Methanogen inhibitors

Abstract

The present invention relates to a class of methanogen inhibitors for ruminants. The invention also extends to the use of such compounds in ruminants to reduce methane production in the rumen and / or to enhance productivity in the ruminant.

Description

[0001] METHANOGEN INHIBITORS

[0002] FIELD OF INVENTION

[0003] The present invention relates to a new class of methanogen inhibitors for ruminants, in particular new compounds of Formula I, or II Formula I;

[0004] Formula II; for ruminants.

[0005] The invention also extends to the use of such compounds in ruminants to reduce methane production in the rumen and / or to enhance productivity in the ruminant.

[0006] BACKGROUND OF INVENTION

[0007] Methane is produced as a natural consequence of digestion of feed by bacteria, fungi and protozoa in ruminant animals. This fermentation leads to the production of volatile fatty acids and peptides for the host. Fermentation also produces copious quantities of CO2and H2which are used by methanogenic archaea within the rumen to produce methane, which is ultimately released from the rumen, mostly through eructation.

[0008] The methane forming methanogens are members of the Archaea, and are quite different in a number of features to bacteria, fungi and protozoa. Methanogens have a number of unusual and archaeal-specific features, including cell wall structures, lipids, cofactors, and amino acid synthesis pathways, as well as their signature energy metabolism that is linked to methane production. They represent only about 1-4% of the rumen microbial community. It is known that, due to the unique metabolic pathways of methanogens and their low numbers, methanogen- specific inhibitors can be developed that do not adversely affect the fermentation of feed. It has been recognised that the release of such methane is deleterious for two reasons. One is that methane is a greenhouse gas and the other is that the methane loss represents a loss of energy for the ruminant. It has been previously recognised that if one could inhibit or reduce the release of methane from ruminants that the impact of methane on the environment and atmosphere would be reduced and productivity gains might be achieved in the ruminants.

[0009] It is therefore an object of the present invention to overcome the above mentioned difficulties or to at least provide the public with a useful alternative.

[0010] SUMMARY OF INVENTION

[0011] In one aspect the present disclosure provides a compound of Formula I wherein R may be selected from:

[0012] -C1-C6-(C=O)OH; or

[0013] -aryl-C(=O)-OH, -aryl-C(=O)-O-C1-C6, -aryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -aryl-C1-C6-

[0014] OH, -aryl-C1-C6-(C=O)OH, or

[0015] -aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-

[0016] , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0017] -aryl-C(=O)-NH-S(O)2-C1-C6, -aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-C(=O)-NH- S(O)2-aryl, -aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -aryl-C(=O)-NH-S(O)2-heteroaryl, -aryl-

[0018] C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0019] -aryl-C(=O)-NH-S(O)2-NH2, -aryl-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-C(=O)-NH-S(O)2-NH-

[0020] C3-C8-cycloalkyl, -aryl-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, - aryl-C(=O)-NH-S(O)2-NH-heteroaryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -aryl- C(=O)-NH-S(O)2-N(C1-C6)2, , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or

[0021] -aryl-NH-C(=O)-NH-S(O)2-C1-C6, -aryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-NH-

[0022] C(=O)-NH-S(O)2-aryl, -aryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0023] -aryl-NH-C(=O)-NH-S(O)2-NH2, -aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-NH-C(=O)-

[0024] NH-S(O)2-NH-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-

[0025] S(O)2-NH-C1-C6-aryl, -aryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2, , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or

[0026] -aryl-S(O)2-OH, -aryl-S(O)2-NH2, -aryl-S(O)2-NH-C1-C6, -aryl-S(O)2-N(C1-C6)2,

[0027] , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0028] -aryl-S(O)2-NH-C3-C8-cycloalkyl, or

[0029] , wherein J is a 5 membered heterocycle ring containing up to 4 heteroatoms selected from _-N=, - NH-, or -O-; or

[0030] -heteroaryl-C(=O)-OH, -heteroaryl-C(=O)-O-C1-C6, -heteroaryl-C(=O)-O-C1-C6-O-(C=O)- C1-C6, -heteroaryl-C1-C6-OH, -heteroaryl-C1-C6-(C=O)OH, or -heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8- , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, -NC1-C6-, -S- or -O-; or

[0031] -heteroaryl-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, heteroaryl-C(=O)-NH-S(O)2-aryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-aryl, -heteroaryl-

[0032] C(=O)-NH-S(O)2-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0033] -heteroaryl-C(=O)-NH-S(O)2-NH2, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -heteroaryl-

[0034] C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -heteroaryl-

[0035] C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-heteroaryl, -heteroaryl-

[0036] C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2, , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or

[0037] -heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl,

[0038] -heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0039] -heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -heteroaryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, - heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-NH-C(=O)-NH-S(O)2-

[0040] NH-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-

[0041] N(C1-C6)2, , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; wherein P may be a 5 to 10 membered aryl ring or rings optionally containing one or more heteroatoms, and wherein P may be further substituted with one or more halo, -C1-C6-alkyl, - C1-C6-alkyl substituted with one or more halo or hydroxy; -C3-C8-cycloalkyl, -CN, hydroxy, - O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, - S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-

[0042] C6-alkyl, -N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or aryl, aryl substituted with one or more, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-aryl; C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6- alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or heteroaryl; heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6- alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-heteroaryl; C1-C6-heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6- alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1- C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1- C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0043] -O-aryl; -O-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6- alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0044] -O-C1-C6-aryl; -O-C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6- alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6- alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -

[0045] N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or wherein Q may be selected from and wherein R3, R4, or R6are independently selected from -H, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo; and or a salt thereof.

[0046] In one example R is selected from:

[0047] -C1-C6-(C=O)OH; or

[0048] -aryl-C(=O)-OH, or

[0049] -heteroaryl-C(=O)-OH; or

[0050] -aryl-C(=O)-NH-S(O)2-C1-C6.

[0051] In one example R is -aryl-C(=O)-OH.

[0052] In one example R is -phenyl-C(=O)-OH.

[0053] In one example R is -heteroaryl-C(=O)-OH.

[0054] In one example R is -pyridyl-C(=O)-OH.

[0055] In one example R is -C1-C6-(C=O)OH. In one example R is - (CH2)3-(C=O)OH.

[0056] In one example R is , wherein J is a 5 membered heterocycle ring containing up to

[0057] 4 heteroatoms selected from -N=, -NH-, or -O-.

[0058] In one example R is -phenyl-tetrazole.

[0059] In one example R is -phenyl-oxadiazolone.

[0060] In one example P is selected from aryl or an aryl substituted with one or more halo, - CN, - C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1-C6- alkyl substituted with one or more halo.

[0061] In one example P is selected from aryl substituted with aryl or an aryl substituted with halo,- CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1- C6-alkyl substituted with one or more halo.

[0062] In one example P is selected from phenyl or a phenyl substituted with one or more halo, -CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1-C6- alkyl substituted with one or more halo.

[0063] In one example P is phenyl substituted with halo.

[0064] In one example P is phenyl substituted with -Cl.

[0065] In one example P is selected from phenyl substituted with phenyl or a phenyl substituted with halo, -CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or - O-C1-C6-alkyl substituted with one or more halo.

[0066] In one example P is phenyl substituted with a phenyl.

[0067] In one example P is phenyl substituted with a phenyl substituted with halo.

[0068] In one example P is phenyl substituted with a phenyl substituted with -C1.

[0069] In one example P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl.

[0070] In one example P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl substituted with one or more halo. In one example P is phenyl substituted with a phenyl substituted with -OCH2CF3.

[0071] In one example P is phenyl substituted with a phenyl substituted with -O-C3-alkyl.

[0072] In one example P is phenyl substituted with a phenyl substituted with -OPr.

[0073] In one example P is phenyl substituted with a phenyl substituted with -OnPr.

[0074] In one example P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl substituted with one or more halo.

[0075] In one example P is phenyl substituted with a phenyl substituted with -CH2CF3.

[0076] In one example P is phenyl substituted with a phenyl substituted with a halo and a -O-C3- alkyl.

[0077] In one example P is phenyl substituted with a phenyl substituted with -F and a -O-C3-alkyl.

[0078] In one example P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl and a - O-C1-C6-alkyl.

[0079] In one example P is phenyl substituted with a phenyl substituted with a -C1-C3-alkyl and a - O-C3-alkyl.

[0080] In one example P is phenyl substituted with a phenyl substituted with -CN and -O-C1-C6- alkyl.

[0081] In one example P is - ary 1-hetero aryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0082] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0083] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1- C6-alkyl. In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C3- alkyl.

[0084] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -CiPr.

[0085] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OnPr.

[0086] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1- C6-alkyl substituted with one or more halo.

[0087] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OCF3.

[0088] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with - OCH2CF3.

[0089] In one example P is -aryl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0090] In one example P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0091] In one example P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with - O-C1-C6-alkyl.

[0092] In one example P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with - O'Pr.

[0093] In one example P is -phenyl-pyridyl and wherein the pyridyl is substituted with -O-C1-C6- alkyl substituted with one or more halo.

[0094] In one example P is -phenyl-pyridyl and wherein the pyridyl is substituted with -OCH2CF3.

[0095] In one example P is -heteroaryl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo. In one example P is -heteroaryl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0096] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl.

[0097] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C3- alkyl.

[0098] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -CiPr.

[0099] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OnPr.

[0100] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl substituted with one or more halo.

[0101] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OCF3.

[0102] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -

[0103] OCH2CF3.

[0104] In one example P is -pyridyl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0105] In one example P is -pyridyl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0106] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl.

[0107] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C3-alkyl.

[0108] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -CiPr. In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OnPr.

[0109] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl substituted with one or more halo.

[0110] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCF3. In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCH2CF3.

[0111] In one example Q is selected from:

[0112] In one example Q is selected from:

[0113] In one example Q. is selected from:

[0114] In one example Q is In one example the compound or salt of Formula I is selected from one or more of the following:

[0115]

[0116] In one example the compound of Formula I is: or a salt thereof. In one example the compound of Formula I is: or a salt thereof.

[0117] In one example the compound of Formula I is:

[0118]

[0119] In one example the compound of Formula I is:

[0120] In one example the compound of Formula I is:

[0121] In one example the compound of Formula I is: or a salt thereof. In one example the compound of Formula I is: or a salt thereof.

[0122] In one example the compound of Formula I is: or a salt thereof.

[0123] In one example the compound of Formula I is: or a salt thereof. or a salt thereof. In one example the compound of Formula I is: or a salt thereof. In one example the compound of Formula I is: or a salt thereof.

[0124] In one example the compound of Formula I is: or a salt thereof.

[0125] In one example the compound of Formula I is: or a salt thereof.

[0126] In one example the compound of Formula I is: or a salt thereof.

[0127] In one example the compound of Formula I is: or a salt thereof.

[0128] In one example the compound of Formula I is: or a salt thereof. In one example the compound of Formula I is: or a salt thereof.

[0129] In one example the compound of Formula I is or a salt thereof.

[0130] In one example the compound of Formula I is: or a salt thereof.

[0131] In one example the compound of Formula I is: or a salt thereof.

[0132] In one example the compound of Formula I is: or a salt thereof.

[0133] In one example the compound of Formula I is: or a salt thereof.

[0134] In one example the compound of Formula I is: or a salt thereof.

[0135] In one example the compound of Formula I is: or a salt thereof.

[0136] In one example the compound of Formula I is: or a salt thereof.

[0137] In one example the compound of Formula I is: or a salt thereof.

[0138] In one example the compound of Formula I is: or a salt thereof.

[0139] In one example the compound of Formula I is: or a salt thereof.

[0140] In another aspect, there is provided a compound of Formula II wherein R may be selected from:

[0141] -C1-C6-(C=O)OH; or

[0142] -aryl-C(=O)-OH, -aryl-C(=O)-O-C1-C6, -aryl-C(=O)-O-C1-C6-O-(C=O)-Ci-C6, -aryl-C1-C6-

[0143] OH, -aryl-C1-C6-(C=O)OH or -aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-

[0144] N(C1-C6)2, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0145] -aryl-C(=O)-NH-S(O)2-C1-C6, -aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-C(=O)-NH- S(O)2-aryl, -aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -aryl-C(=O)-NH-S(O)2-heteroaryl, -aryl- C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0146] -aryl-C(=O)-NH-S(O)2-NH2, -aryl-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-C(=O)-NH-S(O)2-NH- C3-C8-cycloalkyl, -aryl-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, - aryl-C(=O)-NH-S(O)2-NH-heteroaryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -aryl-

[0147] , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or

[0148] -aryl-NH-C(=O)-NH-S(O)2-C1-C6, -aryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-NH-

[0149] C(=O)-NH-S(O)2-aryl, -aryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0150] -aryl-NH-C(=O)-NH-S(O)2-NH2, -aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-NH-C(=O)-

[0151] NH-S(O)2-NH-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-

[0152] S(O)2-NH-C1-C6-aryl, -aryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2,

[0153] , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or -aryl-S(O)2-OH, -aryl-S(O)2-NH2, -aryl-S(O)2-NH-C1-C6, -aryl-S(O)2-N(C1-C6)2, , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0154] -aryl-S(O)2-NH-C3-C8-cycloalkyl, or , wherein J is a 5 membered heterocycle ring containing up to 4 heteroatoms selected from , or -O-; or

[0155] -heteroaryl-C(=O)-OH, -heteroaryl-C(=O)-O-C1-C6, -heteroaryl-C(=O)-O-C1-C6-O-(C=O)- C1-C6, -heteroaryl-C1-C6-OH, -heteroaryl-C1-C6-(C=O)OH, or

[0156] -heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8- , wherein J is a

[0157] 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, -NC1-C6-, -S- or -O-; or

[0158] -heteroaryl-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, heteroaryl-C(=O)-NH-S(O)2-aryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-aryl, -heteroaryl-

[0159] C(=O)-NH-S(O)2-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0160] -heteroaryl-C(=O)-NH-S(O)2-NH2, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -heteroaryl-

[0161] C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -heteroaryl-

[0162] C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-heteroaryl, -heteroaryl-

[0163] C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2,

[0164] , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or -heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl,

[0165] -heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0166] -heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -heteroaryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, - heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-NH-C(=O)-NH-S(O)2- NH-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2- , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; wherein P may be a 5 to 10 membered aryl ring or rings optionally containing one or more heteroatoms, and wherein P may be further substituted with one or more halo, -C1-C6-alkyl, - C1-C6-alkyl substituted with one or more halo or hydroxy; -C3-C8-cycloalkyl, -CN, hydroxy, - O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, - S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1- wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O- ; or aryl, aryl substituted with one or more, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-aryl; C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-

[0167] , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or heteroaryl; heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6- alkyl)2, wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-heteroaryl; C1-C6-heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6- alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1- C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1- C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl,

[0168] , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0169] -O-aryl; -O-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6- alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0170] -O-C1-C6-aryl; -O-C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6- alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6- alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -

[0171] N(C1-C6-alkyl)2, , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or wherein Q may be selected from and wherein R3, R4, or R6are independently selected from -H, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo; and

[0172] In one example R is selected from: -C1-C6-(C=O)OH; or

[0173] -aryl-C(=O)-OH, or

[0174] -heteroaryl-C(=O)-OH; or

[0175] -aryl-C(=O)-NH-S(O)2-C1-C6.

[0176] In one example R is -aryl-C(=O)-OH.

[0177] In one example R is -phenyl-C(=O)-OH.

[0178] In one example R is -heteroaryl-C(=O)-OH.

[0179] In one example R is -pyridyl-C(=O)-OH.

[0180] In one example R is -C1-C6-(C=O)OH.

[0181] In one example R is - (CH2)3-(C=O)OH.

[0182] In one example R is , wherein J is a 5 membered heterocycle ring containing up to

[0183] 4 heteroatoms selected from -N=, -NH-, or -O-.

[0184] In one example R is -phenyl-tetrazole.

[0185] In one example R is -phenyl-oxadiazolone.

[0186] In one example P is selected from aryl or an aryl substituted with one or more halo, - CN, - C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1-C6- alkyl substituted with one or more halo.

[0187] In one example P is selected from aryl substituted with aryl or an aryl substituted with halo,- CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1- C6-alkyl substituted with one or more halo.

[0188] In one example P is selected from phenyl or a phenyl substituted with one or more halo, -CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1-C6- alkyl substituted with one or more halo.

[0189] In one example P is phenyl substituted with halo. In one example P is phenyl substituted with -Cl.

[0190] In one example P is selected from phenyl substituted with phenyl or a phenyl substituted with halo, -CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or - O-C1-C6-alkyl substituted with one or more halo.

[0191] In one example P is phenyl substituted with a phenyl.

[0192] In one example P is phenyl substituted with a phenyl substituted with halo.

[0193] In one example P is phenyl substituted with a phenyl substituted with -Cl.

[0194] In one example P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl.

[0195] In one example P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl substituted with one or more halo.

[0196] In one example P is phenyl substituted with a phenyl substituted with -OCH2CF3.

[0197] In one example P is phenyl substituted with a phenyl substituted with -O-C3-alkyl.

[0198] In one example P is phenyl substituted with a phenyl substituted with -OPr.

[0199] In one example P is phenyl substituted with a phenyl substituted with -OnPr.

[0200] In one example P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl substituted with one or more halo.

[0201] In one example P is phenyl substituted with a phenyl substituted with -CH2CF3.

[0202] In one example P is phenyl substituted with a phenyl substituted with a halo and a -O-C3- alkyl.

[0203] In one example P is phenyl substituted with a phenyl substituted with -F and a -O-C3-alkyl.

[0204] In one example P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl and a -

[0205] O-C1-C6-alkyl.

[0206] In one example P is phenyl substituted with a phenyl substituted with a -C1-C3-alkyl and a - O-C3-alkyl. In one example P is phenyl substituted with a phenyl substituted with -CN and -O-C1-C6- alkyl.

[0207] In one example P is - ary 1-hetero aryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0208] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0209] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1- C6-alkyl.

[0210] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C3- alkyl.

[0211] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -CiPr.

[0212] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OnPr.

[0213] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1- C6-alkyl substituted with one or more halo.

[0214] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OCF3.

[0215] In one example P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -

[0216] OCH2CF3.

[0217] In one example P is -aryl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0218] In one example P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0219] In one example P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with - O-C1-C6-alkyl.

[0220] In one example P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with - O'Pr.

[0221] In one example P is -phenyl-pyridyl and wherein the pyridyl is substituted with -O-C1-C6- alkyl substituted with one or more halo.

[0222] In one example P is -phenyl-pyridyl and wherein the pyridyl is substituted with -OCH2CF3.

[0223] In one example P is -heteroaryl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0224] In one example P is -heteroaryl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0225] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl.

[0226] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C3- alkyl.

[0227] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -CiPr.

[0228] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OnPr.

[0229] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl substituted with one or more halo.

[0230] In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OCF3. In one example P is a heteroaryl-phenyl and wherein the phenyl is substituted with - OCH2CF3.

[0231] In one example P is -pyridyl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0232] In one example P is -pyridyl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0233] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl.

[0234] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C3-alkyl.

[0235] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -CiPr.

[0236] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OnPr.

[0237] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6- alkyl substituted with one or more halo.

[0238] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCF3.

[0239] In one example P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCH2CF3.

[0240] In one example Q is selected from:

[0241] In one example Q is selected from:

[0242] In one example Q. is selected from:

[0243] In one example Q is In one example the compound or salt of Formula II is selected from one or more of the following:

[0244] In one example the compound of Formula II is: or a salt thereof.

[0245] In one example the compound of Formula II is: or a salt thereof. In one example the compound of Formula II is: or a salt thereof.

[0246] In one example the compound of Formula II is: or a salt thereof.

[0247] In one example the compound of Formula II is: or a salt thereof.

[0248] In one example the compound of Formula II is: or a salt thereof.

[0249] In one example the compound of Formula II is: or a salt thereof.

[0250] In one example the compound of Formula II is: or a salt thereof.

[0251] In one example the compound of Formula II is: or a salt thereof.

[0252] In one example the compound of Formula II is: or a salt thereof.

[0253] In one example the compound of Formula II is: or a salt thereof.

[0254] In one example the compound of Formula II is: or a salt thereof. In one example the compound of Formula II is: or a salt thereof.

[0255] In one example the compound of Formula II is: or a salt thereof.

[0256] In one example the compound of Formula II is: or a salt thereof.

[0257] In one example the compound of Formula II is: or a salt thereof.

[0258] In one example the compound of Formula II is or a salt thereof.

[0259] In another aspect, the present invention provides the compound of Formula I or II as defined above for reducing the formation of methane from the digestive actions of ruminants and / or for improving ruminant performance.

[0260] In one example a compound of Formula I or II as defined above is for reducing the formation of methane from the digestive actions of ruminants.

[0261] In one example a compound of Formula I or II as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 10%.

[0262] In another example of a compound of Formula I or II as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 15%.

[0263] In yet another example the compound of Formula I, or II as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 20%.

[0264] In one aspect the present invention further provides a method for reducing the production of methane emanating from a ruminant and / or for improving ruminant animal performance, comprising administering orally to the ruminant an effective amount of at least one compound of Formula I or II or a salt thereof to the ruminant. Oral administration is to be understood as a route involving drenching, addition to feed, water source or pasture; or manual administration of a bolus or a capsule.

[0265] In one example the effective amount of at least one compound of Formula I or II or a salt thereof is administered at least once-daily to the ruminant.

[0266] In one example the effective amount of at least one compound of Formula I or II or a salt thereof reduces the production of methane emanating from the ruminant by at least 10% per day.

[0267] In one example the effective amount of at least one compound of Formula I or II or a salt thereof reduces the production of methane emanating from the ruminant by at least 15% per day.

[0268] In one example the effective amount of at least one compound of Formula I or II or a salt thereof reduces the production of methane emanating from the ruminant by at least 20% per day.

[0269] In a further aspect of the present invention there is provided a composition for oral administration comprising at least one compound of Formula I or II or a salt thereof for reducing the production of methane emanating from a ruminant, and the composition further including at least one agriculturally and orally acceptable excipient.

[0270] In one example the composition is adapted for use as a feed additive.

[0271] In one example the composition is adapted for use as a water additive.

[0272] In another example the composition is adapted for use as a ruminant lick.

[0273] In one example the composition is adapted for use as an oral drench.

[0274] In another example the composition is adapted for use as a rumen bolus or capsule.

[0275] In one example the composition is adapted to reduce the production of methane emanating from the ruminant by at least 10% per day.

