


1255
 9i


147


1154
 9j


558


1173
 9j


133


1190
 9j


126


1254
 9j


187


1282
 9j


128


323
10



494


324
10

941
1215
1265


325
10


478


686
10


552


650
 10a


960


666
 10a


359


670
 10a


650


900
 10a


543


659
 10b


576


697
 10b


431


901
 10b


816


902
 10b


585


326
11


1336


327
11


904
2005


328
11


378


329
11



520


330
11


197


331
11


310


332
11


182


333
11


291


334
11


259


335
11
170
438
839
1059


336
11


223


337
11
103
166
272
671


504
11


178.5


543
11


158


684
11


645


897
11


1234


898
11


520


908
11


217


929
11


301


930
11


807


338
12


2111
791


342
12



288


343
13


1371


344
13


238


345
13


744


347
14


125


1059
14


507


1060
14


671


1065
14


531


1066
14


609


1096
14


449


1101
14


501


1157
14


252


1160
14


260


1183
14


549


1342
14


346


1343
14


838


1351
14


718


1352
14


548


1353
14


545


1354
14


750


1075
 14a


833


350
17



498


903
 17a


908


690
 17b


367


357
20


152


358
21


556


359
21


176


360
21


819


361
21


186


364
21


581


365
21


971


665
21


507


679
21


751


685
21


756


736
21


499


907
21


867


366
22


432


367
22


701


368
22


434


906
22


896


927
22


850


928
22


1207


370
23


888


371
23


1138


879
23


1027


880
23


945


680
 23a


356


661
24


764


668
24


679


883
24


767


379
26



760


380
26



773


381
26



520


397
27



243


398
27


392


400
27



1076


401
27



762


402
27


97


403
27


188


405
27



1591


406
27


99


407
27

127
441
743


957
27


1442


960
27


896


962
27


1213


967
27


1373


972
27


683


983
27


194


987
27


320


978
 27a


570


968
 27b


360


410
28



720


411
28



741


412
28



1271


413
28



1693


414
28



1608


415
28



1629


416
28


228


973
28


806


419
29


109


422
29


120


423
29


529


424
29


436


662
29


274.5


427
30


163


428
30


734


429
30


318


430
30


114


431
30


703


432
30


321


677
 30a


141


433
31


159


508
31


119


651
31


258


876
31


363


434
32



737


435
32



198


453
35


917


454
35


1066


455
35


1013


548
35


280


959
35


861


956
 35a


514


969
 35a


515


494
39



1121


642
40


170


996
42


458


997
42


761


1016
42


536


547
42


652


985
42


1116


995
42


1080


998
42


639


999
42


458


1007
42


180


1008
42


1125


1009
42


706


771
  42.9


465


1025
43


851


507
44


190


518
44


86


663
44


588


875
44

232
499
1285


877
44


475


904
44


392


909
44


144


660
45


410


683
45


335


878
45


288


689
 45b


136


1010
46


1953


1011
46


994


1019
46


287


1021
46


232


1023
46


262


1024
46


281


1012
 46a


173


1020
 46a


135


1022
 46a


189


542
47


366


671
49


1035


1365
50


909


1063
52


846


1092
52


838


1315
52


486


1316
53


602


1317
53


722


1319
53


1276


1142
 53a


1314


1318
 53a


1282


1086
54


488


1130
54


553


1137
54


582


1170
54


258


884
55


425


885
55


722


1081
55


622


1099
55


508


881
 55a


847


882
 55a


697


994
 55a


1014


1026
56


1014


1027
56


785


1028
56


647


612
59


106


613
59


165


614
59


87


615
59


123


616
59


92


1074
59


303


1091
59


450


1093
59


472


1104
59


334


1108
59

117
204
456


1114
59


293


1117
59


437


1124
59


506


1138
59


271


1144
59


212


1168
59


780


1172
59


931


1185
59


241


1188
59


187


1200
59


231


1208
59


212


1221
59

198
197.5
522


1234
59


226


1253
59

110
190
407


1259
59


159


1265
59


192


1322
59


457


1323
59


297


1405
59


197


1406
59


169


1136
 59a


325


1161
 59a


459


1162
 59a


237


1064
60


570


1167
60


345


1186
60


393


509
61


242


653
61


861


895
61


1207


701
62


475


1084
62


1165


1100
62


1133


1132
62


1259


1148
62


344


1155
62


617


1347
62


741


572
 62a


397


634
 62a


301


1340
 62a


761


1341
 62a


1149


1344
 62a


543


1345
 62a


459


982
63


762


986
64


626


570
65


210


691
65


840


695
65


497


1058
65


590


1095
65


484


1098
65


296


1346
65


406


506
67


132


673
67


280


896
67


648


664
 67a


498


699
 67a


253


505
 67b


236.5


657
 67b


581


674
 67b


891


692
 67b


284


899
 67b


1092


649
68


1017


700
68


547


705
 68a


487


574
69


207


1069
70


696


1348
70


1428


1349
70


846


1111
 70a


508


1350
 70a


873









Example 3
MGL ThermoFluor® Assay—Mutant
The ThermoFluor (TF) assay is a 384-well plate-based binding assay that measures thermal stability of proteins1,2. The experiments were carried out using instruments available from Johnson & Johnson Pharmaceutical Research & Development, LLC. TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47). Final TF assay conditions used for MGL studies were 0.07 mg/ml of mutant MGL, 100 μM ANS, 200 mM NaCl, 0.001% Tween-20 in 50 mM PIPES (pH=7.0).
Screening compound plates contained 100% DMSO compound solutions at a single concentration. For follow-up concentration-response studies, compounds were arranged in a pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds were serially diluted in 100% DMSO across 11 columns within a series. Columns 12 and 24 were used as DMSO reference and contained no compound. For both single and multiple compound concentration-response experiments, the compound aliquots (46 nL) were robotically predisposed directly into 384-well black assay plates (Abgene: TF-0384/k) using the Hummingbird liquid handler. Following compound dispension, protein and dye solutions were added to achieve the final assay volume of 3 μL. The assay solutions were overlayed with 1 μL of silicone oil (Fluka, type DC 200: 85411) to prevent evaporation.
Bar-coded assay plates were robotically loaded onto a thermostatically controlled PCR-type thermal block and then heated from 40 to 90° C. degrees at a ramp-rate of 1° C./min for all experiments. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6), supplied via fiber optics and filtered through a band-pass filter (380-400 nm; >60D cutoff). Fluorescence emission of the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) filtered to detect 500±25 nm, resulting in simultaneous and independent readings of all 384 wells. A single image with 20-sec exposure time was collected at each temperature, and the sum of the pixel intensity in a given area of the assay plate was recorded vs temperature and fit to standard equations to yield the Tm1.

    1. Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. (2001) J Biomol Screen 6, 429-40.
    2. Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Biochemistry 44, 5258-66.


The Kd values for compounds of Formula (I) were determined from a fit of the equation to the concentration-response plot of the fractional activity as a function of Tm. For some experiments, quantitative NMR spectroscopy (qNMR) was used to measure concentration of the initial 100% DMSO compound solutions and, using the same fitting method, qKd values were determined










BIOLOGICAL DATA TABLE 3








MGL mutant




MGL mutant
ThermoFluor qKd (μM)


Cpd
Example
ThermoFluor Kd (μM)
(using qNMR conc.)


















