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 Formula I; for ruminants.

[0004] 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.

[0005] BACKGROUND OF INVENTION

[0006] 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.

[0007] 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.

[0008] 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. 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.

[0009] SUMMARY OF INVENTION

[0010] A compound of Formula I

[0011] Formula I wherein R may be selected from:

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

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

[0014] -C(=O)-C1-C6-C(=O)-NH2, -C(=O)-C1-C6-C(=O)-NH-C1-C6, -C(=O)-C1-C6-C(=O)-NH-C3- wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0015] -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, - C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6-aryl, -C(=O)-C1- C6-C(=O)-NH-S(O)2-heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0016] -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH2, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-C1-C6, -C(=O)- C1-C6-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-aryl, - C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH- heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH- C1-C6-heteroaryl, -C(=O)-C1-C6-C(=O)-NH- , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-aryl, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2- heteroaryl, or

[0017] -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-NH2, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-NH-C1-C6, -

[0018] C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-NH-C(=O)-NH-

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

[0020] 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] -C1-C6-C(=O)-OH, -C1-C6-C(=O)-O-C1-C6, -C1-C6-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -C1-C6-

[0022] OH, or

[0023] -C1-C6-C(=O)-NH2, -C1-C6-C(=O)-NH-C1-C6, -C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6- , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0024] -C1-C6-C(=O)-NH-S(O)2-C1-C6, -C1-C6-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6-C(=O)- NH-S(O)2-aryl, -C1-C6-C(=O)-NH-S(O)2-C1-C6-aryl, -C1-C6-C(=O)-NH-S(O)2-heteroaryl, - C1-C6-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0025] -C1-C6-C(=O)-NH-S(O)2-NH2, -C1-C6-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-C(=O)-NH- S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-C(=O)-NH-S(O)2- NH-C1-C6-aryl, -C1-C6-C(=O)-NH-S(O)2-NH-heteroaryl, -C1-C6-C(=O)-NH-S(O)2-NH- C1-

[0026] C6-heteroaryl,

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

[0028] NH-C(=O)-NH-S(O)2-aryl, -C1-C6-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0029] -C1-C6-NH-C(=O)-NH-S(O)2-NH2, -C1-C6-NH-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-NH-

[0030] C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-NH-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-

[0031] C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-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 or

[0032] -C(=O)-aryl-C(=O)-OH, -C(=O)-aryl-C(=O)-O-C1-C6, -C(=O)-aryl-C(=O)-O-C1-C6-O-

[0033] (C=O)-C1-C6, -C(=O)-aryl-OH, or

[0034] -C(=O)-aryl-C(=O)-NH2, -C(=O)-aryl-C(=O)-NH-C1-C6, -C(=O)-aryl-C(=O)-NH-C3-C8-

[0035] -C(=O)-aryl-C(=O)- N cycloalkyl, -C(=O)-aryl-C(=O)-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

[0036] -C(=O)-aryl-C(=O)-NH-S(O)2-C1-C6, -C(=O)-aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, - C(=O)-aryl-C(=O)-NH-S(O)2-aryl, -C(=O)-aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -C(=O)-aryl- C(=O)-NH-S(O)2-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0037] -C(=O)-aryl-C(=O)-NH-S(O)2-NH2, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-C1-C6, -C(=O)-aryl- C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-aryl, -C(=O)- aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-heteroaryl, - C(=O)-aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-N(C1- , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or

[0038] -C(=O)-aryl-NH-C(=O)-NH-S(O)2-C1-C6, -C(=O)-aryl-NH-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C(=O)-aryl-NH-C(=O)-NH-S(O)2-aryl, -C(=O)-aryl-NH-C(=O)-NH-S(O)2- heteroaryl, or

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

[0040] -aryl-C(=O)-OH, -aryl-C(=O)-O-C1-C6, -aryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -aryl-C1-C6-

[0041] OH, -aryl-C1-C6-(C=O)OH, or

[0042] -aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-

[0043] , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0044] -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-

[0045] C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0046] -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-

[0047] 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- -aryl-

[0048] 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

[0049] -aryl-NH-C(=O)-NH-S(O)2-C1-C6, -aryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -aryl-NH-

[0050] C(=O)-NH-S(O)2-aryl, -aryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0051] -aryl-NH-C(=O)-NH-S(O)2-NH2, -aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -aryl-NH-C(=O)-

[0052] NH-S(O)2-NH-C3-C8-cycloalkyl, -aryl-NH-C(=O)-NH-S(O)2-NH-aryl, -aryl-C(=O)-NH-

[0053] S(O)2-NH-C1-C6-aryl, -aryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2, or 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

[0054] -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

[0055] -aryl-S(O)2-NH-C3-C8-cycloalkyl, or

[0056] -C(=O)-heteroaryl-C(=O)-OH, -C(=O)-heteroaryl-C(=O)-O-C1-C6, -C(=O)-heteroaryl-C(=O)-

[0057] O-C1-C6-O-(C=O)-C1-C6, -C(=O)-aryl-OH, or

[0058] -C(=O)-heteroaryl-C(=O)-NH2, -C(=O)-heteroaryl-C(=O)-NH-C1-C6, -C(=O)-heteroaryl- C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-heteroaryl-C(=O)-N(C1-C6)2, or 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 -C(=O)-heteroaryl-C(=O)-NH-S(O)2-C1-C6, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2- C1-C6-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-heteroaryl, -C(=O)-heteroaryl-C(=O)-NH- S(O)2-C1-C6-heteroaryl, or

