The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, [structure] that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

Description

254 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent application No. 61/376,141, filed Aug. 23, 2010, and U.S. provisional patent application No. 61/492,634, filed Jun. 2, 2011.

›FIELD OF THE INVENTION

The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, as defined herein, that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or the pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

›BACKGROUND OF THE INVENTION

Glucokinase (GK) is a member of a family of four hexokinases that are critical in the cellular metabolism of glucose. Specifically GK, also known as hexokinase IV or hexokinase D, facilitates glucose induced insulin secretion from pancreatic β-cells as well as glucose conversion into glycogen in the liver. GK has a unique catalytic activity that enables the enzyme to be active within the physiological range of glucose (from 5 mM glucose to 10 mM glucose).

Genetically modified mouse models support the role of GK playing an important role in glucose homeostasis. Mice lacking both copies of the GK gene die soon after birth from severe hyperglycemia, whereas mice lacking only one copy of the GK gene present with only mild diabetes. Mice that are made to overexpress the GK gene in their livers are hypoglycemic.

Numerous human mutations in the GK gene have been identified, with the vast majority of them resulting in proteins with impaired or absent enzymatic activity. These loss-of-function mutations are thought to contribute to the hyperglycemia seen with maturity-onset diabetes of the young type II (MODY-2). A small fraction of these mutations result in a GK with increased catalytic function. These individuals present with moderate to severe hypoglycemia.

GK activity in the liver is transiently regulated by glucokinase regulatory protein (GKRP). GK catalytic activity is inhibited when GK is bound to GKRP. This interaction is antagonized by increasing concentrations of both glucose and fructose-1-phosphate (F1P). The complex of the two proteins is localized primarily to the nuclear compartment of a cell. Post prandially as both glucose and fructose levels rise, GK released from GKRP translocates to the cytoplasm. Cytoplasmic GK is now free of the inhibitory effects of GKRP and able to kinetically respond to glucose. Evidence from the Zucker diabetic fatty rat (ZDF) indicates that their glucose intolerance may be a result of this mechanism failing to function properly.

A compound that acts directly on GKRP to disrupt its interaction with GK and hence elevate levels of cytoplasmic GK is a viable approach to modulate GK activity. Such an approach would avoid the unwanted hypoglycemic effects of over stimulation of GK catalytic activity, which has been seen in the development of GK activators. A compound having such an effect would be useful in the treatment of diabetes and other diseases and/or conditions in which GKRP and/or GK plays a role. The present invention provides compounds that bind GKRP and disrupts its interaction with GK.

›SUMMARY OF THE INVENTION · 1 of 6

In embodiment 1, the present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof,

wherein:

Y is —CF 3 , —CHF 2 , —CFH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —(CR c R c ) n OR c , or C 3-6 cycloalkyl;

A is

R 3 is a five or six membered aryl ring or five or six membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, O or S, which aryl or heteroaryl ring can be optionally substituted with from one to four is substituents independently selected from C 1-6 alkyl,

—OC 1-6 alkyl, —NR c R c , —CF 3 , —CN, —OH, —NO 2 or halo;

each R b is independently hydrogen,

C 1-6 alkyl,

—S(═O) 2 C 1-6 alkyl,

—C(═O)C 1-6 alkyl,

—CD 3 ,

—(CR c R c ) n CFH 2 ,

—(CR c R c ) n CF 2 H,

—(CR c R c ) n CF 3 ,

—(CR c R c ) n 5 to 10 membered aryl,

—(CR c R c ) n 5 to 10 membered substituted aryl,

—(CR c R c ) n 5 to 10 membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O or S,

—(CR c R c ) n 5 to 10 membered substituted heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O or S,

—(CR c R c ) n 3 to 10 membered cycloalkyl,

—(CR c R c ) n 3 to 10 membered substituted cycloalkyl,

—(CR c R c ) n 3 to 10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O or S, or

—(CR c R c ) n 3 to 10 membered substituted heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O or S, wherein substituted groups can have from one to four substitutents independently selected from —C 1-6 alkyl,

—OC 1-6 alkyl, —NR c R c , —CF 3 , —CN, —(CR c R c ) n OR c , C 3-6 cycloalkyl, halo,

—(CR c R c ) n NR c S(═O) 2 R c , —(CR c R c ) n C(═O)OR c , —(CR c R c ) n C(═O)NR c R c ;

each R c is independently hydrogen or C 1-6 alkyl;

X 1 , X 2 , X 3 and X 4 are each independently selected from CR a or N;

X 5 and X 6 are independently selected from N or CR a ;

X 7 is N or CR 4 ;

X 8 is N or CR 5 ;

each R a , R 4 and R 5 are independently selected from hydrogen,

C 1-6 alkyl,

halo,

—C≡CCF 2 CH 3 ,

—C≡CCF 2 CF 3 ,

—OC 1-6 alkyl,

—(CR b R b ) n NR c R c ,

—(CR b R b ) n CF 3 ,

—(CR b R b ) n OR c ,

—(CR b R b ) n CN,

—(CR b R b ) n NR b (CR b R b ) n OR c ,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n 3 to 10 membered cycloalkyl,

—(CR b R b ) n 3 to 10 membered substituted cycloalkyl,

—(CR b R b ) n 5 to 10 membered heterocycloalkyl,

—(CR b R b ) n 5 to 10 membered substituted heterocycloalkyl,

—C≡C—R b ,

—C≡C—(CR b R b ) n OR c ,

—C≡C—(CR b R b ) n 3 to 10 membered heterocycloalkyl,

—C≡C—(CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—(CR b R b ) n 3 to 10 membered heterocycloalkyl,

—(CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered cycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered substituted cycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered heterocycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—(CR b R b ) n NR b (CR b R b ) n 3 to 10 membered heterocycloalkyl,

—(CR b R b ) n NR b (CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—C≡C—(CR b R b ) n NR b C(═O)OR b ,

—C≡C—(CR b R b ) n NR b R b ,

—C≡C—(CR b R b ) n NR b —S(═O) 2 R b ,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n NR b —S(═O) 2 R b ,

—(CR b R b ) n NR b —C(═O)R b , or

—(CR b R b ) n NR b —S(═O) 2 NR b R b ,

wherein the heteroaryl or heterocycloalkyl groups can have from 1 to 3 heteroatoms independently selected from O, N or S, and wherein substituted groups can have from one to four substitutents independently selected from —C 1-6 alkyl, —OC 1-6 alkyl, —NR c R c , —CF 3 , —CN, —(CR c R c ) n OR c , C 3-6 cycloalkyl, halo,

—(CR c R c ) n NR c S(═O) 2 R c , —(CR c R c ) n C(═O)OR c , —(CR c R c ) n C(═O)NR c R c , 5 to 10 membered aryl, or 5 to 10 membered aryl substituted with from one to four substitutents independently selected from —C 1-6 alkyl, —OC 1-6 alkyl, —NR c R c , —CF 3 , —CN, —(CR c R c ) n OR c , C 3-6 cycloalkyl, halo, —(CR c R c ) n NR c S(═O) 2 R c ,

—(CR c R c ) n C(═O)OR c , —(CR c R c ) n C(═O)NR c R c , or one or more carbon atoms in any ring group may be replaced with —C(═O)— or —S(═O) 2 —; and

›SUMMARY OF THE INVENTION · 2 of 6

each n is independently 0, 1 or 2,

provided that the compound is not 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-((2-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(4-(3-chlorophenylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; or 2-(4-(4-((2-chlorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol.

In embodiment 2, the present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof,

wherein:

Y is —CF 3 , —CHF 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 OH, or C 3-6 cycloalkyl;

A is

R 3 is a five or six membered aryl ring or five or six membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, O or S, which aryl or heteroaryl ring can be optionally substituted with from one to four substituents independently selected from C 1-6 alkyl,

—OC 1-6 alkyl, —NR b R b , —CF 3 , —CN or halo;

each R b is independently hydrogen or C 1-6 alkyl;

X 1 , X 2 , X 3 and X 4 are each independently selected from CR a or N;

each R a , R 4 and R 5 are independently selected from hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, —NR b R b , —CF 3 , halo, —(CR b R b ) n OH, —(CR b R b ) n CN,

—(CR b R b ) n NR b (CR b R b ) n OH,

—(CR b R b ) n NR b (CR b R b ) n 5 to 6 membered aryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 6 membered substituted aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 6 membered aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 6 membered substituted aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 6 membered heteroaryl,

—(CR b R b ) n O(CR b R b ) n 5 to 6 membered substituted heteroaryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 6 membered heteroaryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 6 membered substituted heteroaryl,

—(CR b R b ) n 5 to 6 membered aryl, —(CR b R b ) n 5 to 6 membered substituted aryl,

—(CR b R b ) n 5 to 6 membered heteroaryl,

—(CR b R b ) n 5 to 6 membered substituted heteroaryl, —(CR b R b ) n C 3-6 cycloalkyl,

—(CR b R b ) n substituted C 3-6 cycloalkyl;

—C≡C—CR b R b OH, —C≡C— 3 to 8 membered heterocycloalkyl,

—C≡C— 3 to 8 membered substituted heterocycloalkyl,

—(CR b R b ) n 3 to 8 membered heterocycloalkyl,

—(CR b R b ) n 3 to 8 membered substituted heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl groups can have from 1 to 3 heteroatoms independently selected from O, N or S, and wherein substituted groups can have from one to four substitutents independently selected from —C 1-6 alkyl, —OC 1-6 alkyl, —NR b R b , —CF 3 , —CN, —OH or halo; and

is each n is independently 0, 1 or 2,

In embodiment 3, the present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof,

wherein:

Y is —CF 3 , —CHF 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 OH, or C 3-6 cycloalkyl;

A is

R 3 is a five or six membered aryl ring or five or six membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, O or S, which aryl or heteroaryl ring can be optionally substituted with from one to four substituents independently selected from C 1-6 alkyl,

—OC 1-6 alkyl, —NR b R b , —CF 3 , —CN, —OH, —NO 2 or halo;

is each R b is independently hydrogen,

C 1-6 alkyl,

—(CR c R c ) n CF 3 ,

—(CR c R c ) n 5 to 10 membered aryl,

—(CR c R c ) n 5 to 10 membered substituted aryl,

—(CR c R c ) n 5 to 10 membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O or S,

—(CR c R c ) n 5 to 10 membered substituted heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O or S,

—(CR c R c ) n 3 to 10 membered cycloalkyl,

—(CR c R c ) n 3 to 10 membered substituted cycloalkyl,

—(CR c R c ) n 3 to 10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O or S, or

—(CR b R b ) n NR b S(═O) 2 R b , —(CR b R b ) n C(═O)OR b , —(CR b R b ) n C(═O)NR b R b , 5 to 10 membered aryl, or 5 to 10 membered substituted aryl;

each R c is independently hydrogen or C 1-6 alkyl;

X 1 , X 2 , X 3 and X 4 are each independently selected from CR a or N;

each R a , R 4 and R 5 are independently selected from hydrogen,

C 1-6 alkyl,

halo,

is —OC 1-6 alkyl,

—(CR b R b ) n NR b R b ,

—(CR b R b ) n CF 3 ,

—(CR b R b ) n OH,

—(CR b R b ) n CN,

—(CR b R b ) n NR b (CR b R b ) n OH,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n O(CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n NR b (CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n 3 to 10 membered cycloalkyl,

—(CR b R b ) n 3 to 10 membered substituted cycloalkyl,

—C≡C—R b ,

—C≡C—(CR b R b ) n OR b ,

—C≡C— 3 to 10 membered heterocycloalkyl,

›SUMMARY OF THE INVENTION · 3 of 6

—C≡C— 3 to 10 membered substituted heterocycloalkyl,

—(CR b R b ) n 3 to 10 membered heterocycloalkyl,

—(CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered cycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered substituted cycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered heterocycloalkyl,

—(CR b R b ) n O(CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—(CR b R b ) n NR b (CR b R b ) n 3 to 10 membered heterocycloalkyl,

—(CR b R b ) n NR b (CR b R b ) n 3 to 10 membered substituted heterocycloalkyl,

—C≡C—(CR b R b ) n NR b C(═O)OR b ,

—C≡C—(CR b R b ) n NR b R b ,

—C≡C—(CR b R b ) n NR b —S(═O) 2 R b ,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n S(CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n S(═O) 2 (CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n S(═O)(CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n S(═O)(CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered aryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered substituted aryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered heteroaryl,

—(CR b R b ) n NR b S(═O) 2 (CR b R b ) n 5 to 10 membered substituted heteroaryl,

—(CR b R b ) n NR b —S(═O) 2 R b ,

—(CR b R b ) n NR b —C(═O)R b , or

—(CR b R b ) n NR b —S(═O) 2 NR b R b ,

wherein the heteroaryl or heterocycloalkyl groups can have from 1 to 3 heteroatoms independently selected from O, N or S, and wherein substituted groups can have from one to four substitutents independently selected from —C 1-6 alkyl, —OC 1-6 alkyl, —NR b R b , —CF 3 , —CN, —(CR b R b ) n OH, C 3-6 cycloalkyl, halo,

—(CR b R b ) n NR b S(═O) 2 R b , —(CR b R b ) n C(═O)NR b R b , 5 to 10 membered aryl, or 5 to 10 membered substituted aryl, or a carbon atom in any ring group may be replaced with —C(═O)— or —S(═O) 2 —; and

each n is independently 0, 1 or 2,

In embodiment 4, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein R 3 is thienyl.

In embodiment 5, the present invention provides compounds in accordance with any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, wherein A is

In embodiment 6, the present invention provides compounds in accordance with any one of embodiments 1 to 5, or pharmaceutically acceptable salts thereof, wherein A is

In embodiment 7, the present invention provides compounds in accordance with any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, wherein A is

In embodiment 8, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein R 3 is thienyl, phenyl, pyridyl, pyrazolyl, imidazolyl, furyl, thiazolyl or thiadiazolyl, which can be optionally substituted with from one to four substituents independently selected from C 1-6 alkyl, —OC 1-6 alkyl, —NR c R c , —CF 3 , —CN or halo.

In embodiment 9, the present invention provides compounds in accordance with any one of embodiments 1 to 8, or pharmaceutically acceptable salts thereof, wherein —CH 2 OH, —CF 3 , —CH 3 or cyclopropyl.

In embodiment 10, the present invention provides compounds in accordance with any one of embodiments 1 to 8, or pharmaceutically acceptable salts thereof, wherein Y is —CF 3 .

In embodiment 11, the present invention provides compounds in accordance with any one of embodiments 1 to 8, or pharmaceutically acceptable salts thereof, wherein Y is —CH 3 .

In embodiment 12, the present invention provides compounds in accordance with any one of embodiments 1 to 3, 4 or 8, or pharmaceutically acceptable salts thereof, wherein

A is

and R 4 and R 5 are hydrogen.

In embodiment 13, the present invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 and X 4 are CR a .

In embodiment 14, the present invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 and X 4 are CH.

In embodiment 15, the present invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein X 1 and X 3 are CR a and X 2 and X 4 are N.

In embodiment 16, the present invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein at least one of X 1 , X 2 , X 3 or X 4 is N.

In embodiment 17, the present invention provides compounds in accordance with any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, wherein

A is

and R 4 and R 5 are independently hydrogen, halo or —CH 3 .

In embodiment 18, the present invention provides compounds in accordance with any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, wherein

A is

and R 4 is hydrogen and R 5 is —CH 3 .

In embodiment 19, the present invention provides compounds in accordance with any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, wherein

A is

›SUMMARY OF THE INVENTION · 4 of 6

and R 4 is hydrogen and R 5 is —CH 2 -morpholino.

In embodiment 20, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein

R 3 is thienyl, phenyl, pyridyl, pyrazolyl, imidazolyl, furyl, thiazolyl or thiadiazolyl, which can be optionally substituted with from one to four substituents independently selected from C 1-6 alkyl, —OC 1-6 alkyl, —NR c R c , —CF 3 , —CN or halo;

A is

Y is —CH 2 OH, —CF 3 , —CH 3 or cyclopropyl.

In embodiment 21, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein

A is

X 2 and X 4 are N; and

Y is —CF 3 , —CH 3 or cyclopropyl.

In embodiment 22, the present invention provides compounds in accordance with any one of embodiments 20 to 21, or pharmaceutically acceptable salts thereof, wherein Y is —CF 3 or —CH 3 .

In embodiment 23, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein

A is

Y is —CF 3 or —CH 3 ; and

X 1 , X 2 , X 3 and X 4 are CH or X 1 and X 2 are CH, and X 3 and X 4 are N.

In embodiment 24, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein

R 3 is

A is

Y is —CF 3 or —CH 3 ; and

X 1 , X 2 , X 3 and X 4 are CH or X 1 and X 2 are CH, and X 3 and X 4 are N.

In embodiment 25, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein

R 3 is

A is

R 4 —C≡C—H or —C≡C—C 1-6 alkyl;

R 5 is hydrogen;

Y is —CF 3 or —CH 3 ; and

X 1 , X 2 , X 3 and X 4 are CH or X 1 and X 2 are CH, and X 3 and X 4 are N.

In embodiment 26, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein

R 3 is thienyl, or phenyl, pyridyl, pyrazolyl, imidazolyl, furyl, thiazolyl or thiadiazolyl, which can be optionally substituted with from one to four substituents independently selected from C 1-6 alkyl, —OC 1-6 alkyl, —NR c R c , —CF 3 , —CN or halo;

A is

Y is —CF 3 or —CH 3 ; and

X 1 , X 2 , X 3 and X 4 are CH or —C—CH 3 .

In embodiment 27, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein R 3 is

In embodiment 28, the present invention provides compounds in accordance with any one of embodiments 1 to 3, or pharmaceutically acceptable salts thereof, wherein R 3 is

In embodiment 29, the present invention provides the compounds, or pharmaceutically acceptable salts thereof, selected from:

1,1,1,3,3,3-hexafluoro-2-(4-(4-(3-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-((2-methylphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-((1-methyl-1h-pyrazol-3-yl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-pyridinylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-((5-methyl-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-((3R)-3-cyclopropyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol; 1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)phenyl)-3-pyridinyl)-2-propanol; 2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol; 2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol; 2-methyl-4-(4-(phenylsulfonyl)-4′-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol; 1,1,1,3,3,3-hexafluoro-2-(4′-(phenylsulfonyl)-4-biphenylyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)-1-piperazinyl)-3-pyridinyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((3S)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-((2S)-4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2R)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-(4-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1-trifluoro-2-(4-(2-((3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-((2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1-trifluoro-2-(4-(2-((2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol; 2-methyl-2-(((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol; (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile; (3R)-1-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol; 1,1,1-trifluoro-2-(4-(2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1-trifluoro-2-(4-(2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(4-(1H-imidazol-4-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-(2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; (2S)-3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; (2R)-3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; 2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol; 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol; 1,1,1,3,3,3-hexafluoro-2-(6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(3′-methoxy-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(3′-fluoro-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(3-(3-pyridinyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(3-(3-thiophenyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2′-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5′-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4-biphenylol; 1,1,1-trifluoro-2-(3-(3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; or 1,1,1-trifluoro-2-(4-(2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

›SUMMARY OF THE INVENTION · 5 of 6

In embodiment 30, the present invention provides the compounds, or pharmaceutically acceptable salts thereof, selected from:

8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[321]octan-6-ol (exo); (1S,5S,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[321]octan-6-ol; 8-(((2S)-4-(phenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; 8-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; (2S)-3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; (2R)-3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; 1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-((2S)-2-((1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-((3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-((2S)-2-((3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-(4-((2-amino-5-pyrimidinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo); 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one; 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo); 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one; 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); 1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(4-((4-aminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-((4-amino-3-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 3-((4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)phenol; 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one; 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one; 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one; 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo); (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo); 1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo); 1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; N-((4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide; N-(((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1Rr)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide; N-(((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methane sulfonamide; N-(((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methane sulfonamide; N-(((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methane sulfonamide; (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate; N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide; 1,1,1-trifluoro-2-(4-((2S)-2-((3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-((2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((3-methyl-3-oxetanyl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-((tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-((tetrahydro-2H-pyran-4-ylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-(cis-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 125: 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3R)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3R)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; 2-(4-(4-((4-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-one; 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (endo); 3-fluoro-9-(((2S)-1-(4-(1,2,2,2-tetrafluoro-1-methylethyl)phenyl)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonane (exo); 2-(4-((2S)-2-((3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone; (3S)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-piperidinol; 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 2-(2-((2S)-4-((2-amino-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-(2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol; 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-2-ol; 3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-ol; 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxyprop-1-ynyl)-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol; 1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol; 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxy-1-pentyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 4-methyl-1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol; 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxy-4-methyl-1-pentyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; tert-butyl (3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-yl)carbamate; 2-(3-(3-amino-1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; N-(3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-yl)methanesulfonamide; 2-(4′-((6-amino-3-pyridinyl)sulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol; 1-(2-(4-(phenylsulfonyl)-1-piperidinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol; 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxypent-1-ynyl)-4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol; 2-(4-(4-(6-aminopyridazin-3-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-(2-aminophenylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-(2,6-diaminopyridin-3-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; (S)-2-(2-(4-(2-aminophenylsulfonyl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoro-2-propanol; (2-(4-((2S)-4-((2-aminophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-(4-bromothiophen-3-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((S)-2-((1h-imidazol-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-((S)-2-((5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(4-((S)-2-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-(2-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-(4-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol; 3-((1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(thiophen-2-ylsulfonyl)piperazin-2-yl)methyl)phenol; 4-((1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(thiophen-2-ylsulfonyl)piperazin-2-yl)methyl)phenol; 2-((1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(thiophen-2-ylsulfonyl)piperazin-2-yl)methyl)phenol; 4-(((2S)-4-(2-thiophensulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-piperazinone; 3,3-dimethyl-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-piperazinone; 3-(1-methylethyl)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-piperazinone; (3S-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-piperazinone; 5-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-piperazinone; 4-(((S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone; (3R)-4-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone; (3S)-4-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone; 3-(1-methylethyl)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-2-piperazinone; 1,1,1-trifluoro-2-(4-((2R)-2-((phenylsulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-((phenylsulfonyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-((phenylsulfonyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2R)-2-((phenylsulfonyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((3-fluorophenyl)sulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((3-fluorophenyl)sulfonyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((3-fluorophenyl)sulfinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((4-fluorophenyl)sulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((4-fluorophenyl)sulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2R)-2-(((4-fluorophenyl)sulfinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide; N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)benzenesulfonamide; 2-(4-((2S)-2-((bis(1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-(1-methylethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide; N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)benzenesulfonamide; N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide; 2-(4-((2S)-2-((cyclopropylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; N-cyclopropyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-(2-methylpropyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-(cyclopropylmethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; N-phenyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; 2-(4-((2S)-2-((di-3-oxetanylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-2-((3-oxetanylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; N-3-oxetanyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-methyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N,N-dimethyl-N′-(1-methylethyl)-N′-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)sulfamide; 2-methyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide; 2-methyl-N-phenyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide; N-cyclobutyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-cyclobutyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide; 2,2,2-trifluoro-N-(2-methylpropyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)ethanesulfonamide; N,N-dimethyl-N-(2-methylpropyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)sulfamide; N-((3-methyl-3-oxetanyl)methyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-methyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide; N-(cyclobutylmethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; 1,1,1-trifluoro-2-(4-((2R)-2-(((2-fluorophenyl)sulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; N-benzyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-(3-pyridinylmethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-(1-phenylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; 2-methyl-N-3-pyridinyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide; N-phenyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide; 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 3,3-dimethyl-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-2-piperazinone; (S)-4-((4-((5-aminothiophen-2-yl)sulfonyl)-1-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrimidin-2-yl)piperazin-2-yl)methyl)-3,3-dimethylpiperazin-2-one; 5,5-dimethyl-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2,4-imidazolidinedione; N-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-n-(2-methylpropyl)methanesulfonamide; N-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide; N-(((2S)-4-((2-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide; N-(((2R)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide; N-(((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide; N-(((2R)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide; N-(((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide; 4-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3,3-dimethyl-2-piperazinone; 5-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-5,7-diazaspiro[3.4]octane-6,8-dione; N-(((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)propane-2-sulfonamide; N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-butanesulfonamide; 1,1,1-trifluoro-2-(2-(2-(prop-1-yn-1-yl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; or 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol.

›SUMMARY OF THE INVENTION · 6 of 6

In embodiment 31, the present invention provides the compounds, or pharmaceutically acceptable salts thereof, selected from:

2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 5,5-dimethyl-3-(1-methylethyl)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2,4-imidazolidinedione; 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(2-hydroxypropyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-( 2 H 3 )-1-propyn-1-yl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(cyclopropylethynyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol; 2-(4-(4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(2-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(2-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; N-(1-phenylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; 2-methyl-N-3-pyridinyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide; 4-fluoro-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)benzenesulfonamide; N-(4-fluorophenyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide; N-(4-fluorophenyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide; 1,1,1,3,3,3-hexafluoro-2-(4-(2-((2-methoxy-3-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-(2-((6-methoxy-2-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 4-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-piperazinyl)methyl)-2(1H)-pyridinone; 2-(4-(4-((4-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(4-(4-((2,4-diaminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(3-(1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; 2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-(6-((6-amino-3-pyridinyl)sulfonyl)-3-pyridinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-methylphenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(2-(2-(1-propyn-1-yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; 1,1,1-trifluoro-2-(4-((2S)-4-(2-thiophenylsulfonyl)-2-((3-(trifluoromethyl)-1-piperazinyl)methyl)-1-piperazinyl)phenyl)-2-propanol; 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol; (S)-5-methyl-4-(((S)-4-(tiophen-2-ylsulfonyl)-1-(4-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)morpholin-3-one; or 2-(4-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol.

In embodiment 32, the present invention provides methods of treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, Syndrome X, or polycystic ovarian syndrome, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound in accordance with any one of embodiments 1 to 31, or a pharmaceutically acceptable salts thereof.

In embodiment 33, the present invention provides the methods of embodiment 32 wherein the treatment is for type 2 diabetes.

In embodiment 34, the present invention provides pharmaceutical compositions comprising a compound in accordance with any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

›DETAILED DESCRIPTION · 1 of 9

The present invention provides compounds of Formula I, as defined above, or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions comprising a compound of Formula I, or pharmaceutically acceptable salts thereof, and methods of treating diseases and/or conditions, such as diabetes, using compounds of Formula I, or pharmaceutically acceptable salts thereof.

The term “alkyl” means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as C 1-8 alkyl.

The term “alkoxy” means an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. Common alkoxy groups are C 1-8 alkoxy.

The term “halogen” or “halo” means chlorine, fluorine, bromine or iodine.

The term “alkenyl” means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds. Representative examples alkenyl groups include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl. Common alkenyl groups are C 2-8 alkenyl.

The term “alkynyl” means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds. Representative examples of alkynyl groups include ethynyl, propynyl (propargyl) and butynyl. Common alkynyl groups are C 2-8 alkynyl.

The term “cycloalkyl” means a cyclic, nonaromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl group can contain one or more double bond. Examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cycloalkyl groups are C 3-8 cycloalkyl groups.

The term “perfluoroalkyl” means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms. Common perfluoroalkyl groups are C 1-8 perfluoroalkyl. An example of a common perfluoroalkyl group is —CF 3 .

The term “acyl” means a group derived from an organic acid by removal of the hydroxy group (—OH). For example, the acyl group CH 3 C(═O)— is formed by the removal of the hydroxy group from CH 3 C(═O)OH.

The term “aryl” means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.

The term “heteroatom” as used herein means an oxygen, nitrogen or sulfur atom.

The term “heteroaryl” means a cyclic, aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groups are five to thirteen membered rings that contain from 1 to 4 heteroatoms. Heteroaryl groups that are five and six membered rings that contain 1 to 3 heterotaoms are particularly common.

The term “heterocycloalkyl” means a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran. Common heterocycloalkyl groups are three to ten membered rings containing from 1 to 4 heteroatoms. Heterocycloalkyl groups that are five and six membered rings that contain 1 to 2 heterotaoms are particularly common.

It is also noted that the cyclic ring groups, i.e., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, can comprise more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also intended that the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.

Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and pyrazinyl.

Representative examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally having one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, and 1,3-oxathiolyl.

Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyndazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-(3 oxathiazinyl, and 1,4,2-oxadiazinyl.

›DETAILED DESCRIPTION · 2 of 9

Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.

Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.

Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, optionally having one to four heteroatoms, are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo[b]thienyl, benzo[c]thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.

A cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term “pyridyl” includes 2-, 3-, or 4-pyridyl, and the term “thienyl” includes 2-, or 3-thienyl.

The term “substituted” means that a hydrogen atom on a molecule or group is replaced with a group or atom. Typical substitutents include: halogen, C 1-8 alkyl, hydroxyl, C 1-8 alkoxy, —NR x R x , nitro, cyano, halo or perhaloC 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —SR x , —S(═O) 2 R x , —C(═O)OR x , —C(═O)R x , wherein each R x is independently hydrogen or C 1 -C 8 alkyl. It is noted that when the substituent is —NR x R x , the R x groups may be joined together with the nitrogen atom to form a ring.

The term “oxo”, when used as a substituent, means the ═O group, which is typically attached to a carbon atom.

A group or atom that replaces a hydrogen atom is also called a substituent.

Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.

The symbol “—” represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

The term “therapeutically effective amount” means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.

The term “patient” means animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.

The term “pharmaceutically acceptable” means that the referenced substance, such as a compound of the present invention or a formulation containing a compound of the present invention, or a particular excipent, are suitable for administration to a patient.

The terms “treating”, “treat” or “treatment” and the like include preventative (e.g., prophylactic) and palliative treatment.

The term “patient in need thereof” means a patient who has or is at risk of having a GKRP/GK mediated disease or condition, such as type 2 diabetes.

The term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.

The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.

In addition, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds. The other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially. For example, in the case of tablets, the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order. In addition, it should be recognized that the compositions may be different forms. For example, one or more compound may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.

The compounds of the present invention may be used in the manufacture of a medicament for the treatment of a disease and/or condition mediated by GKRP/GK, such as type 2 diabetes.

The compounds of the present invention may be used in combination with other pharmaceutically active compounds. It is noted that the term “pharmaceutically active compounds” can include biologics, such as proteins, antibodies and peptibodies. Examples of other pharmaceutically active compounds include, but are not limited to: (a) dipeptidyl peptidase IV (DPP-IV) inhibitors such as Vildagliptin (Novartis), Sitagliptin (Merck&Co.), Saxagliptin (BMS) Allogliptin (Takeda); (b) insulin sensitizers including (i) PPARγ agonists such as the glitazones (e.g., troglitazone, pioglitazone, edaglitazone, rosiglitazone, and the like) and other PPAR ligands, including PPARα/γ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) incretin and incretin mimetics such as (i) Exenatide available from Amylin Pharmaceuticals, (i) amylin and amylin mimetics such as pramlintide acetate, available as Symlin®, (iii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists, (iv) GIP, GIP mimetics and GIP receptor agonists; (e) sulfonylureas and other insulin secretagogues, such as tolbutamide, glyburide, gliclazide, glipizide, glimepiride, meglitinides, and repaglinide; (f) α-glucosidase inhibitors (such as acarbose and miglitol); (g) glucagon receptor antagonists; (h) PACAP, PACAP mimetics, and PACAP receptor agonists; (i) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants such as cholestyramine, colestipol and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors such as avasimibe, and (viii) anti-oxidants such as probucol; (j) PPARδ agonists such as GW-501516 from GSK; (k) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentemine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, MTP inhibitors, squalene synthase inhibitor, lipoxygenase inhibitor, ACAT inhibitor, Neuropeptide Cannabinoid CB-1 receptor antagonists, CB-1 receptor inverse agonists and antagonists, fatty acid oxidation inhibitors, appetite suppressants (l) adrenergic receptor agonists, melanocortin receptor agonists, in particular—melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists; (m) ileal bile acid transporter inhibitors; (n) agents intended for use in inflammatory conditions such as aspirin, non steroidal anti-inflammatory drugs, glucocorticoids, azalfidine, and selective cyclooxygenase-2 inhibitors; (o) antihypertensive agents such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, fosinoprol, ramipril, spirapril, tandolapril), angiotensin-II (AT-1) receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan), beta blockers and calcium channel blockers; and (p) glucokinase activators (GKAs); (q) agents which can be used for the prevention, delay of progression or treatment of neurodegenerative disorders, cognitive disorders or a drug for improving memory such as anti-inflammatory drugs, antioxidants, neuroprotective agents, glutamate receptor antagonists, acetylcholine esterase inhibitors, butyrylcholinesterase inhibitors, MAO inhibitors, dopamine agonists or antagonists, inhibitors of gamma and beta secretases, inhibitors of amyloid aggregation, amyloid beta peptide, antibodies to amyloid beta peptide, inhibitors of acetylcholinesterase, glucokinase activators, agents directed at modulating GABA, NMDA, cannabinoid, AMPA, kainate, phosphodiesterase (PDE), PKA, PKC, CREB or nootropic systems; (r) leukocyte growth promotors intended for the treatment and prevention of reduced bone marrow production, infectious diseases, hormone dependent disorders, inflammatory diseases, HIV, allergies, leukocytopenia, and rheumatism; (s) SGLT2 inhibitor; (t) glycogen phosphorylase inhibitor; (u) aP2 inhibitors; (v) aminopeptidase N inhibitor (w) vasopeptidase inhibitors like neprilysin inhibitors and/or ACE inhibitors or dual NEP/ACE inhibitor; (x) growth hormone secretagogue for enhancing growth hormone levels and for treating growth retardation/dwarfism or metabolic disorders or where the disorder is an injury, or a wound in need of healing, or a mammalian patient recovering from surgery; (y) 5-HT 3 or 5-HT 4 receptor modulators (tegaserod, cisapride, nor-cisapride, renzapride, zacopride, mosapride, prucalopride, buspirone, norcisapride, cilansetron, ramosetron, azasetron, ondansetron, etc.); (Za) aldose reductase inhibitors; (Zb) sorbitol dehydrogenase inhibitors; (Zc) AGE inhibitors; (Zd) erythropoietin agonist such as EPO, EPO mimetics, and EPO receptor agonists. The compounds of the present invention may also be used in combination with GPR40 agonists.

›DETAILED DESCRIPTION · 3 of 9

Examples of glucokinase activators that can be used in combination with the compounds of the present invention include those set forth in published PCT patent application no. WO 2009/042435, published Apr. 2, 2009. Examples of specific compounds, or pharmaceutically acceptable salts thereof, disclosed in the published application that may be used in combination with the compounds of the present invention, or pharmaceutically acceptable salts thereof, include compounds selected from:

(S)-1-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5-trifluoromethyl-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5-phenylthio-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5-phenylthio-3-(pyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethane-1,2-diol; (S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5(2hydroxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(4-fluorophenoxy)-5-pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol; (S)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol; (R)-1-(2-(3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)-ethane-1,2-diol; (1S)-1-(5-(5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5-bromo-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (R)-1-(2-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)thiazol-4-yl)-ethane-1,2-diol; (S)-1-(5-(5-(2-hydroxyethylthio)-3-(pyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5-bromo-3-(1-methyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(3-(1-methyl-1H-pyrazol-4-yloxy)-5-(2-methylpyridin-3-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; (S)-1-(5-(5-(2-methylpyridin-3-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)-pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

D 2 = CH D 2 = N

D 2 = CH R = Et, iPr, CH 2 OH, CH 2 CH 2 OH, or CF 3 D 2 = N R = Et, iPr, CH 2 OH, CH 2 CH 2 OH, or CF 3

D 2 = CH D 2 = N

D 2 = CH R A , R B , R C are independently H or Me D 2 = N R A , R B , R C are independently H or Me

D 2 = CH D 2 = N

D 2 = CH R = S-pyrid-2-yl, CF 3 , S-2- methylpyrid-3-yl D 2 = N R = S-pyrid-2-yl, CF 3 , S-2- methylpyrid-3-yl

D 2 = CH D 2 = N

D 2 = CH R D = H, Me, or CF 3 D 2 = N R D = H, Me, or CF 3

D 2 = CH R D is H, CF 3 or (1-6C alkyl) D 2 = N R D is H, CF 3 or (1-6C alkyl)

D 2 = CH D 2 = N

D 2 = CH X = CH 2 D 2 = CH 2 X = O D 2 = N X = CH 2 D 2 = N X = O

D 2 = CH D 2 = N

›DETAILED DESCRIPTION · 4 of 9

D 2 = CH D 2 = N

(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl-amino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol;

(S)-1-(5-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl-amino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-2-methyl-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol;

(S)-1-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol;

(S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)-pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol;

(S)-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl-amino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl-amino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(R)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol; or

(R)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol, or the pharmaceutically acceptable salts thereof.

Other compounds that may be used in combination with the compounds of the present invention include the IL1-R1 compounds set forth in U.S. Pat. No. 7,438,910. A particular disease that can be treated with the combination is type 2 diabetes.

The compounds of the present invention can also be used in combination with FGF-21 compounds, and particularly for the treatment of type 2 diabetes. Examples of FGF-21 compounds are disclosed in U.S. Pat. No. 7,671,180; U.S. Pat. No. 7,667,008; U.S. Pat. No. 7,459,540; U.S. Pat. No. 7,696,172; PCT application publication no. WO 2010/042747; and PCT application publication no. WO 2009/149171.

The compounds of the present invention can be also be used in combination with anakinra, particularly for the treatment of type 2 diabetes.

In one particular aspect, the compounds of the present invention may be used in combination with metformin.

The compounds of the present invention are used in the treatment diseases or symptoms mediated by GKRP and/or GK (GKRP/GK). Examples of diseases or symptoms mediated by GKRP/GK include, but are not limited to, Type II (type 2) diabetes and related disorders, such as hyperglycemia, low or impaired glucose tolerance, insulin resistance, obesity, lipid disorders such as dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolernia, low HDL levels, high LDL levels, atherosclerosis, and vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, glomerulosclerosis, foot ulcerations and unlcerative colitis, altered gastrointestinal motility, Syndrome X, ovarian hyperandrogenism, polycystic ovarian syndrome, premenstrual syndrome, other disorders where insulin resistance is a component. In Syndrome X, also known as Metabolic Syndrome, obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk, growth hormone deficiency, neutropenia, neuronal disorders, tumor invasion and metastasis, benign prostatic hypertrophy, gingivitis, osteoporosis, frailty of aging, intestinal injury, benign prostatic hypertrophy (BPH), and sperm motility/male contraception.

The compounds of the present invention are also useful for the prevention, delay of progression or the treatment of an early cardiac or early cardiovascular diseases or damages, renal diseases or damages, heart Failure, or heart Failure associated diseases like (i) cardiovascular diseases or damages e.g. cardiac hypertrophy, cardiac remodelling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or in hypertrophic cardiomyopathy, cardiomyopathy such as dilated cardiomyopathy or hypertrophic cardiomyopathy, mesanglial hypertrophy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass reocclusion, intermittent claudication, diastolic and/or systolic dysfunction, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic medial thickening in arteries and/or large vessels, mesenteric vasculature hypertrophy or artherosclerosis, preferably artherosclerosis in mammalian patients with hypertension of diabetes; (ii) renal diseases or damages like renal hyperfiltration such as after portal renal ablation, proteinuria in chronic renal disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis, hypertensive nephrosclerosis or mesanglial hypertrophy; (iii) Heart Failure to be treated is secondary to idiopathic dilated cardiomyopathy and/or coronary ischemic disease.

›DETAILED DESCRIPTION · 5 of 9

The compounds of the present invention can also be used for the prevention, the delay of the onset, the delay of progression or the treatment of neurodegenerative disorders, cognitive disorders and for improving memory (both short term and long term) and learning ability wherein the (i) neurodegenerative disorder is dementia, senile dementia, schizophrenia, mild cognitive impairment, Alzheimer related dementia, Huntington's chores, tardive dyskinesia, hyperkinesias, mania, Morbus Parkinson, Steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve and brain trauma, vascular amyloidosis, cerebral haemorrhage I with amyloidosis, brain inflammation, Friedrich ataxia, acute confusion disorders, acute confusion disorders with apoptotic necrocytosis, amyotrophic lateral sclerosis, glaucoma, and Alzheimer's disease; (ii) cognitive disorders like cognitive deficits associated with schizophrenia, age-induced memory impairment, cognitive deficits associated with psychosis, cognitive impairment associated with diabetes, cognitive deficits associated with post-stroke, memory defects associated hypoxia, cognitive and attention deficits associated with senile dementia, attention deficits disorders, memory problems associated with mild cognitive impairment, impaired cognitice function associated with vascular dementia, cognitive problems associated with brain tumors, Pick's disease, cognitive deficits due to autism, cognitive deficits post electroconvulsive therapy, cognitive deficits associated with traumatic brain injury, amnesic disorders, deliriums, vitamin deficiency, dementias, impaired cognitive function associated with Parkinson's disease, attention-deficit disorders; (iii) prevention of memory impairment as a result of Alzheimer disease, Creutzfeld-Jakob disease, Pick disease, Huntington disease, AIDS, brain injury, brain aneurysm, epilepsy, stroke, toxicant exposure, mental retardation in children, Huntington's disease; (iv) to improve learning speed and potential in educational and rehabilitation contexts.

The compounds of the present invention can also be used for stimulating an immune response in a subject having or at risk of having cancer wherein the cancer is selected from the group consisting of basal cell carcinomas including cancers of the binary tract, bladder, urinary system, bone, brain, breast, cervical, endometrial, ovarian, uterine, choriocarcinoma, central nervous system, colon and rectal cancers, connective tissue cancer, cancer of the digestive system, esophageal, gastric, stomach, larynx, liver, pancreatic, colorectal, renal cancers; cancers of the urinary system; cancers of eye, head and neck, oral cavity, skin, prostate; cancers of biliary tract, testicular, thyroid; intra-epithelial neoplasm, leukemia, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; and other cancers of the respiratory system, lung, small cell lung, non-small cell lung; lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma; melanoma, myeloma, neuroblastoma, retinoblastoma, fibrosarcoma (bone or connective tissue sarcoma), rhabdomyosarcoma; and other cancers including neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma.

The compounds of the present invention can also be used for the treatment or prophylaxis of chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.

The compounds of the present invention can also be used in the treatment of pain, neuropathic pain, rheumatoid pain, osteoarthritis pain, anesthesia adjunct in mammalian patients undergoing surgery, chronic pain in advanced cancer, treatment of refractory diarrhea, biliary pain caused by gallstones.

The compounds of the present invention can also be used for the treatment of mammalian patients undergoing islet/pancreas transplantation, for the prevention or the delay of transplant rejection, or allograft rejection in transplantation, for improving pancreatic function by increasing the number and size of pancreatic beta-cells in the treatment of Type 1 diabetes patients, and for improving pancreatic function by increasing the number and size of pancreatic beta-cells in general.

Furthermore, the compounds of the present invention can be used for the treatment of mammalian patients with acne, skin disorders (e.g. pigmentation disorders or psoriasis), scleroderma, mycoses; anxiety, anxiety neurosis, major depression disorder, drug abuse, alcohol addiction, insomnia, chronic fatigue, sleep apnea; anorexia nervosa; epilepsy; migraine; encephalomyelitis; osteoarthritis, osteoporosis, calcitonin-induced osteoporosis; male and female sexual dysfunction, infertility; Type 1 diabetes; immunosuppression, HIV infection; hematopoiesis, anemia; and for weight reduction.