1
 1
0.00590



2
 1
0.00049


3
 1
2.50


4
 1
0.143


5
 1
0.0548


6
 1
0.00360


7
 1
0.0466


8
 1
0.111


9
 1
0.00248


10
 1
0.556


11
 1
0.454


12
 1
0.0143


13
 1
0.00300


14
 1
0.250


15
 1
0.286


22
 1
>76.7


23
 1
5.00


24
 1
5.00


25
 1
10.0


26
 1
3.33


567
 1
0.051


579
 1
0.067


581
 1
0.100


587
 1
0.473


595
 1
0.404


598
 1
0.249


1071
 1
0.025


1139
 1
0.017


1147
 1
0.003


1163
 1
0.073


1174
 1
0.015


1201
 1
0.179


1248
 1
0.043


1356
 1
0.002


1357
 1
0.002


1358
 1
0.007


1359
 1
0.008


1360
 1
0.008


1361
 1
0.003


1362
 1
0.001


1363
 1
0.014


1364
 1
0.001


1366
 1
0.012


1382
 1
0.197


1408
 1
0.012


487
 1a
0.00240


586
 1b

0.086


596
 1b

0.628


603
 1b

0.448


630
 1b

0.195


1062
 1b

0.100


1072
 1b

0.007


1073
 1b

0.087


1089
 1b
0.009
0.006


1097
 1b
0.032


1105
 1b

0.023


1107
 1b

0.003


1120
 1b

0.020


1121
 1b

0.042


1126
 1b

0.008


1127
 1b

0.098


1128
 1b

0.018


1134
 1b

0.009


1135
 1b

0.015


1176
 1b

0.161


1181
 1b

0.278


1189
 1b

0.153


1192
 1b

0.035


1197
 1b

0.065


1216
 1b

0.022


1219
 1b

0.025


1230
 1b
0.009


1247
 1b

0.650


1263
 1b

0.215


1312
 1b

0.008


1314
 1b

0.001


1337
 1b
0.040


1338
 1b
0.015


1339
 1b
0.013


1410
 1b

0.014


656
 1c

0.101


1079
 1c

0.272


1184
 1c

0.244


1199
 1c

0.264


1141
 1d
0.088


1151
 1d
0.048


1158
 1d
0.008


592
 1e
0.500


1125
 1e
0.037


1187
 1e
0.197


629
 1f
0.145


1180
 1f

0.019


1313
 1f
0.003
0.001


1409
 1g


27
 2
4.55


28
 2
0.370


29
 2
0.100


30
 2
0.118


31
 2
1.43


32
 2
0.192


33
 2
0.00910


34
 2
0.588


35
 2
0.0833


36
 2
0.0370


37
 2
0.100


38
 2
0.182


39
 2
0.0250


40
 2
0.0242


41
 2
0.00400


42
 2
0.0833


47
 2
0.0909


48
 2
1.00


49
 2
6.67


50
 2
10.0


51
 2
0.250


52
 2
3.33


53
 2
0.100


55
 2
25.0


470
 2
2.94


471
 2
2.50


472
 2
6.67


531
 2
2.733


539
 2
>31.2464


541
 2
1.662


559
 2
100.000


562
 2
>31.2464


565
 2
>31.2464


622
 2
3.601


627
 2
10.000


628
 2
100.000


954
 2

3.438


1266
 2
0.032


1284
 2
0.041


1404
 2
>31.2464


1482
 2
>31.2464


1483
 2
>31.2464


1485
 2
10.000


1464
 2
>31.2464


61
 3
0.0290


676
 3
0.029


703
 3
0.050


716
 3
0.040


722
 3
0.082


741
 3
0.200


753
 3
0.515


921
 3
4.260


1067
 3
0.007


1166
 3
0.010


1235
 3
0.124


1236
 3
0.031


1242
 3
0.197


1243
 3
0.033


1246
 3
0.042


1276
 3
0.807


1283
 3
0.523


1292
 3
0.631


1383
 3
0.108


1400
 3
4.071


1401
 3
1.250


1402
 3
2.000


76
 4
0.333


77
 4
0.00909


78
 4
0.0800


79
 4
0.0266


80
 4
49.5


81
 4
0.0667


82
 4
0.571


83
 4
0.111


474
 4
5.00


103
 4
6.25


104
 4
5.00


105
 4
5.00


106
 4
0.154


107
 4
0.556


108
 4
1.25


109
 4
0.0333


110
 4
5.00


111
 4
10.0


496
 4
0.287


558
 4
0.333


618
 4
0.080


619
 4
0.172


620
 4
0.154


621
 4
0.263


623
 4
1.000


624
 4
0.880


625
 4
>31.2464


626
 4
5.018


150
 5
0.00330


151
 5
0.0250


158
 5
0.476


161
 5
0.0112


162
 5
0.00067


163
 5
0.00345


164
 5
0.00111


166
 5
0.00500


167
 5
0.0558


168
 5
0.0100


169
 5
30.3


170
 5
0.0606


171
 5
0.708


172
 5
0.100


475
 5
0.0250


476
 5
0.0667


477
 5
2.00


478
 5
2.00


479
 5
6.67


298
 5
2.91


113
 5
1.11


114
 5
0.00333


115
 5
0.0370


116
 5
2.00


489
 5
0.0104


490
 5
0.00840


485
 5
0.0257


502
 5
>76.6655


503
 5
0.254


517
 5
0.050


523
 5
0.686


524
 5
1.667


526
 5
4.984


610
 5
1.295


611
 5
5.152


636
 5
0.119


637
 5
0.053


638
 5
0.172
0.264


639
 5
0.132


640
 5
24.998


641
 5
0.118
0.136


643
 5
1.000


644
 5
>76.6655


646
 5
1.608


648
 5
0.146


655
 5
0.029


658
 5

0.402


667
 5
0.013


669
 5
0.005


672
 5
0.016


675
 5

0.025


678
 5
0.031


682
 5

0.014


687
 5
0.004


688
 5
0.046


693
 5
0.060


694
 5

0.048


696
 5

0.063


698
 5

0.085


702
 5

0.207


710
 5

0.197


719
 5

0.119


721
 5
1.138


726
 5
0.127


727
 5

0.251


728
 5


730
 5

0.146


731
 5
0.016


732
 5
0.002


733
 5

0.453


735
 5
0.160


739
 5

0.265


740
 5
0.035


743
 5

0.133


744
 5


746
 5

0.263


747
 5
0.111


748
 5
0.040


750
 5
0.025


751
 5
1.320


755
 5
0.328


756
 5
0.383


758
 5

0.500


760
 5
0.199


762
 5

1.000


763
 5
0.083


766
 5

0.378


770
 5

1.132


772
 5
0.185


774
 5

0.254


776
 5
0.257


779
 5
0.100


782
 5

0.463


783
 5

0.732


785
 5
0.500


786
 5

0.665


787
 5

0.247


788
 5

1.980


791
 5

0.402


792
 5

0.973


793
 5
0.198


794
 5
2.113


795
 5
1.105


796
 5
0.099


797
 5

0.489


799
 5
0.661


800
 5
1.100


804
 5
0.105


808
 5
62.503


809
 5
0.769


814
 5
>31.0027


815
 5
0.250


816
 5

2.842


818
 5
1.000


823
 5

1.251


824
 5

0.074


825
 5

4.855


826
 5

0.663


827
 5
0.500


828
 5
2.633


830
 5

1.963


831
 5
0.270


835
 5

2.454


836
 5

2.252


838
 5
0.978


839
 5

2.500


840
 5
2.000


842
 5
0.986


843
 5
2.134


844
 5
62.503


845
 5

1.619


848
 5
0.833


849
 5
2.697


850
 5
1.000


852
 5

1.977


853
 5
1.000


854
 5
100.000


857
 5
3.334


859
 5
1.429


860
 5
1.759


862
 5
>21.8726


863
 5

4.367


864
 5
2.410


865
 5

2.500


868
 5

>23.126


873
 5

9.198


874
 5

8.461


887
 5
0.009


888
 5
0.000


889
 5
0.002


890
 5
0.001


891
 5
0.008


892
 5
0.007


893
 5
0.005


894
 5
0.006


905
 5
0.044


910
 5
1.331


912
 5
1.319


915
 5
5.000


923
 5
9.931


925
 5
>62.5029


926
 5
9.443


946
 5

1.693


947
 5

0.653


952
 5

0.019


953
 5

>26.872


965
 5
0.035


966
 5
0.334


993
 5
0.333


1017
 5
0.049


1041
 5

0.397


1042
 5

5.000


1053
 5

0.247


1082
 5
0.003


1083
 5

0.065


1119
 5

0.020


1122
 5
0.027


1123
 5

1.351


1146
 5

0.080


1150
 5
0.013


1156
 5
0.090


1179
 5
0.005


1194
 5
0.100


1202
 5
0.065


1203
 5

0.015


1223
 5
0.111


1225
 5
0.042


1245
 5
0.317


1249
 5
0.241


1271
 5
1.000


1272
 5

0.399


1287
 5
0.495


1293
 5
1.667


1298
 5
0.474


1299
 5
1.100


1300
 5
3.334


1305
 5
0.833


1307
 5
4.207


1326
 5
0.004


1327
 5
0.005


1328
 5
0.002


1329
 5
0.006


1330
 5
0.002
0.005


1331
 5

0.010


1332