[0276] In one example the composition is adapted to reduce the production of methane emanating from the ruminant by at least 15% per day. In one example the composition is adapted to reduce the production of methane emanating from the ruminant by at least 20% per day.

[0277] In one example the excipient may include one or more minerals and / or one or more vitamins.

[0278] In one example the excipient may include one or more vitamins selected from vitamin A, vitamin D3, vitamin E, and vitamin K, e.g. vitamin K3, vitamin B12, biotin and choline, vitamin B l, vitamin B2, vitamin B6, niacin, folic acid or the like.

[0279] In one example the excipient may include one or more minerals selected from calcium, phosphorus, sodium, manganese, zinc, iron, copper, chlorine, sulphur, magnesium, iodine, selenium, and cobalt or the like.

[0280] In one example the composition may further include sunflower oil, electrolytes such as ammonium chloride, calcium carbonates, starch, proteins or the like.

[0281] The compounds of the present invention have potential for use in a ruminant to reduce the formation of methane without affecting microbial fermentation in a way that would be detrimental to the ruminant.

[0282] DETAILED DESCRIPTION OF INVENTION

[0283] DEFINTIONS

[0284] The term “ruminant” as used herein is a mammal that is able to acquire nutrients from plantbased food by fermenting it in a specialized foregut (the rumen) prior to digestion, principally through microbial activity. Representative examples of ruminants and other foregut fermenters include cattle, goats, sheep, giraffes, bison, moose, elk, yaks, water buffalo, deer, camels, alpacas, llamas, and antelope.

[0285] The term “effective amount” as used herein refers to an amount of at least one compound of Formula I or a salt thereof that either reduces the production of methane emanating from the ruminant or improves ruminant performance.

[0286] The term “ruminant performance” as used herein refers to improving the productivity of the ruminant, such as increased weight gain, milk yield or quality, wool growth or quality, surviving offspring per parturition, or the like. The term -C1-C6- means a carbon chain having from 1 to 6 carbons and being straight chained or branched, saturated or unsaturated, including but not limited to methyl, ethyl, ethylene, propyl, isopropyl, propylene, butyl, tert-butyl, butylene, pentyl, pentene, hexyl, hexene and the like, wherein the -C1-C6group is optionally substituted with one or more halo.

[0287] The term -C1-C6alkyl - means an alkyl chain having from 1 to 6 carbons, being straight chained or branched including but not limited to methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl and hexyl, wherein the -C1-C6alkyl group is optionally substituted with one or more halo.

[0288] The term “halo” as used herein refers to a halogen atom selected from Cl, Br, or F.

[0289] The term “aryl” as used herein refers to “aryl”, unless specifically limited, denotes a C5-12aryl group, suitably a C6-io aryl group, more suitably a C6-8 aryl group. Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings). Examples of a typical aryl group with one aromatic ring is phenyl. An example of a typical aryl group with two aromatic rings is naphthyl. The aryl group is optionally substituted with one or more -CN, -halo, -C(halo)3,- NH2, -NO2, -NH-( C1-C6alkyl), -N(C1-C6alkyl)2, -C1-C6alkyl, -C1-C6alkyl substituted with one or more halo, -C1-C6alkenyl, -C1-C6alkynyl, -O-Ci-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, aryl or substituted aryl, the substituted aryl, may include a substituted phenyl (benzyl group), a substituted thiophenol, a tosyl group, the substituted aryl group being substituted with one or more -CN, -halo, -C(halo)3,-NH2, -NO2-NH-( C1-C6alkyl), - N(C1-C6alkyl)2, C1-C6alkyl, C1-C6alkenyl and C1-C6alkynyl.

[0290] The term “heteroaryl” as used herein refers to ”, unless specifically limited, denotes an aryl residue, wherein one or more (e.g., 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g., 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O. Exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g., pyrrole, furan, thiophene,); and six membered rings (e.g., pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g., pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g., pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole, oxadiazole, oxadiazolone;. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary bicyclic heteroaryl groups include: indole (e.g., indol-6-yl), benzofuran, benzothiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine. The heteroaryl group is optionally substituted with one or more -CN, -halo, - C(halo)3,-NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, -NO2, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, aryl or substituted aryl, the substituted aryl, may include a substituted phenyl (benzyl group), a substituted thiophenol, a tosyl group, the substituted aryl group being substituted with one or more -CN, -halo, -C(halo)3,-NH2, -NH-( C1-C6alkyl), -N(C1-C6alkyl)2, alkyl, alkenyl and alkynyl.

[0291] The term “heterocyclyl” as used herein includes a “carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). The terms “heterocycle” or “heterocyclyl” includes saturated rings (i.e., heterocycloalkyls), partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.

[0292] Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, thiazolidine-dione; tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, oxadiazolyl, oxadiazolone, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidirtyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,2,5-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl.

[0293] By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4- thiazolyl, or 5-thiazolyl.

[0294] By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3- pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1- imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0295] All possible stereoisomers of the claimed compounds are included in the present disclosure. Where a compound described herein has at least one chiral center, it may accordingly exist as enantiomers. Where a compound possesses two or more chiral centers it may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present disclosure.

[0296] Some of the crystalline forms of the compounds may exist in more than one polymorphic form and as such all forms are intended to be included in the present disclosure. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this disclosure. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

[0297] The present disclosure further includes within its scope prodrugs of the compounds described herein. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired active compound. Thus, in these cases, the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject.

[0298] As used herein, the term “composition” is intended to encompass a product comprising a claimed compound(s) in a therapeutically effective amount, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.

[0299] The term “or a salt thereof,” as used herein, is a salt of an acid or a basic nitrogen atom. Illustrative salts include, but are not limited, to sodium salt, potassium salt, lithium salt, calcium salt, ammonium salt, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, and the like.

[0300] Methods of making Compounds of Formula I

[0301] The following compounds were prepared as follows:

[0302] 3-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 1)

[0303] A solution of 3-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-l / / -pyrazol-1-yl)benzoic acid (100 mg, 0.233 mmol) in DMSO (0.5 mL) was stirred at 110 °C under an oxygen atmosphere (1 atm) for 17 h. The solution was diluted with EtOAc (30 mL) and washed with H2O (3 x 10 mL), then brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (30% EtOAc in Pet. Ether) afforded Compound 1 (18 mg, 18%) as an orange solid.1H NMR (400 MHz, DMSO-d6) 6 13.17 (br s, 1H), 8.99-8.97 (m, 2H), 8.11 (d, 7 = 8.7 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 8.03-8.01 (m, 3H), 7.99-7.96 (m, 1H), 7.76 (dd, 7 = 8.7, 2.1 Hz, 1H), 7.62-7.59 (m, 1H), 7.57-7.53 (m, 4H);13C NMR (101 MHz, DMSO-d6) 5 166.3 (C), 150.5 (C), 146.6 (CH), 146.4 (CH), 143.1 (C), 141.9 (C), 141.8 (C), 139.6 (C), 132.8 (C), 132.0 (C), 131.2 (C), 131.1 (C), 130.3 (CH), 129.7 (CH), 129.6 (CH), 129.4 (CH), 128.9 (CH), 128.71 (CH), 128.66 (CH), 127.2 (CH), 125.7 (CH), 107.0 (CH); HRMS (ESI / Q-TOF) m / z: [M H] calcd for C24H14CIN4O2, 425.0811; found, 425.0810. 4-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 2)

[0304] A suspension of (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg, 0.679 mmol) and 4-hydrazinobenzoic acid (516 mg, 3.39 mmol) in AcOH (4 mL) was stirred under reflux for 6 h. The reaction mixture was poured onto ice-H2O, and the resulting precipitated solids were then collected by filtration and dried in vacuo. Purification by flash column chromatography (30 → 50% EtOAc in Pet. Ether) afforded Compound 2 (23 mg, 8%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.15 (hr s, 1H), 8.99-8.97 (m, 2H), 8.11 (d, J = 8.7 Hz, 1H), 8.08 (d, 7 = 1.9 Hz, 1H), 8.02-7.97 (m, 4H), 7.73 (dd, J = 8.7, 2.0 Hz, 1H), 7.57-7.52 (m, 5H);13C NMR (101 MHz, DMSO-d6) δ 166.5 (C), 150.8 (C), 146.6 (CH), 146.5 (CH), 143.2 (C), 142.7 (C), 141.91 (C), 141.87 (C), 132.9 (C), 131.1 (C), 130.4 (CH), 130.2 (CH), 130.1 (C), 129.6 (CH), 128.9 (CH), 128.7 (CH), 127.2 (CH), 125.0 (CH), 107.5 (CH); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C24H16CIN4O2, 427.0956; found, 427.0957.

[0305] 3-(3-([1,1'-Biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound

[0306] 3)

[0307] A solution of 3-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H -pyrazol-1- yl)benzoic acid (30 mg, 0.06 mmol) in DMSO (0.5 mL) was stirred at 110 °C under an oxygen atmosphere (1 atm) for 17 h. The solution was diluted with EtOAc (30 mL) and washed with H2O (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (50 → 66% EtOAc in Pet. Ether) afforded Compound 3 (11 mg, 39%) as a pale yellow solid.1H NMR (400 MHz, CDCI3) 5 8.88-8.90 (m, 2H), 8.29-8.26 (m, 1H), 8.12-8.01 (m, 5H), 7.73-7.64 (m, 5H), 7.57-7.53 (m, 1H), 7.49- 7.42 (m, 3H), 7.39-7.34 (m, 1H), 7.08 (s, 1H);13C NMR (101 MHz, CDCI3) 5 167.9 (C), 152.6 (C), 145.74 (CH), 145.70 (CH), 143.2 (C), 142.7 (C), 141.3 (C), 140.8 (C), 140.2 (C), 132.0 (C), 131.5 (C), 130.9 (C), 130.5 (CH), 130.2 (CH), 130.1 (CH), 129.6 (CH), 129.4 (CH), 129.1 (CH), 128.9 (CH), 127.57 (CH), 127.52 (CH), 127.1 (CH), 127.0 (CH), 126.4 (CH), 106.8 (CH); HRMS (ESI+ / Q-TOF) m / z. [M+H]+calcd for C30H21N4O2, 469.1665; found, 469.1659.

[0308] 4-(3-([1,1'-Biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 4)

[0309] A suspension of (E)-1-([1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg, 0.60 mmol) and 4-hydrazinobenzoic acid (364 mg, 2.4 mmol) in AcOH (4 mL) was refluxed for 6 h. The reaction mixture was poured onto ice-H2O, and the resulting precipitated solids were then collected by filtration and dried in vacuo. Purification by flash column chromatography (50 → 66% EtOAc in Pet. Ether) afforded Compound 4 (34 mg, 12%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.90-8.92 (m, 2H), 8.17-8.12 (m, 2H), 8.09 (d, 7 = 8.7 Hz, 2H), 8.03 (d, 7 = 7.4 Hz, 2H), 7.77-7.69 (m, 5H), 7.58-7.52 (m, 2H), 7.50- 7.44 (m, 2H), 7.40-7.34 (m, 1H), 7.09 (s, 1H);13C NMR (101 MHz, DMSO-d6) δ 168.8 (C), 152.9 (C), 145.8 (CH), 145.6 (CH), 143.8 (C), 143.2 (C), 142.8 (C), 142.5 (C), 141.4 (C), 140.7 (C), 132.2 (C), 131.4 (C), 131.3 (CH), 130.6 (CH), 130.2 (CH), 129.0 (CH), 128.9 (CH), 128.6 (C), 127.6 (CH), 127.1 (CH), 126.4 (CH), 124.9 (CH), 107.4 (CH); HRMS (ESI+ / Q-TOF) m / r. [M+H]+calcd for C30H21N4O2, 469.1659; found, 469.1659.

[0310] 3-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 5)

[0311] A solution of 3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H- pyrazol-1-yl)benzoic acid (30 mg, 0.06 mmol) in DMSO (0.5 mL) was stirred at 110 °C under an oxygen atmosphere (1 atm) for 17 h. The solution was diluted with EtOAc (30 mL) and washed with H2O (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (50 → 66% EtOAc in Pet. Ether) afforded Compound 5 (12 mg, 38%) as a pale yellow solid.1H NMR (400 MHz, CDCI3) δ 8.88-8.90 (m, 2H), 8.27 (t, J = 2.0 Hz, 1H), 8.12-8.04 (m, 3H), 8.02-7.98 (m, 2H), 7.71-7.64 (m, 3H),

[0312] 7.63-7.54 (m, 3H), 7.46-7.41 (m, 1H), 7.07 (s, 1H), 7.00-6.96 (m, 2H), 4.65-4.56 (m, 1H), 1.38 (d, J = 6.5 Hz, 6H);13C NMR (101 MHz, CDCh) 5 167.7 (C), 157.7 (C), 152.7 (C), 145.74

[0313] (CH), 145.69 (CH), 143.2 (C), 142.7 (C), 140.9 (C), 140.2 (C), 133.0 (C), 132.1 (C), 130.9 (C),

[0314] 130.8 (C), 130.5 (CH), 130.2 (CH), 130.0 (CH), 129.5 (CH), 129.4 (CH), 129.1 (CH), 128.1

[0315] (CH), 127.0 (CH), 126.4 (CH), 116.2 (CH), 106.7 (CH), 70.1 (CH), 22.2 (CH3); HRMS (ESI / Q-TOF) m / z. [M H] calcd for C33H25N4O3525.1932; found 525.1930.

[0316] 4-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 6)

[0317] A solution of 4-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H- pyrazol-1-yl)benzoic acid (39 mg, 0.06 mmol) in DMSO (0.5 mL) was stirred at 110 °C under an oxygen atmosphere (1 atm) for 17 h. The solution was diluted with EtOAc (30 mL) and washed with H2O (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (50 → 66% EtOAc in Pet. Ether) afforded Compound 6 (21 mg, 67%) as a pale yellow solid.1H NMR (400 MHz, CDCI3) δ 8.90-8.89 (m, 2H), 8.17-8.12 (m, 2H), 8.09 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 7.4 Hz, 2H), 7.73 (dd, J = 8.7, 1.6 Hz, 1H), 7.67 (d, 7 = 8.1 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.07 (s, 1H), 6.98 (d, 7 = 8.3 Hz, 2H), 4.65-4.57 (m, 1H), 1.38 (d, 7 = 6.3 Hz, 6H);13C NMR (101 MHz, DMSO-d6) δ 166.5 (C), 157.2 (C), 151.7 (C), 146.5 (CH), 146.4 (CH), 143.0 (C),

[0318] 142.7 (C), 141.9 (C), 141.86 (C), 139.7 (C), 131.6 (C), 131.3 (C), 130.5 (C), 130.4 (CH), 130.3 (CH), 129.6 (CH), 128.6 (CH), 127.7 (CH), 126.4 (CH), 126.1 (CH), 124.9 (CH), 116.0 (CH), 107.4 (CH), 69.2 (CH), 21.8 (CH3); HRMS (ESI+ / Q-TOF) m / r [M+H]+calcd for C33H27N4O3, 527.2078; found, 527.2077.

[0319] 6-(1-(3-(1H-Tetrazol-5-yl)phenyl)-3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5- yl)quinoxaline (Compound 17)

[0320] To a solution of 3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzonitrile (100 mg, 197 μmol) and triethylamine hydrochloride (81 mg, 591 μmol) in DMF (2 mL) was added sodium azide (38 mg, 591 μmol) in a single portion. The reaction mixture was stirred at reflux overnight then diluted with 0.5 M aq. HC1 (30 mL). The resulting mixture was extracted with EtOAc (4 x 10 mL) and the combined organic extracts were washed with H2O (3 x 10 ml) and brine (1 x 10 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (0 → 20% MeOH in EtOAc) to afford Compound 17 (67 mg, 62%) as a pale- brown solid.1H NMR (400 MHz, DMSO-d6) δ 9.01 - 8.95 (m, 2H), 8.29 (t, J = 1.9 Hz, 1H), 8.17 - 8.04 (m, 5H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.55 - 7.48 (m, 1H), 7.03 (d, J = 8.6 Hz, 2H), 4.69 (hept, J = 6.0 Hz, 1H), 1.31 (d, 7 = 5.9 Hz, 6H);13C NMR (101 MHz, DMSO-d6) 6 157.25, 155.17, 151.50, 146.56, 146.40, 142.98, 141.94, 141.82, 140.34, 139.65, 131.62, 131.18, 130.55, 130.40, 130.29, 129.59, 128.62, 127.69, 127.58, 126.43, 126.27, 126.03, 125.83, 123.51, 116.00, 107.05, 69.21, 21.84; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C33H27N8O 551.2302; found 551.2296.

[0321] 3-(3-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Compound 18)

[0322] A solution of N'-hydroxy-3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzimidamide (75.0 mg, 0.139 mmol), CDI (42.0 mg, 0.259 mmol) and DBU (0.03 mL, 0.201 mmol) in 1,4-di oxane (2 mL) was heated at 110 °C in a microwave for 1 h. The solution was diluted with EtOAc (30 mL) and washed with 1 M aq. HC1 (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (80 → 100% EtOAc in Pet. Ether) afforded Compound 18 (12.7 mg, 16%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 13.06 (br s, 1H), 8.98-8.98 (m, 2H), 8.13-8.04 (m, 5H), 7.87-7.85 (m, 1H), 7.79- 7.75 (m, 3H), 7.68 (d, J= 8.6 Hz, 2H), 7.63-7.59 (m, 1H), 7.56-7.52 (m, 2H), 7.03 (d, J= 8.7 Hz, 2H), 4.68 (hept, J = 6.1 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H); HRMS (ESE / Q-TOF) m / z: [M-H]- calcd for C34H25N6O3565.1993; found 565.1992.

[0323] 3-(3-(6-(4-Isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 19)

[0324] To a solution of methyl 3-(3-(6-(4-isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzoate (37.8 mg, 0.070 mmol) in MeOH-THF (0.7 mL, 1:1 v / v) was added 1 M aq. NaOH (0.35 mL). The reaction mixture was stirred at RT for 17 h then quenched with 0.1 M aq. HC1 (4 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 x 5 mL) to afford Compound 19 (26.6 mg, 72%) as an amorphous pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J = 2.5 Hz, 1H), 8.99-8.97 (m, 2H), 8.37 (dd, J = 8.4, 2.2 Hz, 1H), 8.12-8.09 (m, 4H), 8.03-8.01 (m, 2H), 7.99-7.97 (m, 1H), 7.77 (dd, J = 8.7, 2.0 Hz, 1H), 7.63-7.61 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 8.9 Hz, 2H), 4.72 (hept, J = 6.0 Hz, 1H), 1.31 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, DMSO-d6) δ 166.8 (C), 159.0 (C), 155.9 (C), 149.5 (C), 147.1 (CH), 147.0 (CH), 143.6 (C), 142.4 (C), 142.3 (C), 140.1 (C), 134.1 (CH), 131.6 (C) 130.9 (C), 130.8 (CH), 130.2 (CH), 130.1 (CH), 129.3 (CH), 129.2 (CH), 128.4 (CH), 126.4 (C), 126.3 (CH), 119.8 (CH), 116.1 (CH), 107.6 (CH), 69.7 (CH), 22.3 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C32H26N5O3, 528.2030; found, 528.2026.

[0325] 3-(3-(4-(6-Isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 20) To a solution of methyl 3-(3-(4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzoate (30.0 mg, 0.055 mmol) in MeOH-THF (0.6 mL, 1:1 v / v) was added 1 M aq. NaOH (0.28 mL). The reaction mixture was stirred at RT for 17 h then quenched with 0.1 M aq. HC1 (4 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 x 5 mL) to afford Compound 20 (20.6 mg, 70%) as an amorphous pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.99-8.97 (m, 2H), 8.56 (d, J = 2.6 Hz, 1H), 8.12-8.02 (m, 6H), 7.98-7.96 (m, 1H), 7.81-7.76 (m, 3H), 7.63-7.60 (m, 1H), 7.57- 7.53 (m, 2H), 6.85 (d, J = 8.5 Hz, 1H), 5.32 (hept, J = 6.2 Hz, 1H), 1.33 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, DMSO-d6) δ 166.3 (C), 162.5 (C), 151.3 (C), 146.6 (CH), 146.5 (CH), 144.7 (CH), 143.0 (C), 141.9 (C), 141.8 (C), 139.7 (C), 137.4 (CH), 136.8 (C), 132.0 (C), 131.3 (C), 131.2 (C), 130.3 (CH), 129.7 (CH), 129.6 (CH), 129.4 (CH), 128.6 (CH), 128.3 (C), 126.6 (CH), 126.1 (CH), 125.7 (CH), 111.2 (CH), 107.1 (CH), 67.6 (CH), 21.9 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C32H26N5O3, 528.2030; found, 528.2028.

[0326] 3-(3-(3'-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoic acid (Compound 21)

[0327] To a solution of methyl 3-(3-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6- yl)-1H-pyrazol-1-yl)benzoate (70.0 mg, 0.125 mmol) in MeOH-THF (1.3 mL, 1:1 v / v) was added 1 M aq. NaOH (0.63 mL). The reaction mixture was stirred at RT for 17 h then quenched with 0.1 M aq. HC1 (10 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 x 10 mL) to afford Compound 21 (39.1 mg, 57%) as an amorphous pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13.09 (br s, 1H), 8.98-8.97 (m, 2H), 8.11 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 8.03-8.02 (m, 1H), 7.98-7.96 (m, 1H), 7.80-7.76 (m, 3H), 7.65 (dd, J = 12.9, 2.2 Hz, 1H), 7.63-7.60 (m, 1H), 7.57-7.52 (m, 3H), 7.28 (t, J = 8.9 Hz, 1H), 4.70 (hept, J = 6.1 Hz, 1H), 1.32 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, DMSO-d6) δ 166.3 (C), 152.9 (C, d, J = 243.3 Hz), 151.3 (C), 146.6 (CH), 146.4 (CH), 144.8 (C, d, J = 10.7 Hz), 142.9 (C), 141.9 (C), 141.8 (C), 139.7 (C), 138.4 (C), 132.7 (C, d, J = 7.3 Hz), 132.0 (C), 131.3 (C), 131.2 (C), 130.3 (CH) 129.7 (CH), 129.6 (CH), 129.4 (CH), 128.6 (CH), 126.7 (CH), 126.0 (CH), 125.7 (CH), 122.6 (CH, d, J = 2.7 Hz), 117.3 (CH, d, J = 1.8 Hz), 114.2 (CH, d, J = 19.1 Hz), 107.1 (CH), 71.3 (CH), 21.8 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C33H26FN4O3, 545.1984; found, 545.1982.