Additionally, the compounds of the present invention are useful for the prevention, delay of progression or treatment of (i) bacterial infections from Escherichia coli, Staphylococcus, Streptoococcus, Pseudomonas, Clostridium difficile infection, Legionella, Pneumococcus, Haemophilus, Klebsiella, Enterobacter, Citrobacter, Neisseria, Shigella, Salmonella, Listeria, Pasteurella, Streptobacillus, Spirillum, Treponema, Actinomyces, Borrelia, Corynebacterium, Nocardia, Gardnerella, Campylobacter, Spirochaeta, Proteus, Bacteriodes, Helicobacter pylori , and anthrax infection; (ii) mycobacterial infection from tuberculosis and leprosy; (iii) viral infection from HIV, Herpes simplex virus 1, Herpes simplex virus 2, Cytomegalovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, Epstein Barr virus, rotavirus, adenovirus, influenza A virus, respiratory syncytial virus, varicella-zoster virus, small pox, monkey pox and SARS; (iv) fungal infection from candidiasis, ringworm, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, aspergillosis, chromomycosis, mycetoma infections, pseudallescheriasis, Tinea versicolor infection; (v) parasite infection from amebiasis, Trypanosoma cruzi, Fascioliasis, Leishmaniasis, Plasmodium, Onchocerciasis, Paragonimiasis, Trypanosoma brucei, Pneumocystis, Trichomonas vaginalis, Taenia, Hymenolepsis, Echinococcus, Schistosomiasis, neurocysticerosis, Necator americanus , and Trichuris trichuria.

›DETAILED DESCRIPTION · 6 of 9

Since one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes and bags. Typically, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician or veterinarian.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, is Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a compound of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this and aid in correct administration of the active agents.

In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

The compounds of the present invention and other pharmaceutically active compounds, if desired, can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents.

›DETAILED DESCRIPTION · 7 of 9

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants. The active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.

The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term “salts” refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J Pharm Sci, 66: 1-19 (1977).

Examples of pharmaceutically acceptable esters of the compounds of the present invention include C 1 -C 8 alkyl esters. Acceptable esters also include C 5 -C 7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C 1 -C 4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.

Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C 1 -C 8 alkyl amines, and secondary C 1 -C 8 dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C 1 -C 3 primary alkyl amines and C 1 -C 2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.

The term “prodrug” means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

›DETAILED DESCRIPTION · 8 of 9

To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1 -C 8 alkyl, (C 2 C1 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-m (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1 -C 2 )alkyl, N,N-di(C 1 -C 2 )alkylcarbamoyl-(C 1 -C 2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2-3 )alkyl.

Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, α-amino(C 1 -C 4 )alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, —P(O)(OH) 2 , —P(O)(O(C 1 -C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as S and E, respectively), as well as mixtures, are contemplated.

Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some compounds may be atropisomers (e.g., substituted biaryls).

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.

It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.

Those skilled in the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of a compound. While the name or structure for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention, unless stated otherwise.

It is also intended that the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

The present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. In another aspect, the compounds of the present invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.

Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.

›DETAILED DESCRIPTION · 9 of 9

In synthesizing compounds of the present invention, it may be desirable to use certain leaving groups. The term “leaving groups” (“LG”) generally refer to groups that are displaceable by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.

All patents and other publications recited herein are hereby incorporated by reference in their entirety.

The examples presented below illustrate specific embodiments of the present invention. These examples are meant to be representative and are not intended to limit the scope of the claims in any manner.

›EXAMPLES · 1 of 2

Biological Assays

GKRP LC MS/MS Biochemical Assay

This assay is used to directly measure the formation of 13 C-glucose-6-phosphate from 13 C-glucose by liquid chromatography-mass spectrometry (LC MS/MS). Begin by preparing the following solutions: Compound Buffer (CB): 50 mM Tris, pH 7.5/4 mM MgCl 2 /6% DMSO/fresh 10 mM DTT from 1M frozen stock. Enzyme Buffer (EB): 50 mM Tris, pH 7.5/4 mM MgCl 2 /6% DMSO/fresh 0.1% BSA/fresh 0.01% Brij-35 (10% BSA and 1% Brij-35 stock). GK (Glucokinase) Working Stock (5×): Dilute human His-hepatic GK to 30 nM in EB buffer. Substrate Working Stock (1.47×): Dilute 13C-D-glucose (Sigma-Aldrich, St. Louis, Mo.) to 7.35 mM from 1M stock (1M 13 C-D-glucose=186.11 mg/ml in 50 mM Tris pH 7.5, 4 mM MgCl 2 ) and dilute ATP (EMD Chemical Inc., Gibbstown, N.J.) to 0.3528 mM from frozen 100 mM stock and dilute 20 mM fructose-6-phosphate (F6P) (Sigma-Aldrich, St. Louis, Mo.) to 441 μM in CB buffer. GKRP (Glucokinase Regulatory Protein) (10×): Dilute GKRP to 1 μM from 33.366 mM stock in EB buffer. Combine the following reagents in a 96-well polypropylene plate: 34 μl of Substrate Working Stock (1.47×), 5 μl of 1 μM GKRP (10×), and 1 μl of compound or DMSO. Seal the plate and incubate for 30 minutes at room temperature while mixing. After 30 minutes add 10 μl of GK Working Stock (5×). Re-seal the plate and incubate for another 30 minutes at room temperature while mixing. After the second 30 minutes, stop the reaction by the addition of 50 μl of 100% acetonitrile, seal, and mix for 5-10 minutes. Run 10 μl of this sample through the LC MS/MS (API 3200, Applied Biosystems Inc., Carlsbad, Calif.). Detection settings are for 265.2/78.8 atomic mass units.

GKRP NADPH Coupled Assay

This assay is used as an indirect measure of glucose-6-phosphate (G6P) formed from glucose due to the enzymatic activity of glucokinase. Assay format is the same as for GKRP LC MS/MS Biochemical Assay with the following exceptions. GK Working Stock (5×): Dilute human His-hepatic GK to 20 nM in EB buffer. Stop & Detection Reagent (2×): Dilute β-nicotinamide adenine dinucleotide phosphate sodium salt (β-NADP) (Aldrich-Sigma, St. Louis, Mo.) to 2 mM from 100 mM stock (stock in 10 mM Tris, pH 9.2) and dilute glucose-6-phosphate dehydrogenase (Aldrich-Sigma, St. Louis, Mo.) to 0.04 Unit/μl from 10 Unit/μl (stock in 10 mM Tris pH 7.5/0.05% Brij-35) in 0.2 M Tris, pH 9.2/8% DMSO. After the initial 30 minute incubation add 10 μl of 20 nM GK diluted in EB (5×). Re-seal the plate and incubate for another 1 hour at room temperature while mixing. After 1 hour remove the seal and add 50 μl of Stop & Detection Reagent and incubate for 5 minutes at room temperature while mixing. After 5 minutes read the plate using an Infinite M1000 (Tecan Systems Inc., San Jose Calif.) with the following detection settings: Mode: Fluorescence Top Reading, Excitation Wavelength: 340 nm, Emission Wavelength: 450 nm, Excitation Bandwidth: 20 nm, Emission Bandwidth: 20 nm, Gain: 95, Number of Flashes: 10, Flash Frequency: 400 Hz, Integration Time: 20 μs.

GK-GKRP Binding Assay Protocol

This assay is used to directly measure the interaction between glucokinase (GK) and glucokinase regulatory protein (GKRP). Begin by preparing the following solutions. Assay Buffer: 20 mM Tris, pH 7.5/0.05% BSA/1 mM DTT/1 μM sorbitol-6-phosphate. Assay Procedure: Dilute avi-tagged GKRP to 10.7 nM in assay buffer. Combine the following reagents in a white 96-well half area plate. Pipette 14 μl of the diluted avi-tagged GKRP into each well. Add 1 μl of compound to be tested and incubate at room temperature for 20 minutes. After 20 minutes, add 5 μl of assay buffer containing 6 nM GK-fluorescein. Add 10 μl of AlphaScreen® beads (Perkin Elmer, Waltham Mass.) that have been diluted 1:333 in assay buffer. Incubate in a dark room for 2 hours at room temperature. After 2 hours read the plate using an Envision plate reader (Perkin Elmer, Waltham Mass.).

GKRP LC MS/MS-2 Biochemical Assay

This assay is used to directly measure the formation of 13 C-glucose-6-phosphate from 13 C-glucose by LC MS/MS. Begin by preparing the following solutions: Compound Buffer (CB): 50 mM Tris, pH 7.5/4 mM MgCl 2 /6% DMSO/fresh 10 mM DTT from 1M frozen stock. Enzyme Buffer (EB): 50 mM Tris, pH 7.5/4 mM MgCl 2 /6% DMSO/fresh 0.1% BSA/fresh 0.01% Brij-35 (10% BSA and 1% Brij-35 stock). GK (Glucokinase) Working Stock (5×): Dilute human His-hepatic GK to 30 nM in EB buffer. Substrate Working Stock (1.47×): Dilute 13 C-D-glucose (Sigma-Aldrich, St. Louis, Mo.) to 7.35 mM from 1M stock and dilute ATP (EMD Chemical, Gibbstown, N.J.) to 0.3528 mM from frozen 100 mM stock in CB buffer (1M 13 C-D-glucose=186.11 mg/ml in water). Dilute 20 mM fructose-6-phosphate (F6P) (Sigma-Aldrich, St. Louis, Mo.) to 441 μM in the substrate working stock. GKRP (Glucokinase Regulatory Protein) (10×): Dilute GKRP to 280 nM from 33.366 mM stock in EB buffer. Combine the following reagents in a 96-well polypropylene plate: 34 μL of Substrate Working Stock (1.47×), 5 μl of 280 nM GKRP (10×), and 1 μl of compound or DMSO. Seal the plate and incubate for 30 minutes at room temperature while mixing. After 30 minutes add 10 μl of GK Working Stock (5×). Re-seal the plate and incubate for another 30 minutes at room temperature while mixing. After the second 30 minutes, stop the reaction by the addition of 50 μl of 100% acetonitrile, seal, and mix for 5-10 minutes. Run 10 μl of this sample through the LC MS/MS (API 3200, Applied Biosystems, Carlsbad, Calif.). Detection settings are for 265.2/78.8 atomic mass units.

Results for compounds tested in these biological assays are set forth in the numbered examples below.

The following synthetic schemes show generally how to make compounds of the present invention.

General Synthetic Schemes

The sulfonamide can be synthesized by the reaction of an amine with a substituted sulfonyl chloride in an anhydrous solvent (such as CH 2 Cl 2 , THF or ether) in the presence of a base (either inorganic or amine) such as Et 3 N, DIPEA, K 2 CO 3 , Na 2 CO 3 , or NaOH.

›EXAMPLES · 2 of 2

The N-arylation can be conducted using a variety of bases (such as NaOt-Bu, K 3 PO 4 or LiHMDS), catalyst (such as Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4 ), catalyst ligands (such as RuPhos, BINAP or SPhos), and solvents (such as toluene or dioxane).

The carbinol functionality can be installed, for example, using n-BuLi (or t-BuLi) with THF or diethyl ether as the reaction solvent.

The amine coupling can accomplished using a variety of both coupling reagents (for example, TBTU, HATU or EDC) and solvents (for example, CH 2 Cl 2 , DMF or DMSO). The removal of the Boc protection group can be achieved by a number of conditions including: neat TFA, a TFA/CH 2 Cl 2 solution or a 4N HCl solution in dioxane. The cyclization proceeds with an amine base (such as NH 3 , Et 3 N, or DIPEA) in alcoholic solvent (such as MeOH).

The amine substitution can be accomplished using a variety of inorganic bases (such as K 2 CO 3 , Na 2 CO 3 , or Cs 2 CO 3 ) in polar aprotic solvents (such as MeCN, DMF or DMSO).

The Suzuki reaction with the aryl bromide can be achieved using a variety of bases (such as Cs 2 CO 3 , K 2 CO 3 , or Na 2 CO 3 ), catalysts (such as Pd(dppf)Cl 2 , or Pd(PPh 3 ) 4 ), and solvents (such as DME, EtOH, DMF or EtOH)

The following abbreviations may be used herein:

HATU [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Hünig's base or DIPEA diisopropylethylamine dppf 1,1′-bis(diphenylphosphanyl)ferrocene dba 1,5-diphenylpenta-1,4-dien-3-one LAH lithium aluminum hydride TMS trimethylsilyl EDC 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine HOBt 1-hydroxybenzotriazole TLC thin layer chromatography MHz megahertz br. broad s singlet d doublet t triplet dt doublet of triplet dd doublet of doublet quin quintuplet q quartet ˜ about +ve or pos. ion positive ion Δ heat Ac acetyl AcOH Acetic acid Ac 2 O acetic anhydride ACN acetonitrile A-phos, Am-Phos (bis[4-di-tert-butylphosphino)-N,N-dimethylaniline]palladium dichloride) aq aqueous ATP adenosine 5′-triphosphate BOC or Boc tert-butyloxycarbonyl Bu butyl Bn benzyl Calcd or Calc'd calculated Conc. concentrated DCE 1,2-dichloroethane DCM dichloromethane DEA diethylamine DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine DME dimethoxyl ethyl ether DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DTT dithiothreitol ESI or ES electrospray ionization Et ethyl Et 2 O diethyl ether Et 3 N triethylamine EtOAc ethyl acetate EtOH ethyl alcohol FBS fetal bovine serum g grams h hour HCO 2 H formic acid Hex hexanes HOAc acetic acid HPLC high pressure liquid chromatography IPA or iPrOH isopropyl alcohol iPr 2 NEt N-ethyl diisopropylamine KOAc potassium acetate LC MS, LC-MS or LC/MS liquid chromatography mass spectroscopy LDA lithium diisopropylamide LHMDS or LiHMDS lithium hexamethyldisilazide LiTMP lithium tetramethylpiperidide m/z mass divided by charge mCPBA or MCPBA m-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeI iodomethane MeOH methyl alcohol mg milligrams min minutes mL milliliters MS mass spectra MsCl mesylchloride NaBH 4 sodium borohydride NaHMDS sodium hexamethyldisilazide NaOtBu sodium tert-butoxide NBS N-bromosuccinimide n-BuLi n-butyllithium NMO N-methylmorpholine-N-oxide NMP 1-methyl-2-pyrrolidinone NMR nuclear magnetic resonance Pd 2 dba 3 tris(dibenzylideneacetone)dipalladium(0) PMB paramethoxybenzyl RT or rt room temperature Sat. or sat'd or satd saturated SFC supercritical fluid chromatography RhPhos 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t- RuPhos Palladacycle butylether adduct TFA trifluoroacetic acid THF tetrahydrofuran Ti(O-iPr) 4 titanium isopropoxide TPAP tetrapropylammonium perruthenate Tris tris(hydroxymethyl)aminomethane xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl

It is noted that when a percent (%) is used with regard to a liquid, it is a percent by volume with respect to the solution. When used with a solid, it is the percent with regard to the solid composition. Throughout the Examples, chromatography columns are used for separations and purifications. Below are some representative suppliers of columns: Phenomenex, Torrance, Calif. (e.g., Gemini); Diacel Inc., Fort Lee, N.J. (e.g., Chiralcel®, Chiralpak®); Krackeler Scientific, Albany, N.Y. (e.g., AccuBOND).

Intermediate A: (S)-3-(benzyloxymethyl)piperazine-2,5-dione

A 1 L round-bottomed flask was charged with O-benzyl-N-(tert-butoxycarbonyl)-L-serine (150 g, 508 mmol, Sigma-Aldrich, St. Louis, Mo.), glycine methyl ester hydrochloride (65.0 g, 518 mmol, Sigma-Aldrich, St. Louis, Mo.), HATU (203 g, 533 mmol, Sigma-Aldrich, St. Louis, Mo.) and DMF (400 mL). Hünig's base (177 mL, 1016 mmol) was added over a period of 1 h. After the addition was complete the mixture was diluted with EtOAc (600 mL) and washed with water (450 mL). The organic layer was then dried (MgSO 4 ) and concentrated. The crude material was dissolved in CH 2 Cl 2 (500 mL) and the precipitate that resulted was filtered off and discarded. TFA (157 mL) was added to the solution over a period of 1 h and after this time the reaction was concentrated to give the TFA salt as an oil. To this salt was added 800 mL of 2 M NH 3 in MeOH and the resulting solution was stirred overnight. Another 500 mL of 2M NH 3 in MeOH was added and stirring was continued for 4 h. After removing approx. half of the MeOH in vacuo, a white solid precipitated. This white solid was collected by filtration and rinsed with 1 L of diethyl ether. The solid was dried overnight under reduced pressure (<1 Torr; 133 Pa) to give (S)-3-(benzyloxymethyl)piperazine-2,5-dione (72.75 g, 311 mmol).

Intermediate B: ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate

›Step 1: (3S)-3-((benzyloxy)methyl)-2,5-piperazinedione

A 1-L round-bottomed flask was charged with O-benzyl-N-(tert-butoxycarbonyl)-L-serine (150 g, 508 mmol, Sigma-Aldrich, St. Louis, Mo.), glycine methyl ester hydrochloride (65.0 g, 518 mmol, Sigma-Aldrich, St. Louis, Mo.), HATU (203 g, 533 mmol, Sigma-Aldrich, St. Louis, Mo.) and DMF (400 mL). At room temperature, Hünig's base (177 mL, 1016 mmol) was added over a period of 1 h. The mixture was then diluted with EtOAc (1000 mL) and washed with water (4×450 mL). The organic extract was then dried (MgSO 4 ), filtered, and concentrated. The crude material was dissolved in CH 2 Cl 2 (500 mL) and the precipitate that formed was filtered off and discarded. TFA (157 mL) was then added to the solution over a period of 1 h. The mixture was concentrated to give the TFA salt as an oil. To this was added 800 mL of 2 M NH 3 in MeOH (Sigma-Aldrich, St. Louis, Mo.). The resulting solution was stirred at room temperature for 12 h. After that time, another 500 mL 2M NH 3 in MeOH was added and stirring was continued for 4 h. After removing approximately half of the volatiles in vacuo, a white solid precipitated. The solid was collected by filtration and rinsed with 1 L of diethyl ether. The solid was dried overnight under reduced pressure (<1 Torr; 133 Pa) to give (S)-3-(benzyloxymethyl)piperazine-2,5-dione (72.8 g).

›Step 2: (2R)-2-((benzyloxy)methyl)piperazine dihydrochloride

A solution of LAH (1.87 g, 49.3 mmol) in THF (50 mL) was chilled to 0° C. To this mixture was added (3S)-3-((benzyloxy)methyl)-2,5-piperazinedione (3.85 g, 16.44 mmol) slowly portion wise. The mixture was allowed to warm to room temperature and then heated at reflux for 1 h. Afterwards, the mixture was chilled to 0° C. and the reaction was quenched with an excess of solid sodium sulfate decahydrate (approximately 50 g). After stirring at room temperature for 1 h, the mixture was filtered. The filtrate was concentrated to give (R)-2-(benzyloxymethyl)piperazine (2.60 g) as a yellow oil. To this was added excess HCl (4M in dioxane) to deliver (2R)-2-((benzyloxy)methyl)piperazine dihydrochloride.

›Step 3: (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine

A 1-L round-bottomed flask was charged with (R)-2-(benzyloxymethyl)piperazine dihydrochloride (55.5 g, 199 mmol) and 300 mL of CH 2 Cl 2 . After cooling to 0° C., triethylamine (111 mL, 795 mmol) and 2-thiophenesulfonyl chloride (36.3 g, 199 mmol, Sigma-Aldrich, St. Louis, Mo.) were added. This mixture was stirred at 0° C. for 30 min and then diluted with water. The organics were separated, dried (MgSO 4 ), filtered and concentrated to give a brown oil. Purification via column chromatography on silica gel (25 to 100% EtOAc in hexanes) gave (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g) as a light-brown solid.

Step 4: 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (43.8 g, 163 mmol, Example 27, Step 1), (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g, 136 mmol), 200 mL of toluene, and sodium tert-butoxide (32.6 g, 339 mmol). After bubbling nitrogen gas through the solution for 5 min, chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.99 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.63 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 12 h. After that time, the mixture was diluted with water and extracted with EtOAc, dried (MgSO 4 ), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 60% EtOAc in hexanes) gave 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g) as a yellow foam.

Step 5: 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 2-L round-bottomed flask was charged with 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g, 101 mmol) and 200 mL of CH 2 Cl 2 . After cooling to 0° C., BCl 3 (1M in CH 2 Cl 2 , 302 mL, 302 mmol, Sigma-Aldrich, St. Louis, Mo.) was added over 10 min. After 30 min at 0° C., the mixture was carefully diluted with MeOH and then concentrated and purified via column chromatography on silica gel (0 to 3% MeOH in CH 2 Cl 2 ) to give 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (42.7 g) as a tan foam.

Step 6: ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate

A 1-L round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (42.7 g, 95 mmol), 200 mL of CH 2 Cl 2 , and triethylamine (15.18 mL, 109 mmol). After cooling to 0° C., methanesulfonyl chloride (7.75 g, 99 mmol) was added. After 5 min, another 1 equiv of triethylamine and methanesulfonyl chloride were added. The mixture was then diluted with water and extracted with CH 2 Cl 2 . The combined organics were dried (MgSO 4 ), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 50% EtOAc in hexanes) gave ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (35.0 g) as a light-yellow brittle foam.

1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.68 (dd, J=4.99, 1.08 Hz, 1H), 7.60 (dd, J=3.81, 1.08 Hz, 1H), 7.47 (d, J=8.61 Hz, 2H), 7.19 (dd, J=4.99, 3.81 Hz, 1H), 6.89 (d, J=8.80 Hz, 2H), 4.38-4.48 (m, 1H), 4.22-4.31 (m, 2H), 3.92 (d, J=11.93 Hz, 1H), 3.84 (d, J=11.15 Hz, 1H), 3.45-3.54 (m, 1H), 3.31 (td, J=11.93, 3.52 Hz, 1H), 2.97 (s, 3H), 2.77 (d, J=11.74 Hz, 1H), 2.65 (td, J=11.15, 3.33 Hz, 1H), 1.74 (s, 3H). m/z (ESI, +ve ion) 529.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.357 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.827 μM.

Intermediate C: (2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine

›Step 1: methyl (2E)-2-((tert-butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-2-propenoate

To a solution of tetrahydro-2H-pyran-4-carbaldehyde (5.0 g, 43.9 mmol, Frontier Scientific Inc., Logan, Utah) in CH 2 Cl 2 (100 mL) at room temperature was added (rac)-Boc-α-phosphonoglycine trimethyl ester (14.4 g, 48.3 mmol, Sigma-Aldrich, St. Louis, Mo.) followed by DBU (7.3 mL, 48.3 mmol). The reaction was stirred overnight before being diluted with water (100 mL) and extracted with CH 2 Cl 2 (2×200 mL). The layers were separated and the organic extracts were washed with water (2×100 mL), dried (MgSO 4 ), filtered, and concentrated. The crude material was purified by silica gel column chromatography (0 to 70% hexanes in EtOAc) to give methyl (2E)-2-((tert-butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-2-propenoate.

›Step 2: methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alaninate

A 250-mL pressure tube was charged with methyl (2E)-2-((tert-butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-2-propenoate (8.75 g, 30.7 mmol), MeOH (100 mL), and rhodium[(1R,1′R,2R,2′R)-2,2′-bis(1,1-dimethylethyl)-2,2′,3,3′-tetrahydro-1,1′-bi-1H-isophosphindole-κP2,κP2′][(1,2,5,6-η)-1,5-cyclooctadiene]tetrafluoroborate (0.209 g, 0.30 mmol, ChiralQuest, Monmouth Junction, N.J.). The mixture was stirred under a 50 psi (344 kilopascal) hydrogen atmosphere for 3 h. The mixture was then filtered through a pad of silica, washing with 1:1 EtOAc in hexanes, and then concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alaninate.

›Step 3: N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine

A 500-mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alaninate (8.81 g, 30.7 mmol), 100 mL of THF, 100 mL of water and lithium hydroxide (2.20 g, 92 mmol). After stirring overnight at room temperature, the mixture was concentrated and acidified to pH 3 with concentrated aqueous HCl. The mixture was then extracted with EtOAc, dried (MgSO 4 ), filtered, and concentrated to give N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (8.00 g) as a white solid.

›Step 4: methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate

A 100-mL round-bottomed flask was charged with N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (3.11 g, 11.38 mmol), HATU (5.41 g, 14.22 mmol), glycine methyl ester hydrochloride (1.714 g, 13.65 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10 mL of DMF. To this was added Hünig's base (4.37 mL, 25.03 mmol). After 30 min at room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The layers were separated and the organic extracts were washed with water (2×100 mL) and brine (50 mL), dried (MgSO 4 ), filtered and concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate (3.00 g) as a yellow oil.

›Step 5: (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione

A 250-mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate (3.00 g, 8.71 mmol), 10 mL of CH 2 Cl 2 , and 5 mL of TFA. After 10 min at room temperature, the mixture was concentrated then dissolved in 2N NH 3 in MeOH (20 mL) and stirred at room temperature for 4 h. The reaction was then concentrated and triturated with ether to give (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g) as a white solid.

›Step 6: (2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine

A 250-mL round-bottomed flask was charged with (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g, 6.78 mmol), 50 mL of THF, and LAH (1M in THF, 27.1 mL, 27.1 mmol, Sigma-Aldrich, St. Louis, Mo.). After heating at reflux for 2 h, the mixture was allowed to cool to room temperature. Sodium sulfate decahydrate (10 g) was then added and the mixture was stirred at temperature for 1 h. The mixture was filtered and the filtrate was concentrated to give (2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (0.950 g, 5.16 mmol) as a colorless oil.

Intermediate D (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 500-mL round-bottomed flask was charged with 5-bromo-2-chloropyrimidine (10.0 g, 52 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of ether. After cooling to −78° C., n-BuLi (2.5 M in hexanes, 22.8 mL, 57 mmol) was added. This mixture was stirred at −78° C. for 10 min, then 1,1,1,3,3,3-hexafluoro-2-propanone (Sigma-Aldrich, St. Louis, Mo.) was bubbled through the solution for 5 min. After stirring for an additional 10 min, the reaction was quenched with saturated aqueous NH 4 Cl. The solution was extracted with EtOAc, dried (MgSO 4 ), filtered, and concentrated. Purification via column chromatography on silica gel (twice, 0 to 50% EtOAc in hexanes then 0 to 4% MeOH in CH 2 Cl 2 ) gave (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (3.25 g) as a yellow solid.

Intermediate E: 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol

A 500-mL round-bottomed flask was charged with 5-bromo-2-chloropyrimidine (8.53 g, 44.1 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of ether. After cooling to −78° C., n-BuLi (2.5 M in hexanes, 27.6 mL, 44.1 mmol) was added. This mixture was stirred at −78° C. for 10 min, then 1,1,1,tri-fluoro-2-propanone (14.82 g, 132 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After stirring for an additional 10 min at −78° C., the reaction was quenched with saturated aqueous NH 4 Cl. The solution was extracted with EtOAc, dried (MgSO 4 ), filtered, and concentrated. Purification via column chromatography on silica gel (0 to 85% EtOAc in hexanes) gave 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.70 g) as a white solid.

›Examples11

›Example 1

1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (2.27 g, 6.92 mmol, published PCT patent application no. WO 2006/094842), 20 mL of CH 2 Cl 2 and triethylamine (1.45 mL, 10.4 mmol). To this was added 2-thiophenesulfonyl chloride (1.39 mL, 7.61 mmol, Sigma-Aldrich, St. Louis, Mo.) and the mixture was stirred at room temperature for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL). The combined extracts were dried (MgSO 4 ) and concentrated. This oil was purified by column chromatography (120 g silica gel, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (2.35 g) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.70-7.65 (m, 1H) 7.64-7.56 (m, 3H), 7.23-7.18 (m, 1H), 7.02-6.94 (m, 2H), 3.43-3.36 (m, 4H), 3.33-3.25 (m, 4H). m/z (ESI, +ve ion) 475.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.332 μM; GK-GKRP EC 50 (LC MS/MS)=0.500 μM.

›Example 2

1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure for Example 1, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and benzenesulfonyl chloride (Sigma-Aldrich, St. Louis, Mo.) delivered 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.85-7.77 (m, 2H), 7.67-7.54 (m, 5H), 7.01-6.92 (m, 2H), 3.39-3.28 (m, 4H), 3.27-3.21 (m, 4H). m/z (ESI, +ve ion) 469.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.803 μM; GK-GKRP EC 50 (LC MS/MS)=1.10 μM.

›Example 3

1,1,1,3,3,3-hexafluoro-2-(4-(4-(3-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (50 mg, 0.152 mmol, published PCT patent application no. WO 2006/094842) and triethylamine (63.6 μL, 0.457 mmol) in 1,2-dichloroethane (1.5 mL) was added 3-thiophenesulfonyl chloride (1M in dichloroethane, 168 μL, 0.168 mmol, ASDI, Newark, Del.). The reaction was shaken on an orbital shaker for 18 h. The reaction solvent was removed under reduced pressure and the crude product was purified by reverse-phase preparative HPLC using a Sunfire Prep C18 OBD (100×19 mm, 5 μm) column, 0.1% TFA in MeOH/H 2 O, gradient (65% to 95% over 4.5 min) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(3-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35-8.27 (m, 1H), 7.85 (dd, J=5.1, 2.9 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.33-3.28 (m, 4H), 3.07-3.01 (m, 4H). m/z (ESI, +ve ion) 475.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.597 μM; GK-GKRP EC 50 (LC MS/MS)=0.964 μM.

›Example 4

1,1,1,3,3,3-hexafluoro-2-(4-(4-((2-methylphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 2-methyl-benzene-1-sulfonyl chloride (ASDI, Newark, Del.) provided 1,1,1,3,3,3-hexafluoro-2-(4-(4-((2-methylphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.87-7.80 (m, 1H), 7.64-7.56 (m, 1H), 7.52-7.41 (m, 4H), 7.02 (d, J=9.2 Hz, 2H), 3.32-3.24 (m, 4H), 3.20-3.11 (m, 4H), 2.60 (s, 3H). m/z (ESI, +ve ion) 483.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.27 μM; GK-GKRP EC 50 (LC MS/MS)=1.71 μM.

›Example 5

1,1,1,3,3,3-hexafluoro-2-(4-(4-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 1-methyl-1H-pyrazole-3-sulfonyl chloride (Maybridge, Cambridge, UK) provided 1,1,1,3,3,3-hexafluoro-2-(4-(4-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J=8.6 Hz, 2H), 7.46 (d, J=2.2 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 6.69 (d, J=2.2 Hz, 1H), 4.00 (s, 3H), 3.34 (br. s., 8H). m/z (ESI, +ve ion) 473.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.58 μM; GK-GKRP EC 50 (LC MS/MS)=5.38 μM.

›Example 6

1,1,1,3,3,3-hexafluoro-2-(4-(4-((2-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 2-fluorobenzene-1-sulfonyl chloride (ASDI, Newark, Del.) provided 1,1,1,3,3,3-hexafluoro-2-(4-(4-((2-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.90-7.84 (m, 1H), 7.63-7.52 (m, 3H), 7.30 (t, J=7.7 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 6.92-6.87 (m, 2H), 3.39-3.27 (m, 8H). m/z (ESI, +ve ion) 487.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.88 μM; GK-GKRP EC 50 (LC MS/MS)=1.52 μM.

›Example 7

1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-pyridinylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 2-pyridinesulfonyl chloride hydrochloride (J & W PharmLab, Levittown, Pa.) provided 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-pyridinylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (d, J=4.09 Hz, 1H), 8.01-7.88 (m, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.54-7.46 (m, 1H), 6.89 (d, J=8.8 Hz, 2H), 3.59-3.49 (m, 4H), 3.31 (d, J=4.8 Hz, 4H). m/z (ESI, +ve ion) 470.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.78 μM; GK-GKRP EC 50 (LC MS/MS)=3.29 μM.

›Example 8

1,1,1,3,3,3-hexafluoro-2-(4-(4-((5-methyl-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 5-methylthiophene-2-sulfonyl chloride (Maybridge, Cambridge, UK) provided 1,1,1,3,3,3-hexafluoro-2-(4-(4-((5-methyl-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR MHz, CDCl 3 ) δ 7.58 (d, J=8.3 Hz, 2H), 7.37 (d, J=3.5 Hz, 1H), 6.89 (d, J=8.9 Hz, 2H), 6.82 (d, J=2.6 Hz, 1H), 3.32 (d, J=4.8 Hz, 4H), 3.21 (d, J=5.4 Hz, 4H), 2.53 (s, 3H). m/z (ESI, +ve ion) 489.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=4.58 μM; GK-GKRP EC 50 (LC MS/MS)=11.40 μM.

›Example 9

2-(4-(4-(3-chlorophenylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 3-chlorobenzene-1-sulfonyl chloride (ASDI, Newark, Del.) provided 2-(4-(4-(3-chlorophenylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1 H NMR (300 MHz, CDCl 3 ) δ 7.79 (t, J=1.8 Hz, 1H), 7.69 (dt, J=7.8, 1.3 Hz, 1H), 7.63-7.49 (m, 4H), 6.93-6.87 (m, 2H), 3.36-3.31 (m, 4H), 3.24-3.18 (m, 4H). m/z (ESI, +ve ion) 503.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=4.41 μM; GK-GKRP EC 50 (LC MS/MS)=3.71 μM.

›Example 10

2-(4-(4-((2-chlorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Following the procedure reported for Example 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (published PCT patent application no. WO 2006/094842) and 2-chlorobenzene-1-sulfonyl chloride (ASDI, Newark, Del.) provided 2-(4-(4-((2-chlorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1 H NMR (300 MHz, CDCl 3 ) δ 8.08 (dd, J=7.8, 1.4 Hz, 1H), 7.60-7.49 (m, 4H), 7.45-7.39 (m, 1H), 6.94-6.88 (m, 2H), 3.48-3.44 (m, 4H), 3.30 (dd, J=6.3, 3.9 Hz, 4H). m/z (ESI, +ve ion) 503.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.95 μM; GK-GKRP EC 50 (LC MS/MS)=2.60 μM.

›Example 11

1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Step 1: (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate

A 20 mL vial was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.725 g, 2.24 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.517 g, 2.58 mmol, Sigma-Aldrich, St. Louis, Mo.), sodium tert-butoxide (0.475 g, 4.94 mmol), and 4 mL of anhydrous toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.016 g, 0.034 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.010 g, 0.011 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and the mixture was heated at 100° C. for 12 h. After that time, the reaction was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organics were separated and dried (MgSO 4 ) to give (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.300 g) as an orange oil which was used without purification.

›Step 2: (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)-2-propanol hydrochloride

A 100 mL round-bottomed flask was charged with (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.250 g, 0.565 mmol) and 10 mL of 4N HCl in dioxane. After 2 h at room temperature, the mixture was concentrated to give (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)-2-propanol hydrochloride as a yellow foam (0.214 g) which was used without purification.

Step 3: 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported above for Example 1, (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)-2-propanol hydrochloride and 2-thiophenesulfonyl chloride (Sigma-Aldrich, St. Louis, Mo.) delivered 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (dd, J=5.0, 1.3 Hz, 1H), 7.66 (dd, J=3.8, 1.3 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.28 (dd, J=5.0, 3.8 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 4.26-4.17 (m, 1H), 3.77-3.71 (m, 1H), 3.57-3.47 (m, 2H), 3.26 (td, J=11.8, 3.5 Hz, 1H), 2.80 (dd, J=11.3, 3.3 Hz, 1H), 2.64 (td, J=11.2, 3.5 Hz, 1H), 1.18 (J=6.5 Hz, 3H). m/z (ESI, +ve ion) 489.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.217 μM; GK-GKRP EC 50 (LC MS/MS)=0.371 μM.

›Example 12

1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: (S)-2-methyl-4-(phenylsulfonyl)piperazine hydrochloride

A 500 mL round-bottomed flask was charged with (S)-2-methylpiperazine (5.00 g, 49.9 mmol), 100 mL of CH 2 Cl 2 , and Hünig's base (9.59 mL, 54.9 mmol). After cooling to 0° C., benzenesulfonyl chloride (6.76 mL, 52.4 mmol, Sigma-Aldrich, St. Louis, Mo.) was slowly added. The mixture was stirred at 0° C. for 1 h, then diluted with water (50 mL) and extracted with CH 2 Cl 2 (2×50 mL). The organic extracts were dried (MgSO 4 ) and concentrated to give an oil. Purification via column chromatography (120 g of silica, 0 to 10% MeOH in CH 2 Cl 2 ) gave the free base as an oily solid. This residue was dissolved in EtOAc (100 mL) and acidified with 4N HCl in dioxane (3.5 mL). The resulting white solid was collected by filtration to give (S)-2-methyl-4-(phenylsulfonyl)piperazine hydrochloride (4.25 g).

Step 2: 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 20 mL vial was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.52 g, 4.70 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (S)-2-methyl-4-(phenylsulfonyl)piperazine hydrochloride (1.00 g, 3.61 mmol), sodium tert-butoxide (1.13 g, 11.7 mmol), and 10 mL of anhydrous toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.051 g, 0.11 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.033 g, 0.036 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and the mixture was heated at 100° C. for 12 h. After that time, the reaction was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organics were dried (MgSO 4 ) and concentrated to give an oil that was purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.310 g). 1 H NMR (400 MHz, CD 3 OD) δ 7.83-7.74 (m, 2H), 7.72-7.60 (m, 3H), 7.53 (d, J=8.8 Hz, 2H), 6.94 (d, J=9.2 Hz, 2H), 4.18-4.02 (m, 1H), 3.70 (dd, J=2.4, 11.2 Hz, 1H), 3.56-3.36 (m, 2H), 3.20 (dt, J=3.4, 11.8 Hz, 1H), 2.69 (dd, J=3.4, 11.4 Hz, 1H), 2.53 (dt, J=3.5, 11.2 Hz, 1H), 1.13 (d, J=6.5 Hz, 3H). M/Z (ESI, +ve ion) 483.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.821 μM; GK-GKRP EC 50 (LC MS/MS)=0.884 μM.

›Examples3

›Example 13

2-(4-(2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

To a solution of 2-(2,5-dichlorophenyl)piperazine (316 mg, 1.369 mmol, Ark Pharm, Libertyville, Ill.) in CH 2 Cl 2 (7.0 mL) was added 2-thiophenesulfonyl chloride (250 mg, 1.369 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (572 μL, 4.11 mmol). The reaction was stirred at 23° C. for 18 h, after which time the mixture was concentrated to dryness. To this intermediate was added 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (368.3 mg, 1.369 mmol, Example 27, step 1), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (95.8 mg, 0.734 mmol, Strem Chemical Inc, Newburyport, Mass.) tris(dibenzylideneacetone)dipalladium (0) (62.7 mg, 0.068 mmol, Strem Chemical Inc, Newburyport, Mass.), 10 mL of toluene (9.78 mL) and sodium tert-butoxide (315.7 mg, 3.28 mmol). The reaction was heated to 90° C. and stirred for 20 h. After that time, the mixture was cooled to room temperature, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (50 g of silica, 10 to 40% EtOAc in hexanes) followed by reverse-phase preparative HPLC using a Phemomenex Gemini-NX C 18 110 A column (150×30 mm), eluting with 0.1% TFA in CH 3 CN/H 2 O (10% to 90% over 16.5 min) to provide 2-(4-(2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of 4 isomers.

(2S)-2-(4-((2S)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2R)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (300 MHz, CDCl 3 ) δ 7.63 (d, J=5.0 Hz, 1H), 7.55 (dd, J=3.65, 1.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.24 (s, 1H), 7.14 (dd, J=4.9, 3.9 Hz, 1H), 7.08 (dd, J=8.5, 2.5 Hz, 1H), 6.85 (d, J=8 62 Hz, 2H), 4.84 (dd, J=9.0, 3.4 Hz, 1H), 3.73-3.90 (m, 2H), 3.60 (d, J=12.3 Hz, 1H), 3.19-3.31 (m, 1H), 3.00-3.11 (m, 1H), 2.59-2.71 (m, 1H), 1.68 (d, J=3.5 Hz, 3H). m/z (ESI, +ve ion) 586.8 (M+Na) + . GK-GKRP EC 50 (NADPH-coupled)=2.64 μM; GK-GKRP EC 50 (LC MS/MS)=1.96 μM.

›Example 14

2-(4-((3R)-3-cyclopropyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 20 mL vial was charged with toluene (1.2 mL), sodium tert-butoxide (69.2 mg, 720 μmol) were added to (R)-2-cyclopropyl-piperazine (59.7 mg, 300 μmol, Anichem, North Brunswick, N.J.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (97 mg, 300 μmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos), (21.0 mg, 45.0 μmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (13.7 mg, 15.00 μmol, Strem Chemical Inc, Newburyport, Mass.). The reaction was heated to 90° C. for 40 h, then cooled to 23° C., and diluted with water (15 mL) and extracted with CH 2 Cl 2 (15 mL). The organic layer was loaded onto an AccuBOND II SCX cartridge (Krackeler Scientific, Inc., Albany, N.Y.) (6 g), washed with MeOH (5 mL) and eluted with 2N NH 3 in MeOH (10 mL) to give (R)-2-(4-(3-cyclopropylpiperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. To this was added a solution of 2-thiophenesulfonyl chloride (54.8 mg, 300 μmol, Sigma-Aldrich, St. Louis, Mo.) and Hünig's base (57.5 μL, 330 μmol) in CH 2 Cl 2 (0.6 mL). The reaction was stirred at 23° C. for 18 h and then concentrated to dryness. The crude material was purified by reverse-phase preparative HPLC using a Gemini C 18 100 A column (150×30 mm), eluting with 0.1% TFA in CH 3 CN/H 2 O (10% to 90% over 12 min) to give 2-(4-((3R)-3-cyclopropyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (s, 1H), 7.93 (dd, J=5.3 1.3 Hz, 1H), 7.71 (dd, J=3.7, 1.1 Hz, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.18 (dd, J=4.8, 4.0 Hz, 1H), 6.95 (d, J=9.7 Hz, 2H), 2.67 (dd, J=12.5, 3.7 Hz, 1H), 2.52-2.60 (m, 4H), 1.30-1.42 (m, 1H), 0.35-0.56 (m, 6H). m/z (ESI, +ve ion) 515.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=5.0 μM.

›Example 15

1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol

›Step 1: 1-(phenylsulfonyl)piperazine hydrochloride

A 500 ml, round-bottomed flask was charged with 1-Boc-piperazine (18.55 g, 100 mmol, Sigma-Aldrich, St. Louis, Mo.), triethylamine (18.05 mL, 129 mmol), and 200 mL of CH 2 Cl 2 . To this was added benzenesulfonyl chloride (16.05 mL, 124 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min, the mixture was diluted with water (150 mL) and the layers were separated. The organics were dried (MgSO 4 ) and concentrated to give a white solid. This solid was dissolved in EtOAc (300 mL) and 150 mL of 4N HCl in dioxane. After 3 h at 65° C., the white precipitate was filtered to give 1-(phenylsulfonyl)piperazine hydrochloride (21.0 g) as a white solid.

›Step 2: 2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanone

A 125 ml, pressure tube was charged with 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (7.31 g, 38.1 mmol, Sigma-Aldrich, St. Louis, Mo.), 1-(phenylsulfonyl)piperazine hydrochloride (5.00 g, 19.0 mmol), 20 mL of CH 3 CN, and triethylamine (7.96 mL, 57.1 mmol). The tube was sealed and heated at 110° C. for 3 h. After that time, the mixture was diluted with EtOAc (100 mL) and water (50 mL). The organics were separated, dried (MgSO 4 ) and concentrated to give a white solid. This solid was slurried with hexane (150 mL) to give 2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanone (3.85 g) as a bright white solid.