 5

0.008


1333
 5

0.040


1334
 5

0.080


1378
 5
0.025


1379
 5
0.042


1381
 5
0.083


1384
 5
0.061


1385
 5
0.206


1386
 5
0.133


1392
 5
0.659


1395
 5
1.805


1396
 5
0.317


1397
 5
0.500


1403
 5
1.688


1407
 5
0.005


1412
 5
0.241


1444
 5
>31.0027


1445
 5
>31.2464


1491
 5
12.500


1434
 5
53.753


1477
 5
>31.2464


1432
 5

>28.4381


1489
 5
100.000


1490
 5
>31.2464


1481
 5
>31.2464


1436
 5
100.000


1473
 5
6.667


1475
 5
>31.2464


1446
 5
62.503


1447
 5

3.334


1448
 5
7.091


1449
 5
3.194


1450
 5

12.639


1451
 5

>16.248


1452
 5

5.424


1453
 5

10.000


223
 6
0.00670


225
 6
0.0200


226
 6
0.0200


229
 6
0.0125


231
 6
0.143


233
 6
1.32


234
 6
0.0476


235
 6
0.588


236
 6
0.200


237
 6
0.00100


238
 6
0.0333


239
 6
0.00500


240
 6
0.0232


241
 6
0.00050


242
 6
0.00400


243
 6
0.0167


244
 6
0.00200


245
 6
0.00950


246
 6
0.0167


247
 6
0.00040


248
 6
0.00670


249
 6
0.0100


250
 6
0.00170


251
 6
0.0143


252
 6
0.0500


253
 6
0.0215


254
 6
0.00590


255
 6
0.0270


256
 6
0.0333


257
 6
0.00330


258
 6
0.00330


259
 6
0.00770


260
 6
0.0200


261
 6
0.00910


262
 6
0.00250


263
 6
0.00500


264
 6
0.0100


265
 6
0.0198


266
 6
0.0160


267
 6
0.0125


268
 6
0.0250


488
 6
0.321


1070
 6
0.006


1102
 6
0.006


295
 7
0.833


296
 7
0.476


297
 7
0.333


308
 8
10.0


309
 8
0.253


310
 8
0.250


311
 8
0.0800


312
 8
0.0250


480
 8
>76.7


1057
 8

0.016


1078
 8

0.005


1085
 8

0.008


1087
 8

0.023


1094
 8

0.012


1112
 8

0.046


1118
 8

0.053


1140
 8
0.112


1143
 8

0.070


1145
 8

0.061


1169
 8

0.053


1217
 8

0.104


1222
 8
0.068


1232
 8
0.345


1256
 8
0.393


1258
 8
0.020


1262
 8
0.278


1269
 8
1.165


1308
 8
2.056


1310
 8
8.348


1324
 8
0.016


1325
 8
0.006


1335
 8

0.011


1336
 8

0.002


1398
 8
0.182


1423
 8

0.176


1424
 8

0.124


1425
 8

0.019


1426
 8

0.029


1427
 8

0.010


1428
 8

0.018


1429
 8

0.097


186-A
 8
0.016


567-A
 8

0.124


1478
 8
>31.2464


1465
 8
>31.2464


314
 9
0.0392


316
 9
0.0165


317
 9
0.0100


318
 9
0.0165


606
 9
0.067


647
 9
>31.2464


654
 9
0.040


681
 9

0.067


713
 9
0.100


718
 9
0.072


723
 9

0.292


745
 9

0.283


767
 9


775
 9
0.333


806
 9

0.989


812
 9
0.644


817
 9


820
 9

0.996


822
 9


829
 9
0.500


832
 9
0.059


856
 9

0.855


918
 9
2.500


1054
 9
0.001
0.001


1055
 9

0.020


1056
 9

0.012


1068
 9

0.002


1077
 9

0.020


1088
 9
0.001


1090
 9

0.010


1106
 9
0.006
0.005


1110
 9

0.010


1116
 9

0.001


1129
 9

0.074


1131
 9
0.016


1152
 9
0.007


1153
 9

0.004


1178
 9

0.238


1198
 9
0.030


1224
 9

0.189


1226
 9

0.193


1233
 9
0.190


1261
 9
0.831


1277
 9

2.722


1279
 9

1.864


1286
 9
0.032


1295
 9

1.509


1302
 9
2.500


1306
 9

12.193


1320
 9

0.015


1367
 9
0.002


1368
 9

0.001


1369
 9

0.002


1370
 9

0.013


1371
 9

0.003


1372
 9

0.002


1373
 9

0.004


1413
 9

0.003


1492
 9
18.763


1499
 9
60.618


126
 9b
0.0921


128
 9b
0.00400


129
 9b
0.0100


130
 9b
0.250


131
 9b
0.0941


132
 9b
0.250


568
 9b

0.099


569
 9b

0.059


571
 9b
0.046
0.080


573
 9b

0.100


577
 9b

0.026


578
 9b

0.195


580
 9b

0.118


583
 9b

0.051


590
 9b

0.182


599
 9b
0.481


566
 9c

0.031


1375
 9c

0.003


1421
 9c

0.044


582
 9d
0.119


588
 9d

0.512


594
 9d

0.743


1109
 9d
0.022


1113
 9d

0.010


1133
 9d
0.036


1159
 9d
0.003


1171
 9d
0.024


1177
 9d

0.088


1182
 9d

0.210


633
 9e
0.157


1115
 9e

0.005


575
 9f

0.083


576
 9f

0.088


1080
 9f

0.006


1374
 9f

0.007


1376
 9f

0.013


1419
 9f
0.004


1420
 9f

0.080


1422
 9f

0.195


1165
 9g

0.090


1210
 9g

0.097


601
 9i
0.527


602
 9i
0.500


607
 9i
1.000


608
 9i
1.674


609
 9i
1.000


980
 9i
5.000


989
 9i
1.250


990
 9i
1.000


991
 9i
0.200


1252
 9i
0.386


1255
 9i
0.048


1290
 9i
0.643


1389
 9i
0.422


1154
 9j
0.006


1173
 9j
0.007


1190
 9j
0.008


1191
 9j
0.011


1193
 9j
0.017


1220
 9j
0.015


1237
 9j
0.064


1238
 9j
0.125


1251
 9j
0.146


1254
 9j
0.100


1257
 9j
0.009


1282
 9j
0.200


1380
 9j
0.246


323
10
0.00130


324
10
0.00040


325
10
0.0927


686
10

0.002


749
10

0.036


778
10

1.195


801
10
52.505


833
10

3.334


666
10a
0.002
0.003


670
10a
0.001
0.001


900
10a
0.001
0.001


659
10b

0.006


697
10b

0.024


901
10b

0.001


902
10b

0.004


326
11
0.00040


327
11
0.0137


328
11
0.0816


329
11
0.0626


330
11
0.438


331
11
0.00690


332
11
0.109


333
11
0.00390


334
11
0.132


335
11
0.00193


336
11
0.00950


337
11
0.0498


504
11
0.024


516
11
0.040


543
11
0.038


684
11
0.004


742
11
0.020


810
11
0.290


897
11
0.002


898
11
0.009


908
11
0.093


929
11
0.020


930
11
0.005


338
12
0.00110


343
13
0.00040


344
13
0.0100


345
13
0.00310


511
13
0.002


515
13
0.011


591
13
0.007


347
14
0.125


600
14

1.968


605
14
1.892


917
14
4.995


919
14
100.000


920
14
100.000


924
14
100.000


1059
14

0.066


1060
14

0.032


1065
14

0.036


1066
14

0.031


1096
14

0.080


1101
14

0.044


1157
14

0.179


1160
14

0.139


1183
14

0.067


1321
14

0.067


1342
14
0.136


1343
14
0.077


1351
14

0.043


1352
14

0.008


1353
14

0.018


1354
14

0.009


1075
14a

0.010


1149
14a

0.004


1175
14a

0.010


1205
14a

0.008


1196
14b

0.370


1204
14b

0.249


1211
14b

0.106


1241
14b

0.638


1244
14b

0.589


1209
14c

0.942


1213
14c

0.765


1294
14d

4.412


1303
14d

7.115


1443
14d
>31.2464


1476
14d

7.208


546
17
12.365


1437
17
33.335


1486
17
>31.2464


538
17a
2.594


861
17a
2.625


903
17a
0.078


690
17b
0.104


357
20
0.238


358
21
0.0650


359
21
0.0829


360
21
0.0680


361
21
0.144


362
21
2.40


363
21
6.76


665
21
0.058


685
21
0.067


729
21
0.185


736
21
0.067


366
22
0.0353


367
22
0.0853


368
22
0.0551


370
23
0.00100


680
23a
0.053


1458
23a
100.000


372
24
0.0494


373
24
0.00550


374
24
0.00220


375
24
0.229


661
24
0.047


668
24
0.025


805
24
6.405


883
24
0.059


376
25
7.14


377
25
>76.7


378
25
>76.7


379
26
0.0400


393
26
0.0909


394
26
0.846


395
26