[0328] 3-(3-(4'-Isopropoxy-3'-methyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoic acid (Compound 22)

[0329] To a solution of methyl 3-(3-(4'-isopropoxy-3'-methyl[1,1'- biphenyl]-4-yl)-5-(quinoxalin-6- yl)-1H-pyrazol-1-yl)benzoate (55.0 mg, 99 μmol) in MeOH-THF (1.5 mL, 1:2 v / v) was added 1 M aq. NaOH (0.5 mL). The reaction mixture was stirred at RT for 18 h then quenched with 0.1 M aq. HC1 (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford Compound 22 (49.5 mg, 92%) as an amorphous pale-yellow solid.1H NMR (500 MHz, DMSO-d6) δ 13.20 (br s, 1H), 8.98-8.97 (m, 2H), 8.11 (d, 7 = 8.7 Hz, 1H), 8.09 (d, 7= 1.9 Hz, 1H), 8.04-8.02 (m, 3H), 7.98-7.96 (m, 1H), 7.78 (dd, 7 = 8.7, 2.0 Hz, 1H), 7.74 (d, 7 = 8.4 Hz, 2H), 7.62-7.60 (m, 1H), 7.56-7.51 (m, 4H), 7.05 (d, 7 = 8.7 Hz, 1H), 4.65 (hept, 7 = 6.0 Hz, 1H), 2.22 (s, 3H), 1.31 (d, 7 = 6.0 Hz, 6H);13C NMR (125 MHz, DMSO-d6) 6 166.3 (C), 155.5 (C), 151.4 (C), 146.6 (CH), 146.4 (CH), 142.9 (C), 141.9 (C), 141.8 (C), 139.8 (C), 139.7 (C), 132.0 (C), 131.30 (C), 131.28 (C), 130.5 (C), 130.3 (CH), 129.7 (CH), 129.6 (CH), 129.4 (CH), 128.8 (CH), 128.6 (CH), 127.2 (C), 126.4 (CH), 126.0 (CH), 125.7 (CH), 125.0 (CH), 113.4 (CH), 107.0 (CH), 69.7 (CH), 22.1 (CH3), 16.3 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C34H29N4O3, 541.2234; found, 541.2231. 3-(3-(3'-Cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoic acid (Compound 23)

[0330] To a solution of methyl 3-(3-(3'-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6- yl)-1H-pyrazol-1-yl)benzoate (35.2 mg, 0.063 mmol) in MeOH-THF (1.0 mL, 1:1 v / v) was added 1 M aq. NaOH (0.52 mL). The reaction mixture was stirred at RT for 15 h then quenched with 0.1 M aq. HC1 (4 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 x 5 mL) to afford Compound 23 (16.8 mg, 49%) as an amorphous pale yellow solid.1H NMR (500 MHz, DMSO-d6) δ 8.99-8.97 (m, 2H), 8.14 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.09-8.02 (m, 5H), 7.98-7.96 (m, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.78 (dd, J = 8.7, 2.0 Hz, 1H), 7.62-7.61 (m, 1H), 7.57 (s, 1H), 7.55 (t, J = 7.88 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 4.87 (hept, J = 6.0 Hz, 1H), 1.36 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, DMSO-d6) δ 166.3 (C), 158.8 (C), 151.2 (C), 146.6 (CH), 145.5 (CH), 143.0 (C), 141.9 (C), 141.8 (C), 139.7 (C), 137.5 (C), 132.9 (CH), 132.2 (C), 131.54 (CH), 131.46 (C), 131.2 (C), 130.3 (CH), 129.7 (CH), 129.6 (CH), 129.4 (CH), 128.7 (CH), 128.6 (CH), 126.8 (CH), 126.1 (CH), 125.7 (CH), 116.5 (C), 114.8 (CH), 107.1 (CH), 102.1 (C), 71.6 (CH), 21.7 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C34H26N5O3, 552.2030; found, 552.2026.

[0331] 3-(5-(Quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1- yl)benzoic acid (Compound 24)

[0332] To a solution of methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4- yl)-1H-pyrazol-1-yl)benzoate (54.4 mg, 0.094 mmol) in THF (2.7 mL) was added 1 M aq. LiOH (0.94 mL). The reaction mixture was stirred at RT for 17 h then quenched with 1 M aq. HC1 (10 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 x 5 mL). The crude residue was purified by flash chromatography (0 → 20% MeOH in EtOAc) to afford Compound 24 (14.5 mg, 27%) as an amorphous yellow solid.1H NMR (500 MHz, DMSO-d6) δ 8.99-8.97 (m, 2H), 8.12-8.02 (m, 5H), 7.98-7.96 (m, 1H), 7.79-7.73 (m, 5H), 7.63-7.60 (m, 1H), 7.57-7.53 (m, 2H), 7.18 (d, J = 9.0 Hz, 2H), 4.84 (q, J = 8.9 Hz, 2H);13C NMR (125 MHz, DMSO-d6) δ 166.3 (C), 156.7 (C), 151.3 (C), 146.6 (CH), 146.4 (CH), 142.9 (C), 141.9 (C), 141.8 (C), 139.7 (C), 139.2 (C), 133.5 (C), 132.0 (C), 131.3 (C), 130.9 (C), 130.3 (CH), 129.7 (CH), 129.6 (CH), 129.4 (CH), 128.6 (CH), 127.8 (CH), 126.7 (CH), 126.1 (CH), 126.0 (CH), 125.7 (CH), 124.1 (C, q, J = 278.2 Hz), 115.4 (CH), 107.1 (CH), 64.7 (CH2, q, J= 34.1 Hz); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C32H22F3N4O3, 567.1639; found, 567.1636.

[0333] 3-(5-(Quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-1H-pyrazol-1- yl)benzoic acid (Compound 25)

[0334] To a solution of methyl 3-(5-(quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)-1H-pyrazol-1-yl)benzoate (118 mg, 0.203 mmol) in MeOH-THF (2 mL, 1 : 1 v / v) was added 1 M aq. NaOH (1 mL). The reaction mixture was stirred at 40 °C for 16 h then quenched with 0.1 M aq. HC1 (4 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 x 5 mL) to afford Compound 25 (104 mg, 90%) as an amorphous off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.98-8.97 (m, 2H), 8.62-8.61 (m, 1H), 8.21 (dd, J= 8.6, 2.6 Hz, 1H), 8.12-8.08 (m, 4H), 8.03-8.02 (m, 1H), 7.98-7.96 (m, 1H), 7.83 (d, J= 8.4 Hz, 2H), 7.78 (dd, J= 8.7, 2.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.56-7.52 (m, 2H), 7.11 (d, J = 7.8 Hz, 1H), 5.06 (q, J= 9.1 Hz, 2H);13C NMR (101 MHz, DMSO-d6) δ 166.4 (C), 160.7 (C), 151.1 (C), 146.6 (CH), 146.4 (CH), 144.4 (CH), 143.0 (C), 141.9 (C), 141.8 (C), 139.7 (C), 138.4 (CH), 136.2 (C), 131.6 (C), 131.2 (C), 130.4 (C), 130.3 (CH), 129.6 (CH), 129.2 (CH), 128.7 (CH), 128.6 (CH), 126.9 (CH), 126.1 (CH), 125.8 (CH), 124.1 (C, q, J = 278 Hz), 110.8 (CH), 107.1 (CH), 61.4 (CH2, q, J= 34.6 Hz). 3-(3-(4'-Isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic add

[0335] (Compound 26)

[0336] To a solution of methyl 3-(3-(4'-isopropyl-[l,T-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-l / / - pyrazol-1-yl)benzoate (40 mg, 78 μmol) in THF (4 mL) was added 1 M aq. LiOH (1 mL). The reaction mixture was stirred at RT overnight then quenched with 0.1 M aq. HC1 (50 mL). The resulting mixture was extracted with EtOAc (4 x 10 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford Compound 26 (39 mg, quant.) as an amorphous pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.98 (d, J = 1.9 Hz, 1H), 8.97 (d, J = 1.9 Hz, 1H), 8.13 - 8.02 (m, 5H), 7.97 (dt, J = 7.6, 1.4 Hz, 1H), 7.80 - 7.74 (m, 3H), 7.67 (d, J = 8.6 Hz, 2H), 7.64 - 7.59 (m, 1H), 7.58 - 7.52 (m, 2H), 7.36 (d, J = 8.5 Hz, 2H), 2.94 (hept, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H);13C NMR (101 MHz, DMSO-d6) δ 166.29, 151.35, 147.82, 146.56, 146.40, 142.90, 141.89, 141.78, 139.87, 137.13, 132.00, 131.24, 131.07, 130.31, 129.66, 129.57, 129.36, 128.60, 126.90, 126.83, 126.48, 126.02, 125.69, 107.02, 33.08, 23.81; HRMS (ESI+ / Q-TOF) m / v [M+H]+calcd for C33H27N4O2511.2128; found 511.2126.

[0337] 3-(5-(Quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1- yl)benzoic acid (Compound 27)

[0338] To a solution of methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4- yl)-1H-pyrazol-1-yl)benzoate (50.1 mg, 0.089 mmol) in THF (2.5 mL) was added 1 M aq. LiOH (0.89 mL). The reaction mixture was stirred at RT for 24 h then quenched with 0.1 M aq. HC1 (10 mL). The resulting precipitate was collected by vacuum filtration and washed with H2O (4 × 5 mL). The crude residue was purified by flash chromatography (0 → 20% MeOH in EtOAc) to afford Compound 27 (18.0 mg, 37%) as an amorphous off-white solid.1H NMR (500 MHz, DMSO-d6) δ 8.98-8.97 (m, 2H), 8.12-8.08 (m, 4H), 8.02-8.01 (m, 1H), 7.98-7.96 (m, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.79-7.77 (m, 3H), 7.59-7.47 (m, 5H), 3.72 (q, J = 11.6 Hz, 2H);13C NMR (125 MHz, DMSO-d6) δ 151.2 (C), 146.6 (CH), 146.4 (CH), 142.9 (C), 141.9 (C), 141.8 (C), 139.6 (C), 139.3 (C), 139.2 (C), 131.6 (C), 131.3 (C), 130.9 (CH), 130.3 (CH), 129.6 (CH), 129.5 (CH), 128.7 (CH), 128.6 (CH), 127.1 (CH), 126.7 (CH), 126.4 (C, q, J = 277 Hz), 126.1 (CH), 125.8 (CH), 107.0 (CH), 38.1 (CH2, q, J = 28.4 Hz); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C32H22F3N4O2, 551.1689; found, 551.1687.

[0339] 3-(5-(Benzo[c][l,2,5]oxadiazol-5-yl)-3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1- yl)benzoic acid (Compound 28)

[0340] To a solution of methyl 3-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(4'-isopropoxy-[1,1'-biphenyl]- 4-yl)-1H-pyrazol-1-yl)benzoate (37 mg, 69 μmol) in THF (3 mL) was added 1 M aq. LiOH (1 mL). The reaction mixture was stirred at RT overnight then quenched with 0.1 M aq. HC1 (40 mL). The resulting mixture was extracted with EtOAc (4 x 10 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford Compound 28 (30 mg, 84%) as an amorphous off-white solid.1H NMR (500 MHz, Acetone- d6) δ 8.22 (t, J = 1.9 Hz, 1H), 8.10 - 8.05 (m, 4H), 7.97 (dd, J = 9.3, 1.1 Hz, 1H), 7.75 - 7.70 (m, 3H), 7.66 (d, J = 8.7 Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.50 (dd, J = 9.3, 1.4 Hz, 1H), 7.41 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.68 (hept, J = 6.0 Hz, 1H), 1.33 (d, J = 6.1 Hz, 6H);13C NMR (126 MHz, Acetone--d6) δ 166.61, 158.74, 152.97, 150.04, 149.36, 143.13, 141.45,

[0341] 140.99, 134.83, 134.18, 133.30, 132.84, 131.80, 130.46, 130.01, 129.71, 128.68, 127.49,

[0342] 126.99, 126.76, 117.47, 116.95, 116.41, 108.01, 70.32, 22.29; HRMS (ESL / Q-TOF) m / z: [M-H]- calcd for C31H23N4O4515.1725; found 515.1721.

[0343] 4-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoic acid (Compound 29)

[0344] To a solution containing a ca. 2:1 mixture of ethyl 4-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)- 5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoate and ethyl 4-(5-(4'-isopropoxy-[1,1'-biphenyl]- 4-yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoate (7.4 mg, 14 μmol) in THF-MeOH (2 mL, 3:1 v / v) was added 1 M aq. LiOH (0.5 mL). The reaction mixture was stirred at RT for two days then quenched with 0.1 M aq. HC1 (10 mL). The resulting mixture was extracted with EtOAc (4 x 3 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a ca. 2: 1 mixture of Compound 29:1H NMR (300 MHz, DMSO-d6) δ 9.04 (d, J = 1.9 Hz, 1H), 9.03 (d, J = 1.9 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.07 (dd, J = 8.7, 2.0 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.74 - 7.60 (m, 6H), 7.13 (s, 1H), 7.08 - 6.97 (m, 3H), 4.74 - 4.60 (m, 1H), 4.39 - 4.24 (m, 2H), 2.34 - 2.17 (m, 2H), 2.11 - 1.96 (m, 2H), 1.33 - 1.28 (m, 6H); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C30H29N4O3493.2234; found 493.2229; and 4-(5-(4'-isopropoxy-[1,1'-biphenyl]-4- yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoic acid as an amorphous off-white solid (7 mg, quant.).

[0345] Methods of making Compounds of Formula II

[0346] The following compounds were prepared as follows:

[0347] 3-(5-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoic acid (Compound 30)

[0348] To a solution of methyl 3-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzoate (31 mg, 56 μmol) in THF (3 mL) was added 1 M aq. LiOH (1 mL). The reaction mixture was stirred at RT overnight then quenched with 0.1 M aq. HC1 (40 mL). The resulting mixture was extracted with EtOAc (4 x 10 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford Compound 30 (22 mg, 74%) as an amorphous off-white solid.1H NMR (500 MHz, Acetone-d6) δ 8.94 (d, J = 1.8 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 1.9 Hz, 1H), 8.56 (dd, J = 8.7, 1.9 Hz, 1H), 8.22 (t, J = 1.9 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.08 (dt, J = 7.7, 1.4 Hz, 1H), 7.71 -

[0349] 7.66 (m, 3H), 7.66 - 7.58 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 7.01 (d, J = 8.8 Hz,

[0350] 2H), 4.68 (hept, J = 6.0 Hz, 1H), 1.32 (d, J = 6.0 Hz, 6H);13C NMR (126 MHz, Acetone-d6) δ 158.96, 151.61, 146.91, 146.19, 145.86, 144.27, 143.82, 141.75, 141.45, 135.60, 132.72,

[0351] 130.74, 130.28, 130.20, 130.14, 129.61, 129.14, 128.79, 128.73, 127.33, 127.09, 126.12,

[0352] 116.92, 107.08, 70.34, 22.27; HRMS (ESI / Q-TOF) m / z. [M-H]" calcd for C33H25N4O3525.1932; found 525.1931.

[0353] 4-(5-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoic acid (Compound 31)

[0354] To a solution of ethyl 4-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H- pyrazol-1-yl)butanoate (9 mg, 18 μmol) in a mixture of THF-MeOH (2 mL, 3:1 v / v) was added 1 M aq. LiOH (0.5 mL). The reaction mixture was stirred at RT overnight then quenched with 0.1 M aq. HC1 (10 mL). The resulting mixture was extracted with EtOAc (4 x 3 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford Compound 31 (8.8 mg, quant.) as an amorphous off-white solid.1H NMR (400 MHz, Acetone-d6) δ 8.91 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.48 (dd, J = 8.8, 1.9 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.70 - 7.65 (m, 4H), 7.08 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.70 (hept, J = 6.0 Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 2.27 - 2.19 (m, 2H), 1.34 (d, J = 6.0 Hz, 6H);13C NMR (101 MHz, acetone-d6) δ 158.05, 148.76, 145.82, 145.33, 144.93, 143.41, 142.64, 140.90, 135.45, 132.04, 129.58, 129.31, 128.62, 127.93, 127.84, 126.62, 124.46, 116.11, 103.91, 69.48, 48.82, 25.42, 21.38. The following precursor or intermediate compounds referred to above were prepared as follows:

[0355] 3-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid

[0356] A suspension of (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg, 0.68 mmol) and 3-hydrazinobenzoic acid (104 mg, 0.68 mmol) in AcOH-nBuOH (15 mL, 1:2 v / v) was stirred at 120 °C for 4 h (before returning to room temperature). The reaction mixture was then concentrated in vacuo and the resulting residue was purified by flash column chromatography (5% MeOH in DCM) to afford 3-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)- 4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (60 mg, 21%) as abrown solid.1H NMR (400 MHz, CDCl3) δ 9.94 (br s, 1H), 8.82 (s, 2H), 8.10 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.67 (m, 3H), 7.50 (d, 7 = 6.7 Hz, 1H), 7.35-7.20 (m, 4H), 5.58 (dd, J = 11.5, 6.3 Hz, 1H), 3.92 (dd, J = 16.7, 12.8 Hz, 1H), 3.19 (dd, 7 = 17.1, 6.4 Hz, 1H);13C NMR (101 MHz, CDCI3) δ 171.3 (C), 146.5 (C), 145.5 (CH), 145.2 (CH), 144.4 (C), 144.2 (C), 143. 0 (C), 142.5 (C), 135.0 (C), 131.0 (CH), 130.8 (C), 129.3 (CH), 129.0 (CH), 128.2 (CH), 127.2 (CH), 126.4 (CH), 121.3 (CH), 118.3 (CH), 114.8 (CH), 64.0 (CH), 43.4 (CH2); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C24H18ClN4O2, 429.1113; found, 429.1123.

[0357] (E)-1-(4-Chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0358] To a solution of quinoxaline-6-carbaldehyde (2.00 g, 12.6 mmol) and 4-chloroacetophenone (1.64 mL, 12.6 mmol) in EtOH (120 mL) at 0 °C was added dropwise 2 M aq. NaOH (32 mL), and the reaction mixture stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solids were then collected by filtration, washed with H2O and dried in vacuo to afford (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (2.43 g, 65%) as a colourless solid, which was used in the next step without further purification.

[0359] 3-(3-([1,1'-Biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid

[0360] A suspension of (E)-1-([1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (300 mg, 0.90 mmol) and 3-hydrazinobenzoic acid (137 mg, 0.90 mmol) in AcOH-nBuOH (18 mL, 1:2 v / v) was stirred at 120 °C for 4 h. A second portion of 3-hydrazinobenzoic acid was added (137 mg, 0.90 mmol) and the mixture was stirred at 120 °C for a further 2 h. The reaction mixture was then concentrated in vacuo and the resulting residue was diluted with EtOAc (50 mL) and washed with H2O (2 x 30 mL), then brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (50 → 100% EtOAc in Pet. Ether, then 10% MeOH in DCM) afforded 3-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)- 4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (68 mg, 16%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.83 (br s, 1H), 8.95-8.93 (m, 2H), 8.13 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.81-7.71 (m, 6H), 7.54-7.46 (m, 2H), 7.42-7.38 (m, 1H), 7.37- 7.23 (m, 3H), 5.95 (dd, J = 12.2, 5.8 Hz, 1H), 4.11 (dd, J = 17.6, 12.3 Hz, 1H), 3.40-3.34 (m, 1H);13C NMR (101 MHz, DMSO-d6) δ 167.4 (C), 148.1 (C), 146.1 (CH), 145.8 (CH), 144.1 (C), 144.0 (C), 142.2 (C), 141.7 (C), 140.5 (C), 139.4 (C), 131.6 (C), 131.0 (C), 130.5 (CH), 129.3 (CH), 129.0 (CH), 128.2 (CH), 127.8 (CH), 126.9 (CH), 126.6 (CH), 125.9 (CH), 119.7 (CH), 117.0 (CH), 113.6 (CH), 62.7 (CH), 42.7 (CH2); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C30H23N4O2, 471.1816; found, 471.1812.

[0361] (E)-1-([1,1'- Biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0362] To a solution of quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol) and 4 -acetylbiphenyl (248 mg, 1.26 mmol) in EtOH (12 mL) at 0 °C was added dropwise 2 M aq. NaOH (3.2 mL), and the reaction mixture stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solids were then collected by filtration, washed with H2O and dried in vacuo to afford (E)-1-([1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (350 mg, 83%) as a beige solid, which was used in the next step without further purification. 3-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1- yl)benzoic acid

[0363] A suspension of (E)-1-(4'-isopropoxy-[1,1'-biphcnyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1- one (128 mg, 0.32 mmol) and 3-hydrazinobenzoic acid (194 mg, 1.28 mmol) in AcOH (4 mL) was refluxed for 6 h. The reaction mixture was poured onto ice- H2O, and the resulting precipitated solids were then collected by filtration and dried in vacuo. Purification by flash column chromatography (50 → 66% EtOAc in Pet. Ether) afforded 3-(3-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (80 mg, 47%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.93-8.92 (m, 2H), 8.11 (d, J = 9.3 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.78 (dd, J = 8.3, 1.9 Hz, 1H), 7.74- 7.67 (m, 3H), 7.65-7.61 (m, 2H), 7.32-7.22 (m, 3H), 7.01 (d, J = 9.3 Hz, 2H), 5.92 (dd, J = 12.0, 5.7 Hz, 1H), 4.72-4.62 (m, 1H), 4.08 (dd, J = 16.4, 12.4 Hz, 1H), 3.41-3.34 (m, 1H), 1.28 (d, J = 5.7 Hz, 6H);13C NMR (101 MHz, DMSO-d6) δ 167.3 (C), 157.4 (C), 148.2 (C), 146.1 (CH), 145.8 (CH), 144.1 (C), 142.2 (C), 141.7 (C), 140.3 (C), 131.6 (C), 131.4 (C), 130.5 (CH), 130.1 (C), 129.3 (CH), 128.2 (CH), 127.7 (CH), 126.5 (CH), 126.2 (CH), 125.9 (CH), 119.6 (CH), 116.9 (CH), 116.0 (CH), 113.6 (CH), 69.2 (CH), 62.6 (CH), 42.8 (CH2), 21.8 (CH3); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C33H29N4O3, 529.2234; found, 529.2234.