›Step 3: 1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol

A 100 mL round-bottom flask was charged with 2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanone (0.50 g, 1.26 mmol) and 10 mL of THF. After cooling to 0° C., cyclopropylmagnesium bromide (5.02 mL, 0.5 M in THF, 2.51 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min, the mixture was quenched with saturated aqueous NH 4 Cl (15 mL), extracted with EtOAc (2×50 mL), dried (MgSO 4 ), and concentrated to give an oil. This oil was purified via column chromatography (40 g of silica, 0 to 40% EtOAc in hexanes) to give 1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol (0.375 g) as a mixture of two enantiomers.

(1R)-1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol; (1S)-1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.88-7.78 (m, 2H), 7.74-7.57 (m, 3H), 7.48 (s, 2H), 6.96-6.83 (m, 2H), 3.28-3.23 (m, 4H), 3.18-3.05 (m, 4H), 1.61-1.48 (m, 1H), 0.76-0.63 (m, 1H), 0.58-0.46 (m, 1H), 0.44-0.34 (m, 1H), 0.30-0.20 (m, 1H). m/z (ESI, +ve ion) 441.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.62 μM; GK-GKRP EC 50 (LC MS/MS)=2.77 μM.

›Example 16

1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

›Step 1: tert-butyl (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate

A 250 mL pressure vessel was charged with (S)-4-(tert-butoxycarbonyl)-2-methylpiperazine (4.17 g, 21.84 mmol, Sigma-Aldrich, St. Louis, Mo.), 5-bromo-2-chloropyrimidine (4.22 g, 21.84 mmol, Combi-Blocks, San Diego, Calif.), triethylamine (6.09 mL, 43.7 mmol), and 50 mL of dioxane. The tube was sealed and heated at 110° C. for 24 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The organics were dried (MgSO 4 ) and concentrated to give an oil that was purified via column chromatography (120 g silica, 0 to 30% EA/Hex) to give tert-butyl (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate (6.15 g) as a white solid.

Step 2: (3S)-3-methyl-4-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-1-piperazinecarboxylate

A 250 mL round-bottomed flask was charged with tert-butyl (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate (4.00 g, 11.2 mmol) and 20 mL of THF. After cooling to −78° C., n-BuLi (5.15 mL, 2.5 M in hexanes, 12.9 mmol) was added. This mixture was stirred at −78° C. for 10 min, then 1,1,1-trifluoro-2-propanone (2.51 mL, 22.4 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The mixture was stirred at −78° C. for an additional 1 h, then quenched with saturated aqueous NH 4 Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried (MgSO 4 ), concentrated and purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give (3S)-3-methyl-4-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (1.12 g) as a white foam.

›Step 3: 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride

A 100 mL round-bottomed flask was charged with ((3S)-3-methyl-4-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (1.12 g, 2.87 mmol), 10 mL of EtOAc, and 3 mL of 4N HCl in dioxane. The mixture was heated at 80° C. for 3 h. The resulting white precipitate was collected by filtration to give 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (1.05 g)

Step 4: 1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

A 100 mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydro chloride (0.250 g, 0.763 mmol) and 10 mL of CH 2 Cl 2 . To this was added 2-thiophenesulfonyl chloride (0.153 g, 0.839 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min, the mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (2×50 mL). The combined extracts were dried (MgSO 4 ), concentrated, and purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.125 g) as mixture of two isomers.

(2S)-1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 8.50 (s, 2H), 7.86 (dd, J=1.2, 5.1 Hz, 1H), 7.63 (dd, J=1.2, 3.7 Hz, 1H), 7.27-7.21 (m, 1H), 5.08 (br. s., 1H), 4.68 (d, J=13.5 Hz, 1H), 3.86-3.74 (m, 1H), 3.68-3.60 (m, 1H), 3.38-3.29 (m, 1H), 2.61-2.56 (m, 1H), 2.43 (dt, J=3.5, 11.8 Hz, 1H), 1.70 (s, 3H), 1.33 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 437.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.00 μM; GK-GKRP EC 50 (LC MS/MS)=1.10 μM.

This mixture of isomers was resolved using preparative SFC (Chiralcel® OJ-H column (250 mm×21 mm, 5 μm) eluting with 90% liquid CO 2 in 10% i-PrOH (0.2% diethylamine) at a flow rate of 70.0 mL/min) to give two products in greater than 95% diastereomeric excess.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ 8.49 (s, 2H), 7.85 (d, J=1.0 Hz, 1H), 7.61 (dd, J=1.0, 3.7 Hz, 1H), 7.34-7.12 (m, 1H), 5.06 (s, 1H), 4.67 (d, J=13.7 Hz, 1H), 3.78 (br. s., 1H), 3.62 (s, 1H), 3.39-3.29 (m, 1H), 2.63-2.51 (m, 1H), 2.42 (dt, J=3.5, 11.8 Hz, 1H), 1.69 (s, 3H), 1.31 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 437.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.865 μM; GK-GKRP EC 50 (LC MS/MS)=1.16 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ 8.48 (s, 2H), 7.89-7.79 (m, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.32-7.02 (m, 1H), 5.06 (s, 1H), 4.66 (d, J=14.7 Hz, 1H), 3.78 (d, J=11.2 Hz, 1H), 3.62 (d, J=11.7 Hz, 1H), 3.42-3.29 (m, 1H), 2.57 (dd, J=3.6, 11.6 Hz, 1H), 2.41 (dt, J=3.6, 11.9 Hz, 1H), 1.68 (s, 3H), 1.30 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 437.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.547 μM; GK-GKRP EC 50 (LC MS/MS)=0.806 μM.

›Example 17

1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)phenyl)-3-pyridinyl)-2-propanol

›Step 1: 1-bromo-4-(phenylsulfonyl)benzene

A 500 mL round-bottomed flask was charged with 4-bromobenzenesulfonyl chloride (10.00 g, 39.1 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of benzene and aluminum chloride (6.26 g, 47.0 mmol). After stirring at room temperature for 12 h, the mixture was diluted water (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried (MgSO 4 ) and concentrated to give 1-bromo-4-(phenylsulfonyl)benzene (10.50 g) as a white solid.

›Step 2: 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane

A 250 mL round-bottomed flask was charged with 1-bromo-4-(phenylsulfonyl)benzene (2.50 g, 8.41 mmol), bis(pinacolato)diboron (2.46 g, 9.67 mmol, Sigma-Aldrich, St. Louis, Mo.), 1,1′bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.344 g, 0.421 mmol, Sigma-Aldrich, St. Louis, Mo.), potassium acetate (2.48 g, 25.2 mmol), and 50 ml, of dioxane. This mixture was heated at 100° C. for 12 h and then cooled to room temperature. The reaction was diluted with EtOAc (200 mL), filtered, and concentrated to give a dark solid. This solid was slurried with cold (0° C.) MeOH (50 mL) to give 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (2.20 g) as a gray solid.

›Step 3: 5-bromo-2-(4-(phenylsulfonyl)phenyl)pyridine

A 100 ml, pressure vessel was charged with 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (1.00 g, 2.91 mmol), 2,5-dibromopyridine (0.860 g, 3.63 mmol, Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (1.20 g, 8.72 mmol), tetrakis(triphenylphosphine)palladium (0) (0.168 g, 0.145 mmol, Strem Chemical Inc, Newburyport, Mass.), 16 mL of 1,2-dimethoxyethane, and 4 mL of water. The vessel was sealed and the reaction was heated at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL), separated, dried (MgSO 4 ) and concentrated to give an oil. Purification via column chromatography (40 g of silica gel, 0 to 50% EtOAc in hexanes) produced a yellow solid that was slurried with cold (0° C.) MeOH (20 mL) to give 5-bromo-2-(4-(phenylsulfonyl)phenyl)pyridine (0.450 g).

›Step 4: 1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)phenyl)-3-pyridinyl)-2-propanol

A 250 mL round-bottomed flask was charged with 5-bromo-2-(4-(phenylsulfonyl)phenyl)pyridine (0.45 g, 1.20 mmol) and 15 mL of THF. After cooling to −78° C., n-BuLi (0.60 mL, 2.5 M in hexanes, 1.50 mmol) was added drop-wise. The resulting black solution was stirred for 15 min at −78° C. and then 1,1,1,3,3,3-hexafluoro-2-propanone (Sigma-Aldrich, St. Louis, Mo.) was bubbled thru the solution for 3 min. The reaction was then quenched with saturated aqueous NH 4 Cl (20 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were dried (MgSO 4 ), concentrated, and purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)phenyl)-3-pyridinyl)-2-propanol (0.025 g) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.95 (s, 1H), 8.38-8.15 (m, 3H), 8.13-7.88 (m, 5H), 7.61 (s, 3H). m/z (ESI, +ve ion) 462.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.63 μM; GK-GKRP EC 50 (LC MS/MS)=1.71 μM.

›Example 18

2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol

›Step 1: 4-bromo-2-chloro-1-(phenylsulfonyl)benzene

A 500 mL round-bottomed flask was charged with 4-bromo-2-chlorobenzene-1-sulfonyl chloride (10.0 g, 34.5 mmol, Sigma-Aldrich, St. Louis, Mo.), ferric chloride (2.80 g, 17.2 mmol), and 200 mL of benzene. The mixture was heated at reflux for 12 h then diluted with water (100 mL) and extracted with CH 2 Cl 2 (2×300 mL). The combined organic layers were dried (MgSO 4 ) and concentrated to give a brown solid that was slurried with EtOH (100 mL) to give 4-bromo-2-chloro-1-(phenylsulfonyl)benzene (7.50 g).

Steps 2, 3 and 4: 2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol

Following the procedure outlined for Example 17 (with 1,1,1-trifluoro-2-propanone replacing 1,1,1,3,3,3-hexafluoro-2-propanone), 4-bromo-2-chloro-1-(phenylsulfonyl)benzene was converted to 2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol (mixture of two enantiomers).

(2S)-2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 8.95-8.88 (m, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.31-8.21 (m, 2H), 8.19-8.11 (m, 1H), 8.06-7.95 (m, 3H), 7.74-7.66 (m, 1H), 7.62 (s, 2H), 1.81 (s, 3H). m/z (ESI, +ve ion) 441.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.75 μM; GK-GKRP EC 50 (LC MS/MS)=3.57 μM.

›Example 19

2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol

›Step 1: 2-(3-chloro-4-(phenylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Following the procedure described for Example 17 (Step 2), 4-bromo-2-chloro-1-(phenylsulfonyl)benzene provided 2-(3-chloro-4-(phenylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

›Step 2: 2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol

Following the procedure described for Example 17 (Step 3), 2-(3-chloro-4-(phenylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane coupled with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (example 27, step 1) to deliver 2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol (mixture of two enantiomers).

(2R)-2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 8.43 (d, J=8.2 Hz, 1H), 8.02-7.81 (m, 4H), 7.79-7.68 (m, 5H), 7.66-7.58 (m, 2H), 1.77 (s, 3H). m/z (ESI, +ve ion) 441.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.58 μM; GK-GKRP EC 50 (LC MS/MS)=4.23 μM.

›Example 20

2-methyl-4-(4-(phenylsulfonyl)-4′-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol

A 20 mL vial was charged with 2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol (0.300 g, 0.680 mmol, Example 19), 2-methyl-3-butyn-2-ol (0.099 mL, 1.021 mmol, Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (0.235 g, 1.701 mmol), 2 mL of dimethylacetamide, 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl (XPhos) (9.73 mg, 0.020 mmol, Strem Chemical Inc, Newburyport, Mass.), and tris(dibenzylideneacetone)dipalladium (0) (0.021 g, 0.020 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and heated at 100° C. for 2 h. After that time, the mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 40% EtOAc in hexane) to give 2-methyl-4-(4-(phenylsulfonyl)-4′-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol (0.035 g) as a mixture of two enantiomers.

2-methyl-4-(4-(phenylsulfonyl)-4′-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol; 2-methyl-4-(4-(phenylsulfonyl)-4′-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol. 1 H NMR (400 MHz, CD 3 OD) δ 8.34 (d, J=8.2 Hz, 1H), 8.05 (d, J=7.8 Hz, 2H), 7.92-7.81 (m, 2H), 7.79-7.66 (m, 5H), 7.64-7.55 (m, 2H), 1.77 (s, 3H), 1.59 (s, 6H). m/z (ESI, +ve ion) 471.0 (M-OH) + . GK-GKRP EC 50 (NADPH-coupled)=1.80 μM; GK-GKRP EC 50 (LC MS/MS)=2.25 μM.

›Example 21

1,1,1,3,3,3-hexafluoro-2-(4′-(phenylsulfonyl)-4-biphenylyl)-2-propanol

›Step 1: 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-propanol

A 150 ml, pressure vessel was charged with 4 bis(pinacolato)diboron (4.72 g, 18.57 mmol, Sigma-Aldrich, St. Louis, Mo.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (5.00 g, 15.48 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), potassium acetate (4.56 g, 46.4 mmol), 1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.632 g, 0.774 mmol), and 25 ml, of dioxane. After 3 h at 100° C., the mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was concentrated and purified via column chromatography (0 to 25% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-propanol (3.50 g) as a white solid.

›Step 2: 1,1,1,3,3,3-hexafluoro-2-(4′-(phenylsulfonyl)-4-biphenylyl)-2-propanol

A 100 mL pressure vessel was charged with 1-bromo-4-(phenylsulfonyl)benzene (1.00 g, 3.37 mmol, Example 17, step 1), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-propanol (1.62 g, 4.37 mmol), potassium carbonate (1.40 g, 10.10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.194 g, 0.168 mmol), 20 mL of 1,2-dimethoxyethane, and 5 mL of water. The vessel was sealed and the reaction was heated to 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL), separated, dried (MgSO 4 ) and concentrated to give an oil. Purification via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) produced a yellow solid that was slurried with cold (0° C.) MeOH (25 mL) to give 1,1,1,3,3,3-hexafluoro-2-(4′-(phenylsulfonyl)-4-biphenylyl)-2-propanol (0.650 g). 1 H NMR (400 MHz, CD 3 OD) δ 8.08-7.95 (m, 4H), 7.91-7.74 (m, 6H), 7.69-7.54 (m, 3H). m/z (ESI, +ve ion) 461.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.66 μM; GK-GKRP EC 50 (LC MS/MS)=3.96 μM.

›Example 22

1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)-1-piperazinyl)-3-pyridinyl)-2-propanol

›Step 1: 1-(5-bromo-2-pyridinyl)-4-(phenylsulfonyl)piperazine

A 350 ml, pressure vessel was charged with 4-(phenylsulfonyl)piperazine hydrochloride (1.50 g, 5.71 mmol, Example 15, step 1), 2,5-dibromopyridine (1.76 g, 7.42 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of toluene, sodium tert-butoxide (1.37 g, 14.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.105 g, 0.114 mmol, Strem Chemical Inc, Newburyport, Mass.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (0.198 g, 0.343 mmol, Strem Chemical Inc, Newburyport, Mass.). The tube was sealed and heated at 110° C. for 3 h. After that time, the reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried (MgSO 4 ) and concentrated to give a yellow solid. This solid was slurried with cold (0° C.) MeOH (25 mL) to give 1-(5-bromo-2-pyridinyl)-4-(phenylsulfonyl)piperazine (0.957 g) as a light yellow solid.

›Step 2: 1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)-1-piperazinyl)-3-pyridinyl)-2-propanol

A 250 mL round-bottomed flask was charged with 1-(5-bromo-2-pyridinyl)-4-(phenylsulfonyl)piperazine (0.96 g, 2.50 mmol) and 15 mL of THF. After cooling to −78° C., n-BuLi (1.20 mL, 3.0 mmol, 2.5 M in hexanes) was added drop-wise. After stirring at −78° C. for 15 min, 1,1,1,3,3,3-hexafluoro-2-propanone (Sigma-Aldrich, St. Louis, Mo.) was bubbled through the solution for 3 min. The reaction was then quenched with saturated aqueous NH 4 Cl (20 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated to give an oil that was purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(6-(4-(phenylsulfonyl)-1-piperazinyl)-3-pyridinyl)-2-propanol (0.44 g) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.46-8.22 (m, 1H), 7.91-7.46 (m, 6H), 6.93-6.69 (m, 1H), 3.87-3.58 (m, 4H), 3.17-2.96 (m, 4H). m/z (ESI, +ve ion) 470.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.73 μM; GK-GKRP EC 50 (LC MS/MS)=2.08 μM.

›Example 23

1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

›Step 1: 5-bromo-2-(4-(phenylsulfonyl)-1-piperazinyl)pyrimidine

A 250 mL round-bottomed flask was charged with 1-(phenylsulfonyl)piperazine hydrochloride (4.08 g, 15.51 mmol, Example 15, step 1), 5-bromo-2-chloropyrimidine (2.50 g, 12.92 mmol, Sigma-Aldrich, St. Louis, Mo.), and 20 mL of dioxane. To this was added triethylamine (4.50 mL, 32.3 mmol). After stirring at room temperature for 3 h, the mixture was diluted with water (50 mL) and the resulting precipitate was collected by filtration to give 5-bromo-2-(4-(phenylsulfonyl)-1-piperazinyl)pyrimidine (2.50 g) as a white solid.

›Step 2: 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

A 100 mL round-bottomed flask was charged with 5-bromo-2-(4-(phenylsulfonyl)-1-piperazinyl)pyrimidine (1.00 g, 2.61 mmol) and 20 mL of THF. After cooling to −78° C., n-BuLi (1.31 mL, 2.5 M in hexanes, 3.26 mmol) was added. This mixture was stirred at −78° C. for 10 min, and then 1,1,1,3,3,3-hexafluoro-2-propanone (Sigma-Aldrich, St. Louis, Mo.) was bubbled through the solution for 5 min. The mixture was stirred at −78° C. for an additional 30 min, then quenched with saturated aqueous NH 4 Cl (50 mL) and extracted with EtOAc (2×50 mL). This oil was purified by column chromatography (twice, first with 0 to 40% EtOAc in hexanes (40 g of silica) then 0 to 10% MeOH in CH 2 Cl 2 (40 g of silica)) to give 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.078 g) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.54 (s, 2H), 7.89-7.79 (m, 2H), 7.74-7.50 (m, 3H), 4.12-3.78 (m, 4H), 3.21-2.92 (m, 4H). m/z (ESI, +ve ion) 470.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.02 μM; GK-GKRP EC 50 (LC MS/MS)=1.31 μM.

›Example 24

1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine

A 500 mL round-bottomed flask was charged with 1-(4-bromophenyl)piperazine (10.00 g, 41.5 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of CH 2 Cl 2 . To this was slowly added triethylamine (6.94 mL, 49.8 mmol) and benzenesulfonyl chloride (6.15 mL, 47.7 mmol). After 15 min at room temperature, the mixture was diluted with water (100 mL) and layers were separated. The organics were dried (MgSO 4 ) and concentrated. The resulting solid was slurried with diethyl ether (200 mL) to give 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine (15.00 g) as a white solid.

›Step 2: 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 250 ml, round-bottomed flask was charged with 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine (0.50 g, 1.31 mmol) and 20 mL of THF. After cooling to −78° C., n-BuLi (0.603 mL, 2.5 M in hexanes, 1.51 mmol) was slowly added. The mixture was stirred at −78° C. for 30 min, then 1,1,1-trifluoro-2-propanone (0.441 g, 3.93 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was stirred at −78° C. for 1 h, and then quenched with saturated aqueous NH 4 Cl (15 mL). The organics were extracted with EtOAc (2×50 mL), dried (MgSO 4 ), and concentrated to give an oil. Purification via column chromatography (40 g of silica, 0 to 40% EtOAc in hexanes) produced 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.215 g) as a mixture of two enantiomers.

(2R)-1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.81 (s, 2H), 7.74-7.58 (m, 3H), 7.47-7.38 (m, 2H), 6.93 (s, 2H), 3.28-3.21 (m, 4H), 3.13 (d, J=5.3 Hz, 4H), 1.66 (s, 3H). m/z (ESI, +ve ion) 415.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.84 μM; GK-GKRP EC 50 (LC MS/MS)=3.96 μM.

This mixture was resolved using preparative SFC (AD column (210 mm×25 mm, 10 μm) eluting with 65% liquid CO 2 and 35% MeOH (0.2% diethylamine) flow rate=65 mL, T=40° C.) which gave two products in greater than 99% enantiomeric excess.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ 7.82 (s, 2H), 7.64 (s, 3H), 7.44 (s, 2H), 6.93 (d, J=9.0 Hz, 2H), 3.29-3.23 (m, 4H), 3.17-3.12 (m, 4H), 1.67 (s, 3H). m/z (ESI, +ve ion) 415.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.57 μM; GK-GKRP EC 50 (LC MS/MS)=2.07 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ 7.86-7.79 (m, 2H), 7.74-7.60 (m, 3H), 7.47-7.41 (m, 2H), 6.94 (m, 2H), 3.26 (d, J=5.5 Hz, 4H), 3.15 (d, J=5.5 Hz, 4H), 1.67 (s, 3H). m/z (ESI, +ve ion) 415.1 (M+H) + . GK-GKRP EC 50 (LC MS/MS)=3.01 μM.

›Example 25

1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol

A 20 mL vial was charged with (R)-2-methylpiperazine (0.357 g, 3.56 mmol, Sigma-Aldrich, St. Louis, Mo.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.00 g, 3.10 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium tert-butoxide (0.625 g, 6.50 mmol) and 6 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.022 g, 0.046 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.014 g, 0.015 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed in heated at 100° C. for 12 h. After that time, the mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined extracts were dried (MgSO 4 ) and concentrated to give 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol (0.950 g) as an oil which was used without purification.

Step 2: 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol (0.950 g, 2.78 mmol), 5 mL of CH 2 Cl 2 , 2-thiophenesulfonyl chloride (0.583 g, 3.19 mmol, Sigma-Aldrich, St. Louis, Mo.), and triethylamine (0.580 mL, 4.16 mmol). After 1 h at room temperature, 0.010 g of DMAP was added. After an additional 30 min, the mixture was concentrated and purified via column chromatography (80 g of silica, 0 to 40% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.425 g) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ=7.70-7.46 (m, 4H), 7.12 (dd, J=3.7, 4.9 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.30 (m, 1H), 3.83 (td, J=3.0, 13.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.54-3.38 (m, 2H), 3.31 (s, 1H), 3.07 (dd, J=3.5, 12.3 Hz, 1H), 2.95 (dt, J=3.6, 11.6 Hz, 1H), 1.30 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 488.7 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.36 μM; GK-GKRP EC 50 (LC MS/MS)=2.57 μM.

›Example 26

1,1,1,3,3,3-hexafluoro-2-(4-((3S)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 25, (S)-2-methylpiperazine (Sigma-Aldrich, St. Louis, Mo.) delivered 1,1,1,3,3,3-hexafluoro-2-(4-((3S)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ=7.65-7.54 (m, 4H), 7.12 (dd, J=3.7, 4.9 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.30 (m, 1H), 3.83 (td, J=3.0, 13.1 Hz, 1H), 3.68-3.57 (m, 1H), 3.52-3.36 (m, 2H), 3.31 (s, 1H), 3.07 (dd, J=3.7, 12.3 Hz, 1H), 2.95 (dt, J=3.6, 11.6 Hz, 1H), 1.30 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 488.7 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.42 μM; GK-GKRP EC 50 (LC MS/MS)=3.22 μM.

›Example 27

1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol

A 500 mL round-bottomed flask was charged with 1,4-dibromobenzene (30.27 g, 128 mmol, Sigma-Aldrich, St. Louis, Mo.) and 200 mL of ether. After cooling to −78° C., n-BuLi (59.0 mL, 2.5 M in hexanes, 148 mmol) was added. This mixture was stirred for 15 min at −78° C., then 1,1,1-trifluoro-2-propanone (24.2 mL, 257 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. Stirring was continued at −78° C. for 30 min then the mixture was quenched with 100 mL of saturated aqueous NH 4 Cl. The mixture was extracted with EtOAc (250 mL), dried (MgSO 4 ) and concentrated to give an oil. Purification via column chromatography (330 g of silica, 0 to 30% EtOAc in hexanes) gave 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (21.50 g) as a colorless oil.

›Step 2: (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride

A 500 mL round-bottomed flask was charged with (S)-2-methylpiperazine (10.23 g, 102 mmol, Sigma-Aldrich, St. Louis, Mo.) and 100 mL of CH 2 Cl 2 . After cooling to 0° C., 2-thiophenesulfonyl chloride (18.65 g, 102 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. This mixture was stirred at 0° C. for 15 min then diluted with water (100 mL). The layers were separated and the organics were dried (MgSO 4 ) and concentrated to give an oil. To this oil was added 300 mL of EtOAc and 28 mL of 4 M HCl in dioxane. The resulting white precipitate was collected by filtration to give (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (26 g).

Step 3: 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 100 mL round-bottomed flask was charged with (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (10.0 g, 35.4 mmol), 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (16.7 g, 61.9 mmol, Example 27, step 1), sodium tert-butoxide (13.6 g, 141 mmol) and 20 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.98 g, 4.24 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (1.94 g, 0.265 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h. After that time, the reaction was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined extracts were dried (MgSO 4 ) and concentrated and purified by column chromatography (330 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (13.20 g) as a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

This mixture was resolved using preparative SFC (Chiralcel® OJ-H column (250×30 mm) eluting with 70% liquid CO 2 in 30% MeOH (0.2% diethylamine) at a flow rate of 120.0 mL/min) to give two products in greater than 99% diastereomeric excess.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ 7.91-7.87 (m, 1H), 7.65 (dd, J=1.2, 3.7 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.27 (dd, J=3.8, 5.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.11-4.01 (m, 1H), 3.67-3.59 (m, 1H), 3.45-3.35 (m, 2H), 3.27-3.17 (m, 1H), 2.92-2.84 (m, 1H), 2.72 (dt, J=3.5, 10.9 Hz, 1H), 1.69 (s, 3H), 1.11 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 435.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.616 μM; GK-GKRP EC 50 (LC MS/MS)=0.768 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ 7.89 (dd, J=1.0, 5.1 Hz, 1H), 7.69-7.59 (m, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.31-7.21 (m, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.12-4.01 (m, 1H), 3.63 (dd, J=1.9, 11.2 Hz, 1H), 3.45-3.34 (m, 2H), 3.28-3.18 (m, 1H), 2.95-2.81 (m, 1H), 2.79-2.61 (m, 1H), 1.69 (s, 3H), 1.11 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 435.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.724 μM; GK-GKRP EC 50 (LC MS/MS)=0.972 μM

›Example 28

1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 27 (substituting benzenesulfonyl chloride for 2-thiophenesulfonyl chloride) yielded 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (300 MHz, MeOH) δ 7.72 (d, J=7.3 Hz, 2H), 7.62-7.50 (m, 3H), 7.35 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 3.51 (d, J=11.6 Hz, 1H), 3.34-3.26 (m, 3H), 3.15-3.01 (m, 1H), 2.69 (d, J=11.4 Hz, 1H), 2.53 (t, J=8.9 Hz, 1H), 1.57 (s, 3H), 0.98 (d, J=6.4 Hz, 3H). m/z (ESI, +ve ion) 429.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.12 μM; GK-GKRP EC 50 (LC MS/MS)=4.01 μM

›Example 29

1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: 4-(2-thiophenylsulfonyl)piperazine hydrochloride

A 1 L round-bottomed flask was charged with tert-butyl piperazine-1-carboxylate (20.70 g, 111 mmol, Sigma-Aldrich, St. Louis, Mo.), 300 mL of CH 2 Cl 2 , and triethylamine (17.81 mL, 128 mmol). After cooling to 0° C., 2-thiophenesulfonyl chloride (21.31 g, 117 mmol, Sigma-Aldrich, St. Louis, Mo.) was added and the reaction was stirred at 0° C. for 30 min. The mixture was diluted with water (200 mL) and the layers were separated, dried (MgSO 4 ) and concentrated to give tert-butyl 4-(thiophen-2-ylsulfonyl)piperazine-1-carboxylate (37.0 g) as a white solid. To this solid was added 300 mL of EtOAc, and 4 N HCl in dioxane (100 mL). The mixture was heated to 65° C. to give a clear solution. Over the course of 2 h, a white precipitate formed. The white precipitate was collected by filtration and dried under reduced pressure to give 4-(thiophen-2-ylsulfonyl)piperazine hydrochloride (26.0 g).

›Step 2: 1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 20 ml, vial was charged with 4-(2-thiophenylsulfonyl)piperazine hydrochloride (70 mg, 0.260 mmol), sodium tert-butoxide (45.7 mg, 0.476 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.1 mg, 1.13 μmol, Strem Chemical Inc, Newburyport, Mass.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.6 mg, 3.40 μmol, Strem Chemical Inc, Newburyport, Mass.) and 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (60.9 mg, 0.226 mmol, Example 27, step 1) in toluene (906 μL) was heated to 100° C. for 20 h. The reaction was then cooled to ambient temperature and additional tris(dibenzylideneacetone)dipalladium (0) (1.1 mg, 1.13 μmol, Strem Chemical Inc, Newburyport, Mass.) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (1.6 mg, 3.40 μmol, Strem Chemical Inc, Newburyport, Mass.) were added. The reaction was then heated to 100° C. for an additional 20 h. The reaction was cooled to ambient temperature and diluted with MeOH (2 mL). The reaction was loaded onto a 1 g AccuBOND II SCX cartridge, which was washed with MeOH (5 mL) and eluted with 2 N ammonia in MeOH (5 mL) to give the crude reaction mixture. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (10 g of silica gel, 5%-45% EtOAc in hexanes) to provide 1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two enantiomers.

(2S)-1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (300 MHz, CDCl 3 ) δ 7.64 (d, J=4.7 Hz, 1H) 7.57 (d, J=2.8 Hz, 1H) 7.45 (d, J=8.5 Hz, 2H) 7.17 (t, J=4.3 Hz, 1H) 6.87 (d, J=8.6 Hz, 2H) 3.26 (m, 8H) 2.47 (m, 1H) 1.73 (s, 3H). m/z (ESI, +ve ion) 421.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.563 μM; GK-GKRP EC 50 (LC MS/MS)=0.779 μM.

This mixture was resolved using preparative SFC (Chiralcel® OJ-H column (150×4.6 mm, 5 μm) eluting with 60% liquid CO 2 in 40% EtOH (0.2% diethylamine) at a flow rate of 4.0 mL/min) to give two products in greater than 99% enantiomeric excess.

First Eluting Peak (Peak #1)

1 H NMR (300 MHz, CDCl 3 ) δ 7.64 (d, J=4.4 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.17 (s, 1H), 6.88 (d, J=8.33 Hz, 2H), 3.27 (m, 8H), 1.74 (s, 3H). m/z (ESI, +ve ion) 421.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.546 μM; GK-GKRP EC 50 (LC MS/MS)=0.835 μM.

Second Eluting Peak (Peak #2)

1 H NMR (300 MHz, CDCl 3 ) δ 7.64 (d, J=4.7 Hz, 1H), 7.58 (d, J=2.9 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.17 (t, J=4.2 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 3.27 (m, 8H), 1.74 (s, 3H). m/z (ESI, +ve ion) 421.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.775 μM; GK-GKRP EC 50 (LC MS/MS)=1.17 μM.

›Example 30

1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol

Step 1: tert-butyl (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate

A 100 mL round-bottomed flask was charged with tert-butyl (3S)-3-methyl-1-piperazinecarboxylate (10.0 g, 49.9 mmol), 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (13.43 g, 49.9 mmol, Example 27, step 1), sodium tert-butoxide (10.56 g, 110 mmol) and 100 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.864 g, 3.99 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (1.83 g, 2.00 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h then diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were dried (MgSO 4 ) and purified by column chromatography (330 g of silica, 0 to 50% EtOAc in hexanes) to give tert-butyl (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (13.05 g) as a white solid.

›Step 2: 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride

A 500 mL round-bottomed flask was charged with tert-butyl (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.33 g, 21.5 mmol) and 200 mL of EtOAc. To this was added 20 mL of 4N HCl (80 mmol) in dioxane. After 12 h at reflux, the resulting white precipitate was collected and dried under reduced pressure to give 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (5.45 g) as a white solid.

›Step 3: 1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol

To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (100 mg, 0.277 mmol) and triethylamine (0.115 mL, 0.830 mmol) in CH 2 Cl 2 (4.0 mL) was added 3-furansulfonyl chloride (55.3 mg, 0.332 mmol, Ryan Scientific, Inc., Mt. Pleasant, S.C.). After 30 min at room temperature, the reaction was concentrated and purified via column chromatography (12 g of silica, 0 to 70% EtOAc in hexanes) to yield 1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol (25 mg) as a mixture of two isomers.

(2S)-1,1,1-trifluoro-2-(4-((2S)-4-(2-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-4-(2-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 8.14 (s, 1H), 7.74-7.71 (m, 1H), 7.46 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 6.74-6.72 (m, 1H), 4.08-4.01 (m, 1H), 3.64-3.57 (m, 1H), 3.42-3.33 (m, 2H), 3.24-3.15 (m, 1H), 2.93-2.87 (m, 1H), 2.77-2.69 (m, 1H), 1.68 (ms, 3H), 1.08 (d, J=9.0 Hz, 3H). m/z (ESI, +ve ion) 419.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.12 μM; GK-GKRP EC 50 (LC MS/MS)=50 μM.

›Examples6

›Example 31

1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate

A vial was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.161 g, 0.499 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.100 g, 0.499 mmol, Sigma-Aldrich, St. Louis, Mo.), sodium tert-butoxide (0.115 g, 1.198 mmol), and 2.5 mL of anhydrous toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.035 g, 0.075 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.023 g, 0.025 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and the mixture was heated at 100° C. for 18 h. After that time, the reaction was partitioned between saturated NaHCO 3 (50 mL) and EtOAc (50 mL). The organics were separated, washed with brine (50 mL), and dried (NaSO 4 ) and volatiles were removed in vacuo. The residue was dissolved in 2 mL of CH 2 Cl 2 . To this was added 4 N HCl in dioxane (5 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was dissolved with CH 2 Cl 2 (10 mL). To this was added 1 mL of Hünig's base and 2-thiazolesulfonyl chloride (95 mg, 0.52 mmol, Bioorg. Med. Chem., 2006, 14, 6628). This mixture was stirred at room temperature for 18 h and then concentrated, the residue was dissolved in methanol (3 mL), and filtered through a 0.45 micron filter. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (10 μm), 150×30 mm, eluting with a 0.1% TFA in CH 3 CN/H 2 O, gradient (10% to 90% over 20 min) to afford 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (41 mg) as an orange oil. 1 H NMR (300 MHz, MeOH) δ 8.06 (d, J=3.1 Hz, 1H), 7.98 (d, J=2.9 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.17 (d, J=3.4 Hz, 1H), 3.83 (s, 1H), 3.64 (d, J=12.1 Hz, 1H), 3.47 (d, J=2.9 Hz, 1H), 3.07-3.27 (m, 2H), 2.87-3.04 (m, 1H), 2.15 (s, 3H). m/z (ESI, +ve ion) 490.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.561 μM; GK-GKRP EC 50 (LC MS/MS)=0.702 μM.

›Example 32

1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate

2-(4-Bromophenyl)-1,1,1-trifluoro-2-propanol (330 mg, 1.226 mmol, Example 27, step 1), benzyl 1-piperazinecarboxylate (270 mg, 1.226 mmol, Sigma-Aldrich, St. Louis, Mo.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (86 mg, 0.184 mmol, Strem Chemical Inc, Newburyport, Mass.), sodium tert-butoxide (283 mg, 2.94 mmol), and tris(dibenzylideneacetone)dipalladium (0) (56.2 mg, 0.061 mmol, Strem Chemical Inc, Newburyport, Mass.) were combined in toluene (5 mL) and stirred in a sealed tube overnight at 100° C. The reaction was poured into saturated aqueous sodium bicarbonate (100 mL) and EtOAc (100 mL). The organic extracts were separated washed with brine (25 mL), dried (Na 2 SO 4 ), filtered and concentrated. The residue was dissolved in methanol (10 mL). Under nitrogen, 10% Pd/C (100 mg) was added and the resulting black suspension was placed under a hydrogen atmosphere (1 atm) for 1 h. After that time, the mixture was filtered through a 0.45 micron filter and concentrated. This crude material, 2-thiazolesulfonyl chloride (225 mg, 1.225 mmol, Bioorg. Med. Chem., 2006, 14, 6628), and Hünig's base (214 μL, 1.225 mmol) were combined in CH 2 Cl 2 (10 mL). This was allowed to stir for at room temperature 3 h. After that time, the reaction was concentrated then dissolved in methanol (3 mL) and filtered through a 0.45 micron filter. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini (C 18 column (150×30 mm, 10 μm) eluting with a 0.1% TFA in CH 3 CN/H 2 O, gradient (10% to 90% over 30 min)) to afford 1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (120 mg) as a mixture of two enantiomers.

(2S)-1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate; (2R)-1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (d, J=3.1 Hz, 1H), 7.67 (d, J=3.1 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 3.48-3.58 (m, 4H), 3.27-3.38 (m, 4H), 1.76 (s, 3H). m/z (ESI, +ve ion) 421.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.18 μM; GK-GKRP EC 50 (LC MS/MS)=4.75 μM.

›Example 33

1,1,1,3,3,3-hexafluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate

1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (150 mg, 0.457 mmol, published PCT patent application no. WO 2006/094842) was suspended in 20 mL of CH 2 Cl 2 . To this was added 2-thiazolesulfonyl chloride (84 mg, 0.457 mmol, Bioorg. Med. Chem., 2006, 14, 6628) and Hünig's base (0.2 mL). After stirring for 20 min at room temperature, the reaction was concentrated and then re-dissolved in methanol (3 mL). The crude material was purified by reverse-phase preparative HPLC (Phenomenex Gemini C 18 column (150×30 mm, 10 μm), eluting with a 0.1% TFA in CH 3 CN/H 2 O, gradient (0% to 100% over 20 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (36 mg) as a white powder. 1 H NMR (300 MHz, CD 3 OD) δ 8.09 (d, J=3.1 Hz, 1H), 8.01 (d, J=3.1 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.9 Hz, 2H), 3.44 (m, 4H), 3.35 (m, 4H). m/z (ESI, +ve ion) 476.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.664 μM; GK-GKRP EC 50 (LC MS/MS)=0.842 μM.

›Example 34

1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate

Following the procedure described for Example 33, (S)-1,1,1-trifluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)propan-2-ol (Example 30) provided 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate as a mixture of two isomers.

The mixture was resolved by chiral SFC (Chiralcel® OJ-H column (250 mm×20 mm, 5 μm) eluting with 70% liquid CO 2 and 30% MeOH (0.2% diethylamine), EtOH, i-PrOH (1:1:1)) to give two products in greater than 95% diastereomeric excess.

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (300 MHz, MeOH) δ 8.07 (d, J=3.2 Hz, 1H) 7.98 (d, J=3.1 Hz, 1H) 7.46 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 4.14-3.95 (m, 1H), 3.77 (dd, J=11.5, 1.7 Hz, 1H), 3.63-3.47 (m, 1H), 3.44-3.33 (m, 1H), 3.26-3.11 (m, 2H), 3.09-2.93 (m, 1H), 1.68 (s, 3H), 1.07 (d, J=6.4 Hz, 3H). m/z (ESI, +ve ion) 436.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.5 μM.

Second Eluting Peak (Peak #2):

1 H NMR (300 MHz, MeOH) δ 8.07 (d, J=3.1 Hz, 1H) 7.99 (d, J=3.1 Hz, 1H) 7.46 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 4.11-3.97 (m, 1H), 3.83-3.72 (m, 1H), 3.60-3.49 (m, 1H), 3.42-3.33 (m, 1H), 3.27-3.13 (m, 2H), 3.10-2.96 (m, 1H), 1.68 (s, 3H) 1.08 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion) 436.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.94 μM; GK-GKRP EC 50 (LC MS/MS)=1.92 μM.

›Example 35

2-(4-(((2S)-4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

N-(5-(((3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinyl)sulfonyl)-1,3,4-thiadiazol-2-yl)acetamide was synthesized following the procedure reported for Example 30, replacing 3-furansulfonyl chloride with 5-(acetylamino)-1,3,4-thiadiazole-2-sulfonyl chloride ( Eur. J. Med. Chem., 2006, 41, 918). A solution of N-(5-((3S)-3-methyl-4-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-1-ylsulfonyl)-1,3,4-thiadiazol-2-yl)acetamide (85 mg, 0.172 mmol) in aqueous 5N HCl (5 mL, 5.00 mmol) was heated to 100° C. for 3 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×100 mL). The organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated. The crude material was purified by column chromatography (12 g of silica, 0 to 100% (10% [2M ammonia in methanol]/CH 2 Cl 2 ) in CH 2 Cl 2 ) to yield 2-(4-((2S)-4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (20 mg) as a mixture of 2 isomers.

(2S)-2-(4-((2S)-4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.47 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 4.10-4.03 (m, 1H), 3.80-3.74 (m, 1H), 3.57-3.51 (m, 1H), 3.42-3.36 (m, 1H), 3.29-3.17 (m, 2H), 3.15-3.07 (m, 1H), 1.68 (s, 3H), 1.10-1.06 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 452.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.04 μM; GK-GKRP EC 50 (LC MS/MS)=5.62 μM.

›Example 36

1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-alanylglycinate

A 100 mL round-bottomed flask was charged with N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-alanine (3.11 g, 11.38 mmol, Acros/Fisher Scientific, Waltham, Mass.), HATU (5.41 g, 14.22 mmol, Oakwood, West Columbia, S.C.), glycine methyl ester hydrochloride (1.714 g, 13.65 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10 mL of DMF. To this was added Hünig's base (4.37 mL, 25.03 mmol). After 30 min at room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The layers were separated and the organic extracts were washed with water (2×100 mL) and brine (50 mL), dried (MgSO 4 ) and concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-alanylglycinate (3.00 g) as a yellow oil

›Step 2: 3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione

A 250 mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-alanylglycinate (3.00 g, 8.71 mmol), 10 mL of CH 2 Cl 2 , and 5 mL of TFA. After 10 min, the mixture was concentrated then re-dissolved in MeOH (50 mL) and triethylamine (10 mL) and then heated at reflux for 18 h. After that time, the white precipitate formed was collected by filtration to give 3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g) as a white solid.

›Step 3: 2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine

A 250 ml, round-bottomed flask was charged with 3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g, 6.78 mmol), 50 mL of THF, and lithium aluminum hydride (27.1 mL, 1M in THF, 27.1 mmol). After refluxing for 2 h, the mixture was cooled to room temperature where sodium sulfate decahydrate (10 g) was added. After stirring at room temperature for 1 h, the mixture was filtered and the filtrate was concentrated to give 2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine (0.950 g) as a colorless oil.

›Step 4: 3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride

A 100 mL round-bottomed flask was charged with 2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine (0.950 g, 5.16 mmol), 20 mL of CH 2 Cl 2 , triethylamine (0.790 mL, 5.67 mmol), and 2-thiophenesulfonyl chloride (0.942 mL, 5.16 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min at room temperature, the mixture was diluted with water (50 mL) and CH 2 Cl 2 (50 mL), the organics were separated, dried (MgSO 4 ) and concentrated to give a dark oil. To this oil was added 50 mL of ether and 10 mL of 1N HCl in ether. The resulting white precipitate was collected by filtration to give 3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride (1.45 g) as an orange solid.

Step 5: 1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 100 ml, round-bottomed flask was charged with 3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride (0.250 g, 0.681 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.330 g, 1.02 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium tert-butoxide (0.196 g, 2.04 mmol) and 10 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.032 g, 0.068 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.031 g, 0.034 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h and then diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO 4 ), concentrated, and purified by reverse-phase preparative HPLC (Phenomenex Gemini C 18 column (150×30 mm, 10 μm), eluting with a 0.1% TFA in CH 3 CN/H 2 O (10% to 90% over 25 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.008 g) as a mixture of two enantiomers.