[0059] -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH2, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, - C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-heteroaryl-C(=O)-NH- S(O)2-NH-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-heteroaryl- C(=O)-NH-S(O)2-NH-heteroaryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH- C1-C6-heteroaryl, -C(=O)-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

[0060] -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2- C3-C8-cycloalkyl, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -C(=O)-heteroaryl-NH- C(=O)-NH-S(O)2-heteroaryl, or

[0061] -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-NH- C1-C6, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-heteroaryl- NH-C(=O)-NH-S(O)2-NH-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, C(=O)-heteroaryl-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 or

[0062] -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

[0063] 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, -NC1-C6-, -S- or -O-; or

[0064] -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-

[0065] C(=O)-NH-S(O)2-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0066] -heteroaryl-C(=O)-NH-S(O)2-NH2, -heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -heteroaryl-

[0067] C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -heteroaryl-

[0068] C(=O)-NH-S(O)2-NH-C1-C6-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-heteroaryl, -heteroaryl-

[0069] C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2, or 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

[0070] -heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl,

[0071] -heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0072] -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-

[0073] NH-aryl, -heteroaryl-C(=O)-NH-S(O)2-NH-Ci-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-; or -C1-C6-aryl-C(=O)-OH, -C1-C6-aryl-C(=O)-O-C1-C6, -C1-C6-aryl-C(=O)-O-C1-C6-O-(C=O)- C1-C6, -C1-C6-aryl-C1-C6-OH, or

[0074] -C1-C6-aryl-C(=O)-NH2, -C1-C6-aryl-C(=O)-NH-C1-C6, -C1-C6-aryl-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

[0075] -C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6, -C1-C6-aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6- aryl-C(=O)-NH-S(O)2-aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -C1-C6-aryl-C(=O)- NH-S (O)2-heteroaryl, -C i -C6-aryl-C(=O)-NH-S (O)2-C i -C6-heteroaryl, or

[0076] -C1-C6-aryl-C(=O)-NH-S(O)2-NH2, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-aryl-

[0077] C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-aryl-

[0078] C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-heteroaryl, -C1-C6-aryl-

[0079] C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -C1-C6-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

[0080] -C1-C6-aryl-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2- heteroaryl, or

[0081] -C1-C6-aryl-NH-C(=O)-NH-S(O)2-NH2, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -C1- C6-aryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-NH- aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-N(C1- , wherein J 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-S(O)2-OH, -C1-C6-aryl-S(O)2-NH2, -C1-C6-aryl-S(O)2-NH-C1-C6, -C1-C6-aryl-

[0082] / ' 1 '1 or 2

[0083] -C1-C6-aryl-S(O)2-N J \

[0084] 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

[0085] -C1-C6-aryl-S(O)2-NH-C3-C8-cycloalkyl,

[0086] -C1-C6-heteroaryl-C(=O)-OH, -C1-C6-heteroaryl-C(=O)-O-C1-C6, -C1-C6-heteroaryl-C(=O)-

[0087] O-C1-C6-O-(C=O)-C1-C6, -C1-C6-heteroaryl-C1-C6-OH, or

[0088] -C i -C6-heteroaryl-C(=O)-NH2, -C i -C6-heteroaryl-C(=O)-NH-C i-C6, -C i -C6-heteroaryl-

[0089] C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-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

[0090] -C1-C6-heteroaryl-C(=O)-NH-S(O)2-C1-C6, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-C1- C6-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-heteroaryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2- C1-C6-heteroaryl, or

[0091] -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH2, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, - C1-C6heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-NH-

[0092] S(O)2-NH-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-heteroaryl- C(=O)-NH-S(O)2-NH-heteroaryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, - C1-C6-heteroaryl-C(=O)-NH-S(O)2-N(Ci-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

[0093] -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C3-

[0094] Cs-cycloalkyl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-heteroaryl-NH-C(=O)- NH-S(O)2-heteroaryl, or

[0095] -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH- C1-C6, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-NH-

[0096] C(=O)-NH-S(O)2-NH-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6- heteroaryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2,

[0097] / ' 1 '1 or 2

[0098] -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-N J \ , wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or wherein Pi may be a 5 to 10 membered aryl ring or rings optionally containing one or more heteroatoms, and wherein Pi 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, -SFe, -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-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-Ci -C6-alkyl substituted with one or more halo, -SFe, -NO2, -NH2, -NH-Ci -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, -SFe, -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, -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, -SFe, -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 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, -SFe, -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 -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- alk 0yl substituted with one or more halo, -SFe, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, ^1 or 2

[0099] , wherein M is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or

[0100] -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, -SFe, -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 wherein Qi may be selected from wherein R3, R4, or R6are independently selected from -H, halo, hydroxy, C1-C6alkyl or C1-C6alkoxy, alkoxy substituted with one or more halo, aryl optionally substituted with one or more halo, hydroxy, alkoxy, alkoxy substituted with one or more halo; or a salt thereof, with the proviso that the compound its salt is excluded.

[0101] In one example R may be selected from:

[0102] -C(=O)-C1-C6-C(=O)-OH, -C(=O)-C1-C6-C(=O)-O-C1-C6, -C(=O)-C1-C6-C(=O)-O-C1-C6-O- (C=O)-C1-C6, or

[0103] -C(=O)-C1-C6-C(=O)-NH2, -C(=O)-C1-C6-C(=O)-NH-C1-C6, -C(=O)-C1-C6-C(=O)-N(C1- C6)2,

[0104] -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, -C(=O)-C1-C6- , wherein J is a

[0105] 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, NC1-C6-, -S- or -O-; or

[0106] -C1-C6-C(=O)-OH, or

[0107] -aryl-C(=O)-OH, or

[0108] -aryl-C(=O)-NH-S(O)2-C1-C6.