[0364] (E')-1-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0365] To a solution of quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol) and 1-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)ethan-1-one (254 mg, 1.00 mmol) in EtOH (8 mL) at 0 °C was added dropwise 2 M aq. NaOH (2.0 mL), and the reaction mixture stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solids were then collected by filtration, washed with H2O and dried in vacuo to afford (E)-1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3- (quinoxalin-6-yl)prop-2-en-1-one (128 mg, 33%) as a yellow solid, which was used in the next step without further purification. 4-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1- yl)benzoic acid

[0366] A suspension of (E)-1-(4'-isopropoxy[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1- one (200 mg, 0.51 mmol) and 4-hydrazinobenzoic acid (114 mg, 0.75 mmol) in AcOH (4 mL) was refluxed for 6 h. The reaction mixture was poured onto ice- H2O, and the resulting precipitated solids were then collected by filtration and dried in vacuo. Purification by flash column chromatography (50 → 66% EtOAc in Pet. Ether) afforded 4-(3-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (90 mg, 33%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.91-8.93 (m, 2H), 8.12 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.77-7.69 (m, 5H), 7.67-7.62 (m, 2H), 7.13 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 5.70 (dd, J = 12.1, 4.9 Hz, 1H), 4.72-4.63 (m, 1H), 4.11 (dd, J = 18.1, 11.9 Hz, 1H), 3.38 (dd, J = 18.1, 4.9 Hz, 1H), 1.29 (d, 7 = 6.1 Hz, 6H);13C NMR (101 MHz, DMSO-d6) δ 167.1 (C), 157.4 (C), 149.7 (C), 146.8 (C), 146.4 (CH), 146.1 (CH), 145.8 (CH), 143.7 (C), 142.1 (C), 141.7 (C), 140.6 (C), 131.3 (C), 130.9 (CH), 130.5 (CH), 129.9 (C), 128.0 (CH), 127.7 (CH), 126.8 (CH), 126.2 (CH), 125.8 (CH), 120.2 (C), 116.0 (CH), 112.0 (CH), 69.2 (CH), 62.0 (CH), 42.7 (CH2), 21.8 (CH3); HRMS (ESI+ / Q- TOF) m / z: [M+H]+calcd for C33H29N4O3, 529.2234; found, 529.2223.

[0367] 3-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzonitrile

[0368] A suspension of 3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro- 1H -pyrazol-1-yl)benzonitrile (790 mg, 1.55 mmol) and Dess-Martin periodinane (1.52 g, 3.59 mmol) in CH3CN (15.5 mL) was stirred at reflux for 3 h. The reaction mixture was quenched with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(30 mL, 1:1 v / v) and extracted with DCM (3 x 60 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford 3-(3-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzonitrile (487 mg, 62%) as an amorphous orange solid.1H NMR (400 MHz, CDCI3) δ 8.90-8.88 (m, 2H), 8.12- 8.10 (m, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.82 (t, J = 1.7 Hz, 1H), 7.67-7.57 (m, 7H), 7.44 (t, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.98 (d, 7 = 8.7 Hz, 2H), 4.61 (hept, 7 = 6.1 Hz, 1H), 1.38 (d, 7 = 6.1 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 157.8 (C), 153.2 (C), 146.1 (CH), 145.9 (CH), 143.2 (C), 142.93 (C), 142.86 (C), 141.2 (C), 140.7 (C), 132.9 (C), 131.7 (C), 131.1 (CH), 130.5 (C), 130.4 (CH), 130.3 (CH), 130.2 (CH), 129.4 (CH), 129.2 (CH), 128.4 (CH), 128.2 (CH), 127.1 (CH), 126.4 (CH), 117.8 (C), 116.3 (CH), 113.6 (C), 107.5 (CH), 70.1 (CH), 22.2 (CH3); HRMS (ESI+ / Q-TOF) m / z: [M+Na]+calcd for C33H25N5O23Na 530.1951; found 530.1947.

[0369] 3-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1- yl)benzonitrile

[0370] A suspension of (E)-1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1- one (1.04 g, 2.63 mmol) and 3-hydrazinylbenzonitrile (1.73 g, 10.2 mmol) in glacial AcOH (32 mL) was stirred at reflux for 5 h. The reaction mixture was added dropwise to ice-H2O (100 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (50% → 66% EtOAc in Pet. Ether) to afford 3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5- (quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzonitrile (801 mg, 60%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.84 (s, 2H), 8.12 (d, 7 = 8.7 Hz, 1H), 8.05 (d, 7 = 1.9 Hz, 1H), 7.78 (d, 7 = 8.4 Hz, 2H), 7.69 (dd, 7 = 8.7. 2.0 Hz, 1H), 7.60 (d, 7 = 8.5 Hz, 2H), 7.54 (d, 7 = 8.8 Hz, 2H), 7.422-7.417 (m, 1H), 7.21-7.19 (m, 2H), 7.03-7.00 (m, 1H), 6.97 (d, 7 = 9.0 Hz, 2H), 5.52 (dd, 7 = 12.3, 6.4 Hz, 1H), 4.60 (hept, 7 = 6.0 Hz, 1H), 4.01 (dd, 7 = 17.3, 12.3 Hz, 1H), 3.29 (dd, 7 = 17.2, 6.4 Hz, 1H), 1.37 (d, 7 = 6.1 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 158.0 (C), 148.5 (C), 145.7 (CH), 145.4 (CH), 144.7 (C), 143.5 (C), 143.2 (C), 142.8 (C), 141.9 (C), 132.5 (C), 131.4 (CH), 130.0 (C), 129.9 (CH), 128.1 (CH), 127.7 (CH), 126.9 (CH), 126.6 (CH), 126.5 (CH), 122.5 (CH), 119.4 (C), 117.1 (CH), 116.4 (CH), 116.3 (CH), 113.0 (C), 70.1 (CH), 63.7 (CH), 43.7 (CH2), 22.2 (CH3); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C33H28N5O 510.2288; found 510.2284.

[0371] N'-Hydroxy-3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzimidamide

[0372] A solution of 3-(3-(4'-isopropoxy[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzonitrile (152 mg, 0.299 mmol), hydroxylamine hydrochloride (30.1 mg, 0.433 mmol) and DIPEA (0.15 mL, 0.861 mmol) in EtOH (4 mL) was heated at 80 °C in a microwave for 1 h. Purification by automated silica gel column chromatography (70% → 80% EtOAc in Pet. Ether) afforded Af-hydroxy-3-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzimidamide (103 mg, 63%) as an amorphous pale yellow solid.1H NMR (500 MHz, CDCI3) δ 8.87 (s, 2H), 8.15 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.85 (br s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.63-7.61 (m, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.34-7.33 (m, 2H), 7.04 (s, 1H), 6.98 (d, J = 8.6 Hz, 2H), 4.84 (br s, 2H), 4.61 (hept, J = 6.0 Hz, 1H), 1.38 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, CDCI3) δ 157.7 (C), 152.6 (C), 152.0 (C), 145.9 (CH), 145.7 (CH), 143.2 (C), 143.0 (C), 142.7 (C), 140.9 (C), 140.3 (C), 134.0 (C),

[0373] 133.1 (C), 132.2 (C), 130.9 (C), 130.6 (CH), 130.0 (CH), 129.5 (CH), 129.2 (CH), 128.2 (CH),

[0374] 127.1 (CH), 126.8 (CH), 126.4 (CH), 125.4 (CH), 122.9 (CH), 116.3 (CH), 106.7 (CH), 70.1 (CH), 22.2 (CH3); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C33H29N6O2541.2347; found 541.2340.

[0375] Methyl 3-(3-(6-(4-isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate A suspension of methyl 3-(3-(6-(4-isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate (64.0 mg, 0.118 mmol) and Dess-Martin periodinane (122 mg, 0.287 mmol) in CH3CN (1.1 mL) was stirred at reflux for 2 h. The reaction mixture was quenched with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(5 mL, 1:1 v / v) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3- (3-(6-(4-isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoate (42.3 mg, 66%) as an amorphous orange solid.1H NMR (400 MHz, CDCI3) δ 9.17 (d, J = 2.0 Hz, 1H), 8.85 (s, 2H), 8.29 (dd, J = 8.3, 2.1 Hz, 1H), 8.20-8.19 (m, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.06-7.98 (m, 4H), 7.76 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.7, 1.9 Hz, 1H), 7.52-7.49 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 4.63 (hept, J = 6.0 Hz, 1H), 3.86 (s, 3H), 1.37 (d, J = 6.1 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 166.0 (C), 159.1 (C), 156.9 (C), 150.0 (C), 147.1 (CH), 145.9 (CH), 145.8 (CH), 143.4 (C), 142.9 (C), 142.7 (C), 140.0 (C), 133.9 (CH), 131.8 (C), 131.7 (C), 131.4 (C), 130.4 (CH), 130.1 (CH), 129.6 (CH), 129.4 (CH), 129.2 (CH), 128.3 (CH), 126.5 (CH), 126.2 (C), 119.8 (CH), 116.1 (CH), 106.6 (CH), 70.0 (CH), 52.5 (CH3), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C33H28N5O3, 542.2187; found, 542.2183.

[0376] Methyl 3-(3-(6-(4-isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H- pyrazol- 1 -yl)benzoate

[0377] A suspension of (E)-1-(6-(4-isopropoxyphenyl)pyridin-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1- one (0.2 g, 514 μmol) and methyl 3-hydrazinobenzoate hydrochloride (387 mg, 1.91 mmol) in glacial AcOH (6.4 mL) was stirred at reflux for 6 h. The reaction mixture was added dropwise to ice- H2O (50 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (33% EtOAc in Pet. Ether) to afford methyl 3-(3-(6-(4- isopropoxyphenyl)pyridin-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (75.7 mg, 27%) as a yellow solid.1H NMR (400 MHz, CDCI3) δ 8.83 (s, 2H), 8.22 (dd, J = 8.4, 2.3 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.81-7.80 (m, 1H), 7.75-7.72 (m, 2H), 7.50-7.45 (m, 2H), 7.29-7.21 (m, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.64 (dd, J = 12.5, 6.6 Hz, 1H), 4.63 (hept, J = 6.0 Hz, 1H), 4.02 (dd, J = 17.1, 12.7 Hz, 1H), 3.85 (s, 3H), 3.29 (dd, J = 17.2, 6.7 Hz, 1H), 1.37 (d, J = 6.4 Hz, 6H); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C33H30N5O3, 544.2343; found, 544.2337.

[0378] (E)-1-(6-(4-Isopropoxyphenyl)pyridin-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0379] To a suspension of quinoxaline-6-carbaldehyde (250 mg, 1.58 mmol) and 1-(6-(4- isopropoxyphenyl)pyridin-3-yl)ethan-1-one (0.415 mg, 1.63 mmol) in EtOH (2.8 mL) at 0 °C was added dropwise glacial AcOH (0.1 mL) and piperidine (0.17 mL). The reaction was stirred at reflux for 24 h then allowed to cool to RT. The resulting precipitated solids were collected by vacuum filtration and washed with H2O (3 x 5 mL). The crude residue was purified by automated silica gel column chromatography (20% → 50% EtOAc in Pet. Ether) to afford (E)- 1-(6-(4-isopropoxyphenyl)pyridin-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (428 mg, 69%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 9.324-9.317 (m, 1H), 8.90-8.87 (m, 2H), 8.38-8.34 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 8.11-8.04 (m, 4H), 7.84 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 15.7 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 4.66 (hept, J = 6.1 Hz, 1H), 1.39 (d, J = 6.1 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 188.3 (C), 160.8 (C), 160.1 (C), 150.2 (CH), 146.0 (CH), 145.9 (CH), 144.3 (C), 143.6 (CH), 143.3 (C), 137.0 (CH), 136.6 (C), 131.0 (CH), 130.8 (C), 130.53 (CH), 130.48 (C), 129.1 (CH), 128.5 (CH), 124.1 (CH), 119.5 (CH), 116.2 (CH), 70.2 (CH), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C25H22N3O2, 396.1707; found, 396.1704. l-(6-(4-Isopropoxyphenyl)pyridin-3-yl)ethan-1-one To a suspension of l-(6-bromopyridin-3-yl)ethan-1-one (1.21 g, 6.06 mmol), 4- isopropoxyphenylboronic acid (1.04 g, 5.77 mmol) and K3PO4(2.38 g, 11.2 mmol) in a mixture of DMF-H2O (56 mL, 1:1 v / v) was added Pd(OAc)2(129 mg, 575 μmol) in a single portion. The reaction was stirred at 80 °C for 17 h then allowed to cool to RT, diluted with H2O (50 mL) and extracted with Et2O (2 x 100 mL). The combined organic extracts were washed with brine (3 x 100 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% → 20% EtOAc in Pet. Ether) to afford 1-(6-(4-isopropoxyphenyl)pyridin-3-yl)ethan-1-one (936 mg, 62%) as an amorphous white solid.1H NMR (400 MHz, CDCI3) δ 9.19-9.18 (m, 1H), 8.26-8.23 (m, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.78-7.76 (m, 1H), 7.00 (d, J = 8.9 Hz, 2H), 4.65 (hept, J = 7.3 Hz, 1H), 2.65 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 196.6 (C), 160.8 (C), 160.0 (C), 150.3 (CH), 136.4 (CH), 130.5 (C), 130.1 (C), 129.0 (CH), 119.3 (CH), 116.1 (CH), 70.2 (CH), 26.8 (CH3), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+Na]+calcd for C16H17NO223Na, 278.1152; found, 278.1150.

[0380] Methyl 3-(3-(4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate

[0381] A suspension of methyl 3-(3-(4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate (54.0 mg, 0.099 mmol) and Dess-Martin periodinane (101 mg, 0.238 mmol) in CH3CN (1 mL) was stirred at reflux for 3 h. The reaction mixture was quenched with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(5 mL, 1:1 v / v) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3- (3-(4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoate (36.9 mg, 69%) as a yellow film.1H NMR (400 MHz, CDCI3) δ 8.87 (s, 2H), 8.45 (d, J = 2.4 Hz, 1H), 8.21 (t, J = 1.8 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 8.06-8.02 (m, 4H), 7.84 (dd, J = 8.5,

[0382] 2.5 Hz, 1H), 7.64-7.62 (m, 3H), 7.53-7.50 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.36 (hept, J = 6.2 Hz, 1H), 3.88 (s, 3H), 1.39 (d, J = 6.3 Hz, 6H);13C NMR (125 MHz, CDCI3) δ 166.0 (C), 163.2 (C), 152.4 (C), 145.9 (CH), 145.7 (CH), 145.1 (CH), 143.2 (C), 142.9 (C), 142.7 (C), 140.2 (C), 138.1 (C), 137.4 (CH), 132.0 (C), 131.7 (C),

[0383] 131.5 (C), 130.4 (CH), 130.0 (CH), 129.6 (CH), 129.34 (CH), 129.30 (CH), 129.2 (C), 129.1 (CH), 127.0 (CH), 126.6 (CH), 126.5 (CH), 111.6 (CH), 106.7 (CH), 68.3 (CH), 52.5 (CH3), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C33H28N5O3, 542.2187; found, 542.2185.

[0384] Methyl 3-(3-(4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H- pyrazol-1-yl)benzoate

[0385] A suspension of (E)-1-(4-(6-isopropoxypyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1- one (0.369 g, 932 μmol) and methyl 3-hydrazinobenzoate hydrochloride (724 mg, 3.57 mmol) in glacial AcOH (11.7 mL) was stirred at reflux for 6 h. The reaction mixture was added dropwise to ice-H2O (100 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (50% → 66% EtOAc in Pet. Ether) to afford methyl 3-(3- (4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1- yl)benzoate (57.8 mg, 11%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.84-8.83 (m, 2H), 8.41 (d, J = 2.4 Hz, 1H), 8.12-8.09 (m, 2H), 7.84-7.79 (m, 4H), 7.74 (dd, J = 8.7, 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.46-7.44 (m, 1H), 7.29-7.20 (m, 2H), 6.77 (d, J = 8.6 Hz, 1H), 5.63 (dd, J = 12.3, 6.5 Hz, 1H), 5.35 (hept, J = 6.2 Hz, 1H), 4.02 (dd, J = 17.1, 12.4 Hz, 1H), 3.85 (s, 3H), 3.29 (dd, J = 17.1, 6.5 Hz, 1H), 1.38 (d, J = 6.1 Hz, 6H); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C33H30N5O3, 544.2343; found, 544.2341.

[0386] (E)-1-(4-(6-Isopropoxypyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0387] To a suspension of quinoxaline-6-carbaldehyde (247 mg, 1.56 mmol) and 1-(4-(6- isopropoxypyridin-3-yl)phenyl)ethan-1-one (0.378 mg, 1.48 mmol) in EtOH (2.8 mL) at 0 °C was added dropwise glacial AcOH (0.1 mL) and piperidine (0.17 mL). The reaction was stirred at reflux for 25 h then allowed to cool to RT. The resulting precipitated solids were collected by vacuum filtration and washed with H2O (3 x 5 mL). The crude residue was purified by automated silica gel column chromatography (20% → 50% EtOAc in Pet. Ether) to afford (E)- 1-(4-(6-isopropoxypyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (428 mg, 73%) as an amorphous light-brown solid.1H NMR (400 MHz, CDCI3) δ 8.90-8.87 (m, 2H), 8.46 (d, J = 3.1 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.18-8.14 (m, 3H), 8.11-8.09 (m, 1H), 8.04 (d, J = 15.4 Hz, 1H), 7.85 (dd, J = 8.6, 2.6 Hz, 1H), 7.79 (d, J = 15.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 1H), 5.38 (hept, J = 6.2 Hz, 1H), 1.39 (d, J = 6.3 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 189.2 (C), 163.8 (C), 145.9 (CH), 145.7 (CH), 145.6 (CH), 144.1 (C), 143.3 (C), 143.0 (CH), 142.9 (C), 137.4 (CH), 136.8 (C), 136.5 (C), 130.6 (CH), 130.4 (CH), 129.5 (CH), 128.6 (CH), 128.3 (C), 126.8 (CH), 124.5 (CH), 111.9 (CH), 68.6 (CH), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C25H22N3O2, 396.1707; found, 396.1703.

[0388] 1-(4-(6-Isopropoxypyridin-3-yl)phenyl)ethan-1-one

[0389] To a suspension of 5-bromo-2-isopropoxypyridine (0.34 mL, 2.18 mmol), (4- acetylphenyl)boronic acid (0.360 g, 2.19 mmol) and K3PO4(0.980 g, 4.62 mmol) in a mixture of DMF-H2O (22 mL, 1:1 v / v) was added Pd(OAc)2(52 mg, 231 μmol) in a single portion. The reaction was stirred at RT for 3 h then diluted with H2O (25 mL) and extracted with Et2O (2 x 30 mL). The combined organic extracts were washed with brine (3 x 50 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% EtOAc in Pet. Ether) to afford 1-(4-(6-isopropoxypyridin- 3-yl)phenyl)ethan-1-one (470 mg, 85%) as an amorphous white solid.1H NMR (400 MHz, CDCI3) δ 8.42 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 8.6, 2.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 5.36 (hept, J = 6.2 Hz, 1H), 1.38 (d, J = 6.3 Hz, 6H);13C NMR (100 MHz, CDC13) 6 197.7 (C), 163.7 (C), 145.5 (CH), 142.8 (C), 137.5 (CH), 135.9 (C), 129.3 (CH), 128.4 (C), 126.7 (CH), 111.9 (CH), 68.6 (CH), 26.8 (CH3), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C16H18NO2, 256.1332; found, 256.1330.

[0390] Methyl 3-(3-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzoate

[0391] A suspension of methyl 3-(3-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6- yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (230 mg, 0.410 mmol) and Dess-Martin periodinane (390 mg, 0.919 mmol) in CH3CN (4.1 mL) was stirred at reflux for 2.5 h. The reaction mixture was diluted with DCM (20 mL) and then washed with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(3 x 10 mL, 1:1 v / v). The combined aqueous layers were extracted with DCM (30 mL) and then the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3- (3-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate (80.5 mg, 35%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.86 (s, 3H), 8.21-8.20 (m, 1H), 8.11 (d, J = 1.9 Hz, 1H), 8.06-7.99 (m, 4H), 7.65-7.61 (m, 3H), 7.53-7.50 (m, 1H), 7.43-7.34 (m, 3H), 7.08-7.04 (m, 1H), 4.59 (hept, J = 6.0 Hz, 1H), 3.87 (s, 3H), 1.40 (d, J = 6.2 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 166.1 (C), 154.1 (C, d, J = 245 Hz), 152.4 (C), 145.9 (CH), 145.7 (CH), 145.5 (C, d, J = 10.9 Hz), 143.3 (C), 143.0 (C), 142.8 (C), 140.2 (C), 139.7 (C), 134.5 (C, d, J= 6.6 Hz), 132.1 (C), 131.7 (C), 131.6 (C), 130.5 (CH), 130.1 (CH), 129.6 (CH), 129.36 (CH), 129.34 (CH), 129.1 (CH), 127.1 (CH), 126.5 (CH), 126.5 (CH), 122.6 (CH, d, 7 = 2.9 Hz), 118.1 (CH, d, J = 1.9 Hz), 115.0 (CH, d, J = 19.7 Hz), 106.8 (CH), 72.7 (CH), 52.5 (CH3), 22.3 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C34H28FN4O3, 559.2140; found, 559.2136. Methyl 3-(3-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate

[0392] A suspension of (E)-1-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop- 2-en-1-one (0.4 g, 970 μmol) and methyl 3-hydrazinobenzoate hydrochloride (743 mg, 3.67 mmol) in glacial AcOH (12.1 mL) was stirred at reflux for 6 h. The reaction mixture was added dropwise to ice- H2O (100 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (50% → 66% EtOAc in Pet. Ether) to afford methyl 3-(3- (3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1- yl)benzoate (254 mg, 48%) as an amorphous yellow solid.1H NMR (500 MHz, CDCI3) δ 8.83— 8.82 (m, 2H), 8.10 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.81-7.80 (m, 3H), 7.73 (dd, J = 8.7, 1.9 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.46-7.44 (m, 1H), 7.36 (dd, J = 12.3, 2.3 Hz, 1H), 7.33-7.30 (m, 1H), 7.28-7.26 (m, 1H), 7.24-7.20 (m, 1H), 7.05 (app. t, J = 8.6 Hz, 1H), 5.62 (dd, J = 12.3, 6.5 Hz, 1H), 4.59 (hept, J = 6.1 Hz, 1H), 4.01 (dd, J = 17.2, 12.3 Hz, 1H), 3.85 (s, 3H), 3.28 (dd, J = 17.1, 6.6 Hz, 1H), 1.40 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, CDCI3) δ 167.4 (C), 154.0 (C, d, J = 246 Hz), 147.2 (C), 145.6 (CH), 145.3 (CH), 144.5 (C), 144.2 (C), 143.3 (C), 142.8 (C), 140.3 (C), 134.0 (C, d, J = 6.5 Hz), 131.2 (CH), 131.14 (C), 131.11 (C), 129.2 (CH), 128.1 (CH), 126.9 (CH), 126.62 (CH), 126.58 (CH), 122.6 (CH, d, J = 2.7 Hz), 120.6 (CH), 117.9 (CH, d, J = 1.8 Hz), 117.7 (CH), 115.0 (CH, d, J = 19.1 Hz), 114.4 (CH), 72.6 (CH), 64.0 (CH), 52.2 (CH3), 43.6 (CH2), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C34H30FN4O3, 561.2296; found, 561.2290.