1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.89 (d, J=4.9 Hz, 1H), 7.70-7.61 (m, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.31-7.23 (m, 1H), 6.96 (d, J=9.2 Hz, 2H), 4.18 (br. s., 1H), 3.95-3.64 (m, 4H), 3.60-3.44 (m, 1H), 3.40-3.23 (m, 2H), 2.70 (dd, J=2.9, 11.7 Hz, 1H), 2.57 (dt, J=3.6, 11.4 Hz, 1H), 1.86-1.65 (m, 2H), 1.65-1.38 (m, 3H), 1.38-1.08 (m, 3H). m/z (ESI, +ve ion) 573.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.169 μM; GK-GKRP EC 50 (LC MS/MS)=0.281 μM.

›Examples8

›Example 37

1,1,1-trifluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 36, starting from N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (Acros/Fisher Scientific, Waltham, Mass.) and coupling with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) delivered 1,1,1-trifluoro-2-(4-(-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

This mixture was resolved using chiral SFC (Chiralpak® IA column (250×21 mm, 5 μm) using 30% methanol (0.2% diethylamine) in supercritical CO 2 , total flow was 65 mL/min). Peaks 1 and 2 were purified a second time using SFC (IC column (250×21 mm, 5 μm), with 25% methanol (0.2% diethylamine) in supercritical CO 2 as the eluent). This produced four products with both diastereomeric and enantiomeric excesses over 95%.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ 7.76 (dd, J=1.3, 5.0 Hz, 1H), 7.53 (dd, J=1.3, 3.8 Hz, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.14 (dd, J=3.9, 4.9 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 3.99 (br. s., 1H), 3.84-3.69 (m, 2H), 3.66-3.50 (m, 2H), 3.43-3.23 (m, 1H), 3.18-3.04 (m, 1H), 2.70-2.56 (m, 1H), 2.48 (dt, J=3.5, 11.3 Hz, 1H), 1.75-1.51 (m, 6H), 1.50-0.95 (m, 6H). m/z (ESI, +ve ion) 519.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.111 μM; GK-GKRP EC 50 (LC MS/MS)=0.162 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ 7.76 (dd, J=1.2, 4.9 Hz, 1H), 7.58-7.44 (m, 1H), 7.41-7.23 (m, 2H), 7.21-7.04 (m, 1H), 6.80 (s, 2H), 3.99 (br. s., 1H), 3.85-3.66 (m, 2H), 3.66-3.46 (m, 2H), 3.41-3.26 (m, 2H), 3.18-3.04 (m, 2H), 2.61 (dd, J=3.0, 11.4 Hz, 1H), 2.48 (dt, J=3.6, 11.4 Hz, 1H), 1.66 (m, 1H), 1.57 (m, 4H), 1.51-0.90 (m, 5H). m/z (ESI, +ve ion) 519.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.124 μM; GK-GKRP EC 50 (LC MS/MS)=0.128 μM.

Third Eluting Peak (Peak #3)

1 H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J=4.9 Hz, 1H), 7.66 (s, 1H), 7.47 (s, 2H), 7.27 (d, J=4.7 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 4.20-4.02 (m, 1H), 3.93-3.81 (m, 2H), 3.79-3.63 (m, 2H), 3.53-3.36 (m, 2H), 3.31-3.17 (m, 1H), 2.78-2.69 (m, 1H), 2.60 (dt, J=3.6, 11.3 Hz, 1H), 1.78 (m, 1H), 1.71 (m, 4H), 1.61-1.06 (m, 6H). m/z (ESI, +ve ion) 519.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=13.0 μM.

Fourth Eluting Peak (Peak #4)

1 H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J=4.1 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.32-7.18 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.10 (br. s., 1H), 3.87 (t, J=11.0 Hz, 2H), 3.79-3.61 (m, 2H), 3.57-3.38 (m, 1H), 3.30-3.18 (m, 1H), 2.73 (dd, J=3.3, 11.3 Hz, 1H), 2.66-2.50 (m, 1H), 1.86-1.73 (m, 1H), 1.69 (s, 3H), 1.62-0.87 (m, 8H). m/z (ESI, +ve ion) 519.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=>50 μM.

›Example 38

1,1,1-trifluoro-2-(4-(2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 36, starting from (3S)-3-((tert-butoxycarbonyl)amino)-4-(2-fluorophenyl)butanoic acid (Chem-Impex International, Inc., Wood Dale, Ill.) and coupling with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) delivered 1,1,1-trifluoro-2-(4-(-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(2-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.86 (d, J=4.9 Hz, 1H), 7.64-7.54 (m, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.26-7.16 (m, 2H), 7.14-6.93 (m, 4H), 4.29-4.18 (m, 1H), 3.87-3.76 (m, 1H), 3.61-3.48 (m, 2H), 3.41 (dt, J=3.5, 12.0 Hz, 1H), 3.13-3.01 (m, 1H), 2.85 (dd, J=3.8, 13.2 Hz, 1H), 2.62-2.49 (m, 2H), 1.69 (s, 3H). m/z (ESI, +ve ion) 529.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.515 μM; GK-GKRP EC 50 (LC MS/MS)=0.850 μM.

›Example 39

1,1,1-trifluoro-2-(4-(2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 36, starting from (3S)-3-((tert-butoxycarbonyl)amino)-4-(3-fluorophenyl)butanoic acid (Acros/Fisher Scientific, Waltham, Mass.) and coupling with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) delivered 1,1,1-trifluoro-2-(4-(-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.86 (dd, J=1.2, 5.1 Hz, 1H), 7.64-7.59 (m, 1H), 7.55-7.48 (m, 2H), 7.36-7.15 (m, 2H), 7.11-6.77 (m, 5H), 4.17-4.09 (m, 1H), 3.84 (d, J=10.0 Hz, 1H), 3.61 (d, J=11.3 Hz, 1H), 3.55-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.19-3.04 (m, 1H), 2.69-2.48 (m, 3H), 1.70 (s, 3H). m/z (ESI, +ve ion) 529.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.802 μM; GK-GKRP EC 50 (LC MS/MS)=1.09 μM.

›Example 40

1,1,1-trifluoro-2-(4-(2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 36, starting from (3S)-3-((tert-butoxycarbonyl)amino)-4-(4-fluorophenyl)butanoic acid (Acros/Fisher Scientific, Waltham, Mass.) and coupling with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) delivered 1,1,1-trifluoro-2-(4-(-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(4-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.93-7.81 (m, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.56-7.43 (m, 2H), 7.30-7.15 (m, 3H), 7.08-6.91 (m, 4H), 4.11 (br. s., 1H), 3.84 (d, J=11.0 Hz, 1H), 3.60 (d, J=11.3 Hz, 1H), 3.55-3.46 (m, 1H), 3.40-3.35 (m, 1H), 3.21-2.96 (m, 1H), 2.72-2.47 (m, 3H), 1.70 (s, 3H). m/z (ESI, +ve ion) 529.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.895 μM; GK-GKRP EC 50 (LC MS/MS)=1.25 μM.

›Example 41

1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 36, starting from N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (Acros/Fisher Scientific, Waltham, Mass.) and coupling with benzenesulfonyl chloride (Sigma-Aldrich, St. Louis, Mo.) and 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) and delivered 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four compounds.

(2R)-1,1,1-trifluoro-2-(4-((2R)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.83 (s, 2H), 7.65 (s, 3H), 7.44 (d, J=8.8 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.06 (m, 1H), 3.92-3.82 (m, 2H), 3.80-3.72 (m, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.47-3.37 (m, 1H), 3.31-3.19 (m, 1H), 2.65 (dd, J=3.1, 11.5 Hz, 1H), 2.51 (dt, J=3.6, 11.4 Hz, 1H), 1.83-1.73 (m, 1H), 1.68 (s, 4H), 1.60-1.49 (m, 2H), 1.40-1.03 (m, 5H). m/z (ESI, +ve ion) 513.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.785 μM; GK-GKRP EC 50 (LC MS/MS)=0.572 μM.

›Example 42

1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride

Following the procedure reported for Example 36, starting from N-(tert-butoxycarbonyl)-3-methyl-L-phenylalanine (Sigma-Aldrich, St. Louis, Mo.) and coupling with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol ( Bioorg. Med. Chem. Lett. 2002, 12, 3009) produced the desired product. The free base was acidified with 4 N HCl in dioxane to provide 1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride as a mixture of two enantiomers.

1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(3-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride; 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(3-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride. 1 H NMR (400 MHz, CD 3 OD) δ 7.87-7.83 (m, 1H), 7.62-7.58 (m, 3H), 7.24-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.08-6.99 (m, 5H), 4.17-4.11 (m, 1H), 3.88-3.82 (m, 1H), 3.68-3.56 (m, 2H), 3.42-3.34 (m, 1H), 3.12-3.04 (m, 1H), 2.62-2.53 (m, 2H), 2.51-2.46 (m, 1H), 2.31 (s, 3H). m/z (ESI, +ve ion) 578.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.724 μM; GK-GKRP EC 50 (LC MS/MS)=0.688 μM.

›Example 43

1,1,1,3,3,3-hexafluoro-2-(4-(2-(4-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride

Following the procedure reported for Example 36, starting from N-(tert-butoxycarbonyl)-4-methyl-L-phenylalanine (Sigma-Aldrich, St. Louis, Mo.) and coupling with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol ( Bioorg. Med. Chem. Lett. 2002, 12, 3009) produced the desired product. The free base was acidified with 4N HCl in dioxane to provide 1,1,1,3,3,3-hexafluoro-2-(4-(2-(4-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride as a mixture of two enantiomers.

1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(4-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride; 1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(4-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride. 1 H NMR (400 MHz, CD 3 OD) δ 7.86-7.83 (m, 1H), 7.61-7.56 (m, 3H), 7.24-7.20 (m, 1H), 7.13-7.07 (m, 4H), 7.05-7.00 (m, 2H), 4.15-4.08 (m, 1H), 3.86-3.81 (m, 1H), 3.66-3.55 (m, 2H), 3.41-3.33 (m, 1H), 3.10-3.03 (m, 1H), 2.61-2.53 (m, 2H), 2.51-2.46 (m, 1H), 2.29 (s, 3H). m/z (ESI, +ve ion) 578.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.50 μM; GK-GKRP EC 50 (LC MS/MS)=2.62 μM.

›Example 44

1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: methyl O-benzyl-L-serylglycinate trifluoroacetate

A 250 mL round-bottomed flask was charged with O-benzyl-N-(tert-butoxycarbonyl)-L-serine (7.28 g, 24.65 mmol, Sigma-Aldrich, St. Louis, Mo.), glycine methyl ester hydrochloride (3.09 g, 24.65 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (8.83 mL, 50.5 mmol) and DMF (100 mL). After cooling to 0° C., HATU (9.37 g, 24.65 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After the addition was complete, the reaction was slowly warmed to room temperature and stirred for 3 h. The mixture was diluted with EtOAc (300 mL) and the organic solution was washed with 0.5 N aqueous HCl (150 mL), saturated aqueous NaHCO 3 (150 mL), water (150 mL), and then brine (150 mL). The organic layer was then dried (MgSO 4 ) and concentrated. The crude material was dissolved in a 2:1 CH 2 Cl 2 /TFA solution (100 mL) and stirred for 2 h at room temperature. The mixture was then concentrated and azeotroped with toluene (2×100 mL) to give methyl O-benzyl-L-serylglycinate trifluoroacetate as a yellow tar (9.37 g). The product was taken onto the next step without purification.

›Step 2: 3-((benzyloxy)methyl)-2,5-piperazinedione

A 250 ml, round-bottomed flask was charged with methyl O-benzyl-L-serylglycinate trifluoroacetate (9.37 g, 24.64 mmol) and 3:1 MeOH/triethylamine (50 mL). The mixture was then heated to reflux for 16 h. The reaction was then cooled to room temperature, concentrated, and diluted with ice cold 50% aqueous EtOH (50 mL). The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(benzyloxymethyl)piperazine-2,5-dione (3.95 g) as a white solid.

›Step 3: 2-((benzyloxy)methyl)piperazine

A 250 ml, round-bottomed flask was charged with lithium aluminum hydride (1.871 g, 49.3 mmol) and THF (75 mL). After cooling to 0° C., 3-(benzyloxymethyl)piperazine-2,5-dione (3.85 g, 16.44 mmol) was slowly added. The mixture was warmed to room temperature and then heated at reflux for 1 h. After this time, the mixture was cooled to 0° C. and the reaction was quenched with sodium sulfate decahydrate (20 g) and stirred vigorously for 1 h. The mixture was filtered, and the filtrate was concentrated to give 2-(benzyloxymethyl)piperazine (2.60 g) as a yellow oil. This material was taken to the next step without purification.

›Step 4: 3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl) piperazine

A 250 mL round-bottomed flask was charged with 2-(benzyloxymethyl)piperazine (2.10 g, 10.1 mmol), triethylamine (1.42 mL, 10.2 mmol) and CH 2 Cl 2 (50 mL). After cooling to 0° C., 2-thiophenesulfonyl chloride (1.84 g, 10.1 mmol, Sigma-Aldrich, St. Louis, Mo.) was added slowly via syringe. After 2 h, the mixture was concentrated and diluted with EtOAc (200 mL). The organic solution was washed with 1 N HCl (2×50 mL) and the combined acidic layers made basic with Na 2 CO 3 . The resulting basic solution was extracted with EtOAc (3×100 mL) and the combined organic layers were dried (MgSO 4 ), filtered and concentrated to give 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (1.79 g) as a yellow tar.

Step 5: 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

A mixture of 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (2.95 g, 8.37 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (2.70 g, 10.04 mmol, Example 27, step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.156 g, 0.335 mmol, Strem Chemicals, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.153 g, 0.167 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (2.011 g, 20.92 mmol) and toluene (50 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 100° C. for 16 h. The solution was then diluted with EtOAc (200 mL). The organic solution was washed with water (100 mL) and brine (100 mL) then dried (MgSO 4 ), filtered and concentrated. The crude material was subjected to flash chromatography on silica gel (120 g, 5-80% (10% MeOH-EtOAc) in hexanes) to give 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (3.95 g) as a mixture of four isomers.

(2R)-2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.64-7.58 (m, 2H), 7.42-7.40 (m, 2H), 7.35-7.26 (m, 5H), 7.17-7.15 (m, 1H), 6.84-6.82 (m, 2H), 4.55-4.45 (m, 2H), 4.06-3.99 (m, 2H), 3.82-3.74 (m, 2H), 3.48-3.44 (m, 2H), 3.23-3.17 (m, 1H), 2.72-2.61 (m, 2H), 1.74 (s, 3H). m/z (ESI, +ve ion) 541.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.420 μM; GK-GKRP EC 50 (LC MS/MS)=0.617 μM.

Step 6: 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 250 mL round-bottomed flask was charged with 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (2.93 g, 5.43 mmol) and CH 2 Cl 2 (50 mL) and cooled to −78° C. A 1.0 M solution of BCl 3 (1M in CH 2 Cl 2 , 7.31 mL, 7.31 mmol, Sigma-Aldrich, St. Louis, Mo.) was added slowly to the mixture and the reaction was stirred for 1 h at −78° C. After this time, MeOH (25 mL) was added and the mixture was warmed to room temperature. After the MeOH was removed in vacuo, diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration, dried under reduced pressure to yield 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (2.17 g) as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J=1.3, 5.0 Hz, 1H), 7.58 (dd, J=1.4, 3.7 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.20-7.15 (m, 1H), 6.93-6.85 (m, 2H), 3.97-3.86 (m, 3H), 3.75-3.65 (m, 2H), 3.50-3.46 (m, 1H), 3.33-3.26 (m, 1H), 2.80-2.69 (m, 2H), 1.74 (s, 3H). m/z (ESI, +ve ion) 451.1 (M+H) + The mixture was resolved using chiral SFC(OJH column, 21×250 mm, 5 μM) using 70% supercritical CO 2 /30% iPrOH (0.2% diethylamine) at a flow rate of 65 mL/min) to give 4 products with diastereomeric and enantiomeric excesses greater than 95%.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CDCl 3 ) δ 7.66-7.64 (dd, J=5.0, 1.2 Hz, 1H), 7.59-7.57 (dd, J=3.7, 1.2 Hz, 1H), 7.45-7.42 (d, J=8.8 Hz, 2H), 7.18-7.16 (dd, J=5.0, 3.7 Hz, 1H), 6.90-6.88 (m, 2H), 3.97-3.86 (m, 3H), 3.75-3.67 (m, 2H), 3.50-3.45 (m, 1H), 3.33-3.26 (m, 1H), 2.79-2.68 (m, 2H), 1.74 (s, 3H). m/z (ESI, +ve ion) 451.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.06 μM; GK-GKRP EC 50 (LC MS/MS)=50 μM.

Second Eluting Peak (Peak #2)

Third Eluting Peak (Peak #3)

1 H NMR (400 MHz, CDCl 3 ) δ 7.66-7.64 (dd, J=5.0, 1.1 Hz, 1H), 7.59-7.57 (dd, J=3.7, 1.1 Hz, 1H), 7.45-7.42 (d, J=8.6 Hz, 2H), 7.18-7.16 (dd, J=5.0, 3.7 Hz, 1H), 6.90-6.88 (m, 2H), 3.97-3.86 (m, 3H), 3.75-3.67 (m, 2H), 3.50-3.45 (m, 1H), 3.33-3.26 (m, 1H), 2.79-2.68 (m, 2H), 1.73 (s, 3H). m/z (ESI, +ve ion) 451.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=>50 μM; GK-GKRP EC 50 (LC MS/MS)=>50 μM.

Fourth Eluting Peak (Peak #4)

›Example 45

1,1,1-trifluoro-2-(4-(2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Step 1: (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate

A 25-mL round bottomed flask was charged with 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (400 mg, 0.888 mmol, Example 44), triethylamine (136 μL, 0.977 mmol) and CH 2 Cl 2 (5 mL). After cooling to 0° C., methanesulfonyl chloride (69.2 μL, 0.888 mmol) was slowly added via syringe. The reaction was then warmed to room temperature and stirred for 3 h. After this time, the mixture was concentrated and the crude material was purified by column chromatography (12 g silica gel, 5%-80% (10% MeOH—CH 2 Cl 2 ) in CH 2 Cl 2 ) to give (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (403 mg) as a colorless foam.

Step 2: 1,1,1-trifluoro-2-(4-(2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 20 mL vial was charged with (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (75 mg, 0.142 mmol), (S)-3-methylmorpholine (28.7 mg, 0.284 mmol Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (39.2 mg, 0.284 mmol), and acetonitrile (4 mL). The vial was sealed and heated at 150° C. for 90 min in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden). After this time, the mixture was filtered and the filtrate was concentrated. The crude material was purified via preparatory silica gel TLC (5% MeOH in CH 2 Cl 2 ) to give 1,1,1-trifluoro-2-(4-(2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. This mixture was separated using chiral SFC (ADH column, 21×250 mm, 5 μM) using 69% supercritical CO 2 and 31% MeOH (0.2% diethylamine) with a flow rate of 65 mL/min) to give four isomers with diastereomeric and enantiomeric excesses greater than 95%.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CDCl 3 ) δ 7.66-7.64 (dd, J=5.1, 1.2 Hz, 1H), 7.59-7.57 (dd, J=3.7, 1.2 Hz, 1H), 7.45-7.42 (d, J=8.9 Hz, 2H), 7.19-7.16 (m, J=5.0, 3.7 Hz, 1H), 6.82-6.80 (d, J=8.9 Hz, 2H), 4.09-4.04 (m, 1H), 3.89-3.85 (m, 1H), 3.80-3.75 (m, 1H), 3.73-3.69 (m, 1H), 3.65-3.54 (m, 2H), 3.43-3.38 (m, 1H), 3.30-3.20 (m, 3H), 2.76-2.71 (m, 1H), 2.62-2.50 (m, 2H), 2.40-2.34 (m, 1H), 2.21-2.14 (m, 1H), 1.94-1.89 (m, 1H), 1.74 (s, 3H), 1.03-1.02 (d, J=6.1 Hz, 3H). m/z (ESI, +ve ion) 534.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.052 μM; GK-GKRP EC 50 (LC MS/MS)=0.062 μM.

Second Eluting Peak (Peak #2)

Third Eluting Peak (Peak #3)

1 H NMR (400 MHz, CDCl 3 ) δ 7.66-7.64 (dd, J=5.1, 1.2 Hz, 1H), 7.59-7.57 (dd, J=3.7, 1.2 Hz, 1H), 7.42-7.40 (d, J=8.9 Hz, 2H), 7.19-7.16 (m, J=5.0, 3.7 Hz, 1H), 6.83-6.80 (d, J=8.9 Hz, 2H), 4.11-4.07 (m, 1H), 3.91-3.88 (m, 1H), 3.82-3.77 (m, 1H), 3.68-3.64 (m, 1H), 3.61-3.49 (m, 2H), 3.37-3.27 (m, 2H), 3.19-3.15 (m, 1H), 2.83-2.78 (m, 1H), 2.68-2.59 (m, 2H), 2.56-2.40 (m, 4H), 1.74 (s, 3H), 0.91-0.89 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 534.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=15.1 μM.

Fourth Eluting Peak (Peak #4)

An alternative synthesis is set forth below.

›Step 1: (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine

A 1-L round-bottomed flask was charged with (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (50.00 g, 151 mmol, ASW MedChem, New Brunswick, N.J.), (S)-3-methylmorpholine (16.84 g, 166 mmol, Synthetech, Albany, Oreg.), 100 mL of DMF, HATU (66.2 g, 174 mmol, Oakwood, West Columbia, S.C.), and Hünig's base (33.0 mL, 189 mmol). After stirring at rt for 1.5 h, 500 mL of water was added and the resulting white precipitate was collected by filtration and dried under vacuum to give the intermediate amide. To this was added 100 mL of THF and BH 3 .THF complex (1M in THF, 303 mL, 303 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was heated at 60° C. for 1 h then cooled to 0° C. where 50 mL of MeOH was slowly added. Once bubbling has ceased, the solvent was removed in vacuo. 200 mL of EtOAc and 200 mL of 4M HCl in dioxane were added. The mixture was heated at 75° C. for 1.5 h then allowed to cool to rt. The solid that had formed was collected by filtration and dried under vacuum, to give the amine tris-hydrochloride. 500 mL of DCM and triethylamine (211 mL, 1513 mmol) were added. The mixture was cooled to 0° C. and 2-thiophenesulfonyl chloride (27.6 g, 151 mmol, Sigma-Aldrich) was added portion-wise. After 15 min, 250 mL of water was added and the layers were separated. The organics were dried (MgSO 4 ), filtered and concentrated. The resulting oil was purified by column chromatography on silica gel (0 to 10% MeOH/DCM) to give (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (10.50 g) as a white solid.

Step 2: 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 1-L pressure vessel was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (10.50 g, 30.4 mmol), 100 mL of toluene, (2R)-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (9.81 g, 36.5 mmol, Example 243, Step 1), and sodium tert-butoxide (7.30 g, 76 mmol). Nitrogen gas through the solution for 3 min then RuPhos Palladacycle (1.107 g, 1.520 mmol) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine, RuPhos (0.709 g, 1.520 mmol) were added. The vessel was sealed and heated at 60° C. for 12 h. The mixture diluted with water and extracted with EtOAc. The combined organics were dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-70% EA/Hex) to give a tan foam. To this foam was added 200 mL of IPA and stirred at rt for 1 h. The white solid that had formed was collected by filtration, dissolved in MeOH, then dried under high vac at 70° C. for 1 h to give pure 1,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (8.15 g). This material was identical to peak 2 in example 45.

›Examples18

›Example 46

1,1,1-trifluoro-2-(4-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 45, using 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (AMRI Fine Chemicals, North Syracuse, N.Y.) and (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Example 45, step 1) (using an extra equivalent of potassium carbonate) delivered 1,1,1-trifluoro-2-(4-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.91-7.89 (m, 1H), 7.68-7.66 (m, 1H), 7.47-7.45 (d, J=8.8 Hz, 2H), 7.29-7.17 (m, 1H), 6.93-6.90 (d, J=8.8 Hz, 2H), 4.26-4.20 (m, 2H), 4.11-4.04 (m, 2H), 3.81-3.76 (m, 1H), 3.50-3.45 (m, 1H), 3.26-3.20 (m, 1H), 2.75-2.55 (m, 5H), 2.42-2.39 (m, 1H), 2.28-2.19 (m, 2H), 1.93-1.74 (m, 4H), 1.70 (s, 3H). m/z (ESI, +ve ion) 546.6 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.154 μM; GK-GKRP EC 50 (LC MS/MS)=0.178 μM.

›Example 47

2-(4-(2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the procedure reported for Example 45, using 2,2-dimethylmorpholine (Chembridge, San Diego, Calif.) produced 2-(4-(2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four isomers.

(2R)-2-(4-((2R)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07-8.05 (m, 1H), 7.68-7.66 (m, 1H), 7.37-7.35 (m, 2H), 7.32-7.29 (m, 1H), 6.88-6.86 (m, 2H), 4.15-4.12 (m, 1H), 3.91-3.88 (m, 1H), 3.46-3.42 (m, 4H), 3.13-3.07 (m, 1H), 2.60-2.55 (m, 1H), 2.49-2.38 (m, 3H), 2.27-2.22 (m, 1H), 2.16-2.05 (m, 3H), 1.61 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H). m/z (ESI, +ve ion) 548.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.182 μM; GK-GKRP EC 50 (LC MS/MS)=0.295 μM.

›Example 48

1,1,1-trifluoro-2-(4-(2-((3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 45, using 3-morpholinylmethanol (Tyger Scientific, Ewing, N.J.) produced 1,1,1-trifluoro-2-(4-(2-((3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of eight isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ 8.06 (m, 1H), 7.69 (m, 1H), 7.38-7.31 (m, 3H), 6.88-6.87 (m, 2H), 4.54-4.52 (m, 1H), 4.13-3.95 (m, 2H), 3.50-3.46 (m, 3H), 3.18-3.15 (m, 2H), 2.88-2.60 (m, 3H), 2.59-2.37 (m, 4H), 2.01-1.95 (m, 1H), 1.63-1.61 (m, 2H), 1.61 (s, 3H). m/z (ESI, +ve ion) 550.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.389 μM; GK-GKRP EC 50 (LC MS/MS)=0.606 μM.

›Example 49

1,1,1-trifluoro-2-(4-(2-((2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 45, using 2-methylmorpholine (Tyger Scientific, Ewing, N.J.) produced 1,1,1-trifluoro-2-(4-(2-((2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of eight isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((2R)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((2S)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((2R)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((2S)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((2S)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((2S)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((2R)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((2R)-2-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08-8.06 (m, 1H), 7.71-7.69 (m, 1H), 7.38-7.35 (d, J=9.2 Hz, 2H), 7.31-7.29 (m, 1H), 6.89-6.86 (d, J=9.2 Hz, 2H), 4.13-4.09 (m, 2H), 3.43-3.38 (m, 1H), 3.12-3.06 (m, 1H), 2.85-3.74 (m, 2H), 2.69-2.59 (m, 2H), 2.49-2.40 (m, 3H), 2.13-2.05 (m, 2H), 1.91-1.83 (m, 1H), 1.80-1.71 (m, 1H), 1.61 (s, 3H), 1.60-1.56 (m, 1H), 1.02-0.95 (m, 3H). m/z (ESI, +ve ion) 534.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.647 μM; GK-GKRP EC 50 (LC MS/MS)=0.707 μM.

›Example 50

1,1,1-trifluoro-2-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 45, using (R,R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (Activate Scientific, Ware, UK) produced 1,1,1-trifluoro-2-(4-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.90 (dd, J=1.0, 5.1 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.47 (t, J=8.1 Hz, 2H), 7.28 (dd, J=3.8, 5.0 Hz, 1H), 6.99-6.87 (m, 2H), 4.38-4.36 (m, 1H), 4.05-3.90 (m, 2H), 3.80-3.71 (m, 2H), 3.60-3.44 (m, 3H), 3.27-3.20 (m, 1H), 3.06-3.02 (m, 2H), 2.76-2.51 (m, 3H), 2.40-2.38 (m, 1H), 1.84-1.64 (s, 5H). m/z (ESI, +ve ion) 532.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.670 μM; GK-GKRP EC 50 (LC MS/MS)=0.880 μM.

›Example 51

2-(4-(2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the procedure reported for Example 61, Step 2,4,4-difluoropiperidine hydrochloride (Sigma-Aldrich, St. Louis, Mo.) was coupled with 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde to produce 2-(4-(2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (mixture of four isomers) following purification by prep HPLC (separation method was as follows: Solvents; A=Water w/0.1% NH 4 OH B=MeCN w/0.1% NH 4 OH; 10-90% over 20 min; Column: Phenomenex Gemini-NX C 18 110 A 5 μm, 21×100 mm).

(2R)-2-(4-((2R)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08-8.06 (dd, J=5.1, 1.1 Hz, 1H), 7.70-7.68 (dd, J=3.7, 1.1 Hz, 1H), 7.38-7.34 (d, J=9.2 Hz, 2H), 7.32-7.30 (m, 1H), 6.89-6.87 (d, J=9.2 Hz, 2H), 4.15-4.11 (m, 1H), 3.46-3.38 (m, 3H), 3.15-3.08 (m, 1H), 2.69-2.63 (m, 1H), 2.59-2.52 (m, 2H), 2.46-2.38 (m, 4H), 2.30-2.25 (m, 1H), 1.79-1.73 (m, 4H), 1.61 (s, 3H). m/z (ESI, +ve ion) 554.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.05 μM; GK-GKRP EC 50 (LC MS/MS)=1.53 μM.

›Example 52

1,1,1-trifluoro-2-(4-(2-((2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 45, using 2-morpholinylmethanol (Tyger Scientific, Ewing, N.J.) produced 1,1,1-trifluoro-2-(4-(2-((2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of eight isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((2R)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((2S)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((2R)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((2S)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((2S)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((2S)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((2R)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((2R)-2-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ 7.65-7.64 (m, 1H), 7.60-7.58 (m, 1H), 7.44-7.42 (d, J=8.6 Hz, 2H), 7.18-7.16 (m, 1H), 6.83-6.78 (m, 2H), 4.05-3.90 (m, 2H), 3.83-3.78 (m, 2H), 3.65-3.46 (m, 4H), 3.43-3.37 (m, 1H), 3.28-3.20 (m, 1H), 2.82-2.56 (m, 5H), 2.47-2.26 (m, 2H), 2.09-1.97 (m, 1H), 1.74 (m, 3H). m/z (ESI, +ve ion) 549.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.62 μM; GK-GKRP EC 50 (LC MS/MS)=1.17 μM.

›Example 53

1-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol

Following the procedure reported for Example 61, Step 2,3-azetidinol hydrochloride (Tyger Scientific, Ewing, N.J.) was coupled with 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde to produce 1-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol (mixture of four isomers) following purification by prep HPLC (separation method was as follows: Solvents; A=Water w/0.1% NH 4 OH B=MeCN w/0.1% NH 4 OH; 10-90% over 20 min; Column: Phenomenex Gemini-NX C18 110 A 5 μm, 21×100 mm).

1-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol; 1-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol; 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol; 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08-8.06 (m, 1H), 7.68-7.66 (m, 1H), 7.40-7.38 (d, J=9.2 Hz, 2H), 7.31-7.29 (m, 1H), 6.86-6.84 (d, J=9.2 Hz, 2H), 4.14-4.10 (m, 1H), 3.44-3.38 (m, 4H), 3.06-2.99 (m, 1H), 2.88-2.82 (m, 1H), 2.73-2.70 (m, 1H), 2.57-2.53 (m, 2H), 2.48-2.38 (m, 3H), 2.07-2.04 (m, 1H), 1.62 (s, 3H). m/z (ESI, +ve ion) 506.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.26 μM; GK-GKRP EC 50 (LC MS/MS)=1.79 μM.

›Example 54

2-methyl-2-(((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol

Following the procedure reported for Example 45, 2-amino-2-methyl-1-propanol (Sigma-Aldrich, St. Louis, Mo.) delivered 2-methyl-2-(((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol (mixture of four isomers) after purification by column chromatography (24 g silica gel, 0.5-8% MeOH—CH 2 Cl 2 ).

2-methyl-2-((((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol; 2-methyl-2-((((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol; 2-methyl-2-((((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol; 2-methyl-2-((((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.65-7.64 (m, 1H), 7.58-7.56 (m, 1H), 7.44-7.42 (d, J=8.6 Hz, 2H), 7.18-7.15 (m, 1H), 6.86-6.83 (d, J=8.6 Hz, 2H), 3.93-3.86 (m, 2H), 3.78-3.73 (m, 1H), 3.51-3.46 (m, 1H), 3.34-3.21 (m, 3H), 2.92-2.87 (m, 1H), 2.72-2.59 (m, 3H), 1.74 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H). m/z (ESI, +ve ion) 522.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.97 μM; GK-GKRP EC 50 (LC MS/MS)=2.78 μM

›Example 55

(4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile

Following the procedure reported for Example 45, using potassium cyanide (Sigma-Aldrich, St. Louis, Mo.) and an extra equivalent of potassium carbonate produced (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile as a mixture of four isomers.

((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile; ((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile; ((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile; ((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile. 1 H NMR (400 MHz, CDCl 3 ) δ 7.68-7.66 (m, 1H), 7.62-7.60 (m, 1H), 7.48-7.46 (d, J=8.8 Hz, 2H), 7.19-7.17 (m, 1H), 6.87-6.85 (d, J=8.8 Hz, 2H), 4.11-4.04 (m, 2H), 3.89-3.78 (m, 2H), 3.48-3.41 (m, 2H), 3.27-3.20 (m, 1H), 2.77-2.72 (m, 1H), 2.69-2.61 (m, 1H), 1.74 (s, 3H). m/z (ESI, +ve ion) 460.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.03 μM; GK-GKRP EC 50 (LC MS/MS)=3.94 μM.

›Example 56

(3R)-1-((4-(2-thiophenylsulfonyl)-1-((4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol

Following the procedure reported for Example 45, using (3R)-3-pyrrolidinol hydrochloride (Sigma-Aldrich, St. Louis, Mo.) and an extra equivalent of potassium carbonate, produced (3R)-1-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol (mixture of four isomers) after purification by column chromatography (80 g silica gel, 20 to 100% EtOAc in hexanes).

(3R)-1-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol; (3R)-1-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol; (3R)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol; (3R)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyrrolidinol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07-8.05 (m, 1H), 7.69-7.67 (m, 1H), 7.38-7.36 (d, J=9.1 Hz, 2H), 7.32-7.29 (m, 1H), 6.90-6.86 (d, J=9.1 Hz, 2H), 4.71-4.67 (m, 1H), 4.17-4.12 (m, 3H), 3.46-3.41 (m, 2H), 3.17-3.04 (m, 1H), 2.99-3.92 (m, 2H), 2.63-2.59 (m, 1H), 2.48-2.38 (m, 3H), 1.95-1.89 (m, 2H), 1.61 (s, 3H), 1.55-1.50 (m, 1H). m/z (ESI, +ve ion) 520.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.50 μM.

›Example 57

1,1,1-trifluoro-2-(4-(2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 36, starting from N-(tert-butoxycarbonyl)leucine (Sigma-Aldrich, St. Louis, Mo.) and coupling with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) delivered 1,1,1-trifluoro-2-(4-(2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (mixture of four isomers) after purification via column chromatography (40 g silica gel, 0.5-8% MeOH—CH 2 Cl 2 ).

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.64-7.62 (m, 1H), 7.57-7.55 (m, 1H), 7.43-7.40 (d, J=8.8 Hz, 2H), 7.17-7.14 (m, 1H), 6.81-6.79 (d, J=8.8 Hz, 2H), 3.97-3.90 (m, 1H), 3.75-3.68 (m, 2H), 3.44-3.39 (m, 1H), 3.34-3.27 (m, 1H), 2.71-2.67 (m, 1H), 2.63-2.57 (m, 1H), 1.87-1.79 (m, 1H), 1.65-1.60 (m, 1H), 1.74 (s, 3H), 1.23-1.19 (m, 1H), 0.92-0.88 (m, 6H). m/z (ESI, +ve ion) 477.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.655 μM; GK-GKRP EC 50 (LC MS/MS)=1.02 μM.

›Example 58

2-(4-(2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the procedure reported for Example 36, starting from N-(tert-butoxycarbonyl)-3-cyclohexylalanine (Chem-Impex, Wood Dale, Ill.) and coupling with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, step 1) delivered 2-(4-(2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (mixture of four isomers) after purification via column chromatography (40 g silica gel, 0.5 to 8% MeOH—CH 2 Cl 2 ).

(2R)-2-(4-((2R)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.64-7.62 (m, 1H), 7.57-7.55 (m, 1H), 7.43-7.40 (d, J=8.6 Hz, 2H), 7.17-7.14 (m, 1H), 6.81-6.79 (d, J=8.6 Hz, 2H), 3.97-3.90 (m, 1H), 3.77-3.65 (m, 2H), 3.44-3.39 (m, 1H), 3.34-3.27 (m, 1H), 2.73-2.67 (m, 1H), 2.63-2.56 (m, 1H), 2.32-2.31 (m, 1H), 1.83-1.74 (m, 2H), 1.74 (s, 3H), 1.69-1.62 (m, 4H), 1.28-1.15 (m, 4H), 0.90-0.84 (m, 2H). m/z (ESI, +ve ion) 517.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.00 μM; GK-GKRP EC 50 (LC MS/MS)=1.32 μM.

›Example 59

1,1,1-trifluoro-2-(4-(2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 25 ml, round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(thiophen-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (25 mg, 0.055 mmol, Example 44) and DMF (5 mL) was cooled to 0° C. To this solution was added sodium hydride (7.3 mg, 60% by weight in mineral oil, 0.18 mmol). The mixture was warmed to room temperature and stirred for 20 min. After cooling to 0° C., 3-(chloromethyl)pyridine hydrochloride (9.1 mg, 0.055 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was warmed to room temperature and stirred for 2 h. Saturated aqueous NH 4 Cl (0.1 mL) was added and the mixture was then purified by silica gel preparatory TLC (2:1 (5% MeOH-EtOAc) in hexanes) to yield 1,1,1-trifluoro-2-(4-(2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CDCl 3 ) δ 8.40-8.38 (m, 1H), 7.67-7.65 (m, 1H), 7.60-7.58 (m, 1H), 7.52-7.46 (m, 3H), 7.45-7.39 (m, 1H), 7.22-7.18 (m, 2H), 6.88-6.86 (m, 2H), 4.45-4.35 (m, 2H), 4.26-4.22 (m, 1H), 3.91-3.77 (m, 3H), 3.73-3.69 (m, 1H), 3.41-3.27 (m, 2H), 2.84-2.79 (m, 1H), 2.69-2.60 (m, 1H), 1.74 (s, 3H). m/z (ESI, +ve ion) 542.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=4.93 μM; GK-GKRP EC 50 (LC MS/MS)=4.93 μM.

›Example 60

1,1,1,3,3,3-hexafluoro-2-(4-(4-(1H-imidazol-4-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 32, using from 1H-imidazole-4-sulfonyl chloride (Chembridge, San Diego, Calif.)), produced 1,1,1,3,3,3-hexafluoro-2-(4-(4-(1H-imidazol-4-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.7 Hz, 1H), 3.32-3.28 (m, 4H), 3.14-3.10 (m, 4H). m/z (ESI, +ve ion) 458.9 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.34 μM; GK-GKRP EC 50 (LC MS/MS)=2.32 μM.

›Example 61

1,1,1-trifluoro-2-(4-(2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Step 1: 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde

To a suspension of 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(thiophen-3-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol hydrochloride (50 mg, 0.103 mmol, Example 44) in CH 2 Cl 2 (2.0 mL) at room temperature was added solid sodium bicarbonate (17.25 mg, 0.205 mmol) followed by Dess-Martin periodinane (47.9 mg, 0.113 mmol, Sigma-Aldrich, St. Louis, Mo.). The reaction was stirred at this temperature for 30 min and then filtered through a pad of Celite® (diatomaceous earth) eluting with CH 2 Cl 2 . The filtrate was concentrated to yield 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde which was used without purification.

Step 2: 1,1,1-trifluoro-2-(4-(2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

To a solution of 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde (45 mg, 0.100 mmol) and morpholine (26.2 mg, 0.301 mmol, Aldrich, St. Louis, Mo.) in 1,2-dichloroethane (2.0 mL) was added sodium triacetoxyborohydride (106 mg, 0.502 mmol) and acetic acid (5.74 μL, 0.100 mmol). The reaction was stirred at room temperature for 1 h then quenched with methanol (5 mL) and concentrated. The crude material was dissolved in methanol, filtered and purified using prep HPLC (Phenomenex C18 column (150×30 mm) eluting with TFA in CH 3 CN/H 2 O (10% to 90% gradient over 25 min) at a 30 mL/min flow rate) to yield 1,1,1-trifluoro-2-(4-(2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (5 mg) as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.89-7.86 (m, 1H), 7.65-7.63 (m, 1H), 7.46-7.41 (m, 2H), 7.27-7.24 (m, 1H), 6.93-6.89 (m, 2H), 4.09-4.03 (m, 1H), 3.99-3.94 (m, 1H), 3.79-3.72 (m, 1H), 3.60-3.55 (m, 4H), 3.50-3.41 (m, 1H), 3.25-3.12 (m, 1H), 2.78-2.71 (m, 1H), 2.68-2.46 (m, 4H), 2.37-2.30 (m, 2H), 2.28-2.21 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 519.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.230 μM; GK-GKRP EC 50 (LC MS/MS)=0.355 μM.

›Example 62

2-(4-(2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the procedure reported for Example 60, the coupling of 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde with N-benzylmethylamine (Sigma-Aldrich, St. Louis, Mo.) delivered 2-(4-(2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four isomers.

(2R)-2-(4-((2R)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((benzyl(methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.88-7.86 (m, 1H), 7.66-7.64 (m, 1H), 7.44-7.40 (m, 2H), 7.31-7.21 (m, 6H), 6.86-6.82 (m, 2H), 4.08-3.97 (m, 2H), 3.72-3.66 (m, 1H), 3.53-3.45 (m, 2H), 3.43-3.37 (m, 1H), 3.19-3.11 (m, 1H), 2.95-2.87 (m, 1H), 2.70-2.65 (m, 1H), 2.62-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.17 (s, 3H), 1.67 (s, 3H). m/z (ESI, +ve ion) 553.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.01 μM; GK-GKRP EC 50 (LC MS/MS)=1.22 μM.

›Example 63

2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Step 1: tert-butyl (3S)-3-ethyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate

2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.50 g, 1.5 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), tert-butyl (3S)-3-ethyl-1-piperazinecarboxylate hydrochloride (0.40 g, 1.9 mmol, Acesys Pharmatech, North Brunswick, N.J.), sodium tert-butoxide (0.36 g, 3.7 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.11 g, 0.23 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.080 g, 0.077 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (3.1 mL) were added to a high-pressure reaction vessel. This mixture was sealed and heated at 100° C. for 29 h. After that time, the reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc (25 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, the organic material was washed sequentially with saturated aqueous sodium bicarbonate (15 mL) and brine (10 mL), dried (Na 2 SO 4 ), filtered, and concentrated to give tert-butyl (3S)-3-ethyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.71 g) as a brown solid. The material was used in the next step without purification.

›Step 2: 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride

HCl (4.0 M solution with 1,4-dioxane, 3.9 mL, 16 mmol) was added to a stirring solution of tert-butyl (3S)-3-ethyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.71 g, 1.6 mmol) and CH 2 Cl 2 (7.8 mL) at room temperature. After 18 h, the reaction mixture was concentrated to give 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride (0.55 g) as a brown solid. The material was used in the next step without purification.