[0109] In one example R may be selected from -C(=O)-C1-C6-C(=O)-OH, -C(=O)-C1-C6-C(=O)- NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, -C1-C6-C(=O)-OH, -aryl- C(=O)-OH.

[0110] In one example, R may be selected from -C(=O)-C1-C6-C(=O)-OH, -C(=O)-C1-C6-C(=O)- NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, -aryl-C(=O)-OH. In one example R is selected from -C(=O)-C1-C6-C(=O)-OH.

[0111] In one example R is -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6.

[0112] In one example R may be selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, such as - C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6alkyl)2;or -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, such as -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-Ph.

[0113] In one example R is -aryl-C(=O)-OH.

[0114] In one example R is -heteroaryl-C(=O)-OH.

[0115] In one example R is -C(=O)-CH2-CH2-C(=O)-OH.

[0116] In one example R is -C1-C6-C(=O)-OH.

[0117] In one example R is -CH2-CH2-CH2-C(=O)-OH.

[0118] In one example R may be selected from -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-Me, or -C(=O)- CH2-CH2-C(=O)-NH-S(O)2-iPr.

[0119] In one example R is -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-NMe2.

[0120] In one example R is -phenyl-C(=O)-OH.

[0121] In one example R is -pyridyl-C(=O)-OH.

[0122] In one example Pi is aryl or an aryl 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.

[0123] In one example Pi is phenyl substituted with a phenyl substituted with halo.

[0124] In one example Pi is phenyl substituted with a phenyl substituted with -Cl.

[0125] In one example Pi is aryl substituted with aryl or an aryl substituted with halo, -C1-C6-alkyl, - O-C1-C6-alkyl or OC1-C6-alkyl substituted with one or more halo.

[0126] In one example Pi is phenyl or a phenyl substituted with one or more halo, -C1-C6-alkyl, -O- C1-C6-alkyl or OC1-C6-alkyl substituted with one or more halo.

[0127] In one example P1is aryl substituted with an aryl substituted with halo. In one example Pi is phenyl substituted with phenyl or a phenyl 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.

[0128] In one example Pi is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl.

[0129] In one example Pi is phenyl substituted with a phenyl substituted with -O-Cs-alkyl, such as phenyl substituted with a phenyl substituted with -CVPr or such as phenyl substituted with a phenyl substituted with -OnPr.

[0130] In one example Pi is phenyl substituted with a phenyl substituted with -OCF3 or Pi is phenyl substituted with a phenyl substituted with -OCF3 and -F.

[0131] In one example Pi is -aryl-heteroaryl 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.

[0132] In one example Pi is -phenyl-heteroaryl 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.

[0133] In one example Pi is -aryl-pyridyl 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.

[0134] In one example Pi is -phenyl-pyridyl 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.

[0135] In one example Pi is -heteroaryl-aryl 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 Pi is -heteroaryl-phenyl 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.

[0136] In one example Pi is -pyridyl-aryl 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.

[0137] In one example Pi is -pyridyl-phenyl 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.

[0138] In one example Qi is selected from: In one example the compound or salt of Formula I is selected from one or more of the following: In one example the compound of Formula thereof.

[0139] In one example the compound of Formula thereof.

[0140] In one example the compound of Formula thereof.

[0141] In one example the compound of Formula salt thereof.

[0142] In one example the compound of Formula In one example the compound of Formula thereof.

[0143] In one example the compound of Formula thereof.

[0144] In one example the compound of Formula

[0145] In one example the compound of Formula

[0146] In one example the compound of Formula salt thereof. In one example the compound of Formula salt thereof.

[0147] In one example the compound of Formula

[0148] In one example the compound of Formula

[0149] In one example the compound of Formula thereof.

[0150] In one example the compound of Formula thereof. In one example the compound of Formula

[0151] In one example the compound of Formula

[0152] In one example the compound of Formula thereof.

[0153] In one example the compound of Formula thereof.

[0154] In one example the compound of Formula In one example the compound of Formula

[0155] In one example the compound of Formula thereof.

[0156] In another aspect, the present invention provides the compound of Formula I as defined above for reducing the formation of methane from the digestive actions of ruminants and / or for improving ruminant performance.

[0157] In one example a compound of Formula I as defined above is for reducing the formation of methane from the digestive actions of ruminants.

[0158] In one example a compound of Formula I as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 10%.

[0159] In another example of a compound of Formula I as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 15%. In yet another example the compound of Formula I as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 20%.

[0160] 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 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.

[0161] In one example the effective amount of at least one compound of Formula I or a salt thereof is administered at least once-daily to the ruminant.

[0162] In one example the effective amount of at least one compound of Formula I or a salt thereof reduces the production of methane emanating from the ruminant by at least 10% per day.

[0163] In one example the effective amount of at least one compound of Formula I or a salt thereof reduces the production of methane emanating from the ruminant by at least 15% per day.

[0164] In one example the effective amount of at least one compound of Formula I or a salt thereof reduces the production of methane emanating from the ruminant by at least 20% per day.

[0165] 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 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.

[0166] In one example the composition is adapted for use as a feed additive.

[0167] In one example the composition is adapted for use as a water additive.