0.159


396
26
4.27


397
27
0.0333


398
27
0.0869


399
27
0.0408


401
27
0.00167


402
27
0.141


403
27
0.338


404
27
0.00170


405
27
0.00200


406
27
0.932


407
27
0.0988


408
27
1.94


409
27
2.03


483
27
0.0200


552
27
0.400


560
27
0.652


957
27
0.008


960
27
0.036


962
27
0.005


963
27
0.102


967
27
0.044


970
27
0.535


972
27
0.080


983
27
0.019


987
27
0.327


554
27a
1.985


978
27a
0.066


981
27a
0.937


958
27b
0.216


961
27b
0.576


968
27b

1.462


979
27b

1.143


984
27b

1.429


410
28
0.0333


411
28
0.0333


412
28
0.0100


413
28
0.00200


414
28
0.0250


415
28
0.00800


416
28
0.160


417
28
0.0667


418
28
0.500


555
28
2.000


975
28
2.000


974
28a

1.776


419
29
0.123


420
29
0.00500


421
29
0.00400


422
29
0.0532


423
29
0.00690


424
29
0.00941


425
29
0.200


426
29
0.250


662
29
0.100


427
30
0.0335


428
30
0.00330


429
30
0.0331


430
30
0.0667


432
30
0.0250


677
30a

0.432


790
30a

2.494


508
31
0.162


651
31
0.025


738
31
0.291


564
31a
10.000


976
31a
1.837


977
31a
19.999


807
31b

3.652


450
34
0.0500


452
34
0.200


453
35
0.0120


454
35
0.0147


455
35
0.00850


548
35
0.062


959
35
0.044


549
35a
0.060


551
35a
0.180


956
35a
0.081


969
35a
0.069


955
35b
1.111


964
35b

3.198


456
36
>76.7


457
37
4.82


458
37
6.67


459
37
3.33


460
37
9.10


491
39
0.100


492
39
0.167


493
39
0.0250


494
39
0.100


642
40
0.499


645
40
5.443


1488
41
>31.2464


1457
41
>31.2464


997
42
0.041


1006
42
0.667


1016
42
0.460


547
42
0.072


563
42
2.106


985
42
0.005


995
42
0.002


1007
42
0.259


1008
42
0.089


1009
42
0.589


1013
42
0.760


1014
42
0.903


1015
42
1.183


771
42
0.050


948
43
0.030


949
43
0.178


950
43

0.883


1025
43

0.066


507
44
0.317


520
44
2.000


522
44
4.708


525
44
2.500


527
44
10.000


532
44
2.331


533
44
10.000


537
44
3.334


663
44
0.020


715
44
0.167


717
44
0.067


734
44
1.255


752
44
0.095


765
44
3.094


875
44
0.010


877
44
0.100


904
44
0.633


909
44
0.325


913
44
1.000


1484
44
19.999


802
44a

1.667


837
44a

19.999


869
44a

6.202


872
44a

10.000


720
44b
0.347


757
44b
0.781


769
44b
2.000


784
44b
2.149


922
44b
3.890


514
45
0.727


519
45
0.962


660
45
0.065


683
45
0.039


878
45
0.088


1494
45a

7.377


803
45b
2.126


811
45b
3.334


1010
46
0.017
0.040


1011
46
0.124


1018
46
0.207


1019
46
0.166
0.132


1021
46
0.239


1023
46
0.143


1024
46

0.135


1267
46

0.741


1304
46

7.903


1309
46

6.540


1012
46a

3.337


1020
46a
3.004


1022
46a
0.228
1.061


1311
46a

67.499


529
47
0.317


530
47
0.089


542
47
0.014


553
47
0.372


556
47
0.097


557
47
0.114


561
47
0.542


1005
47
0.083


709
48
0.015


671
49

0.018


1365
50
0.002


1417
51
0.025


1418
51
0.054


1063
52
0.003


1092
52
0.005


1315
52
0.002


1316
53
0.002


1317
53
0.002


1319
53

0.001


1142
53a

0.001


1318
53a
0.000


597
54
0.153


1137
54
0.010


1170
54
0.014


1195
54
0.023


884
55

0.017


885
55

0.001


1081
55

0.019


1099
55

0.020


881
55a
0.006


882
55a
0.012


994
55a
0.002


724
55b
0.050


773
55b
0.040


1026
56

0.001


1027
56

0.012


1028
56

0.011


1033
56

0.000


1034
56

0.000


992
57
0.561


1430
57
50.003


1431
57
0.035


911
58
0.333


988
58
0.040


612
59
0.078


613
59
0.051


614
59
0.066


615
59
0.097


616
59
>76.6655


706
59
0.001


1074
59
0.011


1091
59
1.644


1093
59
0.240


1104
59
0.199


1108
59
0.063


1114
59
0.049


1117
59
0.214


1124
59
0.250


1138
59
0.018


1144
59
0.181


1168
59
0.067


1172
59
0.178


1185
59
1.318


1188
59
0.855


1200
59
0.500


1208
59
1.000


1221
59
0.081


1228
59
1.422


1234
59
0.394


1239
59
3.040


1240
59
2.488


1250
59
2.000


1253
59
0.088


1259
59
0.667


1265
59
0.660


1268
59

0.039


1273
59
1.827


1278
59
5.192


1280
59
6.422


1285
59
2.450


1288
59
2.159


1322
59
0.002


1323
59
0.004


1377
59
0.006


1405
59
0.002


1406
59
0.029


1161
59a
0.025


1162
59a

0.014


1260
59a
0.221


759
60

0.037


761
60

0.092


780
60

0.128


834
60

0.234


841
60

0.917


851
60

0.883


1064
60

0.018


1167
60

0.025


1186
60

0.035


1207
60
0.014


1231
60

0.131


1270
60

0.265


1274
60

0.248


1281
60

0.194


777
60a

0.048


789
60a

0.043


798
60a

0.004


858
60a

0.561


866
60a

0.824


1206
60a

0.018


1215
60a

0.006


1227
60a

0.011


1229
60a

0.011


1264
60a

0.251


1289
60a

0.130


1291
60a

0.179


1296
60a

0.197


932
60b
0.008


933
60b
0.034


934
60b
0.025


935
60b
0.034


936
60b
0.012


937
60b
0.096


938
60b
0.091


939
60b
0.302


940
60b
0.259


941
60b
0.389


942
60b
0.135


943
60b
1.045


944
60b
0.802


945
60b
0.083


509
61
0.033


653
61
0.011


895
61
0.000


593
62
0.010


701
62
0.008


1132
62
0.002


572
62a
0.030


634
62a
0.054


1340
62a
0.001


1341
62a
0.001


1344
62a
0.010


1345
62a
0.006


982
63
0.010


986
64
0.005


510
65
0.068


513
65
0.009


528
65
0.049


570
65
0.030


691
65
0.004


695
65
0.001


707
65
0.002


712
65
0.028


714
65
0.005


737
65
0.031


1058
65
0.007


1095
65
0.011


1098
65
0.031


1346
65
0.002


951
66

0.117


506
67
0.059


673
67
0.050


896
67
0.008


512
67a
0.050


664
67a
0.006


699
67a
0.041


505
67b
0.010


657
67b
0.002
0.002


674
67b
0.003


692
67b
0.005


899
67b
0.000


649
68

0.001


700
68

0.006


704
68a
0.017


705
68a
0.012


574
69
0.048


631
70

0.052


632
70

0.037


1069
70
0.028


1348
70
0.000
0.002


1349
70
0.005
0.006


1111
70a

0.009


1350
70a

0.001


1076
70b

0.020


1355
70b

0.002


1414
70c

0.003


1415
70c

0.011


1416
70c

0.015


711
71

0.050


813
71

0.499


1031
71

0.134


1032
71

1.100


1035
71

1.008


1046
71

0.064


1047
71

0.471


1048
71

0.146


1029
72

0.006


1030
72

0.033


1036
72

0.005


1037
72

0.022


1038
72

0.002


1039
72

0.007


1040
72

0.014


1043
72

0.055


1049
72

0.050


1050
72

0.085


1051
72

0.175


1052
72

0.065


1411
72

0.001


1044
72a

0.945


1045
72a

0.190


534

>76.6655


535

10.000


536

10.000


540

>31.2464


725


0.293


847

5.000


867

>31.2464


870

100.000


1487

>31.2464


1454

