Methanogen inhibitor

Abstract

The invention relates to a novel methanogen inhibitor for ruminants. The invention also extends to the use of such compounds in ruminants to reduce methane production in the rumen and / or to increase productivity in ruminants.

Description

Technical Field

[0001] The present invention relates to a new class of methanogen inhibitors for ruminants, in particular to new compounds of formula I, II, III or IV for ruminants.

[0002]

[0003] The invention also extends to the use of such compounds in ruminants to reduce methane production in the rumen and / or to increase the productivity of the ruminant. Background Art

[0004] Methane is produced as a natural result of feed digestion by bacteria, fungi, and protozoa in ruminants. This fermentation leads to the production of volatile fatty acids and peptides in the host. Fermentation also produces large amounts of CO₂ and H₂, which are used by methanogenic archaea in the rumen to produce methane, which is ultimately released from the rumen primarily through belching.

[0005] Methane-forming methanogens are members of the Archaea and differ significantly from bacteria, fungi, and protozoa in many characteristics. Methanogens possess many unusual and archaeal-specific features, including cell wall structure, lipid, cofactor, and amino acid synthesis pathways, and their hallmark energy metabolism associated with methane production. They comprise only approximately 1%-4% of the rumen microbial community. Due to their unique metabolic pathways and low abundance, methanogen-specific inhibitors can be developed that do not adversely affect feed fermentation.

[0006] It is recognized that such methane release is harmful for two reasons. One reason is that methane is a greenhouse gas, and the other reason is that methane loss represents a loss of energy for the ruminant. It has been previously recognized that if methane release from ruminants can be inhibited or reduced, the impact of methane on the environment and atmosphere will be reduced, and increased ruminant productivity can be achieved.

[0007] It is therefore an object of the present invention to overcome the above difficulties or at least to provide the public with a useful alternative. Summary of the Invention

[0008] In one aspect, the present disclosure provides a compound of formula I

[0009]

[0010] Wherein R can be selected from:

[0011] -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

[0012] -C(=O)-C1-C6-C(=O)-NH2, -C(=O)-C1-C6-C(=O)-NH-C1-C6, -C(=O)-C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0013] -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-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

[0014] -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-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-S(O)2-NH-C1-C6-heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0015] -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

[0016] -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)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0017] -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

[0018] -C1-C6-C(=O)-NH2, -C1-C6-C(=O)-NH-C1-C6, -C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0019] -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

[0020] -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-C6-heteroaryl、-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2、 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0021] -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

[0022] -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、 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0023] or

[0024] -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

[0025] -C(=O)-aryl-C(=O)-NH2, -C(=O)-aryl-C(=O)-NH-C1-C6, -C(=O)-aryl-C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0026] -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

[0027] -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 )-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-NH-C1-C6-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0028] -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

[0029] -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-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0030] or

[0031] -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, or

[0032] -aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0033] -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

[0034] -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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0035] -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

[0036] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0037] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0038] -aryl-S(O)2-NH-C3-C8-cycloalkyl, or

[0039] -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

[0040] -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, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0041] -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

[0042] -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 )-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-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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0043] -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

[0044] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0045] or

[0046] -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, or

[0047] -heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0048] -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

[0049] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0050] -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

[0051] -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-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-;

[0052] or

[0053] -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

[0054] -C1-C6-aryl-C(=O)-NH2, -C1-C6-aryl-C(=O)-NH-C1-C6, -C1-C6-aryl-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0055] -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, -C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0056] -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 C1-C6-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-NH-C1-C6-heteroaryl, -C1-C6-aryl-C(=O)-NH-S(O)2-N(C1-C6)2, -C1-C6 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0057] -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

[0058] -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-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0059] -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-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

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

[0061] -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

[0062] -C1-C6-heteroaryl-C(=O)-NH2, -C1-C6-heteroaryl-C(=O)-NH-C1-C6, -C1-C6-heteroaryl-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-N(C1-C6)2,

[0063] wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0064] -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

[0065] -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH2, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -C1-C 6-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-NH-C1-C6-heteroaryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0066] -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0067] -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,

[0068] wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-;

[0069] wherein P may be one or more 5- to 10-membered aryl rings optionally containing one or more heteroatoms, and wherein P may be further substituted by one or more of halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxyl, -C3-C8-cycloalkyl, -CN, hydroxyl, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-, or a C2-C8 cycloheteroalkyl ring including one or more heteroatoms selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0070] Aryl, aryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0071] C1-C6-aryl; C1-C6-aryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0072] Heteroaryl; heteroaryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0073] C1-C6-heteroaryl; C1-C6-heteroaryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO 2、 -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0074] -O-aryl; -O-aryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0075] -O-C1-C6-aryl; -O-C1-C6-aryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or

[0076] Where Q can be selected from

[0077]

[0078] as well as

[0079] wherein R3, R4 or R6 are independently selected from -H, halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogens, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogens; and

[0080] or its salts;

[0081] The premise is that the following compounds

[0082]

[0083] are excluded from the compounds of formula I.

[0084] In one embodiment, R is selected from

[0085] -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

[0086] -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,

[0087] -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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0088] -C1-C6-C(=O)-OH, or

[0089] -aryl-C(=O)-OH, or

[0090] -Aryl-C(=O)-NH-S(O)2-C1-C6.

[0091] In one example, R is 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, and -aryl-C(=O)-OH.

[0092] In one embodiment, R is 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, and -aryl-C(=O)-OH.

[0093] In one example, R is selected from -C(=O)-C1-C6-C(=O)-OH.

[0094] In one example, R is selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6.

[0095] In one embodiment, R is selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl.

[0096] In one embodiment, R is selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2.

[0097] In one example, R is selected from -aryl-C(=O)-OH.

[0098] In one example, R is selected from -C(=O)-CH2-CH2-C(=O)-OH.

[0099] In one example, R is selected from -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-Me.

[0100] In one example, R is selected from -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-iPr.

[0101] In one example, R is selected from -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-Ph.

[0102] In one example, R is selected from -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-NMe2.

[0103] In one example, R is selected from -phenyl-C(=O)-OH.

[0104] In one embodiment, P is aryl or aryl substituted with one or more halogen, -C1-C6-alkyl, or -O-C1-C6-alkyl.

[0105] In one example, P is aryl substituted with aryl or aryl substituted with halogen, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halogens, or -O-C1-C6-alkyl substituted with one or more halogens.

[0106] In one example, P is phenyl or phenyl substituted with one or more halogen, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halogen, or -O-C1-C6-alkyl substituted with one or more halogen.

[0107] In one example, P is phenyl substituted with phenyl or phenyl substituted with halogen, -C1-C6-alkyl, -O-C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halogens, or -O-C1-C6-alkyl substituted with one or more halogens.

[0108] In one example, P is phenyl substituted with halogen substituted phenyl.

[0109] In one example, P is phenyl substituted with -O-C1-C6-alkyl substituted phenyl.

[0110] In one example, P is phenyl substituted with -Cl substituted phenyl.

[0111] In one example, P is phenyl substituted with -OCF3 substituted phenyl.

[0112] In one example, P is phenyl substituted with -OCF3 and -F.

[0113] In one embodiment, P is replaced by -O i Pr substituted phenyl substituted phenyl.

[0114] In one example, P is phenyl substituted with -O-C3-alkyl substituted phenyl.

[0115] In one embodiment, Q is selected from:

[0116]

[0117] In one embodiment, Q is selected from:

[0118]

[0119] In one embodiment, Q is

[0120] In one embodiment, the compound or salt of Formula I is selected from one or more of the following:

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

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

[0140] In one embodiment, the compound of Formula I is: or a salt thereof.

[0141] In one embodiment, the compound of Formula I is: or a salt thereof. In one embodiment, the compound of formula I is: or a salt thereof.

[0142] In one embodiment, the compound of Formula I is: or a salt thereof. In one embodiment, the compound of formula I is: or a salt thereof. In one embodiment, the compound of formula I is: or a salt thereof. In one embodiment, the compound of formula I is: or a salt thereof. In one embodiment, the compound of formula I is: or a salt thereof.

[0143] In one embodiment, the compound of Formula I is:

[0144] or a salt thereof.

[0145] In one embodiment, the compound of Formula I is:

[0146] or a salt thereof.

[0147] In one embodiment, the compound of Formula I is:

[0148] or a salt thereof.

[0149] In another aspect, there is provided a compound of formula IIa

[0150]

[0151] Wherein R can be selected from:

[0152] -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

[0153] -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,

[0154] -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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

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

[0156] -aryl-C(=O)-OH, or

[0157] -aryl-C(=O)-NH-S(O)2-C1-C6;

[0158] Where Q can be selected from

[0159]

[0160] as well as

[0161] wherein R3, R4 or R6 are independently selected from -H, halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy, alkoxy substituted by one or more halogen, aryl optionally substituted by one or more halogen, hydroxy, alkoxy, alkoxy substituted by one or more halogen;

[0162] wherein R9 is selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, aryl or -O-aryl, wherein each C1-C6 alkyl, C1-C6 alkoxy, aryl or -O-aryl may be further substituted with one or more halogen, hydroxy, C1-C6 alkoxy or C1-C6 alkoxy further substituted with one or more halogen; and

[0163] wherein Y is -CH2-, -CHR5, -C(R5)2-, wherein each R5 is independently C1-C6 alkyl; -O- or -S-, -S(O), -S(O)2, -NH-, -NR 10 -, where R 10 is a C1-C6 alkyl group;

[0164] wherein Y1 is optionally present and is -CH2-, -CHR5, -C(R5)2-, wherein each R5 is independently C1-C6 alkyl; -O- or -S-, -S(O), -S(O)2, -NH-, -NR 11 -, and where R 11 is a C1-C6 alkyl group;

[0165] or a salt thereof.

[0166] In one example, R is 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.

[0167] In another example, R is 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 or -aryl-C(=O)-OH.

[0168] In another example, R is -C(=O)-C1-C6-C(=O)-OH.

[0169] In another example, R is -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6.

[0170] In another example, R is selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2 or -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, such as -C(=O)-C1-C6-C(=O)-NH-S(O)2-Ph.

[0171] In another example, R is -aryl-C(=O)-OH.

[0172] In another example, R is -C(=O)-CH2-CH2-C(=O)-OH.

[0173] In another example, R is 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.

[0174] In another example, R is -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-NMe2.

[0175] In another example, R is -phenyl-C(=O)-OH.

[0176] In another example, Q is selected from:

[0177]

[0178] In another example, Q is selected from:

[0179]

[0180] In another example, Q is

[0181] In one example, R9 is aryl or aryl substituted with C1-C6 alkoxy further substituted with one or more halogens.

[0182] In one example, R9 is phenyl or phenyl substituted with C1-C6 alkoxy further substituted with one or more halogens.

[0183] In one example, Y and Y1 are each -CH2-.

[0184] In one embodiment, the compound of formula II is selected from

[0185]

[0186] or a salt thereof.

[0187] In another aspect, the present invention provides a compound of formula I or IIa as defined above for use in reducing the formation of methane from digestion in a ruminant and / or for improving ruminant performance.

[0188] In one example, the compounds of formula I or IIa as defined above are used to reduce the formation of methane from digestion in ruminants.

[0189] In one example, the compound of formula I or IIa as defined above is used to reduce the formation of methane from digestion in ruminants by at least 10%.

[0190] In another example, the compound of formula I or IIa as defined above is used to reduce the formation of methane from digestion in ruminants by at least 15%.

[0191] In yet another example, the compound of formula I or IIa as defined above is used to reduce the formation of methane from digestion in ruminants by at least 20%.

[0192] In one aspect, the present invention further provides a method for reducing methane production in ruminants and / or improving the performance of ruminants, comprising orally administering to the ruminant an effective amount of at least one compound of Formula I or IIa or a salt thereof. Oral administration is understood to include administration by gavage, addition to feed, water source, or pasture, or manual administration of a bolus or capsule.

[0193] In one embodiment, the effective amount of at least one compound of Formula I or IIa or a salt thereof is administered to the ruminant at least once a day.

[0194] In one example, the effective amount of at least one compound of Formula I or IIa or a salt thereof reduces the production of methane by the ruminant by at least 10% per day.

[0195] In one example, the effective amount of at least one compound of Formula I or IIa or a salt thereof reduces the production of methane by the ruminant by at least 15% per day.

[0196] In one example, the effective amount of at least one compound of Formula I or IIa or a salt thereof reduces the production of methane by the ruminant by at least 20% per day.

[0197] In another aspect of the present invention, a composition for oral administration is provided, comprising at least one compound of Formula I or IIa or a salt thereof for use in reducing methane production in ruminants, and further comprising at least one agriculturally and orally acceptable excipient.

[0198] In one example, the composition is suitable for use as a feed additive.

[0199] In one example, the composition is suitable for use as a water additive.

[0200] In another example, the composition is suitable for use as a ruminant lick.

[0201] In one example, the composition is suitable for use as an oral drench.

[0202] In another example, the composition is suitable for use as a rumen bolus or capsule.

[0203] In one example, the composition is suitable for reducing the production of methane by the ruminant by at least 10% per day.

[0204] In one example, the composition is suitable for reducing the production of methane by the ruminant by at least 15% per day.

[0205] In one example, the composition is suitable for reducing the production of methane by the ruminant by at least 20% per day.

[0206] In one example, the excipient can include one or more minerals and / or one or more vitamins.

[0207] In one example, the excipient may include one or more vitamins selected from the group consisting of vitamin A, vitamin D3, vitamin E, and vitamin K, such as vitamin K3, vitamin B12, biotin, and choline, vitamin B1, vitamin B2, vitamin B6, niacin, folic acid, and the like.

[0208] In one example, the excipient may include one or more minerals selected from calcium, phosphorus, sodium, manganese, zinc, iron, copper, chloride, sulfur, magnesium, iodine, selenium, and cobalt.

[0209] In one example, the composition may further include sunflower oil, electrolytes such as ammonium chloride, calcium carbonate, starch, protein, and the like.

[0210] The compounds of the present invention have the potential for use in reducing the formation of methane in ruminants without affecting microbial fermentation in a way that would be harmful to the ruminants. DETAILED DESCRIPTION

[0211] definition

[0212] As used herein, the term "ruminant" is a mammal that is able to obtain nutrients from plant foods by fermenting them in a specialized foregut (rumen) prior to digestion, primarily through microbial activity. Representative examples of ruminants and other foregut fermenters include cattle, goats, sheep, giraffes, bison, moose, elk, yaks, buffalo, deer, camels, alpacas, llamas, and antelopes.

[0213] As used herein, the term "effective amount" refers to an amount of at least one compound of Formula I or a salt thereof that reduces the production of methane produced by a ruminant or improves the performance of a ruminant.

[0214] The term "ruminant performance" as used herein refers to improving the productivity of ruminants, such as increased weight gain, milk yield or quality, wool growth or quality, surviving offspring per farrowing, and the like.

[0215] The term -C1-C6- means a carbon chain having 1 to 6 carbons and being linear or branched, saturated or unsaturated, including but not limited to methyl, ethyl, ethylene, propyl, isopropyl, propylene, butyl, tert-butyl, butylene, pentyl, pentylene, hexyl, hexylene, and the like, wherein the -C1-C6 group is optionally substituted with one or more halogens.

[0216] The term -C1-C6 alkyl- means a straight or branched alkyl chain having 1 to 6 carbons, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, wherein the -C1-C6 alkyl group is optionally substituted with one or more halogens.

[0217] The term "halogen" as used herein refers to a halogen atom selected from Cl, Br or F.

[0218] The term "aryl" as used herein refers to "aryl", unless otherwise specified, indicating a C 5-12 Aryl groups, suitably C 6-10 Aryl groups, more preferably C 6-8 Aryl groups. Aryl groups will contain at least one aromatic ring (e.g., one, two, or three rings). An example of a typical aryl group having one aromatic ring is phenyl. An example of a typical aryl group having two aromatic rings is naphthyl. The aryl group is optionally substituted by one or more of -CN, -halogen, -C(halogen)3, -NH2, -NO2, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C1-C6 alkyl substituted by one or more halogen, -C1-C6 alkenyl, -C1-C6 alkynyl, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, aryl or substituted aryl, the substituted aryl may include substituted phenyl (benzyl group), substituted thiophenol, tosyl group, the substituted aryl group is substituted by one or more -CN, -halogen, -C(halogen)3, -NH2, -NO2-NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkenyl and C1-C6 alkynyl.

[0219] As used herein, the term "heteroaryl" refers to, unless otherwise specified, an aryl residue wherein one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms are replaced by heteroatoms selected from N, S, and O, or a 5-membered aromatic ring comprising one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms selected from N, S, and O. Exemplary monocyclic heteroaryl groups having one heteroatom include: a five-membered ring (e.g., pyrrole, furan, thiophene); and a six-membered ring (e.g., pyridine, such as pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: a five-membered ring (e.g., pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl, imidazol-4-yl); and a six-membered ring (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, benzothiazole, quinazoline and purine. The heteroaryl group is optionally substituted by one or more -CN, -halogen, -C(halogen)3, -NH2, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NO2, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl or substituted aryl, the substituted aryl may include substituted phenyl (benzyl group), substituted thiophenol, tosyl group, the substituted aryl group is substituted by one or more -CN, -halogen, -C(halogen)3, -NH2, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, alkyl, alkenyl and alkynyl.

[0220] As used herein, the term "heterocyclyl" includes "carbocycles" as defined herein, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N, or S). The term "heterocycle" or "heterocyclyl" includes saturated rings (i.e., heterocycloalkyl), partially unsaturated rings, and aromatic rings (i.e., heteroaryl). Substituted heterocyclyls include, for example, heterocycles substituted with any substituent disclosed herein, including carbonyl groups.

[0221] Examples of heterocycles include, for example, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, thiazolidine-dione; tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolyl, isoquinolyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, benzopyranyl, xanthenyl, phenoxathiyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl , carbazolyl, β-carbolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolyl, isoindolyl, quinuclidine, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl.

[0222] By way of example, and not limitation, the carbon-bonded heterocycle is 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, 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, the carbon-bonded heterocycle includes 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.

[0223] By way of example and not limitation, nitrogen-bonded heterocycles are bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, the 2-position of isoindole or isoindoline, the 4-position of morpholine, and the 9-position of carbazole or β-carboline. Still more typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0224] All possible stereoisomers of the claimed compounds are included in the present disclosure. When the compounds described herein have at least one chiral center, they may therefore exist as enantiomers. When a compound has two or more chiral centers, it may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present disclosure.

[0225] Some crystalline forms of a compound may exist in more than one polymorphic form, and therefore all forms are intended to be included in the present disclosure. In addition, some compounds may form solvates (i.e., hydrates) with water or with common organic solvents, and such solvates are also intended to be encompassed within the scope of the present disclosure. These compounds, including their salts, may also be obtained in the form of their hydrates, or include other solvents for their crystallization.

[0226] The present disclosure further includes within its scope prodrugs of the compounds described herein. Generally, such prodrugs will be functional derivatives of the compounds that are readily convertible into the desired active compound in vivo. Thus, in these instances, the term "administering" in the therapeutic methods of the present invention encompasses treating the various conditions described with a prodrug form of one or more of the claimed compounds, provided that such prodrug forms are converted into the above-specified compounds in vivo upon administration to a subject.

[0227] As used herein, the term "composition" is intended to encompass a product comprising a therapeutically effective amount of one or more of the claimed compounds, as well as any product which results, directly or indirectly, from combination of the claimed compounds.

[0228] As used herein, the term "or a salt thereof" refers to a salt of an acidic or basic nitrogen atom. Exemplary salts include, but are not limited to, sodium, potassium, lithium, calcium, ammonium, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, and the like.

[0229] Methods for making compounds of Formula I, Formula II and Formula IV

[0230] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 1)

[0231]

[0232] 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) was added 2 M NaOH (32 mL, 63.2 mmol) dropwise at 0° C., and the reaction mixture was stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (2.43 g), which was used in the next step without further purification.

[0233] To a stirred solution of (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (2.43 g) in EtOH (80 mL) was added hydrazine hydrate (0.77 mL, 50% w / w), and the reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was then collected by filtration, washed with water, and dried in vacuo to give 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow-orange solid (1.80 g), which was used directly in the next step without further purification.

[0234] To a stirred solution of 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (0.50 g) in THF (20 mL) was added succinic anhydride (162 mg, 1.62 mmol), and the reaction mixture was heated at 50° C. for 18 h. The resulting reaction mixture was then concentrated in vacuo and purified by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) to give compound 1 as a brown solid (0.45 g, 31% over 3 steps). 1H NMR (400MHz, CDCl3) δ8.82(2H,s),8.11(1H,d,J=8.7Hz),7.96(1H,d,J=1.9Hz),7.69(2H,d,J=8.6Hz),7.66(1H,dd,J=8.8,2.0H z), 7.41 (2H, d, J = 8.6Hz), 5.83 (1H, dd, J = 11.9, 4.9Hz), 3.88 (1H, dd, J = 17.7, 12.0Hz), 3.32–3.12 (3H, m), 2.75 (2H, t, J = 6.7Hz).

[0235] 4-Oxylidene-4-(3-phenyl-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 1A)

[0236]

[0237] To a solution of quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol) and acetophenone (0.15 mL, 1.26 mmol) in EtOH (12 mL) was added 2 M NaOH (3.2 mL, 6.32 mmol) dropwise at 0° C., and the reaction mixture was stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to afford (E)-1-phenyl-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (190 g), which was used directly in the next step without further purification.

[0238] To a stirred solution of (E)-1-phenyl-3-(quinoxalin-6-yl)prop-2-en-1-one (190 g) in EtOH (8 mL) was added hydrazine hydrate (90 μL, 50% w / w), and the reaction mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was then collected by filtration, washed with water, and dried in vacuo to give 6-(3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (160 mg), which was used directly in the next step without further purification.

[0239] To a stirred solution of 6-(3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (160 mg) in THF (5 mL) was added succinic anhydride (58 mg, 0.58 mmol), and the reaction mixture was heated at 50° C. for 18 h. The resulting reaction mixture was then concentrated in vacuo and purified by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) to give compound 1A as a colorless solid (15 mg, 3% over 3 steps). 1H NMR(400MHz, CDCl3)δ8.80(2H,s),8.09(1H,d,J=8.7Hz),7.98(1H,s),7.77–7.74(2H,m),7.66(1H,dd,J=8.7,1.6Hz),7 .45–7.42(3H,m),5.83(1H,dd,J=11.9,4.9Hz),3.89(1H,dd,J=17.8,12.0Hz),3.32–3.13(3H,m),2.75(2H,t,J=6.7Hz).

[0240] 4-(3-(4-Isopropylphenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 3)

[0241]

[0242] To a solution of quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol) and 4-isopropylacetophenone (204 mg, 1.26 mmol) in EtOH (12 mL) was added 2 M NaOH (3.2 mL, 6.32 mmol) dropwise at 0° C., and the reaction mixture was stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-isopropylphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (300 mg), which was used in the next step without further purification.

[0243] To a stirred solution of (E)-1-(4-isopropylphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg) in EtOH (10 mL) was added hydrazine hydrate (82 μL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo and the resulting residue was poured into ice-water, collected by filtration, and dried in vacuo to give 6-(3-(4-isopropylphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (150 mg), which was used in the next step without further purification.

[0244] In a sealed vial, a mixture of 6-(3-(4-isopropylphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (100 mg) and succinic anhydride (63 mg, 0.63 mmol) in THF (4 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was concentrated in vacuo. Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 3 as a yellow solid (40 mg, 17% over 3 steps). 1 H NMR (500MHz, CDCl3) δ8.82–8.81(2H,m),8.09(1H,d,J=8.7Hz),7.97(1H,d,J=1.8Hz),7.69(2H ,d,J=8.4Hz),7.66(1H,dd,J=8.7,2.0Hz),7.29(2H,d,J=8.2Hz),5.82(1H,dd,J=11.8,4.7Hz), 3.88(1H,dd,J=17.6,11.8Hz),3.29(1H,dt,J=17.5,6.6Hz),3.24(1H,dd,J=17.8,4.9Hz),3.1 6(1H,dt,J=17.5,6.7Hz),2.95(1H,sevenfold,J=6.9Hz),2.74(2H,t,J=6.7Hz),1.26(6H,d,J=6.7Hz); 13 C NMR(125MHz, CDCl3)δ176.2(C),170.4(C),154.9(C),152.3(C),145.4(CH),145.1(CH),1 43.8(C),143.1(C),142.6(C),130.6(CH),128.6(C),128.1(CH),127.1(2xCH),127.0(2x CH),125.9(CH),60.1(CH),42.4(CH2),34.3(CH),29.2(CH2),29.0(CH2),23.9(2xCH3).

[0245] 4-(3-(4-cyclohexylphenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 4)

[0246]

[0247] Compound 4 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 4-cyclohexylacetophenone (255 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(4-cyclohexylphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (300 mg); Step 2: (E)-1-(4-cyclohexylphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (250 mg) and hydrazine hydrate (91 μL, 50% w / v) 1-(4-cyclohexylphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (100 mg, 0.56 mmol) in EtOH (10 mL). 6-(3-(4-cyclohexylphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (100 mg) and succinic anhydride (56 mg, 0.56 mmol) were added to THF (5 mL). Purification by flash column chromatography (EtOAc, pure) gave compound 4 as a colorless solid (70 mg, 18% over 3 steps). 1 H NMR (500MHz, CDCl3) δ8.83–8.81(2H,m),8.10(1H,d,J=8.7Hz),7.98(1H,d,J=1.9Hz),7.68(2H,d,J=8 .4Hz),7.66(1H,dd,J=8.8,2.1Hz),7.27(2H,d,J=8.4Hz),5.81(1H,dd,J=11.8,4.8Hz),3.87(1H,dd,J =17.8,11.8Hz),3.29(1H,dt,J=17.5,6.9Hz),3.23(1H,dd,J=17.6,4.6Hz),3.15(1H,dt,J=17.5,6.7H z),2.74(2H,t,J=6.5Hz),2.56–2.51(1H,m),1.88–1.84(4H,m),1.46–1.35(4H,m),1.30–1.23(2H,m); 13C NMR(125MHz, CDCl3)δ176.4(C),170.4(C),154.9(C),151.5(C),145.3(CH),145.0(CH),1 43.9(C),143.0(C),142.5(C),130.5(CH),128.5(C),128.2(CH),127.5(2xCH),127.0(2x CH),125.9(CH),60.1(CH),44.7(CH),42.4(CH2),34.3(2xCH2),29.1(CH2),29.0(CH2),26.9(2x CH2),26.2(CH2).

[0248] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 5)

[0249]

[0250] Compound 5 was prepared over 3 steps using a method analogous to that described for the preparation of compound 1A: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 4-(trifluoromethyl)acetophenone (237 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-3-(quinoxalin-6-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one as a beige solid (240 mg); Step 2: (E)-3-(quinoxalin-6-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (240 mg) and hydrazine hydrate (91 μL, 50% w / w) in EtOH (8 mL) to give 6-(3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a beige solid (190 mg); and Step 3: 6-(3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (190 mg) and succinic anhydride (56 mg, 0.56 mmol) in THF (5 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 5 as a colorless solid (27 mg, 5% over 3 steps). 1H NMR (400MHz, CDCl3) δ8.81(2H,s),8.11(1H,d,J=8.8Hz),7.97(1H,s),7.86(2H,d,J=8.1Hz),7.69–7.65(3H ,m),5.86(1H,dd,J=12.0,4.8Hz),3.90(1H,dd,J=17.8,12.1Hz),3.31–3.11(3H,m),2.75(2H,t,J=6.6Hz).

[0251] 4-(3-(4-methoxyphenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 6)

[0252]

[0253] Compound 6 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 4-methoxyacetophenone (189 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(4-methoxyphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (316 mg); Step 2: (E)-1-(4-methoxyphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (110 mg) and hydrazine hydrate (47 μL, 50% w / w) in EtOH (10 mL) to give 6-(3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (107 mg); and Step 3: 6-(3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (60 mg) and succinic anhydride (39 mg, 0.39 mmol) in THF (3 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 6 as a yellow solid (20 mg, 20% over 3 steps). 1HNMR(500MHz, CDCl3)δ8.82–8.81(2H,m),8.10(1H,d,J=8.7Hz),7.97(1H,d,J=2.0Hz ),7.71–7.69(2H,m),7.67(1H,dd,J=8.7,2.1Hz),6.96–6.93(2H,m),5.81(1H,dd,J= 11.7,4.7Hz),3.87(1H,dd,J=17.9,11.9Hz),3.86(3H,s),3.29(1H,dt,J=17.5,6.5H z), 3.23 (1H, dd, J = 17.5, 4.7Hz), 3.14 (1H, dt, J = 17.5, 6.7Hz), 2.74 (2H, t, J = 6.6Hz); 13 C NMR(125MHz, CDCl3)δ175.4(C),170.5(C),161.9(C),154.8(C),145.4(CH),145.2(CH),143.8(C),143.1(C),142.7(C),130.7(CH),128. 6(2×CH),128.2(CH),125.9(CH),123.5(C),114.4(2×CH),60.1(CH),55.6(CH3),42.5(CH2),29.2(2×CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 22 H 20 N4NaO4, calculated value 427.1377; measured value 427.1374.

[0254] 4-Oxylidene-4-(3-(4-phenoxyphenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 7)

[0255]

[0256] To a solution of quinoxaline-6-carbaldehyde (500 mg, 3.16 mmol) and 4-phenoxyacetophenone (670 mg, 3.16 mmol) in EtOH (32 mL) was added 2 M NaOH (7.9 mL, 15.8 mmol) dropwise at room temperature, and the reaction mixture was stirred for 4 h. Afterwards, the mixture was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-phenoxyphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (1.00 g), which was used directly in the next step without further purification.

[0257] To a stirred solution of (E)-1-(4-phenoxyphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (500 mg) in EtOH (8 mL) was added hydrazine hydrate (0.26 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo and the resulting residue was poured into ice-water, collected by filtration, and dried in vacuo to give 6-(3-(4-phenoxyphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a brown solid (350 mg), which was used in the next step without further purification.

[0258] In a sealed vial, a mixture of 6-(3-(4-phenoxyphenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (350 mg) and succinic anhydride (191 mg, 1.91 mmol) in THF (10 mL) was subjected to microwave irradiation at 120° C. for 45 min. The resulting precipitate was then collected by filtration, washed with water (3×5 mL), CHCl (3×5 mL), EtOAc (3×5 mL), and then petroleum ether (3×5 mL), and dried in vacuo to afford compound 7 as a colorless solid (147 mg, 20% over 3 steps). 1 H NMR(400MHz,DMSO-d6)δ12.12(1H,br s),8.94–8.92(2H,m),8.08(1H,d,J=8.7Hz),7.89(1H,d,J=1.9Hz),7.85-7. 81(2H,m),7.71(1H,dd,J=8.7,2.0Hz),7.46-7.40(2H,m),7.22-7.18(1H,m) ,7.09-7.06(4H,m),5.83(1H,dd,J=12.0,4.9Hz),3.97(1H,dd,J=18.2,12.0 Hz), 3.26 (1H, dd, J = 18.2, 4.9Hz), 3.11-2.91 (2H, m), 2.49 (2H, t, J = 7.2Hz); 13C NMR(101MHz,DMSO-d6)δ173.7(C),169.1(C),158.7(C),155.8(C),153.9(C),146 .0(CH),145.6(CH),144.2(C),142.1(C),141.6(C),130.2(2×CH),129.8(CH),12 8.8(2×CH),128.1(CH),126.0(C),125.3(CH),124.2(CH),119.3(2×CH),118.3(2 ×CH),59.5(CH),41.8(CH2),28.7(CH2),28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 23 N4O4, calculated value, 467.1714; measured value, 467.1697.

[0259] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 8)

[0260]

[0261] Compound 8 was prepared over 3 steps using a procedure analogous to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 4-(trifluoromethoxy)acetophenone (257 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-3-(quinoxalin-6-yl)-1-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one as a colorless solid (200 mg); Step 2: (E)-3-(quinoxalin-6-yl)-1-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (200 mg) and hydrazine hydrate (72 μL, 50% w / v) 1-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (170 mg, 100 mg) in EtOH (10 mL); and Step 3: 6-(3-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (100 mg) and succinic anhydride (56 mg, 0.56 mmol) in THF (4 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 8 as a yellow solid (72 mg, 21% over 3 steps). 1H NMR (500MHz, CDCl3) δ8.82 (2H, s), 8.11 (1H, d, J = 8.7Hz), 7.97 (1H, d, J = 1.9Hz), 7.80(2H,d,J=9.0Hz),7.66(1H,dd,J=8.7 and 2.1Hz),7.29–7.26(2H,m),5.84(1H,d d,J=11.6,4.9Hz),3.88(1H,dd,J=17.8,12.0Hz),3.26(1H,dt,J=17.4,6.6Hz),3 .23(1H,dd,J=17.5,5.0Hz), 3.14(1H,dt,J=17.5,6.7Hz), 2.74(2H,t,J=6.6Hz).

[0262] 4-(3-(4-bromophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 9)

[0263]

[0264] Compound 9 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 4-bromoacetophenone (251 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(4-bromophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (360 mg); Step 2: (E)-1-(4-bromophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (360 mg) and hydrazine hydrate (0.13 mL, 50% w / w) in EtOH (10 mL) to give 6-(3-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (150 mg); and Step 3: 6-(3-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (150 mg) and succinic anhydride (85 mg, 0.85 mmol) in THF (5 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 9 as a light yellow solid (91 mg, 16% over 3 steps). 1H NMR (400MHz, DMSO-d6) δ12.09(1H,s),8.94–8.93(2H,m),8.08(1H,d,J=8.7Hz),7.90(1H,d,J=1.9Hz),7.79–7.66(5H,m),5.84(1H,dd,J=12 .0,5.1Hz),3.98(1H,dd,J=18.3,12.0Hz),3.35–3.28(1H,m),3.10(1H,dt,J=17.2,6.7Hz),2.97(1H,dt,J=17.2,6.6Hz),2.52–2.49(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),153.6(C),146.0(CH),145.6(CH),144.0(C),142.1(C),141.6(C),131.8(2× CH),130.2(C),129.8(CH),128.7(2×CH),128.1(CH),125.3(CH),123.8(C),59.7(CH),41.6(CH2),28.7(CH2)28.3(CH2).

[0265] 4-(3-(2,4-dichlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 10)

[0266]

[0267] Compound 10 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 2,4-dichloroacetophenone (238 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(2,4-dichlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (310 mg); Step 2: (E)-1-(2,4-dichlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (310 mg) and hydrazine hydrate (0.12 mL, 50 Step 3: 6-(3-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (100 mg) and succinic anhydride (58 mg, 0.58 mmol) in THF (5 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 10 as a light yellow solid (112 mg, 54%). 1 H NMR (400MHz, CDCl3) δ8.84–8.82(2H,m),8.12(1H,d,J=8.7Hz),7.97(1H,d,J=2.0Hz) ,7.79(1H,d,J=8.5Hz),7.68(1H,dd,J=8.7,2.1Hz),7.46(1H,d,J=2.0Hz),7.32(1H, dd,J=8.5,2.1Hz),5.83(1H,dd,J=12.0,4.9Hz),4.08(1H,dd,J=18.3,12.0Hz),3.43 (1H,dd,J=18.3,4.9Hz),3.30–3.22(1H,m),3.16–3.08(1H,m),2.74(2H,t,J=6.7Hz).