[0168] In another example the composition is adapted for use as a ruminant lick.

[0169] In one example the composition is adapted for use as an oral drench.

[0170] In another example the composition is adapted for use as a rumen bolus or capsule.

[0171] In one example the composition is adapted to reduce the production of methane emanating from the ruminant by at least 10% per day.

[0172] In one example the composition is adapted to reduce the production of methane emanating from the ruminant by at least 15% per day.

[0173] In one example the composition is adapted to reduce the production of methane emanating from the ruminant by at least 20% per day.

[0174] In one example the excipient may include one or more minerals and / or one or more vitamins. 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.

[0175] 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.

[0176] In one example the composition may further include sunflower oil, electrolytes such as ammonium chloride, calcium carbonates, starch, proteins or the like.

[0177] 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.

[0178] DETAILED DESCRIPTION OF INVENTION

[0179] DEFINTIONS

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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. 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.

[0184] The term “halo” as used herein refers to a halogen atom selected from Cl, Br, or F.

[0185] The term “aryl” as used herein refers to “aryl”, unless specifically limited, denotes a C5-12aryl group, suitably a C6-10aryl group, more suitably a C6-8aryl 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-C1-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.

[0186] 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-l-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-C6 alkynyl, 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.

[0187] 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 one or more substituents selected from carbonyl groups, halo, -CN, halo, -C1-C6-alkyl, -C1-C6-alkyl optionally substituted with one or more halo, -O-C1-C6-alkyl groups and -O-C1-C6-alkyl optionally substituted with one or more halo.

[0188] 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, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidirtyl, 4-piperidonyl, pyrrolidinyl, 2- pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-l,2, 5-thiadiazinyl, 2H,6H-l,5,2-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, P-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.

[0189] 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.

[0190] 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 P-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1- imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0191] 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.

[0192] 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.

[0193] 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. 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.

[0194] 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.

[0195] Methods of making the Compounds of Formula I

[0196] 4-(5-(4-Chlorophenyl)-3-(quinoxalin-6-yl)-4,5-dihydro-lH-pyrazol-l-yl)-4-oxobutanoic add (Comparison Compound) - Comparison Example

[0197] To a solution of l-(quinoxalin-6-yl)ethan-l-one (200 mg, 1.16 mmol) and 4- chlorobenzaldehyde (163 mg, 1.16 mmol) in EtOH (12 mL) at 0 °C was added dropwise 2 M NaOH (3.2 mL, 6.32 mmol), 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 water and dried in vacuo to afford (E)-3-(4-chlorophenyl)-l-(quinoxalin-6- yl)prop-2-en-l-one (200 mg) as a colourless solid, which was used directly in the next step without further purification.

[0198] To a stirred solution of (E)-3-(4-chlorophenyl)-l-(quinoxalin-6-yl)prop-2-en-l-one (200 mg) in EtOH (8 mL) was added hydrazine hydrate (85 pL, 50% w / w), and the reaction mixture heated under reflux for 2 h. The solvent was then removed in vacuo and the resulting residue was poured onto ice water, collected by filtration and dried in vacuo to afford 6-(5-(4- chlorophenyl)-4,5-dihydro-l / / -pyrazol-3-yl)quinoxaline (150 mg) as a yellow solid, which was used in the next step without further purification.

[0199] In a sealed vial, a mixture of 6-(5-(4-chlorophenyl)-4,5-dihydro-l / / -pyrazol-3- yl)quinoxaline (150 mg) and succinic anhydride (97 mg, 0.97 mmol) in THF (5 mL) was subjected to microwave irradiation (200 W) at 120 °C for 45 min. The resulting reaction mixture was then concentrated in vacuo, with purification by flash column chromatography (EtOAc, neat — > DCM:MeOH, 9:1) affording Comparison Compound as a colourless solid (22 mg, 5% over 3 steps).1H NMR (400 MHz, DMSO-d6) δ 12.15 (1H, br s), 9.01-8.98 (2H, m), 8.41 (1H, dd, J = 8.8, 2.0 Hz), 8.29 (1H, d, J = 1.9 Hz), 8.17 (1H, d, J = 8.9 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz), 5.64 (1H, dd, J = 12.0, 5.0 Hz), 4.07-3.99 (1H, m), 3.41-3.35 (1H, m), 3.10 (1H, dt, J = 17.2, 6.7 Hz), 3.00 (1H, dt, J = 17.2, 6.6 Hz), 2.57-2.52 (2H, m);13C NMR (101 MHz, DMSO-d6) δ 173.7 (C), 169.4 (C), 153.4 (C), 146.5 (CH), 146.3 (CH), 143.1 (C), 142.3 (C), 141.1 (C), 132.7 (C), 131.8 (C), 129.7 (CH), 128.6 (CH), 128.1 (CH), 127.7 (CH), 127.4 (CH), 59.6 (CH), 41.6 (CH2), 28.8 (CH2), 28.4 (CH2); HRMS (ESI / Q- TOF) m / z: [M+Na]+calcd for C21H17ClN4NaO3, 431.0881; found, 431.0879.