Step 3: 2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

2-Thiophenesulfonyl chloride (0.28 g, 1.5 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride (0.55 g, 1.5 mmol), Hünig's base (0.81 mL, 4.6 mmol), and DMF (7.7 mL) at room temperature. After 19 h, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (Na 2 SO 4 ) and purified via column chromatography (40 g of silica, 20 to 33% EtOAc in hexanes) to give 2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.13 g) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.63 (d, J=5.1 Hz, 1H), 7.59-7.49 (m, 3H), 7.19-7.13 (m, 1H), 6.83 (d, J=8.0 Hz, 2H), 3.77 (d, J=11.0 Hz, 3H), 3.49 (d, J=12.7 Hz, 1H), 3.32 (dt, J=3.1, 11.9 Hz, 1H), 3.24 (s, 1H), 2.74-2.51 (m, 2H), 1.89 (ddd, J=7.3, 9.3, 14.0 Hz, 1H), 1.60-1.47 (m, 1H), 0.94 (t, J=7.4 Hz, 3H); m/z (ESI, +ve ion) 503.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.679 μM; GK-GKRP EC 50 (LC MS/MS)=1.37 μM.

›Example 64

2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: (2S)-2-benzylpiperazine dihydrochloride

HCl (4.0 M solution with 1,4-dioxane, 45 mL, 180 mmol) was added to a stirring solution of tert-butyl (3S)-3-benzyl-1-piperazinecarboxylate (5.0 g, 18 mmol, Waterstone Technology, Carmel, Ind.) and CH 2 Cl 2 (36 mL) at room temperature. After 16 h, the reaction mixture was concentrated to give 4.5 g (2S)-2-benzylpiperazine (4.5 g) as its dihydrochloride salt. The material was used in the next step without purification.

›Step 2: (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine

2-Thiophenesulfonyl chloride (2.6 g, 14 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of (2S)-2-benzylpiperazine hydrochloride (4.5 g, 18 mmol), Hünig's base, (16 mL, 90 mmol), and CH 2 Cl 2 (90 mL) at room temperature. After 3 h, silica gel (29 g) was added to the reaction mixture and the volatiles were removed in vacuo. The residue was subjected to column chromatography (120 g of silica, 2% MeOH in CH 2 Cl 2 ) to give (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine (5.0 g) as a pale yellow solid.

Step 3: 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.22 g, 0.68 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine (0.20 g, 0.62 mmol), sodium tert-butoxide (0.19 g, 1.9 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.058 g, 0.12 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.057 g, 0.062 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (2.5 mL) were added to a high-pressure reaction vessel under a nitrogen atmosphere. The vessel was sealed and was heated at 100° C. for 29 h. Then the mixture was allowed to cool to room temperature and then partitioned between EtOAc (15 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (25 mL) and brine (15 mL), dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated, and the solution, and the volatiles were removed in vacuo. The residue was subjected purified via column chromatography using silica gel (twice, 100% CH 2 Cl 2 , then 25% EtOAc in hexanes) to give of 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.048 g) as a colorless solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.72-7.54 (m, 4H), 7.33-7.14 (m, 6H), 6.94 (d, J=7.2 Hz, 2H), 4.04 (d, J=8.2 Hz, 1H), 3.91 (d, J=9.4 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.54 (d, J=11.2 Hz, 1H), 3.42 (t, J=10.9 Hz, 1H), 3.31 (br. s., 1H), 3.21 (t, J=11.7 Hz, 1H), 2.67-2.48 (m, 3H); m/z (ESI, +ve ion) 565.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.308 μM; GK-GKRP EC 50 (LC MS/MS)=0.772 μM.

›Example 65

2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the procedure reported for Example 63, the coupling of (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine and 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (Example 27, step 1) delivered 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers.

The mixture was subjected to chiral SFC (Chiralcel OJ-H column, 250 mm×21 mm, 5.0 μm eluting with 60% liquid CO 2 and 40% MeOH (0.2% diethylamine)) to give two products in greater than 99% diastereomeric excess.

(2S)-2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J=4.9 Hz, 1H), 7.56-7.46 (m, 3H), 7.37-7.30 (m, 2H), 7.29-7.20 (m, 3H), 7.17-7.11 (m, 1H), 6.91 (d, J=9.0 Hz, 2H), 3.99 (d, J=8.8 Hz, 1H), 3.89 (d, J=10.8 Hz, 1H), 3.72 (d, J=11.3 Hz, 1H), 3.53-3.44 (m, 1H), 3.44-3.33 (m, 1H), 3.25-3.10 (m, 1H), 2.68-2.55 (m, 2H), 2.51 (dd, J=2.7, 11.5 Hz, 1H), 2.34 (br. s., 1H), 1.77 (s, 3H). m/z (ESI, +ve ion) 511.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.367 μM; GK-GKRP EC 50 (LC MS/MS)=0.643 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J=4.9 Hz, 1H), 7.56-7.47 (m, 3H), 7.36-7.29 (m, 2H), 7.25-7.21 (m, 3H), 7.17-7.12 (m, 1H), 6.94 (br. s., 2H), 3.99 (dd, J=2.7, 10.8 Hz, 1H), 3.89 (d, J=11.2 Hz, 1H), 3.72 (d, J=11.5 Hz, 1H), 3.54-3.33 (m, 2H), 3.17 (t, J=12.0 Hz, 1H), 2.63 (d, J=12.3 Hz, 2H), 2.55 (br. s., 1H), 2.32 (s, 1H), 1.77 (s, 3H). m/z (ESI, +ve ion) 511.1 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.166 μM; GK-GKRP EC 50 (LC MS/MS)=0.240 μM.

›Example 66

3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol

›Step 1: 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone

2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (2.6 g, 13 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (5.8 mL, 34 mmol), 1-(2-thiophenylsulfonyl)piperazine hydrochloride (3.0 g, 11 mmol, Example 29, step 1), and acetonitrile (22 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 110° C. for 19 h. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (50 mL) and the layers were separated. The organic material was washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated, hexanes (100 mL) was added to the residue and the slurry was filtered to give 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone (2.5 g) as a light tan solid. The material was used in the next step without purification

›Step 2: 1-(2-thiophenylsulfonyl)-4-(4-(1-(trifluoromethyl)ethenyl)phenyl)piperazine

n-BuLi (0.59 mL, 2.5 M solution in toluene, 1.5 mmol) was added to a stirring mixture of methyltriphenylphosphonium bromide (0.53 g, 1.5 mmol) and THF (3.1 mL) at room temperature under a nitrogen atmosphere. After 30 min, a mixture of 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone (0.50 g, 1.2 mmol) and THF (3.1 mL) was added. After an additional 1 h, saturated aqueous ammonium chloride (25 mL) was added, the mixture was partitioned between EtOAc (50 mL) and saturated aqueous ammonium chloride (25 mL). The layers were separated, the organic material was washed sequentially with saturated aqueous ammonium chloride (25 mL) and brine (25 mL), and dried (Na 2 SO 4 ) purified via column chromatography (10 g of silica, 20% EtOAc in hexanes) to provide 1-(2-thiophenylsulfonyl)-4-(4-(1-(trifluoromethyl)ethenyl)phenyl)piperazine (0.23 g) as an off-white solid.

›Step 3: 3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol

Osmium tetroxide (2.4 mL, 4 wt % solution in water, 0.40 mmol) was added to a stirring solution of 1-(2-thiophenylsulfonyl)-4-(4-(1-(trifluoromethyl)ethenyl)phenyl)piperazine (0.16 g, 0.40 mmol) and pyridine (4.0 mL) at room temperature. After 40 min, water (4.0 mL) and Na 2 SO 3 (1.5 g, 12 mmol) were added sequentially, the mixture was partitioned between water (10 mL) and chloroform (25 mL). The layers were separated and the aqueous material was washed with chloroform (2×10 mL). The combined organic material was dried (Na 2 SO 4 ) and purified via column chromatography (10 g of silica, 1% MeOH in CH 2 Cl 2 ). The purified residue was partitioned between water (20 mL) and tert-butanol (20 mL). To this was added sodium sulfite (2.0 g), potassium carbonate (2.0 g), and methanesulfonamide (0.20 g) at room temperature. After 6 h, the reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate (25 mL) and the layers were separated. The organic material was washed sequentially with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), dried (MgSO 4 ), and purified via column chromatography on silica gel (10 g of silica, 1% MeOH in CH 2 Cl 2 ) to yield 3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol as a mixture of enantiomers (0.088 g).

The mixture was subjected to chiral SFC purification (Chiralpak® AS column, 250 mm×21 mm, 10 μm) eluting with 65% liquid CO 2 , 35% MeOH (0.2% diethylamine)) to give two products in greater than 99% enantiomeric excess.

2S)-3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; (2R)-3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol.

First Eluting Peak (Peak #1):

1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J=4.9 Hz, 1H), 7.58 (d, J=3.3 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.17 (t, J=4.3 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.24 (d, J=11.7 Hz, 1H), 3.87 (d, J=11.9 Hz, 1H), 3.36-3.27 (m, 4H), 3.27-3.16 (m, 4H), 1.71 (br. s., 2H). m/z (ESI, +ve ion) 437.0 (M+H) + . GK-GKRP EC 50 (LC MS/MS)=4.43 μM.

Second Eluting Peak (Peak #2):

1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J=4.5 Hz, 1H), 7.61-7.52 (m, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.17 (t, J=3.9 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 4.24 (d, J=11.7 Hz, 1H), 3.86 (d, J=11.7 Hz, 1H), 3.35-3.26 (m, 4H), 3.25-3.16 (m, 4H), 1.66 (br. s., 2H). m/z (ESI, +ve ion) 437.0 (M+H) + . GK-GKRP EC 50 (LC MS/MS)=1.26 μM.

›Example 67

2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol

›Step 1: 1-bromo-4-(1-(trifluoromethyl)ethenyl)benzene

n-BuLi (9.5 mL, 2.5 M solution with toluene, 24 mmol) was added to a stirring mixture of methyltriphenylphosphonium bromide (8.5 g, 24 mmol) and THF (100 mL) at room temperature under a nitrogen atmosphere. After 1 h, 1-(4-bromophenyl)-2,2,2-trifluoroethanone (3.0 mL, 20 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After an additional 1 h, saturated aqueous ammonium chloride (50 mL) was added. The mixture was partitioned between diethyl ether (100 mL) and saturated aqueous ammonium chloride (50 mL). The layers were separated, the organic material was washed sequentially with saturated aqueous ammonium chloride (50 mL) and brine (50 mL), dried (MgSO 4 ), and purified via column chromatography (35 g of silica, 1% EtOAc in hexanes) to provide 1-bromo-4-(1-(trifluoromethyl)ethenyl)benzene (3.5 g) as an orange oil.

›Step 2: 2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol

Osmium tetroxide (4 wt % solution with water, 4.3 mL, 0.70 mmol) was added to a stirring mixture of 1-bromo-4-(1-(trifluoromethyl)ethenyl)benzene (3.5 g, 14 mmol), 4-methylmorpholine N-oxide (1.8 g, 15 mmol), acetone (14 mL), and water (14 mL) at room temperature. After 21 h, Na 2 SO 3 (8.8 g, 70 mmol) was added, the mixture was filtered. Silica gel (20 g) was added to the filtrate, and the volatiles were removed in vacuo. The residue was purified via column chromatography (5% MeOH in CH 2 Cl 2 ) to afford 2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol (3.0 g) as an off-white solid.

Step 3: 2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol

2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol (0.35 g, 1.2 mmol), (3S)-3-methyl-1-(2-thiophenylsulfonyl)piperazine (0.20 g, 0.81 mmol), sodium tert-butoxide (0.27 g, 2.8 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.076 g, 0.16 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.081 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (3.3 mL) were added to a high-pressure reaction vessel. The vessel was sealed and heated at 100° C. for 24 h. After cooling to room temperature, was purified via flash chromatography on silica gel (twice, 2% MeOH in CH 2 Cl 2 then 33% EtOAc in hexanes) to afford 2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol (0.017 g) as a mixture of two isomers.

(2R)-3,3,3-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol; (2S)-3,3,3-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol. 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (dd, J=1.1, 5.0 Hz, 1H), 7.56 (dd, J=1.2, 3.7 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.16 (dd, J=3.9, 4.9 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 4.24 (dd, J=6.3, 11.9 Hz, 1H), 4.05-3.93 (m, 1H), 3.87 (dd, J=7.1, 11.8 Hz, 1H), 3.67 (dd, J=1.8, 11.2 Hz, 1H), 3.59 (s, 1H), 3.45 (dd, J=2.2, 10.9 Hz, 1H), 3.39-3.31 (m, 1H), 3.31-3.19 (m, 1H), 2.89 (dd, J=3.1, 11.2 Hz, 1H), 2.72 (dt, J=3.5, 10.8 Hz, 1H), 1.86 (t, J=6.1 Hz, 1H), 1.16 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 451.1 (M+H) + . GK-GKRP EC 50 (LC MS/MS)=0.670 μM.

›Examples8

›Example 68

2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol

Following the procedure reported for Example 66 the coupling of (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine and 2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol delivered 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol as a mixture of two isomers.

The mixture was resolved via chiral SFC (Chiralpak® AS-H column, 250 mm×21 mm, 5.0 μm) eluting with 73% liquid CO 2 and 27% 20 mM NH 3 in MeOH) to give to give two products in greater than 95% diastereomeric excess.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J=4.9 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.37-7.29 (m, 2H), 7.28-7.19 (m, 3H), 7.14 (t, J=4.4 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 4.27 (d, J=11.7 Hz, 1H), 4.00 (d, J=9.4 Hz, 1H), 3.90 (d, J=11.9 Hz, 2H), 3.73 (d, J=11.3 Hz, 1H), 3.62 (br. s., 1H), 3.53-3.44 (m, 1H), 3.44-3.33 (m, 1H), 3.24-3.13 (m, 1H), 2.68-2.54 (m, 2H), 2.50 (dd, J=2.7, 11.3 Hz, 1H), 1.85 (br. s., 1H). m/z (ESI, +ve ion) 527.0 (M+H) + . GK-GKRP EC 50 (LC MS/MS)=0.870 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J=4.9 Hz, 1H), 7.55-7.52 (m, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.36-7.29 (m, 2H), 7.28-7.20 (m, 3H), 7.17-7.11 (m, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.27 (d, J=11.9 Hz, 1H), 4.05-3.96 (m, 1H), 3.90 (d, J=12.5 Hz, 2H), 3.73 (d, J=11.3 Hz, 1H), 3.64 (br. s., 1H), 3.53-3.45 (m, 1H), 3.44-3.33 (m, 1H), 3.18 (dd, J=11.2, 12.7 Hz, 1H), 2.68-2.54 (m, 2H), 2.50 (dd, J=2.5, 11.3 Hz, 1H), 1.59 (br. s., 1H). m/z (ESI, +ve ion) 527.0 (M+H) + . GK-GKRP EC 50 (LC MS/MS)=0.094 μM.

›Example 69

1,1,1,3,3,3-hexafluoro-2-(6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol trifluoroacetate

Step 1: 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (1.9 g, 5.8 mmol, published PCT patent application no. WO 2006/094842) was dissolved in acetic acid (10 mL). Bromine (1.9 g, 12 mmol) was added drop wise. The reaction was allowed to stir at room temperature until a solid precipitated. The solid was filtered, dissolved in EtOAc (100 mL) and washed with 1 N NaOH (3×50 mL). The organic layer was separated and washed with water (100 mL), brine (50 mL), dried (Na 2 SO 4 ), filtered, and concentrated. The residue was dissolved in CH 2 Cl 2 (20 mL). To this was added Hünig's base (1.0 mL) and 2-thiophenesulfonyl chloride (1.1 g, 5.8 mmol, Sigma-Aldrich, St. Louis, Mo.) at room temperature. After 3 h, the mixture was purified via column chromatography (40 g of silica, 10% EtOAc in hexanes) to afford 2-(3-bromo-4-(4-(thiophenylsulfonyl)piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.5 g).

Step 2: 1,1,1,3,3,3-hexafluoro-2-(6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol trifluoroacetate

2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (90 mg, 0.163 mmol), phenylboronic acid (23.8 mg, 0.195 mmol, Sigma-Aldrich, St. Louis, Mo.), 1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium (II) (13.28 mg, 0.016 mmol, Sigma-Aldrich, St. Louis, Mo.), and cesium carbonate (159 mg, 0.488 mmol) were combined in THF (3 mL) and water (1 mL). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 10 min (100 watts, Powermax feature on, ramp time 5 min). The organic layer was separated and filtered through a PTFE (polytetrafluoroethylene) filter (0.45 micron). This crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (10% to 90% over 20 min) to provide 1,1,1,3,3,3-hexafluoro-2-(6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol trifluoroacetate (43 mg) as a tan oil. 1 H NMR (300 MHz, CD 3 OD) δ 7.89 (d, J=4.8 Hz, 1H), 7.68-7.39 (m, 5H), 7.38-7.20 (m, 4H), 7.14 (d, J=8.6 Hz, 1H), 2.93 (br. s, 8H). m/z (ESI, +ve ion) 550.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.12 μM; GK-GKRP EC 50 (LC MS/MS)=1.75 μM.

›Example 70

1,1,1,3,3,3-hexafluoro-2-(3′-methoxy-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol trifluoroacetate

Following the procedure outlined for Example 69, 3-methoxyphenylboronic acid (26.4 mg, 0.173 mmol, Aldrich, St. Louis, Mo.) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3′-methoxy-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.91 (dd, J=4.9, 1.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.49 (d, J=1.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.28 (dd, J=4.9, 3.9 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 3.81 (s, 3H), 2.95 (br. s, 8H). m/z (ESI, +ve ion) 580.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.34 μM; GK-GKRP EC 50 (LC MS/MS)=1.82 μM.

›Example 71

1,1,1,3,3,3-hexafluoro-2-(3′-fluoro-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol

Following the procedure outlined for Example 69, 3-fluorophenylboronic acid (20.23 mg, 0.145 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3′-fluoro-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol. 1 H NMR (300 MHz, CD 3 OD) δ 7.89 (d, J=4.2 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.53 (s, 1H), 7.42-7.31 (m, 1H), 7.27 (d, J=4.0 Hz, 3H), 7.17 (d, J=8.6 Hz, 1H), 7.09-6.97 (m, 1H), 2.96 (br. s, 8H). m/z (ESI, +ve ion) 568.8 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.67 μM; GK-GKRP EC 50 (LC MS/MS)=1.84 μM.

›Example 72

1,1,1,3,3,3-hexafluoro-2-(3-(3-pyridinyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure outlined for Example 69, 3-pyridineboronic acid (21.33 mg, 0.173 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-pyridinyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 8.67 (d, J=1.6 Hz, 1H), 8.47 (dd, J=4.9, 1.6 Hz, 1H), 8.02-7.94 (m, 1H), 7.89 (dd, J=5.1, 1.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.60-7.53 (m, 2H), 7.43 (dd, J=7.8, 4.9 Hz, 1H), 7.31-7.22 (m, 2H), 2.97 (s, 8H). m/z (ESI, +ve ion) 551.6 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.775 μM; GK-GKRP EC 50 (LC MS/MS)=0.783 μM.

›Example 73

1,1,1,3,3,3-hexafluoro-2-(3-(3-thiophenyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure outlined for Example 69, 3-thiopheneboronic acid (17.8 mg, 0.139 mmol, Sigma-Aldrich, St. Louis, Mo.) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol, the reaction mixture was filtered, concentrated, and the residue was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini-NX (C 18 110 A column (100×21 mm, 5 μm) eluting with 0.1% NH 4 OH in CH 3 CN/H 2 O (5% to 95% over 8 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-thiophenyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J=6.2 Hz, 1H), 7.69-7.62 (m, 2H), 7.53 (m, 3H), 7.38-7.29 (m, 2H), 7.19 (d, J=9.7 Hz, 1H), 2.99-2.94 (m, 4H), 2.93-2.87 (m, 4H). m/z (ESI, +ve ion) 557.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=3.50 μM; GK-GKRP EC 50 (LC MS/MS)=1.90 μM.

›Example 74

2′-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5′-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4-biphenylol

Following the procedure outlined for Example 69, 4-hydroxyphenylboronic acid (19.2 mg, 0.139 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol, the reaction mixture was filtered, concentrated, and the residue was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini-NX (C 18 110 A column (100×21 mm, 5 μm) eluting with 0.1% NH 4 OH in CH 3 CN/H 2 O (5% to 95% over 8 min)) to afford 2′44-(2-thiophenylsulfonyl)-1-piperazinyl)-5′-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4-biphenylol. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J=5.3 Hz, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.38 (s, 1H), 7.36-7.25 (m, 3H), 7.13 (d, J=8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 2H), 2.89 (br. s, 8H). m/z (ESI, +ve ion) 567.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=1.47 μM; GK-GKRP EC 50 (LC MS/MS)=1.37 μM.

›Example 75

1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate

A 350 mL pressure tube was charged with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (7.22 g, 26.8 mmol, Example 27, step 1), N-Boc-piperazine (5.00 g, 26.8 mmol), sodium tert-butoxide (3.87 g, 40.3 mmol), 50 mL of toluene, dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.253 g, 2.68 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (1.229 g, 1.342 mmol, Strem Chemical Inc, Newburyport, Mass.). The tube was sealed and heated at 100° C. for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL) to give a dark oil. Purification via column chromatography (120 g of silica gel, 0 to 40% EtOAc in hexanes) gave tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g) as an off-white brittle foam.

Step 2: tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate

A 500 mL round-bottomed flask was charged with tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g, 23.0 mmol) and 100 mL of EtOH. To this was added bromine (1.30 mL, 25.3 mmol). After 15 min, the reaction was concentrated and purified via column chromatography (120 g of silica, 0 to 40% EtOAc in hexanes) to give tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (6.50 g) as a tan foam.

›Step 3: 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

A 250 mL round-bottomed flask was charged with tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (3.70 g, 8.16 mmol), 25 mL of EtOAc, and 8 mL of 4M HCl in dioxane (32 mmol). After heating at reflux for 30 min, the mixture was cooled and concentrated. The resulting viscous oil was dissolved in 30 mL of CH 2 Cl 2 and triethylamine (3.98 mL, 28.6 mmol). At 0° C., 2-thiophenesulfonyl chloride (1.49 g, 8.16 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at 0° C. After 15 min, the mixture was concentrated then re-dissolved in 5 mL of CH 2 Cl 2 , filtered, and purified via column chromatography (120 g of silica, 0 to 50% EtOAc in hexanes) to give 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (2.75 g) as a white solid.

Step 4: 1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 20 mL vial was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (0.500 g, 1.00 mmol), diisopropylamine (2.14 mL, 15.0 mmol), 2 mL of DMF, tetrakis(triphenylphosphine)palladium (0) (0.116 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), copper (I) iodide (0.019 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.506 g, 3.00 mmol, published PCT patent application no. WO2010030954). The vial was sealed and heated at 100° C. for 3 h. After that time, an additional 20 mol % of both tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide were added and heating was continued for an additional 12 h. The mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 60% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g) as a mixture of two enantiomers.

(2R)-1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (dd, J=1.2, 5.1 Hz, 1H), 7.67 (dd, J=1.2, 3.7 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.29 (dd, J=3.8, 5.0 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 4.76 (d, J=5.5 Hz, 2H), 4.48 (d, J=5.5 Hz, 2H), 3.31-3.25 (m, 4H), 3.25-3.15 (m, 4H), 1.71-1.67 (m, 3H), 1.64 (s, 3H). m/z (ESI, +ve ion) 515.0 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=2.90 μM; GK-GKRP EC 50 (LC MS/MS)=2.80 μM.

›Examples4

›Example 76

1,1,1-trifluoro-2-(4-(2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate

Following the procedure listed for the Example 76, N-(tert-butoxycarbonyl)-3-(4-pyridinyl)-L-alanine (PepTech Corp., Burlington, Mass.) delivered 1,1,1-trifluoro-2-(4-(2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate as a mixture of four isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate. 1 H NMR (300 MHz, CD 3 OD) δ 8.61 (d, J=6.4 Hz, 2H), 7.80-7.93 (m, 3H), 7.62 (dd, J=3.8, 1.2 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.20-7.29 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 4.48 (s, 1H), 3.86 (s, 1H), 3.45-3.63 (m, 3H), 3.34-3.45 (m, 1H), 3.16 (dd, J=13.0, 5.7 Hz, 1H), 2.53-2.71 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 512.2 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.207 μM; GK-GKRP EC 50 (LC MS/MS)=0.522 μM.

›Example 77

8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo)

Step 1: 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (endo)

A 10 mL vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.207 g, 0.391 mmol, Intermediate B), 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (endo) (0.100 g, 0.391 mmol, J. Org. Chem. 2010, 75, 1643), potassium carbonate (0.162 g, 1.173 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 150° C. for 1 h. The mixture was diluted with EtOAc, filtered and the filtrate was concentrated and purified via column chromatography on silica gel (0 to 50% EA/Hex) to 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four endo isomers (0.130 g).

Step 2: 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octa-6-ol (endo)

A 100 mL round-bottomed flask was charged with 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.350 g, 0.537 mmol) and 5 mL of CH 2 Cl 2 . After cooling to 0° C., BCl 3 (1M in CH 2 Cl 2 , 2.15 mL, 2.15 mmol, Sigma-Aldrich, St. Louis, Mo.) was added drop-wise. This mixture was allowed to warm to room temperature then stirred for an additional 15 min. 10 mL of MeOH was added and the mixture was concentrated onto silica gel and purified via column chromatography (0-7% MeOH in CH 2 Cl 2 ) to give 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo) (0.210 g) as a mixture of four isomers. 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (d, J=4.9 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.54 (t, J=7.2 Hz, 2H), 7.28 (t, J=5.3 Hz, 1H), 7.06 (t, J=9.1 Hz, 2H), 4.43-4.62 (m, 2H), 3.39-4.24 (m, 13H), 2.66-2.98 (m, 2H), 2.55 (d, J=3.91 Hz, 1H), 1.69 (br. s., 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.028 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.031 μM.

The individual isomers were isolated using chiral SFC purification (Chrialpak® ASH column (21×250 mm, 5 μm) using 20% ethanol (w/20 mM NH 3 ) in supercritical CO 2 , total flow was 70 mL/min). This method delivered four products with both diastereomeric and enantiomeric excesses over 95%.

(1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.78 (d, J=4.9 Hz, 1H), 7.60-7.45 (m, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.16 (t, J=4.4 Hz, 1H), 6.80 (s, 2H), 4.31-4.07 (m, 3H), 3.92 (d, J=11.2 Hz, 2H), 3.81-3.61 (m, 2H), 3.52 (s, 2H), 3.37 (br. s., 1H), 3.10 (d, J=3.5 Hz, 1H), 2.89 (br. s., 1H), 2.79-2.63 (m, 2H), 2.60-2.15 (m, 4H), 1.58 (s, 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.013 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.038 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.90 (dd, J=1.2, 5.1 Hz, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.34-7.21 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.42-4.27 (m, 1H), 4.09-3.93 (m, 2H), 3.88 (d, J=10.2 Hz, 1H), 3.79 (d, J=11.3 Hz, 1H), 3.69-3.56 (m, 2H), 3.47 (d, J=12.7 Hz, 1H), 3.39-3.35 (m, 1H), 3.22 (dt, J=3.5, 12.1 Hz, 1H), 3.01 (s, 1H), 2.89-2.74 (m, 2H), 2.70-2.48 (m, 4H), 2.47-2.30 (m, 1H), 1.69 (s, 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.011 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.019 μM.

Third Eluting Peak (Peak #3)

1 H NMR (400 MHz, CD 3 OD) δ=7.81-7.73 (m, 1H), 7.58-7.50 (m, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.19-7.12 (m, 1H), 6.80 (d, J=8.8 Hz, 2H), 4.35-4.20 (m, 1H), 3.99 (d, J=11.2 Hz, 1H), 3.84-3.58 (m, 4H), 3.45 (d, J=10.6 Hz, 1H), 3.42-3.28 (m, 2H), 3.07 (dt, J=3.1, 12.0 Hz, 1H), 2.83 (d, J=6.8 Hz, 1H), 2.73 (d, J=6.1 Hz, 1H), 2.62 (dd, J=9.9, 12.6 Hz, 1H), 2.57-2.31 (m, 4H), 2.12 (m, 1H), 1.57 (s, 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.029 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.058 μM.

Fourth Eluting Peak (Peak #4)

1 H NMR (400 MHz, CD 3 OD) δ=7.78 (d, J=4.9 Hz, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.21-7.08 (m, 1H), 6.82 (d, J=8.6 Hz, 2H), 4.33 (br. s., 1H), 4.01-3.58 (m, 5H), 3.56-3.43 (m, 1H), 3.42-3.30 (m, 2H), 3.16-2.38 (m, 7H), 2.25-2.03 (m, 1H), 1.65-1.44 (m, 4H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.042 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.065 μM.

›Example 78

8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[321]octan-6-ol (exo)

Following the scheme reported for Example 77, 3-oxa-8-azabicyclo[3.2.1]octan-6-ol hydrochloride (exo) ( J. Org. Chem. 2010, 75, 1643) delivered 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (exo, mixture of four isomers) after purification via column chromatography on silica gel (0 to 7% MeOH in CH 2 Cl 2 ). 1 H NMR (400 MHz, CD 3 OD) δ=7.89 (d, J=5.1 Hz, 1H), 7.67 (br. s., 1H), 7.44 (dd, J=8.8, 12.5 Hz, 2H), 7.28 (t, J=4.0 Hz, 1H), 6.92 (dd, J=6.8, 8.8 Hz, 2H), 4.64-4.37 (m, 1H), 4.28-3.72 (m, 3H), 3.62-2.83 (m, 10H), 2.70-2.50 (m, 3H), 2.24-2.03 (m, 1H), 1.76-1.64 (m, 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.042 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.050 μM.

The individual isomers were isolated using two sequential chiral SFC purifications. The first used a Chiralpak® column (21×250 mm, 5 μm) with 30% methanol (w/20 mM NH 3 ) at a flow rate of 70 mL/min. The second SFC purification used a Chiralcel OJH column (21×250 mm, 5 μm) with 25% MeOH (w/20 mM NH 3 ) and a flow rate of 70 mL/min. This sequence produced the four isomers with both diastereomeric and enantiomeric excesses over 95%.

(1S,5S,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1S,5S,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.89 (d, J=5.1 Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.32-7.19 (m, 1H), 6.98-6.87 (m, 2H), 4.48 (dd, J=2.6, 7.1 Hz, 1H), 4.23 (d, J=11.2 Hz, 1H), 3.99-3.90 (m, J=8.4 Hz, 1H), 3.80 (d, J=10.4 Hz, 1H), 3.61-3.35 (m, 5H), 3.28-3.12 (m, 2H), 3.02 (dd, J=10.2, 13.1 Hz, 1H), 2.93 (s, 1H), 2.68-2.52 (m, 3H), 2.20-2.08 (m, 1H), 1.74-1.64 (m, 4H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.044 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.146 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.89 (d, J=4.9 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.28 (t, J=4.4 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 4.48 (dd, J=2.5, 7.0 Hz, 1H), 4.23 (d, J=11.2 Hz, 1H), 3.94 (br. d, J=8.2 Hz, 1H), 3.80 (br. d, J=11.3 Hz, 1H), 3.60-3.35 (m, 5H), 3.27-3.14 (m, 2H), 3.02 (dd, J=10.2, 13.1 Hz, 1H), 2.93 (br. s, 1H), 2.69-2.52 (m, 3H), 2.13 (dd, J=7.2, 13.3 Hz, 1H), 1.74-1.69 (m, 4H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.049 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.060 μM.

Third Eluting Peak (Peak #3)

1 H NMR (400 MHz, CD 3 OD) δ=7.89 (d, J=4.9 Hz, 1H), 7.66 (d, J=3.7 Hz, 1H), 7.44 (s, 2H), 7.34-7.17 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.59-4.42 (m, 1H), 4.12 (d, J=11.0 Hz, 1H), 4.05 (br. s., 1H), 3.77 (d, J=9.8 Hz, 1H), 3.58-3.36 (m, 4H), 3.30-3.21 (m, 3H), 3.05-2.97 (m, 1H), 2.95 (s, 1H), 2.91-2.81 (m, 1H), 2.68-2.49 (m, 2H), 2.20 (dd, J=7.4, 13.3 Hz, 1H), 1.91-1.81 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.033 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.036 μM

Fourth Eluting Peak (Peak #4)

1 H NMR (400 MHz, CD 3 OD) δ=7.77 (d, J=4.9 Hz, 1H), 7.54 (d, J=2.7 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.22-7.04 (m, 1H), 6.81 (d, J=8.8 Hz, 2H), 4.39 (dd, J=2.9, 7.2 Hz, 1H), 4.10-3.87 (m, 2H), 3.73-3.57 (m, 1H), 3.50-2.72 (m, 10H), 2.58-2.37 (m, 2H), 2.12 (s, 1H), 1.78 (br. s., 1H), 1.61-1.51 (m, 3H). m/z (ESI, +ve ion) 562.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.04 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.046 μM.

›Example 79

8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol

›Step 1: 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane

A 250-mL round-bottomed flask was charged with tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (4.40 g, 13.78 mmol J. Org. Chem. 2010, 75, 1643) and 15 mL of CH 2 Cl 2 . To this was added TFA (10.61 mL, 138 mmol). After 2 h at room temperature, the mixture was concentrated and diluted with saturated aqueous NaHCO 3 and CH 2 Cl 2 . The layers were separated, the organics were dried (MgSO 4 ), filtered, and concentrated to give a white solid. This solid was slurried with 50 mL of diethyl ether. The resulting white solid was collected by filtration to give 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane (3.02 g)

Step 2: 6-(benzyloxy)-8-((2R)-2-piperazinylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane tris-hydrochloride

A 100-mL round-bottomed flask was charged with (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (0.83 g, 2.5 mmol, ASW MedChem, New Brunswick, N.J.), 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane (0.50 g, 2.3 mmol,) HATU (1.04 g, 2.7 mmol), 5 mL of DMF and Hünig's base (0.60 mL, 3.4 mmol). After stirring at room temperature for 1 h, the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water, dried with MgSO 4 , filtered, and concentrated to give (2R)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)carbonyl)-1,4-piperazinedicarboxylate (1.35 g) as a yellow oil. To this was added 20 mL of THF and BH 3 .THF (1M solution in THF, 12.70 mL, 12.70 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was heated at 50° C. for 2 h, then allowed to cool to room temperature and carefully quenched with 10 mL of MeOH. The solvent was removed and replaced with 30 mL of EtOAc. To this was added 10 mL of 4N HCl in dioxane. The mixture was heated at 70° C. for 2 h. The white precipitate which formed was collected by filtration and washed with 100 mL of EtOAc to give 6-(benzyloxy)-8-((2R)-2-piperazinylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane as its tris hydrochloride salt (0.89 g).

Step 3: 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol

A 100-mL round-bottomed flask was charged with (6-(benzyloxy)-8-((2R)-2-piperazinylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane tris hydrochloride (0.40 g, 0.94 mmol), 15 mL of CH 2 Cl 2 , and triethylamine (0.65 mL, 4.7 mmol). To this was added 2-thiophenesulfonyl chloride (0.19 g, 1.03 mmol, Sigma-Aldrich, St. Louis, Mo.). After stirring at room temperature for 15 min, the mixture was diluted with water and extracted with 50 mL of CH 2 Cl 2 . The combined extracts were dried (MgSO 4 ), filtered, and concentrated to give a viscous oil. Purification via column chromatography on silica gel (0 to 8% MeOH in CH 2 Cl 2 ) gave the intermediate amine. To this amine was (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.26 g, 0.94 mmol, Intermediate D), 5 ml, of dioxane, and Hünig's base (0.16 mL, 0.94 mmol). The mixture was heated at 85° C. for 12 h then concentrated and purified via column chromatography on silica gel (0-60% EtOAc in hexane) to give a white solid. This solid was dissolved in 5 mL of CH 2 Cl 2 and cooled to 0° C. To this was added BCl 3 (1M in CH 2 Cl 2 , 0.94 mL, 0.94 mmol, Sigma-Aldrich, St. Louis, Mo.). After stirring at 0° C. for 1.5 h, the mixture was quenched with MeOH (5 mL) and concentrated. Purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 ) gave 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (0.18 g) as a white solid (mixture of two isomers). 1 H NMR (400 MHz, CD 3 OD) δ=8.56 (s, 2H), 7.87 (d, J=4.9 Hz, 1H), 7.65 (d, J=2.9 Hz, 1H), 7.28-7.20 (m, 1H), 4.97-4.87 (br. s., 1H), 4.75-4.69 (m, 1H), 4.52-4.35 (m, 1H), 4.10-4.00 (m, 1H), 3.95-3.86 (m, 1H), 3.85-3.47 (m, 3H), 3.28-3.10 (m, 2H), 3.03-2.81 (m, 2H), 2.80-2.64 (m, 2H), 2.57-2.34 (m, 3H), 1.67-1.64 (m, 1H). m/z (ESI, +ve ion) 618.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.039 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.058 μM.

The individual isomers were isolated using chiral SFC (Chiralpak® AS-H column (21×250 mm, 5 μm) using 30% iPrOH (w/20 mM NH 3 ) in supercritical CO 2 , total flow was 70 mL/min). This produced two isomers with diastereomeric excess over 99%.

(1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol; (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[321]octan-6-ol

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=8.55 (s, 2H), 7.87 (d, J=4.9 Hz, 1H), 7.64 (d, J=3.5 Hz, 1H), 7.35-7.17 (m, 1H), 4.94 (br. s., 1H), 4.70 (br. d, J=13.3 Hz, 1H), 4.52-4.35 (m, 1H), 4.00 (d, J=11.5 Hz, 1H), 3.92 (d, J=10.6 Hz, 1H), 3.82 (br. d, J=11.5 Hz, 1H), 3.64-3.47 (m, 2H), 3.40 (d, J=10.2 Hz, 1H), 3.23 (dt, J=3.4, 13.0 Hz, 1H), 3.10 (br. s., 1H), 2.99 (d, J=4.5 Hz, 1H), 2.89 (dd, J=8.1, 12.8 Hz, 1H), 2.80-2.64 (m, 1H), 2.57-2.39 (m, 3H), 1.64 (dd, J=3.7, 13.1 Hz, 1H). m/z (ESI, +ve ion) 618.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.049 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.050 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=8.56 (s, 2H), 7.87 (d, J=4.9 Hz, 1H), 7.65 (d, J=2.9 Hz, 1H), 7.28-7.20 (m, 1H), 4.87 (br. s., 1H), 4.72 (d, J=14.1 Hz, 1H), 4.49 (br. s., 1H), 4.10 (d, J=11.2 Hz, 1H), 3.95-3.86 (m, 1H), 3.85-3.71 (m, 2H), 3.61-3.43 (m, 2H), 3.28-3.10 (m, 2H), 3.03-2.81 (m, 2H), 2.70 (br. s., 1H), 2.57-2.34 (m, 3H), 1.66 (br. d, J=11.2 Hz, 1H). m/z (ESI, +ve ion) 618.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.032 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.073 μM.

›Examples3

›Example 80

8-(((2S)-4-(phenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol

A 100-mL round-bottomed flask was charged with (6-(benzyloxy)-8-((2R)-2-piperazinylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane tris-hydrochloride (0.350 g, 0.820 mmol, Example 79, Step 2), triethylamine (0.514 mL, 3.69 mmol), and 10 mL of CH 2 Cl 2 . To this was added benzenesulfonyl chloride (0.106 mL, 0.820 mmol, Sigma-Aldrich, St. Louis, Mo.). After 10 min, the mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organics were dried (MgSO 4 ), filtered, concentrated and purified by column chromatography on silica gel (0-6% MeOH/CH 2 Cl 2 ) to give the intermediate amine. To this was added (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.35 g, 1.23 mmol), 3 mL of dioxane, and Hünig's base (0.143 mL, 0.820 mmol). This mixture was heated at 85° C. for 12 h then concentrated and purified via column chromatography on silica gel (0 to 60% EtOAc in hexanes) to give the intermediate benzyl protected alcohol (0.215 g). To this oil was dissolved in 10 mL of CH 2 Cl 2 . After cooling to 0° C., BCl 3 (1M in CH 2 Cl 2 , 1.25 mL, 1.25 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The mixture was stirred at 0° C. for 30 min then 5 mL of MeOH was added. The reaction was concentrated and the resulting solid was slurried with ether. The solid was collected by filtration to give 8-(((2S)-4-(phenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (0.135 g) as a mixture of two isomers.

(1R,5R,6R)-8-(((2S)-4-(phenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol and (1S,5S,6S)-8-(((2S)-4-(phenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol. 1 H NMR (400 MHz, CD 3 OD) δ=8.66 (s, 2H), 7.90-7.50 (m, 5H), 5.39 (br. s., 1H), 4.92 (s, 2H), 4.57-3.65 (m, 9H), 3.59-3.39 (m, 2H), 3.00-2.71 (m, 1H), 2.67-2.54 (m, 1H), 2.47-2.36 (m, 1H), 2.09-2.01 (m, 1H). m/z (ESI, +ve ion) 612.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.125 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.136 μM.

›Example 81

8-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol

A 100-mL round-bottomed was charged with 6-(benzyloxy)-8-((2R)-2-piperazinylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane tris-hydrochloride (0.400 g, 0.937 mmol, Example 79, Step 2), 10 mL of CH 2 Cl 2 , and thiazole-2-sulfonyl chloride (0.210 g, 1.031 mmol, Bioorg. Med. Chem., 2006, 14, 6628). The mixture was diluted with water and extracted with EtOAc. The combined organics were dried (MgSO 4 ), filtered, and concentrated to give an oil. Purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 , delivered the intermediate amine. To this was added 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.066 g, 0.23 mmol, Intermediate D), 2 mL of dioxane, and Hünig's base (0.049 mL, 0.281 mmol). The mixture was heated at 85° C. for 12 h then cooled to room temperature and purified by column chromatography on silica gel (0 to 50% EtOAc in hexanes) to give the intermediate benzyl protected alcohol. To this was added 4 mL of CH 2 Cl 2 and BCl 3 (1M in CH 2 Cl 2 , 0.937 mL, 0.937 mmol, Sigma-Aldrich, St. Louis, Mo.). After 30 min at room temperature, 5 mL of MeOH was added and the mixture was concentrated and purified by column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 ) to give 8-(((S)-1-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrimidin-2-yl)-4-(thiazol-2-ylsulfonyl)piperazin-2-yl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (0.015 g) as a mixture of two isomers.

(1R,5R,6R)-8-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol and (1S,5S,6S)-8-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol.

1 H NMR (400 MHz, CD 3 OD) δ=8.45 (s, 2H), 7.96-7.94 (m, 1H), 7.88 (s, 1H), 4.84 (br. s., 1H), 4.61 (br. d, J=12.7 Hz, 1H), 4.44-4.28 (m, 1H), 4.18-3.96 (m, 1H), 3.89-3.58 (m, 2H), 3.53-3.25 (m, 3H), 3.17-2.68 (m, 6H), 2.63-2.49 (m, 1H), 2.42-2.22 (m, 1H), 1.58-1.50 (m 1H). m/z (ESI, +ve ion) 619.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.177 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.287 μM.

›Example 82

1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

›Step 1: (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate

A 2 L round-bottomed flask was charged with ((S)-3-methylmorpholine (10.10 g, 100 mmol, Synthetech, Albany, Oreg.), HATU (39.7 g, 104 mmol), (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (30.0 g, 91 mmol, ASW MedChem, Inc, New Brunswick, N.J.), and 100 mL of DMF. To this was added Hünig's base (20.3 mL, 114 mmol). After stirring at room temperature for 1 h, the mixture was diluted with water (1 L) and then extracted with 750 mL of ether. The organic layer was separated and washed with water (4×500 mL), saturated is aqueous NaHCO 3 (250 mL), brine (250 mL), dried with MgSO 4 , filtered, and concentrated to give (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (31.83 g) as a white solid.