[0268] 4-(3-(3,4-dichlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 11)

[0269]

[0270] Compound 11 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 3,4-dichloroacetophenone (238 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(3,4-dichlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (350 mg); Step 2: (E)-1-(3,4-dichlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (350 mg) and hydrazine hydrate (0.13 mL, 50 Step 3: 6-(3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (70 mg) and succinic anhydride (41 mg, 0.41 mmol) in THF (4 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 11 as a brown solid (32 mg, 6%). 1 H NMR (500MHz, CDCl3) δ8.82–8.80(2H,m),8.10(1H,d,J=8.8Hz),7.95(1H,d,J=1.6Hz),7.8 2(1H,d,J=1.9Hz),7.64(1H,dd,J=8.7,1.9Hz),7.57(1H,dd,J=8.3,2.0Hz),7.50(1H,d,J= 8.5Hz),5.84(1H,dd,J=12.0,5.0Hz),3.84(1H,dd,J=17.8,12.1Hz),3.29(1H,dt,J=17.6, 7.6Hz), 3.19 (1H, dd, J = 17.8, 5.1Hz), 3.13 (1H, dt, J = 17.6, 6.7Hz), 2.75 (2H, t, J = 6.8Hz); 13C NMR(125MHz, CDCl3)δ176.4(C),170.4(C),152.2(C),145.4(CH),145.1(CH),143.4(C),143.0(C),142.5(C),134.9(C),133.4(C),131.1(C) ,131.0(CH),130.7(CH),128.6(CH),128.0(CH),125.9(2×CH),60.5(CH2),42.1(CH2),29.1(CH2),28.7(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 21 H 16 Cl2N4NaO3, calculated value 465.0492; measured value 465.0506.

[0271] 4-(3-([1,1'-biphenyl]-2-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 12)

[0272]

[0273] To a solution of quinoxaline-6-carboxaldehyde (237 mg, 1.50 mmol) and 2-acetylbiphenyl (294 mg, 1.50 mmol) in EtOH (12 mL) was added 2M NaOH (3.8 mL, 7.50 mmol) dropwise at room temperature, and the reaction mixture was stirred for 1 h. Afterwards, the solution was cooled to 0 ° C and water was added to the reaction mixture (12 mL). The precipitated solid obtained was then collected by filtration, washed with water and dried in vacuo to obtain (E) -1- ([1,1'-biphenyl] -2-yl) -3- (quinoxaline-6-yl) prop-2-ene-1-one as a yellow solid (353 mg), which was used directly in the next step without further purification.

[0274] A mixture of (E)-1-([1,1'-biphenyl]-2-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (329 mg) and hydrazine hydrate (0.18 mL, 50% w / w) in THF (8 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (294 mg, 2.94 mmol) was added and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 12 as a yellow solid (194 mg, 31% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.84–8.81(2H,m),8.05(1H,d,J=8.7Hz),7.82(1H,d,J=1.9Hz),7.75(1 H,dd,J=7.3,1.6Hz),7.51–7.41(3H,m),7.35(1H,dd,J=7.1,1.6Hz),7.27–7.25(2H,m),7.22 –7.15(3H,m),5.59(1H,dd,J=11.8,4.5Hz),3.21(1H,dd,J=18.1,11.8Hz),3.10(1H,dt,J=17 .4, 6.6Hz), 2.99 (1H, dt, J = 17.4, 6.8Hz), 2.69 (2H, t, J = 7.0Hz), 2.50 (1H, dd, J = 18.1, 4.6Hz); 13 C NMR(101MHz, CDCl3)δ176.4(C),170.4(C),156.8(C),145.3(CH),145.0(CH),143.5( C),142.9(C),142.5(C),142.0(C),141.1(C),130.9(CH),130.6(C),130.4(CH),130. 1(CH),129.4(CH),129.0(2×CH),128.5(2×CH),128.2(CH),127.8(CH),127.7(CH),1 25.7(CH),60.0(CH),44.5(CH2),29.1(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 23 N4O3, calculated value 451.1765; measured value 451.1757.

[0275] 4-(3-([1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 13)

[0276]

[0277] To a solution of quinoxaline-6-carbaldehyde (237 mg, 1.50 mmol) and 3-acetylbiphenyl (294 mg, 1.50 mmol) in EtOH (12 mL) was added 2 M NaOH (3.8 mL, 7.50 mmol) dropwise at room temperature, and the reaction mixture was stirred for 1 h. Afterwards, the solution was cooled to 0 ° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-([1,1′-biphenyl]-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a yellow solid (405 mg), which was used directly in the next step without further purification.

[0278] A mixture of (E)-1-([1,1'-biphenyl]-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (405 mg) and hydrazine hydrate (0.22 mL, 50% w / w) in THF (10 mL) was stirred at reflux for 22 h. Succinic anhydride (361 mg, 3.61 mmol) was then added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2 x 30 mL) followed by brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Purification by flash column chromatography (CHCl, neat → CHCl / MeOH, 9:1) afforded compound 13 as a yellow solid (115 mg, 17% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.80–8.78(2H,m),8.10(1H,d,J=8.7Hz),7.99(1H,d,J=1 .9Hz),7.95(1H,t,J=1.6Hz),7.73(1H,dt,J=7.7,1.3Hz),7.70–7.64(2H,m),7 .62–7.59(2H,m),7.53–7.43(3H,m),7.40–7.34(1H,m),5.84(1H,dd,J=11.9,4 .9Hz),3.92(1H,dd,J=17.7,11.9Hz),3.33–3.15(3H,m),2.75(2H,t,J=6.8Hz); 13CNMR(101MHz,CDCl3)δ176.2(C),170.4(C),154.5(C),145.4(CH),145.1(CH),143.8 (C),143.0(C),142.6(C),142.1(C),140.4(C),131.6(C),130.6(CH),129.6(CH),129 .4(CH),129.0(2×CH),128.2(CH),127.9(CH),127.3(2×CH),125.9(CH),125.7(CH),1 25.6(CH),60.2(CH),42.5(CH2),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 23 N4O3, calculated value 451.1765; measured value 451.1775.

[0279] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 14)

[0280]

[0281] Compound 14 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (237 mg, 1.50 mmol), 1-(4'-(trifluoromethoxy)biphenyl-3-yl)ethanone (420 mg, 1.50 mmol) and 2M NaOH (3.8 mL, 7.50 mmol) in EtOH (12 mL) gave (E)-3-(quinoxalin-6-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)prop-2-en-1-one as an off-white solid (631 mg); Step 2: (E)-3-(quinoxalin-6-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)prop-2-en-1-one (350 mg) and hydrazine hydrate (0.10 mL, 50% w / w) in THF (7 mL) followed by the addition of succinic anhydride (250 mg, 2.50 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → CH 2 Cl 2 / MeOH, 9:1) gave compound 14 as an off-white solid (45 mg, 10% over 2 steps). 1H NMR(400MHz,DMSO-d6)δ12.08(1H,s),8.94–8.92(2H,m),8.09(1H,d,J=8.7Hz),8 .02(1H,t,J=1.4Hz),7.92-7.78(5H,m),7.74(1H,dd,J=8.7,2.0Hz),7.60(1H,t,J =7.8Hz),7.46(2H,d,J=8.0Hz),5.87(1H,dd,J=12.0,5.0Hz),4.04(1H,dd,J=18.3 ,12.0Hz),3.46(1H,dd,J=18.3,5.0Hz),3.17-2.96(2H,m),2.52(2H,t,J=6.9Hz); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),154.4(C),148.1(C,J C-F =1.8Hz),146.0(CH),145.6(CH),144.2(C),142.1(C),141.6(C),139.3(C),138.8(C),131.7(C),129.8(CH), 129.5(CH),128.8(2×CH),128.8(CH),128.2(CH),125.9(CH),125.4(CH),125.3(CH),121.5(2×CH),120.1(C,J C-F =255Hz),59.6(CH),41.8(CH2),28.7(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 21 F3N4NaO4, calculated value, 557.1407; measured value, 557.1412.

[0282] 4-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 15)

[0283]

[0284] Compound 15 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 4-acetylbiphenyl (248 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-([1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a beige solid (350 mg); Step 2: (E)-1-([1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg) and hydrazine hydrate (73 μL, 50% w / v) 1H-pyrazol-5-yl)quinoxaline (100 mg) and succinic anhydride (59 mg, 0.59 mmol) in THF (4 mL). Purification by flash column chromatography (EtOAc, neat → CHCl / MeOH, 9:1) gave compound 15 as a yellow solid (27 mg, 14% over 3 steps). 1 H NMR (500MHz, CDCl3) δ8.83(2H,s),8.12(1H,d,J=8.7Hz),7.99(1H,d,J=1.9Hz),7.84(2H,d,J =8.5Hz),7.70–7.66(3H,m),7.63(2H,dd,J=8.5,1.4Hz),7.47(2H,t,J=8.0Hz),7.39(1H,tt,J =7.2,2.0Hz),5.86(1H,dd,J=11.9,4.7Hz),3.94(1H,dd,J=17.9,11.9Hz),3.34(1H,dt,J=17 .4, 6.6Hz), 3.31 (1H, dd, J = 17.5, 4.9Hz), 3.20 (1H, dt, J = 17.5, 6.8Hz), 2.76 (2H, t, J = 6.6Hz); 13C NMR(125MHz, CDCl3)δ174.9(C),170.6(C),154.7(C),145.5(CH),145.2(CH),143 .7(C),143.6(C),143.1(C),142.7(C),140.1(C),130.8(CH),129.8(C),129.1(2x CH),128.2(CH),128.1(CH),127.6(2x CH),127.4(2xCH),127.2(2x CH),126.0(CH),60.3(CH),42.4(CH2),29.2(CH2),29.0(CH2).

[0285] 4-(3-(4'-Fluoro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 16)

[0286]

[0287] To a solution of quinoxaline-6-carbaldehyde (316 mg, 2.00 mmol) and 1-(4'-fluorobiphenyl-4-yl)ethanone (428 mg, 2.00 mmol) in EtOH (20 mL) was added 2M NaOH (5.00 mL, 10.00 mmol) dropwise at room temperature, and the reaction mixture was stirred for 2 h. Afterwards, the mixture was cooled to 0°C, and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (709 mg), which was used directly in the next step without further purification.

[0288] To a stirred solution of (E)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (300 mg) in EtOH (5 mL) was added hydrazine hydrate (0.16 mL, 50% w / w), and the reaction mixture was heated at reflux for 3 h. The solvent was then removed in vacuo, the residue poured into ice water, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 6-(3-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a brown solid (310 mg), which was used in the next step without further purification.

[0289] In a sealed vial, a mixture of 6-(3-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (310 mg) and succinic anhydride (168 mg, 1.68 mmol) in THF (4 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was diluted with CHCl (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with CHCl (3×30 mL). The combined organic layers were washed with water (3×30 mL) and then brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by flash column chromatography (CHCl / MeOH, 20:1) gave compound 16 as a beige solid (63 mg, 16% over 3 steps). 1 H NMR(400MHz,DMSO-d6)δ12.08(1H,br s),8.94–8.92(2H,m),8.09(1H,d,J=8.7Hz),7.92-7.89(3H,m),7.79-7.71(5H,m),7.32(2H,t,J=8.9Hz),5.85(1H,dd, J=12.0,5.0Hz),4.01(1H,dd,J=18.3,12.0Hz),3.35(1H,dd,J=18.3,5.0Hz),3.15-2.95(2H,m),2.52(2H,t,J=6.9Hz); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.2(C),162.1(C,J C-F =244Hz),154.1(C),146.0(CH),145.6(CH),144.2(C),142.1(C),141.6(C),140.8(C),135.6(C,J C-F =3.1Hz),130.0(C),129.8(CH),128.8(2×CH,J C-F =8.2Hz),128.1(2×CH),127.4(CH),126.9(2×CH),125.3(CH),115.8(2×CH,J C-F =21.2Hz),59.6(CH),41.8(CH2),28.8(CH2),28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 27 H 21 FN4NaO3, calculated value, 491.1490; measured value, 491.1488.

[0290] 4-(3-(2'-chloro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 17)

[0291]

[0292] To a solution of quinoxaline-6-carboxaldehyde (200 mg, 1.26 mmol) and 1-(2'-chlorobiphenyl-4-yl)ethanone (291 mg, 1.26 mmol) in EtOH (12 mL) was added 2 M NaOH (3.2 mL, 6.32 mmol) dropwise at 0 ° C., and the reaction mixture was stirred for 18 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to give (E)-1-(2'-chloro-[1,1'-biphenyl]-4-yl)-3-(quinoxaline-6-yl)prop-2-en-1-one as an off-white solid (402 mg), which was used directly in the next step without further purification.

[0293] To a stirred solution of (E)-1-(2'-chloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg) in EtOH (5 mL) was added hydrazine hydrate (67 μL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo, and the resulting residue was diluted in EtOAc (30 mL) and washed with water (2×20 mL) then brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 6-(3-(2'-chloro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as an orange wax (208 mg), which was used in the next step without further purification.

[0294] In a sealed vial, a mixture of 6-(3-(2'-chloro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (208 mg) and succinic anhydride (108 mg, 1.08 mmol) in THF (4 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 17 as an orange solid (21 mg, 7% over 3 steps). 1HNMR(400MHz,DMSO-d6)δ12.13(1H,br s),8.95–8.92(2H,m),8.09(1H,d,J=8.7Hz),7.92–7.90(3H,m),7.73(1H,d d,J=8.7,2.0Hz),7.62–7.52(3H,m),7.48–7.40(3H,m),5.86(1H,dd,J=11. 9,4.9Hz),4.03(1H,dd,J=17.9,12.2Hz),3.36(1H,dd,J=18.3,5.1Hz),3.1 1(1H,dt,J=17.2,6.7Hz),2.99(1H,dt,J=17.2,6.6Hz),2.54–2.50(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),154.1(C),146.0(CH),145.6(CH),144.2 (C),142.1(C),141.6(C),140.6(C),139.0(C),131.4(CH),131.2(C),130.4(C),129. 9(CH),129.8(CH),129.7(2×CH),129.6(CH),128.1(CH),127.6(CH),126.6(2×CH),12 5.4(CH),59.6(CH),41.7(CH2),28.8(CH2),28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 27 H 21 ClN4NaO3, calculated value, 507.1194; measured value, 507.1187.

[0295] 4-(3-(3'-chloro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 18)

[0296]

[0297] To a solution of quinoxaline-6-carboxaldehyde (350 mg, 2.21 mmol) and 1-(3'-chlorobiphenyl-4-yl)ethanone (510 mg, 2.21 mmol) in EtOH (22 mL) was added 2 M NaOH (5.5 mL, 11.0 mmol) dropwise at 0 ° C., and the reaction mixture was stirred for 16 h (while gradually warming to room temperature). The resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(3'-chloro-[1,1'-biphenyl]-4-yl)-3-(quinoxaline-6-yl)prop-2-en-1-one as a light pink solid (820 mg), which was used directly in the next step without further purification.

[0298] To a stirred solution of (E)-1-(3'-chloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (500 mg) in EtOH (8 mL) was added hydrazine hydrate (0.25 mL, 50% w / w), and the reaction mixture was heated at reflux for 3 h. The solvent was then removed in vacuo, the residue poured into ice water, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 6-(3-(3'-chloro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a brown solid (350 mg), which was used in the next step without further purification.

[0299] In a sealed vial, a mixture of 6-(3-(3'-chloro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (350 mg) and succinic anhydride (182 mg, 1.82 mmol) in THF (10 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was diluted with CHCl (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with CHCl (3×30 mL). The combined organic layers were washed with water (3×30 mL) and then brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by flash column chromatography (CHCl / MeOH, 100:1 → CHCl / MeOH, 25:1) gave compound 18 as a light brown solid (262 mg, 40% over 3 steps). 1H NMR (400MHz, CDCl3) δ8.80–8.79(2H,m),8.09(1H,d,J=8.7Hz),7.99(1H,d,J=1.7Hz),7.83-7.80(2H,m),7.67(1H,dd,J=8.7,2.0Hz),7.62-7.58(3 H,m),7.49-7.46(1H,m),7.39-7.34(2H,m),5.84(1H,dd,J=11.9,4.9Hz) ,3.89(1H,dd,J=17.7,11.9Hz),3.33-3.13(3H,m),2.75(2H,t,J=6.8Hz); 13 C NMR(101MHz, CDCl3)δ176.9(C),170.3(C),153.9(C),145.3(CH),145.0(CH),143.9( C),142.9(C),142.4(C),142.0(C),141.9(C),135.0(C),130.6(C),130.5(CH),130. 3(CH),128.2(CH),128.0(CH),127.5(2×CH),127.4(2×CH),127.3(CH),125.8(CH),1 25.3(CH),60.2(CH),42.3(CH2),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 22 ClN4O3, calculated value, 485.1375; measured value, 485.1386.

[0300] 4-(3-(4'-chloro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 19)

[0301]

[0302] Compound 19 was prepared over 3 steps using a method similar to that described for the preparation of compound 3 - Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 1-(4'-chlorobiphenyl-4-yl)ethanone (291 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (402 mg); Step 2: (E)-1-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (200 mg) and hydrazine hydrate (67 μL, 50% w / w) in EtOH (5 mL) to give 6-(3-(4'-chloro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as an off-white solid (168 mg); and Step 3: 6-(3-(4'-chloro-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (150 mg) and succinic anhydride (78 mg, 0.78 mmol) in THF (3 mL). Purification by flash column chromatography (EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 19 as an off-white solid (28 mg, 10% over 3 steps). 1 H NMR(400MHz,DMSO-d6)δ12.08(1H,brs),8.94–8.92(2H,m),8.09(1H,d,J=8.7Hz) ,7.93–7.88(3H,m),7.83–7.69(5H,m),7.59–7.51(2H,m),5.86(1H,dd,J=11.9,5. 0Hz),4.02(1H,dd,J=18.1,12.0Hz),3.38–3.34(1H,m),3.11(1H,dt,J=17.2,6.7H z),2.99(1H,dt,J=17.2,6.6Hz),2.53–2.50(2H,m); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 27 H 21 ClN4NaO3, calculated value, 507.1194; measured value, 507.1182.

[0303] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 20)

[0304]

[0305] To a solution of quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol) and 1-(4'-(trifluoromethyl)biphenyl-4-yl)ethanone (264 mg, 1.00 mmol) in EtOH (8 mL) was added 2M NaOH (2.5 mL, 5.0 mmol) dropwise at room temperature, and the reaction mixture was stirred for 3 h. Afterwards, the solution was cooled to 0°C, and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-3-(quinoxalin-6-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one as an off-white solid (319 mg), which was used directly in the next step without further purification.

[0306] A mixture of (E)-3-(quinoxalin-6-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one (319 mg) and hydrazine hydrate (0.15 mL, 50% w / w) in THF (6 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (237 mg, 2.37 mmol) was added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 20 as a yellow solid (20 mg, 4% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.80(2H,s),8.10(1H,d,J=8.7Hz),7.98(1H,s),7.85(2H,d,J=8.5Hz),7.71–7.65(7H,m),5.85(1H, dd,J=11.9,4.9Hz),3.92(1H,dd,J=17.7,11.9Hz),3.35–3.15(3H,m),2.76(2H,t,J=6.7Hz); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 28 H 22 F3N4O3, calculated value, 519.1639; measured value, 519.1639.

[0307] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 21)

[0308]

[0309] To a solution of compound 9 (68 mg, 0.15 mmol) in DMF / water (1.5 mL, 1:1 v / v) were added 3-(trifluoromethoxy)phenylboronic acid (62 mg, 0.30 mmol), tripotassium phosphate (127 mg, 0.60 mmol), and palladium acetate (3.4 mg, 10 mol%). The reaction mixture was stirred at 110°C for 24 h. Water (15 mL) was added to the mixture, and the suspension was acidified to approximately pH 2 by the addition of 1M aqueous HCl. The aqueous layer was then extracted with ethyl acetate (2 x 15 mL), and the combined organic layers were washed with water (3 x 15 mL) and then brine (15 mL), dried over anhydrous NaSO, filtered through celite, and concentrated in vacuo. Purification by flash column chromatography (CHCl, neat → CHCl / MeOH, 9:1) gave compound 21 as a brown solid (42 mg, 53%). 1 HNMR(400MHz, CDCl3)δ8.81(2H,s),8.11(1H,d,J=8.7Hz),7.99(1H,s),7.84(2H,d,J= 8.5Hz),7.68(1H,dd,J=8.7,1.8Hz),7.64(2H,d,J=8.5Hz),7.54(1H,dt,J=8.0,1.4Hz ),7.51–7.42(2H,m),7.26–7.23(1H,m),5.85(1H,dd,J=11.9,4.9Hz),3.92(1H,dd,J= 17.7,12.0Hz),3.33–3.15(3H,m),2.76(2H,t,J=6.7Hz); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 21 F3N4NaO4, calculated value, 557.1407; measured value, 557.1406.

[0310] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 22)

[0311]

[0312] To a solution of quinoxaline-6-carbaldehyde (316 mg, 2.00 mmol) and 1-(4'-(trifluoromethoxy)biphenyl-4-yl)ethanone (560 mg, 2.00 mmol) in EtOH (10 mL) was added 2M NaOH (5.0 mL, 10.0 mmol) dropwise at room temperature, and the reaction mixture was stirred for 2 h. Afterwards, the mixture was cooled to 0°C, and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-3-(quinoxalin-6-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one as an off-white solid (841 mg), which was used directly in the next step without further purification.

[0313] To a stirred solution of (E)-3-(quinoxalin-6-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one (300 mg) in EtOH (5 mL) was added hydrazine hydrate (0.13 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo, the residue poured into ice water, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 6-(3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a brown solid (310 mg), which was used in the next step without further purification.

[0314] In a sealed vial, a mixture of 6-(3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (310 mg) and succinic anhydride (143 mg, 1.43 mmol) in THF (4 mL) was subjected to microwave irradiation at 120°C for 45 min. The resulting reaction mixture was diluted with CHCl (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with CHCl (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and then brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by flash column chromatography (CHCl / MeOH, 20:1) gave compound 22 as a light brown solid (50 mg, 13% over 3 steps). 1H NMR (400MHz, CDCl3) δ8.81(2H,s),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=1.6Hz),7.85-7.82(2H,m),7.69-7.61(5H,m),7.32-7.29(2H,m ),5.85(1H,dd,J=11.9,4.9Hz),3.92(1H,dd,J=17.7,11.9Hz),3.33-3.13(3H,m),2.76(2H,t,J=6.9Hz); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 21 F3N4NaO4, calculated value, 557.1407; measured value, 557.1397.

[0315] 4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 23)

[0316]

[0317] Compound 23 was prepared using a method similar to that described for the preparation of compound 21: compound 9 (50 mg, 0.11 mmol), 4-methylphenylboronic acid (30 mg, 0.22 mmol), tripotassium phosphate (93 mg, 0.44 mmol) and palladium acetate (2.5 mg, 10 mol%) in DMF / water (1 mL, 1:1 v / v). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → CH2Cl2 / MeOH, 9:1) gave compound 23 as an orange solid (42 mg, 82%). 1 H NMR (400MHz, CDCl3) δ8.81 (2H, s), 8.10 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 1.9Hz ),7.81(2H,d,J=8.6Hz),7.68(1H,dd,J=8.7,1.9Hz),7.64(2H,d,J=8.5Hz),7 .52(2H,d,J=8.2Hz),7.28–7.26(2H,m),5.84(1H,dd,J=11.9,4.9Hz),3.91(1 H,dd,J=17.7,11.9Hz),3.33–3.15(3H,m),2.75(2H,t,J=6.8Hz),2.40(3H,s); 13C NMR(101MHz, CDCl3)δ176.2(C),170.4(C),154.3(C),145.3(CH),145.1(CH),143.9 (C),143.5(C),143.0(C),142.6(C),138.1(C),137.2(C),130.6(CH),129.8(2×CH) ,129.6(C),128.2(CH),127.4(2×CH),127.3(2×CH),127.0(2×CH),125.9(CH),60.2 (CH),42.4(CH2),29.2(CH2),28.9(CH2),21.3(CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 24 N4NaO3, calculated value, 487.1741; measured value, 487.1740.

[0318] 4-(3-(4'-Isopropyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 24)

[0319]

[0320] Compound 24 was prepared using a method similar to that described for the preparation of compound 21: compound 9 (100 mg, 0.22 mmol), 4-isopropylphenylboronic acid (72 mg, 0.44 mmol), tripotassium phosphate (187 mg, 0.88 mmol) and palladium acetate (4.9 mg, 10 mol%) in DMF / water (2 mL, 1:1 v / v). Compound 24 was purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → CH2Cl2 / MeOH, 9:1) to give compound 24 as an orange solid (74 mg, 68%). 1H NMR (400MHz, CDCl3) δ8.82–8.79(2H,m),8.10(1H,d,J=8.7Hz),7.99(1H,d,J=1. 8Hz),7.81(2H,d,J=8.6Hz),7.70–7.62(3H,m),7.56(2H,d,J=8.3Hz),7.33(2H,d ,J=8.1Hz),5.84(1H,dd,J=11.8,4.9Hz),3.91(1H,dd,J=17.7,11.9Hz),3.33–3 .14(3H,m),2.96(1H,sevenfold,J=6.9Hz),2.75(2H,t,J=6.8Hz),1.29(6H,d,J=6.9Hz); 13 C NMR(101MHz, CDCl3)δ176.5(C),170.4(C),154.4(C),149.0(C),145.3(CH),145.1 (CH),143.8(C),143.5(C),143.0(C),142.6(C),137.6(C),130.6(CH),129.6(C),1 28.2(CH),127.4(4×CH),127.2(2×CH),127.1(2×CH),125.9(CH),60.2(CH),42.4( CH2),34.0(CH),29.2(CH2),29.0(CH2),24.1(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 30 H 29 N4O3, calculated value, 493.2234; measured value, 493.2234.

[0321] 4-(3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 25)

[0322]

[0323] Compound 25 was prepared using a method similar to that described for the preparation of compound 21: compound 9 (68 mg, 0.15 mmol), 4-methoxyphenylboronic acid (46 mg, 0.30 mmol), tripotassium phosphate (127 mg, 0.60 mmol) and palladium acetate (3.4 mg, 10 mol%) in DMF / water (1.5 mL, 1:1 v / v). Purification by flash column chromatography (CHCl, neat → CHCl / MeOH, 9:1) gave compound 25 as a yellow solid (32 mg, 44%).1 H NMR(400MHz,DMSO-d6)δ12.07(1H,br s),8.94–8.92(2H,m),8.08(1H,d,J=8.7Hz),7.91(1H,d,J=1.9Hz),7.86(2 H,d,J=8.5Hz),7.75–7.66(5H,m),7.04(2H,d,J=8.9Hz),5.84(1H,dd,J=11. 9,5.0Hz),4.00(1H,dd,J=18.1,12.0Hz),3.80(3H,s),3.36–3.30(1H,m),3. 11(1H,dt,J=17.2,6.7Hz),2.98(1H,dt,J=17.1,6.6Hz),2.53–2.49(2H,m); 13 CNMR(101MHz,DMSO-d6)δ173.8(C),169.2(C),159.4(C),154.2(C),146.0(CH),145. 6(CH),144.2(C),142.2(C),141.59(C),141.55(C),131.4(C),129.8(CH),129.2(C) ,128.1(CH),127.9(2×CH),127.4(2×CH),126.3(2×CH),125.3(CH),114.5(2×CH),59 .6(CH),55.2(CH3),41.8(CH2),28.8(CH2),28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 28 H 25 N4O4, calculated value, 481.1870; measured value, 481.1870.

[0324] 4-(3-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 26)

[0325]

[0326] Compound 26 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(2',4'-dichlorobiphenyl-4-yl)ethanone (265 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (344 mg); Step 2: (E)-1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (344 mg) and hydrazine hydrate (0.16 mL, 50% w / w) in THF (7 mL) followed by the addition of succinic anhydride (255 mg, 2.55 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 26 as a yellow solid (93 mg, 18% over 2 steps). 1 HNMR(400MHz,DMSO-d6)δ12.09(1H,s),8.94–8.92(2H,m),8.08(1H,d,J=8.7Hz),7.92– 7.90(3H,m),7.76(1H,d,J=2.1Hz),7.73(1H,dd,J=8.7,2.0Hz),7.55–7.52(3H,m),7.4 7(1H,d,J=8.3Hz),5.86(1H,dd,J=11.9,4.9Hz),4.02(1H,dd,J=18.2,12.0),3.39–3.3 3(1H,m),3.11(1H,dt,J=17.1,6.7Hz),2.99(1H,dt,J=17.2,6.6Hz),2.52–2.49(2H,m); 13CNMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),154.0(C),146.0(CH),145.6(CH),144. 1(C),142.1(C),141.6(C),139.4(C),138.0(C),133.3(C),132.6(C),132.3(CH),130 .7(C),129.8(CH),129.7(2×CH),129.4(CH),128.1(CH),127.8(CH),126.7(2×CH),12 5.4(CH),59.7(CH),41.7(CH2),28.8(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 27 H 20 Cl2N4NaO3, calculated value, 541.0805; measured value, 541.0806.

[0327] 4-(3-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 27)

[0328]

[0329] Compound 27 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (237 mg, 1.50 mmol), 1-(3',4'-dichlorobiphenyl-4-yl)ethanone (398 mg, 1.50 mmol) and 2M NaOH (3.8 mL, 7.50 mmol) in EtOH (12 mL) gave (E)-1-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (486 mg); Step 2: (E)-1-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (270 mg) and hydrazine hydrate (0.12 mL, 50% w / w) in THF (10 mL) followed by the addition of succinic anhydride (200 mg, 2.00 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → CH 2 Cl 2 / MeOH, 9:1) gave compound 27 as a yellow solid (97 mg, 22% over 2 steps). 1HNMR(400MHz,DMSO-d6)δ12.09(1H,s),8.94–8.92(2H,m),8.08(1H,d,J=8.7Hz), 8.02(1H,s),7.92–7.90(3H,m),7.85(2H,d,J=8.6Hz),7.74–7.71(3H,m),5.86(1 H,dd,J=11.9,5.0Hz),4.02(1H,dd,J=18.2,12.0Hz),3.36(1H,dd,J=18.3,5.2Hz ),3.12(1H,dt,J=17.1,6.7Hz),2.99(1H,dt,J=17.2,6.6Hz),2.53–2.50(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),154.0(C),146.0(CH),145.6(CH),144. 1(C),142.1(C),141.6(C),139.7(C),139.0(C),131.9(C),131.1(CH),130.9(C),130 .7(C),129.8(CH),128.5(CH),128.1(CH),127.4(2×CH),127.1(2×CH),126.9(CH),1 25.4(CH),59.6(CH),41.7(CH2),28.8(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 21 Cl2N4O3, calculated value, 519.0985; measured value, 519.0965.

[0330] 4-(3-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 28)

[0331]

[0332] Compound 28 was prepared over 2 steps using a procedure similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (158 mg, 1.00 mmol), 1-(3',5'-dichlorobiphenyl-4-yl)ethanone (265 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-1-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a yellow solid (353 mg); Step 2: (E)-1-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (353 mg) and hydrazine hydrate (0.16 mL, 50% w / w) in THF (7 mL) were added followed by the addition of succinic anhydride (261 mg, 2.61 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 28 as a yellow solid (88 mg, 17% over 2 steps). 1 HNMR(400MHz, CDCl3)δ8.82–8.81(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d, J=1.9Hz),7.83(2H,d,J=8.6Hz),7.68(1H,dd,J=8.7,2.0Hz),7.59(2H,d,J=8 .6Hz),7.47(2H,d,J=1.9Hz),7.36(1H,t,J=1.8Hz),5.85(1H,dd,J=11.9,4.9 Hz), 3.91 (1H, dd, J = 17.7, 12.0Hz), 3.34–3.14 (3H, m), 2.76 (2H, t, J = 6.7Hz); 13 C NMR(101MHz, CDCl3)δ176.7(C),170.4(C),153.8(C),145.4(CH),145.1(CH) ,143.8(C),143.1(C),143.0(C),142.6(C),140.6(C),135.7(2×C),131.2(C) ,130.6(CH),128.2(CH),127.9(CH),127.6(4×CH),125.9(CH),125.7(2×CH),60.3(CH),42.3(CH2),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 27 H 20Cl2N4NaO3, calculated value, 541.0805; measured value, 541.0790.

[0333] 4-Oxylidene-4-(3-(5-phenylpyridin-2-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 29)

[0334]

[0335] To a solution of quinoxaline-6-carbaldehyde (193 mg, 1.22 mmol) and 1-(5-phenylpyridin-2-yl)ethanone (240 mg, 1.22 mmol) in EtOH (12 mL) was added 2 M NaOH (3.0 mL, 6.10 mmol) dropwise at 0° C., and the reaction mixture was stirred for 3 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to afford (E)-1-(5-phenylpyridin-2-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a beige solid (320 mg), which was used in the next step without further purification.

[0336] To a stirred solution of (E)-1-(5-phenylpyridin-2-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (320 mg) in EtOH (7 mL) was added hydrazine hydrate (0.18 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo, the residue poured into ice water, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 6-(3-(5-phenylpyridin-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (300 mg), which was used in the next step without further purification.

[0337] In a sealed vial, a mixture of 6-(3-(5-phenylpyridin-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (300 mg) and succinic anhydride (171 mg, 1.71 mmol) in THF (10 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (CH2Cl2 / MeOH, 20:1) gave compound 29 as an off-white solid (110 mg, 20% over 3 steps). 1H NMR(400MHz,DMSO-d6)δ12.13(1H,br s),8.97-8.92(3H,m),8.25-8.18(2H,m),8.08(1H,d,J=8.7Hz),7.92(1H,d,J=1.4Hz),7.80-7.73(3H,m),7.55-7.45(3H,m),5 .87(1H,dd,J=12.1,5.2Hz),4.07(1H,dd,J=18.7,12.1Hz),3.33(1H,dd,J=18.7,5.2Hz),3.18-3.00(2H,m),2.54-2.50(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.6(C),155.1(C),148.8(C),147.5(CH),146 .0(CH),145.6(CH),144.0(C),142.1(C),141.6(C),136.3(C),136.2(C),134.7(CH ),129.9(CH),129.2(2×CH),128.6(CH),128.1(CH),126.9(2×CH),125.4(CH),121. 2(CH),59.8(CH),41.9(CH2),28.7(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 26 H 21 N5NaO3, calculated value, 474.1537; measured value, 474.1520.