[0200] 4-(5-([l,l'-Biphenyl]-4-yl)-3-(quinoxalin-6-yl)-4,5-dihydro-lH-pyrazol-l-yl)-4- oxobutanoic add (Compound 1)

[0201] To a solution of l-(quinoxalin-6-yl)ethan-l-one (150 mg, 0.87 mmol) and 4- biphenylcarboxaldehyde (158 mg, 0.87 mmol) in EtOH (6 mL) at room temperature was added dropwise 2 M NaOH (1.7 mL, 3.4 mmol), and the reaction mixture was stirred for 3 h. After, the solution was cooled down to 0 °C and the resulting precipitated solids were then collected by filtration, washed with water and dried in vacuo to afford (E)-3-([l,l'-biphenyl]-4-yl)-l- (quinoxalin-6-yl)prop-2-en-l-one (283 mg) as a yellow solid, which was used directly in the next step without further purification.

[0202] A mixture of (E)-3-([1,1'-biphenyl]-4-yl)-l-(quinoxalin-6-yl)prop-2-en-l-one (283 mg) and hydrazine hydrate (111 μL, 50% w / w) in THF (8 mL) was stirred under reflux for 2 h. After, succinic anhydride (234 mg, 2.34 mmol) was added, and the reaction mixture was stirred under reflux for a further 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with water (2 x 30 mL), then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (EtOAc — > DCM:MeOH, 10:1) afforded Compound 1 as a yellow solid (112 mg, 29% over 2 steps).1H NMR (400 MHz, DMSO-d6) δ 9.01-8.99 (2H, m), 8.45 (1H, dd, J = 8.9, 1.9 Hz), 8.33 (1H, d, J = 1.8 Hz), 8.19 (1H, d, J = 8.7 Hz), 7.66-7.61 (4H, m), 7.47 (2H, t, J = 7.6 Hz), 7.40-7.33 (3H, m), 5.70 (1H, dd, J = 11.9, 4.9 Hz), 4.08 (1H, dd, J = 18.1, 11.9 Hz), 3.44 (1H, dd, J = 18.1, 4.9 Hz), 3.14-2.97 (2H, m), 2.55 (2H, t, J = 6.3 Hz);13C NMR (101 MHz, DMSO-d6) δ 173.7 (C), 169.3 (C), 153.5 (C), 146.5 (CH), 146.3 (CH), 143.1 (C), 142.4 (C), 141.3 (C), 139.8 (C), 139.2 (C), 132.7 (C), 129.6 (CH), 128.9 (CH), 128.0 (CH), 127.5 (CH), 127.4 (CH), 127.0 (CH), 126.6 (CH), 126.2 (CH), 59.9 (CH), 41.6 (CH2), 28.8 (CH2), 28.4 (CH2); HRMS (ESI+ / Q-TOF) m / z: [M+Na]+calcd for C27H22N4NaO3, 473.1584; found, 473.1583.

[0203] 4-(5-(4'-Isopropoxy-[l,l'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-l- yl)-4-oxobutanoic add (Compound 2)

[0204] Compound 2 was prepared over 2 steps using a method similar to that described for the preparation of Compound 1 - step 1: l-(quinoxalin-6-yl)ethan-l-one (150 mg, 0.87 mmol), 4'- isopropoxy-[ 1,1 '-biphenyl] -4-carbaldehy de (209 mg, 0.87 mmol) and 2 M NaOH (1.7 mL, 3.4 mmol) in EtOH (6 mL) to afford (E)-3-(4'-isopropoxy-[l,l'-biphenyl]-4-yl)-l-(quinoxalin-6- yl)prop-2-en-l-one (228 mg) as a yellow solid; step 2: (E)-3-(4'-isopropoxy-[l,l'-biphenyl]-4- yl)-l-(quinoxalin-6-yl)prop-2-en-l-one (228 mg) and hydrazine hydrate (111 pL, 50% w / w) in THF (8 mL), followed by the addition of succinic anhydride (234 mg, 2.34 mmol). Purification by flash column chromatography (EtOAc — > DCM:MeOH, 10:1) afforded Compound 2 as a yellow solid (128 mg, 29% over 2 steps).1H NMR (400 MHz, DMSO-d6) δ 8.99-8.97 (2H, m), 8.42 (1H, dd, J = 8.9, 1.9 Hz), 8.31 (1H, d, J = 1.8 Hz), 8.16 (1H, d, J = 8.7 Hz), 7.58-7.51 (4H, m), 7.28 (2H, d, J = 8.3 Hz), 6.97 (2H, d, J = 8.3 Hz), 5.65 (1H, dd, J = 11.2, 4.7 Hz), 4.68-4.58 (1H, m), 4.04 (1H, dd, J = 18.1, 11.2 Hz), 3.41 (1H, dd, J = 18.1, 4.9 Hz), 3.14-2.97 (2H, m), 2.53 (2H, t, J = 6.3 Hz), 1.27 (6H, d, J = 6.1 Hz);13C NMR (101 MHz, DMSO-d6) δ 173.8 (C), 169.3 (C), 157.1 (C), 153.5 (C), 146.5 (CH), 146.3 (CH), 143.1 (C),

[0205] 142.4 (C), 140.5 (C), 138.9 (C), 132.8 (C), 131.9 (C), 129.7 (CH), 128.0 (CH), 127.7 (CH),

[0206] 127.5 (CH), 126.4 (CH), 126.2 (CH), 115.9 (CH), 69.2 (CH), 59.9 (CH), 41.7 (CH2), 28.8 (CH2), 28.4 (CH2), 21.8 (CH3); HRMS (ESI+ / Q-TOF) m / z: [M+Na]+calcd for C30H28N4NaO4, 531.2003; found, 531.2028.

[0207] In vitro studies

[0208] 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.

[0209] Rumen in vitro assay method.

[0210] 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.