›Step 2: (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine

A 1 L round-bottomed flask was charged with ((2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (33.76 g, 82 mmol), and 100 mL of THF. To this was added BH 3 .THF (1M in THF, 327 mL, 327 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was heated at 50° C. for 2 h, then cooled to 0° C. and slowly quenched with 100 mL of MeOH. The mixture was concentrated in vacuo and then diluted with 200 mL of EtOAc. To this was added 100 mL of 4N HCl in dioxane. The mixture was heated at 70° C. for 2.5 h and then the resulting white precipitate was collected by filtration to give the amine tris-HCl salt. This solid was suspended in 200 mL of CH 2 Cl 2 and triethylamine (57.0 mL, 408 mmol). After cooling to 0° C., 2-thiophenesulfonyl chloride (14.9 g, 82 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The mixture was stirred at room temperature for 1 h and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO 4 ), filtered, and concentrated to give an oil. Purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 ) gave (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (20.15 g) as a white solid.

Step 3: 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

A 20 mL vial was charged with 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.104 g, 0.370 mmol, Intermediate D), (3S)-3-methyl-4-(425)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (0.155 g, 0.450 mmol), 4 mL of dioxane, and triethylamine (0.18 mL, 1.30 mmol). The vial was sealed and heated at 100° C. for 8 h. The mixture was then concentrated and purified by column chromatography on silica gel (twice, 0 to 60% EtOAc in hexanes followed by 0 to 5% MeOH in CH 2 Cl 2 ) to give 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.065 g) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD) δ=8.65-8.45 (m, 2H), 7.88 (dd, J=1.2, 5.1 Hz, 1H), 7.65 (dd, J=1.2, 3.7 Hz, 1H), 7.37-7.13 (m, 1H), 5.07-4.92 (m, 1H), 4.75 (d, J=13.3 Hz, 1H), 4.11 (d, J=11.3 Hz, 1H), 3.82 (br. s., 1H), 3.76-3.57 (m, 3H), 3.42 (d, J=12.3 Hz, 1H), 3.30-3.18 (m, 2H), 3.17-3.07 (m, 1H), 2.54-2.26 (m, 4H), 2.04 (d, J=9.8 Hz, 1H), 1.10 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 590.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.015 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.026 μM.

›Examples4

›Example 83

3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol

A 20-mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (0.750 g, 2.17 mmol, Example 82), 2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol (0.766 g, 2.69 mmol, Example 67), 6 mL of toluene and sodium tert-butoxide (1.426 mL, 11.65 mmol). After stirring at room temperature for 5 min, dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.167 g, 0.359 mmol, Strem Chemicals Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.164 g, 0.179 mmol, Strem Chemicals Inc, Newburyport, Mass.) were added. The vial was sealed and heated at 100° C. for 1 h. After that time the mixture was cooled to room temperature, diluted with 50 mL MeOH, and filtered. The filtrate was concentrated, re-dissolved in 10 mL of CH 2 Cl 2 and purified via column chromatography on silica gel (80 g, 0 to 75% EtOAc in hexanes) to give 3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol as a mixture of two isomers (0.109 g). 1 H NMR (400 MHz, CD 3 OD) δ=7.91-7.80 (m, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.7, 4.9 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 4.09-3.98 (m, 3H), 3.93-3.85 (m, 1H), 3.79-3.37 (m, 6H), 3.26-3.10 (m, 2H), 2.89-2.81 (m, 1H), 2.64-2.45 (m, 2H), 2.37-2.25 (m, 1H), 2.14-1.99 (m, 1H), 1.94-1.81 (m, 1H), 1.00 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 550.1 (M+H) + . GK-GKRP EC 50 (LC MS/MS-2)=0.019 μM.

This individual isomers were separated using chiral SFC (Chiralpak® AS-H column (21×250 mm, 5 μm) using 30% MeOH (w/20 mM NH 3 ) in supercritical CO 2 , total flow was 65 mL/min). This produced two isomers with diastereomeric excesses over 99%.

(2S)-3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propane diol; (2R)-3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.88 (dd, J=1.2, 5.1 Hz, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.27 (dd, J=3.8, 5.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 4.09-3.98 (m, 3H), 3.93-3.85 (m, 1H), 3.79-3.40 (m, 6H), 3.26-3.10 (m, 2H), 2.89-2.81 (m, 1H), 2.64-2.45 (m, 2H), 2.37-2.25 (m, 1H), 2.14-1.99 (m, 1H), 1.94-1.81 (m, 1H), 1.00 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 550.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.032 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.068 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.91-7.80 (m, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.7, 4.9 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 4.08-3.97 (m, 3H), 3.88 (d, J=11.7 Hz, 1H), 3.80-3.37 (m, 6H), 3.28-3.09 (m, 2H), 2.85 (d, J=11.7 Hz, 1H), 2.64-2.44 (m, 2H), 2.37-2.25 (m, 1H), 2.13-2.00 (m, 1H), 1.89 (br. s., 1H), 1.00 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 550.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.022 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.016 μM.

›Example 84

1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 10-mL microwave vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.140 g, 0.265 mmol, Intermediate B), 2-oxa-6-azaspiro[3.3]heptane (0.026 g, 0.265 mmol. ASW MedChem, Inc. New Brunswick, N.J.), potassium carbonate (0.040 g, 0.291 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 100° C. for 1 h. The mixture was diluted with 5 mL of CH 2 Cl 2 , filtered, and the filtrate was concentrated. The resulting oil was purified by column chromatography on silica gel (20-100% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.045 g) as a mixture of two isomers:

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol and (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=7.89 (d, J=5.1 Hz, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.33-7.21 (m, 1H), 6.97-6.85 (m, 2H), 4.69 (br. s, 4H), 3.90-3.66 (m, 3H), 3.52-3.38 (m, 3H), 3.27-3.11 (m, 1H), 2.97-2.83 (m, 1H), 2.66 (dd, J=2.8, 11.4 Hz, 1H), 2.57 (dt, J=3.8, 11.4 Hz, 1H), 2.36 (br. d, J=12.1 Hz, 1H), 1.69 (s, 3H), 1.24-1.19 (m, 1H), 1.06-0.99 (m, 1H). m/z (ESI, +ve ion) 532.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.667 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.659 μM.

›Example 85

2-(4-((2S)-2-((1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and thiomorpholine 1,1-dioxide (Synthech Development Company, Franklin Park, N.J.) followed by purification via column chromatography on silica gel (0-75% EtOAc in hexanes) delivered 2-(4-((2S)-2-((1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers. (2R)-2-(4-((2S)-2-((1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol and (2S)-2-(4-((2S)-2-((1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=7.91 (dd, J=1.3, 5.0 Hz, 1H), 7.68 (dd, J=1.4, 3.7 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.29 (dd, J=3.7, 5.1 Hz, 1H), 6.98-6.92 (m, 2H), 4.15 (br. s, 1H), 3.98 (br. d, J=11.2 Hz, 1H), 3.83 (br. d, J=11.3 Hz, 1H), 3.47 (d, J=12.5 Hz, 1H), 3.32-3.22 (m, 1H), 3.09-2.75 (m, 9H), 2.74-2.50 (m, 3H), 1.70 (s, 3H). m/z (ESI, +ve ion) 567.8 (M+H) + . GK-GKRP IC 50 (Binding)=0.350 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.475 μM.

›Example 86

1,1,1-trifluoro-2-(4-((2S)-2-((3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: 3-methylthiomorpholine 1,1-dioxide

A 250-mL round-bottomed flask was charged with 3-methylthiomorpholine (1.76 g, 15.0 mmol, J. Org. Chem. 1993, 58, 3905), 25 mL of MeOH, and Boc 2 O (4.10 g, 18.8 mmol, Sigma-Aldrich, St. Louis, Mo.). After stirring at room temperature for 1 h, the mixture was concentrated to give the intermediate Boc-protected sulfide. To this was added 25 mL of CH 2 Cl 2 . After cooling to 0° C., mCPBA (70% by weight, 9.25 g, 37.5 mmol, Sigma-Aldrich, St. Louis, Mo.) was slowly added portion wise. After 2 h at 0° C., the mixture was filtered and the filtrate was concentrated. To this oil was added 25 mL of EtOAc and 20 mL of 4 M HCl in dioxane. This mixture was heated to 70° C. for 2 h and the resulting white solid was removed by filtration. The filtrate was diluted with EtOAc and saturated aqueous K 2 CO 3 . After stirring at room temperature for 1 h, the organics were separated, dried (MgSO 4 ), filtered and concentrated to give 3-methylthiomorpholine 1,1-dioxide (1.45 g) as a yellow oil.

Step 2: 1,1,1-trifluoro-2-(4-((2S)-2-((3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

1 H NMR (400 MHz, CD 3 OD) δ=7.90 (dd, J=1.2, 5.1 Hz, 1H), 7.73-7.59 (m, 1H), 7.55-7.37 (m, 2H), 7.27 (dd, J=3.7, 4.9 Hz, 1H), 6.94 (dd, J=2.9, 9.0 Hz, 2H), 4.14-3.97 (m, 2H), 3.79 (d, J=11.0 Hz, 1H), 3.47-3.17 (m, 3H), 3.11-2.73 (m, 7H), 2.65-2.37 (m, 3H), 1.68 (s, 3H), 1.28-1.21 (m, 3H).). m/z (ESI, +ve ion) 581.9 (M+H) + . GK-GKRP IC 50 (Binding)=0.061 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.115 μM.

›Example 87

2-(4-((2S)-2-((3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

›Step 1: tert-butyl 3-cyclopropyl-4-thiomorpholinecarboxylate

A 1 L round-bottomed flask was charged with 2-aminoethanethiol (15.0 g, 194 mmol, Sigma-Aldrich, St. Louis, Mo.) and 200 mL of MeOH. After cooling to 0° C., 2-bromo-1-cyclopropylethanone (31.7 g, 194 mmol, Tetrahedron, 1987, 43, 4609) was added drop-wise over 5 min. This mixture was stirred at 0° C. for 30 min, then NaBH 4 (7.36 g, 194 mmol) was added portion-wise. After 1 h, Boc 2 O (42.4 g, 194 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After stirring at room temperature for 3 h, the mixture was concentrated and diluted with 200 mL EtOAc and 50 mL of water. The organics were separated, dried with MgSO 4 , filtered and concentrated to give an oil. Purification via column chromatography on silica gel (0-15% EtOAc in hexanes) gave tert-butyl 3-cyclopropyl-4-thiomorpholinecarboxylate (40.0 g) as an oil that slowly solidified.

›Step 2: 3-cyclopropylthiomorpholine 1,1-dioxide hydrochloride

A 500 mL round-bottomed flask was charged with tert-butyl 3-cyclopropyl-4-thiomorpholinecarboxylate (14.4 g, 59.2 mmol) and 100 mL of CH 2 Cl 2 . After cooling to 0° C., mCPBA (70% by weight, 29.2 g, 118 mmol) was added over 5 min. This mixture was stirred for 1 h and then filtered. The filtrate was concentrated then re-dissolved in 100 mL of EtOAc. To this was added 100 mL of 4M HCl in dioxane. After heating at 80° C. for 2 h, the white solid that precipitated by collected by filtration to give 3-cyclopropylthiomorpholine 1,1-dioxide hydrochloride (12.05 g)

A 100 mL round-bottomed flask was charged with 3-cyclopropylthiomorpholine 1,1-dioxide hydrochloride (1.00 g, 4.72 mmol) and 10 mL of EtOAc. To this was added 15 mL of saturated aqueous NaHCO 3 . After stirring at room temperature for 15 min, the layers were separated. The organics were dried (MgSO 4 ), filtered, and concentrated to give 3-cyclopropylthiomorpholine 1,1-dioxide (0.800 g) as a colorless oil.

Step 3: 2-(4-((2S)-2-((3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

(2R)-2-(4-((2S)-2-(((3S)-3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-(((3S)-3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-(((3R)-3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-(((3R)-3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

1 H NMR (400 MHz, CD 3 OD) δ=7.75 (dd, J=1.2, 4.9 Hz, 1H), 7.54-7.47 (m, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.13 (dd, J=3.9, 4.9 Hz, 1H), 6.80 (dd, J=6.7, 8.8 Hz, 2H), 4.08-3.89 (m, 2H), 3.84-3.53 (m, 2H), 3.37-2.32 (m, 7H), 1.97-1.81 (m, 1H), 1.60-1.45 (m, 3H), 1.26-0.60 (m, 6H), 0.56-−0.08 (m, 3H). m/z (ESI, +ve ion) 607.8 (M+H) + . GK-GKRP IC 50 (Binding)=0.229 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.246 μM.

›Example 88

2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Step 1: 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 100-mL round-bottomed was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (0.54 g, 1.65 mmol, published PCT patent application no. WO 2006/094842), 10 mL of CH 2 Cl 2 , and 5-bromo-2-thiophenesulfonyl chloride (0.43 g, 1.65 mmol, Sigma-Aldrich, St. Louis, Mo.). To this was added triethylamine (0.28 mL, 2.06 mmol). After 15 min at room temperature, the mixture was diluted with 10 mL of CH 2 Cl 2 and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0-50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.83 g) as a white solid.

Step 2: 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 20-mL vial was charged with 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.89 g, 1.61 mmol), 1,1-diphenylmethanimine (0.35 g, 1.93 mmol), sodium tert-butoxide (0.37 g, 3.87 mmol), and 6 mL of toluene. To this was added tris(dibenzylideneacetone)dipalladium (0) (0.15 g, 0.16 mmol, Strem Chemical Inc, Newburyport, Mass.) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.251 g, 0.403 mmol, Sigma-Aldrich, St. Louis, Mo.). Oxygen free nitrogen gas was bubbled through the solution for 2 min and then the vial was sealed and heated at 80° C. for 12 h. The black mixture was then diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated to give a black tar. Purification via column chromatography on silica gel (0 to 60% EtOAc in hexanes) gave the intermediate imine. To this was added 15 mL of 5M HCl and 15 mL of THF. After 15 min, 15 mL of 5 M NaOH was added and the mixture was extracted with EtOAc (50 mL). The organics were dried (MgSO 4 ), filtered, and collected to give an orange foam. Purification via column chromatography on silica gel (0-70% EtOAc in hexanes) gave an orange oil. 25 mL of ether and 50 mL of hexanes were and added and the resulting white solid was collected by filtration to give 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.32 g). 1 H NMR (400 MHz, CD 3 OD) δ=7.57 (d, J=8.8 Hz, 2H), 7.22 (d, J=4.1 Hz, 1H), 7.03 (d, J=9.2 Hz, 2H), 6.07 (d, J=4.1 Hz, 1H), 3.39-3.26 (m, 4H), 3.21-3.10 (m, 4H). m/z (ESI, +ve ion) 490.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.302 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.150 μM.

›Example 89

2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate

A 350-mL pressure vessel was charged with (tert-butyl (3S)-3-methyl-1-piperazinecarboxylate (15.0 g, 74.9 mmol, Sigma-Aldrich, St. Louis, Mo.), 5-bromo-2-chloropyrimidine (14.49 g, 74.9 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of dioxane, and triethylamine (11.48 mL, 82 mmol). The vessel was sealed and heated at 100° C. for 12 h. The mixture was concentrated and then dissolved in 200 mL of EtOAc and 150 mL of water. The organics were separated, dried (MgSO 4 ), filtered, and concentrated to give an oil. Purification via column chromatography on silica gel (0 to 40% EtOAc in hexanes) gave (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate (23.5 g) as a white solid.

Step 2: 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol di hydrochloride

A 500-mL round-bottomed flask was charged with (3S)-4-(5-bromo-2-pyrimidinyl)-3-methyl-1-piperazinecarboxylate (2.40 g, 6.72 mmol) and 50 mL of diethyl ether. After cooling to −78° C., n-BuLi (2.5 M in hexanes, 5.46 mL, 8.73 mmol) was added. The resulting suspension was stirred for 10 min at −78° C., then 1,1,1,3,3,3-hexafluoro-2-propanone (Sigma-Aldrich, St. Louis, Mo.) was bubbled through the solution for 5 min. After an additional 10 min at −78° C., 100 mL of water was added and the mixture was allowed to warm to room temperature. The organic layer was separated dried (MgSO 4 ), filtered and concentrated. Purification by column chromatography on silica gel (0 to 40% EtOAc in hexanes) gave the amine as an oil. To this was added 15 mL of EtOAc, and hydrochloric acid (4M in dioxane 7.31 mL, 29.3 mmol). After heating at 75° C. for 12 h, the suspension was cooled to room temperature and the white precipitate was collected by filtration to give 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol as its di-hydrochloride salt (1.48 g).

Step 3: 2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 250-mL round-bottomed flask was charged with (1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (1.48 g, 3.55 mmol), 25 mL of CH 2 Cl 2 , and triethylamine (1.48 mL, 10.7 mmol). After cooling to 0° C., 5-bromothiophenesulfonyl chloride (0.93 g, 3.55 mmol. Sigma-Aldrich, St. Louis, Mo.) was added and the solution was stirred for 15 min at 0° C. 100 mL of water was then added and the layers were separated. The organics were dried (MgSO 4 ), filtered, and concentrated to give a tar that was purified by column chromatography on silica gel (0-60% EtOAc in hexanes) to give 2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (2.01 g) as an off-white foam.

Step 4: 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 250-mL round-bottomed flask was charged with (2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.00 g, 1.76 mmol), 1,1-diphenylmethanimine (0.382 g, 2.11 mmol), 30 mL of toluene, sodium tert-butoxide (0.405 g, 4.22 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.273 mL, 0.439 mmol, Sigma-Aldrich, St. Louis, Mo.), and tris(dibenzylideneacetone)dipalladium (0) (0.101 g, 0.176 mmol, Strem Chemicals, Newburyport, Mass.). The round-bottomed flask was sealed and heated at 90° C. for 15 h. After that time, the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was concentrated to give a brown oil. To this was added 25 mL of THF and 15 mL of 5M HCl in dioxane. After 15 min, 17 mL of 5M NaOH was added and the mixture was extracted with EtOAc. The layers were separated, the organics were dried (MgSO 4 ), filtered, and concentrated to give an orange oil. Purification via column chromatography on silica gel (120 g of silica, 0 to 65% EtOAc in hexanes) gave 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.510 g) as a tan solid. 1 H NMR (400 MHz, CD 3 OD) δ=8.57 (s, 2H), 7.19 (d, J=4.1 Hz, 1H), 6.04 (d, J=4.1 Hz, 1H), 5.10 (br. s., 1H), 4.71 (d, J=13.7 Hz, 1H), 3.71 (d, J=11.7 Hz, 1H), 3.56 (d, J=11.5 Hz, 1H), 3.31-3.23 (m, 1H), 2.61 (dd, J=3.7, 11.5 Hz, 1H), 2.46 (dt, J=3.5, 11.8 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 506.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.252 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.161 μM.

›Example 90

2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

›Step 1: 1,1,1-trifluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride

A 350-mL pressure vessel was charged with tert-butyl 1-piperazinecarboxylate (15.00 g, 81 mmol, Sigma-Aldrich, St. Louis, Mo.), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (22.75 g, 85 mmol, Example 27, step 1), sodium tert-butoxide (15.48 g, 161 mmol), and 100 mL of toluene. Oxygen-free nitrogen gas was bubbled through the solution for 5 min then 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.50 g, 3.22 mmol) and tris(dibenzylideneacetone)dipalladium (0) (1.48 g, 1.61 mmol) were added. The vessel was sealed and heated to 90° C. for 2 h. After that time, the mixture was diluted with 150 mL of EtOAc and filtered. The filtrate was concentrated and then 300 mL of EtOAc and 100 mL of 4N HCl in dioxane were added. After 1.5 h at 70° C., the mixture was concentrated. The resulting solid was slurried with diethyl ether and collected by filtration to give 1,1,1-trifluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (22.3 g) as an off-white solid.

›Step 2: 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

A 250-mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (2.66 g, 7.65 mmol), 5-bromothiophenesulfonyl chloride (2.00 g, 7.65 mmol, Sigma-Aldrich, St. Louis, Mo.), 25 mL of CH 2 Cl 2 , and triethylamine (3.73 mL, 26.8 mmol). After stirring at room temperature for 15 min, the mixture was diluted with CH 2 Cl 2 (50 mL) and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0 to 50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (2.10 g) as an off-white solid.

›Step 3: 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

A 20-mL vial was charged with 1,1-diphenylmethanimine (0.44 g, 2.40 mmol), 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (1.00 g, 2.003 mmol), sodium tert-butoxide (0.46 mL, 4.81 mmol), and 10 mL of toluene. To this was added tris(dibenzylideneacetone)dipalladium (0) (0.18 g, 0.20 mmol, Strem Chemicals, Newburyport, Mass.) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.31 g, 0.50 mmol, Sigma-Aldrich, St. Louis, Mo.). The vial was sealed and heated at 80° C. for 12 h. The mixture was then diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated and the dissolved in 15 mL of THF. To this was added 5 M HCl (15.0 mL, 75 mmol). After stirring at room temperature for 30 min, the pH was adjusted to 12 by 5N NaOH. The mixture was extracted with EtOAc, dried with MgSO 4 , filtered, and concentrated. Purification via column chromatography on silica gel (0-70% EtOAc in hexanes) gave a white foam. To this was added 25 mL of ether and 25 mL of hexanes. The resulting suspension was stirred at room temperature for 5 min. The white solid was collected by filtration to give 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.42 g).

(2S)-2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ=7.48 (d, J=8.8 Hz, 2H), 7.23 (d, J=4.1 Hz, 1H), 7.03-6.91 (m, 2H), 6.08 (d, J=4.1 Hz, 1H), 3.32-3.27 (m, 4H), 3.21-3.15 (m, 4H), 1.70 (s, 3H). m/z (ESI, +ve ion) 436.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.448 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.836 μM.

›Example 91

2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride

A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (70.8 g, 219 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), tert-butyl piperazine-1-carboxylate (40.0 g, 215 mmol, Sigma-Aldrich, St. Louis, Mo.), 200 mL of toluene, and sodium tert-butoxide (43.3 g, 451 mmol). Nitrogen gas was bubbled through the solution for 5 min then chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (1.57 g, 2.15 mmol, Strem Chemicals Inc, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (2.00 g, 4.30 mmol, Strem Chemicals Inc, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 2 h. The mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give an oil. To this material was added 200 mL of EtOAc and 200 mL of 4N HCl in dioxane. The solution was heated at 80° C. for 12 h and the resulting suspension was then allowed to cool to room temperature. The solid precipitate was collected by filtration to give 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (76.2 g) as a white solid.

Step 2: 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 250-mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (2.50 g, 6.23 mmol), 20 mL of CH 2 Cl 2 , triethylamine (3.47 mL, 24.93 mmol), and 6-chloropyridine-3-sulfonyl chloride (1.32 g, 6.23 mmol, Organic Process Research & Development 2009, 13, 875). After stirring at room temperature for 30 min, water was added and the layers were separated. The organics were dried (MgSO 4 ), filtered, and concentrated to give an oily solid. To this material was added 10 mL of EtOH and concentrated ammonium hydroxide (9.95 mL, 255 mmol). The vessel was sealed and heated at 120° C. for 12 h. After the mixture was allows to cool to room temperature, EtOAc (100 mL) and water (50 mL) were added. The organics were separated, dried (MgSO 4 ), filtered and concentrated to give an oil. Purification via column chromatography on silica gel (0 to 70% EtOAc in hexanes) delivered 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.65 g) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD) δ=8.30 (d, J=2.3 Hz, 1H), 7.74 (dd, J=2.4, 8.9 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.64 (d, J=8.8 Hz, 1H), 3.35-3.30 (m, 4H), 3.17-3.11 (m, 4H). m/z (ESI, +ve ion) 484.9 (M+H) + . GK-GKRP IC 50 (Binding)=0.085 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.142 μM.

›Examples7

›Example 92

2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

This compound was synthesized following the procedure outlined for Example 91, Step 2. The reaction of (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)-2-propanol (Example 11) and 6-chloropyridine-3-sulfonyl chloride ( Organic Process Research & Development 2009, 13, 875) followed by amination with NH 4 OH and purification via column chromatography on silica gel (0-70% EtOAc in hexanes) delivered 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ=8.31 (d, J=2.2 Hz, 1H), 7.74 (dd, J=2.4, 8.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 6.65 (d, J=9.0 Hz, 1H), 4.22-4.12 (m, 1H), 3.72-3.63 (m, 1H), 3.54-3.42 (m, 2H), 3.21 (dt, J=3.4, 11.7 Hz, 1H), 2.75 (dd, J=3.2, 11.2 Hz, 1H), 2.58 (dt, J=3.2, 11.1 Hz, 1H), 1.15 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 498.8 (M+H) + . GK-GKRP IC 50 (Binding)=0.205 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.233 μM.

›Example 93

2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

This compound was synthesized following the procedure outlined for Example 91, Step 2. The reaction of (1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol (Example 89) and 6-chloropyridine-3-sulfonyl chloride ( Organic Process Research & Development 2009, 13, 875) followed by amination with NH 4 OH and purification via column chromatography on silica gel (0-75% EtOAc in hexanes) delivered 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ=8.56 (s, 2H), 8.29 (d, J=2.2 Hz, 1H), 7.72 (dd, J=2.4, 8.9 Hz, 1H), 6.62 (d, J=9.0 Hz, 1H), 5.09 (br. s., 1H), 4.71 (d, J=13.3 Hz, 1H), 3.81-3.71 (m, 1H), 3.61 (d, J=11.5 Hz, 1H), 3.31-3.24 (m, 1H), 2.55 (dd, J=3.7, 11.5 Hz, 1H), 2.39 (dt, J=3.5, 11.8 Hz, 1H), 1.32 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 500.9 (M+H) + . GK-GKRP IC 50 (Binding)=0.190 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.196 μM.

›Example 94

1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

A 20-mL vial was charged with (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (0.75 g, 2.6 mmol, Example 27), (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.92 g, 3.3 mmol, Intermediate D), 15 mL of dioxane, and Hünig's base (1.2 mL, 6.6 mmol). The mixture was heated at 85° C. for 12 h and then concentrated and purified via column chromatography on silica gel (0 to 50% EtOAc in hexanes) delivered 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.360 g). 1 H NMR (400 MHz, CD 3 OD) δ=8.58 (s, 2H), 7.87 (d, J=5.1 Hz, 1H), 7.66-7.63 (m, 1H), 7.28-7.23 (m, 1H), 5.14 (br. s., 1H), 4.76 (d, J=13.9 Hz, 1H), 3.83 (d, J=11.3 Hz, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.40 (s, 1H), 2.69-2.58 (m, 1H), 2.47 (dt, J=3.6, 12.0 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 491.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.362 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.470 μM.

›Example 95

2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

This compound was synthesized following the procedure outlined for Example 91, Step 2. The reaction of 1,1,1-trifluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (Example 90) and 6-chloropyridine-3-sulfonyl chloride ( Organic Process Research & Development 2009, 13, 875) followed by amination with NH 4 OH and purification via column chromatography on silica gel (0 to 75% EtOAc in hexanes) delivered 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol of two isomers.

(2S)-2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol and (2R)-2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ=8.30 (d, J=2.2 Hz, 1H), 7.74 (dd, J=2.4, 8.9 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 1H), 3.30-3.24 (m, 4H), 3.18-3.08 (m, 4H), 1.68 (s, 3H). m/z (ESI, +ve ion) 431.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.359 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.605 μM.

›Example 96

2-(4-(4-((2-amino-5-pyrimidinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 100-mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.45 g, 1.13 mmol, Example 91), 10 mL of CH 2 Cl 2 , triethylamine (0.63 mL, 4.51 mmol), and 2-chloro-5-pyrimidinesulfonyl chloride (0.24 g, 1.13 mmol, Matrix Scientific, Columbia, S.C.). After stirring for 15 min at room temperature, the mixture was concentrated then diluted with 10 mL of EtOH and 10 mL of NH 4 OH. The mixture was stirred at room temperature for an additional 1 h and then diluted with EtOAc. The organics were separated, dried (MgSO 4 ), filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 65% EtOAc in hexanes) to give 2-(4-(4-((2-amino-5-pyrimidinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.22 g). 1 H NMR (400 MHz, CD 3 OD) δ=8.58 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.03 (d, J=9.2 Hz, 2H), 3.38-3.34 (m, 4H), 3.22-3.17 (m, 4H). m/z (ESI, +ve ion) 485.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.258 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.518 μM.

›Example 97

2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Step 1: 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 250-mL round-bottomed flask was charged with 5-bromo-2-chloro-3-fluoropyridine (0.50 g, 2.38 mmol, Sigma-Aldrich, St. Louis, Mo.) and 20 mL of diethyl ether. After cooling to −78° C., n-BuLi (2.5 M in hexanes, 0.95 mL, 2.38 mmol) was added. After 5 min at −78° C., sulfur dioxide (Sigma-Aldrich, St. Louis, Mo.) was bubbled through the solution for 1 min. The mixture was allowed to warm to room temperature and then concentrated. 20 mL of CH 2 Cl 2 was then added along with 1-chloro-2,5-pyrrolidinedione (NCS) (0.381 g, 2.85 mmol, Sigma-Aldrich, St. Louis, Mo.). After 30 min at room temperature, 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.95 g, 2.38 mmol, Example 91) and triethylamine (1.33 mL, 9.50 mmol) were added. After 10 min, 50 mL of water was added and the layers were separated. The organics were dried (MgSO 4 ), filtered and concentrated. The residue was purified via column chromatography on silica gel (0 to 50% EtOAc in hexanes) to give 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.750 g) as a white foam.

Step 2: 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 100-mL pressure vessel was charged with 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.725 g, 1.389 mmol), 5 mL of EtOH, and concentrated ammonium hydroxide (10 mL, 257 mmol). The vessel was sealed and the mixture was heated to 125° C. for 18 h. After that time, the mixture was diluted with water and extracted with CH 2 Cl 2 (3×100 mL). The combined extracts were dried (MgSO 4 ), filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 70% EtOAc in hexanes) and to give 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.375 g) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ=8.18 (d, J=1.4 Hz, 1H), 7.62 (dd, J=1.9, 10.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 3.35-3.29 (m, 4H), 3.19-3.14 (m, 4H). m/z (ESI, +ve ion) 503.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.163 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.299 μM.

›Example 98

9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

›Step 1: (2R)-2-((7-oxa-3-oxa-9-azabicyclo[3.3.1]non-9-yl)carbonyl)-1,4-piperazinedicarboxylate · 1 of 2

A 100-mL round-bottomed flask was charged with (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.86 g, 8.64 mmol, ASW MedChem Inc., New Brunswick, N.J.), 3-oxa-9-azabicyclo[3.3.1]nonan-7-one (1.22 g, 8.64 mmol, published PCT patent application no. WO 2007/022502), HATU (3.61 g, 9.51 mmol, Oakwood Products, Inc., West Columbia, S.C.), Hünig's base (3.06 mL, 17.28 mmol) and DMF (20 mL). After 1 h, the mixture was diluted with water (150 mL) and EtOAc (150 mL) and the layers were separated. The organic layer was washed with water (3×100 mL), dried (Na 2 SO 4 ), filtered, and concentrated to give (2R)-2-((7-oxo-3-oxa-9-azabicyclo[3.3.1]non-9-yl)carbonyl)-1,4-piperazinedicarboxylate (3.9 g) as an oil.

Step 2: (2S)-2-((7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate (endo)

A 250-mL round-bottomed flask was charged with (2R)-2-((7-oxo-3-oxa-9-azabicyclo[3.3.1]non-9-yl)carbonyl)-1,4-piperazinedicarboxylate (3.9 g, 8.6 mmol) and THF (50 mL). BH 3 .THF (1.0 M in THF, 34.4 mL, 34.4 mmol, Sigma-Aldrich, St. Louis, Mo.) was added carefully at room temperature. After gas evolution ceased the reaction was heated at 50° C. for 2 h, the reaction was then cooled and carefully quenched with MeOH (100 mL). The reaction was concentrated onto silica gel and purified via column chromatography (120 g silica gel, 0 to 100% EtOAc in hexanes) to give (2S)-2-((7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate (endo) (1.6 g).

Step 3: (2S)-2-((7-oxo-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate and (2S)-2-((7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate (endo)

A 250-mL round-bottomed flask was charged with oxalyl chloride (5.27 mL, 10.53 mmol, Sigma-Aldrich, St. Louis, Mo.) and CH 2 Cl 2 (50 mL) and cooled to −78° C. DMSO (1.5 mL, 21.1 mmol) was added and after gas evolution ceased (5 min) (2S)-2-((7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate (endo) (1.6 g, 3.5 mmol) was added as a solution in CH 2 Cl 2 (10 mL). The reaction was stirred at this temp for 1 h. Triethylamine (4.89 mL, 35.1 mmol) was added and the reaction was warmed to room temperature for 12 h. Saturated aqueous NaHCO 3 (100 mL) and EtOAc (150 mL) were added and the layers were separated. The organic layer was washed with water (3×100 mL), dried (Na 2 SO 4 ), concentrated and purified via column chromatography (80 g silica gel, 0 to 100% EtOAc in hexanes) to give a 1:1 mixture of (2S)-2-((7-oxo-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate and (2S)-2-((7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate (endo) (0.5 g).

Step 4: 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

A 100-mL round-bottomed flask was charged with (2S)-2-((7-oxo-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate and (2S)-2-((7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-1,4-piperazinedicarboxylate (endo) (0.5 g) in EtOAc (20 mL) and 4N HCl in dioxane (0.85 mL, 3.4 mmol) was added. The reaction was heated to 70° C. for 2 h and after this time the precipitate was filtered, collected and dried. This material was dissolved in CH 2 Cl 2 (10 mL). Triethylamine (0.75 mL, 5.4 mmol) followed by 5-nitrothiophene-2-sulfonyl chloride (0.26 g, 1.13 mmol, Enamine Building Blocks, Kiev, Ukraine) as a solution in CH 2 Cl 2 (5 mL) were then added. After 10 min at room temperature, the reaction was concentrated onto silica and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.54 g).

Step 5: 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

A 20-mL vial was charged with 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.53 g, 1.9 mmol), Hünig's base (0.67 mL, 3.8 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.53 g, 1.88 mmol, Intermediate D) and dioxane (10 mL). The vial was, sealed and heated at 100° C. overnight. The crude reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.46 g) as a 1:1 mixture.

Step 6: 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

A 50-mL round-bottomed flask was charged with 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.10 g, 0.15 mmol), acetic acid (5 mL) and iron filings (0.04 g, 0.74 mmol). The reaction was stirred vigorously at 50° C. for 20 min. Saturated aqueous NaHCO 3 (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The organic extracts were washed with water (3×100 mL), dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (10% to 100% over 15 min) to give and 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (0.030 g) and 9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.030 g).

›Step 1: (2R)-2-((7-oxa-3-oxa-9-azabicyclo[3.3.1]non-9-yl)carbonyl)-1,4-piperazinedicarboxylate · 2 of 2

9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo)

1 H NMR (400 MHz, CD 3 OD) δ=8.56 (s, 2H), 7.21 (d, J=4.1 Hz, 1H), 6.03 (d, J=4.1 Hz, 1H), 4.67 (d, J=12.9 Hz, 1H), 3.93 (d, J=11.35 Hz, 1H), 3.85 (br. s., 1H), 3.56-3.81 (m, 5H), 3.30-3.36 (m, 1H), 3.25-3.06 (m, 1H), 3.02-2.89 (m, 1H), 2.82 (d, J=19.2 Hz, 3H), 2.61-2.41 (m, 2H), 2.33-2.12 (m, 2 H), 1.54 (t, J=12.8 Hz, 2H). m/z (ESI, +ve ion) 647.4 (M+H) + . GK-GKRP IC 50 (Binding)=0.002 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.019 μM.

9-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

1 H NMR (400 MHz, CD 3 OD) δ=8.42-8.69 (m, 2H), 7.22 (d, J=4.3 Hz, 1H), 6.04 (d, J=4.1 Hz, 1H), 5.06-4.95 (m, 1H), 4.71 (d, J=11.2 Hz, 1H), 3.98 (d, J=11.9 Hz, 1H), 3.81-3.72 (m, 1H), 3.69-3.68 (m, 1H), 3.70-3.54 (m, 3H), 3.52-3.43 (m, 1H), 3.26-3.18 (m, 1H), 3.17-3.01 (m, 2H), 2.97-2.81 (m, 1H), 2.77-2.46 (m, 4H), 2.22 (d, J=15.6 Hz, 2H). m/z (ESI, +ve ion) 645.3 (M+H) + . GK-GKRP IC 50 (Binding)=0.016 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.040 μM.

›Examples3

›Example 99

9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

Step 1: 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

A 25-mL round-bottomed flask was charged with a 1:1 mixture of 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (300 mg, 0.44 mmol, Example 98, Step 5), potassium hydroxide (749 mg, 13.34 mmol), MeOH (5 mL) and water (2 mL) and was stirred at room temperature for 30 min. The solvent was removed in vacuo and then diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layers were dried (Na 2 SO 4 ), filtered, and concentrated to give 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (215 mg) which were used without purification.

Step 2: 9-(425)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

A 25-mL round-bottomed flask was charged with a 1:1 mixture of 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (215 mg, 0.44 mmol), triethylamine (0.19 mL, 1.33 mmol) and CH 2 Cl 2 (5 mL). 6-chloropyridine-3-sulfonyl chloride (94 mg, 0.44 mmol, Organic Process Research & Development 2009, 13, 875) was added as a solution in CH 2 Cl 2 (2 mL) and the reaction was stirred at room temperature for 20 min. The reaction was then concentrated onto silica and purified via column chromatography (12 g silica gel, 0 to 100% EtOAc in hexanes) to give 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg).

Step 3: 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

A 30-mL sealed tube was charged with 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg, 0.076 mmol), ammonium hydroxide (266 mg, 7.59 mmol) and EtOH (5 mL) and was heated to 150° C. o/n. The reaction was diluted with water (50 mL) and EtOAc (100 mL) and the organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated. The resulting residue was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (10% to 100% over 15 min) to give 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (12 mg) and 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (10 mg).

9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo)

1 H NMR (400 MHz, CD 3 OD) δ=8.50 (s, 2H), 8.24 (s, 1H), 7.73 (d, J=11.2 Hz, 1H), 6.62 (d, J=9.0 Hz, 1H), 4.67 (d, J=14.7 Hz, 1H), 3.96 (d, J=11.7 Hz, 1H), 3.88-3.75 (m, 3H), 3.72-3.59 (m, 3H), 3.25-3.10 (m, 2H), 3.00-2.89 (m, 1H), 2.87-2.70 (m, 3H), 2.59-2.38 (m, 2H), 2.35-2.11 (m, 2H), 1.54 (m, J=12.5 Hz, 2H). m/z (ESI, +ve ion) 642.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.003 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.025 μM.

9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

1 H NMR (400 MHz, CD 3 OD) δ=8.59 (s, 2H), 8.31 (d, J=2.3 Hz, 1H), 7.74 (dd, J=8.9, 2.4 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.07-4.93 (m, 1H), 4.70 (d, J=14.1 Hz, 1H), 4.02 (d, J=11.9 Hz, 1H), 3.83 (d, J=13.1 Hz, 1H), 3.72-3.54 (m, 3H), 3.52-3.44 (m, 2H), 3.28-3.23 (m, 2H), 3.11-3.00 (m, 1H), 2.99-2.85 (m, 1H), 2.76-2.60 (m, 2H), 2.60-2.38 (m, 2H), 2.22 (d, J=15.6 Hz, 2H). m/z (ESI, +ve ion) 640.3 (M+H) + . GK-GKRP IC 50 (Binding)=0.075 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.097 μM.

›Example 100

8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo)

Step 1: 6-(benzyloxy)-8-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octane (endo)

A 50-mL round-bottomed flask was cooled to 0° C. and charged with 6-(benzyloxy)-8-((R)-piperazin-2-ylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane trihydrochloride (endo) (700 mg, 1.64 mmol, Example 79, Step 3), triethylamine (1.14 mL, 8.20 mmol) and CH 2 Cl 2 (10 mL). This was followed by thiophene-2-sulfonyl chloride (300 mg, 1.64 mmol, Sigma-Aldrich, St. Louis, Mo.) as a solution in CH 2 Cl 2 (5 mL). After 10 min, the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 6-(benzyloxy)-8-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octane (endo) (250 mg) as a mixture of two isomers.

Step 2: 2-(2-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (endo)

A 20-mL vial was charged with 6-(benzyloxy)-8-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octane (endo) (250 mg, 0.54 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1-trifluoropropan-2-ol (244 mg, 1.078 mmol, Intermediate E), Hünig's base (0.29 mL, 1.62 mmol) and dioxane (5 mL). The reaction was heated to 120° C. for 12 h. The mixture was then concentrated onto silica gel and purified via column chromatography (120 g silica gel, 0 to 100% EtOAc in hexanes) to give 2-(2-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (endo) (170 mg) as a mixture of four isomers.

Step 3: 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo)

A 25-mL round-bottomed flask was cooled to 0° C. and charged with 2-(2-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (endo) (170 mg, 0.26 mmol) and CH 2 Cl 2 (5 mL). BCl 3 (1M in CH 2 Cl 2 , 4.20 mL, 4.20 mmol) was added slowly. After 15 min at 0° C., the reaction was carefully quenched with MeOH and concentrated. The resultant foam was then recrystallized from MeOH/ether to yield an off-white solid which was purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (120 mg) (endo) as a mixture of four isomers.

This individual isomers were isolated using two separate chiral SFC methods: Chiralpak® ADH column (21×250 mm, 5 μm) using 35% ethanol (w/DEA) in supercritical CO 2 (total flow was 70 mL/min) was used to separate peaks 1 and 2 from one another and from peaks 3 and 4 and Chiralpak® ASH column (21×250 mm, 5 μm) using 35% ethanol (w/DEA) in supercritical CO 2 (total flow was 70 mL/min) was used to separate peaks 3 and 4 from one another. This produced four isomers with both diastereomeric and enantiomeric excesses over 95%.

(1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1R,5R,6R)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo); (1S,5S,6S)-8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo).

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.85 (dd, J=5.1, 1.2 Hz, 1H), 7.64 (dd, J=3.7, 1.2 Hz, 1H), 7.23 (dd, J=5.0, 3.8 Hz, 1H), 4.64 (d, J=12.9 Hz, 1H), 4.61-4.40 (m, 1H), 4.15-4.14 (m, 1H), 4.18-4.06 (m, 1H), 3.90 (d, J=11.2 Hz, 1H), 3.84-3.69 (m, 2H), 3.58 (d, J=10.6 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 3.23-3.07 (m, 2H), 2.99-2.89 (m, 1H), 2.89-2.75 (m, 1H), 2.68-2.55 (m, 1H), 2.54-2.31 (m, 3H), 1.69 (s, 3H), 1.66-1.57 (m, 1H). m/z (ESI, +ve ion) 564.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.022 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.041 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.85 (dd, J=5.1, 1.2 Hz, 1H), 7.63 (dd, J=3.8, 1.1 Hz, 1H), 7.23 (dd, J=5.0, 3.8 Hz, 1H), 4.95-4.86 (m, 1H), 4.64 (d, J=13.3 Hz, 1H), 4.49-4.36 (m, 1H), 3.99 (s, 1H), 3.92 (d, J=10.8 Hz, 1H), 3.79 (d, J=11.3 Hz, 1H), 3.53-3.67 (m, 2H), 3.45-3.37 (m, 1H), 3.25-2.97 (m, 3H), 2.96-2.82 (m, 1H), 2.79-2.60 (m, 1H), 2.59-2.35 (m, 3H), 1.69 (s, 3H), 1.67-1.62 (m, 1H). m/z (ESI, +ve ion) 564.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.051 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.057 μM.