[0393] (E)-1-(3'-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0394] To a suspension of quinoxaline-6-carbaldehyde (204 mg, 1.29 mmol) and l-(3'-fluoro-4'- isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (349 mg, 1.28 mmol) in EtOH (11 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (2.6 mL). The reaction was allowed to gradually warm to RT and stirred for 23 h. Upon completion, the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 20 mL) to afford (E)-1-(3'-fluoro-4'- isopropoxy[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (459 mg, 87%) as an amorphous pale-yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, CDCI3) δ 8.90-8.87 (m, 2H), 8.35 (d, J = 1.6 Hz, 1H), 8.18-8.09 (m, 4H), 8.04 (d, J = 15.7 Hz, 1H), 7.79 (d, J = 15.9 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.42 (dd, J = 12.2, 2.3 Hz, 1H), 7.39-7.37 (m, 1H), 7.08 (app. t, J = 8.5 Hz, 1H), 4.63 (hept, J = 6.0 Hz, 1H), 1.41 (d, J = 6.1 Hz, 6H);13C NMR (125 MHz, CDCI3) δ 189.3 (C), 153.9 (C, d, J = 246 Hz), 146.3 (C, d, J= 10.8 Hz), 146.0 (CH), 145.7 (CH), 144.5 (C), 144.1 (C), 143.3 (C), 143.0 (CH), 136.8 (C), 136.5 (C), 133.2 (C, d, J = 6.4 Hz), 130.7 (CH), 130.4 (CH), 129.4 (CH), 128.6 (CH), 127.0 (CH), 124.5 (CH), 123.1 (CH, d, J = 2.8 Hz), 117.7 (CH, d, J = 2.0 Hz), 115.3 (CH, d, J = 19.8 Hz), 72.5 (CH), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C26H22FN2O2, 413.1660; found, 413.1659.

[0395] 1-(3'-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one

[0396] To a suspension of 4-bromo-2-fluoro-1-isopropoxybenzene (0.457, 1.96 mmol), (4- acetylphenyl)boronic acid (0.64 g, 3.90 mmol) and K3PO4(0.832 g, 3.92 mmol) in a mixture of DMF-H2O (20 mL, 1:1 v / v) was added Pd(OAc)2(58 mg, 259 μmol) in a single portion. The reaction was stirred at 40 °C for 5 h then diluted with H2O (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (5 x 50 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (5% EtOAc in Pet. Ether) to afford 1-(3'-fluoro-4'- isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (375 mg, 77%) as an amorphous white solid.1H NMR (400 MHz, CDCI3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 12.3, 2.2 Hz, 1H), 7.35-7.32 (m, 1H), 7.06 (app. t, J = 8.5 Hz, 1H), 4.61 (hept, J = 6.1 Hz, 1H), 2.63 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 197.8 (C), 154.0 (C, d, 7 = 246 Hz), 146.2 (C, d, J = 10.9 Hz), 144.4 (C, d, J = 1.8 Hz), 135.9 (C), 133.3 (C, d, J = 6.6 Hz), 129.1 (CH), 126.8 (CH), 123.0 (CH, d, J = 2.9 Hz), 117.8 (CH, d, J = 2.4 Hz), 115.3 (CH, d, J = 19.8), 72.6 (CH), 26.8 (CH3), 22.2 (CH3); HRMS (ESI+ / TOF-Q) m / z [M+H]+calcd for C17H18FO2, 273.1285; found, 273.1284.

[0397] Methyl 3-(3-(4'-isopropoxy-3'-methyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzoate

[0398] A suspension of methyl 3-(3-(4'-isopropoxy-3'-methyl[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6- yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (80 mg, 0.144 mmol) and Dess-Martin periodinane (130 mg, 0.307 mmol) in CH3CN (2 mL) was stirred at reflux for 2.5 h. The reaction mixture was diluted with DCM (10 mL) and then washed with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(3 x 10 mL, 1:1 v / v). The combined aqueous layers were extracted with DCM (30 mL) and then the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3- (3-(4'-isopropoxy-3'-methyl[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate (56.4 mg, 71%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.86 (s, 2H), 8.22-8.21 (m, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.06-7.98 (m, 4H), 7.66 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.53-7.50 (m, 1H), 7.46-7.39 (m, 3H), 7.05 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.58 (hept, J = 6.0 Hz, 1H), 3.87 (s, 3H), 2.29 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 166.1 (C), 156.1 (C), 152.7 (C), 145.9 (CH), 145.7 (CH), 143.1 (C), 142.9 (C), 142.7 (C), 141.1 (C), 140.2 (C), 132.7 (C), 132.1 (C), 131.7 (C), 130.8 (C), 130.5 (CH), 130.0 (CH), 129.62 (CH), 129.55 (CH), 129.31 (CH), 129.28 (CH), 129.0 (CH), 128.3 (C), 127.0 (CH), 126.5 (CH), 126.3 (CH), 125.2 (CH), 113.4 (CH), 106.7 (CH), 70.5 (CH), 52.4 (CH3), 22.4 (CH3), 16.7 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C35H3IN4O3, 555.2390; found, 555.2386.

[0399] Methyl 3-(3-(4'-isopropoxy-3'-methyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate

[0400] To a cooled suspension of quinoxaline-6-carbaldehyde (98.9 mg, 0.614 mmol) and l-(3'- fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (165 mg, 0.614 mmol) in EtOH (4.9 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (1.3 mL). The reaction was allowed to gradually warm to RT and stirred for 2 d. The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL) to afford (E)-1-(4'-isopropoxy-3'-methyl-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (0.12 g) as an amorphous yellow solid, which was used in the next step without further purification. HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C27H25N2O2, 409.1911; found, 409.1909. A suspension of (E)-1-(4'- isopropoxy-3'-methyl-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (0.12 g, 291 μmol) and methyl 3-hydrazinobenzoate hydrochloride (223 mg, 1.10 mmol) in glacial AcOH (3.6 mL) was stirred at reflux for 7 h. The reaction mixture was added dropwise to icc- H2O (50 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (50% → 66% EtOAc in Pet. Ether) to afford methyl 3-(3-(4'-isopropoxy-3'-methyl-[1,1'- biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (93 mg, 56%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.86-8.82 (m, 2H), 8.11-8.09 (m, 2H), 7.81-7.78 (m, 3H), 7.73 (dd, 7 = 8.8, 1.9 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.46-7.38 (m, 3H), 7.29-7.20 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 5.59 (dd, J = 12.3, 6.5 Hz, 1H), 4.57 (hept, J = 6.2 Hz, 1H), 4.00 (dd, 7 = 17.1, 12.3 Hz, 1H), 3.85 (s, 3H), 3.28 (dd, 7 = 17.1, 6.5 Hz, 1H), 2.28 (s, 3H), 1.37 (d, 7 = 6.0 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 167.4 (C), 156.3 (C),

[0401] 147.5 (C), 145.5 (CH), 145.2 (CH), 144.6 (C), 144.4 (C), 143.3 (C), 142.7 (C), 141.8 (C), 132.3 (C), 131.13 (CH), 131.08 (C), 130.4 (C), 129.5 (CH), 129.2 (CH), 128.4 (C), 128.1 (CH), 126.9 (CH), 126.6 (CH), 126.5 (CH), 125.3 (CH), 120.5 (CH), 117.7 (CH), 114.4 (CH), 113.3 (CH),

[0402] 70.5 (CH), 64.0 (CH), 52.2 (CH3), 43.6 (CH2), 22.4 (CH3), 16.7 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C35H33N4O3, 557.2547; found, 557.2535.

[0403] 1-(4'-Isopropoxy-3'-methyl-[1,1'-biphenyl]-4-yl)ethan-1-one

[0404] To a suspension of 4-bromo-1-isopropoxy-2-methylbenzene (0.492, 2.15 mmol), (4- acetylphenyl)boronic acid (0.384 g, 2.34 mmol) and K3PO4(0.964 g, 4.54 mmol) in a mixture of DMF-H2O (22 mL, 1:1 v / v) was added Pd(OAc)2(58 mg, 258 μmol) in a single portion. The reaction was stirred at RT for 4 d then heated to 60 °C and stirred for a further 22h. The reaction mixture was then diluted with H2O (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (5 x 50 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% EtOAc in Pet. Ether) to afford 1-(4'-isopropoxy-3'-methyl-[1,1'- biphenyl]-4-yl)ethan-1-one (253 mg, 44%) as an amorphous yellow solid.1H NMR (500 MHz, CDCI3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.44-7.41 (m, 2H), 6.92 (d, J = 8.6 Hz, 1H), 4.59 (hept, J = 6.0 Hz, 1H), 2.62 (s, 3H), 2.28 (s, 3H), 1.38 (d, J = 6.1Hz, 6H);13C NMR (125 MHz, CDCI3) δ 197.9 (C), 156.7 (C), 145.8 (C), 135.2 (C), 131.6 (C), 129.8 (CH), 129.0 (CH), 128.5 (C), 126.7 (CH), 125.6 (CH), 113.1 (CH), 70.4 (CH), 26.7 (CH3), 22.4 (CH3), 16.7 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C18H21O2, 269.1536; found, 269.1536.

[0405] Methyl 3-(3-(3'-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H- pyrazol- 1 -yl)benzoate

[0406] A suspension of methyl 3-(3-(3'-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6- yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (140 mg, 0.247 mmol) and Dess-Martin periodinane (255 mg, 0.543 mmol) in CH3CN (2.5 mL) was stirred at reflux for 30 min. The reaction mixture was diluted with DCM (10 mL) and then washed with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(3 x 10 mL, 1:1 v / v). The combined aqueous layers were extracted with DCM (30 mL) and then the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3- (3-(3'-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate (68.1 mg, 49%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.87 (s, 2H), 8.22-8.21 (m, 1H), 8.12 (d, J = 1.9 Hz, 1H), 8.07-8.02 (m, 4H), 7.84 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.64-7.61 (m, 3H), 7.53-7.50 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.07-7.05 (m, 2H), 4.71 (hept, J = 6.0 Hz, 1H), 3.88 (s, 3H), 1.45 (d, J = 6.0 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 166.1 (C), 159.5 (C), 152.3 (C), 146.0 (CH), 145.8 (CH), 143.4 (C), 143.0 (C), 142.8 (C), 140.2 (C), 138.7 (C), 133.6 (C), 132.7 (CH), 132.3 (CH), 132.0 (C), 131.8 (C), 130.5 (CH), 130.1 (CH), 129.7 (CH), 129.40 (CH), 129.38 (CH), 129.2 (CH), 127.1 (CH), 126.7 (CH), 126.6 (CH), 116.8 (C), 114.3 (CH), 106.8 (CH), 103.7 (C), 72.3 (CH), 52.5 (CH3), 22.1 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C35H28N5O3, 566.2187; found, 566.2184.

[0407] Methyl 3-(3-(3'-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5- dihydro- 1H-pyrazol- 1 -yl)benzoate

[0408] A suspension of (E)-4-isopropoxy-4'-(3-(quinoxalin-6-yl)acryloyl)-[1,1'-biphenyl]-3- carbonitrile (0.216 g, 524 μmol) and methyl 3-hydrazinobenzoate hydrochloride (420 mg, 2.07 mmol) in glacial AcOH (6.5 mL) was stirred at reflux for 6 h. The reaction mixture was added dropwise to ice-H2O (100 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (50% → 66% EtOAc in Pet. Ether) to afford methyl 3-(3- (3'-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1- yl)benzoate (126 mg, 42%) as an amorphous yellow solid1H NMR (400 MHz, CDCI3) δ 8.83 (s, 2H), 8.11 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.84-7.79 (m, 4H), 7.76-7.73 (m, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.47-7.44 (m, 1H), 7.29-7.21 (m, 2H), 7.05 (d, J = 9.0 Hz, 1H), 5.64 (dd, J = 12.3, 6.5 Hz, 1H), 4.70 (hept, J = 6.1 Hz, 1H), 4.02 (dd, J = 17.1, 12.4 Hz, 1H), 3.85 (s, 3H), 3.29 (dd, J = 17.1, 6.5 Hz, 1H), 1.44 (d, J = 6.0 Hz, 6H); HRMS (ESEQ-TOF) m / z: molecular ion not observed. (E)-4-Isopropoxy-4'-(3-(quinoxalin-6-yl)acryloyl)-[1,1'-biphenyl]-3-carbonitrile

[0409] To a suspension of quinoxaline-6-carbaldehyde (303 mg, 1.91 mmol) and 4'-acetyl-4- isopropoxy-[ 1,1 '-biphenyl] -3 -carbonitrile (534 mg, 1.91 mmol) in EtOH (15.3 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (3.8 mL). The reaction was allowed to gradually warm to RT and stirred for 17 h. The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 20 mL) to afford(E)-4-isopropoxy-4'-(3-(quinoxalin-6-yl)acryloyl)- [1,1'-biphenyl] -3 -carbonitrile (769 mg, 96%) as an amorphous pale-yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.90-8.87 (m, 2H), 8.35 (d, J = 1.7 Hz, 1H), 8.18-8.15 (m, 3H), 8.10 (dd, J = 8.8, 1.8 Hz, 1H), 8.04 (d, J = 15.7 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.81-7.76 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.9 Hz, 1H), 4.73 (hept, J = 6.1 Hz, 1H), 1.46 (d, J = 6.0 Hz, 6H);13C NMR (125 MHz, CDCI3) δ 189.2 (C), 160.0 (C), 146.0 (CH), 145.8 (CH), 144.1 (C), 143.4 (C), 143.3 (C), 143.2 (CH), 136.9 (C), 136.7 (C), 133.0 (CH), 132.6 (CH), 132.4 (C), 130.7 (CH), 130.4 (CH), 129.5 (CH), 128.6 (CH), 126.9 (CH), 124.3 (CH), 116.5 (C), 114.2 (CH), 103.8 (C), 72.3 (CH), 22.0 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C27H22N3O2, 420.1707; found, 420.1706.

[0410] 4'-Acetyl-4-isopropoxy-[1,1'-biphenyl]-3-carbonitrile

[0411] To a suspension of 5-bromo-2-isopropoxybenzonitrile (0.519, 2.16 mmol), (4- acetylphenyl)boronic acid (0.366 g, 2.23 mmol) and K3PO4(0.965 g, 4.55 mmol) in a mixture of DMF-H2O (21 mL, 1:1 v / v) was added Pd(OAc)2(46.1 mg, 205 μmol) in a single portion. The reaction was stirred at RT for 4 d then diluted with H2O (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (5 x 50 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% EtOAc in Pet. Ether) to afford 4'-acetyl-4-isopropoxy- [1,1'-biphenyl]-3-carbonitrile (541 mg, 90%) as an amorphous off-white solid.1H NMR (400 MHz, CDCI3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.7, 2.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 9.0 Hz, 1H), 4.72 (hept, J = 6.1 Hz, 1H), 2.64 (s, 3H), 1.44 (d, J = 6.0 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 197.6 (C), 160.0 (C), 143.3 (C), 136.2 (C), 133.0 (CH), 132.6 (CH), 129.3 (CH), 126.8 (CH), 116.5 (C), 114.2 (CH), 103.8 (C), 72.4 (CH), 26.8 (CH3), 22.0 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C18H18NO2, 280.1332; found, 280.1331.

[0412] Methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)-1H- pyrazol- 1 -yl)benzoate

[0413] A suspension of methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4- yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (87.3 mg, 0.150 mmol) in DMSO (1.3 mL) was stirred at 110 °C under an oxygen atmosphere for 17 h. The solution was allowed to cool to RT and then diluted with EtOAc (90 mL) and washed with H2O (3 x 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)-1H-pyrazol- 1-yl)benzoate (54.4 mg, 63%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ

[0414] 8.87 (s, 2H), 8.22-8.21 (m, 1H), 8.12 (d, J = 1.9 Hz, 1H), 8.07-8.01 (m, 4H), 7.67-7.62 (m, 5H), 7.53-7.51 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.08-7.04 (m, 3H), 4.42 (q, J = 8.1 Hz, 2H),

[0415] 3.88 (s, 3H); HRMS (ESI / Q-TOF) m / z: molecular ion not observed.

[0416] Methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)-4,5- dihydro- 1H-pyrazol- 1 -yl)benzoate

[0417] A suspension of (E)-3%quinoxalin-6-yl)-1-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4- yl)prop-2-en-1-one (0.119 g, 275 μmol) and methyl 3-hydrazinobenzoate hydrochloride (194 mg, 957 μmol) in glacial AcOH (2.8 mL) was stirred at reflux for 6 h. The reaction mixture was added dropwise to ice- H2O (50 mL), and the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (33% — > 50% — > 66% EtOAc in Pet. Ether) to afford methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H- pyrazol-1-yl)benzoate (87.3 mg, 55%) as an amorphous yellow solid.1H NMR (500 MHz, CDCI3) δ 8.83 (s, 2H), 8.11-8.08 (m, 2H), 7.81-7.80 (m, 3H), 7.73 (dd, J = 8.8, 2.0 Hz, 1H), 7.60-7.57 (m, 4H), 7.46-7.44 (m, 1H), 7.28-7.26 (m, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 5.60 (dd, J = 12.3, 6.5 Hz, 1H), 4.39 (q, J = 8.1 Hz, 2H), 4.00 (dd, J = 17.0, 12.4 Hz, 1H), 3.28 (dd, J = 17.1, 6.5 Hz, 1H);13C NMR (125 MHz, CDCI3) δ 167.4 (C), 157.3 (C), 147.2 (C), 145.6 (CH), 145.3 (CH), 144.5 (C), 144.2 (C), 143.3 (C), 142.7 (C), 140.9 (C), 134.9 (C), 131.15 (CH), 131.10 (C), 131.0 (C), 129.2 (CH), 128.4 (CH), 128.1 (CH), 127.0 (CH), 126.61 (CH), 126.56 (CH), 123.4 (C, q, J = 278 Hz), 120.6 (CH), 117.7 (CH), 115.5 (CH), 114.4 (CH), 66.0 (CH2, q, J= 35.7 Hz), 64.0 (CH), 52.2 (CH3), 43.6 (CH2); HRMS (ESI+ / TOF- Q) m / z: [M+H]+calcd for C33H26F3N4O3, 583.1951; found, 583.1949.

[0418] (E)-3-(Quinoxalin-6-yl)-1-(4'-(2,2,2-trifhioroethoxy)-[l,r-biphenyl]-4-yl)prop-2-en-1- one

[0419] To a suspension of quinoxaline-6-carbaldehyde (158 mg, 0.94 mmol) and 1-(4'-(2,2,2- trifluoroethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (240 mg, 0.94 mmol) in EtOH (7.8 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (1.9 mL). The reaction was allowed to gradually warm to RT and stirred for 17 h. The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 20 mL) to afford (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2- trifluoroethoxy)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one (256 mg, 69%) as an amorphous pale- yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.89-8.86 (m, 2H), 8.34 (d, J = 1.8 Hz, 1H), 8.17-8.08 (m, 4H), 8.03 (d, J = 15.7 Hz, 1H), 7.78 (d, J = 15.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 4.42 (q, J = 8.1 Hz, 2H);13C NMR (100 MHz, CDCI3) δ 189.4 (C), 157.8 (C), 146.0 (CH), 145.7 (CH), 145.1 (C), 144.1 (C), 143.3 (C), 143.0 (CH), 136.9 (C), 136.5 (C), 134.3 (C), 130.6 (CH), 130.4 (CH), 129.4 (CH), 128.8 (CH), 128.7 (CH), 127.1 (CH), 124.6 (CH), 123.4 (C, q, J = 278 Hz), 115.6 (CH), 66.0 (CH2, q, J = 35.8 Hz); HRMS (ESI+ / TOF-Q) m / z: [M+H]+calcd for C25H18F3N2O2, 435.1315; found, 435.1313. l-(4'-(2,2,2-Trifluoroethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one

[0420] To a stirred suspension of 1-(4-iodophenyl)ethan-1-one (0.629 g, 2.55 mmol) and (4-(2,2,2- trifluoroethoxy)phenyl)boronic acid (0.496 g, 2.25 mmol) iniPrOH (6.2 mL) was added Pd(OAc)2(4 mg, 17 μmol), PPI13 (11.5 mg, 43.8 μmol), 2 M aq. Na2CO3(1.7 mL) and H2O (1.2 mL). The reaction was heated to reflux and stirred for 2 h, then allowed to cool to RT. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (15 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo onto Celite®. The crude residue was purified by flash chromatography (5% → 10% EtOAc in Pet. Ether) to afford l-(4'-(2,2,2-trifluoroethoxy)-[1,1'- biphenyl]-4-yl)ethan-1-one (575 mg, 87%) as an amorphous white solid.1H NMR (400 MHz, CDCI3) δ 8.02 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 4.41 (q, J = 8.1 Hz, 2H), 2.63 (s, 3H);13C NMR (100 MHz, CDCI3) δ 197.8 (C), 157.7 (C), 145.0 (C), 135.8 (C), 134.4 (C), 129.1 (CH), 128.8 (CH), 127.0 (CH), 123.4 (C, q, J = 278 Hz), 115.6 (CH), 66.1 (CH2, q, J = 35.7 Hz), 26.8 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+Na]+calcd for C16H13F3O223Na, 317.0760; found, 317.0758.