[0211] 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 fluidbuffer 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 pM 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.

[0212] The Comparison Compound, for example, was tested using the 60 mL rumen in vitro assay system at 50 pM and 10 pM final concentrations and compared to a positive control with 30 pM BES. At 30 pM, BES inhibition levels were 70.5% inhibition at 10 hours and 55.6% inhibition at 18 hours.

[0213] 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 J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6-aryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-C(=O)-C1-C6-C(=O)-NH-S(O)2-NH2, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-C1-C6, -C(=O)- C1-C6-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-aryl, - C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH- heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH- C1-C6-heteroaryl, -C(=O)-C1-C6-C(=O)-NH-, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-aryl, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2- heteroaryl, or-C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-NH2, -C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-NH-C1-C6, - C(=O)-C1-C6-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-NH-C(=O)-NH- S(O)2-NH-aryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-C1-C6-NH-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-C1-C6-C(=O)-OH, -C1-C6-C(=O)-O-C1-C6, -C1-C6-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -C1-C6- OH, or-C1-C6-C(=O)-NH2, -C1-C6-C(=O)-NH-C1-C6, -C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or-C1-C6-C(=O)-NH-S(O)2-C1-C6, -C1-C6-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6-C(=O)- NH-S(O)2-aryl, -C1-C6-C(=O)-NH-S(O)2-C1-C6-aryl, -C1-C6-C(=O)-NH-S(O)2-heteroaryl, - C1-C6-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-C1-C6-C(=O)-NH-S(O)2-NH2, -C1-C6-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-C(=O)-NH-S(O)2- NH-C1-C6-aryl, -C1-C6-C(=O)-NH-S(O)2-NH-heteroaryl, -C1-C6-C(=O)-NH-S(O)2-NH- C1-, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-C1-C6-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-NH-C(=O)-NH-S(O)2-heteroaryl, or-C1-C6-NH-C(=O)-NH-S(O)2-NH2, -C1-C6-NH-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-NH- C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-NH-C(=O)-NH-S(O)2-NH-aryl, -C1-C6- C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-NH-C(=O)-NH-S(O)2-N(C1-C6)2, or 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 or-C(=O)-aryl-C(=O)-OH, -C(=O)-aryl-C(=O)-O-C1-C6, -C(=O)-aryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -C(=O)-aryl-OH, or-C(=O)-aryl-C(=O)-NH2, -C(=O)-aryl-C(=O)-NH-C1-C6, -C(=O)-aryl-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-C(=O)-aryl-C(=O)-NH-S(O)2-C1-C6, -C(=O)-aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C(=O)-aryl-C(=O)-NH-S(O)2-aryl, -C(=O)-aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -C(=O)-aryl-C(=O)-NH-S(O)2-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or-C(=O)-aryl-C(=O)-NH-S(O)2-NH2, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-C1-C6, -C(=O)-aryl- C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-aryl, -C(=O)- aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-heteroaryl, - C(=O)-aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-N(C1-, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-C(=O)-aryl-NH-C(=O)-NH-S(O)2-C1-C6, -C(=O)-aryl-NH-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C(=O)-aryl-NH-C(=O)-NH-S(O)2-aryl, -C(=O)-aryl-NH-C(=O)-NH-S(O)2- heteroaryl, or-C(=O)-aryl-NH-C(=O)-NH-S(O)2-NH2, -C(=O)-aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, - C(=O)-aryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-aryl-NH-C(=O)-NH-S(O)2- NH-aryl, -C(=O)-aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-aryl-NH-C(=O)-NH-S(O)2-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--aryl-C(=O)-NH-S(O)2-N(C1-C6)2,, 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, or 2 aryl-S(O)2-N J \, 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-C(=O)-heteroaryl-C(=O)-OH, -C(=O)-heteroaryl-C(=O)-O-C1-C6, -C(=O)-heteroaryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -C(=O)-aryl-OH, or-C(=O)-heteroaryl-C(=O)-NH2, -C(=O)-heteroaryl-C(=O)-NH-C1-C6, -C(=O)-heteroaryl- C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-heteroaryl-C(=O)-N(C1-C6)2, or 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-C(=O)-heteroaryl-C(=O)-NH-S(O)2-C1-C6, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-C1-C6-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-heteroaryl, -C(=O)-heteroaryl-C(=O)-NH- S(O)2-C1-C6-heteroaryl, or-C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH2, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-heteroaryl-C(=O)-NH- S(O)2-NH-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C(=O)-heteroaryl- C(=O)-NH-S(O)2-NH-heteroaryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH- C1-C6-heteroaryl, -C(=O)-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-C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2- C3-C8-cycloalkyl, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -C(=O)-heteroaryl-NH- C(=O)-NH-S(O)2-heteroaryl, or-C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-NH- C1-C6, -C(=O)-heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C(=O)-heteroaryl- NH-C(=O)-NH-S(O)2-NH-aryl, -C(=O)-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, C(=O)-heteroaryl-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 