Third Eluting Peak (Peak #3)

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.85 (dd, J=5.0, 1.3 Hz, 1H), 7.63 (dd, J=3.7, 1.2 Hz, 1H), 7.23 (dd, J=5.0, 3.8 Hz, 1H), 4.92-4.87 (m, 1H), 4.64 (d, J=13.3 Hz, 1H), 4.51-4.35 (m, 1H), 4.01 (d, J=11.9 Hz, 1 H), 3.90 (s, 1H), 3.79 (d, J=10.0 Hz, 1H), 3.60 (m, J=9.0 Hz, 2H), 3.45-3.38 (m, 1H), 3.24-2.98 (m, 3H), 2.94-2.82 (m, 1H), 2.76-2.60 (m, 1H), 2.56-2.28 (m, 3H), 1.69 (s, 3H), 1.66-1.56 (m, 1H). m/z (ESI, +ve ion) 564.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.031 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.065 μM.

Fourth Eluting Peak (Peak #4)

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.85 (dd, J=4.9, 1.2 Hz, 1H), 7.63 (dd, J=3.7, 1.2 Hz, 1H), 7.23 (dd, J=5.0, 3.8 Hz, 1H), 4.73-4.59 (m, 1H), 4.59-4.42 (m, 1H), 4.23-4.02 (m, 1H), 4.01-3.85 (m, 1H), 3.85-3.74 (m, 2H), 3.67-3.44 (m, 2H), 3.24-3.09 (m, 3H), 3.03-2.78 (m, 2H), 2.76-2.59 (m, 1H), 2.59-2.31 (m, 3H), 1.60-1.74 (m, 4H). m/z (ESI, +ve ion) 564.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.088 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.15 μM.

›Example 101

1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

›Step 1: (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine

A 50-mL round-bottomed flask was cooled to 0° C. and charged with (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine trihydrochloride (1.0 g, 3.24 mmol, Example 82, Step 2), CH 2 Cl 2 (10 mL) and triethylamine (2.3 mL, 16.2 mmol). 2-Thiophenesulfonyl chloride (0.59 g, 3.24 mmol, Sigma-Aldrich, St. Louis, Mo.) was added as a solution in CH 2 Cl 2 (5 mL) and after 10 min the MeOH (20 mL) was added and concentrated onto silica gel. The crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (0.68 g).

Step 2: 1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

A 20 mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (0.68 g, 1.97 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1-trifluoropropan-2-ol (0.45 g, 1.97 mmol, Example 100, Step 1), Hünig's base (0.69 mL, 3.94 mmol) and dioxane (10 mL) heated at 100° C. for one week. The crude reaction was then concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) and the resultant foam triturated with ether to give 1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.5 g) as a mixture of two isomers.

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.86 (dd, J=1.3, 5.0 Hz, 1H), 7.66-7.58 (m, J=2.5 Hz, 1H), 7.24 (dd, J=3.8, 5.0 Hz, 1H), 4.99-4.90 (m, 1H), 4.68 (d, J=13.7 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.83-3.55 (m, 4H), 3.45-3.36 (m, 1H), 3.28-3.04 (m, 3H), 2.52-2.16 (m, 4H), 1.97-1.96 (m, 1H), 1.69 (s, 3H), 1.08 (d, J=6.1 Hz, 3H). m/z (ESI, +ve ion) 536.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.012 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.032 μM.

The individual isomers were isolated using chiral SFC. The method used was as follows: Chiralpak® ASH column (21×250 mm, 5 μm) using 15% ethanol (w/DEA) in supercritical CO 2 (total flow was 70 mL/min). This produced the two isomers with both diastereomeric and enantiomeric excesses over 95%.

(2R)-1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(2-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.85 (d, J=4.9 Hz, 1H), 7.68-7.57 (m, 1H), 7.32-7.17 (m, 1H), 4.98-4.90 (m, 1H), 4.68 (d, J=13.7 Hz, 1H), 4.09 (d, J=11.0 Hz, 1H), 3.83-3.54 (m, 4H), 3.44-3.36 (m, 1H), 3.26-2.97 (m, 3H), 2.57-2.19 (m, 4H), 1.98 (d, J=11.5 Hz, 1H), 1.68 (s, 3H), 1.07 (d, J=6.1 Hz, 3H). m/z (ESI, +ve ion) 536.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.009 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.02 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 7.85 (dd, J=1.3, 5.0 Hz, 1H), 7.63 (dd, J=1.2, 3.7 Hz, 1H), 7.24 (dd, J=3.8, 5.0 Hz, 1H), 5.01-4.89 (m, 1H), 4.68 (d, J=13.3 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.91-3.53 (m, 4H), 3.45-3.35 (m, 1H), 3.27-3.01 (m, 3H), 2.50-2.19 (m, 4H), 2.04-1.91 (m, 1H), 1.69 (s, 3H), 1.07 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 536.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.019 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.03 μM.

›Example 102

1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

›Step 1: (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine

A 50-mL round-bottomed flask was cooled to 0° C. and charged with (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine (100 mg, 0.5 mmol, Example 82, Step 2), CH 2 Cl 2 (5 mL) and triethylamine (0.07 mL, 0.5 mmol). Thiazole-2-sulfonyl chloride (92 mg, 0.5 mmol, Bioorg. Med. Chem., 2006, 14, 6628) was added and after 10 min the reaction was concentrated and acidified with 4 N HCl in dioxane (5 mL). The HCl salt was collected after filtration and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% (2M NH 3 in MeOH) in CH 2 Cl 2 ) to give (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg).

Step 2: 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 20-mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg, 0.61 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (326 mg, 1.21 mmol, Example 27, Step 1), sodium tert-butoxide (175 mg, 1.82 mmol), Pd 2 (dba) 3 (55.5 mg, 0.061 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (42.4 mg, 0.091 mmol, Strem Chemicals, Newburyport, Mass.) and toluene (5 mL). the vial was sealed and heated to 100° C. for 3 h. The reaction was filtered, concentrated and purified via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (5% to 100% over 15 min) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) that was a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1 H NMR (400 MHz, CD 3 OD) δ=8.09 (d, J=3.1 Hz, 1H), 8.01 (d, J=3.1 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.13 (d, J=11.5 Hz, 1H), 4.07-3.97 (m, 1H), 3.93-3.80 (m, 1H), 3.70-3.51 (m, 4H), 3.50-3.40 (m, 1H), 3.28-3.15 (m, 2H), 2.97-2.80 (m, 3H), 2.41-2.26 (m, 1H), 2.16-1.98 (m, 1H), 1.92-1.82 (m, 1H), 1.67 (s, 3H), 1.00 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 535.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.134 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.137 μM.

›Example 103

2-(4-(4-((4-aminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (250 mg, 0.62 mmol, Example 91, Step 1), CH 2 Cl 2 (5 mL) and triethylamine (0.26 mL, 1.87 mmol). 4-Nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C. the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (180 mg).

›Step 2: 2-(4-(4-((4-aminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 100-mL round-bottomed flask was charged with 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (180 mg) and EtOH (20 mL). The reaction was placed under an atmosphere of argon. 10% Pd/C (37.3 mg, 0.351 mmol, Sigma-Aldrich, St. Louis, Mo.) was added and the reaction stirred under a balloon atmosphere of H 2 (0.707 mg, 0.351 mmol) for 12 h. The reaction was carefully filtered through a pad of Celite®(diatomaceous earth), rinsing with EtOH. The crude material was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(4-(4-((4-aminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (90 mg). 1 H NMR (400 MHz, CD 3 OD) δ=7.54 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 3.31-3.26 (m, 4H), 3.11-3.03 (m, 4H). m/z (ESI, +ve ion) 484.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.582 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.828 μM.

›Example 104

2-(4-(4-((4-amino-3-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Step 1: 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydro chloride (500 mg, 1.25 mmol, Example 91, Step 1), CH 2 Cl 2 (10 mL) and triethylamine (0.52 mL, 3.74 mmol). 3-Fluoro-4-nitrobenzenesulfonyl chloride (328 mg, 1.371 mmol, Matrix Scientific, Columbia, S.C.) was added and after 10 min the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (350 mg).

Step 2: 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A 100-mL round-bottomed flask was charged 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (350 mg, 0.66 mmol) and EtOH (40 mL). The reaction was placed under an atmosphere of argon. 10% Pd/C (70.1 mg, 0.66 mmol) was added and the reaction was stirred under a balloon atmosphere of H 2 for 12 h. The reaction was carefully filtered through a pad of Celite, rinsing with EtOH. The crude material was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(4-(4-((4-amino-3-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (60 mg). 1 H NMR (400 MHz, CD 3 OD) δ=7.54 (d, J=8.6 Hz, 2H), 7.40-7.31 (m, 2H), 7.01-6.95 (m, 2H), 6.94-6.86 (m, 1H), 3.31-3.26 (m, 4H), 3.14-3.00 (m, 4H). m/z (ESI, +ve ion) 502.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.999 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.642 μM.

›Example 105

3-((4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)phenol

›Step 1: 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (200 mg, 0.5 mmol, Example 91, Step 1), CH 2 Cl 2 (5 mL) and triethylamine (0.35 mL, 2.5 mmol). 3-Methoxybenzenesulfonyl chloride (113 mg, 0.55 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C., the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol (120 mg).

Step 2: 3-((4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)phenol

A 25 ml, round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol (80 mg, 0.16 mmol) and CH 2 Cl 2 (5 mL). BBr 3 (1M in CH 2 Cl 2 , 0.48 mL, 0.48 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was quenched with MeOH (20 mL), concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 3-((4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)phenol. 1 H NMR (400 MHz, CD 3 OD) δ=7.57 (d, J=9.0 Hz, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.18 (s, 1H), 7.10-7.06 (m, 1H), 7.04 (d, J=9.2 Hz, 2H), 3.37-3.33 (m, 4H), 3.21-3.07 (m, 4H). m/z (ESI, +ve ion) 485.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.949 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.74 μM.

›Examples19

›Example 106

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and 3-oxa-9-azabicyclo[3.3.1]nonan-7-one (published PCT patent application no. WO 2007/022502) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one as a mixture of two isomers.

1 H NMR (400 MHz, CD 3 OD) δ=7.92-7.86 (m, 1H), 7.69-7.64 (m, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.32-7.22 (m, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.22-3.98 (m, 2H), 3.83 (d, J=11.7 Hz, 1H), 3.66-3.58 (m, 2H), 3.57-3.44 (m, 3H), 3.30-3.25 (m, 1H), 3.21-3.11 (m, 2H), 3.04-2.92 (m, 1H), 2.92-2.79 (m, 1H), 2.72-2.51 (m, 3H), 2.43 (dd, J=6.0, 15.6 Hz, 1H), 2.24-2.07 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 574.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.035 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.097 μM.

The individual isomers were isolated using chiral SFC. The method used was as follows: Chiralpak® AD column (21×250 mm, 5 μm) using 40% iPrOH (w/DEA) in supercritical CO 2 (total flow was 70 mL/min). This produced the two isomers with both diastereomeric and enantiomeric excesses over 95%.

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one, 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one.

First Eluting Peak (Peak#1)

1 H NMR (400 MHz, CD 3 OD) δ=7.88 (d, J=1.2 Hz, 1H), 7.66 (dd, J=1.3, 3.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.27 (dd, J=3.8, 5.0 Hz, 1H), 6.95 (s, 2H), 4.22-3.99 (m, 2H), 3.89-3.74 (m, 1H), 3.62-3.57 (m, 2H), 3.56-3.43 (m, 3H), 3.30-3.24 (m, 1H), 3.21-3.07 (m, 2H), 2.98 (dd, J=8.8, 13.5 Hz, 1H), 2.87-2.76 (m, J=5.1 Hz, 1H), 2.73-2.51 (m, 3H), 2.42 (dd, J=5.9, 15.6 Hz, 1H), 2.22-2.06 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 574.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.052 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.088 μM.

Second Eluting Peak (Peak#2)

1 H NMR (400 MHz, CD 3 OD) δ=7.88 (dd, J=1.3, 5.0 Hz, 1H), 7.65 (dd, J=1.4, 3.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.8, 5.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 4.19-3.96 (m, 2H), 3.86-3.74 (m, 1H), 3.62-3.56 (m, 2H), 3.55-3.41 (m, 3H), 3.29-3.21 (m, 1H), 3.20-3.10 (m, 2H), 2.97 (dd, J=8.7, 13.4 Hz, 1H), 2.83 (dd, J=5.3, 13.5 Hz, 1H), 2.71-2.51 (m, 3H), 2.42 (dd, J=5.6, 15.6 Hz, 1H), 2.21-2.04 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 574.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.061 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.142 μM.

›Example 107

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo)

A 25-mL round-bottomed flask was charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (60 mg, 0.11 mmol, Example 106), THF (3 mL) and MeOH (0.5 mL). NaBH 4 (39.6 mg, 1.05 mmol) was added and the reaction stirred at room temperature for 20 min. MeOH (50 mL) was added and then the mixture was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo), 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo).

1 H NMR (400 MHz, CD 3 OD) δ=7.91-7.82 (m, 1H), 7.67-7.60 (m, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.28-7.20 (m, 1H), 6.90 (d, J=9.0 Hz, 2H), 4.07-3.88 (m, 2H), 3.83-3.74 (m, 3H), 3.71-3.55 (m, 3H), 3.50-3.41 (m, 1H), 3.26-3.18 (m, 1H), 2.88-2.77 (m, 1H), 2.76-2.65 (m, 3H), 2.62-2.45 (m, 2H), 2.25-2.12 (m, 1H), 2.12-1.98 (m, 1H), 1.67 (s, 3H), 1.56-1.35 (m, 2H). m/z (ESI, +ve ion) 576.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.005 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.016 μM.

›Example 108

(1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo)

A 25-mL round-bottomed flask was cooled to 0° C. and charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg, 0.087 mmol, Example 106) and THF (5 mL). Methylmagnesium bromide was added (3.0M in THF, 0.15 mL, 0.44 mmol, Sigma-Aldrich, St. Louis, Mo.) and after 20 min another 0.5 equivalent of methylmagnesium bromide was added. The reaction was then quenched with MeOH (50 mL), concentrated onto silica gel, and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc). The material was purified further via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (5% to 100% over 15 min) to give (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.

(1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo), (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo). 1 H NMR (400 MHz, CD 3 OD) δ=7.93-7.81 (m, 1H), 7.68-7.59 (m, 1H), 7.50-7.36 (m, 2H), 7.32-7.17 (m, 1H), 7.00-6.73 (m, 2H), 4.08-3.87 (m, 2H), 3.84-3.58 (m, 5H), 3.51-3.39 (m, 1H), 3.26-3.10 (m, 1H), 2.85-2.49 (m, 5H), 2.03-1.94 (m, 1H), 1.85-1.75 (m, 1H), 1.67 (s, 3H), 1.56-1.48 (m, 1H), 1.46-1.39 (m, 1H), 1.36-1.28 (m, 1H), 1.11 (s, 3H). m/z (ESI, +ve ion) 590.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.027 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.045 μM.

›Example 109

1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo)

A 25-mL round-bottomed flask was charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (50 mg, 0.087 mmol, Example 107) and THF (3 mL). Sodium hydride (60% dispersion in mineral oil, 34.7 mg, 0.869 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at room temperature. After gas evolution had ceased iodomethane (0.054 mL, 0.87 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was stirred at room temperature for 20 min, then MeOH (20 mL) was added and then the reaction concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo) (10 mg) as a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo), (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo).

1 H NMR (400 MHz, CD 3 OD) δ=8.01-7.82 (m, 1H), 7.67-7.62 (m, 1H), 7.39-7.30 (m, 2H), 7.28-7.20 (m, 1H), 7.01-6.81 (m, 2H), 4.10-3.91 (m, 2H), 3.83-3.71 (m, 3H), 3.69-3.56 (m, 3H), 3.53-3.43 (m, 1H), 3.26-3.20 (m, 1H), 3.16 (br. s., 3H), 2.91-2.48 (m, 6H), 2.27-2.13 (m, 1H), 2.13-1.93 (m, 1H), 1.72 (br. s., 3H), 1.56-1.37 (m, 2H). m/z (ESI, +ve ion) 590.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.072 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.081 μM.

›Example 110

1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and (3R)-3-morpholinylmethanol hydrochloride (Tyger Scientific Inc., Ewing, N.J.) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered 1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers.

The individual isomers were isolated using chiral SFC. The method used was as follows: Chiralpak® OJH column (21×250 mm, 5 μm) using 0.2% DEA in methanol/ethanol/isopropanol (1:1:1)) in supercritical CO 2 (total flow was 65 mL/min). This method delivered the pure isomers with both diastereomeric and enantiomeric excesses over 95%.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol;

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.87 (dd, J=1.2, 5.1 Hz, 1H), 7.64 (dd, J=1.3, 3.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.8, 5.0 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 4.11-3.99 (m, 2H), 3.76 (d, J=9.8 Hz, 1H), 3.70-3.65 (m, 1H), 3.62-3.52 (m, 5H), 3.45-3.40 (m, 1H), 3.28-3.22 (m, 1H), 2.90-2.73 (m, 2H), 2.68-2.38 (m, 5H), 1.67 (s, 3H). m/z (ESI, +ve ion) 550.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.101 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.156 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.87 (dd, J=1.3, 5.0 Hz, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.8, 5.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 4.12-4.00 (m, 2H), 3.81-3.73 (m, 1H), 3.71-3.64 (m, 1H), 3.62-3.51 (m, 5H), 3.45-3.38 (m, 1H), 3.28-3.21 (m, 1H), 2.88-2.75 (m, 2H), 2.65-2.40 (m, 5H), 1.67 (s, 3H). m/z (ESI, +ve ion) 550.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.079 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.132 μM.

›Example 111

1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and (3S)-3-morpholinylmethanol hydrochloride (Tyger Scientific Inc., Ewing, N.J.) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers.

The individual isomers were isolated using chiral SFC. The method used was as follows: Chrialpak® ICH column (150×4.6 mm, 5 um) using 40% methanol (20 nM NH3) in supercritical CO 2 (total flow was 70 mL/min). This produced two products with both diastereomeric and enantiomeric excesses over 95%.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol,

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.89 (dd, J=1.2, 4.9 Hz, 1H), 7.65 (dd, J=1.2, 3.7 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.27 (dd, J=3.9, 4.9 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 4.13-3.96 (m, 2H), 3.75 (d, J=3.5 Hz, 3H), 3.62-3.37 (m, 5H), 3.28-3.17 (m, 2H), 2.94-2.77 (m, 1H), 2.65-2.46 (m, 2H), 2.44-2.27 (m, 1H), 2.26-2.06 (m, 2H), 1.68 (s, 3H). m/z (ESI, +ve ion) 550.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.064 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.099 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.88 (dd, J=1.2, 4.9 Hz, 1H), 7.65 (dd, J=1.3, 3.8 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.26 (dd, J=3.8, 5.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.16-4.03 (m, 1H), 4.02-3.93 (m, 1H), 3.82-3.69 (m, 3H), 3.62-3.37 (m, 5H), 3.28-3.17 (m, 2H), 2.93-2.78 (m, 1H), 2.66-2.45 (m, 2H), 2.41-2.22 (m, 1H), 2.20-2.04 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 550.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.067 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.113 μM.

›Example 112

N-((4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl) methanesulfonamide

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and N-(3-morpholinylmethyl)methanesulfonamide hydrochloride (published PCT patent application no. WO 2009/016410) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered N-((4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide as a mixture of four isomers.

This mixture was partially resolved using reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (20% to 50% over 15 min). This separated the compounds into two isolated products that were still a mixture of two isomers.

N-(((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide; N-(((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide; N-(((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide; N-(((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.91-7.85 (m, 1H), 7.67-7.62 (m, 1H), 7.49-7.40 (m, 2H), 7.28-7.24 (m, 1H), 6.98-6.88 (m, 2H), 4.12-3.98 (m, 2H), 3.83-3.73 (m, 1H), 3.60-3.53 (m, 4H), 3.49-3.38 (m, 1H), 3.28-3.12 (m, 3H), 2.95-2.86 (m, 4H), 2.84-2.74 (m, 1H), 2.67-2.37 (m, 5H), 1.67 (s, 3H). m/z (ESI, +ve ion) 627.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.275 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.986 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.93-7.84 (m, 1H), 7.72-7.64 (m, 1H), 7.50-7.40 (m, 2H), 7.31-7.21 (m, 1H), 6.96-6.87 (m, 2H), 4.14-3.95 (m, 2H), 3.87-3.74 (m, 2H), 3.65-3.35 (m, 6H), 3.28-3.20 (m, 1H), 3.09-2.88 (m, 5H), 2.64-2.45 (m, 2H), 2.43-2.34 (m, 1H), 2.20-2.03 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 627.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.21 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.332 μM.

›Example 113

(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and ethyl 3-morpholinylacetate (Matrix Scientific, Columbia, S.C.) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate as a mixture of four isomers.

((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate, ((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate, ((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate, ((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate.

1 H NMR (400 MHz, CD 3 OD) δ=7.94-7.82 (m, 1H), 7.68-7.60 (m, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.30-7.21 (m, 1H), 6.91 (d, J=8.8 Hz, 2H), 4.19-4.07 (m, 3H), 4.04-3.93 (m, 1H), 3.82-3.72 (m, 1H), 3.62-3.37 (m, 5H), 3.27-3.11 (m, 1H), 3.03-2.68 (m, 3H), 2.64-2.34 (m, 5H), 2.27-2.12 (m, 1H), 1.67 (s, 3H), 1.29-1.22 (m, 3H). m/z (ESI, +ve ion) 606.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.333 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.308 μM.

›Example 114

N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide

Step 1: (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid

A 25-mL round-bottomed flask was charged with (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate (70 mg, 0.116 mmol, Example 113), is aqueous 10 M NaOH (0.5 mL, 5.00 mmol) and MeOH (5 mL) and stirred at room temperature for 2 h. The reaction was concentrated to give (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid (65 mg) as a mixture of four isomers. This material was used crude in the next reaction.

Step 2: N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide

A 25-mL round-bottomed flask was charged with (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid (65 mg, 0.113 mmol), dimethylamine (2.0 M in MeOH, 1.69 mL, 3.38 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (0.039 mL, 0.225 mmol), HATU (471 mg, 1.24 mmol) and DMF (3 mL). After stirring at room temperature for 1 h, the reaction was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide (20 mg) as a mixture of four isomers.

N,N-dimethyl-2-((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide, N,N-dimethyl-2-((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide, N,N-dimethyl-2-((3R)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide, N,N-dimethyl-2-((3S)-4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide. 1 H NMR (400 MHz, CD 3 OD) δ=7.94-7.84 (m, 1H), 7.69-7.61 (m, 1H), 7.49-7.38 (m, 2H), 7.29-7.22 (m, 1H), 7.00-6.85 (m, 2H), 4.12-3.96 (m, 2H), 3.82-3.73 (m, 1H), 3.68-3.51 (m, 3H), 3.48-3.40 (m, 2H), 3.27-3.12 (m, 1H), 3.10-3.03 (m, 4H), 2.95-2.71 (m, 5H), 2.69-2.32 (m, 5H), 2.28-2.05 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 605.3 (M+H) + . GK-GKRP IC 50 (Binding)=0.09 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.124 μM.

›Example 115

1,1,1-trifluoro-2-(4-((2S)-2-((3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and 3-(4-fluorophenyl)morpholine (ASDI, Newark, Del.) (using an extra equivalent of potassium carbonate) delivered 1,1,1-trifluoro-2-(4-((2S)-2-((3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers. This isomeric mixture was partially resolved using reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (20% to 60% over 15 min). This separated the compounds into two isolated peaks that were a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol,

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol,

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol,

(2S)-1,1,1-trifluoro-2-(4-((2S)-2-(((3R)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.90-7.83 (m, 1H), 7.65-7.60 (m, 1H), 7.38-7.29 (m, 2H), 7.28-7.23 (m, J=3.9 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=16.6 Hz, 2H), 6.28 (dd, J=2.9, 9.0 Hz, 2H), 4.03 (d, J=11.2 Hz, 1H), 3.81 (d, J=11.3 Hz, 1H), 3.72-3.57 (m, 3H), 3.53 (d, J=8.6 Hz, 1H), 3.35 (s, 2H), 3.29-3.24 (m, 1H), 3.21-3.14 (m, 1H), 3.06-2.91 (m, 1H), 2.55-2.33 (m, 5H), 1.64 (d, J=6.1 Hz, 3H). m/z (ESI, +ve ion) 614.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.589 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.308 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, MeOH) δ=7.94-7.84 (m, 1H), 7.68-7.61 (m, 1H), 7.50-7.39 (m, 4H), 7.30-7.24 (m, 1H), 7.09-7.02 (t, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.28-4.17 (m, 1H), 4.00 (d, J=10.8 Hz, 1H), 3.89 (d, J=10.4 Hz, 1H), 3.81-3.70 (m, 1H), 3.64-3.56 (m, 1H), 3.51-3.43 (m, 1H), 3.40-3.34 (m, 2H), 3.28-3.23 (m, 1H), 3.20-3.08 (m, 2H), 2.95-2.76 (m, 2H), 2.67-2.54 (m, 1H), 2.46-2.32 (m, 1H), 2.25-2.08 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 614.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.836 μM.

›Example 116

1,1,1-trifluoro-2-(4-((2R)-2-((2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 10-mL vial was charged with 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (50 mg, 0.11 mmol, Intermediate B synthesis (Step 5)), THF (3 mL) and sodium hydride (60% dispersion in mineral oil, 13.3 mg, 0.33 mmol). After gas evolution ceased, 2-furanylmethyl methanesulfonate (78 mg, 0.44 mmol, US published patent application no. 2008/0153883) was added and the vial was sealed and heated to 80° C. 12 h. MeOH (10 mL) was added and the reaction was filtered, concentrated and purified by reverse-phase HPLC (Phenomenex Gemini-NX C 18 column, 21×100 mm, 5 μm eluting with A: Water w/0.1% NH 4 OH B: Acetonitrile w/0.1% NH 4 OH) to give 1,1,1-trifluoro-2-(4-((2R)-2-(((2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-((2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2R)-2-((2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ=8.14-8.01 (m, 1H), 7.76-7.66 (m, 1H), 7.64-7.55 (m, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.33-7.25 (m, 1H), 6.86 (d, J=9.0 Hz, 2H), 6.47-6.25 (m, 2H), 4.13-4.02 (m, 1H), 3.74-3.58 (m, 3H), 3.56-3.48 (m, 1H), 3.32-3.25 (m, 2H), 3.13-2.93 (m, 1H), 2.56-2.53 (m, 2H), 2.47-2.39 (m, 1H), 1.63 (s, 3H). m/z (ESI, +ve ion) 531.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.284 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.103 μM.

›Example 117

1,1,1-trifluoro-2-(4-((2R)-2-(((3-methyl-3-oxetanyl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 116, using (3-methyl-3-oxetanyl)methyl methanesulfonate (published PCT patent application no. WO 2010/031713) delivered 1,1,1-trifluoro-2-(4-((2R)-2-(((3-methyl-3-oxetanyl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers after purification by reverse phase HPLC (Phenomenex Gemini-NX C 18 column, 21×100 mm, 5 μm eluting with A: Water w/0.1% NH 4 OH B: Acetonitrile w/0.1% NH 4 OH).

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((3-methyl-3-oxetanyl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((3-methyl-3-oxetanyl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ=8.16-7.99 (m, 1H), 7.77-7.64 (m, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.33-7.25 (m, 1H), 6.89 (d, J=9.0 Hz, 2H), 4.38-4.24 (m, 2H), 4.21-4.16 (m, 1H), 4.15-4.03 (m, 2H), 3.80-3.61 (m, 2H), 3.55-3.44 (m, 3H), 3.32-3.27 (m, 1H), 3.20-3.07 (m, 1H), 2.58-2.54 (m, 2H), 2.48-2.40 (m, 1H), 1.61 (s, 3H), 1.15 (s, 3H). m/z (ESI, +ve ion) 535.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.467 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.463 μM.

›Example 118

1,1,1-trifluoro-2-(4-((2R)-2-((tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 116, using tetrahydro-2-furanylmethyl methanesulfonate ( J. Am. Chem. Soc., 1946, 68, 2743) delivered 1,1,1-trifluoro-2-(4-((2R)-2-((tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers after purification by reverse phase HPLC (Phenomenex Gemini-NX C 18 column, 21×100 mm, 5 μm eluting with A: Water w/0.1% NH 4 OH B: Acetonitrile w/0.1% NH 4 OH)

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((2S)-tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((2R)-tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((2R)-tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((2S)-tetrahydro-2-furanylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ=8.16-7.97 (m, 1H), 7.72-7.64 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.25 (m, 1H), 6.88 (d, J=9.0 Hz, 2H), 4.16-4.05 (m, 1H), 3.87-3.78 (m, 1H), 3.76-3.47 (m, 6H), 3.30-3.25 (m, 2H), 3.16-3.04 (m, 1H), 2.57-2.54 (m, 2H), 2.48-2.39 (m, 1H), 1.87-1.67 (m, 3H), 1.60 (s, 3H), 1.55-1.40 (m, 1H). m/z (ESI, +ve ion) 535.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.57 μM; GK-GKRP EC 50 (LC MS/MS-2)=1.11 μM.

›Example 119

1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Following the procedure reported for Example 116, using 4-(chloromethyl)-1-methyl-1H-imidazole (Synthonix, Wake Forest, N.C.) and purification via column chromatography (12 g silica gel, 5 to 10% CH 2 Cl 2 in MeOH) delivered 1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers after purification by reverse phase HPLC (Phenomenex Gemini-NX C 18 column, 21×100 mm, 5 μm eluting with A: Water w/0.1% NH 4 OH B: Acetonitrile w/0.1% NH 4 OH) 1 H NMR (400 MHz, CD 3 OD) δ=7.90-7.82 (m, 1H), 7.65-7.59 (m, 1H), 7.53-7.48 (m, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.29-7.20 (m, 1H), 7.03-6.97 (m, 1H), 6.88 (d, J=9.0 Hz, 2H), 4.46-4.22 (m, 2H), 4.07-3.95 (m, 1H), 3.88-3.73 (m, 2H), 3.72-3.65 (m, 4H), 3.51-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.21-3.04 (m, 1H), 2.76-2.64 (m, 1H), 2.63-2.50 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 545.3 (M+H) + . GK-GKRP IC 50 (Binding)=0.392 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.169 μM.

The individual isomers were separated using chiral SFC. The method used was as follows: Chrialpak® ADH column (15×2 cm, 5 μm) using 20% methanol (0.1% DEA) in supercritical CO 2 (total flow was 70 mL/min). This produced both isomers with diastereomeric and enantiomeric excesses over 95%.

(2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((1-methyl-1H-imidazol-4-yl)methoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CD 3 OD) δ=7.88 (dd, J=1.2, 4.9 Hz, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.54-7.51 (m, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.8, 5.0 Hz, 1H), 7.06-6.96 (m, 1H), 6.89 (d, J=9.0 Hz, 2H), 4.48-4.28 (m, 2H), 4.09-3.97 (m, 1H), 3.89-3.74 (m, 2H), 3.72-3.62 (m, 4H), 3.52-3.44 (m, 1H), 3.38-3.35 (m, 1H), 3.20-2.99 (m, 1H), 2.76-2.43 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 545.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.972 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.235 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CD 3 OD) δ=7.88 (dd, J=1.2, 4.9 Hz, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.44 (s, 2H), 7.25 (dd, J=3.9, 4.9 Hz, 1H), 7.04-6.99 (m, 1H), 6.89 (d, J=9.0 Hz, 2H), 4.49-4.25 (m, 2H), 4.10-3.97 (m, 1H), 3.90-3.73 (m, 2H), 3.73-3.63 (m, 4H), 3.54-3.43 (m, 1H), 3.38-3.34 (m, 1H), 3.19-3.03 (m, 1H), 2.76-2.64 (m, 1H), 2.63-2.52 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 545.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.979 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.206 μM.

›Example 120

1,1,1-trifluoro-2-(4-((2S)-2-((tetrahydro-2H-pyran-4-ylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and tetrahydro-2H-pyran-4-amine hydrochloride (ASDI, Newark, Del.) using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0-10% MeOH in CH 2 Cl 2 ) delivered 1,1,1-trifluoro-2-(4-((2S)-2-((tetrahydro-2H-pyran-4-ylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((tetrahydro-2H-pyran-4-ylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((tetrahydro-2H-pyran-4-ylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, MeOH) δ=7.91-7.87 (m, 1H), 7.65-7.60 (m, 1H), 7.53-7.47 (d, J=8.8 Hz, 2H), 7.27-7.23 (m, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.39-4.26 (m, 1H), 4.06-3.95 (m, 2H), 3.78-3.61 (m, 3H), 3.51-3.34 (m, 6H), 2.88-2.76 (m, 1H), 2.66-2.47 (m, 1H), 2.06-1.87 (m, 2H), 1.67 (s, 3H), 1.64-1.54 (m, 2H). m/z (ESI, +ve ion) 534.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.493 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.656 μM.

›Example 121

1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Step 1: 1,1,1-trifluoro-2-(4-((2S)-2-((methylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84 The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and methanamine (10 equivalents of a 1.0M solution in THF, Sigma-Aldrich, St. Louis, Mo.) followed by purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 ) delivered 1,1,1-trifluoro-2-(4-((2S)-2-((methylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers after column chromatography on silica gel (0-10% MeOH in CH 2 Cl 2 )

Step 2: 1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A 25-mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-((2S)-2-((methylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (50 mg, 0.108 mmol), 1-methyl-1H-imidazole-4-carbaldehyde (59.4 mg, 0.539 mmol, ASDI, Newark, Del.), sodium triacetoxyborohydride (114 mg, 0.539 mmol, Sigma-Aldrich, St. Louis, Mo.), AcOH (0.617 μl, 10.79 μmol) and DCE (5 mL). The reaction was stirred at room temperature for 12 h. MeOH (20 mL), was added and the mixture was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 5 to 10% CH 2 Cl 2 in MeOH) to give 1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) as a mixture of two isomers.

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=7.93-7.83 (m, 1H), 7.66-7.59 (m, 1H), 7.52-7.48 (m, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.28-7.20 (m, 1H), 6.95-6.77 (m, 3H), 4.05-3.89 (m, 2H), 3.73-3.63 (m, 4H), 3.61-3.53 (m, 1H), 3.43-3.33 (m, 2H), 3.19-3.07 (m, 1H), 3.04-2.96 (m, 1H), 2.64-2.56 (m, 1H), 2.56-2.43 (m, 1H), 2.27 (s, 3H), 2.10-1.98 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 558.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.521 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.362 μM.

›Example 122

1,1,1-trifluoro-2-(4-((2S)-2-(cis-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and cis-hexahydro-2H-furo[2,3-c]pyrrole hydrochloride (Synthonix, Wake Forest, N.C.) (using an extra equivalent of potassium carbonate and heating at 150° C.) delivered 1,1,1-trifluoro-2-(4-((2S)-2-(cis-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers after purification by reverse phase HPLC (Phenomenex Gemini-NX C 18 column, 21×100 mm, 5 μm eluting with A: Water w/0.1% NH 4 OH B: Acetonitrile w/0.1% NH 4 OH).

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2R)-1,1,1-trifluoro-2-(4-((2S)-2-((3aS,6aS)-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((3aS,6aS)-hexahydro-5H-furo[2,3-c]pyrrol-5-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ=8.09-8.03 (m, 1H), 7.70-7.63 (m, 1H), 6.89-6.82 (m, 2H), 7.39-7.33 (m, 1H), 6.89-6.82 (m, 2H), 4.40-4.30 (m, 1H), 4.14-4.02 (m, 1H), 3.87-3.75 (m, 1H), 3.73-3.46 (m, 5H), 3.13-3.00 (m, 1H), 2.93-2.85 (m, 1H), 2.82-2.55 (m, 3H), 2.45-2.27 (m, 2H), 2.18-1.80 (m, 3H), 1.61 (s, 3H), 1.58-1.42 (m, 1H). m/z (ESI, +ve ion) 546.2 (M+H) + . GK-GKRP IC 50 (Binding)=0.555 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.313 μM.

›Example 123

1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and (cis)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (Synthonix, Wake Forest, N.C.) (using an extra equivalent of potassium carbonate) delivered 1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers after purification by reverse phase HPLC (Phenomenex Gemini-NX C 18 column, 21×100 mm, 5 μm eluting with A: Water w/0.1% NH 4 OH B: Acetonitrile w/0.1% NH 4 OH).

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, DMSO-d 6 ) δ=8.13-7.98 (m, 1H), 7.72-7.61 (m, 1H), 7.40-7.33 (m, 2H), 7.32-7.22 (m, 1H), 6.91-6.80 (m, 2H), 4.17-3.99 (m, 1H), 3.87-3.40 (m, 6H), 3.27-3.04 (m, 3H), 2.93-2.82 (m, 1H), 2.68-2.53 (m, 4H), 2.48-2.38 (m, 1H), 2.34-2.19 (m, 2H), 2.13-1.96 (m, 1H), 1.61 (s, 3H). m/z (ESI, +ve ion) 546.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.671 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.731 μM.

›Example 124

2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: (3S)-3-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinecarboxylate

(3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine dihydrochloride (1.26, 4.91 mmol, Example 82, Step 2) was suspended in CH 2 Cl 2 (30 mL) and chilled to 0° C. To this mixture was added triethylamine (1.37 mL, 9.82 mmol) followed by Boc 2 O (1.072 g, 4.91 mmol). The reaction was allowed to gradually warm to room temperature and stirred for 5 h. The mixture was then concentrated and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give (S)-tert-butyl 3-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (1.19 g) as a colorless oil.

Step 2: 1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate

In a 20-mL vial, a mixture of (3S)-3-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinecarboxylate (210 mg, 0.738 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (286 mg, 0.886 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (RuPhos) (17.23 mg, 0.037 mmol, Strem Chemicals, Newburyport, Mass.), Pd 2 (dba) 3 (16.90 mg, 0.018 mmol, Strem Chemicals, Newburyport, Mass.) and sodium tert-butoxide (177 mg, 1.846 mmol) in toluene (5 mL) was heated to 100° C. for 16 h. Afterwards, the mixture was diluted with EtOAc (10 mL) and water (20 mL). The layers were separated and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give the Boc-protected intermediate.

To this was added 10 mL of CH 2 Cl 2 and 10 mL of TFA. The resulting solution was stirred at room temperature for 3 h. The mixture was then concentrated and dried in vacuo to give 1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (45 mg) as a yellow oil.

Step 3: 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

The 1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (115 mg, 0.172 mmol) was dissolved in CH 2 Cl 2 (30 mL) and was chilled to 0° C. To this solution was triethylamine (96 μl, 0.687 mmol) followed by 6-chloropyridine-3-sulfonyl chloride (40.1 mg, 0.189 mmol, Organic Process Research & Development 2009, 13, 875). The mixture was warmed slowly to room temp and stirred for 2 h. Afterwards, the mixture was concentrated to give 2-(4-((S)-4-((6-chloropyridin-3-yl)sulfonyl)-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol.

The crude chloropyridine derivative was dissolved in 2 mL of EtOH and 2 mL of 30% aqueous ammonium hydroxide. This solution was heated to 140° C. for 60 min. The mixture was concentrated in vacuo and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (23 mg) as a foamy solid.

1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (m, 1H), 7.76 (m, 1H), 7.55 (d, J=8.6 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 6.54 (d, J=8.6 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H), 3.89 (m, 1H), 3.76 (m, 1H), 3.68 (m, 1H), 3.59 (m, 2H), 3.44 (m, 1H), 3.25 (m, 3H), 2.74 (m, 1H), 2.45 (m, 3H), 2.20 (m, 1H), 1.96 (m, 1H), 1.03 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 598.6 (M+H) + . GK-GKRP EC 50 (NADPH-coupled)=0.001 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.018 μM.

›Examples6

›Example 125

2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the scheme outlined for Example 124, substituting 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, Step 1) delivered 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers.

(2S)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3R)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3R)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=8.30 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.3, 8.8 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.64 (d, J=9.0 Hz, 1H), 4.05-3.92 (m, 2H), 3.77-3.51 (m, 4H), 3.40 (d, J=12.1 Hz, 1H), 3.29-3.08 (m, 3H), 2.83 (d, J=11.9 Hz, 1H), 2.58-2.40 (m, 2H), 2.31 (m, 1H), 2.09-1.99 (m, 1H), 1.84 (d, J=12.7 Hz, 1H), 1.67 (s, 3H), 0.99 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 544.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.003 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.020 μM.

The individual isomers were separated using chiral SFC. The method used was as follows: Chiralcel® OJ column (21×250 mm, 10 μm) (using 20 mM NH 3 in methanol) in supercritical CO 2 (total flow was 70 mL/min). This separation yielded two products with both diastereomeric and enantiomeric excesses over 95%.

First Eluting Peak (Peak #1).

1 H NMR (400 MHz, CDCl 3 ) δ=8.47 (d, J=2.0 Hz, 1H), 7.76 (dd, J=2.3, 8.8 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.53 (d, J=8.8 Hz, 1H), 4.99 (s, 2H), 4.02 (d, J=10.6 Hz, 1H), 3.84 (m, 1H), 3.72 (t, J=10.2 Hz, 2H), 3.66-3.52 (m, 2H), 3.38 (d, J=12.1 Hz, 1H), 3.31-3.14 (m, 3H), 2.73 (d, J=11.7 Hz, 1H), 2.58-2.41 (m, 3H), 2.37 (m, 1H), 1.91 (d, J=12.3 Hz, 1H), 1.74 (s, 3H), 1.03 (d, J=6.1 Hz, 3H). m/z (ESI, +ve ion) 544.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.004 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.026 μM.

Second Eluting Peak (Peak #2)

›Example 126

2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Following the scheme reported for Example 124, except using (2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine dihydrochloride (Intermediate C) delivered 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.44 (d, J=2.2 Hz, 1H), 7.74 (dd, J=8.8, 2.35 Hz, 1H), 7.54 (d, J=8.6 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 6.53 (d, J=8.8 Hz, 1H), 4.99 (s, 2H), 4.07-3.81 (m, 3H), 3.74 (d, J=11.4 Hz, 1H), 3.66 (d, J=11.2 Hz, 1H), 3.46 (d, J=12.5 Hz, 1H), 3.39-3.21 (m, 3H), 2.64 (dd, J=11.3, 3.03 Hz, 1H), 2.51 (m, 1H), 1.85 (m, 1H), 1.69-1.34 (m, 5H), 1.33-1.14 (m, 1H). m/z (ESI, +ve ion) 583.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.022 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.037 μM.

›Example 127

2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the scheme reported for Example 124, except using (2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine dihydrochloride (Intermediate C) and 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (Example 27, Step 1) yielded 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers (2R)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=8.20 (d, J=2.0 Hz, 1H), 7.67-7.59 (m, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.56-6.49 (m, 1H), 4.00-3.93 (m, 1H), 3.80-3.68 (m, 2H), 3.60 (d, J=11.0 Hz, 1H), 3.49 (d, J=11.5 Hz, 1H), 3.31 (d, J=12.5 Hz, 1H), 3.25-3.17 (m, 2H), 3.15-3.07 (m, 1H), 2.57 (dd, J=2.6, 11.4 Hz, 1H), 2.44 (m, 1H), 1.70-1.62 (m, 1H), 1.57 (s, 3H), 1.57-1.53 (m, 1H), 1.42 (d, J=12.9 Hz, 1H), 1.37-1.28 (m, 1H), 1.25-0.93 (m, 3H). m/z (ESI, +ve ion) 531.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.055 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.058 μM.