[0338] 4-Oxylidene-4-(3-(4-(pyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 30)

[0339]

[0340] To a solution of quinoxaline-6-carbaldehyde (237 mg, 1.50 mmol) and 1-(4-(pyridin-3-yl)phenyl)ethanone (296 mg, 1.50 mmol) in EtOH (12 mL) was added 2 M NaOH (3.8 mL, 7.50 mmol) dropwise at room temperature, and the reaction mixture was stirred at room temperature for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-(pyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (299 mg), which was used directly in the next step without further purification.

[0341] To a stirred solution of (E)-1-(4-(pyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (299 mg) in EtOH (7 mL) was added hydrazine hydrate (0.11 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo and the resulting residue was poured into ice-water, collected by filtration, and dried in vacuo to give 6-(3-(4-(pyridin-3-yl)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as an orange wax (199 mg), which was used in the next step without further purification.

[0342] In a sealed vial, a mixture of 6-(3-(4-(pyridin-3-yl)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (199 mg) and succinic anhydride (113 mg, 1.13 mmol) in THF (5 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was concentrated in vacuo. Purification by flash column chromatography (EtOAc, neat → CHCl / MeOH, 9:1) gave compound 30 as a yellow solid (68 mg, 10% over 3 steps). 1H NMR(400MHz,DMSO-d6)δ12.12(1H,br s),8.96(1H,br s),8.94–8.92(2H,m),8.60(1H,br s),8.14(1H,dt,J=8.0,2.0Hz),8.09(1H,d,J=8.7Hz),7.95–7.85(3H,m),7.86(2H,d ,J=8.6Hz),7.73(1H,dd,J=8.7,2.0Hz),7.51(1H,dd,J=7.9,4.8Hz),5.86(1H,dd,J=1 1.9,5.0Hz),4.02(1H,dd,J=18.2,12.0Hz),3.39–3.33(1H,m),3.12(1H,dt,J=17.3,6 .8Hz),2.99(1H,dt,J=17.1,6.6Hz),2.53–2.49(2H,m); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 26 H 21 N5NaO3, calculated value, 474.1537; measured value, 474.1554.

[0343] 4-(3-(Naphth-2-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 31)

[0344]

[0345] Compound 31 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 2-acetonaphthone (215 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(naphthalen-2-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (300 mg); Step 2: (E)-1-(naphthalen-2-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (250 mg) and hydrazine hydrate (0.10 mL, 50% w / w) in EtOH (10 mL) to give 6-(3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (224 mg); and Step 3: 6-(3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (150 mg) and succinic anhydride (93 mg, 0.93 mmol) in THF (4 mL). Purification by flash column chromatography (EtOAc, neat) gave compound 31 as a colorless solid (149 mg, 50%).1 H NMR (500MHz, CDCl3) δ8.84–8.82(2H,m),8.12(1H,d,J=8.6Hz),8.10(1H,dd,J=8.5,1.7Hz),8.02(1H,d,J=1.9Hz) ,7.96(1H,s),7.90(1H,d,J=8.7Hz),7.87(1H,d,J=7.9Hz),7.84(1H,d,J=7.6Hz),7.71(1H,dd,J=8.8,2.0Hz),7. 55(1H,td,J=6.9,1.4Hz),7.52(1H,td,J=6.9,1.4Hz),5.89(1H,dd,J=11.8,4.8Hz),4.03(1H,dd,J=17.4,11.8Hz ), 3.41 (1H, dd, J = 17.6, 5.0Hz), 3.36 (1H, dt, J = 17.6, 6.7Hz), 3.22 (1H, dt, J = 17.6, 6.9Hz), 2.78 (2H, t, J = 6.6Hz); 13 C NMR(125MHz, CDCl3)δ175.4(C),170.6(C),154.9(C),145.4(CH),145.1(CH), 143.7(C),143.1(C),142.6(C),134.5(C),133.1(C),130.7(CH),128.9(CH),1 28.61(CH),128.56(C),128.2(CH),128.1(CH),127.68(CH),127.65(CH),127 .1(CH),126.0(CH),123.4(CH),60.4(CH),42.4(CH2),29.2(CH2),29.0(CH2).

[0346] 4-(3-(4-chlorophenyl)-5-(quinoxalin-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 32)

[0347]

[0348] Compound 32 was prepared over 3 steps using a procedure analogous to that described for the preparation of compound 3: Step 1: Quinoxaline-2-carbaldehyde (200 mg, 1.26 mmol), 4-chloroacetophenone (0.16 mL, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-1-(4-chlorophenyl)-3-(quinoxalin-2-yl)prop-2-en-1-one as a colorless solid (300 mg); Step 2: (E)-1-(4-chlorophenyl)-3-(quinoxalin-2-yl)prop-2-en-1-one (300 mg) and hydrazine hydrate (0.13 mL, 50% w / w) in EtOH (10 mL) to give 2-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as a yellow solid (250 mg); and Step 3: 2-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (250 mg) and succinic anhydride (162 mg, 1.62 mmol) in THF (8 mL). Purification by flash column chromatography (EtOAc, neat) gave compound 32 as a colorless solid (63 mg, 12%). 1 H NMR(500MHz, CDCl3)δ8.98(1H,s),8.11–8.08(1H,m),8.02–7.99(1H,m),7.75–7.71(4H,m),7.42(2H,d,J=8.7Hz),5.91(1 H,dd,J=11.8,5.9Hz),3.80(1H,dd,J=17.6,11.7Hz),3.68(1H,dd,J=17.7,6.0Hz),3.18–3.14(2H,m),2.73–2.70(2H,m); 13 C NMR(125MHz, CDCl3)δ176.5(C),170.6(C),154.3(C),154.1(C),144.6(CH),142.2(C),14 2.1(C),136.8(C),130.4(CH),130.2(CH),129.6(C),129.32(CH),129.27(CH),129.2(2x CH),128.2(2x CH),60.0(CH),39.7(CH2),29.1(CH2),28.8(CH2).

[0349] 4-(3-(4-chlorophenyl)-5-(quinoxalin-5-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 33)

[0350]

[0351] To a solution of quinoxaline-5-carbaldehyde (237 mg, 1.50 mmol) and 4-chloroacetophenone (0.19 mL, 1.50 mmol) in EtOH (12 mL) was added 2 M NaOH (3.8 mL, 7.50 mmol) dropwise at room temperature, and the reaction mixture was stirred at room temperature for 2 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-chlorophenyl)-3-(quinoxalin-5-yl)prop-2-en-1-one as a yellow solid (424 mg), which was used directly in the next step without further purification.

[0352] To a stirred solution of (E)-1-(4-chlorophenyl)-3-(quinoxalin-5-yl)prop-2-en-1-one (200 mg) in EtOH (5 mL) was added hydrazine hydrate (85 μL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo and the resulting residue was poured into ice-water, collected by filtration, and dried in vacuo to give 5-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline as an orange solid (210 mg), which was used in the next step without further purification.

[0353] In a sealed vial, a mixture of 5-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (210 mg) and succinic anhydride (136 mg, 1.36 mmol) in THF (5 mL) was subjected to microwave irradiation at 120° C. for 45 min. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) then brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. (CHCl, neat → CHCl / MeOH, 95:5) afforded compound 33 as a brown solid (46 mg, 16% over 3 steps). 1 H NMR(400MHz,DMSO-d6)δ12.20(1H,br s),9.03–9.01(2H,m),8.02(1H,dd,J=8.3,1.3Hz),7.80–7.75(3H,m),7.52–7.48(3H,m),6.52(1H,dd,J=12.0,4.9Hz),4.03 (1H,dd,J=18.1,12.1Hz),3.22–3.14(2H,m),2.96(1H,dt,J=17.0,6.5Hz),2.55–2.50(2H,m); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 21 H17 ClN4NaO3, calculated value, 431.0881; measured value, 431.0887.

[0354] 4-(3-(4-chlorophenyl)-5-(quinolin-7-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 34)

[0355]

[0356] Compound 34 was prepared over 3 steps using a method analogous to that described for the preparation of compound 3: Step 1: Quinoline-7-carbaldehyde (200 mg, 1.27 mmol), 4-chloroacetophenone (0.16 mL, 1.27 mmol) and 2M NaOH (3.2 mL, 6.36 mmol) in EtOH (12 mL) to give (E)-1-(4-chlorophenyl)-3-(quinolin-7-yl)prop-2-en-1-one as an off-white solid (374 mg); Step 2: (E)-1-(4-chlorophenyl)-3-(quinolin-7-yl)prop-2-en-1-one (374 mg) and hydrazine hydrate (0.16 mL, 50% w / v) 7-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoline (392 mg) was prepared by adding 1-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoline (5-hydroxy-1H-pyrazol-5-yl) ... 1 H NMR(400MHz,DMSO-d6)δ12.09(1H,br s),8.88(1H,dd,J=4.2,1.8Hz),8.33(1H,d,J=8.3Hz),7.95(1H,d,J=8.5Hz),7.84–7.81(3H,m),7.56–7.49(3H,m),7.45(1H,dd,J=8.5, 1.8Hz),5.79(1H,dd,J=11.9,5.0Hz),3.96(1H,dd,J=18.2,12.0Hz),3.27(1H,dd,J=18.2,5.0Hz),3.11–2.94(2H,m),2.55–2.46(2H,m); 13C NMR(101MHz,DMSO-d6)δ173.7(C),169.2(C),153.4(C),150.8(CH),147.6(C),143.4(C),135.7(CH),134.9(C),129.9(C),128.9(2×CH),128. 8(CH),128.5(2×CH),127.1(C),125.1(CH),124.4(CH),121.4(CH),59.9(CH),41.8(CH2),28.8(CH2)28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 22 H 19 ClN3O3, calculated value, 408.1109; measured value, 408.1105.

[0357] 4-(5-(Benzo[c][1,2,5]oxadiazol-5-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 35)

[0358]

[0359] To a solution of 2,1,3-benzoxadiazole-5-carbaldehyde (222 mg, 1.50 mmol) and 4-chloroacetophenone (0.19 mL, 1.50 mmol) in EtOH (12 mL) was added 2M NaOH (3.8 mL, 7.5 mmol) dropwise at room temperature, and the reaction mixture was stirred for 2 h. Afterwards, the solution was cooled to 0 ° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one as a brown solid (256 mg), which was used directly in the next step without further purification.

[0360] A mixture of (E)-3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one (256 mg) and hydrazine hydrate (0.17 mL, 50% w / w) in THF (7 mL) was stirred at reflux for 5 h. Afterwards, succinic anhydride (270 mg, 2.70 mmol) was added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 35 as a brown solid (24 mg, 4% over 2 steps). 1 H NMR (400MHz, CDCl3) δ7.81 (1H, d, J = 9.4Hz), 7.69–7.67 (3H, m), 7.41 (2H, d, J = 8.6Hz), 7.23 (1H, dd, J = 9.3, 1.5Hz),5.67(1H,dd,J=12.0,5.2Hz),3.83(1H,dd,J=17.8,12.1Hz),3.31–3.01(3H,m),2.79–2.66(2H,m); 13 C NMR(101MHz, CDCl3)δ177.3(C),170.4(C),153.5(C),149.2(C),148.9(C),144.4(C),137.1(C),130.1(CH),129.3(2×CH), 129.2(C),128.1(2×CH),118.1(CH),112.8(CH),60.3(CH),41.3(CH2),29.0(CH2)28.6(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 19 H 15 ClN4NaO4, calculated value, 421.0674; measured value, 421.0670.

[0361] 4-(5-(Benzo[c][1,2,5]thiadiazol-5-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 36)

[0362]

[0363] To a solution of 2,1,3-benzothiadiazole-5-carbaldehyde (246 mg, 1.50 mmol) and 4-chloroacetophenone (0.19 mL, 1.50 mmol) in EtOH (12 mL) was added 2M NaOH (3.8 mL, 7.5 mmol) dropwise at room temperature, and the reaction mixture was stirred for 24 h. Afterwards, the solution was cooled to 0 ° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-3-(benzo[c][1,2,5]thiadiazol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one as an off-white solid (248 mg), which was used directly in the next step without further purification.

[0364] A mixture of (E)-3-(benzo[c][1,2,5]thiadiazol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one (248 mg) and hydrazine hydrate (0.10 mL, 50% w / w) in THF (7 mL) was stirred at reflux for 5 h. Afterwards, succinic anhydride (248 mg, 2.48 mmol) was added and the reaction mixture was further stirred at reflux for 1 h. The reaction mixture was then concentrated in vacuo and purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat). The resulting solid was dissolved in EtOAc (30 mL) and extracted with saturated aqueous NaHCO3 (3×15 mL). The combined aqueous layers were then washed with EtOAc (15 mL) and acidified to approximately pH 3 by the addition of 6M aqueous HCl. The aqueous layer was then extracted with EtOAc (3×15 mL), and the combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give compound 36 as an off-white solid (56 mg, 9% over 2 steps). 1 H NMR (400MHz, CDCl3) δ7.97(1H,d,J=8.9Hz),7.86(1H,s),7.69(2H,d,J=8.7Hz),7.44(1H,dd,J=9.1,1.8Hz),7.41(2H ,d,J=8.7Hz),5.76(1H,dd,J=11.9,5.0Hz),3.84(1H,dd,J=17.8,12.0Hz),3.27–3.09(3H,m),2.73(2H,t,J=6.7Hz); 13C NMR(101MHz, CDCl3)δ177.4(C),170.2(C),155.0(C),154.5(C),153.5(C),142.8(C),137.0(C),129.5(CH),129.3(2×CH), 128.1(2×CH),127.7(C),122.7(CH),118.1(CH),60.4(CH),42.0(CH2),29.1(CH2)28.7(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 19 H 15 ClN4NaO3S, calculated value, 437.0446; measured value, 437.0436.

[0365] 4-(5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 37)

[0366]

[0367] To a solution of piperonal (200 mg, 1.33 mmol) and 4-chloroacetophenone (0.17 mL, 1.33 mmol) in EtOH (11 mL) was added 2 M NaOH (3.3 mL, 6.6 mmol) dropwise at room temperature, and the reaction mixture was stirred for 2 h. Afterwards, the solution was cooled to 0 ° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one as a colorless solid (305 mg), which was used directly in the next step without further purification.

[0368] To a stirred solution of (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one (305 mg) in EtOH (8 mL) was added hydrazine hydrate (0.20 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo, and the resulting residue was diluted in EtOAc (50 mL) and washed with water (2×30 mL) then brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 5-(benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole as an off-white solid (314 mg), which was used in the next step without further purification.

[0369] In a sealed vial, a mixture of 5-(benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (157 mg) and succinic anhydride (104 mg, 1.04 mmol) in THF (4 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → petroleum ether / EtOAc, 7:3). The resulting solid was dissolved in CHCl (30 mL) and washed with water (2×15 mL) and then brine (15 mL), dried over anhydrous Na SO, filtered, and concentrated in vacuo to give compound 37 as an off-white solid (126 mg, 47% over 3 steps). 1 H NMR(400MHz,DMSO-d6)δ12.12(1H,s),7.80(2H,d,J=8.7Hz),7.53(2H,d,J=8.7Hz), 6.83(1H,d,J=8.0Hz),6.73(1H,d,J=1.7Hz),6.68(1H,dd,J=8.1,1.7Hz),6.02–5.9 3(2H,m),5.47(1H,dd,J=11.8,4.7Hz),3.81(1H,dd,J=18.1,11.8Hz),3.12(1H,dd, J=18.1,4.7Hz),3.06–2.84(2H,m),2.50–2.45(2H,m); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 20 H 17 ClN2NaO5, calculated value, 423.0718; measured value, 423.0707.

[0370] 4-(3-(4-Chlorophenyl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 38)

[0371]

[0372] To a solution of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (372 mg, 2.00 mmol) and 4-chloroacetophenone (0.26 mL, 2.00 mmol) in EtOH (16 mL) was added 2M NaOH (5.0 mL, 10.0 mmol) dropwise at room temperature, and the reaction mixture was stirred for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-chlorophenyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)prop-2-en-1-one as a colorless solid (432 mg), which was used directly in the next step without further purification.

[0373] A mixture of (E)-1-(4-chlorophenyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)prop-2-en-1-one (432 mg) and hydrazine hydrate (0.17 mL, 50% w / w) in THF (11 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (402 mg, 4.02 mmol) was added, and the reaction mixture was further stirred at reflux for 1 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure). The resulting solid was dissolved in CHCl3 (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound 38 as a colorless solid (402 mg, 46% over 2 steps). 1 HNMR(400MHz, CDCl3)δ7.67(2H,d,J=8.7Hz),7.41(2H,d,J=8.7Hz),7.00–6.92(3H,m),5.56(1H,dd,J=11.9,4 .9Hz),3.75(1H,dd,J=17.8,11.9Hz),3.24–3.03(3H,m),2.73(2H,t,J=6.7Hz); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 20 H 15 ClF2N2NaO5, calculated value, 459.0530; measured value, 459.0528.

[0374] 4-(3-(4-chlorophenyl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 39)

[0375]

[0376] To a solution of 1,4-benzodioxane-6-carbaldehyde (400 mg, 2.44 mmol) and 4-chloroacetophenone (0.32 mL, 2.44 mmol) in EtOH (24 mL) was added 2M NaOH (6.1 mL, 12.2 mmol) dropwise at 0°C, and the reaction mixture was stirred for 24 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to afford (E)-1-(4-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one as a yellow solid (616 mg), which was used in the next step without further purification.

[0377] To a stirred solution of (E)-1-(4-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one (350 mg) in EtOH (12 mL) was added hydrazine hydrate (0.15 mL, 50% w / w), and the reaction mixture was heated at reflux for 3 h. The solvent was then removed in vacuo and the resulting residue was poured into ice water, collected by filtration, and dried in vacuo to give 3-(4-chlorophenyl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazole as a yellow solid (256 mg), which was used in the next step without further purification.

[0378] In a sealed vial, a mixture of 3-(4-chlorophenyl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazole (200 mg) and succinic anhydride (127 mg, 1.27 mmol) in THF (5 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure). The resulting solid was dissolved in CHCl (30 mL) and washed with water (2×15 mL) and then brine (15 mL), dried over anhydrous Na SO, filtered, and concentrated in vacuo to give compound 39 as a yellow solid (161 mg, 36% over 3 steps). 1H NMR(400MHz,DMSO-d6)δ12.10(1H,br s),7.79(2H,d,J=8.6Hz),7.53(2H,d,J=8.7Hz),6.77(1H,d,J=8.3Hz),6.65–6.62(2H,m),5.43(1H,dd,J=11.7,4.5 Hz),4.19(4H,s),3.78(1H,dd,J=18.1,11.8Hz),3.10(1H,dd,J=18.1,4.6Hz),3.02–2.87(2H,m),2.50–2.46(2H,m); 13 CNMR(101MHz,DMSO-d6)δ173.8(C),169.0(C),153.3(C),143.2(C),142.5(C),135.4(C),134.9(C),130.1(C),128.9(2×CH),128.4(2×CH ),118.2(CH),117.2(CH),114.2(CH),64.1(CH2),64.0(CH2),59.2(CH),41.8(CH2),28.8(CH2)28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 21 H 19 ClN2NaO5, calculated value, 437.0875; measured value, 437.0866.

[0379] 4-(3-([1,1'-biphenyl]-4-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 40)

[0380]

[0381] To a solution of 1,4-benzodioxane-6-carbaldehyde (492 mg, 3.00 mmol) and 4-acetylbiphenyl (589 mg, 3.00 mmol) in EtOH (10 mL) was added 2 M NaOH (7.5 mL, 15.0 mmol) dropwise at 0°C, and the reaction mixture was stirred for 5 h (while gradually warming to room temperature). The resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to afford (E)-1-([1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one as a yellow solid (1.03 g), which was used in the next step without further purification.

[0382] To a stirred solution of (E)-1-([1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one (500 mg) in EtOH (8 mL) was added hydrazine hydrate (0.45 mL, 50% w / w), and the reaction mixture was heated under reflux for 2 h. The solvent was then removed in vacuo, the residue poured into ice water, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 3-([1,1′-biphenyl]-4-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazole as a yellow solid (350 mg), which was used in the next step without further purification.

[0383] In a sealed vial, a mixture of 3-([1,1'-biphenyl]-4-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazole (350 mg) and succinic anhydride (196 mg, 1.96 mmol) in THF (10 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (CH2Cl2 / MeOH, 50:1) gave compound 40 as a yellow solid (153 mg, 23% over 3 steps). 1 H NMR(400MHz, CDCl3)δ7.80(2H,d,J=8.4Hz),7.66-7.62(4H,m),7.47(2H,t,J=7.5Hz),7.41-7.36(1H,m),6.82-6.80(1H,m),6.7 4-6.71(2H,m),5.50(1H,dd,J=11.6,4.5Hz),4.20(4H,s),3.73(1H,dd,J=17.6,11.7Hz),3.20-3.13(3H,m),2.81-2.70(2H,m); 13C NMR(101MHz, CDCl3)δ177.6(C),170.0(C),154.6(C),143.8(C),143.3(C),14 3.2(C),140.2(C),135.1(C),130.2(C),129.0(2×CH),128.0(CH),127.4(2×CH ),127.3(2×CH),127.2(2×CH),118.7(CH),117.8(CH),114.5(CH),64.4(2×CH 2),59.9(CH),42.4(CH2),29.2(CH2),29.1(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 25 N2O5, calculated value, 457.1758; measured value, 457.1770.

[0384] 4-(3-(4-chlorophenyl)-5-(3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 41)

[0385]

[0386] To a solution of 3-methoxybenzaldehyde (200 mg, 1.47 mmol) and 4-chloroacetophenone (0.19 mL, 1.47 mmol) in EtOH (12 mL) was added 2 M NaOH (3.7 mL, 7.4 mmol) dropwise at room temperature, and the reaction mixture was stirred for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-chlorophenyl)-3-(3-methoxyphenyl)prop-2-en-1-one as a colorless solid (345 mg), which was used directly in the next step without further purification.

[0387] To a stirred solution of (E)-1-(4-chlorophenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (345 mg) in EtOH (10 mL) was added hydrazine hydrate (0.24 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo, and the resulting residue was diluted in EtOAc (50 mL) and washed with water (2×30 mL) then brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 3-(4-chlorophenyl)-5-(3-methoxyphenyl)-4,5-dihydro-1H-pyrazole as a yellow solid (363 mg), which was used in the next step without further purification.

[0388] In a sealed vial, a mixture of 3-(4-chlorophenyl)-5-(3-methoxyphenyl)-4,5-dihydro-1H-pyrazole (363 mg) and succinic anhydride (253 mg, 2.53 mmol) in THF (10 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was concentrated in vacuo, diluted in EtOAc (30 mL) and extracted with saturated NaHCO3 aqueous solution (3×30 mL). The combined aqueous layer was washed with EtOAc (30 mL) and acidified to approximately pH 3 by adding 6M HCl aqueous solution. The aqueous layer was then extracted with EtOAc (3×30 mL), and the combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 41 was purified by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) as a colorless solid (34 mg, 6% over 3 steps). 1 H NMR (400MHz, CDCl3) δ7.67(2H,d,J=8.7Hz),7.40(2H,d,J=8.7Hz),7.25–7.20(1H,m),6.79(2H,dd,J=8.0,2.1Hz),6.73(1H,t,J=2.1Hz),5 .55(1H,dd,J=11.8,4.7Hz),3.77(3H,s),3.73(1H,dd,J=17.7,11.8Hz),3.23–3.09(3H,m),2.79–2.66(2H,m); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 20 H 20 ClN2O4, calculated value, 387.1106; measured value, 387.1103.

[0389] 4-(3-(4-chlorophenyl)-5-(2,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 42)

[0390]

[0391] 2,4-Dimethoxybenzaldehyde (299 mg, 1.80 mmol) and 4-chloroacetophenone (0.23 mL, 1.80 mmol) were added to a 5% ethanol solution at room temperature. iTo a solution of 2M NaOH (2.7 mL, 5.40 mmol) in PrOH (14 mL) was added dropwise and the reaction mixture was stirred for 6 h. Next, hydrazine hydrate (0.34 mL, 50% w / w) was added and the reaction mixture was stirred under reflux for 24 h. Afterwards, succinic anhydride (540 mg, 5.40 mmol) was added and the reaction mixture was further stirred under reflux for 1 h. Excess was removed in vacuo. i PrOH, and then the residue was diluted in EtOAc (50 mL) and washed with water (2 × 30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1: 1 → EtOAc, pure) gave compound 42 as a yellow solid (158 mg, 21%). 1 H NMR (400MHz, CDCl3) δ7.66 (2H, d, J = 8.7Hz), 7.38 (2H, d, J = 8.7Hz), 6.95 (1H, d, J = 8.4Hz), 6. 45(1H,d,J=2.3Hz), 6.41(1H,dd,J=8.4,2.4Hz), 5.74(1H,dd,J=11.7,4.7Hz), 3.77(3H,s), 3.76(3H,s),3.64(1H,dd,J=17.6,11.7Hz),3.23(1H,dt,J=17.4,6.7Hz),3.12(1H,dt,J=17 .4, 6.7Hz), 3.03 (1H, dd, J = 17.6, 4.7Hz), 2.74 (2H, t, J = 6.7Hz); HRMS (ESI / Q-TOF) m / z: [M+H] + , C 21 H 22 ClN2O5, calculated value, 417.1212; measured value, 417.1200.

[0392] 4-(3-(4-chlorophenyl)-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 43)

[0393]

[0394] 3,4-Dimethoxybenzaldehyde (100 mg, 0.60 mmol) and 4-chloroacetophenone (78 μL, 0.60 mmol) were added to a 5% ethanol solution at room temperature. iTo a solution of 2M NaOH (1.5 mL, 3.00 mmol) in PrOH (5 mL) was added dropwise, and the solution was stirred for 22 h. Next, hydrazine hydrate (0.15 mL, 50% w / w) and succinic anhydride (240 mg, 2.40 mmol) were added, and the reaction mixture was stirred at reflux for 5 h. A second portion of hydrazine hydrate (0.15 mL, 50% w / w) and succinic anhydride (240 mg, 2.40 mmol) were added, and the mixture was further stirred at reflux for 3 h. Excess HCl was removed in vacuo. i The product was stirred for 2 hours at room temperature for 1 hour.Then the product was stirred for 2 hours at room temperature for 3 hours ... 1 H NMR (400MHz, CDCl3) δ7.68 (2H, d, J = 8.7Hz), 7.40 (2H, d, J = 8.7Hz), 6.80 (1H, d, J = 8.2Hz), 6.77–6.72 (2H, m), 5.53 (1H, dd, J = 11.7, 4. 8Hz),3.84(3H,s),3.83(3H,s),3.72(1H,dd,J=17.7,11.8Hz),3.22–3.08(3H,m),2.73(2H,t,J=7.0Hz); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 21 H 22 ClN2O5, calculated value, 417.1212; measured value, 417.1204.

[0395] 4-(3-(4-chlorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 44)

[0396]

[0397] To a solution of isovanillin (304 mg, 2.00 mmol) and 4-chloroacetophenone (0.26 mL, 2.00 mmol) in EtOH (16 mL) was added 2 M NaOH (5.0 mL, 10.0 mmol) dropwise at room temperature, and the reaction mixture was stirred for 24 h. Afterwards, excess EtOH was removed in a vacuum and water (10 mL) was added, the solution was neutralized by adding a 6 M HCl aqueous solution, and the precipitated solid obtained was collected by filtration, washed with water and dried in a vacuum to obtain (E) -1- (4- chlorophenyl) -3- (3-hydroxy -4- methoxyphenyl) prop-2-ene-1-one as a yellow solid (485 mg), which was used directly in the next step without further purification.

[0398] To a stirred solution of (E)-1-(4-chlorophenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one (485 mg) in EtOH (13 mL) was added hydrazine hydrate (0.31 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo, and the resulting residue was diluted in EtOAc (50 mL) and washed with water (2×30 mL) then brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 5-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)-2-methoxyphenol as a brown solid (478 mg), which was used in the next step without further purification.

[0399] In a sealed vial, a mixture of 5-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)-2-methoxyphenol (478 mg) and succinic anhydride (158 mg, 1.58 mmol) in THF (12 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 44 as a yellow solid (226 mg, 28% over 3 steps). 1H NMR(400MHz, CDCl3)δ7.66(2H,d,J=8.6Hz),7.39(2H,d,J=8.6Hz),6.79–6.73(3H,m),5.50(1H,dd,J=11.7,4.6Hz ),3.84(3H,s),3.69(1H,dd,J=17.7,11.7Hz),3.19–3.08(3H,m),2.78–2.64(2H,m); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 20 H 20 ClN2O5, calculated value, 403.1055; measured value, 403.1049.

[0400] 4-(3-(4-chlorophenyl)-5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 45)

[0401]

[0402] To a solution of vanillin (304 mg, 2.00 mmol) and 4-chloroacetophenone (0.26 mL, 2.00 mmol) in EtOH (2 mL) was added dropwise SOCl (0.10 mL, 1.40 mmol) at 0 ° C., and the reaction mixture was stirred at room temperature for 2 h. Next, the mixture was quenched with water (30 mL), neutralized with saturated NaHCO aqueous solution and extracted with CH Cl (3 × 15 mL). The combined organic layers were then dried over anhydrous Na SO, filtered and concentrated in vacuo to give (E) -1- (4-chlorophenyl) -3- (4-hydroxy-3-methoxyphenyl) prop-2-ene-1-one as a dark oil (577 mg), which was used directly in the next step without further purification.

[0403] To a stirred solution of (E)-1-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one (577 mg) in EtOH (16 mL) was added hydrazine hydrate (0.37 mL, 50% w / w), and the reaction mixture was heated at reflux for 4 h. The solvent was then removed in vacuo, and the resulting residue was diluted in EtOAc (50 mL) and washed with water (2×30 mL) then brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 4-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)-2-methoxyphenol as a brown oil (606 mg), which was used in the next step without further purification.

[0404] In a sealed vial, a mixture of 4-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)-2-methoxyphenol (606 mg) and succinic anhydride (400 mg, 4.00 mmol) in THF (16 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (petroleum ether / EtOAc, 1: 1 → EtOAc, pure). The resulting solid was dissolved in CHCl (30 mL) and washed with water (2×15 mL) and then brine (15 mL), dried over anhydrous Na SO, filtered, and concentrated in vacuo to give compound 45 as a brown solid (81 mg, 10% over 3 steps). 1 HNMR(400MHz,DMSO-d6)δ12.12(1H,br s),8.89(1H,br s),7.79(2H,d,J=8.7Hz),7.53(2H,d,J=8.7Hz),6.73(1H,d,J=2.0Hz),6.68(1H,d, J=8.1Hz),6.55(1H,dd,J=8.2,2.0Hz),5.45(1H,dd,J=11.7,4.6Hz),3.79(1H,dd,J =18.0,11.8Hz),3.72(3H,s),3.11(1H,dd,J=18.1,4.7Hz),3.02(1H,dt,J=17.0,6. 8Hz),2.89(1H,dt,J=17.0,6.5Hz),2.51–2.47(2H,m); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 20 H 20 ClN2O5, calculated value, 403.1055; measured value, 403.1047.

[0405] 4-(3-([1,1'-biphenyl]-4-yl)-5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 46)

[0406]

[0407] To a solution of vanillin (304 mg, 2.00 mmol) and 4-acetylbiphenyl (392 mg, 2.00 mmol) in EtOH (16 mL) was added SOCl2 (0.10 mL, 1.40 mmol) dropwise at 0°C, and the reaction mixture was stirred at room temperature for 24 h. Afterwards, the solution was cooled to 0°C and water (10 mL) was added to the solution, and the resulting precipitated solid was collected by filtration, washed with water and dried in vacuo to give (E)-1-([1,1'-biphenyl]-4-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one as an orange solid (562 g), which was used directly in the next step without further purification.

[0408] A mixture of (E)-1-([1,1'-biphenyl]-4-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one (562 mg) and hydrazine hydrate (0.21 mL, 50% w / w) in THF (14 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (510 mg, 5.10 mmol) was added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 46 as an off-white solid (320 mg, 36% over 2 steps). 1 H NMR (400MHz, DMSO-d6) δ12.08(1H,s),8.88(1H,s),7.87(2H,d,J=8.5Hz),7.78(2H,d,J=8.6Hz),7.73(2H,d,J=7 .2Hz),7.50(2H,t,J=7.5Hz),7.40(1H,t,J=7.3Hz),6.76(1H,d,J=2.0Hz),6.70(1H,d,J=8.1Hz),6.58(1H,dd,J= 8.2,2.0Hz),5.47(1H,dd,J=11.6,4.5Hz),3.84(1H,dd,J=18.0,11.7Hz),3.74(3H,s),3.16(1H,dd,J=18.0,4.6 Hz),3.06(1H,dt,J=17.0,6.8Hz),2.92(1H,dt,J=17.1,6.9Hz),2.54–2.50(2H,m); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 26 H 24N2NaO5, calculated value, 467.1577; measured value, 467.1573.

[0409] 4-(3-(4-chlorophenyl)-5-(3-ethoxy-4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 47)

[0410]

[0411] To a solution of ethyl vanillin (332 mg, 2.00 mmol) and 4-chloroacetophenone (0.26 mL, 2.00 mmol) in EtOH (16 mL) was added SOCl (0.10 mL, 1.40 mmol) dropwise at 0° C., and the reaction mixture was stirred at room temperature for 48 h. Afterwards, the solution was cooled to 0° C. and water (16 mL) was added to the solution, and the resulting precipitated solid was then collected by filtration, washed with water, and dried in vacuo to give (E)-1-(4-chlorophenyl)-3-(3-ethoxy-4-hydroxyphenyl)prop-2-en-1-one as an off-white solid (374 mg), which was used directly in the next step without further purification.

[0412] A mixture of (E) -1- (4- chlorophenyl) -3- (3-ethoxy -4- hydroxyphenyl) prop-2-ene-1-one (374 mg) and hydrazine hydrate (0.15 mL, 50% w / w) in THF (10 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (354 mg, 3.54 mmol) was added and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2 × 30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 47 was purified by flash column chromatography (petroleum ether / EtOAc, 1: 1 → EtOAc, pure) as a colorless solid (342 mg, 41% over 2 steps). 1H NMR(400MHz,DMSO-d6)δ12.07(1H,br s),8.80(1H,br s),7.80(2H,d,J=8.6Hz),7.53(2H,d,J=8.6Hz),6.72(1H,d,J=1.8Hz),6.70(1H,d,J=8.1Hz ),6.56(1H,dd,J=8.1,1.8Hz),5.44(1H,dd,J=11.7,4.5Hz),3.97(2H,q,J=7.0Hz),3.79(1H ,dd,J=18.1,11.8Hz),3.12(1H,dd,J=18.1,4.6Hz),3.01(1H,dt,J=17.0,6.8Hz),2.91(1H, dt,J=17.1,6.6Hz),2.51–2.48(2H,m),1.30(3H,t,J=7.0Hz); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 21 H 21 ClN2NaO5, calculated value, 439.1031; measured value, 439.1025.