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, or 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-Ci-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-; or-C1-C6-aryl-C(=O)-OH, -C1-C6-aryl-C(=O)-O-C1-C6, -C1-C6-aryl-C(=O)-O-C1-C6-O-(C=O)- C1-C6, -C1-C6-aryl-C1-C6-OH, or-C1-C6-aryl-C(=O)-NH2, -C1-C6-aryl-C(=O)-NH-C1-C6, -C1-C6-aryl-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-C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6, -C1-C6-aryl-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6- aryl-C(=O)-NH-S(O)2-aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6-aryl, -C1-C6-aryl-C(=O)- NH-S (O)2-heteroaryl, -C i -C6-aryl-C(=O)-NH-S (O)2-C i -C6-heteroaryl, or-C1-C6-aryl-C(=O)-NH-S(O)2-NH2, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-heteroaryl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, -C1-C6-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-C1-C6-aryl-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2- heteroaryl, or-C1-C6-aryl-NH-C(=O)-NH-S(O)2-NH2, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-NH-C1-C6, -C1- C6-aryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-NH- aryl, -C1-C6-aryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-aryl-NH-C(=O)-NH-S(O)2-N(C1-, wherein J 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-S(O)2-OH, -C1-C6-aryl-S(O)2-NH2, -C1-C6-aryl-S(O)2-NH-C1-C6, -C1-C6-aryl- / ' 1 '1 or 2-C1-C6-aryl-S(O)2-N J \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-C1-C6-aryl-S(O)2-NH-C3-C8-cycloalkyl,-C1-C6-heteroaryl-C(=O)-OH, -C1-C6-heteroaryl-C(=O)-O-C1-C6, -C1-C6-heteroaryl-C(=O)-O-C1-C6-O-(C=O)-C1-C6, -C1-C6-heteroaryl-C1-C6-OH, or-C i -C6-heteroaryl-C(=O)-NH2, -C i -C6-heteroaryl-C(=O)-NH-C i-C6, -C i -C6-heteroaryl-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-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-C1-C6-heteroaryl-C(=O)-NH-S(O)2-C1-C6, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-C3-C8- cycloalkyl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-C1- C6-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-heteroaryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2- C1-C6-heteroaryl, or-C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH2, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, - C1-C6heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6-heteroaryl- C(=O)-NH-S(O)2-NH-heteroaryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-heteroaryl, - C1-C6-heteroaryl-C(=O)-NH-S(O)2-N(Ci-C6)2,, wherein J is a 5 or 6 memberedheterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or-C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C3-Cs-cycloalkyl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-heteroaryl-NH-C(=O)- NH-S(O)2-heteroaryl, or-C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH2, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH- C1-C6, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-NH-aryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6-aryl, -C1-C6- heteroaryl-NH-C(=O)-NH-S(O)2-N(C1-C6)2, / ' 1 '1 or 2-C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-N J \, wherein J is a 5 or 6 membered heterocycle ring optionally including a second heteroatom selected from -NH-, NC1-C6-, -S- or -O-; or wherein Pi may be a 5 to 10 membered aryl ring or rings optionally containing one or more heteroatoms, and wherein Pi 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, -SFe, -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-alkyl substituted with one or more halo, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-Ci -C6-alkyl substituted with one or more halo, -SFe, -NO2, -NH2, -NH-Ci -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, -SFe, -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, -SFe, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-0 ^1 or 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, -SFe, -NO2, -NH2, -NH-C1-C6-alkyl, 0 ^1 or 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- alk 0yl substituted with one or more halo, -SFe, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, ^1 or 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, -SFe, -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 wherein Qi may be selected fromwherein R3, R4, or Re are independently selected from -H, halo, hydroxy, C1-C6alkyl or C1- C6alkoxy, alkoxy substituted with one or more halo, aryl optionally substituted with one or more halo, hydroxy, alkoxy, alkoxy substituted with one or more halo; or a salt thereof, with the proviso that the compoundits salt is excluded2. The compound of claim 1 wherein R may be selected from:-C(=O)-C1-C6-C(=O)-OH, -C(=O)-C1-C6-C(=O)-O-C1-C6, -C(=O)-C1-C6-C(=O)-O-C1-C6-O- (C=O)-C1-C6, or-C(=O)-C1-C6-C(=O)-NH2, -C(=O)-C1-C6-C(=O)-NH-C1-C6, -C(=O)-C1-C6-C(=O)-N(C1-C6)2,-C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, -C(=O)-C1-C6-, wherein J is a5 or 6 membered heterocycle ring optionally including a second heteroatom selected from - NH-, NC1-C6-, -S- or -O-; or-C1-C6-C(=O)-OH, or-aryl-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 may be selected from - C(=O)-C1-C6-C(=O)-OH, -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6, -C(=O)-C1-C6-C(=O)-NH- S(O)2-N(C1-C6)2, -C1-C6-C(=O)-OH, or -aryl-C(=O)-OH.