[0421] Methyl 3-(5-(quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-1H- pyrazol-1-yl)benzoate

[0422] A suspension of methyl 3-(5-(quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (201 mg, 0.344 mmol) and Dess-Martin periodinane (400 mg, 0.758 mmol) in CH3CN (4.4 mL) was stirred at reflux for 2 h. The reaction mixture was diluted with DCM (20 mL) and washed with a mixture of sat. aq. NaHCO, and sat. aq. NaiSiCh (5 x 20 mL, 1 : 1 v / v). The organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (50% EtOAc in Pet. Ether) to afford methyl 3-(5-(quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-1H- pyrazol-1-yl)benzoate (187 mg, 93%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.87 (s, 2H), 8.43 (d, J = 2.2 Hz, 1H), 8.22-8.21 (m, 1H), 8.12 (d, J= 1.8 Hz, 1H), 8.06-8.02 (m, 4H), 7.94-7.91 (m, 1H), 7.64-7.61 (m, 3H), 7.53-7.50 (m, 1H), 7.42 (t, J= 8.9 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J= 8.6 Hz, 1H), 4.83 (q, J= 8.6 Hz, 2H), 3.88 (s, 3H);13C NMR (101 MHz, CDCL) 6 166.1 (C), 161.4 (C), 152.2 (C), 145.9 (CH), 145.7 (CH), 144.7 (CH), 143.4 (C), 142.9 (C), 142.8 (C), 140.2 (C), 138.1 (CH), 137.4 (C), 132.1 (C), 132.0 (C), 131.8 (C), 131.4 (C), 130.4 (CH), 130.1 (CH), 129.6 (CH), 129.38 (CH), 129.36 (CH), 129.1 (CH), 127.2 (CH), 126.7 (CH), 126.6 (CH), 123.9 (C, q, J= 277 Hz), 111.2 (CH), 106.8 (CH), 62.4 (CH2, q, J= 35.9 Hz), 52.5 (CH3).

[0423] Methyl 3-(5-(quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-4,5- diliydro-1H -pyrazol-1-yl)benzoate

[0424] A suspension of (E)-3-(quinoxalin-6-yl)-1-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)prop-2-en-1-one (307 mg, 0.704 mmol) and methyl 3-hydrazinobenzoate hydrochloride (546 mg, 2.69 mmol) in glacial AcOH (8.6 mL) was stirred at reflux for 5 h. The reaction mixture was added dropwise to ice-H2O (100 mL), and then the precipitated solids were collected by vacuum filtration and washed with H2O (3 × 10 mL). The crude residue was purified by automated silica gel column chromatography (50%→ 66% EtOAc in Pet. Ether) to afford methyl 3-(5-(quinoxalin-6-yl)-3-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)- 4,5-dihydro-1H-pyrazol-1-yl)benzoate (261 mg, 63%) as an amorphous yellow solid.1H NMR (400 MHz, CDCI3) δ 8.84-8.82 (m, 2H), 8.39 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 8.8 Hz), 8.09 (d, J = 1.9 Hz, 1H), 7.88 (dd, J= 8.6, 2.6 Hz, 1H), 7.84 (d, J= 8.5 Hz, 2H), 7.82-7.81 (m, 1H), 7.73 (dd, J = 8.7, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.47-7.44 (m, 1H), 7.27-7.20 (m, 2H), 6.96- 6.94 (m, 1H), 5.63 (dd, J= 12.3, 6.5 Hz, 1H), 4.82 (q, J= 8.5 Hz, 2H), 4.02 (dd, J= 17.1, 12.3 Hz, 1H), 3.85 (s, 3H), 3.29 (dd, J = 17.3, 6.7 Hz, 1H);13C NMR (101 MHz, CDCI3) δ 167.3 (C), 161.5 (C), 147.0 (C), 145.6 (CH), 145.3 (CH), 144.7 (CH), 144.5 (C), 144.2 (C), 143.3 (C), 142.8 (C), 138.1 (CH), 138.0 (C), 131.7 (C), 131.20 (CH), 131.16 (C), 131.1 (C), 129.2 (CH), 128.1 (CH), 127.0 (CH), 126.8 (CH), 126.6 (CH), 123.8 (C, q, J= 277 Hz), 120.7 (CH), 117.7 (CH), 114.5 (CH), 111.3 (CH), 64.1 (CH), 62.4 (CH2, q, J= 35.9 Hz), 52.2 (CH3), 43.5 (CH2).

[0425] (E )-3-(Quinoxalin-6-yl)-1-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)prop-2-en-1- one

[0426] To a suspension of quinoxaline-6-carbaldehyde (208 mg, 1.31 mmol) and 1-(4-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)phenyl)ethan-l-one (0.389 mg, 1.31 mmol) in EtOH (10.8 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (2.7 mL). The reaction was allowed to gradually warm to RT and stirred for 18 h. The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 20 mL) to afford (E)-3-(quinoxalin-6-yl)-l-(4-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)phenyl)prop-2-en-1-one (535 mg, 94%) as an amorphous pale- yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.89-8.56 (m, 2H), 8.44 (d, J= 2.3 Hz, 1H), 8.33 (d, J= 1.6 Hz, 1H), 8.17-8.14 (m, 3H), 8.10-8.09 (m, 1H), 8.03 (d, J= 15.7 Hz, 1H), 7.93 (dd, J= 8.7, 2.5 Hz, 1H), 7.76 (d, J= 15.7 Hz, 1H), 7.69 (d, J= 8.4 Hz, 2H), 6.98 (d, J= 8.4 Hz, 1H), 4.83 (q, J= 8.6 Hz, 2H);13C NMR (101 MHz, CDCI3) δ 189.3 (C), 161.9 (C), 146.0 (CH), 145.8 (CH), 145.2 (CH), 144.2 (C), 143.3 (C), 143.2 (CH), 142.2 (C), 138.3 (CH), 137.0 (C), 136.7 (C), 130.7 (CH), 130.5 (C), 130.4 (CH), 129.6 (CH), 128.6 (CH), 127.1 (CH), 124.4 (CH), 123.8 (C, q, J= 278 Hz), 111.4 (CH), 62.4 (CH2, q, J = 36.0 Hz); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C24H17F3N3O2436.1267; found 436.1264.

[0427] 1-(4-(6-(2,2,2-Trifluoroethoxy)pyridin-3-yl)phenyl)ethan-1-one

[0428] To a suspension of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (0.526 g, 2.05 mmol), (4- acetylphenyl)boronic acid (0.347 g, 2.11 mmol) and K3PO4(0.915 g, 4.31 mmol) in a mixture of DMF-H2O (20 mL, 1 : 1 v / v) was added Pd(OAc)2(57.7 mg, 0.257 mmol) in a single portion. The reaction was stirred at RT for 4 h then diluted with H2O (20 mL) and extracted with EtOAc (20 mL). The combined organic extracts were washed with H2O (20 mL) and brine (5 × 20 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo onto C6lite®. The crude residue was purified by silica gel column chromatography (10% EtOAc in Pet. Ether) to afford 1-(4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)ethan-l-one (0.471 g, 78 %) as an amorphous white solid.1H NMR (400 MHz, CDCI3) δ 8.404-8.396 (m, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.89 (dd, J= 8.5, 2.6 Hz, 1H), 7.62 (d, J= 8.54 Hz, 2H), 6.98-6.96 (m, 1H), 4.82 (q, J = 8.6 Hz, 2H), 2.64 (s, 3H);13C NMR (101 MHz, CDCI3) δ 197.6 (C), 161.9 (C), 145.1 (CH), 142.1 (C), 138.3 (CH), 136.3 (C), 130.6 (C), 129.3 (CH), 127.0 (CH), 123.8 (C, q, J = 277 Hz), 111.4 (CH), 62.4 (CH2, q, J= 36.0 Hz), 26.8 (CH3); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C15H13F3NO2296.0893; found 296.0891.

[0429] Methyl 3-(3-(4'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate

[0430] A suspension of methyl 3-(3-(4'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate (30 mg, 57 μmol) and Dess-Martin periodinane (53 mg, 125 μmol) in CH3CN (1 mL) was stirred at reflux for 3 h. The reaction mixture was quenched with sat. aq. NaHCO3(20 mL) and extracted with DCM (4 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo onto C6lite®. The crude residue was purified by automated silica gel column chromatography (10 → 40% EtOAc in Pet. Ether) to afford methyl 3-(3-(4'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H- pyrazol-1-yl)benzoate (26 mg, 88%) as a yellow-green film.1H NMR (400 MHz, CDCI3) δ 8.87 - 8.85 (m, 2H), 8.21 (t, J = 1.9 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 8.08 - 7.98 (m, 4H), 7.70 (d, J = 8.7 Hz, 2H), 7.65 - 7.58 (m, 3H), 7.54 - 7.50 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.34 (d, 7= 8.3 Hz, 2H), 7.06 (s, 1H), 3.87 (s, 3H), 2.97 (hept, 7 = 7.0 Hz, 1H), 1.31 (d, 7 = 6.9 Hz, 6H);13C NMR (101 MHz, CDCI3) 6 166.09, 152.63, 148.38, 145.91, 145.70, 143.22, 142.96, 142.75, 141.21, 140.24, 138.33, 132.12, 131.72, 131.32, 130.49, 130.06, 129.64, 129.35, 129.32, 129.06, 127.42, 127.07, 127.06, 126.55, 126.39, 106.78, 52.47, 33.97, 24.15; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C34H29N4O2525.2285; found 525.2281.

[0431] Methyl 3-(3-(4'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H- pyrazol- 1 -yl)benzoate

[0432] A suspension of (E)-1-(4'-isopropyl-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (233 mg, 617 μmol) and methyl 3-hydrazinobenzoate hydrochloride (500 mg, 2.47 mmol) in glacial AcOH (8 mL) was stirred at reflux overnight. The reaction mixture was diluted with warm MeOH (10 mL) and added dropwise to vigorously stirred ice-H2O (150 mL). The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (20 → 40% EtOAc in Pet. Ether) to afford methyl 3-(3-(4'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5- dihydro- 1 H-pyrazol- 1 -yl)benzoate (239 mg, 74%) as a yellow-green film.1H NMR (400 MHz, CDCI3) δ 8.84 - 8.82 (m, 2H), 8.15 - 8.07 (m, 2H), 7.86 - 7.78 (m, 3H), 7.74 (dd, J = 8.7, 2.1 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.45 (dt, J = 7.4, 1.4 Hz, 1H), 7.32 (d, 7 = 8.1 Hz, 2H), 7.30 - 7.26 (m, 1H), 7.26 - 7.20 (m, 1H), 5.62 (dd, J = 12.3, 6.5 Hz, 1H), 4.02 (dd, 7 = 17.1, 12.3 Hz, 1H), 3.85 (s, 3H), 3.29 (dd, 7 = 17.1, 6.5 Hz, 1H), 2.96 (hept, 7 = 7.0 Hz, 1H), 1.30 (d, 7 = 6.9 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 167.27, 148.55, 147.28, 145.47, 145.14, 144.48, 144.20, 143.20, 142.67, 141.75, 137.90, 131.06, 131.01, 130.83, 129.09, 127.99, 127.13, 127.01, 126.54, 126.40, 120.47, 117.60, 114.31, 63.92, 52.07, 43.51, 33.87, 24.01; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C34H31N4O2527.2441; found 527.2437.

[0433] (E)-1-(4'-Isopropyl-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one

[0434] To a suspension of quinoxaline-6-carbaldehyde (316 mg, 2 mmol) and l-(4'-isopropyl-[1,1'- biphenyl]-4-yl)ethan-1-one (476 mg, 2 mmol) in EtOH (16 mL) was added dropwise a solution of 2 M aq. NaOH (4 mL). The reaction was allowed to gradually warm to RT and stirred overnight. Upon completion, the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL) and ice-cold EtOH (10 mL) to afford (E)-1-(4'-isopropyl-[1,1'- biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (580 mg, 76%) as an amorphous brown solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.89 (d, 7 = 1.8 Hz, 1H), 8.86 (d, 7 = 1.8 Hz, 1H), 8.34 (d, 7 = 1.9 Hz, 1H), 8.18 - 8.12 (m, 3H), 8.09 (dd, 7 = 8.8, 1.9 Hz, 1H), 8.03 (d, 7 = 15.7 Hz, 1H), 7.79 (d, 7 = 15.7 Hz, 1H), 7.75 (d, 7 = 8.6 Hz, 2H), 7.61 (d, 7 = 8.3 Hz, 2H), 7.35 (d, 7 = 7.8 Hz, 2H), 2.98 (hept, 7 = 7.0 Hz, 1H), 1.31 (d, 7 = 6.9 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 189.45, 149.44, 146.02, 145.95, 145.70, 144.11, 143.33, 142.84, 137.41, 136.88, 136.41, 130.62, 130.37, 129.34, 128.64, 127.38, 127.32, 127.25, 124.65, 34.01, 24.08; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C26H23N2O 379.1804; found 379.1802. 1-(4'-Isopropyl-[1,1'-biphenyl]-4-yl)ethan-1-one

[0435] To a suspension of 4’ -iodoacetophenone (750 mg, 3.05 mmol), 4-isopropylphenylboronic acid (500 mg, 3.05 mmol) and K3PO4(1.29 g, 6.1 mmol) in a mixture of DMF-H2O (30 mL, 1:1 v / v) was added Pd(OAc)2(68.4 mg, 305 μmol) in a single portion. The reaction was stirred at RT overnight then diluted with H2O (100 mL) and extracted with Et2O (5 x 20 mL). The combined organic extracts were washed with H2O (4 x 20 mL) and brine (20 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 1-(4'-isopropyl-[1,1'- biphenyl]-4-yl)ethan-1-one (706 mg, 97%) as a grey crystalline solid.1H NMR (400 MHz, CDCI3) δ 8.03 (d, J = 9.1 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 2.98 (hept, J = 7.0 Hz, 1H), 2.64 (s, 3H), 1.31 (d, J = 6.9 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 197.84, 149.31, 145.86, 137.46, 135.75, 129.02, 127.33, 127.20, 127.11, 33.99, 26.74, 24.07; HRMS (ESI+ / Q-TOF) m / z: [M+Na]+calcd for C17H18O23Na 261.1249; found 261.1248.

[0436] Methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)-1H- pyrazol-1-yl)benzoate

[0437] A suspension of methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethyl)[1,1'-biphenyl]-4- yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (80 mg, 0.141 mmol) and Dess-Martin periodinane (140 mg, 0.330 mmol) in CH3CN (1.4 mL) was stirred at reflux for 2 h. The reaction mixture was diluted with DCM (5 mL) and then washed with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(3 x 10 mL, 1:1 v / v). The combined aqueous layers were extracted with DCM (30 mL) and then the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford methyl 3-(5-(quinoxalin-6-yl)- 3-(4'-(2,2,2-trifluoroethyl)[1,1'- biphenyl]-4-yl)-1H-pyrazol-1-yl)benzoate (77.2 mg, 97%) as an amorphous orange solid.1H NMR (400 MHz, CDCI3) δ 8.87 (s, 2H), 8.218-8.209 (m, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.07-8.02 (m, 4H), 7.70 (d, J = 8.3 Hz, 2H), 7.66-7.61 (m, 3H), 7.53- 7.50 (m, 1H), 7.43-7.38 (m, 3H), 7.06 (s, 1H), 3.87 (s, 3H), 3.42 (q, J = 10.8 Hz, 2H);13C NMR (100 MHz, CDCI3) δ 166.1 (C), 152.4 (C), 145.9 (CH), 145.7 (CH), 143.3 (C), 142.9 (C), 142.7 (C), 140.7 (C), 140.5 (C), 140.2 (C), 132.1 (C), 131.9 (C), 131.7 (C), 130.8 (CH), 130.5 (CH), 130.0 (CH), 129.6 (CH), 129.4 (CH), 129.3 (CH), 129.1 (CH), 127.5 (CH), 127.4 (CH), 126.6 (CH), 126.5 (CH), 125.9 (C, q, J = 277 Hz), 106.8 (CH), 52.5 (CH3), 40.1 (CH2, q, J = 29.7 Hz); HRMS (ESI+ / TOF-Q) m / z: [M+Na]+calcd for C33H23F3N4O223Na, 587.1665; found, 587.1664.

[0438] Methyl 3-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)-4,5- dihydro- 1H-pyrazol- 1 -yl)benzoate

[0439] A suspension of (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2-trifluoroethyl)[1,1'- biphenyl]-4-yl)prop- 2-en-1-one (0.199 g, 476 μmol) and methyl 3-hydrazinobenzoate hydrochloride (587 mg, 2.90 mmol) in glacial AcOH (10.1 mL) was stirred at reflux for 4 h. The reaction mixture was added dropwise to ice-H2O (100 mL), and the precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (33% → 50% → 66% EtOAc in Pet. Ether) to afford methyl 3-(5- (quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol- 1-yl)benzoate (205 mg, 76%) as an orange solid.1H NMR (400 MHz, CDCI3) δ 8.84-8.83 (m, 2H), 8.12-8.09 (m, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.815-7.805 (m, 1H), 7.74 (dd, J = 8.7, 2.0 Hz, 1H), 7.65-7.61 (m, 4H), 7.45 (dt, J = 7.4, 1.4 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.30-7.27 (m, 1H), 7.24-7.21 (m, 1H), 5.64 (dd, J = 12.3, 6.5 Hz, 1H), 4.03 (dd, J = 17.1, 12.4 Hz, 1H), 3.85 (s, 3H), 3.42 (q, J = 10.8 Hz, 2H), 3.30 (dd, J = 17.1, 6.5 Hz, 1H);13C NMR (100 MHz, CDCI3) δ 167.4 (C), 147.2 (C), 145.6 (CH), 145.3 (CH), 144.5 (C), 144.3 (C), 143.3 (C), 142.8 (C), 141.1 (C), 140.4 (C), 131.5 (C), 131.21 (CH), 131.15 (C), 130.8 (CH), 129.2 (CH), 128.1 (CH), 127.4 (CH), 126.7 (CH), 126.6 (CH), 120.7 (CH), 117.7 (CH), 114.5 (CH), 64.1 (CH), 52.2 (CH3), 43.6 (CH2), 40.1 (CH2, q, J = 29.9 Hz); HRMS (ESI+ / TOF-Q) m / z: [M+Na]+calcd for C33H25F3N4O223Na, 589.1822; found, 589.1819. (E)-3-(Quinoxalin-6-yl)-1-(4'-(2,2,2-trifhioroethyl)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one

[0440] To a suspension of quinoxaline-6-carbaldehyde (134 mg, 0.846 mmol) and l-(4'-(2,2,2- trifluoroethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one (236 mg, 0.846 mmol) in EtOH (6.8 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (1.7 mL). The reaction was allowed to gradually warm to RT and stirred for 7 h. The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 20 mL) to afford (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2- trifluoroethyl)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one (355 mg, quant.) as an amorphous pale- yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.90-8.87 (m, 2H), 8.35 (d, J = 1.7 Hz, 1H), 8.18-8.15 (m, 3H), 8.10 (dd, J = 8.8, 1.9 Hz, 1H), 8.04 (d, J = 15.7 Hz, 1H), 7.81-7.75 (m, 3H), 7.67 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 3.45 (q, J = 10.8 Hz, 2H);13C NMR (100 MHz, CDCI3) δ 189.5 (C), 146.0 (CH), 145.8 (CH), 145.3 (C), 144.2 (C), 143.4 (C), 143.1 (CH), 139.9 (C), 136.9 (C), 136.8 (C), 131.0 (CH), 130.7 (CH), 130.4 (CH), 129.4 (CH), 128.7 (CH), 127.7 (CH), 127.6 (CH), 124.6 (CH), 40.1 (CH2, q, J = 29.8 Hz); HRMS (ESI+ / TOF-Q) m / z: [M+Na]+calcd for C25H17F3N2O23Na, 441.1185; found, 441.1185. l-(4'-(2,2,2-Trifluoroethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one

[0441] To a suspension of l-bromo-4-(2,2,2-trifluoroethyl)benzene (0.516, 2.16 mmol), (4- acetylphenyl)boronic acid (0.352 g, 2.14 mmol) and K3PO4 (0.897 g, 4.23 mmol) in a mixture of DMF-H2O (21 mL, 1:1 v / v) was added Pd(OAc)2(55.5 mg, 247 μmol) in a single portion. The reaction was stirred at RT for 3 h then diluted with H2O (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (5 x 50 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% EtOAc in Pet. Ether) to afford 1-(4'-(2,2,2- trifluoroethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one (384 mg, 64%) as an amorphous off-white solid.1H NMR (400 MHz, CDCI3) δ 8.04 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.41 (d, 7 = 8.1 Hz, 2H), 3.43 (q, J = 10.8 Hz, 2H), 2.64 (s, 3H);13C NMR (100 MHz, CDCI3) δ 197.8 (C), 145.2 (C), 139.9 (C), 136.2 (C), 130.9 (CH), 130.4 (C, q, J = 3.2 Hz), 129.1 (CH), 127.7 (CH), 127.4 (CH), 125.8 (CF3, J = 277 Hz), 40.1 (CH2, q, 7 = 29.9 Hz), 26.8 (CH3); HRMS (ESI+ / TOF-Q) m / z: [M+Na]+calcd for C16H13F3O23Na, 301.0811; found, 301.0809.

[0442] Methyl 3-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1H- pyrazol- 1 -yl)benzoate

[0443] A suspension of methyl 3-(5-(benzo[c][l,2,5]oxadiazol-5-yl)-3-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (57 mg, 107 μmol) and Dess-Martin periodinane (0.1 g, 236 μmol) in CH3CN (2 mL) was stirred at reflux for 3 h. The reaction mixture was quenched with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(20 mL, 1:1 v / v) and extracted with DCM (4 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (20 → 40% EtOAc in Pet. Ether) to afford methyl 3-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(4'-isopropoxy[1,1'-biphenyl]-4-yl)-1H-pyrazol-1- yl)benzoate (37 mg, 65%) as a pale-orange foam.1H NMR (400 MHz, CDCI3) δ 8.17 (t, 7 = 1.9 Hz, 1H), 8.06 (dt, 7 = 7.8, 1.4 Hz, 1H), 7.97 (d, 7 = 8.4 Hz, 2H), 7.84 -7.83 (m, 1H), 7.77 (dd, 7 = 9.3, 1.1 Hz, 1H), 7.65 (d, 7 = 8.4 Hz, 2H), 7.60 - 7.54 (m, 3H), 7.47 (t, 7 = 7.9 Hz, 1H), 7.25 (dd, 7 = 9.3, 1.4 Hz, 1H), 7.02 (s, 1H), 6.98 (d, 7 = 8.8 Hz, 2H), 4.60 (hept, 7 = 6.0 Hz, 1H), 3.89 (s, 3H), 1.37 (d, 7 = 6.1 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 165.82, 157.73, 152.66, 149.00, 148.30, 142.00, 141.03, 139.87, 133.40, 132.86, 132.47, 131.80, 130.43, 129.55, 129.21, 128.06, 126.99, 126.27, 126.15, 117.00, 116.21, 115.53, 106.92, 70.02, 52.47, 22.12; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C32H27N4O4531.2027; found 531.2027.