[0413] 4-(3-(4-chlorophenyl)-5-(4-fluoro-3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 48)

[0414]

[0415] Compound 48 was prepared over 2 steps using a method analogous to that described for the preparation of compound 20: Step 1: 4-Fluoro-3-methoxybenzaldehyde (308 mg, 2.00 mmol), 4-chloroacetophenone (0.26 mL, 2.00 mmol) and 2M NaOH (5.0 mL, 10.0 mmol) in EtOH (16 mL) to give (E)-1-(4-chlorophenyl)-3-(4-fluoro-3-methoxyphenyl)prop-2-en-1-one as an off-white solid (494 mg); Step 2: (E)-1-(4-chlorophenyl)-3-(4-fluoro-3-methoxyphenyl)prop-2-en-1-one (494 mg) and hydrazine hydrate (0.32 mL, 50% w / w) in THF (14 mL) followed by the addition of succinic anhydride (511 mg, 5.10 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → CH2Cl2 / MeOH, 9:1) gave compound 48 as a yellow solid (97 mg, 12% over 2 steps); 1H NMR (400MHz, CDCl3) δ7.68 (2H, d, J = 8.7Hz), 7.40 (2H, d, J = 8.7Hz), 7.00 (1H, dd, J = 11.0, 8.3Hz), 6.82 (1H, dd, J = 7.9, 2.1Hz), 6.72 (1H, ddd, J = 8.3, 4.1, 2.2Hz),5.53(1H,dd,J=11.8,4.9Hz),3.85(3H,s),3.73(1H,dd,J=17.7,11. 8Hz),3.22–3.05(3H,m),2.73(2H,t,J=6.7Hz); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 20 H 19 ClFN2O4, calculated value, 405.1012; measured value, 405.1010.

[0416] 3-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-3-oxopropanoic acid (Compound 49)

[0417]

[0418] To a stirred solution of 3-methoxy-3-oxyidenepropionic acid (46mg, 0.39mmol) in CH2Cl2 (5mL) was added oxalyl chloride (35μL, 0.41mmol), followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 4h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (5mL), and 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-yl)quinoxaline (100mg, 0.32mmol) was added thereto, followed by pyridine (32μL, 0.40mmol), and the reaction mixture was stirred at room temperature for 18h. The reaction was then quenched with saturated NaHCO3 aqueous solution (5mL), and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1) gave the corresponding methyl ester of compound 49 as a light red solid (77 mg, 59%). 1H NMR (400MHz, CDCl3) δ8.84–8.82(2H,m),8.12(1H,d,J=8.7Hz),8.02(1H,d,J=2.0Hz),7.70(1H,dd,J=8.7,2.1Hz),7.65(2H,d ,J=8.8Hz),7.41(2H,d,J=8.8Hz),5.86(1H,dd,J=11.9,4.9Hz),3.94–3.85(3H,m),3.78(3H,s),3.26(1H,dd,J=17.8,4.9Hz).

[0419] To a stirred solution of the above methyl ester (40 mg, 0.10 mmol) in THF / H O (2.50 mL, 4:1 v / v) was added LiOH H O (8.0 mg, 0.19 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with H O (10 mL) and acidified to approximately pH 1 by adding a 2M HCl aqueous solution, followed by extraction with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated in vacuo to afford compound 49 as a yellow solid (29 mg, 73%). 1 H NMR (400MHz, CDCl3) δ8.87–8.85(2H,m),8.15(1H,d,J=8.6Hz),7.99(1H,d,J=2.1Hz),7.71(2H,d,J=8.8Hz),7.67(1H,d d,J=8.7,2.1Hz),7.45(2H,d,J=8.7Hz),5.86(1H,dd,J=11.8,4.7Hz),3.99–3.91(3H,m),3.34(1H,dd,J=18.0,4.8Hz).

[0420] 5-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-oxopentanoic acid (Compound 50)

[0421]

[0422] To a stirred solution of 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (50 mg, 0.16 mmol) in THF (5 mL) was added glutaric anhydride (37 mg, 0.32 mmol), and the reaction mixture was heated at 50 ° C for 18 h. The resulting reaction mixture was concentrated in vacuo. Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 50 as a light yellow solid (52 mg, 77%).1 H NMR(400MHz, DMSO-d6)δ8.95–8.93(2H,m),8.09(1H,d,J=8.7Hz),7.87(1H, d,J=2.0Hz),7.82(2H,d,J=8.7Hz),7.70(1H,dd,J=8.7,2.0Hz),7.54(2H,d, J=8.7Hz),5.84(1H,dd,J=12.0,5.1Hz),3.96(1H,dd,J=18.2,12.1Hz),3.3 4–3.27(1H,m),2.89–2.75(2H,m),2.27(2H,t,J=7.4Hz),1.83–1.75(2H,m).

[0423] (E)-4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxylidenebut-2-enoic acid (Compound 51)

[0424]

[0425] To a stirred solution of monoethyl fumarate (70mg, 0.49mmol) in CH2Cl2 (5mL) was added oxalyl chloride (45μL, 0.52mmol), followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 4h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (5mL), and 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-yl)quinoxaline (100mg, 0.32mmol) was added thereto, followed by pyridine (32μL, 0.40mmol), and the reaction mixture was stirred at room temperature for 18h. The reaction was quenched with saturated NaHCO3 aqueous solution (5mL), and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The corresponding ethyl ester of compound 51 obtained by flash column chromatography (petroleum ether / EtOAc, 1:1) was a light yellow solid (103mg, 74%). 1H NMR (400MHz, DMSO-d6) δ8.83–8.82(2H,m),8.11(1H,d,J=8.7Hz),8.04(1H,d,J=15.5H z),7.98(1H,d,J=2.0Hz),7.74(2H,d,J=8.6Hz),7.68(1H,dd,J=8.7,2.1Hz),7.44(2H, d,J=8.5Hz),6.89(1H,d,J=15.6Hz),5.91(1H,dd,J=11.8,4.9Hz),4.29(2H,q,J=7.1H z), 3.92 (1H, dd, J = 17.8, 11.8 Hz), 3.29 (1H, dd, J = 17.9, 4.9 Hz), 1.34 (3H, t, J = 7.0 Hz).

[0426] To a stirred solution of the above ethyl ester (60 mg, 0.14 mmol) in THF / H2O (2.50 mL, 4:1 v / v) was added LiOH·H2O (12 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 18 h and then diluted with H2O (10 mL). The reaction mixture was acidified to approximately pH 1 by adding a 2M HCl aqueous solution and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain compound 51 as a yellow solid (29 mg, 51%). 1 H NMR (400MHz, CDCl3) δ8.84(2H,s),8.15–8.10(2H,m),8.00(1H,d,J=1.9Hz),7.75(2H,d,J=8.6Hz),7.69(1H,dd,J=8.9,2.0Hz),7.44 (2H,d,J=8.6Hz), 6.91(1H,d,J=16.0Hz), 5.92(1H,dd,J=11.7,4.8Hz), 3.93(1H,dd,J=17.8,11.8Hz), 3.31(1H,dd,J=17.9,5.0Hz).

[0427] (Z)-4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxylidenebut-2-enoic acid (Compound 52)

[0428]

[0429] To a stirred solution of 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (50 mg, 0.16 mmol) in THF (5 mL) was added maleic anhydride (32 mg, 0.32 mmol), and the reaction mixture was heated at 50° C. for 18 h. The resulting solid was collected by filtration and washed with THF to give compound 52 as a light yellow solid (55 mg, 83%). 1 HNMR(400MHz,DMSO-d6)δ8.95–8.93(2H,m),8.08(1H,d,J=9.1Hz),8.03–7.99(1H,m),7.82–7.77(3H, m),7.54(2H,d,J=8.4Hz),6.29–6.25(1H,m),5.90–5.85(1H,m),4.03–3.94(1H,m),3.34–3.26(1H,m).

[0430] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 53)

[0431]

[0432] To a solution of 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (200 mg, 0.647 mmol) and ethyl 4-oxobutanoate (101 mg, 0.777 mmol) in 1,2-dichloroethane (10 mL) was added sodium triacetoxyborohydride (165 mg, 0.777 mmol) at room temperature, and the reaction mixture was stirred for 72 h. The reaction mixture was then diluted with CH2Cl2 (10 mL) and washed with brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The corresponding ethyl ester of compound 53 was purified by flash column chromatography (petroleum ether / EtOAc, 7:3) as a yellow oil (40 mg, 15%). 1H NMR(500MHz, CDCl3)δ8.87–8.86(2H,m),8.14(1H,d,J=8.7Hz),8.11(1H,d,J=1.9Hz),7 .97(1H,dd,J=8.7,1.9Hz),7.59(2H,d,J=8.6Hz),7.34(2H,d,J=8.6Hz),4.55(1H,dd,J= 13.9,10.4Hz),4.05–3.99(2H,m),3.53(1H,dd,J=16.0,10.3Hz),3.04(1H,dd,J=16.0,1 3.7Hz),3.05–2.93(2H,m),2.48–2.32(2H,m),2.15–1.98(2H,m),1.15(3H,t,J=7.1Hz); 13 CNMR(125MHz,CDCl3)δ173.6(C),148.2(C),145.5(CH),145.2(CH),143.3(C),143.2(C),1 43.0(C),134.6(C),131.4(C),130.3(CH),129.4(CH),128.9(2xCH),128.4(CH),127.1(2x CH),71.4(CH),60.4(CH2),53.3(CH2),43.0(CH2),32.0(CH2),23.3(CH2),14.3(CH3).

[0433] To the above-mentioned ethyl ester (40mg, 0.095mmol) in EtOH / H in the solution of O (4mL, 3:1v / v) add lithium hydroxide (8.0mg, 0.19mmol), and at room temperature stirring reaction 18h.Then the reaction mixture obtained is concentrated in a vacuum and diluted with ethyl acetate (10mL).The organic layer is washed with water (10mL), then acidified to about pH 1 by adding the 1M HCl aqueous solution.Then the organic layer is concentrated in a vacuum to obtain compound 53 as a yellow solid (28mg, 75%). 1H NMR (500MHz, CDCl3) δ8.86–8.84(2H,m),8.14(1H,d,J=8.7Hz),8.12(1H,d,J= 1.9Hz),7.96(1H,dd,J=8.7,1.9Hz),7.59(2H,d,J=8.6Hz),7.35(2H,d,J=8.6 Hz),4.56(1H,dd,J=13.9,10.4Hz),3.55(1H,dd,J=16.0,10.3Hz),3.05(1H,d d,J=16.0,13.7Hz),3.07–2.95(2H,m),2.58–2.43(2H,m),2.18–1.96(2H,m); 13 C NMR(125MHz, CDCl3)δ176.4(C),148.7(C),145.4(CH),145.2(CH),143.1(C) ,143.0(C),142.9(C),134.8(C),131.2(C),130.3(CH),129.4(CH),129.0(2x CH),128.3(CH),127.2(2x CH),71.5(CH),52.8(CH2),42.9(CH2),31.4(CH2),23.2(CH2).

[0434] Ethyl 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate

[0435]

[0436] To a stirred solution of ethylsuccinyl chloride (94 μL, 0.66 mmol) in CHCl (5 mL) was added 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (200 mg, 0.648 mmol) followed by pyridine (63 μL, 0.78 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with saturated aqueous NH4Cl solution (5 mL), and the aqueous layer was separated and then extracted with CHCl. ​​The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound was purified by flash column chromatography (EtOAc, pure) to give a colorless solid (220 mg, 78%). 1HNMR (400MHz, CDCl3) δ8.83–8.81(2H,m),8.10(1H,d,J=8.7Hz),7.96(1H,d,J=2.0Hz),7.71–7.65(3H,m),7.41(2H,d,J=8.8Hz),5.82(1 H,dd,J=12.0,5.0Hz),4.12(2H,q,J=7.1Hz),3.85(1H,dd,J=17.7,12.0Hz),3.24–3.17(3H,m),2.74–2.62(2H,m),1.22(3H,t,J=7.1Hz).

[0437] Pivaloyloxymethyl 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutylidenebutanoate (Compound 54)

[0438]

[0439] At room temperature to compound 1 (50mg, 0.12mmol), chloromethyl pivalate (38mg, 0.25mmol) and NaI (38mg, 0.25mmol) in acetone (5mL) stirring mixture, add DIPEA (25 μ L, 0.14mmol), and the reaction mixture is stirred at room temperature for 18h, then add saturated NH4Cl aqueous solution (20mL) and EtOAc (20mL).Then the aqueous layer is separated and extracted with EtOAc, and the organic layer merged is through anhydrous Na2SO4 drying, filter and concentrate in a vacuum. Obtain compound 54 by flash column chromatography (petroleum ether / EtOAc, 1:1) purification is yellow residue (43mg, 68%). 1 H NMR (400MHz, CDCl3) δ8.83–8.82(2H,m),8.10(1H,d,J=8.7Hz),7.95(1H,d,J=2.0Hz),7.69(2H,d,J=8.6Hz),7.66(1H,dd,J=8.7,2.0Hz),7.41(2H ,d,J=8.6Hz),5.81(1H,dd,J=12.0,5.0Hz),5.76–5.72(2H,m),3.87(1H, dd,J=17.7,12.0Hz),3.25–3.18(3H,m),2.81–2.66(2H,m),1.17(9H,s).

[0440] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(methylsulfonyl)-4-oxylidenebutanamide (Compound 55)

[0441]

[0442] A solution of compound 1 (0.10 g, 0.24 mmol), methanesulfonamide (37 mg, 0.39 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (74 mg, 0.39 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with CHCl (20 mL), washed with 0.2 M aqueous HCl (2 x 20 mL), water (2 x 10 mL), then brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (CHCl / MeOH, 25:1) gave compound 55 as a light brown solid (50 mg, 42%). 1 H NMR (400MHz, CDCl3) δ8.82–8.81(2H,m),8.10(1H,d,J=8.7Hz),7.94(1H,d,J=2.0Hz),7.70–7.63(3H,m),7.43–7.40(2 H,m),5.85(1H,dd,J=11.8,4.7Hz),3.87(1H,dd,J=17.8,11.9Hz),3.32–3.17(3H,m),3.14(3H,s),2.68–2.53(2H,m); 13 C NMR(101MHz, CDCl3)δ171.7(C),170.5(C),154.5(C),145.6(CH),145.4(CH),143.2(C),143.0(C),142.7(C),137.2(C),130.9(CH),129.3(2× CH),129.3(C),128.2(2×CH),128.0(CH),126.0(CH),60.3(CH),42.3(CH2),41.4(CH3),31.4(CH2),29.1(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 22 H 20 ClN5NaO4S, calculated value, 508.0817; measured value, 508.0815.

[0443] 4-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(methylsulfonyl)-4-oxylidenebutanamide (Compound 57)

[0444]

[0445] Compound 57 was prepared by a method similar to that described for the preparation of compound 55 using compound 15 (0.15 g, 0.33 mmol), methanesulfonamide (60 mg, 0.67 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (0.13 g, 0.67 mmol) and 4-(dimethylamino)pyridine (DMAP) (50 mg, 0.40 mmol) in CHCl (3 mL). Purification by flash column chromatography (CHCl / MeOH, 20:1) gave compound 57 as a colorless solid (65 mg, 38%). 1 HNMR(400MHz,DMSO-d6)δ11.72(1H,br s),8.94–8.93(2H,m),8.09(1H,d,J=8.6Hz),7.92–7.90(3H,m),7.80–7.72(5H,m),7.51–7.38(3H,m),5.86(1H, dd,J=11.8,4.8Hz),4.02(1H,dd,J=18.1,12.0Hz),3.39–3.32(1H,m),3.20–3.00(5H,m),2.60(2H,t,J=6.5Hz); 13 C NMR(101MHz,DMSO-d6)δ172.0(C),169.0(C),154.3(C),146.0(CH),145.6(CH),144 .1(C),142.1(C),141.9(C),141.6(C),139.1(C),130.0(C),129.8(CH),129.0(2×CH ),128.1(CH),128.0(CH),127.4(2×CH),127.0(2×CH),126.7(2×CH),125.3(CH),59. 6(CH),41.8(CH2),40.8(CH3),30.1(CH2),28.1(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 25 N5NaO4S, calculated value, 550.1519; measured value, 550.1507.

[0446] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(N,N-dimethylsulfamoyl)-4-oxylidenebutanamide (Compound 59)

[0447]

[0448] Compound 59 was prepared by a method similar to that described for the preparation of compound 55 using compound 1 (0.10 g, 0.24 mmol), N,N-dimethylsulfonamide (45 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (69 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 59 as a colorless solid (98 mg, 79%). 1 H NMR (400MHz, CDCl3) δ9.00(1H,s),8.82(2H,s),8.10(1H,d,J=8.7Hz),7.95(1H,d,J=2.0Hz),7.68(2H,d,J=8.7Hz),7.65(1H,dd,J=8.7,2.0 Hz),7.41(2H,d,J=8.7Hz),5.84(1H,dd,J=11.9,4.8Hz),3.87(1H,dd,J=17.8,11.9Hz),3.34–3.13(3H,m),2.76(6H,s),2.67–2.54(2H,m); 13 C NMR(101MHz, CDCl3)δ171.0(C),170.3(C),154.1(C),145.6(CH),145.3(CH),143.4(C),143.1(C),142.7(C),137.1(C),130.8(CH),129.4(C), 129.3(2×CH),128.2(2×CH),128.1(CH),126.1(CH),60.3(CH),42.3(CH2),38.2(2×CH3),30.9(CH2),29.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 23 H 23 ClN6NaO4S, calculated value, 537.1082; measured value, 537.1083.

[0449] 3-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (Compound 60)

[0450]

[0451] To a suspension of 3-aminobenzoic acid (1.00 g, 7.29 mmol) in concentrated HCl (10 mL) was added dropwise sodium nitrite (601 mg, 8.75 mmol) in water (2.5 mL) at -5°C, and the reaction mixture was stirred for 1 h at -5°C. A solution of tin(II) chloride dihydrate (4.93 g, 21.9 mmol) in water (2.5 mL) was then added dropwise at -5°C, and the reaction mixture was further stirred for 2 h at -5°C. The resulting precipitated solid was collected by filtration, washed with water (10 mL), then diethyl ether (10 mL), and dried in vacuo to give 3-hydrazinobenzoic acid as a colorless solid (754 mg, 68%). 1 H NMR (400MHz, DMSO-d6) δ10.78(3H,s),8.43(1H,s),7.55(1H,s),7.48(1H,d,J=7.5Hz),7.38(1H,t,J=7.7Hz),7.21(1H,d,J=7.2Hz); 13 C NMR (101MHz, DMSO-d6) δ167.06(C), 146.28(C), 131.43(C), 129.04(C), 121.74(CH), 118.44(CH), 114.45(CH).

[0452] (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (0.20 g, 0.68 mmol) and 3-hydrazinobenzoic acid (0.10 g, 0.68 mmol) were stirred in AcOH / n The suspension was stirred for 4 h in BuOH (1:2 v / v, 15 mL) (then returned to room temperature). The reaction mixture was then concentrated in vacuo and the resulting residue was purified by flash column chromatography (CH2Cl2 / MeOH, 20:1) to afford compound 60 as a brown solid (60 mg, 21%). 1 H NMR (400MHz, CDCl3) δ9.94 (1H, br s),8.82(2H,s),8.10(2H,d,J=8.5Hz),7.81(1H,s),7.67(3H,m),7.50(1H,d,J=6.7Hz),7.35–7.20 (4H,m),5.58(1H,dd,J=11.5,6.3Hz),3.92(1H,dd,J=16.7,12.8Hz),3.19(1H,dd,J=17.1,6.4Hz); 13C NMR(101MHz, CDCl3)δ171.3(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(2×C),12 9.3(2×CH),129.0(CH),128.2(CH),127.2(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] + , C 24 H 18 ClN4O2, calculated value, 429.1113; measured value, 429.1123.

[0453] 3-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (Compound 61)

[0454]

[0455] (E)-1-([1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (0.30 g, 0.90 mmol) and 3-hydrazinobenzoic acid (0.14 g, 0.90 mmol) were stirred in AcOH / n To the suspension 4h in BuOH (1:2v / v, 18mL).Add the second portion of 3-hydrazinobenzoic acid (0.14g, 0.90mmol) and stir the mixture further at 120 ℃ for 2h.Then the reaction mixture is concentrated in a vacuum, and the residue obtained is diluted in EtOAc (50mL) and washed with water (2×30mL) and then brine (30mL), through anhydrous Na2SO4 drying, filtered and concentrated in a vacuum.By flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure→CH2Cl2 / MeOH, 9:1) purifying to obtain compound 61 is yellow solid (68mg, 16%). 1HNMR(400MHz,DMSO-d6)δ12.83(1H,br s),8.95–8.93(2H,m),8.13(1H,d,J=8.7Hz),8.04(1H,d,J=2.0Hz),7.90(2H,d,J=8.5Hz),7.81–7.71(6H,m),7.54–7.46(2H,m),7.42–7. 38(1H,m),7.37–7.23(3H,m),5.95(1H,dd,J=12.2,5.8Hz),4.11(1H,dd,J=17.6,12.3Hz),3.40–3.34(1H,m); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 30 H 23 N4O2, calculated value, 471.1816; measured value, 471.1812.

[0456] 5-(2-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxyylideneethyl)thiazolidine-2,4-dione (Compound 63)

[0457]

[0458] A solution of maleic anhydride (10.0 g, 102 mmol) and thiourea (7.76 g, 102 mmol) in concentrated HCl (30 mL) was heated under reflux for 5 h (then returned to room temperature). The precipitated solid was collected by filtration, washed with water (2×20 mL), and dried in vacuo to give 2-(2,4-dioxythiazolidin-5-yl)acetic acid as a transparent crystalline solid (10.6 g, 59%). 1 HNMR (400MHz, DMSO-d6) δ12.72 (1H, s), 11.99 (1H, s), 4.65 (1H, dd, J = 7.7, 4.7Hz), 3.01 (2H, m); 13 CNMR(101MHz,DMSO-d6)δ175.68(C),172.51(C),171.56(C),46.66(CH),35.96(CH2).

[0459] A solution of 2-(2,4-dioxythiazolidin-5-yl)acetic acid (3.50 g, 20.0 mmol) and SOCl2 (3.00 mL, 41.3 mmol) in dry 1,4-dioxane (12 mL) was heated under reflux for 5 h (then returned to room temperature). Hexane (50 mL) was then added to the reaction mixture, and the resulting precipitated solid was collected by filtration, washed with hexane (50 mL) and dried in vacuo to give 2-(2,4-dioxythiazolidin-5-yl)acetyl chloride (3.02 g, 78%) as an orange solid, which was used without further purification.

[0460] To a solution of 6-(3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)quinoxaline (420 mg, 1.36 mmol) in THF (13 mL) was added 2-(2,4-dioxythiazolidin-5-yl)acetyl chloride (527 mg, 2.72 mmol) followed by pyridine (0.16 mL, 2.04 mmol) (in single portions), and the reaction mixture was heated at reflux for 2 h (then returned to room temperature). Water (50 mL) was then added, and the resulting precipitated solid was collected by filtration, washed with CH2Cl2 / MeOH (1:1, 10 mL), CH2Cl2 (10 mL), EtOAc (10 mL), and then petroleum ether (10 mL), and dried in vacuo to afford compound 63 as an off-white solid (150 mg, 24%). 1 H NMR(400MHz, DMSO-d6)δ11.98(1H,s),8.93(2H,d,J=4.9Hz),8.09(1H,dd,J=8.6,6.2Hz),7.94–7.83(3H,m),7.75–7.69(1H, m),7.55(2H,d,J=8.5Hz),5.87(1H,m),4.69(1H,dd,J=9.7,3.3Hz),4.04–3.96(1H,m),3.85–3.71(1H,m),3.54–3.37(2H,m); 13C NMR(101MHz,DMSO-d6)δ176.0(C),172.8(C),172.7*(C),167.1(C),154.7(C),146.1*(CH),146.0(CH ),145.7*(CH),145.6(CH),143.6(C),143.5*(C),142.1(C),141.6(C),135.3(C),130.0(CH),129.9* (CH), 129.6 (C), 129.5* (C), 128.9 (2×CH), 128.7 (2×CH), 128.2 (CH), 128.1* (CH), 125.6 (CH), 125.4* (CH), 59.9 (CH), 59.8* (CH), 46.6* (CH), 46.5 (CH), 41.9 (CH2), 41.8* (CH2), 36.6 (CH2), 36.4* (CH2). * indicates the second stereoisomer. HRMS (ESI / Q-TOF) m / z: [M+H] + , C 22 H 17 ClN5O3S, calculated value, 466.0735; measured value, 466.0719.

[0461] 4-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 64)

[0462]

[0463] Compound 64 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (254 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a light yellow solid (296 mg); Step 2: (E)-1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (296 mg) and hydrazine hydrate (93 μL, 50% w / w) in THF (6 mL) were then added succinic anhydride (225 mg, 2.25 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 64 as a yellow solid (153 mg, 30% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.81–8.80(2H,m),8.10(1H,d,J=8.7Hz),7.99(1H,d,J=1.9Hz),7.79(2H, d,J=8.5Hz),7.68(1H,dd,J=8.7,2.0Hz),7.61(2H,d,J=8.5Hz),7.54(2H,d,J=8.8Hz),6.97(2H, d,J=8.8Hz),5.84(1H,dd,J=11.9,4.8Hz),4.60(1H,sevenfold,J=6.1Hz),3.90(1H,dd,J=17.7,11.9Hz ),3.34–3.24(2H,m),3.17(1H,dt,J=17.3,6.8Hz),2.75(2H,t,J=6.8Hz),1.37(6H,d,J=6.1Hz); 13C NMR(101MHz, CDCl3)δ176.4(C),170.3(C),158.2(C),154.4(C),145.3(CH),145.1(CH ),143.9(C),143.2(C),143.0(C),142.6(C),132.3(C),130.6(CH),129.2(C),128.3(2 ×CH),128.2(CH),127.4(2×CH),127.0(2×CH),125.9(CH),116.4(2×CH),70.2(CH),60 .2(CH),42.4(CH2),29.2(CH2),29.0(CH2),22.2(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 30 H 29 N4O4, calculated value, 509.2183; measured value, 509.2184.

[0464] 4-(3-(4'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 65)

[0465]

[0466] To a solution of compound 9 (77 mg, 0.17 mmol) in DMF / water (3.0 mL, 1:1 v / v) was added 4-(difluoromethoxy)phenylboronic acid (41 mg, 0.22 mmol), tripotassium phosphate (93 mg, 0.44 mmol) and palladium acetate (2.5 mg, 10 mol%). The reaction mixture was stirred at room temperature for 16 h. Water (15 mL) was added to the mixture and the suspension was acidified to approximately pH 2 by the addition of a 1 M aqueous HCl solution. The aqueous layer was then extracted with ethyl acetate (2 × 15 mL), and the combined organic layers were washed with water (3 × 15 mL) and then brine (15 mL), dried over anhydrous Na2SO4, filtered through celite and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→petroleum ether / EtOAc, 8:2→CH2Cl2, pure→CH2Cl2 / MeOH, 9:1) gave compound 65 as an off-white solid (25 mg, 28%).

[0467] 1H NMR (400MHz, CDCl3) δ8.82–8.81(2H,m),8.11(1H,d,J=8.7Hz),7.98(1H,d,J=2.0Hz ),7.83(2H,d,J=8.5Hz),7.68(1H,dd,J=8.7,2.0Hz),7.64–7.59(4H,m),7.22(2H,d ,J=9.0Hz),6.56(1H,t,J=73.7Hz),5.85(1H,dd,J=11.9,4.8Hz),3.92(1H,dd,J=17 .7,11.9Hz),3.36–3.26(2H,m),3.19(1H,dt,J=17.4,6.6Hz),2.76(2H,t,J=6.6Hz); 13 CNMR(75MHz, CDCl3)δ174.0(C),170.3(C),154.6(C),152.3(C),146.6(CH),146.2(CH),145.4(C),143.7(C),143.2(C),142. 3(C),137.9(C),131.6(C),130.9(CH),129.3(CH),128.9(CH),128.2(CH),127.9(CH),126.8(CH),120.3(CH),117.3(CH,t,J C-F =257.4Hz), 61.0(CH), 42.7(CH2), 29.8(CH2), 28.9(CH2).

[0468] 4-(3-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 66)

[0469]

[0470] To a solution of quinoxaline-6-carbaldehyde (237 mg, 1.50 mmol) and 1-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-one (348 mg, 1.50 mmol) in EtOH (12 mL) was added 2M NaOH (3.8 mL, 7.50 mmol) dropwise at room temperature, and the reaction mixture was stirred for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a light yellow solid (492 mg), which was used directly in the next step without further purification.

[0471] A mixture of (E)-1-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (300 mg) and hydrazine hydrate (0.10 mL, 50% w / w) in THF (6 mL) was stirred at reflux for 2 h. Succinic anhydride (242 mg, 2.42 mmol) was then added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2 x 30 mL) followed by brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting solid was washed with CHCl (10 mL) and isolated by filtration. Purification by flash column chromatography (CHCl, neat → CHCl / MeOH, 9:1) afforded compound 66 as an off-white solid (184 mg, 41% over 2 steps). 1 H NMR(400MHz,DMSO-d6)δ12.08(1H,s),8.94–8.92(2H,m),8.08(1H,d,J=8.7Hz),7.92– 7.86(5H,m),7.72(1H,dd,J=8.7,2.0Hz),7.56–7.49(2H,m),7.26(1H,tt,J=9.3,2.3H z),5.86(1H,dd,J=11.9,5.0Hz),4.02(1H,dd,J=18.2,12.0Hz),3.36(1H,dd,J=18.2, 5.1Hz), 3.12(1H,dt,J=17.1,6.7Hz), 2.99(1H,dt,J=17.2,6.5Hz), 2.53–2.50(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),162.9(2×C,dd,J C-F =245.8,13.7Hz),153.9(C),146.0(CH),145.6(CH),144.1(C),142.7(C,t,J C-F =9.8Hz),142.1(C),141.6(C),139.1(C),131.2(C),129.8(CH),128.1(CH),127.4(2×CH),127.2(2×CH),125.4(CH),109.8(2×CH,dd,J C-F =18.8,7.0Hz),103.2(CH,t,J C-F=25.9Hz),59.7(CH),41.7(CH2),28.8(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 21 F2N4O3, calculated value, 487.1576; measured value, 487.1576.

[0472] 4-(3-(3'-Fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 67)

[0473]

[0474] Compound 67 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (316 mg, 2.00 mmol), 1-(3'-fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (596 mg, 2.00 mmol) and 2M NaOH (5.0 mL, 10.0 mmol) in EtOH (16 mL) was added to give (E)-1-(3'-fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (798 mg); Step 2: (E)-1-(3'-fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (400 mg) and hydrazine hydrate (0.11 mL, 50% w / w) in THF (7 mL) was followed by the addition of succinic anhydride (274 mg, 2.74 mmol). Purification by flash column chromatography (CH2Cl2, neat→CH2Cl2 / MeOH, 95:5) gave compound 67 as an off-white solid (171 mg, 31% over 2 steps). 1H NMR (400MHz, CDCl3) δ8.82(2H,s),8.11(1H,d,J=8.7Hz),7.99(1H,s),7.85(2H,d,J=8.2Hz),7.68(1H,dd,J=8.8,2.0Hz),7.61(2H,d,J=8.1Hz),7.4 6–7.40(3H,m),5.86(1H,dd,J=11.9,4.9Hz),3.92(1H,dd,J=17.7,12.0Hz ),3.33–3.25(2H,m),3.19(1H,dt,J=17.3,6.8Hz),2.76(2H,t,J=6.8Hz); 13 C NMR(101MHz,CDCl3)δ176.8(C),170.3(C),154.8(C,d,J C-F =253.0Hz),153.8(C),145.3(CH),145.1(CH),143.8(C),143.0(C),142.6(C),140.84(C,d,J C-F =2.0Hz),140.83(C,d,J C-F =6.7Hz),136.2(C,dq,J C-F =12.7,2.2Hz),131.0(C),130.6(CH),128.2(CH),127.6(2×CH),127.5(2×CH),125.8(CH),124.2(CH),123.2(CH,d,J C-F =3.6Hz),120.6(C,q,J C-F =258.8Hz),116.0(CH,d,J C-F =19.4Hz),60.3(CH),42.3(CH2),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 28 H 21 F4N4O4, calculated value, 553.1493; measured value, 553.1494.

[0475] 4-(3-([1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(methylsulfonyl)-4-oxylidenebutanamide (Compound 68)

[0476]

[0477] Compound 68 was prepared according to a method similar to that described for the preparation of compound 55 using compound 13 (45 mg, 0.10 mmol), methanesulfonamide (14 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (29 mg, 0.15 mmol) and 4-(dimethylamino)pyridine (DMAP) (15 mg, 0.12 mmol) in CHCl (1.0 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure) gave compound 68 as a yellow solid (14 mg, 26%). 1 H NMR (400MHz, DMSO-d6) δ11.71(1H,s),8.94–8.92(2H,m),8.09(1H,d,J=8.7Hz),8.02(1H,s),7.92(1H,d,J=1 .8Hz),7.87(1H,d,J=7.9Hz),7.78(1H,d,J=7.8Hz),7.75–7.72(3H,m),7.58(1H,t,J=7.8Hz),7.48(2H,t,J= 7.5Hz),7.39(1H,t,J=7.3Hz),5.87(1H,dd,J=12.0,5.0Hz),4.05(1H,dd,J=18.3,12.0Hz),3.47(1H,dd,J=1 8.3,5.0Hz),3.19(1H,dt,J=17.2,6.6Hz),3.14(3H,s),3.05(1H,dt,J=17.2,6.8Hz),2.60(2H,t,J=6.6Hz); 13 C NMR(101MHz,DMSO-d6)δ172.0(C),169.1(C),154.7(C),146.0(CH),145.6(CH),144.1(C ),142.1(C),141.6(C),140.7(C),139.4(C),131.6(C),129.8(CH),129.4(CH),129.0(2× CH),128.7(CH),128.2(CH),127.8(CH),126.9(2×CH),125.6(CH),125.3(CH),125.2(CH ),59.6(CH),41.8(CH2),40.8(CH3),30.1(CH2),28.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 28 H 26 N5O4S, calculated value, 528.1700; measured value, 528.1706.