First Eluting Peak (Peak #1)

1 H NMR (400 MHz, CDCl 3 ) δ=8.45 (d, J=2.2 Hz, 1H), 7.73 (dd, J=2.3, 8.8 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.53 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 3.99-3.84 (m, 3H), 3.70 (d, J=10.8 Hz, 1H), 3.62 (d, J=11.3 Hz, 1H), 3.44-3.21 (m, 4H), 2.71-2.63 (m, 1H), 2.61-2.47 (m, 2H), 1.82 (m, 1H), 1.74 (s, 3H), 1.60-1.41 (m, 3H), 1.40-1.16 (m, 2H). m/z (ESI, +ve ion) 529.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.051 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.098 μM.

Second Eluting Peak (Peak #2)

1 H NMR (400 MHz, CDCl 3 ) δ=8.45 (d, J=2.2 Hz, 1H), 7.73 (dd, J=2.3, 8.8 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.53 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 3.98-3.84 (m, 3H), 3.70 (d, J=10.8 Hz, 1H), 3.62 (d, J=11.3 Hz, 1H), 3.44-3.21 (m, 4H), 2.70-2.63 (m, 1H), 2.60-2.47 (m, 2H), 1.82 (m, 1H), 1.74 (s, 3H), 1.60-1.41 (m, 3H), 1.40-1.16 (m, 2H). m/z (ESI, +ve ion) 529.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.048 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.072 μM.

›Example 128

2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Step 1: 1,1,1,3,3,3-hexafluoro-2-(2-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol trifluoroacetate

In a sealed vial a mixture of (S)-tert-butyl 3-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (114 mg, 0.381 mmol) (Example 124, Step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (139 mg, 0.495 mmol) (Intermediate D), and triethylamine (80 μl, 0.571 mmol) in dioxane (20 mL) was heated to 100° C. for 16 h. After the mixture was allowed to cool to room temperature, the solution was absorbed onto silica gel and purified via column chromatography (24 g silica gel, 0 to 100% EtOAc in hexanes) to give the Boc-protected intermediate.

The intermediate was dissolved in 10 mL of CH 2 Cl 2 and 10 mL of TFA: The solution was stirred at room temperature for 2 h. The mixture was then concentrated and dried in vacuo. The resulting 1,1,1,3,3,3-hexafluoro-2-(2-((R)-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol 2,2,2-trifluoroacetate (165 mg) was used as is in the next step without further purification.

Step 2: 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Following the procedure reported for Example 124, Step 3, the reaction of 1,1,1,3,3,3-hexafluoro-2-(2-((R)-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol 2,2,2-trifluoroacetate and 6-chloropyridine-3-sulfonyl chloride ( Organic Process Research & Development 2009, 13, 875) followed by amination delivered 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (55 mg) after purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 ).

1 H NMR (400 MHz, CD 3 OD) δ=8.54 (s, 2H), 8.28 (d, J=2.0 Hz, 1H), 7.72 (dd, J=2.3, 9.0 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 4.94 (d, J=4.5 Hz, 1H), 4.72 (m, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.80-3.53 (m, 4H), 3.42-3.33 (m, 1H), 3.28-3.13 (m, 2H), 3.08 (d, J=12.1 Hz, 1H), 2.51-2.25 (m, 4H), 2.06-1.96 (m, 1H), 1.07 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 600.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.027 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.034 μM.

›Example 129

2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol

Following the scheme reported for Example 128, the reaction of 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (Intermediate E) and 1,1,1,3,3,3-hexafluoro-2-(2-((R)-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol 2,2,2-trifluoroacetate (Example 128) delivered 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (68 mg) as a mixture of two isomers after purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 )

(2R)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=8.49 (s, 2H), 8.28 (s, 1H), 7.76-7.67 (m, 1H), 6.61 (d, J=9.0 Hz, 1H), 4.89 (d, J=10.4 Hz, 1H), 4.64 (d, J=13.3 Hz, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.77-3.66 (m, 2H), 3.66-3.55 (m, 2H), 3.42-3.33 (m, 1H), 3.28-3.04 (m, 3H), 2.49-2.23 (m, 4H), 1.97 (d, J=12.1 Hz, 1H), 1.69 (s, 3H), 1.07 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 546.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.036 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.099 μM.

›Example 130

2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: tert-butyl (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinecarboxylate

(2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)piperazine dihydrochloride (1.49 g, 5.77 mmol, Intermediate C) was suspended in CH 2 Cl 2 (30 mL) and chilled to 0° C. To this mixture was added triethylamine (2.41 mL, 17.3 mmol) followed by Boc 2 O (1.32 g, 6.06 mmol). The reaction was allowed to gradually warm to room temperature and stirred for 3 h. The mixture was then concentrated and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give (S)-tert-butyl 3-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (1.355 g) as a colorless oil.

Step 2: 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol ditrifluoroacetate

In a 20-mL vial a mixture of (S)-tert-butyl 3-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (130 mg, 0.457 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoro-2-propanol (147 mg, 0.549 mmol, Intermediate D), triethylamine (96 μL, 0.686 mmol) and dioxane (20 mL) was heated at 100° C. for 16 h. The mixture was then concentrated and the crude material was absorbed onto silica gel and purified via column chromatography (24 g silica gel, 0 to 100% EtOAc in hexanes). The desired fractions were combined and concentrated to give the Boc-protected intermediate.

The intermediate was dissolved in 20 mL of a 1:1 TFA:CH 2 Cl 2 solution and was stirred at room temp for 2 h. Afterwards, the mixture was concentrated and dried in vacuo. The resulting 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol ditrifluoroacetate (188 mg) was used as is in the next step without further purification.

Step 3: 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Following the procedure reported Example 124, Step 3, the reaction of, 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol ditrifluoroacetate and 6-chloropyridine-3-sulfonyl chloride ( Organic Process Research & Development 2009, 13, 875) followed by amination delivered 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol after purification via column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 ).

1 H NMR (400 MHz, CD 3 OD) δ=8.42 (s, 2H), 8.17 (s, 1H), 7.64-7.56 (m, 1H), 6.50 (d, J=9.0 Hz, 1H), 5.09-4.99 (m, 1H), 4.67 (d, J=13.3 Hz, 1H), 3.84-3.73 (m, 2H), 3.64 (d, J=11.2 Hz, 1H), 3.53 (d, J=11.9 Hz, 1H), 3.33-3.23 (m, 1H), 3.21-3.12 (m, 2H), 2.40 (dd, J=3.5, 11.7 Hz, 1H), 2.27 (m, 1H), 1.74-1.54 (m, 4H), 1.39-1.11 (m, 3H). m/z (ESI, +ve ion) 585.5 (M+H) + . GK-GKRP IC 50 (Binding)=0.062 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.134 μM.

›Examples3

›Example 131

2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

This compound was synthesized following the scheme described for Example 130, except 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (Intermediate E) was substituted for 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol. This route delivered 2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a mixture of two isomers after column chromatography on silica gel (0 to 10% MeOH in CH 2 Cl 2 )

(2R)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CD 3 OD) δ=8.47 (s, 2H), 8.27 (s, 1H), 7.73-7.63 (m, 1H), 6.60 (d, J=8.8 Hz, 1H), 5.18-5.06 (m, 1H), 4.72 (d, J=13.7 Hz, 1H), 3.89 (t, J=9.9 Hz, 2H), 3.72 (d, J=11.3 Hz, 1H), 3.62 (d, J=11.7 Hz, 1H), 3.42-3.18 (m, 3H), 2.52-2.43 (m, 1H), 2.40-2.28 (m, 1H), 1.84-1.63 (m, 7H), 1.50-1.20 (m, 3H). m/z (ESI, +ve ion) 531.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.124 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.102 μM.

›Example 132

1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

In a pressure tube (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine dihydrochloride (133 mg, 0.318 mmol, Example 82, Step 2), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (123 mg, 0.381 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), Pd 2 (dba) 3 (18.28 mg, 0.032 mmol, Strem Chemicals, Newburyport, Mass.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (14.83 mg, 0.032 mmol, Strem Chemicals, Newburyport, Mass.), and sodium tert-butoxide (122 mg, 1.272 mmol) were combined and suspended in toluene (5 mL). Nitrogen gas was bubbled through the solution for 5 min. The reaction vial was sealed and heated to 100° C. for 15 h. The reaction mixture was then diluted with water and EtOAc. The aqueous mixture was extracted with EtOAc (2×20 mL). The organic extracts were combined and dried over MgSO 4 , filtered, and concentrated. The crude material was purified by purified via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in MeCN/H 2 O (10% to 100% over 15 min) to afford 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (23 mg).

1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J=4.9 Hz, 1H), 7.59 (m, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.17 (m, 1H), 6.83 (d, J=9.0 Hz, 2H), 4.10 (m, 1H), 3.91 (m, 1H), 3.81 (m, 1H), 3.69 (m, 1H), 3.58 (m, 2H), 3.46 (m, 1H), 3.25 (m, 3H), 2.75 (m, 1H), 2.54 (m, 2H), 2.39 (m, 1H), 2.21 (m, 1H), 1.97 (m, 1H), 1.03 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 588.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.006 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.009 μM.

›Example 133

2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine

The (S)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine dihydrochloride (390 mg, 1.516 mmol, Intermediate C) was dissolved in CH 2 Cl 2 and the solution was chilled to 0° C. To this solution was added triethylamine (634 μL, 4.55 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (497 mg, 1.90 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirring was continued for 2 h. The mixture was concentrated and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (520 mg).

Step 2: N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine

In a sealed vial (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (540 mg, 1.32 mmol), diacetoxypalladium (14.81 mg, 0.066 mmol, Strem Chemicals, Newburyport, Mass.), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XantPhos) (38.2 mg, 0.066 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (279 mg, 2.90 mmol), and diphenylmethanimine (287 mg, 1.58 mmol, Sigma-Aldrich, St. Louis, Mo.) were combined and suspended in toluene (5 mL). Nitrogen gas was bubbled through the solution for 5 min and then the mixture was heated at 100° C. for 16 h. The solution was diluted with EtOAc (20 mL) and then washed with water (15 mL) and brine (15 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine (465 mg).

Step 3: 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

In a 20-mL vial was charged with N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine (170 mg, 0.334 mmol)), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (187 mg, 0.667 mmol, Intermediate D), and Hünig's base (175 μL, 1.001 mmol), and dioxane (5 mL). The vial was sealed and heated to 90° C. for 16 h. Afterwards, the mixture was concentrated in vacuo. The crude material was dissolved in THF (20 mL) and 4 N HCl in dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated, absorbed onto silica gel, and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (88 mg).

1 H NMR (400 MHz, CDCl 3 ) δ=8.52 (s, 2H), 7.17 (d, J=4.1 Hz, 1H), 6.11 (s, 1H), 5.14 (m, 1H), 4.79 (d, J=13.3 Hz, 1H), 4.27 (s, 2H), 3.99-3.86 (m, 2H), 3.76-3.69 (m, 1H), 3.63 (d, J=11.5 Hz, 1H), 3.39-3.22 (m, 3H), 2.57 (dd, J=3.5, 11.5 Hz, 1H), 2.45 (m, 1H), 1.85-1.71 (m, 3H), 1.63-1.60 (m, 2H), 1.49-1.20 (m, 2H). m/z (ESI, +ve ion) 590.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.047 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.059 μM.

›Examples3

›Example 134

1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

Step 1: 2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A mixture of (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (190 mg, 0.464 mmol, Example 133, Step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (156 mg, 0.557 mmol, Intermediate D), and potassium carbonate (128 mg, 0.928 mmol) in DMF was heated at 100° C. and stirred for 16 h. The mixture was diluted with water (20 mL) and EtOAc (20 mL). The layers were separated and the organics were washed with water (20 mL) and brine (20 mL). The organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give (S)-2-(2-(4-(5-bromothiophen-2-ylsulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (140 mg).

Step 2: 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

In a 50-mL round-bottomed flask a mixture of (S)-2-(2-(4-(5-bromothiophen-2-ylsulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (60 mg, 0.092 mmol) and 10% Pd/C (19.5 mg, 0.018 mmol) in EtOH (10 mL) stirred under 1 atm of H 2 for 8 h. Afterwards, the mixture was filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated and the crude product was purified by carefully filtering through a plug of silica gel using 5% MeOH in CH 2 Cl 2 as the eluent. Concentration of the filtrate yielded 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (32 mg).

1 H NMR (400 MHz, CDCl 3 ) δ=8.51 (s, 2H), 7.61 (dd, J=1.2, 4.9 Hz, 1H), 7.53 (dd, J=1.3, 3.8 Hz, 1H), 7.14 (dd, J=3.8, 5.0 Hz, 1H), 5.15 (m, 1H), 4.81 (d, J=13.5 Hz, 1H), 3.93 (t, J=10.9 Hz, 2H), 3.82 (m, 1H), 3.72 (s, 1H), 3.41-3.24 (m, 3H), 2.54 (dd, J=3.7, 11.5 Hz, 1H), 2.41 (m, 1H), 1.84-1.74 (m, 2H), 1.67-1.55 (m, 2H), 1.48-1.23 (m, 3H). m/z (ESI, +ve ion) 575.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.122 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.079 μM.

›Example 135

2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol

This compound was synthesized according the scheme described for Example 133. For this example racemic 2-(2-chloropyrimidin-5-yl)-1,1,1-trifluoropropan-2-ol (Intermediate E) was used rather than 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol to yield 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers. (2S)-2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=8.43 (s, 2H), 7.16 (d, J=3.9 Hz, 1H), 6.10 (d, J=3.9 Hz, 1H), 5.17-5.09 (m, 1H), 4.82-4.73 (m, 1H), 4.23 (s, 2H), 3.98-3.86 (m, 2H), 3.71 (d, J=11.3 Hz, 1H), 3.65-3.58 (m, 1H), 3.39-3.22 (m, 3H), 2.56 (dd, J=3.6, 11.4 Hz, 1H), 2.48-2.35 (m, 2H), 1.84-1.76 (m, 2H), 1.76-1.70 (m, 3H), 1.63 (d, J=12.7 Hz, 1H), 1.51-1.27 (m, 3H). m/z (ESI, +ve ion) 536.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.055 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.108 μM.

›Example 136

2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

›Step 1: 2-(4-((2S)-2,4-dibenzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

In a sealable vial (S)-1,3-dibenzylpiperazine (0.617 g, 2.316 mmol, Alfa Aeser, Ward Hill, Mass.), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (0.623 g, 2.316 mmol, Example 27, Step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.071 g, 0.058 mmol, Strem Chemicals, Newburyport, Mass.), Pd 2 (dba) 3 (0.067 g, 0.116 mmol, Strem Chemicals, Newburyport, Mass.), and sodium tert-butoxide (0.556 g, 5.79 mmol) were combined and suspended in toluene (5 mL). The vial was purged with N 2 for 5 min and was then heated at 100° C. for 15 h. The mixture was diluted with EtOAc (20 mL), the layers were separated and the organics were washed with water (10 mL) and brine (10 mL). The organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give 2-(4-((2S)-2,4-dibenzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.355 g).

›Step 2: 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

In a 100 mL round bottomed flask a mixture of 2-(4-((2S)-2,4-dibenzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (355 mg, 0.781 mmol) and 10% Pd/C (83 mg) in EtOH (20 mL) was placed under a hydrogen atmosphere (1 atm) 16 h. The mixture was filtered through a pad of Celite® (diatomaceous earth) and then concentrated onto silica gel and purified via column chromatography (40 g, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.210 g).

Step 3: 2-(4-((2S)-2-benzyl-4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

The 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (147 mg, 0.404 mmol) was dissolved in CH 2 Cl 2 (10 mL) was cooled to 0° C. To this solution was added triethylamine (124 μL, 0.889 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (127 mg, 0.485 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was concentrated and absorbed onto silica gel. The crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(4-((2S)-2-benzyl-4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (105 mg).

Step 4: 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

In a 25-mL pressure vessel 2-(4-((2S)-2-benzyl-4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (105 mg, 0.178 mmol), Pd(OAc) 2 (1.999 mg, 8.91 μmol, Strem Chemicals, Newburyport, Mass.), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XantPhos) (5.15 mg, 8.91 μmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (35.9 mg, 0.374 mmol), and diphenylmethanimine (38.0 mg, 0.214 mmol, Sigma-Aldrich, St. Louis, Mo.) were combined and suspended in toluene (5 mL). The mixture was purged with N 2 for 5 min and then heated at 100° C. for 16 h. The solution was diluted with EtOAc (20 mL), the layers were separated. The organic layer was washed with water (10 mL) and brine (10 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel, and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give the imine intermediate.

To this imine was added 10 mL of THF and 2 mL of 4 M HCl in dioxane (10 mL). After stirring at room temperature for 2 h, the solution was diluted with EtOAc (20 mL) and saturated aqueous NaHCO 3 . The basic layer was extracted with 2×EtOAc. The combined organic extracts was dried over MgSO 4 , filtered, and concentrated to give 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (22 mg) as a mixture of two isomers:

(2R)-2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=7.50 (d, J=8.8 Hz, 2H), 7.35-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.16 (d, J=4.1 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.11 (d, J=4.1 Hz, 1H), 4.24 (s, 2H), 3.98 (d, J=8.8 Hz, 1H), 3.81 (d, J=10.8 Hz, 1H), 3.66 (d, J=11.3 Hz, 1H), 3.52-3.43 (m, 1H), 3.36 (m, 1H), 3.22-3.12 (m, 1H), 2.71-2.50 (m, 3H), 1.77 (s, 3H). m/z (ESI, +ve ion) 526.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.250 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.146 μM.

›Example 137

2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol

›Step 1: 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol hydrochloride

A mixture of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (250 mg, 1.25 mmol, CNH Technologies, Woburn, Mass.), 2-(2-chloropyrimidin-5-yl)-1,1,1-trifluoropropan-2-ol (339 mg, 1.50 mmol, Intermediate E), and potassium carbonate (362 mg, 2.62 mmol) in DMF (10 mL) was stirred at 100° C. for 16 h. The mixture was diluted with water (20 mL) and EtOAc (30 mL). The layers were separated and the organics were washed with water (20 mL) and brine (20 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give the Boc-protected product. To this crude intermediate was added 12 mL of EtOAc and 3 mL of 4 M HCl in dioxane. The mixture was heated at reflux for 16 h. The precipitate that had formed was collected by filtration, washed with EtOAc, and to 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol hydrochloride (95 mg).

Step 2: 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol

The 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol hydrochloride (95 mg, 0.291 mmol) was dissolved in CH 2 Cl 2 (15 mL) was chilled to 0° C. To this solution was added triethylamine (101 μL, 0.727 mmol) followed by 5-nitrothiophene-2-sulfonyl chloride (66.2 mg, 0.291 mmol, Enamine Building Blocks, Kiev, Ukraine). The mixture was warmed slowly to room temperature and stirred for 2 h. Afterwards, the mixture was concentrated onto silica gel and then purified via column chromatography (24 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give racemic 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg).

Step 3: 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol

In a 50-mL round bottomed flask, a mixture of 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg, 0.224 mmol), ammonium formate (30.1 mg, 0.478 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10% Pd/C (25.4 mg, 0.024 mmol) in EtOH (10 mL) was stirred under an atmosphere of H 2 (1 atm) for 18 h. Afterwards, the mixture was filtered through a plug of Celite and the filtrate was concentrated to give the crude product. The crude product was dissolved in CH 2 Cl 2 and filtered through a plug of silica gel. The filtrate was concentrated to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (23 mg) as a mixture of two isomers.

(2S)-2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol and (2S)-2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=8.45 (s, 2H), 7.17 (d, J=3.9 Hz, 1H), 6.11 (d, J=4.1 Hz, 1H), 5.08 (m, 1H), 4.68 (d, J=13.5 Hz, 1H), 4.24 (s, 2H), 3.78-3.68 (m, 1H), 3.57 (d, J=11.2 Hz, 1H), 3.38-3.24 (m, 1H), 2.63 (dd, J=3.7, 11.3 Hz, 1H), 2.47 (dt, J=3.3, 11.7 Hz, 1H), 1.74 (s, 3H), 1.34 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 452.5 (M+H) + . GK-GKRP IC 50 (Binding)=0.281 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.658 μM.

›Example 138

2-(4-(4-((4-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

›Step 1: 4-nitrothiophene-2-sulfonyl chloride

To a 150-mL round bottomed flask containing fuming nitric acid (100 mL) was slowly added a solution of thiophene-2-sulfonyl chloride (2.20 g, 12.04 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH 2 Cl 2 (30 mL) at 0° C. The mixture was then gradually warmed to 40° C. then stirred for 2 h at that temperature. The mixture was poured over ice and the mixture was extracted with CH 2 Cl 2 . The combined organics was dried over MgSO 4 , filtered, and concentrated give a mixture of 4-nitrothiophene-2-sulfonyl chloride and 5-nitrothiophene-2-sulfonyl chloride (2.05 g) in a 2:1 ratio.

Step 2: 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

The 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol hydrochloride (306 mg, 0.84 mmol, Example 91, Step 1) was dissolved in CH 2 Cl 2 (20 mL) and the solution was chilled to 0° C. To this solution was added triethylamine (292 μL, 2.10 mmol) followed by 4-nitrothiophene-2-sulfonyl chloride (210 mg, 0.923 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. Afterwards, the mixture was filtered and concentrated, the filtrate was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (5% to 100% over 15 min) to give 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (86 mg).

Step 3: 2-(4-(4-((4-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

In a 50 mL round bottomed flask a mixture of 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (80 mg, 0.154 mmol), ammonium formate (48.6 mg, 0.770 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10% Pd/C (1.639 mg, 0.015 mmol) in EtOH (10 mL) was stirring under an atmosphere of H 2 (1 atm) for 18 h. Afterwards, the reaction mixture was filtered through a plug of Celite® (diatomaceous earth), and the filtrate was concentrated to give the crude product. The crude product was dissolved in CH 2 Cl 2 and filtered through a plug of silica gel. The filtrate was concentrated to give 2-(4-(4-((4-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (23 mg).

1 H NMR (400 MHz, CD 3 OD) δ=7.58 (d, J=8.8 Hz, 2H), 7.19 (d, J=2.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.60 (d, J=1.8 Hz, 1H), 3.40-3.35 (m, 4H), 3.23-3.17 (m, 4H). m/z (ESI, +ve ion) 504.5 (M+H) + . GK-GKRP IC 50 (Binding)=0.310 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.272 μM.

›Example 139

2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

Following the procedure reported for Example 88, 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol hydrochloride (Example 30, Step 2) delivered 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (43 mg) as a mixture of two isomers after column chromatography on silica gel (0-70% EtOAc in hexanes)

(2R)-2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol and (2R)-2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=7.44 (d, J=8.4 Hz, 2H), 7.20 (d, J=3.9 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 6.14 (d, J=4.1 Hz, 1H), 4.27 (s, 2H), 4.02-3.94 (m, 1H), 3.60 (m, 1H), 3.42-3.30 (m, 2H), 3.28-3.19 (m, 1H), 2.92 (dd, J=3.2, 11.1 Hz, 1H), 2.76 (dt, J=3.7, 10.7 Hz, 1H), 1.75 (s, 3H), 1.14 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 450.5 (M+H) + . GK-GKRP IC 50 (Binding)=0.630 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.370 μM.

›Example 140

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-one

›Step 1: 9-azabicyclo[3.3.1]nonan-3-one

A mixture of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one hydrochloride (295 mg, 1.11 mmol, J & W PharmLab, Levittown, Pa.), a five drops of formic acid, and 10% Pd/C (27.4 mg, 0.257 mmol) in EtOH (20 mL) was subjected to a hydrogen atmosphere (50 psi; 344.7 kilopascal) in a Parr shaker apparatus for 18 h. The mixture was filtered through a pad of Celite® (diatomaceous earth) and then concentrated to give crude 9-azabicyclo[3.3.1]nonan-3-one as the formate salt (180 mg).

Step 2: 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-one

This analog was prepared following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and crude 9-azabicyclo[3.3.1]nonan-3-one (with one additional equiv of K 2 CO 3 ) delivered 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-one as a mixture of two isomers after purification by reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (5% to 100% over 15 min.

1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J=5.0 Hz, 1H), 7.59 (m, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.18 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 4.14 (d, J=11.2 Hz, 1H), 3.91 (m, 1H), 3.86 (m, 2H), 3.48 (m, 1H), 3.27 (m, 3H), 2.95 (m, 1H), 2.73 (m, 1H), 2.62 (m, 2H), 2.48 (m, 2H), 2.34 (d, J=2.9 Hz, 1H), 2.19 (m, 2H), 1.77 (m, 2H), 1.74 (s, 3H), 1.45 (m, 2H). m/z (ESI, +ve ion) 572.7 (M+H) + . GK-GKRP IC 50 (Binding)=0.007 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.015 μM.

›Examples11

›Example 141

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (endo)

To a solution of racemic 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[331]nonan-3-one (81 mg, 0.142 mmol, Example 140) in 1 mL of THF and 0.3 mL of MeOH was added sodium borohydride (10.72 mg, 0.284 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to gradually warm to room temperature and stirred for 16 h. The crude material was then diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated and the extracts were washed with water (10 mL) and brine (10 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was by purified via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (5% to 100% over 15 min) to give 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (22 mg) as a mixture of two isomers:

9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (endo) and 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (endo).

1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J=5.0 Hz, 1H), 7.58 (m, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.17 (m, 1H), 6.78 (d, J=8.8 Hz, 2H), 3.99 (m, 1H), 3.79 (m, 2H), 3.67 (m, 1H), 3.43 (m, 1H), 3.23 (m, 1H), 2.99 (m, 2H), 2.78 (m, 1H), 2.64 (m, 2H), 2.54 (m, 2H), 2.22 (m, 2H), 2.01 (m, 1H), 1.74 (s, 3H), 1.67 (d, 2H), 1.40 (m, 1H), 1.18 (m, 3H). m/z (ESI, +ve ion) 574.7 (M+H) + . GK-GKRP IC 50 (Binding)=0.011 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.026 μM.

›Example 142

3-fluoro-9-(((2S)-1-(4-(1,2,2,2-tetrafluoro-1-methylethyl)phenyl)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonane (exo)

A solution of 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (50 mg, 0.087 mmol, Example 141) in CH 2 Cl 2 was chilled to 0° C. To this solution was added Deoxo-Fluor (64.1 μl, 0.174 mmol, Sigma-Aldrich, St. Louis, Mo.) slowly via syringe. The mixture was allowed to slowly warm to room temperature and stirred for an additional 2 h. Saturated aqueous NaHCO 3 was added and the mixture was concentrated and the residue was purified via preparatory TLC eluting with 10% EtOAc in hexanes to yield 3-fluoro-9-(((2S)-1-(4-(1,2,2,2-tetrafluoro-1-methylethyl)phenyl)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonane (15 mg) as a mixture of two isomers:

7-fluoro-9-(((2S)-1-(4-((1S)-1,2,2,2-tetrafluoro-1-methylethyl)phenyl)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonane (exo); 7-fluoro-9-(((2S)-1-(4-((1S)-1,2,2,2-tetrafluoro-1-methylethyl)phenyl)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonane (exo).

1 H NMR (400 MHz, CDCl 3 ) δ=7.65 (d, J=4.7 Hz, 1H), 7.59 (m, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.17 (m, 1H), 6.82-6.76 (m, 2H), 4.11 (d, J=11.0 Hz, 1H), 3.92-3.71 (m, 3H), 3.69-3.61 (m, 2H), 3.44 (d, J=12.9 Hz, 1H), 3.30-3.19 (m, 1H), 2.91-2.74 (m, 2H), 2.69-2.51 (m, 3H), 1.98 (m, 1H), 1.94-1.84 (m, 1H), 1.84-1.77 (m, 1H), 1.74 (s, 3H), 1.73-1.69 (m, 1H). 1.58 (m, 3H), 1.27 (m, 2H). m/z (ESI, +ve ion) 580.65 (M+H) + . GK-GKRP IC 50 (Binding)=0.047 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.189 μM.

›Example 143

2-(4-((2S)-2-((3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

A sealable vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B), 3-ethylmorpholine (43.6 mg, 0.378 mmol, ChemBridge Corporation, San Diego, Calif.), potassium carbonate (52.3 mg, 0.378 mmol), and 4 mL of MeCN. The vial was sealed and heated to 150° C. for 90 min. Afterwards, the reaction mixture was filtered and the filtrate was concentrated. The crude material was purified via preparatory TLC using 5% MeOH in CH 2 Cl 2 eluent to yield 2-(4-((2S)-2-((3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (33 mg) as a mixture of four isomers.

(2S)-2-(4-((2S)-2-(((3R)-3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol, (2S)-2-(4-((2S)-2-(((3S)-3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol, (2R)-2-(4-((2S)-2-(((3S)-3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol, (2R)-2-(4-((2S)-2-(((3R)-3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=7.65 (dd, J=1.2, 5.1 Hz, 1H), 7.58 (m, 1H), 7.45-7.39 (m, 2H), 7.17 (m, 1H), 6.81 (d, J=8.6 Hz, 2H), 4.10-3.95 (m, 1H), 3.91-3.73 (m, 2H), 3.72-3.52 (m, 3H), 3.44-3.30 (m, 2H), 3.30-3.09 (m, 1H), 2.85-2.67 (m, 1H), 2.66-2.45 (m, 2H), 2.45-2.26 (m, 2H), 2.25-2.04 (m, 1H), 1.74 (s, 3H), 1.63 (d, J=3.1 Hz, 1H), 1.48-1.35 (m, 1H), 1.32-1.23 (m, 1H), 0.89-0.75 (m, 3H). m/z (ESI, +ve ion) 548.7 (M+H) + . GK-GKRP IC 50 (Binding)=0.080 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.036 μM.

›Example 144

1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone

Step 1: 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinol

This compound was synthesized following the procedure described for Example 143. The reaction of 4-piperidinol (Sigma-Aldrich, St. Louis, Mo.) and ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) delivered 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinol as a mixture of two isomers after column chromatography on silica gel (5 to 8% MeOH in CH 2 Cl 2 )

Step 2: 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone

A solution of 2.0 M solution of oxalyl chloride in CH 2 Cl 2 (162 μL, 0.323 mmol, Sigma-Aldrich, St. Louis, Mo.) was diluted with CH 2 Cl 2 and then chilled to −78° C. To this solution was added DMSO (45.9 μL, 0.647 mmol). The mixture was stirred for 30 min, and then a solution of 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinol (115 mg, 0.216 mmol) in CH 2 Cl 2 was added to slowly to the mixture. The reaction was stirred for 1 h at −78° C. and then triethylamine (150 μl, 1.078 mmol) was added. Afterwards, the mixture was stirred for 15 min and allowed to slowly warm to room temperature and stirred for additional 4 h. Saturated aqueous NaHCO 3 was added and the mixture was concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone (40 mg) as a mixture of two isomers.

1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone and 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone.

1 H NMR (400 MHz, CDCl 3 ) δ=7.65 (dd, J=0.8, 5.1 Hz, 1H), 7.59 (dd, J=0.9, 3.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.18 (dd, J=4.1, 4.7 Hz, 1H), 6.83 (d, J=8.8 Hz, 2H), 4.10 (m, 1H), 4.00-3.93 (m, 1H), 3.86-3.80 (m, 1H), 3.42 (m, 1H), 3.28 (dd, J=3.4, 11.8 Hz, 1H), 2.94-2.86 (m, 1H), 2.83-2.68 (m, 4H), 2.61 (dt, J=3.6, 11.4 Hz, 1H), 2.50-2.43 (m, 1H), 2.38 (m, 1H), 2.35-2.30 (m, 4H), 1.74 (s, 3H). m/z (ESI, +ve ion) 532.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.564 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.831 μM.

›Example 145

(3S)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-piperidinol

This compound was synthesized following the procedure described for Example 143. The reaction of 3(S)-3-piperidinol hydrochloride (Sigma-Aldrich, St. Louis, Mo.) and ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) delivered (3S)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-piperidinol as a mixture of two isomers after column chromatography on silica gel (5 to 8% MeOH in CH 2 Cl 2 )

(3S)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-piperidinol and (3S)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-piperidinol.

1 H NMR (400 MHz, CDCl 3 ) δ=7.64 (d, J=5.1 Hz, 1H), 7.57 (d, J=3.7 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.17 (t, J=4.3 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 4.01 (m, 1H), 3.90 (d, J=11.2 Hz, 1H), 3.81 (d, J=11.3 Hz, 1H), 3.68 (m, 1H), 3.38 (m, 1H), 3.26 (dt, J=2.7, 11.8 Hz, 1H), 2.69 (m, 1H), 2.62-2.48 (m, 4H), 2.34 (m, 1H), 2.13 (m, 1H), 1.73 (s, 3H), 1.51 (m, 2H), 1.45-1.35 (m, 3H). m/z (ESI, +ve ion) 534.6 (M+H) + . GK-GKRP IC 50 (Binding)=0.628 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.880 μM.

›Example 146

1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol

This compound was synthesized following the procedure described for Example 89, Step 3. Using that protocol, the reaction of thiazole-2-sulfonyl chloride ( Bioorg. Med. Chem., 2006, 14, 6628) with 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (Example 89, Step 3) delivered 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=8.55 (s, 2H), 7.97 (s, 1H), 7.64 (s, 1H), 5.13 (s, 1H), 4.75 (d, J=13.7 Hz, 1H), 3.98 (d, J=10.0 Hz, 1H), 3.83-3.65 (m, 1H), 3.45-3.30 (m, 1H), 2.99 (d, J=11.3 Hz, 1H), 2.91-2.77 (m, 1H), 1.37 (m, 3H). m/z (ESI, +ve ion) 492.4 (M+H) + . GK-GKRP IC 50 (Binding)=0.630 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.867 μM.

›Example 147

2-(2-((2S)-4-((2-amino-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Step 1: 2-(2-((2S)-4-((2-chloro-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

This compound was synthesized following the procedure described for Example 89, Step 3. Using that protocol, the reaction of 2-chlorothiazole-5-sulfonyl chloride (Enamine Building Blocks, Kiev, Ukraine) with 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (Example 89, Step 3) delivered 2-(2-((2S)-4-((2-chloro-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol.

Step 2: 2-(2-((2S)-4-((2-amino-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol

A mixture of 2-(2-((2S)-4-((2-chloro-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (185 mg, 0.352 mmol) in 2 mL of EtOH and 2 mL of 30% NH 4 OH was heated to 140° C. for 30 min. Afterwards, the solution was diluted with EtOAc (20 mL). The solution was transferred to a reparatory funnel and washed with water (10 mL) and brine (10 mL). The combined organics were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH 2 Cl 2 ) to give 2-(2-((2S)-4-((2-amino-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (132 mg).

1 H NMR (400 MHz, CD 3 OD) δ=8.46 (s, 2H), 7.35 (s, 1H), 5.01 (m, 1H), 4.63 (d, J=13.3 Hz, 1H), 3.64 (d, J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 3.25-3.17 (m, 1H), 2.61 (dd, J=3.8, 11.6 Hz, 1H), 2.45 (dt, J=3.5, 11.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 507.5 (M+H) + . GK-GKRP IC 50 (Binding)=0.998 μM.

›Example 148

1,1,1-trifluoro-2-(4-((2S)-2-(2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

Step 1: ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile

This compound was synthesized following the procedure described for Example 143. The reaction of potassium cyanide (Sigma-Aldrich, St. Louis, Mo.) and ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) (using and an extra equivalent of potassium carbonate) delivered ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile as a mixture of two isomers after column chromatography on silica gel (5 to 80% EtOAc in hexanes)

Step 2: ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetic acid hydrochloride

A solution of 2-((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)acetonitrile (1.10 g, 2.40 mmol) and 5 M NaOH (3 mL) in 2:1 water-EtOH (10 mL) was heated to 150° C. and stirred for 1 h. Afterwards, the mixture was diluted with water (30 mL) and then neutralized with concentrated HCl to a pH of about 2 to 3. The aqueous solution was extracted with 3×EtOAc (20 mL). The organic layer was dried over is MgSO 4 , filtered, and concentrated. The crude product was then dissolved in 1 N NaOH. The basic solution was extracted with 2×EtOAc. The basic aqueous solution was then neutralized with concentrated HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The residue was dissolved in EtOAc (30 mL) and the solution was slowly acidified with 1 N HCl in diethyl ether. The resulting precipitate was collected and dried to give ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetic acid hydrochloride (0.655 g).

Step 3: N-methoxy-N-methyl-2-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetamide

A solution of ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetic acid hydrochloride (1.55 g, 3.01 mmol), N,O-dimethylhydroxylamine hydrochloride (0.323 g, 3.31 mmol, Sigma-Aldrich, St. Louis, Mo.), and Hünig's base (1.05 mL, 6.02 mmol) in DMF (20 mL) was stirred at 0° C. To this mixture was added HATU (1.26 g, 3.31 mmol). The reaction was stirred for 3 h at room temperature and then diluted with EtOAc (30 mL) and water (20 mL). The organic layer was separated and then washed with water (2×20 mL) and brine (20 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (80 g silica gel, 0 to 100% EtOAc in hexanes) to give N-methoxy-N-methyl-2-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetamide (1.48 g) as an orange oil.

Step 4: 1-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)-2-propanone

A solution of N-methoxy-N-methyl-2-425)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetamide (1.05 g, 2.013 mmol) in THF was cooled to 0° C. To this was added a solution of methylmagnesium bromide (2.0 M in THF, 1.41 mL, 4.23 mmol, Sigma-Aldrich, St. Louis, Mo.). After addition was complete, the mixture was stirred at 0° C. for 30 min, and then quenched with saturated aqueous NH 4 Cl. The solution was diluted with EtOAc (30 mL) and the organic layer was washed with water (20 mL) and brine (20 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (80 g silica gel, 0 to 100% EtOAc in hexanes) to give 1-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)-2-propanone (0.653 g) as an orange oil.

Step 5: 1,1,1-trifluoro-2-(4-((2S)-2-(2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

A solution of 1-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)-2-propanone (100 mg, 0.210 mmol) and oxetan-3-amine (18.41 mg, 0.252 mmol, J & W PharmLab, Levittown, Pa.) in THF (10 mL) was cooled to 0° C. To this mixture was added Ti(O-iPr) 4 (154 μL, 0.525 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred for 3 h and then a solution of sodium borohydride (11.91 mg, 0.315 mmol, Sigma-Aldrich, St. Louis, Mo.) in MeOH (1 mL) was added. The reaction mixture was stirred at ambient temperature for 4 h. Saturated aqueous NH 4 Cl was added and the mixture was filtered. The filtrate was concentrated and purified via reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in MeCN/H 2 O (5% to 100% over 15 min) to give 1,1,1-trifluoro-2-(4-((2S)-2-(2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (28 mg) as a mixture of four isomers

(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((2S)-2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((2R)-2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, (2R)-1,1,1-trifluoro-2-(4-((2S)-2-((2S)-2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol, and (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((2S)-2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol.

1 H NMR (400 MHz, CDCl 3 ) δ=7.64 (d, J=4.5 Hz, 1H), 7.58-7.53 (m, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.19-7.14 (m, 1H), 6.88-6.81 (m, 2H), 4.78 (t, J=6.8 Hz, 2H), 4.46-4.33 (m, 2H), 4.27-4.05 (m, 1H), 4.02-3.84 (m, 1H), 3.81-3.67 (m, 2H), 3.46-3.38 (m, 1H), 3.36-3.22 (m, 1H), 2.76-2.64 (m, 2H), 2.62-2.52 (m, 2H), 1.96 (m, 1H), 1.80-1.69 (m, 3H), 0.99 (d, J=6.1 Hz, 3H). m/z (ESI, +ve ion) 534.2 (M+H) + . GK-GKRP IC 50 (Binding)=1.116 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.529 μM.

›Example 149

2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Following the procedure described for Example 88, the reaction of (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)-2-propanol (Example 11) delivered 2-(4-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ=7.45 (d, J=8.8 Hz, 2H), 7.10 (d, J=4.3 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 5.95 (d, J=4.1 Hz, 1H), 4.16-3.95 (m, 1H), 3.52 (d, J=9.2 Hz, 1H), 3.43-3.29 (m, 2H), 3.15-3.00 (m, 1H), 2.71 (dd, J=3.3, 11.2 Hz, 1H), 2.55 (dt, J=3.4, 11.3 Hz, 1H), 1.03 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 504.0 (M+H) + . GK-GKRP IC 50 (Binding)=0.450 μM; GK-GKRP EC 50 (LC MS/MS-2)=0.109 μM.

›Example 150

4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol

2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (95 mg, 0.17 mmol, Example 69), potassium (4-(tert-butyldimethylsilyloxy)but-1-ynyl)trifluoroborate (75 mg, 0.26 mmol, ASDI, Newark, Del.), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (14 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), and cesium carbonate (182 mg, 0.56 mmol) were combined in toluene (1.5 mL) and water (0.2 mL). The reaction mixture was purged with nitrogen gas for several minutes and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 135° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH 2 Cl 2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH 2 Cl 2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na 2 SO 4 ), filtered, and concentrated. This crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol (22 mg) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 8.11 (dd, J=1.27, 4.99 Hz, 1H), 7.71 (dd, J=1.37, 3.72 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=8.61 Hz, 1H), 7.35 (dd, J=3.81, 4.99 Hz, 1H), 7.08 (d, J=8.80 Hz, 1H), 4.88 (t, J=5.38 Hz, 1H), 3.50-3.59 (m, 2H), 3.27-3.32 (m, 4H), 3.08-3.15 (m, 4H) 2.56 (t, J=6.70 Hz, 2H); m/z (ESI, +ve ion) 543.1 (M+H) + . GK-GKRP IC 50 (Binding)=0.656 μM. GK-GKRP EC 50 (LC MS/MS-2)=0.895 μM.

›Example 151

4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-2-ol

2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (102 mg, 0.18 mmol, Example 69), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-yn-2-yloxy)silane (86 mg, 0.28 mmol, Combi-Blocks, San Diego, Calif.), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichloromethane complex (15 mg, 0.02 mmol, Sigma-Aldrich, St. Louis, Mo.), and cesium carbonate (180 mg, 0.55 mmol) were combined in DME (1.2 mL) and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 15 min and at 120° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH 2 Cl 2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH 2 Cl 2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na 2 SO 4 ), filtered, and concentrated. The crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C 18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH 3 CN/H 2 O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-2-ol (23 mg) as an off-white solid and a mixture of two enantiomers.

(2S)-4-(2-(4-(2-thiopheny

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IPC · International Patent Classification

Section A — Human necessities

A61K31/497
A61K31/54
A61K31/105
A61K31/535
A01N41/12
A01N41/10
A61K31/495
A61K31/4965
A61K31/445
A61K31/10
A61K31/501
A61K31/435
A61K31/50

Section C — Chemistry; metallurgy

C07D413/00
C07D405/00
C07D211/54
C07D403/00
C07D241/02
C07D497/00
C07D295/00
C07D265/36
C07D401/00
C07D491/00
C07D237/00
C07D409/00
C07D495/00
C07D498/02
C07C317/00
C07D211/82
C07D411/00
C07D279/12
C07C315/00
C07D239/00
C07D211/70

USPC · US Patent Classification

514/210.2514/227.8544/58.2544/370514/710544/105514/254.5514/252.14544/350514/709544/295514/249544/121544/379514/235.8514/254.2514/252.13546/344568/32514/254.1544/357514/230.5544/369514/253.12544/371546/216514/254.8514/252.2514/254.3544/372544/238544/367544/230544/360514/277544/362514/252.11514/255.3514/253.4514/327544/383

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