>31.2464


1505

>31.2464


1455

>31.2464


1456

>31.2464


1435


20.012


1504


1503

>31.2464


1502

>31.2464


1461
 9i
100.000









In Vivo Methods
Example 4
CFA-Induced Paw Radiant Heat Hypersensitivity
Each rat was placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 min. A radiant thermal stimulus (beam of light) was then focused through the glass onto the plantar surface of each hind paw in turn. The thermal stimulus was automatically shut off by a photoelectric relay when the paw was moved or when the cut-off time was reached (20 sec for radiant heat at  ̃5 amps). An initial (baseline) response latency to the thermal stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). 24 h following intraplantar CFA injection, the response latency of the animal to the thermal stimulus was then re-evaluated and compared to the animal's baseline response time. Only rats that exhibited at least a 25% reduction in response latency (i.e., were hyperalgesic) were included in further analysis. Immediately following the post-CFA latency assessment, the indicated test compound or vehicle was administered orally. Post-compound treatment withdrawal latencies were assessed at fixed time intervals, typically 30, 60, 120, 180, and 300 min.
The percent reversal (% R) of hypersensitivity was calculated in one of two different ways: 1) using group mean values or 2) using individual animal values. More specifically:
Method 1. For all compounds, the % R of hypersensitivity was calculated using the mean value for groups of animals at each time point according to the following formula:

% reversal=[(group treatment response—group CFA response)/(group baseline response—group CFA response)]×100

Results are given for the maximum % reversal observed for each compound at any time point tested.

Method 2. For some compounds, the % R of hypersensitivity was calculated separately for each animal according to the following formula:

% reversal=[(individual treatment response−individual CFA response)/(individual baseline response−individual CFA response)]×100.

Results are given as a mean of the maximum % reversal values calculated for each individual animal.








BIOLOGICAL TABLE 4







CFA thermal hypersensitivity














dose



Method 1:
Method 2:



(mg/kg,

no. of
last time
peak %
peak %


cmpd
p.o.)
vehicle
animals
point (min)
reversal
reversal
















5
30
HPβCD
9
180
96.6
100.5


7
30
HPβCD
8
180
77.8
76.2


9
30
HPβCD
8
180
75.4
77.4


39
30
HPβCD
8
180
39.1
39.7


126
10
HPβCD
8
300
40.8
40.4


126
30
HPβCD
8
300
51
79.5


229
30
HPβCD
8
300
55.8
56.6


232
30
HPβCD
8
180
9.6
8


239
30
HPβCD
8
300
81.8
87.5


240
30
HPβCD
8
300
43
44.4


250
30
HPβCD
8
300
41.7
41.9


251
30
HPβCD
8
300
35.1
38.5


253
30
HPβCD
8
300
64.3
87.2


261
30
HPβCD
8
300
26.4
27.5


266
30
HPβCD
8
300
50.5
56.1


314
30
HPβCD
8
180
41
41.2


316
30
HPβCD
8
180
69.3
70.8


317
30
HPβCD
8
300
43


318
30
HPβCD
8
300
44.7


324
30
HPβCD
8
300
48.7
55.8


325
30
HPβCD
9
300
62.1
63.1


326
30
HPβCD
8
300
17.3
17.5


331
30
HPβCD
8
300
14.3


333
30
HPβCD
8
300
27.7


335
30
HPβCD
8
300
108.2
135.2


337
30
HPβCD
9
300
14.3
17.6


345
30
HPβCD
8
300
25
26.3


407
30
HPβCD
8
300
1.6
1.4


485
30
HPβCD
8
300
34.4
32.3


487
30
HPβCD
8
300
109.2
166.5


488
30
HPβCD
8
300
78
85.5


489
30
HPβCD
8
180
27.1
43.5


490
30
HPβCD
8
300
18.4
19.7


509
30
HPβCD
8
300
17.8


567
30
HPβCD
8
300
63.1


571
30
HPβCD
8
300
133.2


572
30
HPβCD
8
300
−5.1


650
30
HPβCD
8
300
29.9


653
30
HPβCD
8
300
−10.7


657
30
HPβCD
8
300
66


662
30
HPβCD
8
300
21
24


663
30
HPβCD
8
300
33.9


666
30
HPβCD
8
300
−3.1


670
30
HPβCD
8
300
20.9


674
30
HPβCD
8
300
57.7


895
30
HPβCD
8
300
23.4


899
30
HPβCD
8
300
80.1


900
30
HPβCD
8
300
8.5


1010
30
HPβCD
8
300
23.4


1054
30
HPβCD
8
300
27.6


1070
30
HPβCD
8
300
25.7
23.1


1088
30
HPβCD
8
300
35.3


1102
30
HPβCD
8
300
38
45.3


1106
30
HPβCD
8
300
45


1108
30
HPβCD
8
300
84.9
99.2


1117
30
HPβCD
8
300
23.2


1124
30
HPβCD
8
300
88.1


1125
30
HPβCD
8
300
64.5
90.3


1132
30
HPβCD
8
300
0


1139
30
HPβCD
8
300
43.8


1141
30
HPβCD
8
300
5.7


1174
30
HPβCD
8
300
13.6


1187
30
HPβCD
8
300
16.3


1221
30
HPβCD
8
300
44.7
46.7


1337
30
HPβCD
8
300
6.7


1338
30
HPβCD
8
300
86.3


1340
30
HPβCD
8
300
13.1


1341
30
HPβCD
8
300
7.5


1357
30
HPβCD
8
300
51
46.1


1358
30
HPβCD
8
300
25.4


1359
30
HPβCD
8
300
5.1
12.7


1360
30
HPβCD
8
300
40.5
40.5


1362
30
HPβCD
8
300
185.9


1363
30
HPβCD
8
300
69.7


1364
30
HPβCD
8
300
17


1366
30
HPβCD
8
300
47.1









Example 5
CFA-Induced Paw Pressure Hypersensitivity
Prior to testing, rats were acclimated to the handling procedure twice a day for a period of two days. The test consisted of placing the left hindpaw on a Teflon® (polytetrafluoroethylene) coated platform and applying a linearly increasing mechanical force (constant rate of 12.5 mmHg/s) in between the third and fourth metatarsal of the dorsum of the rat's hindpaw, with a dome-tipped plinth (0.7 mm in radius), using an analgesy-meter (Stoelting, Chicago, Ill.), also known as a Randall-Selitto apparatus. The endpoint was automatically reached upon hindpaw withdrawal, and the terminal force was noted (in grams). An initial (baseline) response threshold to the mechanical stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). Forty hr following intraplantar CFA injection, the response threshold of the animal to the mechanical stimulus was re-evaluated and compared to the animal's baseline response threshold. A response was defined as a withdrawal of the hindpaw, a struggling to remove the hindpaw or vocalization. Only rats that exhibited at least a 25% reduction in response threshold (i.e., hyperalgesia) were included in further analysis. Immediately following the post-CFA threshold assessment, rats were administered the indicated test compound or vehicle. Post-treatment withdrawal thresholds were assessed at 1 h. Paw withdrawal thresholds were converted to percent reversal of hypersensitivity according to the following formula:

% reversal=[(post treatment response−predose response)/(baseline response−predose response)]×100.