[0478] 4-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(isopropylsulfonyl)-4-oxylidenebutanamide (Compound 69)

[0479]

[0480] Compound 69 was prepared according to a method similar to that described for the preparation of compound 55 using compound 15 (40 mg, 0.090 mmol), propane-2-sulfonamide (17 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (26 mg, 0.14 mmol) and 4-(dimethylamino)pyridine (DMAP) (13 mg, 0.11 mmol) in CHCl (0.9 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 69 as a colorless solid (19 mg, 38%). 1 H NMR (400MHz, CDCl3) δ8.84–8.83(2H,m),8.12(1H,d,J=8.7Hz),7.97(1H,d,J=2.0Hz),7.83(2H,d,J=8.7 Hz),7.69–7.62(5H,m),7.49–7.45(2H,m),7.42–7.37(1H,m),5.86(1H,dd,J=11.8,4.7Hz),3.94(1H,dd ,J=17.7,11.8Hz),3.65(1H,sevenfold,J=6.9Hz),3.38(1H,ddd,J=18.1,7.8,4.5Hz),3.31(1H,dd,J=17.8,4.7 Hz), 3.23 (1H, ddd, J = 18.1, 8.2, 4.6Hz), 2.74–2.61 (2H, m), 1.31 (3H, d, J = 6.9Hz), 1.17 (3H, d, J = 6.9Hz); 13C NMR(101MHz, CDCl3)δ171.6(C),170.4(C),155.2(C),145.5(CH),145.3(CH),143.8(C), 143.5(C),143.1(C),142.7(C),140.1(C),130.8(CH),129.6(C),129.1(2×CH),128.2(CH ),128.1(CH),127.6(2×CH),127.5(2×CH),127.2(2×CH),126.1(CH),60.2(CH),53.8(CH) ,42.4(CH2),31.6(CH2),29.4(CH2),16.0(CH3),15.7(CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 30 H 30 N5O4S, calculated value, 556.2013; measured value, 556.2027.

[0481] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxyylidene-N-(phenylsulfonyl)butanamide (Compound 70)

[0482]

[0483] Compound 70 was prepared according to a method similar to that described for the preparation of compound 55 using compound 1 (0.10 g, 0.24 mmol), benzenesulfonamide (75 mg, 0.48 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (92 mg, 0.48 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2.4 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure) gave compound 70 as a colorless solid (74 mg, 56%). 1H NMR(400MHz,DMSO-d6)δ12.11(1H,s),8.95–8.93(2H,m),8.06(1H,d,J=8.7Hz) ,7.89–7.87(3H,m),7.80(2H,d,J=8.7Hz),7.66(1H,dd,J=8.7,2.0Hz),7.64–7 .60(1H,m),7.54–7.50(4H,m)5.78(1H,dd,J=11.9,5.1Hz),3.94(1H,dd,J=18. 3,12.0Hz),3.29(1H,dd,J=18.3,5.2Hz),3.04–3.89(2H,m),2.59–2.51(2H,m); 13 C NMR(101MHz,DMSO-d6)δ170.8(C),168.9(C),153.6(C),146.0(CH),145.6(CH),1 44.0(C),142.1(C),141.6(C),139.5(C),135.0(C),133.4(CH),129.81(CH),129. 79(C),129.0(2×CH),128.9(2×CH),128.5(2×CH),128.1(CH),127.3(2×CH),125. 4(CH),59.7(CH),41.6(CH2),30.0(CH2),27.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 23 ClN5O4S, calculated value, 548.1154; measured value, 548.1154.

[0484] 4-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(N,N-dimethylsulfamoyl)-4-oxylidenebutanamide (Compound 71)

[0485]

[0486] Compound 71 was prepared according to a method similar to that described for the preparation of compound 55 using compound 15 (40 mg, 0.090 mmol), N,N-dimethylsulfonamide (17 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (26 mg, 0.14 mmol) and 4-(dimethylamino)pyridine (DMAP) (13 mg, 0.11 mmol) in CHCl (0.9 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure) gave compound 71 as a colorless solid (22 mg, 44%). 1 H NMR(300MHz,DMSO-d6)δ11.36(1H,s),8.94–8.92(2H,m),8.08(1H,d,J=8.7Hz),7.93–7.90( 3H,m),7.80(2H,d,J=8.4Hz),7.75–7.72(3H,m),7.50(2H,t,J=7.4Hz),7.40(1H,t,J=7.3Hz ),5.85(1H,dd,J=11.8,4.8Hz),4.02(1H,dd,J=18.2,12.0Hz),3.37(1H,dd,J=18.3,5.0Hz) ,3.18(1H,dt,J=17.0,6.5Hz),3.00(1H,dt,J=17.2,6.2Hz),2.62(6H,s),2.59–2.53(2H,m); 13 C NMR(75MHz,DMSO-d6)δ171.2(C),169.0(C),154.2(C),145.9(CH),145.6(CH),144. 1(C),142.1(C),141.9(C),141.6(C),139.1(C),130.0(C),129.8(CH),129.0(2×CH) ,128.2(CH),128.0(CH),127.4(2×CH),126.9(2×CH),126.7(2×CH),125.4(CH),59.6 (CH),41.7(CH2),37.7(2×CH3),29.6(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 29 H 29 N6O4S, calculated value, 557.1966; measured value, 557.1964.

[0487] 3-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(methylsulfonyl)benzamide (Compound 72)

[0488]

[0489] Compound 72 was prepared according to a method similar to that described for the preparation of compound 55 using compound 25312 (21 mg, 0.050 mmol), methanesulfonamide (9.5 mg, 0.10 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (19 mg, 0.10 mmol) and 4-(dimethylamino)pyridine (DMAP) (7.3 mg, 0.060 mmol) in CHCl (0.7 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure) gave compound 72 as a yellow solid (9.6 mg, 38%). 1 H NMR(400MHz, CDCl3)δ8.83(2H,s),8.10(1H,d,J=8.7Hz),8.00(1H,d,J=1.7Hz),7.69–7.65(4H,m),7.37(2H,d,J=8.6Hz), 7.24–7.13(3H,m),5.59(1H,dd,J=12.3,6.4Hz),3.97(1H,dd,J=17.2,12.4Hz),3.39(3H,s),3.23(1H,dd,J=17.3,6.4Hz); 13 C NMR(101MHz, CDCl3)δ165.7(C),147.4(C),145.7(CH),145.4(CH),144.8(C),1 43.5(C),143.2(C),142.8(C),135.4(C),132.2(C),131.4(CH),130.5(C),129. 9(CH),129.1(2×CH),127.8(CH),127.4(2×CH),126.5(CH),118.3(CH),118.0( CH),112.8(CH),63.9(CH),43.5(CH2),41.9(CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 25 H 21 ClN5O3S, calculated value, 506.1048; measured value, 506.1057.

[0490] 4-(7-Chloro-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-yl)-4-oxobutanoic acid (Compound 73)

[0491]

[0492] Compound 73 was prepared over 3 steps using a method similar to that described for the preparation of compound 3: Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 6-chloro-1-tetralone (220 mg, 1.22 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-6-chloro-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one as a beige solid (360 mg); Step 2: (E)-6-chloro-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (360 mg) and hydrazine hydrate (0.14 mL, 50% w / v) 4-nitropropane; 7-chloro-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (120 mg) and succinic anhydride (72 mg, 0.72 mmol) in THF (5 mL) were added to give 7-chloro-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole as a light brown solid (120 mg). Step 3: 7-chloro-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (120 mg) and succinic anhydride (72 mg, 0.72 mmol) in THF (5 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 73 as a colorless solid (22 mg, 4% over 3 steps). 1 H NMR (400MHz, CDCl3) δ8.84–8.83(2H,m),8.14(1H,d,J=8.7Hz),8.04(1H,d,J=2.0Hz),7.94(1H,d,J=8.4Hz),7.73(1H,dd,J=8.7,2.1Hz),7 .30–7.21(2H,m),5.22(1H,d,J=9.6Hz),3.35–3.15(3H,m),2.96–2.92(2H,m),2.72(2H,t,J=6.6Hz),2.41–2.36(1H,m),2.15-2.04(1H,m).

[0493] 4-Oxylidene-4-(8-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-yl)butanoic acid (Compound 74)

[0494]

[0495] To a solution of quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol) and 7-phenyl-1-tetralone (280 mg, 1.26 mmol) in EtOH (12 mL) was added 2M NaOH (3.2 mL, 6.32 mmol) dropwise at room temperature, and the reaction mixture was stirred for 2 h. The resulting precipitated solid was then collected by filtration, washed with H O, and dried in vacuo to give (E)-7-phenyl-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one as a light brown solid (420 mg), which was used in the next step without further purification.

[0496] To a stirred solution of (E)-7-phenyl-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (100 mg) in EtOH (5 mL) was added hydrazine hydrate (0.10 mL, 50% w / w), and the reaction mixture was heated at reflux for 3 h. The solvent was then removed in vacuo, the residue poured into ice water, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 8-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole as a yellow solid (100 mg), which was used in the next step without further purification.

[0497] In a sealed vial, a mixture of 8-phenyl-3-(quinoxaline-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (100 mg) and succinic anhydride (200 mg, 2.00 mmol) in THF (4 mL) was subjected to microwave irradiation at 120 ° C for 45 min. The resulting reaction mixture was diluted with CH2Cl2 (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with water (3×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (CH2Cl2 / MeOH, 25:1) gave compound 74 as a light brown solid (30 mg, 21% over 3 steps). 1H NMR (400MHz, CDCl3) δ8.83–8.81(2H,m),8.22(1H,d,J=1.9Hz),8.14(1H,d,J=8.7Hz),8.06(1H,d ,J=1.8Hz),7.75(1H,dd,J=8.7,1.9Hz),7.66-7.63(2H,m),7.59(1H,dd,J=8.0,2.0Hz),7.47(2H ,t,J=7.6Hz),7.40-7.35(1H,m),7.26(1H,d,J=8.0Hz),5.24(1H,d,J=9.6Hz),3.36-3.29(1H,m) ,3.27-3.14(2H,m),3.05-2.91(2H,m),2.78-2.70(2H,m),2.42-2.37(1H,m),2.14-2.03(1H,m); 13 C NMR(101MHz, CDCl3)δ176.7(C),171.6(C),155.8(C),145.2(CH),144.8(CH),143.6(C),14 3.0(C),142.4(C),140.1(C),140.0(C),138.3(C),130.4(CH),129.6(CH),129.5(CH),128 .9(CH),127.9(2×CH),127.7(CH),127.4(C),127.1(2×CH),126.0(CH),123.4(CH),67.6(C H),55.6(CH),29.3(CH2),29.0(CH2),28.8(CH2),27.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 29 H 24 N4NaO3, calculated value, 499.1741; measured value, 499.1740.

[0498] 4-Oxylidene-4-(7-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-yl)butanoic acid (Compound 75)

[0499]

[0500] To a solution of quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol) and 6-phenyl-1-tetralone (280 mg, 1.26 mmol) in EtOH (10 mL) was added 2M NaOH (3.2 mL, 6.32 mmol) dropwise at room temperature, and the reaction mixture was stirred at room temperature for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-6-phenyl-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one as an off-white solid (315 mg), which was used directly in the next step without further purification.

[0501] To a stirred solution of (E)-6-phenyl-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (315 mg) in EtOH (7 mL) was added hydrazine hydrate (0.16 mL, 50% w / w), and the reaction mixture was heated at reflux for 2 h. The solvent was then removed in vacuo and the resulting residue was poured into ice-water, collected by filtration, and dried in vacuo to give 7-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole as an off-white solid (262 mg), which was used in the next step without further purification.

[0502] In a sealed vial, a mixture of 7-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (262 mg) and succinic anhydride (139 mg, 1.39 mmol) in THF (5 mL) was subjected to microwave irradiation at 120°C for 45 min. The resulting reaction mixture was diluted with CHCl (20 mL), washed with H0 (20 mL), and the separated aqueous layer was further extracted with CHCl (3 x 30 mL). The combined organic layers were washed with H0 (3 x 30 mL) and then brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by flash column chromatography (EtOAc, neat → CHCl / MeOH, 9:1) gave compound 75 as an off-white solid (192 mg, 32% over 3 steps). 1H NMR(400MHz,DMSO-d6)δ12.09(1H,br s),8.98–8.95(2H,m),8.11(1H,d,J=8.7Hz),8.05(1H,d,J=2.0Hz,),8.01(1H,d,J=8.1Hz), 7.85(1H,dd,J=8.7,2.0Hz),7.74–7.71(2H,m),7.66(1H,dd,J=8.2,1.9Hz),7.61(1H,d,J=1. 8Hz),7.50(2H,t,J=7.5Hz),7.43–7.39(1H,m),5.31(1H,d,J=10.1Hz),3.45(1H,ddd,J=13. 1,10.1,4.9Hz),3.12–2.95(4H,m),2.52–2.48(2H,m),2.37–2.29(1H,m),2.13–2.02(1H,m); 13 C NMR(101MHz,DMSO-d6)δ173.8(C),170.7(C),155.0(C),145.9(CH),145.4(CH),143.9(C),1 42.2(C),141.9(C),141.6(C),140.5(C),139.3(C),129.5(CH),129.0(2×CH),128.3(CH),1 28.0(CH),127.3(CH),126.7(2×CH),126.0(C),125.7(CH),125.03(CH),124.98(CH),66.7( CH),54.5(CH),29.0(CH2),28.7(CH2),28.4(CH2),27.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 29 H 24 N4NaO3, calculated value, 499.1741; measured value, 499.1728.

[0503] 4-Oxylidene-4-(3-(quinoxalin-6-yl)-7-(4-(trifluoromethoxy)phenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-yl)butanoic acid (Compound 76)

[0504]

[0505] Compound 76 was prepared over 3 steps using a procedure analogous to that described for the preparation of compound 75: Step 1: Quinoxaline-6-carbaldehyde (237 mg, 1.50 mmol), 6-(4-(trifluoromethoxy)phenyl)-1-tetralone (459 mg, 1.50 mmol) and 2M NaOH (3.8 mL, 7.50 mmol) in EtOH (12 mL) gave (E)-2-(quinoxalin-6-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydronaphthalen-1(2H)-one as a beige solid (462 mg); Step 2: (E)-2-(quinoxalin-6-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydronaphthalen-1(2H)-one (300 mg) and hydrazine hydrate (0.12 mL, 50% w / v) 4% dextrose; 3-(quinoxalin-6-yl)-7-(4-(trifluoromethoxy)phenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (310 mg) and succinic anhydride (100 mg, 1.00 mmol) in THF (4 mL) were added to give 3-(quinoxalin-6-yl)-7-(4-(trifluoromethoxy)phenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole as a yellow solid (310 mg); and Step 3: 3-(quinoxalin-6-yl)-7-(4-(trifluoromethoxy)phenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (310 mg) and succinic anhydride (100 mg, 1.00 mmol) in THF (4 mL). Purification by flash column chromatography (CHCl / MeOH, 20:1) gave compound 76 as a beige solid (150 mg, 28% over 3 steps). 1 H NMR (400MHz, CDCl3) δ8.81 (2H, s), 8.15-8.07 (3H, m), 7.75 (1H, d, J = 8.7Hz) ,7.62-7.59(2H,m),7.50(1H,dd,J=8.1,1.4Hz),7.38(1H,s),7.29(2H,d,J =8.1Hz),5.24(1H,d,J=9.7Hz),3.36-3.12(3H,m),3.05-2.94(2H,m),2.73 (2H,s),2.43-2.39(1H,m),2.15-2.04(1H,m); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 23 F3N4NaO4, calculated value, 583.1564; measured value, 583.1564.

[0506] 4-(5-(4-Chlorophenyl)-3-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 77)

[0507]

[0508] Compound 77 was prepared over 3 steps using a method similar to that described for the preparation of compound 3 - Step 1: 4-chlorobenzaldehyde (163 mg, 1.16 mmol), 1-(quinoxalin-6-yl)ethanone (200 mg, 1.16 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (12 mL) to give (E)-3-(4-chlorophenyl)-1-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (200 mg); Step 2: (E)-3-(4-chlorophenyl)-1-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid (200 mg) and hydrazine hydrate (85 μL, 5 μL) 0% w / w) in EtOH (8 mL) to give 6-(5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)quinoxaline as a yellow solid (150 mg); and Step 3: 6-(5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)quinoxaline (150 mg) and succinic anhydride (97 mg, 0.97 mmol) in THF (5 mL). Purification by flash column chromatography (EtOAc, neat → CH2Cl2 / MeOH, 9:1) gave compound 77 as a colorless solid (22 mg, 5% over 3 steps). 1 HNMR(400MHz,DMSO-d6)δ12.15(1H,br s),9.00–8.98(2H,m),8.41(1H,dd,J=8.8,1.9Hz),8.30(1H,d,J=1.8Hz),8.17(1H,d,J=8.8Hz),7.38(2H,d,J=8.5Hz),7.28(2H, d,J=8.5Hz), 5.63(1H,dd,J=12.0,5.0Hz), 4.07–3.99(1H,m), 3.37(1H,dd,J=18.2,5.0Hz), 3.12–2.95(2H,m), 2.54–2.50(2H,m).

[0509] 4-Oxylidene-4-(3-(4'-propoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 78)

[0510]

[0511] Compound 78 was prepared over 2 steps using a method similar to that described for the preparation of compound 1A - Step 1: Quinoxaline-6-carboxaldehyde (100 mg, 0.632 mmol), 1-(4'-propoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (161 mg, 0.632 mmol) and 2M NaOH (1.6 mL, 3.16 mmol) in EtOH (5 mL) gave (E)-1-(4'-propoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a yellow solid (249 mg); Step 2: (E)-1-(4'-propoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (249 mg) and hydrazine hydrate (79 μL, 50% w / w) in THF (5 mL) were then added succinic anhydride (190 mg, 1.90 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → CH2Cl2 / MeOH 9:1) gave compound 78 as a yellow solid (83.6 mg, 26% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.81–8.80(2H,m),8.10(1H,d,J=8.7Hz),7.99(1H,d,J=2.0Hz),7.79(2H,d,J=8 .5Hz),7.67(1H,dd,J=8.8,2.0Hz),7.61(2H,d,J=8.5Hz),7.55(2H,d,J=8.8Hz),6.98(2H,d,J=8.8Hz ),5.83(1H,dd,J=11.9,4.9Hz),3.97(2H,t,J=6.6Hz),3.90(1H,dd,J=17.7,11.9Hz),3.35–3.23(2H, m), 3.18 (1H, dt, J = 17.3, 6.8Hz), 2.75 (2H, t, J = 6.7Hz), 1.84 (2H, sixfold, J = 7.1Hz), 1.06 (3H, t, J = 7.4Hz); 13CNMR(101MHz, CDCl3)δ176.4(C),170.4(C),159.5(C),154.5(C),145.4(CH),145.1(CH), 143.9(C),143.3(C),143.0(C),142.6(C),132.4(C),130.6(CH),129.2(C),128.24(2×CH) ,128.19(CH),127.4(2×CH),127.0(2×CH),125.9(CH),115.1(2×CH),69.8(CH2),60.2(CH) ,42.4(CH2),29.2(CH2),29.0(CH2),22.7(CH2),10.7(CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 28 N4NaO4, calculated value, 531.2003; measured value, 531.2003.

[0512] 4-(3-(4'-Ethoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 79)

[0513]

[0514] Compound 79 was prepared in 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (79 mg, 0.5 mmol), 1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (113 mg, 0.5 mmol) and 2M NaOH (1.0 mL, 2.0 mmol) in EtOH (4 mL) to give (E)-1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (25 μL, 50% w / w) in THF (2 mL) were then added succinic anhydride (50 mg, 0.5 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 79 as a colorless solid (6 mg, 3% over 2 steps); 1H NMR (400MHz, CDCl3) δ8.83–8.80 (2H, m), 8.11 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 1.7Hz), 7.84–7.79(2H,m),7.70–7.66(1H,m),7.64–7.60(2H,m),7.58–7.53(2H,m),7.05–6.9 6(2H,m),5.84(1H,dd,J=11.8,4.1Hz),4.12–4.04(2H,m),3.91(1H,dd,J=17.5,11.8H z),3.35–3.25(2H,m),3.22–3.14(1H,m),2.75(2H,t,J=6.8Hz),1.45(3H,t,J=7.1Hz); 13 C NMR(101MHz, CDCl3)δ175.6(C),170.4(C),159.2(C),154.6(C),145.3(CH),14 5.1(CH),143.7(C),143.2(C),143.0(C),142.6(C),132.3(C),130.6(CH),129 .1(C),128.2(2×CH),128.1(CH),127.3(2×CH),126.9(2×CH),125.5(CH),115. 0(2×CH),63.7(CH2),60.1(CH),42.3(CH2),29.8(CH2),29.1(CH2),14.9(CH3).

[0515] 4-(3-(4'-Butoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 80)

[0516]

[0517] Compound 80 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (210 mg, 1.33 mmol), 1-(4'-butoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (357 mg, 1.33 mmol) and 2M NaOH (3.3 mL, 6.65 mmol) in EtOH (10.5 mL) was added to give (E)-1-(4'-butoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a light yellow solid without further purification (464 mg); Step 2: (E)-1-(4'-butoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (464 mg) and hydrazine hydrate (150 μL, 50% w / w, 2.28 mmol) in THF (9 mL) was followed by the addition of succinic anhydride (342 mg, 3.42 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → EtOAc / MeOH, 19:1) gave compound 80 as a yellow solid (179 mg, 26% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.82–8.81 (2H, m), 8.11 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 1.9Hz), 7.80 (2H, dt, J = 8. 8,1.9Hz),7.68(1H,dt,J=8.7,2.0Hz),7.62(2H,dt,J=8.6,1.9Hz),7.55(2H,dt,J=9.4,2.5Hz),6.98(2 H,dt,J=9.4,2.5Hz),5.84(1H,dd,J=11.9,4.8Hz),4.01(2H,t,J=6.5Hz),3.92(1H,dd,J=17.7,11.8Hz) ,3.35–3.15(3H,m),2.76(2H,t,J=6.7Hz),1.83–1.76(2H,m),1.56–1.47(2H,m),0.99(3H,t,J=7.4Hz); 13C NMR(101MHz, CDCl3)δ175.8(C),170.5(C),159.5(C),154.6(C),145.4(CH),145.1(CH),143. 8(C),143.3(C),143.1(C),142.7(C),132.3(C),130.7(CH),129.1(C),128.25(2×CH),128.1 7(CH),127.4(2×CH),127.0(2×CH),125.9(CH),115.1(2×CH),68.2(CH2),60.2(CH),42.4(CH 2),31.5(CH2),29.2(CH2),29.0(CH2),19.4(CH2),14.0(CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 31 H 30 N4NaO4, calculated value, 545.2159; measured value, 545.2160.

[0518] 4-(3-(4'-(tert-Butoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 81)

[0519]

[0520] Compound 81 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 1-(4'-(tert-butoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (339 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.32 mmol) in EtOH (10 mL) gave (E)-1-(4'-(tert-butoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (422 mg); Step 2: (E)-1-(4'-(tert-butoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (422 mg) and hydrazine hydrate (0.13 mL, 50% w / w) in THF (8 mL) were then added succinic anhydride (310 mg, 3.10 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 81 as a yellow solid (151 mg, 23% over 2 steps). 1H NMR (400MHz, CDCl3) δ8.81–8.79(2H,m),8.10(1H,d,J=8.7Hz),7.99(1H,d,J=2.1Hz),7 .80(2H,d,J=8.5Hz),7.67(1H,dd,J=8.7,2.0Hz),7.63(2H,d,J=8.5Hz),7.52(2H,d,J=8 .6Hz),7.07(2H,d,J=8.6Hz),5.83(1H,dd,J=11.9,4.9Hz),3.90(1H,dd,J=17.7,11.9H z),3.32–3.23(2H,m),3.18(1H,dt,J=17.2,6.8Hz),2.75(2H,t,J=6.8Hz),1.39(9H,s); 13 C NMR(101MHz, CDCl3)δ176.8(C),170.3(C),155.8(C),154.3(C),145.3(CH),145.1(CH) ,143.9(C),143.1(C),143.0(C),142.5(C),135.0(C),130.6(CH),129.5(C),128.2(CH ),127.7(2×CH),127.4(2×CH),127.2(2×CH),125.9(CH),124.5(2×CH),79.0(C),60.2( CH),42.3(CH2),29.2(CH2),29.03(3×CH3),28.96(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 31 H 30 N4NaO4, calculated value, 545.2159; measured value, 545.2154.

[0521] 4-(3-(4'-Isobutoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 82)

[0522]

[0523] Compound 82 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (79 mg, 0.5 mmol), 1-(4'-cyclopropyloxy-[1,1'-biphenyl]-4-yl)ethan-1-one (134 mg, 0.5 mmol) and 2M NaOH (1.0 mL, 2.0 mmol) in EtOH (4 mL) to give (E)-1-(4'-isobutoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-isobutoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (25 μL, 50% w / w) in THF (2 mL) were then added succinic anhydride (50 mg, 0.5 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 82 as a colorless solid (60 mg, 23% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.83–8.79(2H,m),8.12(1H,d,J=8.7Hz),7.99(1H,d,J=1.7Hz),7.8 1–7.78(2H,m),7.67(1H,dd,J=8.8,1.9Hz),7.63–7.59(2H,m),7.56–7.52(2H,m),7.04–6 .92(2H,m),5.84(1H,dd,J=11.5,4.8Hz),3.90(1H,dd,J=17.5,12.0Hz),3.77(2H,d,J=6. 4Hz),3.36–3.12(3H,m),2.75(2H,t,J=6.7Hz),2.17–2.06(1H,m),1.04(6H,d,J=6.5Hz); 13 C NMR(101MHz, CDCl3)δ176.4(C),170.3(C),159.5(C),154.3(C),145.3(CH),145.0(CH),1 43.8(C),143.2(C),142.9(C),142.5(C),132.2(C),130.5(CH),129.1(C),128.09(2×CH), 128.05(CH),127.3(2×CH),126.9(2×CH),125.8(CH),115.1(2×CH),74.6(CH2),60.1(CH), 42.3(CH2),29.1(CH2),28.9(CH2),28.3(CH),19.3(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+Na]+ , C 31 H 30 N4NaO4, calculated value, 545.2159; measured value, 545.2160.

[0524] 4-(3-(4'-(sec-butoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 83)

[0525]

[0526] Compound 83 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (184 mg, 1.16 mmol), 1-(4'-(sec-butoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (312 mg, 1.16 mmol) and 2M NaOH (2.9 mL, 5.80 mmol) in EtOH (9 mL) was added to give (E)-1-(4'-(sec-butoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid without further purification (400 mg); Step 2: (E)-1-(4'-(sec-butoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (400 mg) and hydrazine hydrate (122 μL, 50% w / w, 1.96 mmol) in THF (8 mL) was followed by the addition of succinic anhydride (294 mg, 2.94 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 83 as a beige solid (147 mg, 24% over 2 steps). 1H NMR (400MHz, CDCl3) δ8.82–8.81(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=1.9Hz),7.80–7.78(2H,m), 7.68(1H,dd,J=8.7,2.1Hz),7.63–7.60(2H,m),7.54(2H,dt,J=9.4,2.5Hz), 6.97(2H,dt,J=9.4,2.5Hz), 5.84 (1H, dd, J = 11.9, 4.8 Hz), 4.35 (1H, sextet, J = 6.0 Hz), 3.91 (1H, dd, J = 17.7, 11.9 Hz), 3.34–3.14 (3H, m), 2.75 (2H, t, J = 6.7 Hz), 1.81–1.73 (1H, m), 1.70–1.61 (1H, m), 1.33 (3H, d, J = 6.1 Hz), 1.00 (3H, t, J = 7.4 Hz); 13 C NMR(101MHz, CDCl3)δ176.2(C),170.4(C),158.6(C),154.5(C),145.3(CH),145.1(CH),143 .9(C),143.3(C),143.0(C),142.6(C),132.2(C),130.6(CH),129.1(C),128.3(2×CH),128. 2(CH),127.4(2×CH),127.0(2×CH),125.9(CH),116.4(2×CH),75.3(CH),60.2(CH),42.4(CH 2),29.3(CH2),29.2(CH2),29.0(CH2),19.4(CH3),9.9(CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 31 H 30 N4NaO4, calculated value, 545.2159; measured value, 545.2160.

[0527] 4-(3-(4'-cyclopropyloxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 84)

[0528]

[0529] Compound 84 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (79 mg, 0.5 mmol), 1-(4'-cyclopropyloxy-[1,1'-biphenyl]-4-yl)ethan-1-one (102 mg, 0.4 mmol) and 2M NaOH (1.0 mL, 2.0 mmol) in EtOH (4 mL) to give (E)-1-(4'-cyclopropyloxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-cyclopropyloxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (25 μL, 50% w / w) in THF (2 mL) were then added succinic anhydride (50 mg, 0.5 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 84 as a colorless solid (42 mg, 21% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.86–8.78(2H,m),8.11(1H,d,J=8.7Hz),7.98(1H,d,J=1.7H z),7.82–7.72(2H,m),7.68(1H,dd,J=8.8,2.1Hz),7.64–7.60(2H,m),7.58–7.54(2 H,m),7.17–7.11(2H,m),5.84(1H,dd,J=11.5,4.8Hz),3.92(1H,dd,J=17.5,12.0H z),3.34–3.12(1H,m),3.36–3.11(3H,m),2.76(2H,t,J=6.5Hz),0.83–0.78(4H,m); 13 C NMR(101MHz, CDCl3)δ176.1(C),170.3(C),159.2(C),154.4(C),145.3(CH),145.1( CH),143.7(C),143.2(C),143.0(C),142.6(C),132.8(C),130.6(CH),129.2(C),12 8.1(3×CH),127.3(2×CH),127.0(2×CH),125.9(CH),115.6(2×CH),60.1(CH),51.1( CH),42.3(CH2),29.2(CH2),28.9(CH2),6.3(2×CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 26N4NaO4, calculated value, 529.1846; measured value, 529.1847.

[0530] 4-(3-(4'-(cyclopentyloxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 85)

[0531]

[0532] Compound 85 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (79 mg, 0.5 mmol), 1-(4'-(cyclopentyloxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (140 mg, 0.5 mmol) and 2M NaOH (1.0 mL, 2.0 mmol) in EtOH (4 mL) was added to give (E)-1-(4'-(cyclopentyloxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-(cyclopentyloxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (25 μL, 50% w / w) in THF (2 mL) were added, followed by the addition of succinic anhydride (50 mg, 0.5 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 85 as a colorless solid (56 mg, 21% over 2 steps); 1 H NMR(400MHz,DMSO-d6)δ8.79–8.73(2H,m),8.01(1H,d,J=8.7Hz),7.99(1H,d,J=1.7Hz), 7.88–7.82(2H,m),7.72–7.61(3H,m),7.61–7.54(2H,m),6.97–6.92(2H,m),5.82(1H,dd ,J=11.5,4.8Hz),4.87–4.79(m,1H),3.96(1H,dd,J=17.5,12.0Hz),3.29(1H,dd,J=17.8 ,5.4Hz),3.22–3.02(2H,m),2.57(2H,t,J=6.7Hz),1.97–1.68(6H,m),1.68–1.57(2H,m); 13C NMR(101MHz,DMSO-d6)δ173.7(C),169.2(C),157.7(C),154.2(C),145.9(CH),145.5(CH),144.2 (C),142.1(C),141.6(2×C),131.0(C),129.8(CH),129.1(C),128.1(CH),127.8(2×CH),127.3(2x CH),126.2(2×CH),125.3(CH),115.9(2×CH),78.7(CH),59.5(CH),41.7(CH2),3 2.2(2×CH2),28.7(CH2),28.3(CH2),23.6(2×CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 32 H 30 N4NaO4, calculated value, 557.2159; measured value, 557.2159.

[0533] 4-(3-(4'-Isobutyl-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 86)

[0534]

[0535] Compound 86 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4'-isobutyl-[1,1'-biphenyl]-4-yl)ethan-1-one (252 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) to give (E)-1-(4'-isobutyl-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-3-(quinoxalin-6-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) in THF (4 mL) were then added succinic anhydride (400 mg, 4.00 mmol). Purification by flash column chromatography (EtOAc, neat) gave compound 86 as a colorless solid (151 mg, 30% over 2 steps); 1H NMR (400MHz, CDCl3) δ8.81 (2H, s), 8.11 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 1.7Hz), 7.84–7.79(2H,m),7.71–7.63(3H,m),7.56–7.51(2H,m),7.25–7.21(2H,m),5.84 (1H,dd,J=11.8,4.1Hz),3.92(1H,dd,J=17.5,11.8Hz),3.37–3.11(3H,m),2.76( 2H,t,J=6.8Hz), 2.52(2H,d,J=7.3Hz), 1.98–1.84(1H,m), 0.94(6H,d,J=6.7Hz); 13 CNMR(101MHz, CDCl3)δ176.2(C),170.3(C),154.4(C),145.2(CH),145.0(CH),143.8(C), 143.5(C),142.9(C),142.5(C),141.9(C),137.4(C),130.6(CH),129.8(2×CH),129.4(C), 128.2(CH),127.3(2×CH),127.29(2×CH),126.8(2×CH),125.8(CH),60.1(CH),45.1(CH2), 42.3(CH2),30.3(CH),29.1(CH2),28.9(CH2),22.5(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 31 H 30 N4NaO3, calculated value, 529.2210; measured value, 529.2209.

[0536] 4-(3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 87)

[0537]

[0538] Compound 87 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)ethan-1-one (252 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) was added to give (E)-1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) were added to THF (4 mL), followed by the addition of succinic anhydride (129 mg, 1.29 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 87 as a colorless solid (120 mg, 24% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.83–8.79(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=1.7Hz),7.85–7.78(2H,m),7.69–7.64(3H,m),7.59–7.55(2H ,m),7.51–7.47(2H,m),5.84(1H,dd,J=11.5,4.8Hz),3.91(1H,dd,J=17.5,12.0Hz),3.36–3.12(3H,m),2.76(2H,t,J=6.5Hz),1.37(9H,m); 13 CNMR(101MHz, CDCl3)δ176.3(C),170.3(C),154.4(C),151.3(C),145.3(CH),145. 0(CH),143.8(C),143.4(C),143.0(C),142.5(C),137.1(C),130.6(CH),129.5(C), 128.1(CH),127.3(4×CH),126.8(2×CH),126.0(2×CH),125.9(CH),60.2(CH),42.3( CH2),34.7(C),31.4(3×CH3),29.1(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 31 H 30 N4NaO3, calculated value, 529.2210; measured value, 529.2208.

[0539] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 88)

[0540]

[0541] Compound 88 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (103 mg, 0.650 mmol), 1-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one (181 mg, 0.650 mmol) and 2M NaOH (1.6 mL, 3.25 mmol) in EtOH (5 mL) to give (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one as an off-white solid (242 mg); Step 2: (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one (242 mg) and hydrazine hydrate (72 μL, 50% w / w) in THF (5 mL) followed by the addition of succinic anhydride (174 mg, 1.74 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, neat) gave compound 88 as a yellow solid (180 mg, 52% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.81–8.80(2H,m),8.10(1H,d,J=8.8Hz),7.99(1H,d,J=2.0H z),7.83(2H,d,J=8.6Hz),7.68(1H,dd,J=8.8,2.0Hz),7.65(1H,d,J=8.6Hz),7.61( 2H,d,J=8.3Hz),7.39(2H,d,J=8.0Hz),5.84(1H,dd,J=11.9,4.9Hz),3.90(1H,dd, J=17.7,11.9Hz),3.42(2H,q,J=10.8Hz),3.32–3.15(3H,m),2.76(2H,t,J=6.9Hz); 13C NMR(101MHz, CDCl3)δ176.9(C),170.3(C),154.1(C),145.3(CH),145.1(CH),143.9(C),14 3.0(C),142.7(C),142.5(C),140.0(C),130.9(2×CH),130.6(CH),130.2(C),130.0(C,q,J C-F =2.9Hz),128.2(CH),127.5(2×CH),127.5(2×CH),127.4(2×CH),125.9(CH),125.8(C,q,J C-F =277.0Hz),60.2(CH),42.3(CH2),40.0(CH2,q,J C-F =29.7Hz),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 29 H 23 F3N4NaO3, calculated value, 555.1614; measured value, 555.1615.