[0444] Methyl 3-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate A suspension of (E)-3-(benzo[c][l,2,5]oxadiazol-5-yl)-1-(4'-isopropoxy-[1,1'-biphenyl]-4- yl)prop-2-en-1-one (0.1 g, 260 μmol) and methyl 3-hydrazinobenzoate hydrochloride (210 mg, 1.04 mmol) in glacial AcOH (4.3 mL) was stirred at reflux overnight. The reaction mixture was diluted with warm MeOH (10 mL) and added dropwise to vigorously stirred ice- H2O (100 mL). The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (10 → 40% EtOAc in Pet. Ether) to afford methyl 3-(5-(benzo[c][l,2,5]oxadiazol-5-yl)-3-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoate (57 mg, 32%) as a red-brown film.1H NMR (300 MHz, CDCI3) δ 7.82 (dd, J = 9.3, 1.0 Hz, 1H), 7.80 - 7.71 (m, 4H), 7.59 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.48 (dt, J = 6.6, 1.8 Hz, 1H), 7.35 (dd, J = 9.3, 1.4 Hz, 1H), 7.32 - 7.22 (m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.42 (dd, J = 12.3, 6.5 Hz, 1H), 4.59 (hept, J = 6.0 Hz, 1H), 3.94 (dd, J = 17.4, 12.4 Hz, 1H), 3.86 (s, 3H), 3.22 (dd, J = 17.2, 6.5 Hz, 1H), 1.36 (d, J = 6.1 Hz, 6H);13C NMR (75 MHz, CDCI3) δ 167.26, 158.01, 149.24, 148.98, 147.75, 145.46, 144.43, 141.81, 132.52, 131.21, 130.30, 130.10, 129.37, 128.14, 126.87, 126.54, 120.91, 118.50, 117.72, 116.34, 114.19, 113.07, 70.13, 63.93, 52.26, 42.60, 22.19; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C32H29N4O4533.2183; found 533.2178.

[0445] (E)-3-(Benzo[c][l,2,5]oxadiazol-5-yl)-1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)prop-2-en-1- one

[0446] To a suspension of benzo[c][1,2,5]oxadiazole-5-carbaldehyde (173 mg, 1.17 mmol) and l-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (0.3 g, 1.17 mmol) in MeOH (10 mL) at 0 °C was added dropwise a solution of 4 M aq. NaOH (1.2 mL). The reaction was allowed to gradually warm to RT and stirred overnight. The reaction mixture was poured into ice-H2O and the precipitated solids were collected by vacuum filtration. The collected solid was washed with H2O (3 x 10 mL), ice-cold EtOH (10 mF) and Et2O (10 mL) to afford (E)-3- (benzo[c] [1,2,5]oxadiazol-5-yl)-1 -(4'-isopropoxy- [1,1 '-biphenyl] -4-yl)prop-2-en- 1 -one (132 mg, 29%) as an amorphous brown solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.09 (d, J = 8.3 Hz, 2H), 8.01 (s, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.86 (d, J = 15.7 Hz, 1H), 7.77 (dd, 7 = 9.6, 1.3 Hz, 1H), 7.74 - 7.65 (m, 3H), 7.59 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.62 (hept, J = 6.0 Hz, 1H), 1.38 (d, J = 6.0 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 188.81, 158.48, 149.51, 149.09, 145.87, 141.42, 138.34, 135.49, 131.69, 129.83, 129.27, 128.42, 126.79, 125.65, 117.80, 117.23, 116.25, 70.05, 22.05; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C24H21N2O3385.1547; found 385.1547.

[0447] Ethyl 4-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1- yl)butanoate (left structure) and ethyl 4-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3- (quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoate (right structure)

[0448] To a solution of 6-(3-(4'-isopropoxy[1,1'- biphenyl]-4-yl)-1H-pyrazol-5-yl)quinoxaline (138 mg, 338 μmol) and K2CO3(140 mg, 1.02 mmol) in DMF (6 mF) was added dropwise ethyl 4- bromobutyrate (58 pF, 407 μmol). The reaction mixture was stirred at reflux overnight then diluted with 1 M aq. HC1 (30 mF). The resulting mixture was extracted with EtOAc (4 x 10 mF) and the combined organic extracts were washed with H2O (3 x 10 ml) and brine (1 x 10 mF), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (20 → 60% EtOAc in Pet. Ether) to afford ethyl 4-(5-(4'-isopropoxy[1,1'- biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1- yl)butanoate (9 mg, 5%) as a pale-yellow solid.1H NMR (400 MHz, CDCI3) δ 8.84 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H), 8.41 (dd, 7 = 8.8, 1.9 Hz, 1H), 8.14 (d, 7 = 8.8 Hz, 1H), 7.68 (d, 7 = 7.9 Hz, 2H), 7.57 (d, 7 = 8.7 Hz, 2H), 7.51 (d, 7 = 8.1 Hz, 2H), 6.99 (d, 7 = 9.1 Hz, 2H), 6.80 (s, 1H), 4.62 (hept, 7 = 6.1 Hz, 1H), 4.31 (t, 7 = 6.8 Hz, 2H), 4.04 (q, 7 = 7.1 Hz, 2H), 2.37 (t, 7 = 7.1 Hz, 2H), 2.25 (p, 7 = 7.1 Hz, 2H), 1.38 (d, 7 = 5.9 Hz, 6H), 1.18 (t, 7 = 7.1 Hz, 3H);13C NMR (101 MHz, CDCI3) δ 172.71, 157.94, 149.28, 145.53, 144.43, 143.53, 142.86, 141.40, 135.51, 132.39, 129.67, 129.34, 128.42, 128.16, 127.00, 126.00, 124.96, 116.24, 104.15, 70.03, 60.51, 48.88, 31.21, 25.63, 22.11, 14.10; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C32H33N4O3521.2547; found 521.2540.

[0449] A second fraction (7 mg) containing a ca. 2:1 mixture of ethyl 4-(3-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)-5-(quinoxalin-6-yl)-1H-pyrazol-1-yl)butanoate:1H NMR (300 MHz, CDCI3) δ 8.92 (d, J = 1.9 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.25 - 8.22 (m, 1H), 8.22 - 8.21 (m, 1H), 7.94 - 7.87 (m, 3H), 7.72 - 7.49 (m, 4H), 7.04 - 6.94 (m, 2H), 6.77 (s, 1H), 4.68 - 4.54 (m, 1H), 4.36 (t, J = 6.7 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 2.42 - 2.16 (m, 4H), 1.41 - 1.36 (m, 6H), 1.14 (t, J = 7.1 Hz, 3H); HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C32H33N4O3521.2547; found 521.2540; and ethyl 4-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin- 6-yl)-1H-pyrazol-1-yl)butanoate was also isolated, which was used in the next step without further purification.

[0450] 6-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)quinoxaline

[0451] A solution of 6-(3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5- yl)quinoxaline (353 mg, 864 μmol) in DMSO (5 mL) was heated to 110 °C overnight under an atmosphere of O2. The reaction mixture was added dropwise to vigorously stirred ice-H2O (30 mL) and the resulting precipitate was collected by vacuum filtration. The crude residue was purified by automated silica gel column chromatography (40 → 80% EtOAc in Pet. Ether) to afford 6-(3-(4'-isopropoxy[1,1'- biphenyl]-4-yl)-1H-pyrazol-5-yl)quinoxaline (114 mg, 32%) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.80 - 13.59 (m, 1H), 9.01 - 8.92 (m, 2H), 8.61 - 8.53 (m, 1H), 8.50 - 8.30 (m, 1H), 8.25 - 8.13 (m, 1H), 8.02 - 7.87 (m, 2H), 7.81 - 7.62 (m, 4H), 7.56 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.68 (hept, J = 6.0 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H); HRMS (ESI / Q-TOF) m / z: [M-H]" calcd for C26H21N4O 405.1721; found 405.1718.

[0452] Methyl 3-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1- yl)benzoate A suspension of methyl 3-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-4,5- dihydro-1H-pyrazol-1-yl)benzoate (38 mg, 70 μmol) and Dess-Martin periodinane (66 mg, 155 μmol) in CH3CN (1.3 mL) was stirred at reflux for 3 h. The reaction mixture was quenched with a mixture of sat. aq. NaHCO3and sat. aq. Na2S2O3(20 mL, 1:1 v / v) and extracted with DCM (4 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel column chromatography (20 → 60% EtOAc in Pet. Ether) to afford methyl 3-(5-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)-3-(quinoxalin-6-yl)-1H-pyrazol-1-yl)benzoate (31 mg, 80%) as a yellow-green film.1H NMR (400 MHz, CDCI3) δ 8.86 (d, J = 1.9 Hz, 1H), 8.83 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.50 (dd, J = 8.7, 1.9 Hz, 1H), 8.26 (t, J = 1.9 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.03 (dt, J = 7.8, 1.4 Hz, 1H), 7.58 - 7.49 (m, 5H), 7.43 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.60 (hept, J = 6.1 Hz, 1H), 3.91 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 166.11, 157.93, 150.96, 145.40, 145.00, 143.48, 143.11, 141.19, 140.30, 134.84, 132.24, 131.48, 129.86, 129.42, 129.15, 129.03, 128.73, 128.40, 128.08, 128.03, 126.81, 126.31, 125.60, 116.23, 106.07, 70.02, 52.39, 22.09; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C34H29N4O3541.2234; found 541.2229.

[0453] Methyl 3-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-4,5-dihydro-1H- pyrazol- 1 -yl)benzoate

[0454] A suspension of (E)-3-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1-(quinoxalin-6-yl)prop-2-en-1- one (0.1 g, 253 μmol) and methyl 3-hydrazinobenzoate hydrochloride (205 mg, 1.01 mmol) in glacial AcOH (3.2 mL) was stirred at reflux overnight. The reaction mixture was diluted with warm MeOH (10 mL) and added dropwise to vigorously stirred ice- H2O (100 mL). The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 10 mL). The crude residue was purified by automated silica gel column chromatography (20 → 60% EtOAc in Pet. Ether) to afford methyl 3-(5-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)- 4,5-dihydro-1H-pyrazol-1-yl)benzoate (38 mg, 28%) as a yellow-green film.1H NMR (400 MHz, CDCI3) δ 8.80 (d, J = 1.9 Hz, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.56 (dd, J = 8.9, 1.9 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.92 - 7.88 (m, 1H), 7.56 - 7.43 (m, 5H), 7.35 (d, J = 8.3 Hz, 2H), 7.29 - 7.23 (m, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.47 (dd, J = 12.4, 6.7 Hz, 1H), 4.56 (hept, J = 6.1 Hz, 1H), 4.00 (dd, J = 17.1, 12.4 Hz, 1H), 3.89 (s, 3H), 3.34 (dd, J = 17.1, 6.7 Hz, 1H), 1.34 (d, J = 6.0 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 167.29, 157.64, 146.12, 145.41, 144.68, 144.08, 143.52, 143.46, 140.59, 139.74, 134.56, 132.70, 131.02, 129.63, 129.08, 128.06, 128.01, 127.55, 126.31, 125.78, 120.79, 117.79, 116.13, 114.69, 69.97, 64.44, 52.13, 43.16, 22.09; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C34H31N4O3543.2391; found 543.2389.

[0455] (E')-3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-1-(quinoxalin-6-yl)prop-2-en-1-one

[0456] To a suspension of 4'-isopropoxy-[1,1'-biphenyl]-4-carbaldehyde (550 mg, 2.28 mmol) and 1- (quinoxalin-6-yl)ethan-1-one (394 mg, 2.28 mmol) in EtOH (18 mL) at 0 °C was added dropwise a solution of 2 M aq. NaOH (4.6 mL). The reaction was allowed to gradually warm to RT and stirred overnight. The precipitated solids were collected by vacuum filtration and washed with H2O (3 x 20 mL) and ice-cold EtOH (1 x 20 mL) to afford (E)-3-(4'-isopropoxy- [1,1 '-biphenyl] -4-yl)- 1-(quinoxalin-6-yl)prop-2-en-1-one (611 mg, 68%) as an amorphous yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 8.96 - 8.94 (m, 2H), 8.78 (d, J = 1.9 Hz, 1H), 8.42 (dd, J = 8.8, 2.0 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 15.7 Hz, 1H), 7.76 - 7.69 (m, 3H), 7.64 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.61 (hept, J = 6.1 Hz, 1H), 1.38 (d, J = 6.0 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 189.46, 158.26, 146.71, 145.86, 145.13, 143.57, 142.69, 139.39, 132.98, 132.28, 130.79, 130.37, 129.35, 129.06, 128.29, 127.22, 120.93, 116.34, 70.14, 22.20; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C26H23N2O2395.1754; found 395.1752. 4'-Isopropoxy-[1,1'-biphenyl]-4-carbaldehyde

[0457] To a suspension of 4 -bromobenzaldehyde (514 mg, 2.77 mmol), 4-isopropoxyphenyl boronic acid (500 mg, 2.77 mmol) and K3PO4(1.18 g, 5.54 mmol) in a mixture of DMF-H2O (28 mL, 1:1 v / v) was added Pd(OAc)2(62 mg, 277 μmol) in a single portion. The reaction was stirred at RT overnight then diluted with H2O (100 mL) and extracted with Et20 (5 x 20 mL). The combined organic extracts were washed with H2O (4 x 20 mL) and brine (1 x 20 mL) then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 4'-isopropoxy-[1,1'- biphenyl]-4-carbaldehyde (623 mg, 94%) as an amorphous off-white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3) δ 10.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.62 (hept, J = 6.2 Hz, 1H), 1.38 (d, 7 = 6.1 Hz, 6H);13C NMR (101 MHz, CDCI3) δ 192.02, 158.64, 147.00, 134.77, 131.86, 130.44, 128.63, 127.13, 116.36, 70.15, 22.17; HRMS (ESI+ / Q-TOF) m / z: [M+H]+calcd for C16H17O2241.1223; found 241.1223.

[0458] In vitro studies

[0459] The compounds of the present invention were initially screened for activity using an in vitro fully automated incubation system for the measurement of total gas production and gas composition (methane and hydrogen). The system used is described in detail in the paper by Muetzel et al. (2014; Animal Feed Science and Technology 196, 1-11). The system in this specification is referred to as the rumen in vitro system or RIV. The RIV system provides a relatively simple tool for determining the rate and production of methane and also whether the rate and production of methane is inhibited or reduced by a particular compound or feed.

[0460] Rumen in vitro assay method.

[0461] Rumen in vitro assays use rumen fluid from donor animals (typically either sheep or cattle) which is typically combined with a buffer and then incubated in sealed fermentation vessels at 39 °C for either 24 or 48 h. These assays systems have been well-characterised and used by the scientific community over the last two decades (Rymer et al. 2005). The system that has been used here to characterise the effects of inhibitors on methane production and gas production, and the formation of H2, was described by Muetzel et al. (2014). Rumen in vitro assay systems reflect what can occur in the rumen in vivo, but only short-term, due to their short incubation times (typically not exceeding 48 h) which is limited by its buffering capacity and the fact that it is a closed system.

[0462] Stock solutions of inhibitors were re-suspended in dimethylformamide (DMF) at concentrations 1000-fold higher than the highest used for the assays. Any further dilutions were also prepared using DMF. The total amount of inhibitor solution added to the rumen fluid- buffer mixture (60 mL) was 60 pl. Incubations used 60 ml of medium containing 12 ml of filtered rumen fluid and 48 ml of buffer in serum bottles for 24-48 h, essentially as described by Muetzel et al. (2014). Two fistulated cattle were used as donor animals for rumen fluid and treatments were incubated in duplicate bottles. Sets of duplicate incubation vials that contained ryegrass (with rumen fluid-buffer mixture), and ryegrass with 30 μM bromoethanesulfonate (BES) were also incubated as negative and positive controls, respectively. One experiment consists of 2 replicates of an inhibitor at any one concentration run at the same time, and a run can contain up to 32 bottle, including positive (30 pM BES) and negative (no inhibitor added) controls.

[0463] Compound 1, for example, was tested using the 60 mL rumen in vitro assay system at 10 μM, and 2 μM final concentrations and compared to a positive control with 30 μM BES. At 30 μM, BES inhibition levels were 70.5% inhibition at 10 hours and 55.6% inhibition at 18 hours.

[0464] Table 1

[0465] In vivo trial methods

[0466] The trial for testing the effects of Compound 5 on methane emissions from sheep over a 30- day period in methane measurement chambers was approved by the Grasslands Animal Ethics Committee. Five sheep were used for the Compound 5 treatment group. The animals received a general-purpose diet (GP) at 1.5 x maintenance energy requirements throughout the trials consisting of 500 g hay, 100 g soybean meal, 290 g barley, 100 g molasses, 6 g mineral mix and 5.5 g dicalcium phosphate dihydrate. During the time in the respiration chambers the animals had free access to water, with the feed offered twice a day at approximately 9:00 and 16:00 h in equal amounts. Feed refusals were weighed.

[0467] The animals were adapted to GP diet for 14 days prior to entering the methane measurement chambers. Rumen contents were sampled by stomach tubing after being released from the respiration chambers, to allow for the future examination of any effects on volatile fatty acids (VFAs). Rumen samples from stomach tubing were immediately subsampled for short chain fatty acid (SCFA) analysis (1.8 ml). The samples were centrifuged (21,000 g, 10 min, 4 °C). An aliquot of 0.9 ml of the supernatant was collected into 0.1 ml of internal standard (20 mM ethylbutyrate in 20% w / v phosphoric acid) for SCFA analysis and stored at -20 °C. SCFA samples were thawed and centrifuged (21,000 g, 10 min, 4 °C) and 0.8 ml of the supernatant was collected into a crimp cap glass vial. GC vials were stored at 4 °C until analysis. From the remaining supernatant 0.2 ml was collected into 1.5 mF tubes (Eppendorf, Hamburg, Germany) for derivatised SCFA analysis. SCFA were analysed by a Shimadzu GC-2010 Plus gas chromatograph and AOC-6000 autosampler (Shimadzu Corporation, Kyoto, Japan).

[0468] After the 14-day acclimatisation period, methane emissions were measured in open circuit respiration chambers as described in Chapter 1 of the technical manual on respiration chamber design (http: / / www.globalresearchalliance.org / wp-content / uploads / 2012 / 03 / GRA-MAN- Facility-BestPract-2012-ch 13.pdf ). Dry matter intake (DMI, kg / d) was recorded during methane measurements from the weight difference of feed offered and refused. The first measurement period in the chambers (48 hours; Period 1) served as a control for each animal. After a week the sheep received Compound 5 initially at 15 mg per day (Period 2), which was increased to 45 mg / day (Periods 3-6).

[0469] Results

[0470] Methane gas outputs in open circuit respiration chambers were determined. Background methane emissions were measured over two days (Period 1). In the following week dosing started in the treatment group on the first day of a 4-day chamber period (Period 2).

[0471] This was followed by weekly measurement periods (Periods 3-6, each 2 days). Methane inhibition during the dosing periods is summarised in Table 1.

[0472] Table 1 Average methane inhibition (%) (Av ± SD) resulting from dosing Compound 5 in feed to sheep, twice daily.

[0473] Methane yields (g CFU / kg DMI) were compared to those from the same animals at the start of the trial (Period 1), prior to them receiving any inhibitor. Dose (mg / day) in each period is indicated. Methane inhibition is an average from all animals in the group. The present invention and its examples have been described in detail. However, the scope of the present invention is not intended to be limited to the particular examples of the invention described in the specification. Various modifications, substitutions, and variations can be made to the disclosed material without departing from the spirit and / or essential characteristics of the present invention. Accordingly, one of ordinary skill in the art will readily appreciate from the disclosure that later modifications, substitutions, and / or variations performing substantially the same function or achieving substantially the same result as examples described herein may be utilized according to such related examples of the present invention. Thus, the following claims are intended to encompass within their scope modifications, substitutions, and variations to the examples of the invention disclosed herein.

Claims

Claims1. A compound of Formula Iwherein R may be selected from:-C1-C6-(C=O)OH; or-aryl-C(=O)-OH, -aryl-C(=O)-O-C1-C6, -aryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -aryl-C1-C6-OH, -aryl-C1-C6-(C=O)OH, or-aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-aryl-C(=O)-NH-S(O)2-C1-C6, -aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-C(=O)-NH-S(O)2-aryl, -aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -aryl-C(=O)-NH-S(O)2-heteroaryl, -aryl- C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-aryl-C(=O)-NH-S(O)2-NH2, -aryl-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-C(=O)-NH-S(O)2-NH- C3-C8-cycloalkyl, -aryl-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, - aryl-C(=O)-NH-S(O)2-NH-heteroaryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -aryl- wherein J is a 5 or 6membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-aryl-NH-C(=O)-NH-S(O)2-C1-C6, -aryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-aryl, -aryl-NH-C(=O)-NH-S(O)2-heteroaryl, or-aryl-NH-C(=O)-NH-S(O)2-NH2, -aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-NH-C(=O)- NH-S(O)2-NH-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -aryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2,, wherein J is a 5 or 6 membered heterocycle ringoptionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-aryl-S(O)2-OH, -aryl-S(O)2-NH2, -aryl-S(O)2-NH-C1-C6, -aryl-S(O)2-N(C1-C6)2,, wherein J is a 5 or 6 membered heterocycle ring optionallyincluding a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-aryl-S(O)2-NH-C3-C8-cycloalkyl, or, wherein J is a 5 membered heterocycle ring containing up to 4 heteroatoms selected from _-N=, - NH-, or -O-; or-heteroaryl-C(=O)-OH, -heteroaryl-C(=O)-O-C1-C6, -heteroaryl-C(=O)-O-C1-C6-O-(C=O)- C1-C6, -heteroaryl-C1-C6-OH, -heteroaryl-C1-C6-(C=O)OH, or-heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8-, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, -NC1-C6-, -S- or -O-; or-heteroaryl-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, heteroaryl-C(=O)-NH-S(O)2-aryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-heteroaryl-C(=O)-NH-S(O)2-NH2, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -heteroaryl- C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -heteroaryl- C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-heteroaryl, -heteroaryl- C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2,, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or-heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -heteroaryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, - heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-NH-C(=O)-NH-S(O)2- NH-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-, wherein J is a 5 or 6 memberedheterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; wherein P may be a 5 to 10 membered aryl ring or rings optionally containing one or more heteroatoms, and wherein P may be further substituted with one or more halo, -C1-C6-alkyl, - C1-C6-alkyl substituted with one or more halo or hydroxy; -C3-C8-cycloalkyl, -CN, hydroxy, - O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, - S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1- C6-alkyl, -N(C1-C6-alkyl)2,, wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or aryl, aryl substituted with one or more, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkylsubstituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5 or 6 membered heterocycle ring optionally including asecond heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-aryl; C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or heteroaryl; heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C 1 -C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6- alkyl)2, wherein M is a 5 or 6 membered heterocycle ring optionally includinga second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-heteroaryl; C1-C6-heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6- alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1- C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1- C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl,-N(C1-C6-alkyl)2,, wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-O-aryl; -O-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6- alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2,, wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-O-C1-C6-aryl; -O-C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6- alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6- alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2,wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or wherein Q may be selected fromand wherein R3, R4, or R6are independently selected from -H, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo; and or a salt thereof.