4. The compound as claimed in any one of claims 1 to 3, wherein R is C(=O)-C1-C6- C(=O)-OH.

5. The compound as claimed in claim 4, wherein R is -C(=O)-CH2-CH2-C(=O)-OH.

6. The compound as claimed in any one of claims 1 to 3, wherein R may be selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, such as-C(=O)-C1-C6-C(=O)-NH-S(O)2- N(C1-C6alkyl)2;or -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, such as -C(=O)-CH2-CH2-C(=O)- NH-S(O)2-Ph.

7. The compound as claimed in any one of claims 1 to 3, wherein R is -C(=O)-C1-C6- C(=O)-NH-S(O)2-C1-C6.

8. The compound as claimed in claim 7, wherein R may be selected from -C(=O)-CH2- CH2-C(=O)-NH-S(O)2-Me, or -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-iPr.

9. The compound as claimed in claim 7, wherein R is -C(=O)-CH2-CH2-C(=O)-NH- S(O)2-NMe2.

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

11. The compound as claimed in claim 10, wherein R is -phenyl-C(=O)-OH.

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

13. The compound as claimed in claim 12, wherein R is -pyridyl-C(=O)-OH.

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

15. The compound as claimed in claim 1 or claim 14, wherein R is -CH2-CH2-CH2-C(=O)-OH.

16. The compound as claimed in any one of claims 1 to 15, wherein Pi is aryl substituted with aryl or an aryl 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.

17. The compound as claimed in claim 16, wherein Pi is aryl substituted with an aryl substituted with halo.

18. The compound as claimed in any one of claims 1 to 16, wherein Pi is phenyl substituted with phenyl or a phenyl 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.

19. The compound as claimed in claim 18, wherein Pi is phenyl substituted with a phenyl substituted with halo.

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

21. The compound as claimed in claim 20, wherein Pi is phenyl substituted with a phenyl substituted with -O-C1-C6-alkyl.

22. The compound as claimed in claim 21, wherein Pi is phenyl substituted with a phenyl substituted with -O-Cs-alkyl, such as phenyl substituted with a phenyl substituted with -O'Pr or such as phenyl substituted with a phenyl substituted with -OnPr.

23. The compound as claimed in any one of claims 1 to 15, wherein Pi 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.

24. The compound as claimed in claim 23, wherein Pi 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.

25. The compound as claimed in claim 23, wherein Pi 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.

26. The compound as claimed in claim 25, wherein Pi 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.

27. The compound as claimed in any one of claims 1 to 15, wherein Pi 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.

28. The compound as claimed in claim 27, wherein Pi 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.

29. The compound as claimed in claim 27, wherein Pi 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.

30. The compound as claimed in claim 29, wherein Pi 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.

31. The compound as claimed in any one of claims 1 to 15, wherein Pi is aryl or an aryl 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.

32. The compound as claimed in claim 31, wherein Pi is phenyl or a phenyl 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.

33. The compound as claimed in any one of claims 1 to 32, wherein Qi is selected from:

34. The compound as claimed in claim 33, wherein Qi is selected from:ft y35. The compound as claimed in claim 33 or claim 34 wherein Qi is N36. The compound as claimed in claim 1, wherein the compound or salt of Formula I is selected from one or more of the following:

37. The compound as claimed in claim 1, wherein Formula I is38. The compound as claimed in claim 1, wherein Formula I is39. The compound of Formula I, as claimed in any one of claims 1 to 38 for reducing the formation of methane from the digestive actions of ruminants and / or for improving ruminant performance.

40. The compound of Formula I as claimed in any one of claims 1 to 38 for reducing the formation of methane from the digestive actions of ruminants.

41. The compound of Formula I as claimed in any one of claims 1 to 38 for reducing the formation of methane from the digestive actions of ruminants by at least 10%.

42. The compound of Formula I as claimed in any one of claims 1 to 38 is for reducing the formation of methane from the digestive actions of ruminants by at least 15%.

43. The compound of Formula I as claimed in any one of claims 1 to 38 is for reducing the formation of methane from the digestive actions of ruminants by at least 20%.

44. 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 a salt thereof as defined in any one of claims 1 to 38 to the ruminant.

45. The method as claimed in claim 44, wherein the effective amount of at least one compound of Formula I, or a salt thereof as defined in any one of claims 1 to 32 is administered at least once-daily to the ruminant.

46. The method as claimed in claim 44 or claim 45, wherein the effective amount of at least one compound of Formula I, or a salt thereof as defined in any one of claims 1 to 31 reduces the production of methane emanating from the ruminant by at least 10% per day.

47. The method as claimed in any one of claims 44 to 46, wherein the effective amount of at least one compound of Formula I, or a salt thereof as defined in any one of claims 1 to 32 reduces the production of methane emanating from the ruminant by at least 15% per day.

48. The method as claimed in any one of claims 44 to 48 wherein the effective amount of at least one compound of Formula I or a salt thereof as defined in any one of claims 1 to 32 reduces the production of methane emanating from the ruminant by at least 20% per day.

49. A composition for oral administration comprising at least one compound of Formula I or a salt thereof as defined in any one of claims 1 to 38 for reducing the production of methane emanating from a ruminant, and the composition further including at least one agriculturally and orally acceptable excipient.

50. The composition as claimed in claim 49, being adapted for use as a feed additive.

51. The composition as claimed in claim 49, being adapted for use as a water additive.

52. The composition as claimed in claim 49, being adapted for use as a ruminant lick.

53. The composition as claimed in claim 49, being adapted for use as an oral drench.

54. The composition as claimed in claim 49, being adapted for use as a rumen bolus or capsule.

55. The composition as claimed in any one of claims 49 to 54, being adapted to reduce the production of methane emanating from the ruminant by at least 10% per day.

56. The composition as claimed in any one of claims 49 to 55, being adapted to reduce the production of methane emanating from the ruminant by at least 15% per day.

57. The composition as claimed in any one of claims 49 to 56, being to reduce the production of methane emanating from the ruminant by at least 20% per day.

58. The composition as claimed in any one of claims 49 to 57, wherein the excipient may include one or more minerals and / or one or more vitamins.

59. The composition as claimed in any one of claims 49 to 58, 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 B12, biotin and choline, vitamin Bl, vitamin B2, vitamin B6, niacin, folic acid or the like.

60. The composition as claimed in any one of claims 49 to 50, 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.

61. The composition as claimed in any one of claims 49 to 60 further including sunflower oil, electrolytes such as ammonium chloride, calcium carbonates, starch, proteins or the like.

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