[0542] 4-(3-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 89)

[0543]

[0544] Compound 89 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (303 mg, 1.91 mmol), 1-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one (460 mg, 1.91 mmol) and 2M NaOH (4.80 mL, 9.60 mmol) in EtOH (15 mL) was added to give (E)-1-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid without further purification (550 mg); Step 2: (E)-1-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (550 mg) and hydrazine hydrate (180 μL, 50% w / w, 2.89 mmol) in THF (12 mL) was followed by the addition of succinic anhydride (434 mg, 4.34 mmol). Purification by flash column chromatography (EtOAc / petroleum ether, 4:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 89 as a yellow solid (280 mg, 30% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.82–8.81(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=1.8Hz),7.83(2H,d,J=8.4Hz),7.69–7.60(5H,m),7.43(2H,d, J=8.1Hz),5.85(1H,dd,J=11.9,4.8Hz),4.51(2H,s),3.92(1H,dd,J=17.7,11.9Hz),3.43(3H,s),3.34–3.15(3H,m),2.76(2H,t,J=6.7Hz); 13 CNMR(101MHz, CDCl3)δ175.9(C),170.4(C),154.4(C),145.4(CH),145.1(CH),143.8( C),143.3(C),143.1(C),142.7(C),139.5(C),138.3(C),130.7(CH),129.9(C),128.4( 2×CH),128.2(CH),127.5(2×CH),127.4(2×CH),127.2(2×CH),125.9(CH),74.5(CH2),6 0.3(CH),58.4(CH3),42.4(CH2),29.2(CH2),29.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] +, C 29 H 26 N4NaO4, calculated value, 517.1846; measured value, 517.1845.

[0545] 4-(3-(3'-methoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 90)

[0546]

[0547] Compound 90 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (226 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid without further purification (340 mg); Step 2: (E)-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (340 mg) and hydrazine hydrate (115 μL, 50% w / w, 1.86 mmol) in THF (7 mL) were followed by the addition of succinic anhydride (278 mg, 2.78 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 90 as a colorless solid (104 mg, 22% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.81–8.80(2H,m),8.10(1H,d,J=8.7Hz),7.99(1H,d,J= 1.9Hz),7.82(2H,d,J=8.4Hz),7.69–7.64(3H,m),7.38(1H,t,J=8.0Hz),7.20 (1H,dt,J=7.9,2.0Hz),7.14(1H,t,J=2.0Hz),6.94–6.92(1H,m),5.84(1H,dd ,J=11.8,4.9Hz),3.95–3.86(4H,m),3.34–3.13(3H,m),2.75(2H,t,J=6.7Hz); 13C NMR(101MHz, CDCl3)δ176.3(C),170.4(C),160.2(C),154.3(C),145.4(CH),145.1(CH), 143.8(C),143.4(C),143.0(C),142.6(C),141.7(C),130.7(CH),130.11(CH),130.06(C) ,128.2(CH),127.6(2×CH),127.4(2×CH),125.9(CH),119.7(CH),113.4(CH),113.1(CH) ,60.2(CH),55.5(CH3),42.4(CH2),29.2(CH2),29.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 24 N4NaO4, calculated value, 503.1690; measured value, 503.1688.

[0548] 4-(3-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 91)

[0549]

[0550] Compound 91 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (261 mg, 1.65 mmol), 1-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (445 mg, 1.65 mmol) and 2M NaOH (4.15 mL, 8.30 mmol) in EtOH (13 mL) was added to give (E)-1-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a beige solid without further purification (480 mg); Step 2: (E)-1-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (480 mg) and hydrazine hydrate (145 μL, 50% w / w, 2.34 mmol) in THF (10 mL) was followed by the addition of succinic anhydride (351 mg, 3.51 mmol). Purification by flash column chromatography (EtOAc, neat → EtOAc / MeOH, 9:1 → Acetone / MeOH, 9:1) gave compound 91 as a dark yellow solid (147 mg, 17% over 2 steps). 1H NMR (400MHz, CDCl3) δ8.82 (2H, s), 8.11 (1H, d, J = 8.7Hz), 7.99 (1H, s), 7.80 (2H, d, J = 8. 2Hz),7.68(1H,dd,J=8.7,1.4Hz),7.62(2H,d,J=8.2Hz),7.56(2H,d,J=8.6Hz),7.02(2H ,d,J=8.6Hz),5.84(1H,dd,J=11.8,4.7Hz),4.18(2H,t,J=4.6Hz),3.92(1H,dd,J=17.7 ,11.9Hz),3.78(2H,t,J=4.6Hz),3.47(3H,s),3.35–3.16(3H,m),2.75(2H,t,J=6.6Hz); 13 C NMR(101MHz, CDCl3)δ175.3(C),170.5(C),159.1(C),154.7(C),145.4(CH),145.2(CH),1 43.7(C),143.2(C),143.1(C),142.7(C),132.8(C),130.7(CH),129.2(C),128.3(2×CH), 128.1(CH),127.4(2×CH),127.1(2×CH),126.0(CH),115.2(2×CH),71.2(CH2),67.6(CH2) ,60.3(CH),59.4(CH3),42.4(CH2),29.2(CH2),29.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 28 N4NaO5, calculated value, 547.1952; measured value, 547.1954.

[0551] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 92)

[0552]

[0553] Compound 92 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (294 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) was added to give (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-3-(quinoxalin-6-yl)-1-(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) in THF (4 mL) was added, followed by the addition of succinic anhydride (400 mg, 4.00 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 92 as a colorless solid (186 mg, 34% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.80–8.77(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=1.7Hz),7.84–7.79(2H,m),7.68–7.54(5H,m),7.05–6. 99(2H,m),5.84(1H,dd,J=11.8,4.1Hz),4.43–4.34(2H,m),3.87(1H,dd,J=17.5,11.8Hz),3.33–3.11(3H,m),2.75(2H,t,J=6.8Hz); 13 C NMR(101MHz, CDCl3)δ176.8(C),170.2(C),157.4(C),154.0(C),145.2(CH),144.9(CH),143.9(C),142.8(C),142.4(C),1 42.3(C),134.4(C),130.4(CH),129.6(C),128.4(2×CH),128.1(CH),127.3(2×CH),127.0(2×CH),125.7(CH),123.4(C,q,J C-F =268Hz),115.4(2×CH),66.0(CH2,q,J C-F =36Hz),60.1(CH),42.2(CH2),29.2(CH2),28.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C29 H 23 F3N4NaO, calculated value, 571.1564; measured value, 571.1563.

[0554] 4-(3-(4'-(Isopropylthio)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 93)

[0555]

[0556] Compound 93 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4'-(isopropylthio)-[1,1'-biphenyl]-4-yl)ethan-1-one (270 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) was added to give (E)-1-(4'-(isopropylthio)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-(isopropylthio)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) in THF (4 mL) was then added succinic anhydride (129 mg, 1.29 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 93 as a colorless solid (100 mg, 19% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.83–8.79(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J =1.7Hz),7.85–7.78(2H,m),7.69–7.61(3H,m),7.57–7.55(2H,m),7.48–7.4 2(2H,m),5.84(1H,dd,J=11.5,4.8Hz),3.90(1H,dd,J=17.5,12.0Hz),3.50– 3.38(1H,m),3.36–3.12(3H,m),2.76(2H,t,J=6.7Hz),1.33(6H,d,J=6.5Hz); 13C NMR(101MHz, CDCl3)δ176.7(C),170.2(C),154.1(C),145.2(CH),145.0(CH),143.8(C ),142.9(C),142.6(C),142.5(C),138.2(C),135.9(C),131.9(2×CH),130.5(CH),129. 9(C),128.1(CH),127.4(2×CH),127.3(2×CH),127.2(2×CH),125.8(CH),60.1(CH),42. 2(CH2),38.1(CH),29.2(CH2),28.9(CH2),23.2(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 28 N4NaO3S, calculated value, 547.1774; measured value, 547.1769.

[0557] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 94)

[0558]

[0559] Compound 94 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)ethan-1-one (296 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) was added to give (E)-3-(quinoxalin-6-yl)-1-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)prop-2-en-1-one as a yellow solid; Step 2: Crude (E)-3-(quinoxalin-6-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) were added to THF (4 mL), followed by the addition of succinic anhydride (400 mg, 4.00 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 94 as a colorless solid (186 mg, 34% over 2 steps); 1H NMR (400MHz, CDCl3) δ8.79(2H,s),8.10(1H,d,J=8.7Hz),7.99(1H,d,J=1.7Hz),7.87–7.81(2H ,m),7.76–7.61(7H,m),5.85(1H,dd,J=11.8,4.1Hz),3.34–3.12(3H,m),2.75(2H,t,J=6.8Hz); 13 C NMR(101MHz, CDCl3)δ176.8(C),170.3(C),153.8(C),145.2(CH),145.0(CH),143.8 (C),142.9(C),142.6(C),142.4(C),141.7(C),136.8(2×CH),131.1(CF3),130.8(C ),130.5(CH),128.2(CH),128.1(2×CH),127.6(2×CH),127.4(2×CH),125.7(CH),12 3.9(C),60.1(CH),42.2(CH2),29.2(CH2),28.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 21 F3N4NaO3S, calculated value, 573.1179; measured value, 573.1162.

[0560] 4-(3-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 95)

[0561]

[0562] To a solution of compound 9 (80 mg, 0.18 mmol) in DMF / water (2.0 mL, 1:1 v / v) was added (4-(dimethylamino)phenyl)boric acid (59 mg, 0.36 mmol), tripotassium phosphate (0.19 g, 0.90 mmol) and palladium acetate (4.0 mg, 10 mol%). The reaction mixture was stirred at 80 ° C for 16 h. The reaction mixture was then diluted with EtOAc (10 mL), neutralized with a 0.5 M HCl aqueous solution, and the separated aqueous layer was further extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 95 was purified by flash column chromatography (DCM / MeOH, 10: 1) to give a yellow solid (30 mg, 34%). 1H NMR(400MHz,CDCl3)δ8.84(2H,br s),8.13(1H,d,J=8.7Hz),8.00(1H,d,J=1.9Hz),7.82(2H,d,J=8.4Hz),7.69(1H,dd,J=8.6,2.0Hz),7.66–7.62(4H,m),7.27(2H, d,J=8.4Hz), 5.85(1H,dd,J=11.9,4.7Hz), 3.92(1H,dd,J=17.6,11.8Hz), 3.36–3.16(3H,m), 3.13(6H,s), 2.76(2H,t,J=6.6Hz).

[0563] 4-Oxylidene-4-(3-(4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 96)

[0564]

[0565] Compound 96 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (261 mg, 1.65 mmol), 1-(4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)ethan-1-one (461 mg, 1.65 mmol) and 2M NaOH (4.15 mL, 8.30 mmol) in EtOH (13 mL) was added to give (E)-1-(4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid without further purification (605 mg); Step 2: (E)-1-(4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (605 mg) and hydrazine hydrate (180 μL, 50% w / w, 2.89 mmol) in THF (12 mL) was followed by the addition of succinic anhydride (434 mg, 4.34 mmol). Purification by flash column chromatography (EtOAc / petroleum ether, 4:1 → EtOAc, neat → EtOAc / MeOH, 9:1) gave compound 96 as a yellow solid (320 mg, 36% over 2 steps). 1H NMR (400MHz, CDCl3) δ8.81 (2H, s), 8.11 (1H, d, J = 8.6Hz), 7.99 (1H, d, J = 2.0Hz), 7.78 (2H,d,J=8.4Hz),7.67(1H,dd,J=8.7,1.9Hz),7.63(2H,d,J=8.4Hz),7.54(2H,d,J=8 .8Hz), 7.00(2H,d,J=8.8Hz), 5.83(1H,dd,J=11.9,4.7Hz), 3.91(1H,dd,J=17.6,11. 8Hz),3.36–3.15(7H,m),2.75(2H,t,J=6.7Hz),1.75–1.68(4H,m),1.64–1.58(2H,m); 13 C NMR(101MHz, CDCl3)δ175.9(C),170.4(C),154.7(C),152.0(C),145.4(CH),145.1(CH),14 3.8(C),143.4(C),143.1(C),142.6(C),130.7(CH),130.0(C),128.7(C),128.2(CH),127. 8(2×CH),127.4(2×CH),126.6(2×CH),125.9(CH),116.4(2×CH),60.2(CH),50.2(2×CH2),4 2.4(CH2),29.2(CH2),29.1(CH2),25.8(2×CH2),24.5(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 32 H 31 N5NaO3, calculated value, 556.2319; measured value, 556.2319.

[0566] 4-(3-(3'-methoxy-[1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 97)

[0567]

[0568] Compound 97 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (79 mg, 0.5 mmol), 1-(3'-methoxy-[1,1'-biphenyl]-3-yl)ethan-1-one (113 mg, 0.5 mmol) and 2M NaOH (1.0 mL, 2.0 mmol) in EtOH (4 mL) was added to give (E)-1-(3'-methoxy-[1,1'-biphenyl]-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(3'-methoxy-[1,1'-biphenyl]-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (25 μL, 50% w / w) in THF (2 mL) were added, followed by the addition of succinic anhydride (50 mg, 0.5 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 97 as a colorless solid (65 mg, 27% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.83–8.78(2H,m),8.12(1H,d,J=8.7Hz),7.98(1H,d,J=1.8Hz ),7.94(1H,t,J=1.3Hz),7.73–7.68(3H,m),7.49(1H,t,J=7.8Hz),7.37(1H,t,J=7. 8Hz),7.20–7.11(2H,m),6.95–6.90(m,1H),5.85(1H,dd,J=11.5,4.8Hz),4.01–3.8 9(m,1H),3.82(3H,s),3.37–3.25(2H,m),3.23–3.16(1H,m),2.75(2H,t,J=6.6Hz); 13 C NMR(101MHz, CDCl3)δ176.4(C),170.4(C),160.1(C),154.4(C),145.3(CH),145.0(CH),143. 8(C),142.9(C),142.5(C),141.94(C),141.92(C),131.5(C),130.6(CH),130.0(CH),129.6(C H),129.3(CH),128.1(CH),125.8(CH),125.76(CH),125.6(CH),119.8(CH),113.2(CH),113.1 (CH),60.1(CH3),55.5(CH),42.4(CH2),29.1(CH2),28.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] +, C 28 H 24 N4NaO4, calculated value, 503.1690; measured value, 503.1688.

[0569] 4-Oxylidene-4-(5-(quinoxalin-6-yl)-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)butanoic acid (Compound 98)

[0570]

[0571] Compound 98 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)ethan-1-one (280 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-3-(quinoxalin-6-yl)-1-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)prop-2-en-1-one as a colorless solid without further purification (400 mg); Step 2: (E)-3-(quinoxalin-6-yl)-1-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)prop-2-en-1-one (400 mg) and hydrazine hydrate (120 μL, 50% w / w, 1.90 mmol) in THF (8 mL) was followed by the addition of succinic anhydride (286 mg, 2.85 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, neat) gave compound 98 as beige crystals (105 mg, 20% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.81(2H,s),8.11(1H,d,J=8.6Hz),7.99(1H,s),7.93(1H,s),7.76(1H,d,J=7.5Hz),7.68(1H,d,J=8.7Hz),7.63(1H,d,J=7.4H z),7.54–7.43(4H,m),7.24(1H,d,J=7.8Hz),5.86(1H,dd,J=11.7,4.5Hz) ,3.94(1H,dd,J=17.6,12.0Hz),3.33–3.14(3H,m),2.75(2H,t,J=6.4Hz); 13C NMR(101MHz, CDCl3)δ176.6(C),170.4(C),154.2(C),149.9(C),145.4(CH),145.1(CH),143.8(C),143.0(C),142.6(C),140.6(C),1 31.8(C),130.7(CH),130.4(CH),129.61(CH),129.57(CH),128.2(CH),126.4(CH),125.9(CH),125.8(CH),125.5(CH),120.7(C,q,J C-F =257.2Hz),120.2(CH),120.0(CH),60.3(CH),42.4(CH2),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 21 F3N4NaO4, calculated value, 557.1407; measured value, 557.1407.

[0572] 4-(3-(4'-methoxy-[1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 99)

[0573]

[0574] Compound 99 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (79 mg, 0.5 mmol), 1-(4'-methoxy-[1,1'-biphenyl]-3-yl)ethan-1-one (113 mg, 0.5 mmol) and 2M NaOH (1.0 mL, 2.0 mmol) in EtOH (4 mL) was added to give (E)-1-(4'-methoxy-[1,1'-biphenyl]-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4'-methoxy-[1,1'-biphenyl]-3-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (25 μL, 50% w / w) in THF (2 mL) were added, followed by the addition of succinic anhydride (50 mg, 0.5 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 99 as a colorless solid (74 mg, 31% over 2 steps); 1H NMR(400MHz,DMSO-d6)δ11.62(1H,br s),8.98–8.91(2H,m),8.12(1H,d,J=8.7Hz),7.99(1H,t,J=1.3Hz),7.95(1H,d, J=1.8Hz),7.85–7.80(1H,m),7.79–7.73(2H,m),7.73–7.68(2H,m),7.57(1H,t, J=8.1Hz),7.12–6.51(2H,m),5.89(1H,dd,J=11.5,4.8Hz),4.13–4.01(m,1H),3 .82(3H,s),3.47(1H,dd,J=17.5,12.0Hz),3.20–2.96(2H,m),2.59–2.53(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.3(C),159.2(C),154.6(C),145.9(CH),145.5( CH),144.2(C),142.1(C),141.5(C),140.3(C),131.7(C),131.5(C),129.7(CH),129.3 (CH),128.2(2×CH),128.0(2×CH),125.3(CH),124.8(CH),124.6(CH),114.4(2×CH),5 9.5(CH),55.2(CH3),41.8(CH2),28.7(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 24 N4NaO4, calculated value, 503.1690; measured value, 503.1688.

[0575] 4-(3-(3'-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 100)

[0576]

[0577] Compound 100 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carboxaldehyde (32 mg, 0.20 mmol), 1-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)ethan-1-one (55 mg, 0.20 mmol) and 2M NaOH (0.50 mL, 1.00 mmol) in EtOH (2.0 mL) to give (E)-1-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (64 mg); Step 2: (E)-1-(3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (63.5 mg) and hydrazine hydrate (19 μL, 50% w / w) in THF (1.5 mL) followed by the addition of succinic anhydride (46 mg, 0.46 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 100 as a yellow solid (49 mg, 47% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.82–8.80(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=2.0Hz),7.80(2H ,d,J=8.5Hz),7.68(1H,dd,J=8.8,2.0Hz),7.59(2H,d,J=8.5Hz),7.37–7.30(2H,m),7.05(1H,t ,J=8.5Hz),5.84(1H,dd,J=11.9,4.9Hz),4.60(1H,sevenfold,J=6.1Hz),3.91(1H,dd,J=17.7,11.9Hz) ,3.36–3.24(2H,m),3.17(1H,dt,J=17.3,6.8Hz),2.75(2H,t,J=6.7Hz),1.40(6H,d,J=6.0Hz); 13 C NMR(101MHz, CDCl3)δ176.5(C),170.4(C),154.2(C),154.0(C,d,J C-F =245.7Hz),146.0(C,d,J C-F =10.6Hz),145.4(CH),145.1(CH),143.8(C),143.1(C),142.6(C),142.0(C),133.6(C,d,J C-F=6.6Hz),130.6(CH),129.8(C),128.2(CH),127.5(2×CH),127.0(2×CH),125.9(CH),122.8(CH,d,J C-F =3.2Hz),117.9(CH,d,J C-F =2.5Hz),115.1(CH,d,J C-F =19.8Hz),72.6(CH),60.3(CH),42.4(CH2),29.2(CH2),29.0(CH2),22.2(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 27 FN4NaO4, calculated value, 549.1909; measured value, 549.1912.

[0578] 4-(3-(2'-Fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 101)

[0579]

[0580] Compound 101 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (200 mg, 1.26 mmol), 1-(2'-fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (376 mg, 1.26 mmol) and 2M NaOH (3.2 mL, 6.30 mmol) in EtOH (10 mL) was added to give (E)-1-(2'-fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (492 mg); Step 2: (E)-1-(2'-fluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (250 mg) and hydrazine hydrate (71 μL, 50% w / w) in THF (5 mL) was followed by the addition of succinic anhydride (171 mg, 1.71 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 101 as an off-white solid (148 mg, 42% over 2 steps). 1H NMR (400MHz, CDCl3) δ8.82–8.81(2H,m),8.11(1H,d,J=8.7Hz),7.99(1H,d,J=1.9H z),7.84(2H,d,J=8.6Hz),7.68(1H,dd,J=8.7,2.0Hz),7.60–7.58(2H,m),7.49(1H ,t,J=8.5Hz),7.14–7.07(2H,m),5.86(1H,dd,J=11.9,4.9Hz),3.91(1H,dd,J=17. 7,11.9Hz),3.33–3.24(2H,m),3.18(1H,dt,J=17.3,6.8Hz),2.76(2H,t,J=6.8Hz); 13 C NMR(101MHz,CDCl3)δ176.8(C),170.4(C),159.7(C,d,J C-F =251.5Hz),153.9(C),149.6–149.3(C,m),145.3(CH),145.1(CH),143.8(C),142.9(C),142.5(C),136.8(C,d,J C-F =1.8Hz),131.4(CH,d,J C-F =4.3Hz),130.8(C),130.6(CH),129.4(2×CH,d,J C-F =2.7Hz),128.2(CH),127.1(2×CH),127.0(C,d,J C-F =13.4Hz),125.8(CH),120.5(C,q,J C-F =258.6Hz),117.0(CH,d,J C-F =4.0Hz),109.8(CH,d,J C-F =26.6Hz),60.3(CH),42.3(CH2),29.2(CH2),28.9(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 28 H 21 F4N4O4, calculated value, 553.1493; measured value, 553.1490.

[0581] 4-(3-(3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 102)

[0582]

[0583] Compound 102 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-one (314 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) was added to give (E)-1-(3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) in THF (4 mL) was added, followed by the addition of succinic anhydride (129 mg, 1.29 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 102 as a colorless solid (142 mg, 25% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.80–8.77(2H,m),8.11(1H,d,J=8.7Hz),7.98(1H,d,J=1.7Hz),7.87–7.81(2H,m),7.72–7.65(2H,m),7.62–7.56(2H,m) ,7.53–7.48(1H,m),7.42–7.37(1H,m),5.85(1H,dd,J=12.5,4.1Hz),3.90(1H,dd,J=17.5,12.0Hz),3.34–3.12(3H,m),2.76(2H,t,J=6.5Hz),; 13 C NMR(101MHz, CDCl3)δ176.8(C),170.2(C),153.7(C),145.3(CH),145.0(CH),144.95(C),143.7(C),142.9(C),142.5(C),140.6(C),1 40.2(C),130.9(C),130.5(CH),129.4(C),128.1(CH),128.0(CH),127.5(2×CH),127.46(2×CH),126.5(CH),125.8(CH),123.4(C,q,J C-F=268Hz),123.0(CH),60.2(CH),42.2(CH2),29.1(CH2),28.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 20 ClF3N4NaO4, calculated value, 591.1017; measured value, 591.1031.

[0584] 4-(3-(4-(Benzo[d][1,3]dioxol-5-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 103)

[0585]

[0586] Compound 103 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)ethan-1-one (240 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) gave (E)-1-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) in THF (4 mL) were then added succinic anhydride (129 mg, 1.29 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 103 as a colorless solid (100 mg, 20% over 2 steps); 1H NMR (400MHz, DMSO-d6) δ12.09(1H,s),8.10(1H,d,J=9.3Hz),7.93(1H,d,J=1.7Hz) ,7.89–7.84(2H,m),7.77–7.71(3H,m),7.35–7.33(1H,d,J=9.3Hz),7.25(1H,dd,J= 7.8,2.0Hz),7.04(1H,d,J=7.8Hz),7.51–7.47(2H,m),6.09(2H,s),5.86(1H,dd,J= 11.5,4.8Hz),4.02(1H,dd,J=17.8,12.0Hz),3.43–3.30(3H,m),3.17–2.94(2H,m); 13 CNMR(101MHz,DMSO-d6)δ173.7(C),169.2(C),154.1(C),148.1(C),147.3(C),146.0(CH ),145.6(CH),144.2(C),142.1(C),141.5(C),133.3(C),129.8(CH),129.5(C),128.1(CH ),127.3(2×CH),127.2(C),126.6(2×CH),125.3(CH),120.5(CH),108.7(CH),107.0(CH), 101.3(CH2),59.5(CH),41.7(CH2),28.7(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 22 N4NaO5, calculated value, 517.1482; measured value, 517.1482.

[0587] 4-(3-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 104)

[0588]

[0589] Compound 104 was prepared over 2 steps using a procedure analogous to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)ethan-1-one (276 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.0 mmol) in EtOH (8 mL) was added to give (E)-1-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid; Step 2: Crude (E)-1-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one and hydrazine hydrate (54 μL, 50% w / w) in THF (4 mL) was added, followed by the addition of succinic anhydride (129 mg, 1.29 mmol). Purification by flash column chromatography (EtOAc→DCM / MeOH 10:1) gave compound 104 as a colorless solid (137 mg, 26% over 2 steps); 1 H NMR (400MHz, CDCl3) δ8.84–8.79(2H,m),8.11(1H,d,J=9.3Hz),7.98(1H,d,J=1.7Hz),7.85–7.78(2H,m),7.68(1H,dd,J=8.7,2.0Hz),7.59–7.55(2H ,m),7.33–7.28(2H,m),7.13(1H,d,J=8.3Hz),5.86(1H,dd,J=11.5,4.8Hz ),3.91(1H,dd,J=17.8,12.0Hz),3.35–3.12(3H,m),2.75(2H,d,J=6.6Hz); 13 C NMR(101MHz, CDCl3)δ176.2(C),170.3(C),154.0(C),145.3(CH),145.1(CH),144 .5(C),143.7(C),143.0(C),142.6(C),142.1(C),136.7(C),131.8(C),130.6(CH ),130.3(C),128.1(CH),127.5(4×CH),125.8(CH),122.7(CH),109.8(CH),108.5 (CH),60.2(CH),42.3(CH2),29.1(CH2),28.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 20F2N4NaO5, calculated value, 553.1294; measured value, 553.1292.

[0590] 4-(3-(4-(Benzofuran-5-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 105)

[0591]

[0592] Compound 105 was prepared using a method similar to that described for the preparation of compound 21: compound 9 (70 mg, 0.15 mmol), benzofuran-5-boronic acid (50 mg, 0.31 mmol), tripotassium phosphate (0.13 g, 0.62 mmol) and palladium acetate (3.5 mg, 10 mol%) in DMF / water (1.6 mL, 1:1 v / v). Compound 105 was purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → EtOAc / MeOH, 99:1) to give compound 105 as a yellow solid (35 mg, 46%). 1 H NMR (400MHz, DMSO-d6) δ12.07(1H,s),8.94–8.92(2H,m),8.09(1H,d,J=8.8Hz),8.05(1H,d,J=2. 2Hz),8.00(1H,dd,J=1.9,0.7Hz),7.92–7.89(3H,m),7.81(2H,d,J=8.6Hz),7.74–7.65(3H,m),7. 03(1H,dd,J=2.2,0.9Hz),5.86(1H,dd,J=11.9,5.0Hz),4.02(1H,dd,J=18.1,12.0Hz),3.35(1H,d d,J=18.2,5.0Hz),3.12(1H,dt,J=17.1,6.7Hz),3.00(1H,dt,J=17.1,6.6Hz),2.54–2.50(2H,m); 13CNMR(101MHz,DMSO-d6)δ173.7(C),169.2(C),154.2(C),154.2(C),146.9(CH),146.0(CH), 145.6(CH),144.2(C),142.3(C),142.1(C),141.6(C),134.5(C),129.8(CH),129.6(C),128 .1(CH),128.0(C),127.4(2×CH),127.2(2×CH),125.3(CH),123.5(CH),119.5(CH),111.7(C H),107.0(CH),59.6(CH),41.8(CH2),28.8(CH2),28.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 29 H 22 N4NaO4, calculated value, 513.1533; measured value, 513.1532.

[0593] 4-(3-(4-(1H-indol-5-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 106)

[0594]

[0595] Compound 106 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4-(1H-indol-5-yl)phenyl)ethan-1-one (235 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-1-(4-(1H-indol-5-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a green solid (278 mg); Step 2: (E)-1-(4-(1H-indol-5-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (150 mg) and hydrazine hydrate (50 μL, 50% w / w) in THF (3 mL) were then added succinic anhydride (120 mg, 1.20 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 106 as a yellow solid (70 mg, 27% over 2 steps). 1H NMR(400MHz,THF-d8)δ10.83(1H,br s),10.25(1H,s),8.78–8.75(2H,m),8.01(1H,d,J=8.7Hz),7.97(1H,d,J=2.1Hz),7.88–7.85(3H, m),7.73(2H,d,J=8.6Hz),7.70(1H,dd,J=8.7,2.1Hz),7.42–7.41(2H,m),7.24(1H,dd,J=3.2,2.4 Hz),6.50–6.48(1H,m),5.82(1H,dd,J=12.0,5.1Hz),3.96(1H,dd,J=17.7,12.1Hz),3.31(1H,dd, J=17.8,5.1Hz),3.17(1H,dt,J=17.0,7.1Hz),3.06(1H,dt,J=17.1,7.1Hz),2.58(2H,t,J=7.1Hz); 13 C NMR(101MHz,THF-d8)δ174.2(C),170.2(C),154.5(C),146.5(CH),146.1(CH),145.75(C),1 45.72(C),144.3(C),143.7(C),137.5(C),132.4(C),131.0(CH),130.5(C),130.0(C),129. 0(CH),128.1(2×CH),127.9(2×CH),127.3(CH),126.4(CH),121.6(CH),119.7(CH),112.4(C H),103.0(CH),61.2(CH),42.9(CH2),30.2(CH2),29.2(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 29 H 23 N5NaO3, calculated value, 512.1693; measured value, 512.1693.

[0596] 4-(3-(4-(6-isopropoxypyridin-3-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 107)

[0597]

[0598] Compound 107 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (294 mg, 1.86 mmol), 1-(4-(6-isopropoxypyridin-3-yl)phenyl)ethan-1-one (475 mg, 1.86 mmol) and 2M NaOH (4.65 mL, 9.30 mmol) in EtOH (15 mL) gave (E)-1-(4-(6-isopropoxypyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a colorless solid without further purification (637 mg); Step 2: (E)-1-(4-(6-isopropoxypyridin-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (637 mg) and hydrazine hydrate (200 μL, 50% w / w, 3.22 mmol) in THF (13 mL) was then added succinic anhydride (483 mg, 4.83 mmol). Purification by flash column chromatography (EtOAc / petroleum ether, 9:1 → EtOAc, neat → EtOAc / MeOH, 9:1 → acetone / MeOH, 9:1) gave compound 107 as a light yellow solid (142 mg, 15% over 2 steps). 1 H NMR (400MHz, CDCl3) δ8.81(2H,s),8.41(1H,d,J=2.5Hz),8.11(1H,d,J=8.7Hz),7.99( 1H,d,J=1.7Hz),7.84–7.79(3H,m),7.68(1H,dd,J=8.7,1.9Hz),7.59(2H,d,J=8.3Hz) ,6.77(1H,d,J=8.7Hz),5.85(1H,dd,J=11.9,4.9Hz),5.34(1H,sevenfold,J=6.2Hz),3.92(1H ,dd,J=17.7,11.9Hz),3.34–3.15(3H,m),2.76(2H,t,J=6.7Hz),1.38(6H,d,J=6.2Hz); 13C NMR(101MHz, CDCl3)δ176.0(C),170.4(C),163.5(C),154.2(C),145.4(CH),145.3(CH), 145.2(CH),143.8(C),143.1(C),142.7(C),140.5(C),137.3(CH),130.7(CH),129.8(C) ,128.6(C),128.2(CH),127.6(2×CH),126.9(2×CH),125.9(CH),111.9(CH),68.6(CH),6 0.3(CH),42.4(CH2),29.2(CH2),28.9(CH2),22.2(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 29 H 27 N5NaO4, calculated value, 532.1955; measured value, 532.1956.

[0599] 4-(3-(4-(Furan-3-yl)phenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 108)

[0600]

[0601] Compound 108 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: Quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol), 1-(4-(furan-3-yl)phenyl)ethan-1-one (186 mg, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) gave (E)-1-(4-(furan-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a yellow solid (251 mg); Step 2: (E)-1-(4-(furan-3-yl)phenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (150 mg) and hydrazine hydrate (57 μL, 50% w / w) in THF (4 mL) were then added succinic anhydride (138 mg, 1.38 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 108 as a yellow solid (113 mg, 43% over 2 steps). 1H NMR(400MHz,DMSO-d6)δ12.10(1H,br s),8.94–8.92(2H,m),8.31(1H,dd,J=1.6,0.9Hz),8.08(1H,d,J=8.7Hz),7.90(1H,d,J=2 .0Hz),7.82(2H,d,J=8.6Hz),7.78(1H,t,J=1.7Hz),7.74–7.70(3H,m),7.04(1H,dd,J=1. 9,0.9Hz),5.84(1H,dd,J=11.9,5.0Hz),3.99(1H,dd,J=18.2,12.0Hz),3.33(1H,dd,J=18 .1,5.0Hz),3.11(1H,dt,J=17.1,6.7Hz),2.97(1H,dt,J=17.2,6.6Hz),2.52–2.50(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.8(C),169.2(C),154.2(C),146.0(CH),145.6(CH), 144.6(CH),144.2(C),142.2(C),141.6(C),140.2(CH),134.0(C),129.8(CH),1 29.4(C),128.2(CH),127.3(2×CH),125.7(2×CH),125.3(CH),125.2(C),108.6( CH),59.5(CH),41.8(CH2),28.7(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 25 H 20 N4NaO4, calculated value, 463.1377; measured value, 463.1378.

[0602] 4-(3-(3-Fluoro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 109)

[0603]

[0604] To a solution of quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol) and 1-(3-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one (214 mg, 1.00 mmol) in EtOH (8 mL) was added 2M NaOH (2.5 mL, 5.00 mmol) dropwise at room temperature, and the reaction mixture was stirred for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(3-fluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as an off-white solid (340 mg), which was used directly in the next step without further purification.