BIOLOGICAL TABLE 5







CFA induced paw pressure hypersensitivity



















percent


cmpd
N
dose
route of administration
vehicle
time (h)
reversal
















487
8
30
s.c.
HPβCD
1
61.8


1362
10
30
s.c.
HPβCD
1
56.7









Example 6
Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain—Cold Acetone-Hypersensitivity Test
Male Sprague-Dawley rats (225-450 g) were used to evaluate the ability of selected compounds to reverse CCI-induced cold hypersensitivity. Four loose ligatures of 4-0 chromic gut were surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennett et al. (Bennett G J, Xie Y K. Pain 1988, 33(1): 87-107). Fourteen to 35 days following CCI surgery, subjects were placed in elevated observation chambers containing wire mesh floors, and five applications of acetone (0.05 mL/application separated by about 5 min) were spritzed onto the plantar surface of the paw using a multidose syringe. An abrupt withdrawal or lifting of the paw was considered a positive response. The number of positive responses was recorded for each rat over the five trials. Following baseline withdrawal determinations, compounds were administered in the indicated vehicle, by the indicated route (see Table 6). The number of withdrawals was re-determined 1 to 4 h after compound administration. Results are presented as a percent inhibition of shakes, which was calculated for each subject as [1−(test compound withdrawals/pre-test withdrawals)]×100 and then averaged by treatment.







BIOLOGICAL TABLE 6







CCI induced cold sensitivity


















last








time




dose
route of

point
peak percent


cpd
N
(mg/kg)
administration
vehicle
(h)
inhibition
















5
9
30
p.o.
HPβCD
4
26.7


335
9
30
p.o.
HPβCD
4
100


487
9
30
p.o.
HPβCD
4
100


1362
6
3
p.o.
HPβCD
4
70.0









Example 7
Spinal Nerve Ligation (SNL) Model of Neuropathic Pain—Tactile Allodynia Test
For lumbar 5 (L5) spinal nerve ligation (SNL) studies, anesthesia was induced and maintained on isoflurane inhalation. Fur was clipped over the dorsal pelvic area, and a 2-cm skin incision was made just left of midline over the dorsal aspect of the L4-S2 spinal segments, followed by separation of the paraspinal muscles from spinous processes. The transverse process of L6 was then carefully removed, and the L5 spinal nerve was identified. The left L5 spinal nerve was then ligated tightly with 6-0 silk thread, the muscle was sutured with 4-0 vicryl, and the skin was closed with wound clips. Following surgery, s.c. saline (5 mL) was administered.
Behavioral testing was performed four weeks post-ligation. Following baseline von Frey determinations to verify the presence of mechanical allodynia, L5 SNL rats were orally administered the indicated vehicle or drug. Tactile allodynia was quantified at 30, 60, 100, 180 and 300 min post-dosing by recording the force at which the paw ipsilateral to the nerve ligation was withdrawn from the application of a series of calibrated von Frey filaments (0.4, 0.6, 1.0, 2.0, 4, 6, 8 and 15 g; Stoelting; Wood Dale, Ill.). Beginning at an intermediate stiffness (2.0 g), filaments were applied to the mid-plantar hind paw for approximately 5 seconds. to determine the response threshold, a brisk paw withdrawal led to the presentation of the next lighter stimulus, whereas a lack of a withdrawal response led to the presentation of the next stronger stimulus. A total of four responses after the first threshold detection were collected. The 50% withdrawal thresholds were interpolated by the method of Dixon, Efficient analysis of experimental observations. Annu. Rev. Pharmacol. Toxicol. 20:441-462 (1980) as modified by Chaplan et. al., Quantitative assessment of tactile allodynia in the rat paw, J. Neurosci. Methods. 53(1):55-63 (1994) and when response thresholds fell above or below the range of detection, respective values of 15.0 or 0.25 g were assigned. Threshold data from von Frey filament testing were reported as withdrawal threshold in grams. Data were normalized and results are presented as % MPE (maximum possible effect) of the drug calculated according to the following formula:




  
    %
    ⁢
    
      
    
    ⁢
    MPE
  
  =
  
    
      
        
          x
          ⁢
          
            
          
          ⁢
          g
          ⁢
          
            /
          
          ⁢
          force
        
        -
        
          baseline
          ⁢
          
            
          
          ⁢
          g
          ⁢
          
            /
          
          ⁢
          force
        
      
      
        
          15
          ⁢
          
            
          
          ⁢
          g
          ⁢
          
            /
          
          ⁢
          force
        
        -
        
          baseline
          ⁢
          
            
          
          ⁢
          g
          ⁢
          
            /
          
          ⁢
          force
        
      
    
    ×
    100
  











BIOLOGICAL TABLE 7







Spinal nerve ligation - tactile allodynia















dose
route of

last time
peak %


cmpd
N
(mg/kg)
administration
vehicle
point (h)
MPE
















335
6
30
p.o.
HPβCD
4
50.1


487
6
30
p.o.
HPβCD
4
61.2


1362
6
30
p.o.
HPβCD
4
84.3









While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

## Claims

1. A compound of Formula (I)



wherein
Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
Group a) is

i) substituted C6-10 aryl,
ii) C3-8 cycloalkyl,
iii) trifluoromethyl; or
iv) heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furazan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl, and [1,2,3]thiadiazolyl;
wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
Group b) is

i) C6-10aryl;
ii) heteroaryl selected from the group consisting of thiazolyl, pyridinyl, indolyl, indazolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, imidazo[1,2-a]pyridin-2-yl, quinolinyl, thienyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-thieno[2,3-c]pyrazol-5-yl, and benzimidazolyl;
iii) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
iv) 2-oxo-3,3-bis-(3-trifluoromethylphenylmethyl)-2,3-dihydro-1H-indol-5-yl;
v) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
vi) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
vii) 2,3-dihydro-1H-indolyl;
viii) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
ix) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
x) 1,1,3-tris-(3-trifluoromethylphenylmethyl)indan-2-on-6-yl; or
xi) 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C6-10 aryl(C1-4alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) 3-trifluoromethyl-phenylaminocarbonylmethoxy;
iv) C6-10aryl(C1-4)alkylthio;
v) phenyl(C1-4)alkylsulfonyl;
vi) phenylcarbonyl optionally substituted with chloro or fluoro;
vii) 2,3-dihydro-1H-indol-5-ylcarbonyl;
viii) N-methyl-N-phenyl-aminocarbonyl-methyl;
ix) pyrrolidin-1-ylcarbonylmethyl;
x) phenyl(C2-6)alkynyl;
xi) heteroaryl(C1-6)alkyl wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
xii) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
xiii) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent;
xiv) heteroaryl-(Q)-C1-6alkyl wherein Q is O or S; wherein heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4-alkyl, trifluoromethyl, or chloro substituent; and
xv) phenyl-(Q)-C1-6alkyl wherein Q is O, S, SO2, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkoxycarbonylamino; C1-4alkyl; cyanomethyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C1-4alkylcarbonyl; C1-4alkoxycarbonyl; cyano; carboxy; aminocarbonyl; C1-4alkylaminocarbonyl; di(C1-4alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy; aminosulfonyl; di(C1-4alkyl)aminosulfonyl; C1-4alkylsulfonyl; di(C1-4alkyl)aminosulfonyl; and NRcRd; wherein Rc is hydrogen or C1-6alkyl and wherein Rd is hydrogen, C1-6alkyl, cyano(C1-4alkyl, C3-8cycloalkyl, C1-6alkylcarbonyl, C3-8cycloalkylcarbonyl, C3-8cycloalkyl(C1-4)alkyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C6-10arylcarbonyl; di(C1-4alkyl)aminosulfonyl, and C1-4alkylsulfonyl;
s is 0, 1 or 2; provided that when s is 2, R1 is independently selected from the group consisting of phenyl, C1-3alkyl, and C6-10aryl(C1-3)alkyl;
when s is 1, R1 is C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spiro[used cyclopropyl, 3-oxo, or aryl(C1-3)alkyl;
or, when s is 2 and R1 is C1-3alkyl, the C1-3alkyl substituents are taken with the piperizinyl ring to form a 3,8-diaza-bicyclo[3.2.1]octanyl or 2,5-diaza-bicyclo[2.2.2]octanyl ring system;
provided that a compound of formula (I) is other than
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)phenyl, and s is 0;
or a compound wherein Y is thiazol-2-yl, Z is 4-(phenylmethyl)phenyl, s is 1, and R1 is 3-phenyl;
a compound wherein Y is thiazol-2-yl, Z is 2-(pyridin-4-ylmethyl)-3H-benzimidazol-4-yl, and s is 0;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein
Group a) is
i) substituted C6-10 aryl,
ii) trifluoromethyl; or
iii) heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, pyrrolyl, and pyridinyl;
wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl.