2. The compound as claimed in claim 1, wherein R is selected from:-C1-C6-(C=O)OH; or-aryl-C(=O)-OH, or-heteroaryl-C(=O)-OH; or-aryl-C(=O)-NH-S(O)2-C1-C6.

3. The compound as claimed in claim 1 or claim 2, wherein R is -aryl-C(=O)-OH.

4. The compound as claimed in any one of claims 1 to 3, wherein R is -phenyl-C(=O)- OH.

5. The compound as claimed in claim 1 or claim 2, wherein R is -heteroaryl-C(=O)-OH.

6. The compound as claimed in claim 1 or claim 5, wherein R is -pyridyl-C(=O)-OH.

7. The compound as claimed in claim 1 or claim 2, wherein R is -C1-C6-(C=O)OH.

8. The compound as claimed in claim 7, wherein R is - (CH2)3-(C=O)OH.

9. The compound as claimed in claim 1, wherein R is wherein J is a 5membered heterocycle ring containing up to 4 heteroatoms selected from -N=, -NH-, or -0-.

10. The compound as claimed in claim 9, wherein R is -phenyl-tetrazole.

11. The compound as claimed in claim 9, wherein R is -phenyl-oxadiazolone.

12. The compound as claimed in any one of claims 1 to 11, wherein P is selected from aryl or an aryl substituted with one or more halo, - CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6- alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

13. The compound as claimed in any one of claims 1 to 11, wherein P is selected from aryl substituted with aryl or an aryl substituted with halo,-CN, -C1-C6-alkyl, -O-C1-C6-alkyl, - C1-C6-alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

14. The compound as claimed in any one of claims 1 to 11, wherein P is selected from phenyl or a phenyl substituted with one or more halo, -CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1- C6-alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

15. The compound as claimed in claim 14 wherein P is phenyl substituted with halo.

16. The compound as claimed in claim 15, wherein P is phenyl substituted with -Cl.

17. The compound as claimed in any one of claims 1 to 11, wherein P is selected from phenyl substituted with phenyl or a phenyl substituted with halo, -CN, -C1-C6-alkyl, -O-C1- C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

18. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl.

19. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with halo.

20. The compound as claimed in claim 19, wherein P is phenyl substituted with a phenyl substituted with -Cl.

21. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl.

22. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl substituted with one or more halo.

23. The compound as claimed in claim 22, wherein P is phenyl substituted with a phenyl substituted with -OCH2CF3.

24. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with -O-C3-alkyl.

25. The compound as claimed in claim 24, wherein P is phenyl substituted with a phenyl substituted with -OPr.

26. The compound as claimed in claim 24, wherein P is phenyl substituted with a phenyl substituted with -OnPr.

27. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl substituted with one or more halo.28 The compound as claimed in claim 27, wherein P is phenyl substituted with a phenyl substituted with -CH2CF3.29 The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with a halo and a -O-C3-alkyl.

30. The compound as claimed in claim 29, wherein P is phenyl substituted with a phenyl substituted with -F and a -O-C3-alkyl.

31. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl and a -O-C1-C6-alkyl.

32. The compound as claimed in claim 31, wherein P is phenyl substituted with a phenyl substituted with a -C1-C3-alkyl and a -O-C3-alkyl.

33. The compound as claimed in claim 17, wherein P is phenyl substituted with a phenyl substituted with -CN and -O-C1-C6-alkyl.

34. The compound as claimed in any one of claims 1 to 11, wherein P is -aryl-heteroaryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O- C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

35. The compound as claimed in claim 34, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

36. The compound as claimed in claim 35, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1-C6-alkyl.

37. The compound as claimed in claim 36, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C3-alkyl.

38. The compound as claimed in claim 37, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OPr.

39. The compound as claimed in claim 37, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OnPr.

40. The compound as claimed in claim 35, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

41. The compound as claimed in claim 40, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OCF3.

42. The compound as claimed in claim 40, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OCH2CF3.

43. The compound as claimed in claim 34, wherein P is -aryl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1- C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O- C1-C6-alkyl optionally substituted with one or more halo.

44. The compound as claimed in claim 34, wherein P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1- C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O- C1-C6-alkyl optionally substituted with one or more halo.

45. The compound as claimed in claim 44, wherein P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with -O-C1-C6-alkyl.

46. The compound as claimed in claim 45, wherein P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with -OPr.

47. The compound as claimed in claim 44, wherein P is -phenyl-pyridyl and wherein the pyridyl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

48. The compound as claimed in claim 47, wherein P is -phenyl-pyridyl and wherein the pyridyl is substituted with -OCH2CF3.

49. The compound as claimed in any one of claims 1 to 11, wherein P is -heteroaryl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from - halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6- alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

50. The compound as claimed in claim 49, wherein P is -heteroaryl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, - C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and - O-C1-C6-alkyl optionally substituted with one or more halo.

51. The compound as claimed in claim 50, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl.

52. The compound as claimed in claim 51, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C3-alkyl.

53. The compound as claimed in claim 52, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OPr.

54. The compound as claimed in claim 52, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OnPr.

55. The compound as claimed in claim 50, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

56. The compound as claimed in claim 55, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OCF3.

57. The compound as claimed in claim 55, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OCH2CF3.

58. The compound as claimed in claim 49, wherein P is -pyridyl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl,-C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

59. The compound as claimed in claim 58, wherein P is -pyridyl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1- C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O- C1-C6-alkyl optionally substituted with one or more halo.

60. The compound as claimed in claim 59, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl.

61. The compound as claimed in claim 60, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C3-alkyl.

62. The compound as claimed in claim 61, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OPr.

63. The compound as claimed in claim 61, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OnPr.

64. The compound as claimed in claim 59, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

65. The compound as claimed in claim 64, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCF3.

66. The compound as claimed in claim 65, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCH2CF3.

67. The compound as claimed in any one of claims 1 to 66 wherein Q is selected from:

68. The compound as claimed in any one of claims 1 to 67 wherein Q is selected from:

69. The compound as claimed in any one of claims 1 to 68 wherein Q is selected from:

70. The compound as claimed in any one of claims 1 to 69 wherein Q is71. The compound as claimed in claim 1, wherein the compound or salt of Formula I is selected from one or more of the following:

72. The compound as claimed in claim 1, wherein the compound of Formula I is: or a salt thereof.

73. The compound as claimed in claim 1, wherein the compound of Formula I is: or a salt thereof.

74. The compound as claimed in claim 1, wherein the compound of Formula I is: or a salt thereof.

75. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

76. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

77. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

78. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

80. The compound as claimed in claim 1, wherein the compound of Formula I is: or a salt thereof.

81. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

82. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

83. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

84. The compound as claimed in claim 1, wherein the compound of Formula I is: or a salt thereof.

85. The compound as claimed in claim 1, wherein the compound of Formula I is: or a salt thereof.

86. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

87. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

88. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

89. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

90. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

91. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

92. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

93. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

94. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

95. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

96. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

97. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

98. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

99. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

100. The compound as claimed in claim 1, wherein the compound of Formula I is:or a salt thereof.

101. A compound of Formula IIwherein R may be selected from:-C1-C6-(C=O)OH; or-aryl-C(=O)-OH, -aryl-C(=O)-O-C1-C6, -aryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -aryl-C1-C6-OH, -aryl-C1-C6-(C=O)OH, or-aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)- wherein J is a 5 or 6 membered heterocycle ringoptionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-aryl-C(=O)-NH-S(O)2-C1-C6, -aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-C(=O)-NH-S(O)2-aryl, -aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -aryl-C(=O)-NH-S(O)2-heteroaryl, -aryl- C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-aryl-C(=O)-NH-S(O)2-NH2, -aryl-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-C(=O)-NH-S(O)2-NH- C3-C8-cycloalkyl, -aryl-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, - aryl-C(=O)-NH-S(O)2-NH-heteroaryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -aryl-, wherein J is a 5 or 6membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-aryl-NH-C(=O)-NH-S(O)2-C1-C6, -aryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-aryl, -aryl-NH-C(=O)-NH-S(O)2-heteroaryl, or-aryl-NH-C(=O)-NH-S(O)2-NH2, -aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-NH-C(=O)- NH-S(O)2-NH-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -aryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2,, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-aryl-S(O)2-OH, -aryl-S(O)2-NH2, -aryl-S(O)2-NH-C1-C6, -aryl-S(O)2-N(C1-C6)2,, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-aryl-S(O)2-NH-C3-C8-cycloalkyl, or, wherein J is a 5 membered heterocycle ring containing up to 4 heteroatomsselected from; or-heteroaryl-C(=O)-OH, -heteroaryl-C(=O)-O-C1-C6, -heteroaryl-C(=O)-O-C1-C6-O-(C=O)- C1-C6, -heteroaryl-C1-C6-OH, -heteroaryl-C1-C6-(C=O)OH, or-heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8-, wherein J is a5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, -NC1-C6-, -S- or -O-; or-heteroaryl-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, heteroaryl-C(=O)-NH-S(O)2-aryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-heteroaryl-C(=O)-NH-S(O)2-NH2, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2,, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl,-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or-heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -heteroaryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, - heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-NH-C(=O)-NH-S(O)2- NH-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-, wherein J is a 5 or 6 memberedheterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; wherein P may be a 5 to 10 membered aryl ring or rings optionally containing one or more heteroatoms, and wherein P may be further substituted with one or more halo, -C1-C6-alkyl, - C1-C6-alkyl substituted with one or more halo or hydroxy; -C3-C8-cycloalkyl, -CN, hydroxy, - O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, - S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-, wherein M is a 5 or 6 membered heterocycle ringoptionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or aryl, aryl substituted with one or more, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2,, wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-aryl; C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-, wherein M is a 5 or 6 membered heterocycle ring optionally includinga second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or heteroaryl; heteroaryl substituted with one or more halo, -C i -C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1- C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1- C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6- alkyl)2,, wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or C1-C6-heteroaryl; C1-C6-heteroaryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6- alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1- C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1- C6-alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, wherein M is a 5 or 6 membered heterocycle ring optionallyincluding a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-O-aryl; -O-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6- alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6- alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2,, wherein M is a 5 or 6 membered heterocycle ring optionally including asecond heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-O-C1-C6-aryl; -O-C1-C6-aryl substituted with one or more halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6- alkyl, -O-C1-C6-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6- alkyl, -S-C1-C6-alkyl substituted with one or more halo, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2,wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or wherein Q may be selected fromand wherein R3, R4, or Re are independently selected from -H, halo, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halo, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halo; and or a salt thereof.

102. The compound as claimed in claim 101, wherein R is selected from:-C1-C6-(C=O)OH; or-aryl-C(=O)-OH, or-heteroaryl-C(=O)-OH; or-aryl-C(=O)-NH-S(O)2-C1-C6.

103. The compound as claimed in claim 101 or claim 102, wherein R is -aryl-C(=O)-OH.

104. The compound as claimed in any one of claims 101 to 103, wherein R is -phenyl- C(=O)-OH.

105. The compound as claimed in claim 101 or claim 102, wherein R is -heteroaryl-C(=O)- OH.

106. The compound as claimed in claim 101 or claim 105, wherein R is -pyridyl-C(=O)- OH.

107. The compound as claimed in claim 101 or claim 102, wherein R is -C1-C6-(C=O)OH.

108. The compound as claimed in claim 107, wherein R is - (CH2)3-(C=O)OH.

109. The compound as claimed in claim 101, wherein R iswherein J is a 5 membered heterocycle ring containing up to 4 heteroatoms selected from -N=, -NH-, or -O-.

110. The compound as claimed in claim 109, wherein R is -phenyl-tetrazole.

111. The compound as claimed in claim 109, wherein R is -phenyl-oxadiazolone.

112. The compound as claimed in any one of claims 101 to 111, wherein P is selected from aryl or an aryl substituted with one or more halo, - CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6- alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

113. The compound as claimed in any one of claims 101 to 111, wherein P is selected from aryl substituted with aryl or an aryl substituted with halo,-CN, -C1-C6-alkyl, -O-C1-C6-alkyl, - C1-C6-alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

114. The compound as claimed in any one of claims 101 to 111, wherein P is selected from phenyl or a phenyl substituted with one or more halo, -CN, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1- C6-alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

115. The compound as claimed in claim 114 wherein P is phenyl substituted with halo.

116. The compound as claimed in claim 115, wherein P is phenyl substituted with -Cl.

117. The compound as claimed in any one of claims 101 to 111, wherein P is selected from phenyl substituted with phenyl or a phenyl substituted with halo, -CN, -C1-C6-alkyl, -O-C1- C6-alkyl, -C1-C6-alkyl substituted with one or more halo, or -O-C1-C6-alkyl substituted with one or more halo.

118. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl.

119. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with halo.

120. The compound as claimed in claim 119, wherein P is phenyl substituted with a phenyl substituted with -Cl.

121. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl.

122. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl substituted with one or more halo.

123. The compound as claimed in claim 122, wherein P is phenyl substituted with a phenyl substituted with -OCH2CF3.

124. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with -O-C3-alkyl.

125. The compound as claimed in claim 124, wherein P is phenyl substituted with a phenyl substituted with -OPr.

126. The compound as claimed in claim 124, wherein P is phenyl substituted with a phenyl substituted with -OnPr.

127. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl substituted with one or more halo.128 The compound as claimed in claim 127, wherein P is phenyl substituted with a phenyl substituted with -CH2CF3.129 The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with a halo and a -O-C3-alkyl.

130. The compound as claimed in claim 129, wherein P is phenyl substituted with a phenyl substituted with -F and a -O-C3-alkyl.

131. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with a -C1-C6-alkyl and a -O-C1-C6-alkyl.

132. The compound as claimed in claim 131, wherein P is phenyl substituted with a phenyl substituted with a -C1-C3-alkyl and a -O-C3-alkyl.

133. The compound as claimed in claim 117, wherein P is phenyl substituted with a phenyl substituted with -CN and -O-C1-C6-alkyl.

134. The compound as claimed in any one of claims 101 to 111, wherein P is -aryl- heteroaryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

135. The compound as claimed in claim 134, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is optionally substituted with one or more substituents selected from -halo, - CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

136. The compound as claimed in claim 135, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1-C6-alkyl.

137. The compound as claimed in claim 136, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C3-alkyl.

138. The compound as claimed in claim 137, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OPr.

139. The compound as claimed in claim 137, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OnPr.

140. The compound as claimed in claim 135, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

141. The compound as claimed in claim 140, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OCF3.

142. The compound as claimed in claim 140, wherein P is -phenyl-heteroaryl and wherein the heteroaryl is substituted with -OCH2CF3.

143. The compound as claimed in claim 134, wherein P is -aryl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1- C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O- C1-C6-alkyl optionally substituted with one or more halo.

144. The compound as claimed in claim 134, wherein P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1- C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O- C1-C6-alkyl optionally substituted with one or more halo.

145. The compound as claimed in claim 144, wherein P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with -O-C1-C6-alkyl.

146. The compound as claimed in claim 145, wherein P is -phenyl-pyridyl and wherein the pyridyl is optionally substituted with -OPr.

147. The compound as claimed in claim 144, wherein P is -phenyl-pyridyl and wherein the pyridyl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

148. The compound as claimed in claim 147, wherein P is -phenyl-pyridyl and wherein the pyridyl is substituted with -OCH2CF3.

149. The compound as claimed in any one of claims 101 to 111, wherein P is -heteroaryl- aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1- C6-alkyl and -O-C1-C6-alkyl optionally substituted with one or more halo.

150. The compound as claimed in claim 149, wherein P is -heteroaryl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, - C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and - O-C1-C6-alkyl optionally substituted with one or more halo.

151. The compound as claimed in claim 150, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl.

152. The compound as claimed in claim 151, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C3-alkyl.

153. The compound as claimed in claim 152, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OPr.

154. The compound as claimed in claim 152, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OnPr.

155. The compound as claimed in claim 150, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

156. The compound as claimed in claim 155, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OCF3.

157. The compound as claimed in claim 155, wherein P is a heteroaryl-phenyl and wherein the phenyl is substituted with -OCH2CF3.

158. The compound as claimed in claim 149, wherein P is -pyridyl-aryl and wherein the aryl is optionally substituted with one or more substituents selected from -halo, -CN, -C1-C6- alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O-C1- C6- alkyl optionally substituted with one or more halo.

159. The compound as claimed in claim 158, wherein P is -pyridyl-phenyl and wherein the phenyl is optionally substituted with one or more substituents selected from -halo, -CN, -C1- C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl and -O- C1-C6-alkyl optionally substituted with one or more halo.

160. The compound as claimed in claim 159, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl.

161. The compound as claimed in claim 160, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C3-alkyl.

162. The compound as claimed in claim 161, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OPr.

163. The compound as claimed in claim 161, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OnPr.

164. The compound as claimed in claim 159, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -O-C1-C6-alkyl substituted with one or more halo.

165. The compound as claimed in claim 164, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCF3.

166. The compound as claimed in claim 165, wherein P is a -pyridyl-phenyl and wherein the phenyl is substituted with -OCH2CF3.

167. The compound as claimed in any one of claims 101 to 166 wherein Q is selected from:

168. The compound as claimed in any one of claims 101 to 167 wherein Q is selected from:

169. The compound as claimed in any one of claims 101 to 168 wherein Q is selected from:

170. The compound as claimed in any one of claims 101 to 169 wherein Q is171. The compound as claimed in claim 101, wherein the compound or salt of Formula II is selected from one or more of the following:

172. The compound as claimed in claim 101, wherein the compound Formula II is or a salt thereof.

173. The compound as claimed in claim 101, wherein the compound Formula II is or a salt thereof.

174. The compound as claimed in claim 4101, wherein the compound Formula II is or a salt thereof.

175. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

176. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

177. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

178. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

179. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

180. The compound as claimed in claim 101, wherein the compound Formula II is or a salt thereof.

181. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

182. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

183. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

184. The compound as claimed in claim 101, wherein the compound Formula II is or a salt thereof.

185. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

186. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

187. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

188. The compound as claimed in claim 101, wherein the compound Formula II isor a salt thereof.

189. The compound of Formula I or II as claimed in any one of claims 1 to 188 for reducing the formation of methane from the digestive actions of ruminants and / or for improving ruminant performance.

190. The compound of Formula I or II as claimed in any one of claims 1 to 188 for reducing the formation of methane from the digestive actions of ruminants.

191. The compound of Formula I or II as claimed in any one of claims 1 to 188 for reducing the formation of methane from the digestive actions of ruminants by at least 10%.

192. The compound of Formula I or II as claimed in any one of claims 1 to 188 for reducing the formation of methane from the digestive actions of ruminants by at least 15%.

193. The compound of Formula I or II as claimed in any one of claims 1 to 188 for reducing the formation of methane from the digestive actions of ruminants by at least 20%.

194. A method for reducing the production of methane emanating from a ruminant and / or for improving ruminant animal performance, comprising administering orally to the ruminant an effective amount of at least one compound of Formula I or II or a salt thereof, as claimed in any one of claims 1 to 188.

195. The method as claimed in claim 194, wherein the effective amount of at least one compound of Formula I or II or a salt thereof is administered at least once-daily to the ruminant.

196. The method as claimed in claim 194 or claim 195, wherein the effective amount of at least one compound of Formula I or II or a salt thereof reduces the production of methane emanating from the ruminant by at least 10% per day.

197. The method as claimed in any one of claims 194 to 196, wherein the effective amount of at least one compound of Formula I or II or a salt thereof reduces the production of methane emanating from the ruminant by at least 15% per day.

198. The method as claimed in any one of claims 194 to 197, wherein the effective amount of at least one compound of Formula I or II or a salt thereof reduces the production of methane emanating from the ruminant by at least 20% per day.

199. A composition for oral administration comprising at least one compound of Formula I or II or a salt thereof as claimed in any one of claims 1 to 188 for reducing the production of methane emanating from a ruminant, and the composition further including at least one agriculturally and orally acceptable excipient.

200. The composition as claimed in claim 199, being adapted for use as a feed additive.

201. The composition as claimed in claim 199, being adapted for use as a water additive.

202. The composition as claimed in claim 109, adapted for use as a ruminant lick.

203. The composition as claimed in claim 199, adapted for use as an oral drench.

204. The composition as claimed in claim 199, adapted for use as a rumen bolus or capsule.

205. The composition as claimed in any one of claims 199 to 204, being adapted to reduce the production of methane emanating from the ruminant by at least 10% per day.

206. The composition as claimed in any one of claims 199 to 205, being adapted to reduce the production of methane emanating from the ruminant by at least 15% per day.

207. The composition as claimed in any one of claims 199 to 206, being adapted to reduce the production of methane emanating from the ruminant by at least 20% per day.

208. The composition as claimed in any one of claims 199 to 207, wherein the excipient may include one or more minerals and / or one or more vitamins.

209. The composition as claimed in any one of claims 199 to 208, wherein the excipient may include one or more vitamins selected from vitamin A, vitamin D3, vitamin E, and vitamin K, e.g. vitamin K3, vitamin B 12, biotin and choline, vitamin B l, vitamin B2, vitamin B6, niacin, folic acid or the like.

210. The composition as claimed in any one of claims 199 to 209, wherein the excipient may include one or more minerals selected from calcium, phosphorus, sodium, manganese, zinc, iron, copper, chlorine, sulphur, magnesium, iodine, selenium, and cobalt or the like.

211. The composition as claimed in any one of claims 199 to 210 further including sunflower oil, electrolytes such as ammonium chloride, calcium carbonates, starch, proteins or the like.

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