[0605] A mixture of (E)-1-(3-fluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (340 mg) and hydrazine hydrate (0.12 mL, 50% w / w) in THF (8 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (288 mg, 2.88 mmol) was added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting solid was washed with CH2Cl2 and isolated by filtration to give compound 109 as an off-white solid (328 mg, 70% over 2 steps). 1 H NMR (400MHz, DMSO-d6) δ12.08(1H,s),8.95–8.93(2H,m),8.09(1H,d,J=8.7Hz),8.01(1H,t,J=8.3 Hz),7.92(1H,d,J=2.0Hz),7.79–7.76(2H,m),7.74(1H,dd,J=8.7,2.0Hz),7.70–7.65(2H,m),7.52 –7.48(2H,m),7.45–7.41(1H,m),5.83(1H,dd,J=12.0,5.1Hz),4.09(1H,ddd,J=18.3,12.1,1.9Hz) ,3.35–3.29(1H,m),3.11(1H,dt,J=17.2,6.7Hz),2.98(1H,dt,J=17.2,6.5Hz),2.53–2.50(2H,m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.5(C),160.7(C,d,J C-F =252.8Hz),150.4(C,d,J C-F=4.0Hz),146.0(CH),145.6(CH),144.0(C),144.0(C,d,J C-F =8.4Hz),142.1(C),141.6(C),137.7(C,d,J C-F =1.7Hz),129.8(CH),129.6(CH,d,J C-F =3.6Hz),129.1(2×CH),128.6(CH),128.1(CH),126.8(2×CH),125.4(CH),122.8(CH,d,J C-F =2.8Hz),117.8(C,d,J C-F =11.1Hz),114.4(CH,d,J C-F =23.1Hz),59.3(CH),43.8(CH2,d,J C-F =6.2Hz),28.8(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 22 FN4O3, calculated value, 469.1670; measured value, 469.1671.

[0606] 4-(3-(2-Fluoro-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 110)

[0607]

[0608] A solution of quinoxaline-6-carbaldehyde (158 mg, 1.00 mmol) in EtOH (4 mL) was stirred at room temperature for 10 min, and then 2M NaOH (0.50 mL, 1.00 mmol) was added at 0°C. Next, 1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one (214 mg, 1.00 mmol) was added portionwise over 30 min, and the reaction mixture was stirred at 0°C for an additional 1 h. Afterwards, the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one as a brown solid (142 mg), which was used directly in the next step without further purification.

[0609] A mixture of (E)-1-(2-fluoro-[1,1'-biphenyl]-4-yl)-3-(quinoxalin-6-yl)prop-2-en-1-one (110 mg) and hydrazine hydrate (39 μL, 50% w / w) in THF (2.5 mL) was stirred at reflux for 2 h. Succinic anhydride (93 mg, 0.93 mmol) was then added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (30 mL) and washed with water (2×20 mL) followed by brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Purification by flash column chromatography (CHCl, neat → CHCl / MeOH, 95:5) afforded compound 110 as a beige solid (25 mg, 7% over 2 steps). 1 H NMR (400MHz, DMSO-d6) δ12.09(1H,s),8.95–8.93(2H,m),8.09(1H,d,J=8.6Hz),7.92(1H,d, J=2.0Hz),7.77–7.70(3H,m),7.66(1H,t,J=8.1Hz),7.61–7.58(2H,m),7.53–7.48(2H,m),7. 46–7.42(1H,m),5.87(1H,dd,J=12.0,5.1Hz),4.01(1H,dd,J=18.2,12.0Hz),3.37(1H,dd,J= 18.3, 5.1Hz), 3.11 (1H, dt, J = 17.2, 6.7Hz), 2.99 (1H, dt, J = 17.2, 6.6Hz), 2.53–2.50 (2H, m); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),169.4(C),159.0(C,d,J C-F =246.6Hz),153.3(C),146.0(CH),145.6(CH),144.0(C),142.1(C),141.6(C),134.4(C),132.3(C,d,J C-F =8.6Hz),131.16(CH,d,J C-F =3.7Hz),129.8(C,d,J C-F =13.4Hz),129.8(CH),128.8(2×CH),128.7(2×CH),128.3(CH),128.1(CH),125.4(CH),123.2(CH),114.3(CH,d,J C-F=24.5Hz),59.8(CH),41.7(CH2),28.7(CH2),28.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 27 H 22 FN4O3, calculated value, 469.1670; measured value, 469.1670.

[0610] 4-(3-([1,1'-biphenyl]-4-yl)-5-(benzo[c][1,2,5]oxadiazol-5-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 111)

[0611]

[0612] To a solution of 2,1,3-benzoxadiazole-5-carbaldehyde (296 mg, 2.00 mmol) and 4-acetylbiphenyl (0.33 mL, 2.00 mmol) in EtOH (16 mL) was added 2 M NaOH (1.0 mL, 2.0 mmol) dropwise at 0° C., and the reaction mixture was stirred at 0° C. for 3 h. After that, the resulting precipitated solid was collected by filtration, washed with water and dried in vacuo to give (E)-1-([1,1′-biphenyl]-4-yl)-3-(benzo[c][1,2,5]oxadiazol-5-yl)prop-2-en-1-one as a green solid (535 mg), which was used directly in the next step without further purification.

[0613] A mixture of (E)-1-([1,1'-biphenyl]-4-yl)-3-(benzo[c][1,2,5]oxadiazol-5-yl)prop-2-en-1-one (250 mg) and hydrazine hydrate (95 μL, 50% w / w) in THF (6 mL) was stirred at reflux for 2 h. Afterwards, succinic anhydride (230 mg, 2.30 mmol) was added, and the reaction mixture was further stirred at reflux for 1 h. The resulting mixture was diluted in EtOAc (50 mL) and washed with water (2×30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 3:7 → EtOAc, neat) gave compound 111 as an orange solid (300 mg, 73% over 2 steps). 1H NMR (400MHz, CDCl3) δ7.84–7.81(3H,m),7.73–7.72(1H,m),7.68(2H,d,J=8.7Hz ),7.64–7.61(2H,m),7.49–7.45(2H,m),7.41–7.37(1H,m),7.28–7.26(1H,m),5. 69(1H,dd,J=12.0,5.1Hz),3.88(1H,dd,J=17.8,12.0Hz),3.32–3.23(1H,m),3.2 2(1H,dd,J=17.7,5.1Hz),3.12(1H,ddd,J=17.4,7.2,5.9Hz),2.82–2.69(2H,m); 13 CNMR(101MHz,CDCl3)δ177.4(C),170.3(C),154.3(C),149.3(C),148.9(C) ,144.6(C),143.8(C),140.1(C),130.2(CH),129.6(C),129.1(2×CH),128. 2(CH),127.7(2×CH),127.4(2×CH),127.2(2×CH),118.1(CH),112.8(CH),60.2(CH),41.4(CH2),29.1(CH2),28.7(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 25 H 20 N4NaO4, calculated value, 463.1377; measured value, 463.1377.

[0614] 4-(3-(4-chlorophenyl)-5-(3,4-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (Compound 112)

[0615]

[0616] Compound 112 was prepared over 2 steps using a method similar to that described for the preparation of compound 20 - Step 1: 3,4-difluorobenzaldehyde (142 mg, 1.00 mmol), 4-chloroacetophenone (0.13 mL, 1.00 mmol) and 2M NaOH (2.5 mL, 5.00 mmol) in EtOH (8 mL) to give (E)-1-(4-chlorophenyl)-3-(3,4-difluorophenyl)prop-2-en-1-one as a colorless solid (198 mg); Step 2: (E)-1-(4-chlorophenyl)-3-(3,4-difluorophenyl)prop-2-en-1-one (198 mg) and hydrazine hydrate (89 μL, 50% w / w) in THF (6 mL) followed by the addition of succinic anhydride (213 mg, 2.13 mmol). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 112 as an off-white solid (106 mg, 27% over 2 steps). 1 H NMR(400MHz, CDCl3)δ7.67(2H,d,J=8.7Hz),7.40(2H,d,J=8.8Hz),7.14–7.07(1H,m),7.02(1H,ddd,J=10.9,7.4,2.2Hz),6.98–6.94(1H ,m),5.54(1H,dd,J=11.9,4.8Hz),3.74(1H,dd,J=17.8,11.9Hz),3.18(1H,dt,J=17.4,6.7Hz),3.12–3.04(2H,m),2.73(2H,t,J=6.7Hz); 13 C NMR(101MHz, CDCl3)δ177.8(C),170.1(C),153.4(C),151.5(C,dd,J C-F =71.6,12.4Hz),149.1(C,dd,J C-F =70.4,12.7Hz),138.5(C),136.9(C),129.5(C),129.3(2×CH),128.1(2×CH),121.9(CH,dd,J C-F =5.9,3.2Hz),118.0(CH,d,J C-F =17.6Hz),114.9(CH,d,J C-F =18.0Hz),59.6(CH),42.2(CH2),29.0(CH2),28.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 19 H 15ClF2N2NaO3, calculated value, 415.0631; measured value, 415.0629.

[0617] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxydebutanamide (Compound 113)

[0618]

[0619] A mixture of (E)-1-(4-chlorophenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one (0.15 g, 0.51 mmol), 4-hydrazino-4-oxylidenebutanamide (67 mg, 0.51 mmol), and NaOH (20 mg, 0.51 mmol) in EtOH (3.0 mL) was heated at 80°C for 18 h. The resulting reaction mixture was then diluted with EtOAc (20 mL), washed with water (20 mL), and the separated aqueous layer was further extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and then brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (EtOAc, neat → EtOAc / MeOH, 20:1) gave compound 113 as a yellow solid (50 mg, 24%). 1 H NMR(300MHz, CDCl3)δ8.82–8.81(2H,m),8.10(1H,d,J=8.7Hz),7.95(1H,d,1.9Hz),7.70–7.63(3H,m),7.42–7 .38(2H,m),5.80(1H,dd,J=12.3,6.4Hz),3.85(1H,dd,J=17.2,12.3Hz),3.26–3.17(3H,m),2.62–2.52(2H,m).

[0620] 3-(3-([1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (Compound 114)

[0621]

[0622] A suspension of (E)-1-([1,1'-biphenyl]-3-yl)-3-(quinoxaline-6-yl)prop-2-en-1-one (200 mg, 0.595 mmol) and 3-hydrazinobenzoic acid (455 mg, 2.97 mmol) in AcOH (4 mL) was stirred at reflux for 6 h. The reaction mixture was poured into ice water, collected by filtration and dried in vacuo. Compound 114 was purified by flash column chromatography (petroleum ether / EtOAc, 7:3 → petroleum ether / EtOAc, 1:1) to give a yellow solid (31 mg, 11%, approximately 90% purity). 1 H NMR(400MHz, CDCl3)8.85–8.84(2H,m),8.13–8.11(2H,m),7.95(1H,t,J=1.8Hz),7.80–7.74(3H,m),7.64–7.57(3H,m),7.53–7.45(4H ,m),7.41–7.35(2H,m),7.29–7.25(1H,m),5.65(1H,dd,J=12.3,6.4Hz),4.06(1H,dd,J=17.2,12.3Hz),3.33(1H,dd,J=17.1,6.5Hz); 13 CNMR(101MHz, CDCl3)δ171.1(C),147.7(C),145.5(CH),145.2(CH),144.6(C),144.4(C),143. 1(C),142.7(C),141.9(C),140.9(C),132.8(C),131.1(CH),130.4(C),129.3(CH),129.2(CH) ,129.0(2×CH),128.2(CH),128.1(CH),127.7(CH),127.4(2×CH),126.5(CH),125.0(CH),124. 9(CH),121.2(CH),118.6(CH),114.7(CH),64.0(CH),43.7(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 30 H 22 N4NaO2, calculated value, 493.1635; measured value, 493.1638.

[0623] 4-(3-(4-Chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (Compound 115)

[0624]

[0625] Compound 115 was prepared using a method similar to that described for the preparation of compound 114 using (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). Purification by flash column chromatography (petroleum ether / EtOAc, 7:3 → petroleum ether / EtOAc, 1:1) gave compound 115 as a yellow solid (26 mg, 9%). 1 H NMR(400MHz,DMSO-d6)δ12.32(1H,br s),8.92(2H,s),8.11(1H,d,J=8.7Hz),7.98(1H,d,J=2.0Hz),7.82(2H,d,J=8.6Hz),7.75–7.71(3H,m),7.51(2H,d,J=8 .6Hz), 7.12(2H,d,J=9.0Hz), 5.99(1H,dd,J=12.2,5.1Hz), 4.07(1H,dd,J=17.8,12.3Hz), 3.35(1H,dd,J=18.0,5.2Hz); 13 CNMR(101MHz,DMSO-d6)δ167.1(C),148.9(C),146.7(C),146.1(CH),145.8(CH),143.5(C),142.1(C),141.7(C),133.8(C),130.9(2×CH),130.6 (C),130.5(CH),128.8(2×CH),128.0(CH),127.8(2×CH),125.8(CH),120.5(C),112.2(2×CH),62.2(CH),42.5(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 24 H 18 ClN4O2, calculated value, 429.1113; measured value, 429.1112.

[0626] N-(Methylsulfonyl)-4-oxydeoxy-4-(5-(quinoxalin-6-yl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)butanamide (Compound 116)

[0627]

[0628] Compound 116 was prepared according to a method similar to that described for the preparation of compound 55 using compound 8 (0.10 g, 0.22 mmol), methanesulfonamide (31 mg, 0.33 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (63 mg, 0.33 mmol) and 4-(dimethylamino)pyridine (DMAP) (32 mg, 0.26 mmol) in CHCl (2.2 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 116 as a colorless solid (74 mg, 63%). 1 H NMR (400MHz, CDCl3) δ9.57(1H,s),8.82(2H,s),8.11(1H,d,J=8.7Hz),7.95(1H,d,J=2.0Hz),7.79(2H,d,J=8.9Hz),7.64(1H,dd,J=8.7,2.0 Hz),7.28(2H,d,J=9.2Hz),5.87(1H,dd,J=11.8,4.7Hz),3.88(1H,dd,J=17.8,11.8Hz),3.33–3.17(3H,m),3.15(3H,s),2.72–2.52(2H,m); 13 C NMR(101MHz, CDCl3)δ171.7(C),170.5(C),154.2(C),151.1(C),145.6(CH),145.4(CH),143.2(C),143. 0(C),142.7(C),130.8(CH),129.4(C),128.6(2×CH),128.0(CH),126.0(CH),121.3(2×CH),120.5(C,q,J C-F =258.4Hz),60.3(CH),42.4(CH2),41.3(CH3),31.2(CH2),29.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 23 H 21 F3N5O5S, calculated value, 536.1210; measured value, 536.1211.

[0629] 4-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(methylsulfonyl)-4-oxylidenebutanamide (Compound 117)

[0630]

[0631] A solution of compound 64 (41 mg, 0.080 mmol), methanesulfonamide (11 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (23 mg, 0.12 mmol) and 4-(dimethylamino)pyridine (DMAP) (12 mg, 0.096 mmol) in CHCl (0.8 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with CHCl (30 mL), washed with 0.2 M aqueous HCl (2 x 15 mL), water (2 x 15 mL), then brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 117 as an off-white solid (23 mg, 50%). 1 H NMR (400MHz, CDCl3) δ8.81(2H,s),8.11(1H,d,J=8.7Hz),7.98(1H,d,J=2.0Hz),7.78(2H, d,J=8.5Hz),7.66(1H,dd,J=8.7,2.1Hz),7.62(2H,d,J=8.5Hz),7.55(2H,d,J=8.8Hz),6. 97(2H,d,J=8.8Hz),5.86(1H,dd,J=11.7,4.6Hz),4.61(1H,sevenfold,J=6.1Hz),3.90(1H,dd,J= 17.7,11.8Hz),3.35–3.18(3H,m),3.15(3H,s),2.69–2.52(2H,m),1.37(6H,d,J=6.0Hz); 13 C NMR(101MHz, CDCl3)δ171.8(C),170.4(C),158.3(C),155.5(C),145.5(CH),145.3(CH),1 43.53(C),143.46(C),143.1(C),142.7(C),132.2(C),130.8(CH),128.8(C),128.3(2×CH) ,128.1(CH),127.5(2×CH),127.0(2×CH),126.0(CH),116.4(2×CH),70.2(CH),60.2(CH), 42.4(CH2),41.3(CH3),31.4(CH2),29.2(CH2),22.2(2×CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 31 H 32N5O5S, calculated value, 586.2119; measured value, 586.2119.

[0632] N-(Isopropylsulfonyl)-4-oxyde-4-(5-(quinoxalin-6-yl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)butanamide (Compound 118)

[0633]

[0634] Compound 118 was prepared according to a method similar to that described for the preparation of compound 55 using compound 8 (46 mg, 0.10 mmol), propane-2-sulfonamide (25 mg, 0.20 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (38 mg, 0.20 mmol) and 4-(dimethylamino)pyridine (DMAP) (15 mg, 0.12 mmol) in CHCl (1.0 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure) gave compound 118 as a colorless solid (37 mg, 65%). 1 H NMR (400MHz, CDCl3) δ9.31(1H,s),8.81(2H,s),8.10(1H,d,J=8.7Hz),7.95(1H,d,J=2.0Hz),7.78( 2H,d,J=8.8Hz),7.64(1H,dd,J=8.7,2.1Hz),7.28(2H,d,J=9.0Hz),5.87(1H,dd,J=11.8,4.7Hz),3. 87(1H,dd,J=17.8,11.9Hz),3.63(1H,sevenfold,J=6.9Hz),3.33(1H,dt,J=17.9,6.4Hz),3.22(1H,dd,J=1 7.8,4.7Hz),3.20–3.11(1H,m),2.65(2H,t,J=6.4Hz),1.27(3H,d,J=6.9Hz),1.11(3H,d,J=6.8Hz); 13 C NMR(101MHz, CDCl3)δ171.6(C),170.5(C),154.0(C),151.1(C),145.6(CH),145.3(CH),143.3(C),143. 0(C),142.6(C),130.8(CH),129.4(C),128.6(2×CH),128.0(CH),126.0(CH),121.2(2×CH),120.5(C,q,J C-F=258.2Hz),60.3(CH),53.8(CH),42.3(CH2),31.3(CH2),29.1(CH2),15.9(CH3),15.7(CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 25 H 25 F3N5O5S, calculated value, 564.1523; measured value, 564.1524.

[0635] 4-(3-([1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(isopropylsulfonyl)-4-oxylidenebutanamide (Compound 119)

[0636]

[0637] Compound 119 was prepared according to a method similar to that described for the preparation of compound 117 using compound 13 (68 mg, 0.15 mmol), propane-2-sulfonamide (28 mg, 0.22 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (43 mg, 0.22 mmol) and 4-(dimethylamino)pyridine (DMAP) (22 mg, 0.18 mmol) in CHCl (1.5 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 119 as a colorless solid (42 mg, 50%). 1 H NMR (400MHz, CDCl3) δ8.80(2H,s),8.10(1H,d,J=8.7Hz),7.98(1H,d,J=2.0Hz),7.95(1H,t,J=1.8Hz) ,7.72–7.59(5H,m),7.52–7.44(3H,m),7.38(1H,t,J=7.3Hz),5.88(1H,dd,J=11.8,4.6Hz),3.92(1H, dd,J=17.8,11.8Hz),3.64(1H,sevenfold,J=7.0Hz),3.37(1H,dt,J=17.9,6.4Hz),3.28(1H,dd,J=17.8,4.7H z), 3.17 (1H, dt, J = 17.7, 6.4Hz), 2.66 (2H, t, J = 6.5Hz), 1.27 (3H, d, J = 6.8Hz), 1.11 (3H, d, J = 6.8Hz); 13CNMR(101MHz, CDCl3)δ171.7(C),170.5(C),155.4(C),145.5(CH),145.2(CH),143.5(C),143. 0(C),142.6(C),142.2(C),140.3(C),131.3(C),130.7(CH),129.8(CH),129.4(CH),129.1(2× CH),128.1(CH),128.0(CH),127.3(2×CH),126.0(CH),125.8(CH),125.7(CH),60.2(CH),53.7 (CH),42.5(CH2),31.4(CH2),29.2(CH2),15.9(CH3),15.7(CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 30 H 30 N5O4S, calculated value, 556.2013; measured value, 556.2009.

[0638] 4-(3-(4'-Isopropoxy-[1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(isopropylsulfonyl)-4-oxylidenebutanamide (Compound 120)

[0639]

[0640] Compound 120 was prepared according to a method similar to that described for the preparation of compound 117 using compound 64 (46 mg, 0.090 mmol), propane-2-sulfonamide (17 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (26 mg, 0.14 mmol) and 4-(dimethylamino)pyridine (DMAP) (13 mg, 0.11 mmol) in CHCl (0.9 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 120 as a yellow solid (27 mg, 49%). 1H NMR (400MHz, CDCl3) δ9.25 (1H, br s),8.83–8.82(2H,m),8.11(1H,d,J=8.7Hz),7.97(1H,d,J=2.0Hz),7.79(2H,d,J=8.7Hz),7.67(1H, dd,J=8.7,2.1Hz),7.63(2H,d,J=8.7Hz),7.55(2H,d,J=8.9Hz),6.98(2H,d,J=8.9Hz),5.85(1H,dd, J=11.8,4.6 Hz), 4.61 (1H, septet, J=6.0 Hz), 3.92 (1H, dd, J=17.7,11.8 Hz), 3.66 (1H, septet, J=6.8 Hz), 3.41–3.17 (3H, m), 2.73–2.61 (2H, m), 1.37 (6H, d, J=6.1 Hz), 1.30 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=6.8 Hz); 13 C NMR(101MHz, CDCl3)δ171.6(C),170.4(C),158.3(C),155.3(C),145.5(CH),145.3(CH),143. 5(2×C),143.1(C),142.7(C),132.2(C),130.8(CH),128.9(C),128.3(2×CH),128.1(CH),127 .5(2×CH),127.0(2×CH),126.1(CH),116.4(2×CH),70.2(CH),60.2(CH),53.8(CH),42.4(CH2 ),31.7(CH2),29.4(CH2),22.2(2×CH3),16.0(CH3),15.7(CH3); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 33 H 36 N5O5S, calculated value, 614.2432; measured value, 614.2432.

[0641] N-(tert-Butylsulfonyl)-4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxylidenebutanamide (Compound 121)

[0642]

[0643] Compound 121 was prepared according to a method similar to that described for the preparation of compound 117 using compound 1 (0.10 g, 0.24 mmol), tert-butylsulfonamide (49 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (69 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2.4 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 121 as an off-white solid (66 mg, 52%). 1 H NMR (400MHz, CDCl3) δ8.80(2H,s),8.08(1H,d,J=8.8Hz),7.94(1H,d,J=2.0Hz),7.67(2H,d,J=8.6Hz),7.63(1H,dd,J=8.7,2.1Hz),7 .40(2H,d,J=8.7Hz),5.82(1H,dd,J=11.9,4.8Hz),3.84(1H,dd,J=17.7,11.9Hz),3.30–3.14(3H,m),2.75–2.60(2H,m),1.29(9H,s); 13 CNMR(101MHz, CDCl3)δ170.8(C),170.4(C),154.1(C),145.5(CH),145.3(CH),143.4(C),143.1(C),142.7(C),137.1(C),130.8(CH),129.4(C),129 .3(2×CH),128.2(2×CH),128.1(CH),126.0(CH),62.1(C),60.3(CH),42.3(CH2),31.8(CH2),29.3(CH2),24.3(3×CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 25 H 26 ClN5NaO4S, calculated value, 550.1286; measured value, 550.1289.

[0644] 4-(3-([1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxyylidene-N-(phenylsulfonyl)butanamide (Compound 122)

[0645]

[0646] Compound 122 was prepared according to a method similar to that described for the preparation of compound 117 using compound 13 (68 mg, 0.15 mmol), benzenesulfonamide (35 mg, 0.22 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (43 mg, 0.22 mmol) and 4-(dimethylamino)pyridine (DMAP) (22 mg, 0.18 mmol) in CHCl (1.5 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 122 as a colorless solid (50 mg, 56%). 1 H NMR (400MHz, DMSO-d6) δ12.11(1H,s),8.95–8.93(2H,m),8.07(1H,d,J=8.7Hz),7.99(1H,t,J=1. 8Hz),7.90–7.87(3H,m),7.83(1H,dt,J=7.6,1.3Hz),7.77(1H,ddd,J=7.8,1.9,1.1Hz),7.73–7.6 8(3H,m),7.63–7.59(1H,m),7.58–7.45(5H,m),7.41–7.37(1H,m),5.81(1H,dd,J=11.9,5.0Hz),4 .02(1H,dd,J=18.3,12.0Hz),3.43(1H,dd,J=18.3,5.0Hz),3.08–2.93(2H,m),2.61–2.52(2H,m); 13 C NMR(101MHz,DMSO-d6)δ170.9(C),168.9(C),154.6(C),146.0(CH),145.6(CH),144.1(C),142 .1(C),141.6(C),140.7(C),139.5(C),139.4(C),133.4(CH),131.6(C),129.8(CH),129.4(CH) ,129.0(4×CH),128.7(CH),128.1(CH),127.8(CH),127.3(2×CH),126.8(2×CH),125.6(CH),125 .3(CH),125.1(CH),59.6(CH),41.8(CH2),30.0(CH2),27.8(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 33 H 28 N5O4S, calculated value, 590.1857; measured value, 590.1857.

[0647] 4-(3-([1,1'-biphenyl]-4-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxyylidene-N-(phenylsulfonyl)butanamide (Compound 123)

[0648]

[0649] Compound 123 was prepared according to a method similar to that described for the preparation of compound 55 using compound 15 (59 mg, 0.13 mmol), benzenesulfonamide (31 mg, 0.20 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (37 mg, 0.20 mmol) and 4-(dimethylamino)pyridine (DMAP) (19 mg, 0.16 mmol) in CHCl (1.3 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure) gave compound 123 as a yellow solid (25 mg, 33%). 1 H NMR (400MHz, CDCl3) δ9.95 (1H, br s),8.83(2H,s),8.11(1H,d,J=8.7Hz),7.98(1H,d,J=2.1Hz),7.97–7.9 4(2H,m),7.80(2H,d,J=8.6Hz),7.68–7.60(5H,m),7.54–7.50(1H,m),7. 49–7.37(5H,m),5.90(1H,dd,J=11.7,4.5Hz),3.91(1H,dd,J=17.7,11.8 Hz),3.27(1H,dd,J=17.8,4.6Hz),3.27–3.13(2H,m),2.68–2.53(2H,m); 13 C NMR(101MHz, CDCl3)δ170.5(C),170.4(C),155.4(C),145.6(CH),145.3(CH),143.9(C),143. 4(C),143.1(C),142.7(C),140.1(C),139.1(C),133.7(CH),130.8(CH),129.6(C),129.1(2×C H),128.9(2×CH),128.4(2×CH),128.2(CH),128.1(CH),127.6(2×CH),127.5(2×CH),127.2(2 ×CH),126.0(CH),60.2(CH),42.5(CH2),31.5(CH2),29.0(CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C33 H 27 N5NaO4S, calculated value, 612.1676; measured value, 612.1673.

[0650] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxyylidene-N-(o-tolylsulfonyl)butanamide (Compound 124)

[0651]

[0652] Compound 124 was prepared according to a method similar to that described for the preparation of compound 117 using compound 1 (0.10 g, 0.24 mmol), o-toluenesulfonamide (62 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (69 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2.4 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 124 as a colorless solid (89 mg, 66%). 1 H NMR (400MHz, DMSO-d6) δ12.17(1H,s),8.94–8.93(2H,m),8.04(1H,d,J=8.7Hz),7.91(1H,dd,J=7. 9,1.4Hz),7.87(1H,d,J=2.0Hz),7.79(2H,d,J=8.6Hz),7.65(1H,dd,J=8.7,2.1Hz),7.52(2H,d,J= 8.6Hz),7.47(1H,td,J=7.5,1.5Hz),7.34–7.29(2H,m),5.78(1H,dd,J=12.0,5.1Hz),3.93(1H,dd, J=18.3,12.0Hz),3.28(1H,dd,J=18.3,5.2Hz),3.02–2.89(2H,m),2.57–2.55(2H,m),2.54(3H,s); 13C NMR(101MHz,DMSO-d6)δ170.7(C),168.9(C),153.6(C),146.0(CH),145.6(CH),143.9(C) ,142.1(C),141.6(C),137.5(C),136.8(C),135.0(C),133.2(CH),132.2(CH),129.9(CH) ,129.80(CH),129.79(C),128.8(2×CH),128.5(2×CH),128.1(CH),126.0(CH),125.4(CH) ,59.7(CH),41.6(CH2),29.9(CH2),27.9(CH2),19.4(CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 24 ClN5NaO4S, calculated value, 584.1130; measured value, 584.1131.

[0653] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxyylidene-N-toluenesulfonylbutyramide (Compound 125)

[0654]

[0655] Compound 125 was prepared by a method similar to that described for the preparation of compound 117 using compound 1 (0.10 g, 0.24 mmol), p-toluenesulfonamide (62 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (69 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2.4 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 125 as a colorless solid (76 mg, 56%). 1H NMR (400MHz, DMSO-d6) δ12.02(1H,s),8.95–8.93(2H,m),8.06(1H,d,J=8.7Hz),7.88(1H,d,J=2.0Hz ),7.80(2H,d,J=8.7Hz),7.76(2H,d,J=8.4Hz),7.66(1H,dd,J=8.7,2.0Hz),7.53(2H,d,J=8.7Hz),7. 32(2H,d,J=8.7Hz), 5.79(1H,dd,J=12.0,5.1Hz), 3.94(1H,dd,J=18.3,12.1Hz), 3.28(1H,dd,J=18.4 ,5.2Hz),3.00(1H,dt,J=17.2,6.6Hz),2.92(1H,dt,J=17.2,6.7Hz),2.54–2.51(2H,m),2.34(3H,s); 13 C NMR(101MHz,DMSO-d6)δ170.7(C),168.9(C),153.6(C),146.0(CH),145.6(CH),144. 0(C),143.9(C),142.1(C),141.6(C),136.6(C),135.0(C),129.82(C),129.79(CH), 129.4(2×CH),128.9(2×CH),128.5(2×CH),128.0(CH),127.4(2×CH),125.4(CH),59. 7(CH),41.7(CH2),30.0(CH2),27.8(CH2),21.0(CH3); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 28 H 24 ClN5NaO4S, calculated value, 584.1130; measured value, 584.1131.

[0656] N-(N,N-dimethylsulfamoyl)-4-oxyylidene-4-(5-(quinoxalin-6-yl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)butanamide (Compound 126)

[0657]

[0658] Compound 126 was prepared by a method similar to that described for the preparation of compound 55 using compound 8 (46 mg, 0.10 mmol), N,N-dimethylsulfonamide (25 mg, 0.20 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (38 mg, 0.20 mmol) and 4-(dimethylamino)pyridine (DMAP) (15 mg, 0.12 mmol) in CHCl (1.0 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, neat) gave compound 126 as a colorless solid (38 mg, 67%). 1 H NMR (400MHz, CDCl3) δ9.02(1H,s),8.81(2H,s),8.10(1H,d,J=8.7Hz),7.95(1H,d,J=2.0H z),7.78(2H,d,J=9.0Hz),7.65(1H,dd,J=8.7,2.0Hz),7.28(2H,d,J=9.0Hz),5.85(1H,dd, J=11.8,4.7Hz),3.88(1H,dd,J=17.8,11.9Hz),3.30(1H,ddd,J=18.1,7.4,5.4Hz),3.23(1 H,dd,J=17.7,4.8Hz),3.17(1H,ddd,J=18.0,7.7,5.6Hz),2.76(6H,s),2.67–2.54(2H,m); 13 C NMR(101MHz, CDCl3)δ171.0(C),170.4(C),153.8(C),151.0(C,q,J C-F =1.8Hz),145.6(CH),145.3(CH),143.4(C),143.1(C),142.7(C),130.8(CH) ,129.5(C),128.6(2×CH),128.0(CH),126.1(CH),121.3(2×CH),120.5(C,q,J C-F =258.3Hz),60.3(CH),42.3(CH2),38.2(2×CH3),30.9(CH2),29.3(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 24 H 24 F3N6O5S, calculated value, 565.1475; measured value, 565.1475.

[0659] 4-(3-([1,1'-biphenyl]-3-yl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(N,N-dimethylsulfamoyl)-4-oxylidenebutanamide (Compound 127)

[0660]

[0661] Compound 127 was prepared by a method similar to that described for the preparation of compound 117 using compound 13 (68 mg, 0.15 mmol), N,N-dimethylsulfonamide (28 mg, 0.22 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (43 mg, 0.22 mmol) and 4-(dimethylamino)pyridine (DMAP) (22 mg, 0.18 mmol) in CHCl (1.5 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, neat) gave compound 127 as a colorless solid (58 mg, 69%). 1 H NMR (400MHz, CDCl3) δ8.81(2H,s),8.10(1H,d,J=8.7Hz),7.97(2H,d,J=11.1Hz),7.73–7.60(5H,m),7.53–7.45(3H,m),7.39(1H,t,J=7.3Hz),5. 87(1H,dd,J=11.8,4.6Hz),3.94(1H,dd,J=17.8,11.8Hz),3.39–3.28(2H ,m),3.20(1H,ddd,J=18.1,7.5,5.4Hz),2.76(6H,s),2.68–2.56(2H,m); 13 C NMR(101MHz, CDCl3)δ171.1(C),170.4(C),155.3(C),145.5(CH),145.3(CH),143.6(C), 143.1(C),142.7(C),142.2(C),140.4(C),131.4(C),130.8(CH),129.8(CH),129.4(CH), 129.1(2×CH),128.1(CH),128.0(CH),127.3(2×CH),126.1(CH),125.8(CH),125.7(CH), 60.2(CH),42.5(CH2),38.2(2×CH3),31.0(CH2),29.4(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 29 H 29N6O4S, calculated value, 557.1966; measured value, 557.1965.

[0662] 4-(3-(4-chlorophenyl)-5-(quinoxalin-6-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxyylidene-N-(pyrrolidin-1-ylsulfonyl)butanamide (Compound 128)

[0663]

[0664] Compound 128 was prepared by a method similar to that described for the preparation of compound 117 using compound 1 (0.10 g, 0.24 mmol), pyrrolidine-1-sulfonamide (54 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (69 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (DMAP) (35 mg, 0.29 mmol) in CHCl (2.4 mL). Purification by flash column chromatography (petroleum ether / EtOAc, 1:1→EtOAc, pure) gave compound 128 as a colorless solid (73 mg, 56%). 1 H NMR (400MHz, CDCl3) δ8.81(2H,s),8.09(1H,d,J=8.7Hz),7.95(1H,d,J=2.1Hz),7.68(2H,d,J=8.9Hz),7.64(1H,dd,J=8.7,2.0Hz),7.40(2H,d,J= 8.9Hz),5.83(1H,dd,J=11.8,4.8Hz),3.85(1H,dd,J=17.7,11.9Hz),3.4 3–3.28(4H,m),3.28–3.12(3H,m),2.66–2.54(2H,m),1.68–1.59(4H,m); 13 C NMR(101MHz, CDCl3)δ170.8(C),170.4(C),154.0(C),145.5(CH),145.3(CH ),143.5(C),143.1(C),142.7(C),137.1(C),130.8(CH),129.4(C),129.3( 2×CH),128.2(2×CH),128.0(CH),126.0(CH),60.3(CH),48.7(2×CH2),42.3(CH2),30.8(CH2),29.2(CH2),25.7(2×CH2); HRMS(ESI / Q-TOF)m / z:[M+Na] + , C 25 H 25ClN6NaO4S, calculated value, 563.1239; measured value, 563.1239.