3. The compound of claim 2 wherein
Group a) is
i) substituted C6-10 aryl,
ii) trifluoromethyl; or
iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl.

4. The compound of claim 3 wherein
Group a) is
i) substituted phenyl,
ii) trifluoromethyl; or
iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
wherein phenyl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl.

5. The compound of claim 1 wherein
Group b) is
i) C6-10 aryl;
ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
v) 2,3-dihydro-1H-indolyl;
vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C6-10 aryl(C1-4alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) C6-10aryl(C1-4)alkylthio;
iv) phenyl(C1-4)alkylsulfonyl;
v) phenylcarbonyl optionally substituted with chloro or fluoro;
vi) 2,3-dihydro-1H-indol-5-ylcarbonyl;
vii) N-methyl-N-phenyl-aminocarbonyl-methyl;
viii) phenyl(C2-6)alkynyl;
ix) heteroaryl(C1-6)alkyl wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
x) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
xi) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
xii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, SO2, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkoxycarbonylamino; C1-4alkyl; cyanomethyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C1-4alkylcarbonyl; C1-4alkoxycarbonyl; cyano; carboxy; aminocarbonyl; C1-4alkylaminocarbonyl; di(C1-4alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxyl; di(C1-4alkyl)aminosulfonyl; and NRcRd; wherein Rc is hydrogen or C1-6alkyl and wherein Rd is hydrogen, C1-6alkyl, cyano(C1-4)alkyl, C3-8cycloalkyl, C1-6alkylcarbonyl, C3-8cycloalkylcarbonyl, C3-8cycloalkyl(C1-4)alkyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C6-10arylcarbonyl; di(C1-4alkyl)aminosulfonyl, and C1-4alkylsulfonyl.

6. The compound of claim 5 wherein
Group b) is
i) C6-10 aryl;
ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
v) 2,3-dihydro-1H-indolyl;
vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) C6-10aryl(C1-4alkylthio;
iv) phenylcarbonyl optionally substituted with chloro or fluoro;
v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
vi) N-methyl-N-phenyl-aminocarbonyl-methyl;
vii) phenyl(C2-6)alkynyl;
viii) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
ix) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
x) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio.

7. The compound of claim 6 wherein
Group b) is
i) C6-10 aryl;
ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, and indazolyl;
iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
v) 2,3-dihydro-1H-indolyl;
vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C6-10 aryl(C1-4alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) C6-10aryl(C1-4alkylthio;
iv) phenylcarbonyl optionally substituted with chloro or fluoro;
v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
vi) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
vii) heteroaryl(C1-2)alkylthio, wherein heteroaryl is pyridinyl; wherein said pyridinyl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
viii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio.

8. The compound of claim 1 wherein s is 0 or 1.

9. The compound of claim 1 wherein R1 is phenyl or C1-3alkyl.

10. The compound of claim 9 wherein R1 is methyl.

11. A compound of Formula (I)



wherein
Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
Group a) is

i) substituted C6-10 aryl,
ii) trifluoromethyl; or
iii) heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, pyrrolyl, and pyridinyl;
wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4-alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
Group b) is

i) C6-10 aryl;
ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
v) 2,3-dihydro-1H-indolyl;
vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
viii) 1,1,3-tris-(3-trifluoromethylphenylmethyl)indan-2-on-6-yl; or
ix) 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of
i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) C6-10aryl(C1-4alkylthio;
iv) phenyl(C1-4)alkylsulfonyl;
v) phenylcarbonyl optionally substituted with chloro or fluoro;
vi) 2,3-dihydro-1H-indol-5-ylcarbonyl;
vii) N-methyl-N-phenyl-aminocarbonyl-methyl;
viii) phenyl(C2-6)alkynyl;
ix) heteroaryl(C1-6)alkyl wherein heteroaryl is selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothienyl, and thienyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, bromo, or chloro substituent;
x) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
xi) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
xii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, SO2, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkoxycarbonylamino; C1-4alkyl; cyanomethyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C1-4alkylcarbonyl; C1-4alkoxycarbonyl; cyano; carboxy; aminocarbonyl; C1-4alkylaminocarbonyl; di(C1-4alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxyl; di(C1-4alkyl)aminosulfonyl; and NRcRd; wherein Rc is hydrogen or C1-6alkyl and wherein Rd is hydrogen, C1-6alkyl, cyano(C1-4)alkyl, C3-8cycloalkyl, C1-6alkylcarbonyl, C3-8cycloalkylcarbonyl, C3-8cycloalkyl(C1-4)alkyl, aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C6-10arylcarbonyl; di(C1-4alkyl)aminosulfonyl, and C1-4alkylsulfonyl;

s is 0 or 1;
R1 is phenyl or C1-3alkyl;
provided that a compound of formula (I) is other than
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)phenyl, and s is 0; or
a compound wherein Y is thiazol-2-yl, Z is 4-(phenylmethyl)phenyl, s is 1, and R1 is 3-phenyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

12. A compound of Formula (I)



wherein
Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
Group a) is

i) substituted C6-10 aryl,
ii) trifluoromethyl; or
iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
wherein C6-10 aryl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
Group b) is

i) C6-10 aryl;
ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, indazolyl, and benzimidazolyl;
iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
v) 2,3-dihydro-1H-indolyl;
vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl;
vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl; or
viii) 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

i) C6-10 aryl(C1-4alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) C6-10aryl(C1-4alkylthio;
iv) phenylcarbonyl optionally substituted with chloro or fluoro;
v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
vi) N-methyl-N-phenyl-aminocarbonyl-methyl;
vii) phenyl(C2-6)alkynyl;
viii) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
ix) heteroaryl(C1-2)alkylthio, wherein heteroaryl is selected from the group consisting of pyridinyl, thiazolyl, benzothienyl, and thienyl; wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
x) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4)alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio;

s is 0 or 1;
R1 is phenyl or methyl;
provided that a compound of Formula (I) is other than
a compound wherein Y is thiazol-2-yl, Z is 4-(phenylmethyl)phenyl, s is 1, and R1 is 3-phenyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