[0665] 4-Oxylidene-4-(6-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-yl)butanoic acid (Compound 129)

[0666]

[0667] To a solution of quinoxaline-6-carbaldehyde (277 mg, 1.75 mmol) and 5-phenyl-1-tetralone (389 mg, 1.75 mmol) in EtOH (14 mL) was added 2M NaOH (4.4 mL, 8.75 mmol) dropwise at room temperature, and the reaction mixture was stirred for 3 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give (E)-5-phenyl-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one as a colorless solid (520 mg), which was used directly in the next step without further purification.

[0668] To a stirred solution of (E)-5-phenyl-2-(quinoxalin-6-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (300 mg) in EtOH (7 mL) was added hydrazine hydrate (0.10 mL, 50% w / w), and the reaction mixture was heated under reflux for 2 h. Afterwards, the solution was cooled to 0° C., and the resulting precipitated solid was collected by filtration, washed with water, and dried in vacuo to give 6-phenyl-3-(quinoxalin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole as a yellow solid (259 mg), which was used in the next step without further purification.

[0669] A mixture of 6-phenyl-3-(quinoxaline-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole (259 mg) and succinic anhydride (103 mg, 1.03 mmol) in THF (5 mL) was stirred at reflux for 1 h. The solvent was then removed in vacuo, and the crude material was purified by flash column chromatography (petroleum ether / EtOAc, 1:1 → EtOAc, pure → CH2Cl2 / MeOH, 9:1). The resulting solid was washed with CH2Cl2 and isolated by filtration to afford compound 129 as an off-white solid (154 mg, 32% over 3 steps). 1HNMR(400MHz,DMSO-d6)δ12.07(1H,s),8.95–8.93(2H,m),8.09(1H,d,J=8.7Hz),8.0 2–7.99(2H,m),7.81(1H,dd,J=8.7,2.0Hz),7.46–7.35(4H,m),7.32–7.29(3H,m),5. 28(1H,d,J=9.7Hz),3.43(1H,ddd,J=14.0,9.7,4.8Hz),3.11–2.84(3H,m),2.64–2.5 9(1H,m),2.50–2.47(2H,m),2.26–2.23(1H,m),1.91(1H,ddd,J=12.8,12.8,4.6Hz); 13 C NMR(101MHz,DMSO-d6)δ173.7(C),170.6(C),155.6(C),145.9(CH),145.5(CH),143.9(C),1 42.2(C),142.0(C),141.6(C),140.4(C),137.1(C),131.7(CH),129.5(CH),128.8(2×CH),1 28.33(2×CH),128.28(CH),127.4(C),127.3(CH),126.6(CH),125.8(CH),123.7(CH),66.7( CH),54.1(CH),29.0(CH2),28.4(CH2),27.4(CH2),27.1(CH2); HRMS(ESI / Q-TOF)m / z:[M+H] + , C 29 H 25 N4O3, calculated value, 477.1921; measured value, 477.1921.

[0670] In vitro studies

[0671] The compounds of the present invention were initially screened for activity using a fully automated in vitro incubation system designed to measure total gas production and gas composition (methane and hydrogen). The system used is described in detail in a paper by Muetzel et al. (2014; Animal Feed Science and Technology 196, 1-11). The system herein is referred to as the Rumen In Vitro System, or RIV. The RIV system provides a relatively simple tool for determining methane production and rate, and whether these rates and rates are inhibited or reduced by a specific compound or feed.

[0672] Rumen in vitro assay method.

[0673] Rumen in vitro assays use rumen fluid from a donor animal (usually sheep or cattle), which is typically combined with a buffer and then incubated in a sealed fermentation vessel at 39°C for 24 or 48 hours. These assay systems have been well characterized and used by the scientific community over the past two decades (Rymer et al., 2005). Muetzel et al. (2014) describe the system used here to characterize the effects of inhibitors on methane and gas production, as well as H2 formation. Rumen in vitro assay systems reflect what occurs in vivo in the rumen, but only in the short term because their incubation time is short (usually no more than 48 hours), which is limited by its buffering capacity and the fact that it is a closed system.

[0674] The inhibitor stock solution was resuspended in dimethylformamide (DMF) at a concentration 1000-fold the highest concentration used in the assay. Any further dilutions were also prepared in DMF. The total amount of inhibitor solution added to the rumen fluid-buffer mixture (60 mL) was 60 μl. Serum bottles were incubated for 24-48 h using 60 ml of medium containing 12 ml of filtered rumen fluid and 48 ml of buffer, essentially as described by Muetzel et al. (2014). Two fistulated cattle were used as donor animals for the rumen fluid and incubated in replicate bottles. Multiple replicate incubation vials containing ryegrass (with the rumen fluid-buffer mixture) and ryegrass with 30 μM bromoethane sulfonate (BES) were also incubated as negative and positive controls, respectively. One experiment consisted of 2 replicates of inhibitor run at any one concentration at the same time, and a run could contain up to 32 vials, including positive (30 μM BES) and negative (no inhibitor added) controls.

[0675] For example, Compound 1 was tested at final concentrations of 50 μM, 10 μM, and 2 μM using a 60 mL rumen in vitro assay system 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.

[0676] Table 1

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696] In vivo studies

[0697] The animal experiments described in this manual were reviewed and approved by the Grasslands Animal Ethics Committee (Palmerston North, New Zealand), and all animals were cared for in accordance with the Code of Ethical Conduct (Animal Welfare Act, 1999) and its amendments.

[0698] Mouse toxicity test

[0699] The potential toxicology of compound 19 was tested according to OECD 423. The mouse test used two groups of three mice (female Swiss mice, not pregnant) in each group, all of which were about 8-9 weeks old. On the test day, food was stopped 1-2 hours before dosing. After fasting, the animals were weighed and the test substance was administered. Feeding was resumed 1-2 hours after administration of the compound. The compound was administered in a single dose (up to 0.3 ml per dose) by oral gavage in corn oil at a selected dose, and the time was recorded. After dosing, the mice were observed individually, observed at least once during the first 30 minutes, regularly observed within the first 24 hours, with special attention to the first 4 hours, and then observed every day for a total of 14 days. Every seven days (days 0, 7, and 14), the mice were weighed. All observations of each individual animal were systematically recorded. These observations included (if present): tremor, convulsions, salivation, diarrhea, lethargy, sleep, coma, and changes in fur, skin, eyes, mucous membranes, respiration, motor activity, and behavior.Compound 19 had no adverse effects at 300 mg / kg.

[0700] In vivo assay

[0701] Example 1 - In vivo study of methane emissions from sheep

[0702] As required by ACVM regulations, the test for the test of the impact of compound 19 on the methane emissions of sheep in a 96-hour period in a methane measurement chamber has been approved by the Grassland Animal Ethics Committee, and the use of these compounds in animals has been approved by the New Zealand Food Safety Authority (New Zealand Food Safety Authority). Each compound 19 treatment group uses three sheep. During the entire trial, these animals received a general diet (GP) consisting of 500g hay, 100g soybean meal, 290g barley, 100g molasses and 10g mineral mixture according to 1.5 times of maintenance energy requirements. During the time in the respiration chamber, animals had free access to water, and an equal amount of feed was provided at approximately 9:00 and 16:00h twice a day. The remaining refusals feed was weighed.

[0703] Before entering the methane measurement chamber, allow animals to adapt to the GP diet for 14 days. Before measuring methane emissions in the respiratory chamber and on the second day after release from the chamber, rumen contents were sampled by gastric tube to examine any effects on volatile fatty acids (VFA) in the future. Rumen samples from gastric tubes were immediately subsampled for short-chain fatty acid (SCFA) analysis (1.8 ml). The samples were centrifuged (20,000 g, 10 min, 4 ° C). 0.9 ml of supernatant aliquots were collected into 0.1 ml internal standard (19.8 mM ethyl butyrate in 20% v / v phosphoric acid) for SCFA analysis and stored at -20 ° C. SCFA samples were thawed and centrifuged (20,000 g, 10 min, 4 ° C), and 800 μ l of supernatant was collected into a crimp cap glass bottle. SCFA (Attwood et al., 1998) were analyzed by HP 6890 gas chromatograph.

[0704] After a 14-day acclimatization period, methane emissions were measured in an open-circuit respiration chamber as described in Chapter 1 of the Technical Manual for Respiration Chamber Design (http: / / www.globalresearchalliance.org / wp-content / uploads / 2012 / 03 / GRA-MAN-Facility-BestPract-2012-ch13.pdf). During the methane measurement period, dry matter intake (DMI, kg / d) was recorded based on the weight difference between the provided and remaining uneaten feed. The first day in the chamber (24-hour period) served as a control for each animal. Over the next three days, the sheep received 121.3 mg of Compound 19 per day (72-hour period, Period 2).

[0705] result

[0706] Methane gas output was determined over a 96-hour period (the first 24 hours were used for background measurements (Period 1), followed by three days of dosing) in an open-circuit respiration chamber and is summarized in Table 1 .

[0707] Table 1. % methane inhibition produced by once daily gavage of Compound 19 at a dose of 121.3 mg / day - average values ​​of 3 animals in each of the control and Compound 19 groups.

[0708]

[0709] It is expected that the RIV results for compounds of Formula I will be somewhat predictive of in vivo activity in reducing methane production in the rumen.

[0710] Example 2 - In vivo study of methane emissions from sheep

[0711] The test of the test of the impact of compound 60, compound 69, compound 67 and compound 64 on the methane emission of sheep in the time period of 96 hours in the methane measurement chamber has been approved by the Grassland Animal Ethics Committee. Each compound 60 and compound 69 treatment group uses three sheep, while each compound 67 and compound 64 treatment group uses six sheep. During the whole test period, these animals accept a general diet (GP) according to 1.5 times of maintaining energy demand, which consists of 500g hay, 100g soybean meal, 290g barley, 100g molasses and 10g mineral mixture. During the time in the respiratory chamber, animals have free access to water, and twice a day at about 9:00 and 16:00h an equal amount of feed is provided. The remaining uneaten feed is weighed.

[0712] The animals were acclimated to the GP diet for 14 days before entering the methane measurement chamber. Rumen contents were sampled via a gastric tube before methane emissions were measured in the respiration chamber and on the second day after release from the chamber to allow for future examination of any effects on volatile fatty acids (VFA). Rumen samples from the gastric tube were immediately subsampled for short chain fatty acid (SCFA) analysis (1.8 ml). The samples were centrifuged (20,000 g, 10 min, 4°C). Aliquots of 0.9 ml of the supernatant were collected into 0.1 ml of internal standard (19.8 mM ethyl butyrate in 20% v / v phosphoric acid) for SCFA analysis and stored at -20°C. The SCFA samples were thawed and centrifuged (20,000 g, 10 min, 4°C) and 800 μl of supernatant were collected into press-capped glass vials. SCFA were analyzed by HP 6890 gas chromatograph ( Attwood et al., 1998 ).

[0713] After a 14-day acclimation period, methane emissions were measured in an open-circuit respiration chamber as described in Chapter 1 of the Technical Manual for Respiration Chamber Design ( http: / / www.globalresearchalliance.org / wp-content / uploads / 2012 / 03 / GRA-MAN-Facility-BestPract-2012-ch13.pdf During the methane measurement period, dry matter intake (DMI, kg / d) was recorded based on the weight difference between the provided and remaining uneaten feed. The first day in the room (24-hour period; Time Period 1) served as a control for each animal. Over the next three days, the sheep received 412, 311, 414, and 344 mg of Compound 60, Compound 69, Compound 67, and Compound 64, respectively, daily (72-hour period; Time Period 2).

[0714] result

[0715] Methane gas output was determined over a 96-hour period (the first 24 hours were used for background measurements (Period 1), followed by three days of dosing (Period 2)) in an open-circuit respiration chamber and is summarized in Table 2.

[0716] Table 2. % methane inhibition produced by twice daily dosing of Compound 60, Compound 69, Compound 67, and Compound 64 in the feed to sheep. Methane inhibition is the average of all animals in each control and treatment group.

[0717]

[0718]

[0719] Example 3 In vivo cattle study on methane emissions

[0720] The test of the test of the influence of compound 64 of various dosage on the methane emission of cattle in four 48-hour time periods in the methane measurement chamber has obtained the approval of the grassland animal ethics committee.Each of two compound 64 treatment groups uses four cows (Friesian (Friesian) milk heifers, about 400kg).During the whole test period, these animals accept general diet (GP) according to 1.5 times of maintaining energy demand, and it is composed of 500g hay, 100g soybean meal, 290g barley, 100g molasses and 10g mineral mixture.During the time in the respiratory chamber, animals have free drinking water, and twice a day at about 9:00 and 16:00h provide equal amounts of feed.Remaining uneaten feed is weighed.

[0721] The animals were acclimated to the GP diet for 14 days before entering the methane measurement chamber. Rumen contents were sampled via a gastric tube before methane emissions were measured in the respiration chamber and on the second day after release from the chamber to allow for future examination of any effects on volatile fatty acids (VFA). Rumen samples from the gastric tube were immediately subsampled for short chain fatty acid (SCFA) analysis (1.8 ml). The samples were centrifuged (20,000 g, 10 min, 4°C). Aliquots of 0.9 ml of the supernatant were collected into 0.1 ml of internal standard (19.8 mM ethyl butyrate in 20% v / v phosphoric acid) for SCFA analysis and stored at -20°C. The SCFA samples were thawed and centrifuged (20,000 g, 10 min, 4°C) and 800 μl of supernatant were collected into press-capped glass vials. SCFA were analyzed by HP 6890 gas chromatograph ( Attwood et al., 1998 ).

[0722] After a 14-day acclimation period, methane emissions were measured in an open-circuit respiration chamber as described in Chapter 1 of the Technical Manual for Respiration Chamber Design ( http: / / www.globalresearchalliance.org / wp-content / uploads / 2012 / 03 / GRA-MAN-Facility-BestPract-2012-ch13.pdf). During the methane measurement period, dry matter intake (DMI, kg / d) was recorded according to the weight difference of the provided and remaining uneaten feed. Chamber measurement was performed once a week for five weeks. The first time period in the chamber (a 48-hour time period; Time period 1) served as the control for each animal. Over the next three to five days, two groups of cattle (low-dose and high-dose groups) received 50 and 150 mg of compound 64 every day, respectively, and were then measured in the chamber (a 48-hour time period; Time period 2). The cattle then received 150 and 450 mg of compound 64 every day, respectively, and the methane measurement in the chamber was performed once a week (a 48-hour time period; Time periods 3, 4, and 5).

[0723] result

[0724] Methane gas output was determined for four 48 hour treatment periods (Periods 2-5) in the open circuit respiration chamber and is summarized in Table 1. Little or no uneaten feed remained.

[0725] Table 1. % methane inhibition produced by twice daily dosing of Compound 64 in the feed to cattle. Methane inhibition is the average of all animals in each treatment group.

[0726]

[0727] The present invention and examples thereof have been described in detail. However, the scope of the present invention is not intended to be limited to the specific examples of the invention described in the specification. Various modifications, substitutions, and variations may be made to the disclosed materials without departing from the spirit and / or essential characteristics of the invention. Therefore, one of ordinary skill in the art will readily understand from this disclosure that subsequent modifications, substitutions, and / or variations that perform substantially the same functions or achieve substantially the same results as the examples described herein may be utilized based on such related examples of the present invention. Therefore, the following claims are intended to cover within their scope modifications, substitutions, and variations to the examples of the invention disclosed herein.

[0728] Numbering implementation method

[0729] 1 A compound of formula II

[0730]

[0731] Wherein R can be selected from:

[0732] or

[0733] -C(=O)-C1-C6-C(=O)-NH2, -C(=O)-C1-C6-C(=O)-NH-C1-C6, -C(=O)-C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0734] -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-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

[0735] -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-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-S(O)2-NH-C1-C6-heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0736] -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

[0737] -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)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0738] -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

[0739] -C1-C6-C(=O)-NH2, -C1-C6-C(=O)-NH-C1-C6, -C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0740] -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

[0741] -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-C6-heteroaryl、-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2、 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0742] -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

[0743] -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、 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0744] or

[0745] -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

[0746] -C(=O)-aryl-C(=O)-NH2, -C(=O)-aryl-C(=O)-NH-C1-C6, -C(=O)-aryl-C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0747] -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

[0748] -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 )-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-NH-C1-C6-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0749] -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

[0750] -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-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0751] or

[0752] -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, or

[0753] -aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0754] -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

[0755] -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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0756] -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

[0757] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0758] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0759] -aryl-S(O)2-NH-C3-C8-cycloalkyl, or

[0760] -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

[0761] -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, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0762] -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

[0763] -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 )-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-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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0764] -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

[0765] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0766] or

[0767] -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, or

[0768] -heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0769] -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

[0770] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0771] -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

[0772] -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-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-;

[0773] or

[0774] -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

[0775] -C1-C6-aryl-C(=O)-NH2, -C1-C6-aryl-C(=O)-NH-C1-C6, -C1-C6-aryl-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0776] -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, -C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0777] -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 6-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-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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0778] -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

[0779] -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-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0780] -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-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0781] -C1-C6-aryl-S(O)2-NH-C3-C8-cycloalkyl, or

[0782] -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

[0783] -C1-C6-heteroaryl-C(=O)-NH2, -C1-C6-heteroaryl-C(=O)-NH-C1-C6, -C1-C6-heteroaryl-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-N(C1-C6)2,

[0784] wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0785] -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

[0786] -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH2, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C1-C6, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-C3-C8-cycloalkyl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-NH-aryl, -C1-C 6-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-NH-C1-C6-heteroaryl, -C1-C6-heteroaryl-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0787] -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C1-C6, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-C3-C8-cycloalkyl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-aryl, -C1-C6-heteroaryl-NH-C(=O)-NH-S(O)2-heteroaryl, or

[0788] -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,

[0789] wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-;

[0790] or

[0791] Where Q can be selected from

[0792]

[0793] as well as

[0794] wherein R3, R4 or R6 are independently selected from -H, halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy, alkoxy substituted by one or more halogen, aryl optionally substituted by one or more halogen, hydroxy, alkoxy, alkoxy substituted by one or more halogen;

[0795] wherein R9 is selected from -H, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, aryl or -O-aryl, wherein each C1-C6 alkyl, C1-C6 alkoxy, aryl or -O-aryl may be further substituted with one or more halogen, hydroxy, C1-C6 alkoxy or C1-C6 alkoxy further substituted with one or more halogen; and

[0796] wherein Y is -CH2-, -CHR5, -C(R5)2-, wherein each R5 is independently C1-C6 alkyl; -O- or -S-, -S(O), -S(O)2, -NH-, -NR 10 -, where R 10 is a C1-C6 alkyl group;

[0797] or a salt thereof.

[0798] 2. The compound according to embodiment 1, wherein R is selected from

[0799] -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

[0800] -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,

[0801] -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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0802] -C1-C6-C(=O)-OH, or

[0803] -aryl-C(=O)-OH, or

[0804] -Aryl-C(=O)-NH-S(O)2-C1-C6.

[0805] 3. The compound according to embodiment 1 or 2, wherein R is 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.

[0806] 4. A compound according to any one of embodiments 1 to 3, wherein R is 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 or -aryl-C(=O)-OH.

[0807] 5. A compound according to any one of embodiments 1 to 3, wherein R is -C(=O)-C1-C6-C(=O)-OH.

[0808] 6. A compound according to any one of embodiments 1 to 5, wherein R is -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6.

[0809] 7. A compound according to any one of embodiments 1 to 6, wherein R is selected from -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2 or -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, such as -C(=O)-C1-C6-C(=O)-NH-S(O)2-Ph.

[0810] 8. A compound according to any one of embodiments 1 to 4, wherein R is -aryl-C(=O)-OH.

[0811] 9. A compound according to any one of embodiments 1 to 4, wherein R is -C(=O)-CH2-CH2-C(=O)-OH.

[0812] 10. The compound according to embodiment 6, wherein R is 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.

[0813] 11. A compound according to embodiment 7, wherein R is -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-NMe2.

[0814] 12. A compound according to embodiment 8, wherein R is -phenyl-C(=O)-OH.

[0815] 13. A compound according to any one of embodiments 1 to 12, wherein Q is selected from:

[0816]

[0817] 14. The compound according to embodiment 13, wherein Q is selected from:

[0818]

[0819] 15. The compound according to embodiment 13 or 14, wherein Q is

[0820] 16. A compound according to any one of embodiments 1 to 15, wherein R9 is aryl, or aryl substituted with one or more -OC1-C6 alkyl or halogen.

[0821] 17. A compound according to any one of embodiments 1 to 16, wherein Y is -CH2-.

[0822] 18. A compound according to any one of embodiments 1 to 17, wherein the compound of formula II is selected from

[0823]

[0824] or a salt thereof.

[0825] 19 A compound of formula III

[0826]

[0827] Wherein R can be selected from:

[0828] or

[0829] -C(=O)-C1-C6-C(=O)-NH2, -C(=O)-C1-C6-C(=O)-NH-C1-C6, -C(=O)-C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-C1-C6-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0830] -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-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

[0831] -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-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-S(O)2-NH-C1-C6-heteroaryl, -C(=O)-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0832] -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

[0833] -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)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0834] -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

[0835] -C1-C6-C(=O)-NH2, -C1-C6-C(=O)-NH-C1-C6, -C1-C6-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0836] -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

[0837] -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-C6-heteroaryl、-C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2、 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0838] -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

[0839] -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、 wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0840] or

[0841] -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

[0842] -C(=O)-aryl-C(=O)-NH2, -C(=O)-aryl-C(=O)-NH-C1-C6, -C(=O)-aryl-C(=O)-NH-C3-C8-cycloalkyl, -C(=O)-aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0843] -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

[0844] -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 )-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-NH-C1-C6-heteroaryl, -C(=O)-aryl-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0845] -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

[0846] -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-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0847] or

[0848] -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, or

[0849] -aryl-C(=O)-NH2, -aryl-C(=O)-NH-C1-C6, -aryl-C(=O)-NH-C3-C8-cycloalkyl, -aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0850] -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

[0851] -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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0852] -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

[0853] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0854] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0855] -aryl-S(O)2-NH-C3-C8-cycloalkyl, or

[0856] -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

[0857] -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, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0858] -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

[0859] -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 )-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-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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0860] -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

[0861] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0862] or

[0863] -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, or

[0864] -heteroaryl-C(=O)-NH2, -heteroaryl-C(=O)-NH-C1-C6, -heteroaryl-C(=O)-NH-C3-C8-cycloalkyl, -heteroaryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0865] -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

[0866] -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 heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0867] -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

[0868] -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-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-;

[0869] or

[0870] -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

[0871] -C1-C6-aryl-C(=O)-NH2, -C1-C6-aryl-C(=O)-NH-C1-C6, -C1-C6-aryl-C(=O)-NH-C3-C8-cycloalkyl, -C1-C6-aryl-C(=O)-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-C6-, -S-, or -O-; or

[0872] -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, -C1-C6-aryl-C(=O)-NH-S(O)2-C1-C6-heteroaryl, or

[0873] -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 6-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-NH-C1-C6-heteroaryl, -C1-C6-aryl-C(=O)...

Claims

1. A compound of formula I Wherein R can 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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-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; wherein P may be one or more 5 to 10 membered aryl rings optionally containing one or more heteroatoms, and wherein P may be further substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogens, hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogens, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogens, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S-, or -O-; or a C2-C8 cycloheteroalkyl ring including one or more heteroatoms selected from -NH-, -NC1-C6-, -S-, or -O-; or Aryl, aryl substituted by one or more of the following: halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogen or hydroxy, -C3-C8-cycloalkyl, -CN, hydroxy, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more halogen, -C1-C6-alkyl substituted by one or more -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted by one or more -O-C1-C6-alkyl, -O-C3-C8-cycloalkyl, -SH, -S-C1-C6-alkyl, -S-C1-C6-alkyl substituted by one or more halogen, -SF6, -NO2, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, wherein M is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, -NC1-C6-, -S- or -O-; or heteroaryl; heteroaryl substituted by one or more -O-C1-C6-alkyl, or aryl fused to a 5-6 membered heterocyclic ring having one or more -O- or -N- groups, the heterocyclic ring being optionally substituted by one or more halogen or -C1-C6-alkyl or O-C1-C6-alkyl, or -O-aryl; Where Q can be selected from wherein R3, R4 or R6 are independently selected from -H, halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted with one or more halogens, -CN, hydroxyl, -O-C1-C6-alkyl, -O-C1-C6-alkyl substituted with one or more halogens; and or its salts; The premise is that the following compounds are excluded from the compounds of formula I.

2. The compound according to claim 1, wherein R is 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.

3. The compound according to claim 1 or claim 2, wherein R is 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.

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

5. The compound according to claim 1, wherein R is -C(=O)-C1-C6-C(=O)-NH-S(O)2-C1-C6.

6. The compound according to claim 1, wherein R is 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-C6 alkyl)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 according to claim 1, wherein R is -aryl-C(=O)-OH.

8. The compound according to claim 1, wherein R is -C(=O)-CH2-CH2-C(=O)-OH.

9. The compound according to claim 1 or claim 5, wherein R is 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.

10. The compound according to claim 1, wherein R is selected from -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-NMe2.

11. The compound according to claim 1, wherein R is -phenyl-C(=O)-OH.

12. The compound according to any one of claims 1 to 11, wherein P is aryl or aryl substituted by one or more halogen, -C1-C6-alkyl or -O-C1-C6-alkyl.

13. The compound according to claim 12, wherein P is aryl substituted by aryl or aryl substituted by halogen, -C1-C6-alkyl, -O-C1-C6-alkyl or -OC1-C6-alkyl substituted by one or more halogens.

14. The compound according to claim 12 or claim 13, wherein P is phenyl or phenyl substituted by one or more halogen, -C1-C6-alkyl, -O-C1-C6-alkyl or -OC1-C6-alkyl substituted by one or more halogen.

15. The compound according to claim 13, wherein P is phenyl substituted by phenyl or phenyl substituted by halogen, -C1-C6-alkyl, -C1-C6-alkyl substituted by one or more halogens, -O-C1-C6-alkyl or -OC1-C6-alkyl substituted by one or more halogens.

16. The compound according to claim 15, wherein P is phenyl substituted by halogen substituted phenyl.

17. The compound according to claim 16, wherein P is phenyl substituted with -Cl substituted phenyl.

18. The compound according to claim 15, wherein P is phenyl substituted by -O-C1-C6-alkyl, such as phenyl substituted by -O-C1-C6-alkyl. i Pr substituted phenyl substituted phenyl.

19. The compound according to claim 18, wherein P is phenyl substituted by -O-C3-alkyl.

20. The compound according to claim 18, wherein P is phenyl substituted by phenyl substituted by -OCF3, or P is phenyl substituted by phenyl substituted by -OCF3 and -F.

21. A compound according to any one of claims 1 to 20, wherein Q is selected from:

22. The compound according to claim 21, wherein Q is selected from:

23. A compound according to claim 21 or claim 22, wherein Q is 24. A compound according to any one of claims 1 to 23, wherein The compound of formula I is selected from one or more of the following: or a salt thereof.

25. A compound of formula I, or a salt thereof.

26. A compound of formula I, or a salt thereof.

27. A compound of formula I, or a salt thereof.

28. A compound of formula I, or a salt thereof.

29. A compound of formula I, or a salt thereof.

30. A compound of formula I, or a salt thereof.

31. A compound of formula I, or a salt thereof.

32. A compound of formula I, or a salt thereof.

33. A compound of formula I, or a salt thereof.

34. A compound of formula I, or a salt thereof.

35. A compound of formula I, or a salt thereof.

36. A compound of formula I, or a salt thereof.

37. A compound of formula IIa Wherein R can 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-C(=O)-NH-S(O)2-N(C1-C6)2, wherein J is a 5- or 6-membered heterocyclic ring optionally including a second heteroatom selected from -NH-, NCI-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; Where Q can be selected from as well as Wherein R3, R4 or R6 are independently selected from -H, halogen, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, alkoxy substituted by one or more halogens, aryl optionally substituted by one or more halogens, hydroxyl, alkoxy, alkoxy substituted by one or more halogens; wherein R9 is selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, aryl or -O-aryl, wherein each C1-C6 alkyl, C1-C6 alkoxy, aryl or -O-aryl may be further substituted with one or more halogen, hydroxyl, C1-C6 alkoxy or C1-C6 alkoxy further substituted with one or more halogen; and wherein Y is -CH2-, -CHR5, -C(R5)2-, wherein each R5 is independently C1-C6 alkyl; -O- or -S-, -S(O), -S(O)2, -NH-, -NR 10 -, where R 10 is a C1-C6 alkyl group; wherein Y1 is optionally present and is -CH2-, -CHR5, -C(R5)2-, wherein each R5 is independently C1-C6 alkyl; -O- or -S-, -S(O), -S(O)2, -NH-, -NR 11 -, and where R 11 is a C1-C6 alkyl group; or a salt thereof.

38. The compound according to claim 37, wherein R is 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.

39. A compound according to claim 37 or claim 38, wherein R is 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 or -aryl-C(=O)-OH.

40. A compound according to any one of claims 37 to 39, wherein R is -C(=O)-C1- C6-C(=O)-OH.

41. A compound according to any one of claims 37 to 40, wherein R is -C(=O)-C1- C6-C(=O)-NH-S(O)2-C1-C6.

42. A compound according to any one of claims 37 to 41, wherein R is selected from -C(=O)- C1-C6-C(=O)-NH-S(O)2-N(C1-C6)2 or -C(=O)-C1-C6-C(=O)-NH-S(O)2-aryl, Such as -C(=O)-C1-C6-C(=O)-NH-S(O)2-Ph.

43. A compound according to any one of claims 37 to 39, wherein R is -aryl-C(=O)-OH.

44. A compound according to any one of claims 37 to 39, wherein R is -C(=O)-CH2- CH2-C(=O)-OH.

45. The compound according to claim 41, wherein R is 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.

46. ​​The compound according to claim 42, wherein R is -C(=O)-CH2-CH2-C(=O)-NH-S(O)2-NMe2.

47. The compound according to claim 43, wherein R is -phenyl-C(=O)-OH.

48. A compound according to any one of claims 37 to 47, wherein Q is selected from:

49. The compound according to claim 48, wherein Q is selected from:

50. A compound according to claim 48 or claim 49, wherein Q is 51. A compound according to any one of claims 37 to 50, wherein R9 is aryl or aryl substituted by C1-C6 alkoxy or C1-C6 alkoxy further substituted by one or more halogens.

52. The compound according to claim 51, wherein Aryl is phenyl or phenyl substituted by C1-C6 alkoxy further substituted by one or more halogens.

53. A compound according to any one of claims 37 to 52, wherein Y and Y1 are each -CH2-.

54. A compound according to any one of claims 37 to 53, wherein The compound of formula II is selected from or a salt thereof.

55. A compound of formula I or IIa as defined in any one of claims 1 to 54 for use in reducing the formation of methane from digestion in a ruminant and / or for improving ruminant performance.

56. A compound of formula I or Ha as defined in any one of claims 1 to 54 for use in reducing the formation of methane from digestion in ruminants.

57. A compound of formula I or Ha as defined in any one of claims 1 to 54 for use in reducing the formation of methane from digestion in ruminants by at least 10%.

58. A compound of formula I or Ha as defined in any one of claims 1 to 54 for use in reducing the formation of methane from digestion in ruminants by at least 15%.

59. A compound of formula I or Ha as defined in any one of claims 1 to 54 for use in reducing the formation of methane from digestion in ruminants by at least 20%.

60. A method for reducing the production of methane from ruminants and / or for improving the performance of ruminants, said method comprising orally administering to said ruminants an effective amount of at least one compound of formula I or IIa as defined in any one of claims 1 to 54 or a salt thereof.

61. The method of claim 60, wherein: The effective amount of at least one compound of formula I or IIa as defined in any one of claims 1 to 54 or a salt thereof is administered to the ruminant at least once a day.

62. The method of claim 60 or claim 61, wherein: Said effective amount of at least one compound of formula I or IIa as defined in any one of claims 1 to 54 or a salt thereof reduces the production of methane produced by said ruminant by at least 10% per day.

63. The method according to any one of claims 48 to 50, wherein: Said effective amount of at least one compound of formula I or IIa as defined in any one of claims 1 to 54 or a salt thereof reduces the production of methane produced by said ruminant by at least 15% per day.

64. The method according to any one of claims 48 to 51, wherein: Said effective amount of at least one compound of formula I or IIa as defined in any one of claims 1 to 54 or a salt thereof reduces the production of methane produced by said ruminant by at least 20% per day.

65. A composition for oral administration comprising at least one compound of formula I or IIa as defined in any one of claims 1 to 54 or a salt thereof for use in reducing the production of methane produced in ruminants, and further comprising at least one agriculturally and orally acceptable excipient.

66. A composition according to claim 65 suitable for use as a feed additive.

67. The composition of claim 65, suitable for use as a water additive.

68. The composition of claim 65, suitable for use as a ruminant lick.

69. The composition of claim 65, suitable for use as an oral drench.

70. The composition of claim 65, suitable for use as a rumen bolus or capsule.

71. A composition according to any one of claims 65 to 70, suitable for reducing the production of methane produced by the ruminant by at least 10% per day.

72. The composition of any one of claims 65 to 71, suitable for reducing the production of methane produced by the ruminant by at least 15% per day.

73. A composition according to any one of claims 65 to 72 for use in reducing the production of methane from the ruminant by at least 20% per day.

74. A composition according to any one of claims 65 to 73, wherein The excipients may include one or more minerals and / or one or more vitamins.

75. A composition according to any one of claims 65 to 74, wherein The excipient may include one or more vitamins selected from the group consisting of vitamin A, vitamin D3, vitamin E and vitamin K, such as vitamin K3, vitamin B12, biotin and choline, vitamin B1, vitamin B2, vitamin B6, niacin, folic acid and the like.

76. A composition according to any one of claims 65 to 75, wherein The excipient may include one or more minerals selected from calcium, phosphorus, sodium, manganese, zinc, iron, copper, chloride, sulfur, magnesium, iodine, selenium, cobalt, and the like.

77. A composition according to any one of claims 65 to 76, further comprising sunflower oil, electrolytes such as ammonium chloride, calcium carbonate, starch, protein, etc.

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