13. A compound of Formula (I)



wherein
Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);
Group a) is

i) substituted phenyl,
ii) trifluoromethyl; or
iii) heteroaryl selected from the group consisting of thiazolyl, pyrrolyl, and pyridinyl;
wherein phenyl is substituted with; and the heteroaryl is optionally substituted with; one substituent selected from the group consisting of fluoro, chloro, bromo, C1-4alkyl, cyano, C1-4alkylcarbonylamino, and trifluoromethyl;
Group b) is

i) C6-10 aryl;
ii) heteroaryl selected from the group consisting of pyridinyl, indolyl, and indazolyl;
iii) 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl;
iv) 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
v) 2,3-dihydro-1H-indolyl;
vi) 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl; or
vii) 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl;
wherein C6-10 aryl, 2,3-dihydro-1H-indolyl, and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C1-4alkyl, C1-4alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of
i) C6-10 aryl(C1-4)alkyl; wherein C1-4alkyl is optionally substituted with one to two fluoro substituents;
ii) C6-10aryl(C1-4)alkoxy;
iii) C6-10aryl(C1-4alkylthio;
iv) phenylcarbonyl optionally substituted with chloro or fluoro;
v) 2,3-dihydro-1H-indol-5-ylcarbonyl;
vi) heteroaryl(C1-6)alkoxy wherein heteroaryl is selected from the group consisting of pyridinyl and quinolinyl, wherein said heteroaryl is optionally substituted with a C1-4alkyl, trifluoromethyl or bromo substituent;
vii) heteroaryl(C1-2)alkylthio, wherein heteroaryl is pyridinyl; wherein said pyridinyl is optionally substituted with a C1-4alkyl, trifluoromethyl, or chloro substituent; and
viii) phenyl-(Q)-C1-6alkyl wherein Q is O, S, or NH; and phenyl is optionally independently substituted with one to three substitutents selected from the group consisting of bromo, chloro, C1-4alkyl, C1-4alkoxy, and trifluoromethyl;
wherein phenyl of the C6-10 aryl(C1-4)alkyl, C6-10aryl(C1-4)alkylthio, phenyl(C1-4alkylsulfonyl, and C6-10aryl(C1-4)alkoxy substituents is optionally independently substituted with one to two substituents selected from the group consisting of C1-4alkyl; C1-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; and trifluoromethylthio;

s is 0 or 1;
R1 is methyl;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

14. A compound of Formula (I)



selected from the group consisting of:
a compound wherein Y is thiazol-2-yl, Z is 4-phenylmethyl-phenyl, s is 1, and R1 is 2-methyl;
a compound wherein Y is thiazol-2-yl, Z is 4-phenylmethyl-phenyl, s is 1, and R1 is 3-methyl;
a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(pyridin-4-ylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-fluoro-4-(3,4-dichlorophenylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(3-chlorophenylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(pyridin-3-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-pyridin-4-ylmethoxy-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(3,4-dichlorophenylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-fluoro-4-(2,3-dichlorophenylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-chloro-4-(pyridin-2-ylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylmethylthio)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(2,3-dichlorophenylmethylthio)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3,4-dichlorophenylmethylthio)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(4-chlorophenylmethylthio)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(pyridin-3-ylmethylthio)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenoxymethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylthiomethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylaminomethyl)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(3-chlorophenylthiomethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenylthiomethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-chlorophenylmethoxy)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(3-chlorophenylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenoxymethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenylmethoxy)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(5-chloro-thien-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(5-chloro-thien-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(5-chloro-thien-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(3-chlorophenylaminomethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(4-chlorophenoxymethyl)-4-methyl-thiazol-5-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 2-(4-chlorophenoxymethyl)-4-methyl-thiazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(quinolin-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(quinolin-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-chlorophenylaminomethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(quinolin-2-ylmethoxy)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethylsulfonyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethylthio)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(3-trifluoromethylphenylmethylthio)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethylthio)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylsulfonylmethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethyl-phenylsulfonylmethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(5-chloro-pyridin-3-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(5-chloro-pyridin-3-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(phenylmethyl)-1H-benzimidazol-4-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(5-chloro-pyridin-3-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(4-trifluoromethyl-phenyl-fluoromethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(6-bromo-pyridin-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-(6-bromo-pyridin-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(4-trifluoromethylphenylmethyl)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(phenyl-difluoromethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(6-bromo-pyridin-2-ylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(2,3-dihydro-1H-indol-5-ylcarbonyl)-1H-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(2-fluoro-phenylmethyl)-3H-benzimidazol-4-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(3-fluoro-phenylmethyl)-3H-benzimidazol-4-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(4-chlorophenylmethyl)-3H-benzimidazol-4-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-oxo-3,3-bis-(3-trifluoromethylphenylmethyl)-2,3-dihydro-1H-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(phenylmethyl)-indol-3-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-phenylmethyl-2,3-dihydro-1H-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethyl)phenyl, and s is 0;
a compound wherein Y is 4-(4-trifluoromethylphenylmethyl)phenyl, Z is thiazol-4-yl, and s is 0;
a compound wherein Y is 4-(4-trifluoromethylphenylmethyl)phenyl, Z is thiazol-2-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethyl)phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 4-(4-trifluoromethyl-phenylmethyl)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(phenylethyl)-1H-benzimidazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(phenylmethyl)-3H-benzimidazol-5-yl, and s is 0;
a compound wherein Y is 2-(phenylethyl)-3H-benzimidazol-5-yl, Z is thiazol-4-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 2-(phenylmethyl)-1H-benzimidazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(phenylmethyl)-1H-benzimidazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-(2-fluorophenylaminomethyl)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-(4-trifluoromethylphenyl-methyl)-4-fluoro-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-(4-trifluoromethylphenyl-methyl)-4-fluoro-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl, and s is 0;
a compound wherein Y is 1H-pyrrol-2-yl, Z is 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl, and s is 0;
a compound wherein Y is 1H-pyrrol-2-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
a compound wherein Y is isothiazol-5-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 2-methyl-3-(4-trifluoromethylphenyl-methyl)-phenyl, and s is 0;
a compound wherein Y is 2-methyl-3-(4-trifluoromethylphenyl-methyl)phenyl, Z is thiazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(phenylcarbonyl)phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
a compound wherein Y is 1H-pyrrol-2-yl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl, and s is 0;
a compound wherein Y is trifluoromethyl, Z is 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 7-(4-chloro-benzylidene)-1-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl, and s is 0;
a compound wherein Y is 1H-pyrrol-2-yl, Z is 4-{1-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 3-(4-fluorophenylcarbonyl)-indol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-methyl-3-(4-fluorophenylmethyl)-indol-6-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 1-methyl-3-(4-fluorophenylmethyl)-indol-6-yl, and s is 0;
a compound wherein Y is 1H-pyrrol-2-yl, Z is 1-methyl-3-(4-fluorophenylmethyl)-indol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylmethyl)-1H-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(4-fluorophenylmethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(N-methyl-N-phenyl-aminocarbonyl-methyl)-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-4-yl, Z is 1-(N-methyl-N-phenyl-aminocarbonyl-methyl)-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-methyl-3-(3-fluorophenylmethyl)-indol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-methyl-3-(phenylmethyl)-indol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(pyrrolidin-1-ylcarbonylmethyl)-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-trifluoromethyl-phenylmethyl)-1H-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(4-trifluoromethylphenylmethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(3-trifluoromethyl-phenylmethyl)-1H-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(3-trifluoromethylphenylmethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is (1-phenyl-ethyl)-2H-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethyl-phenylaminocarbonylmethoxy)-phenyl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-aminosulfonyl-phenylmethyl)-2,5-dimethyl-pyrrol-3-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-aminocarbonyl-phenylmethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-cyano-phenylmethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(pyridin-4-ylmethyl)-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(pyridin-4-ylmethyl)-indol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(pyridin-3-ylmethyl)-indol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(4-fluoro-phenylethyl)-indazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenylmethyl)-indazol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 2-(4-fluoro-phenylmethyl)-indazol-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1-(4-chloro-phenylmethyl)-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1,1,3-tris-(3-trifluoromethylphenylmethyl)indan-2-on-6-yl, and s is 0;
a compound wherein Y is thiazol-2-yl, Z is 1,1,3-tris-(phenylmethyl)indan-2-on-6-yl, and s is 0;

or a pharmaceutically acceptable salt form thereof.

15. A pharmaceutical composition comprising a compound of claim 1 or 14 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

16. A pharmaceutical composition of claim 15, wherein the composition is a solid oral dosage form.

17. A pharmaceutical composition of claim 15, wherein the composition is a syrup, an elixir, or a suspension.

18. A method for treating inflammatory pain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 14.

19. The method of claim 18 wherein the inflammatory pain is due to inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.