Compositions comprising werner syndrome helicase inhibitors and methods of using the same

Abstract

The presently disclosed subject matter relates to compositions comprising Werner Syndrome Helicase (WRN) inhibitors and methods of using the same.

Description

[0001] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAME CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 665,217, June 27, 2024, the contents of which are incorporated by reference in their entireties, and to which priority is claimed. TECHNICAL FIELD The subject matter described herein relates to compositions comprising Werner Syndrome Helicase (WRN, also known as Werner Syndrome RecQ Helicase or Werner Syndrome ATP-Dependent Helicase) inhibitors and methods of using the same. BACKGROUND The WRN gene encodes a helicase that falls within the RecQ DNA helicase subfamily and is directly involved in DNA damage repair. While WRN has previously been shown to exhibit tumor suppressive activity, an activity that correlates well with its activity in DNA damage repair, certain cancer cells have been shown to be dependent on the presence of WRN. For example, certain cancers associated with deficient DNA mismatch repair (dMMR), which often exhibit high levels of microsatellite instability (microsatellite instability-high or MSI-H cancers), depend on WRN activity for continued survival. In view of WRN’s essential role in such cancers, there remains a need in the art to identify WRN inhibitors for use in the treatment of such dMMR and / or MSI-H cancers. SUMMARY OF THE INVENTION In certain aspects, the compositions and methods described herein relate to compositions comprising WRN helicase inhibitors and methods of their use in treating disease, e.g., cancer. In certain embodiments, the compositions and methods described herein relate to a compound selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(5,6- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- dihydro-8H-imidazo[2,1- ethyl-6-[4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- c][1,4]oxazin-2-yl)-5-ethyl-6-(4-(5- methylpyrimidine-4- methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl)-7-oxo- {4H,6H,7H-pyrazolo[3,2- methylbenzo[d]oxazol-4-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- c][1,4]oxazin-2-yl}- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-(5-ethyl- (trifluoromethyl)phenyl]-2-[2-(2,3- ethyl-6-[4-(5-hydroxy-6- 2-{2H,3H-furo[2,3-b]pyridin-5-yl}- dihydro-1-benzofuran-7-yl)-5- methylpyrimidine-4- 6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-2-(2- methylpyrimidine-4- methylpyrimidine-4- methyl-1,3-benzothiazol-4-yl)-7- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyrimidin-4-yl}acetamide yl)acetamide yl]acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-(3,4- (trifluoromethyl)phenyl]-2-[2-(3,4- (trifluoromethyl)phenyl]-2-{5- dihydro-2H-1-benzopyran-5-yl)-5- dihydro-2H-1-benzopyran-8-yl)-5- ethyl-6-[4-(5-hydroxy-6-methylpyri ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- midine-4-carbonyl)piperazin-1-yl]- methylpyrimidine-4- methylpyrimidine-4- 7-oxo-2-{1H,3H,4H-pyrano[4,3- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- c]pyridin-8-yl}-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyri midin-4-yl}acetamide yl]acetamide yl]acetamide

[0002] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(2-(3,4- (trifluoromethyl)phenyl)-2-(2-(1,1- ethyl-6-[4-(5-hydroxy-6- dihydro-1H-pyrano[3,4-c]pyridin- dimethyl-1,3- methylpyrimidine-4- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- dihydroisobenzofuran-5-yl)-5- carbonyl)piperazin-1-yl]-7-oxo-2- methylpyrimidine-4- ethyl-6-(4-(5-hydroxy-6- {5H,6H,8H-pyrano[3,4-b]pyridin- carbonyl)piperazin-1-yl)-7-oxo- methylpyrimidine-4- 3-yl}-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyri midin- carbonyl)piperazin-1-yl)-7-oxo- a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- N-(2-chloro-4- phenyl] [2-(3,3-dimethyl-1,3- (trifluoromethyl)phenyl)-2-(2-(5,6- (trifluoromethyl)phenyl)-2-(5-ethyl- dihydro-5-isobenzofuranyl)-6- dihydro-4H-pyrrolo[1,2-b]pyrazol- 6-(4-(5-hydroxy-6- ethyl-5-{4-[(5-hydroxy-6-methyl-4- 3-yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- pyrimidinyl) carbonyl]-1- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-2- piperazinyl}-4-oxo-1,3,3a,7- carbonyl)piperazin-1-yl)-7-oxo- (4,5,6,7-tetrahydropyrazolo[1,5- tetraaza-7-indenyl] acetamide [1,2,4]triazolo[1,5-a]pyrimidin- a]pyridin-3-yl)-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide

[0003] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl][6-ethyl-2- (trifluoromethyl)phenyl](6-ethyl-5- ethyl-6-[4-(5-hydroxy-6- (6-fluoro-2,3-dihydro-1- {4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- benzofuran-5-yl)-5-{4-[(5-hydroxy- pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl]-2-(2- 6-methyl-4-pyrimidinyl)carbonyl]- piperazinyl}-2-(3-methyl-2,3- methyl-2,3-dihydro-1-benzofuran- 1-piperazinyl}-4-oxo-1,3,3a,7- dihydro-1-benzofuran-5-yl)-4-oxo- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- tetraaza-7-indenyl] 1,3,3a,7-tetraaza-7- a]pyrimidin-4-yl}acetamide indenyl)acetamide

[0004] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- 6-(4-(5-hydroxy-6- {4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl)-2-(7- piperazinyl}-4-oxo-2-(1,1,3,3- methyl-2,3-dihydrobenzofuran-5- tetramethyl-1,3-dihydro-5- yl)-7-oxo-[1,2,4]triazolo[1,5- isobenzofuranyl)-1,3,3a,7-tetraaza- a]pyrimidin-4(7H)-yl)acetamide 7-indenyl)acetamide N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl][2-(1,3- 2-(7-fluoro-2,3-dihydrobenzofuran- 6-(4-(5-hydroxy-6- dimethyl-2-oxo-1,3-dihydro-1,3- 5-yl)-6-(4-(5-hydroxy-6- methylpyrimidine-4- benzimidazol-5-yl)-6-ethyl-5-{4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(6- [(5-hydroxy-6-methyl-4- carbonyl)piperazin-1-yl)-7-oxo- methyl-2,3-dihydrobenzofuran-5- pyrimidinyl)carbonyl]-1- [1,2,4]triazolo[1,5-a]pyrimidin- yl)-7-oxo-[1,2,4] triazolo[1,5- piperazinyl}-4-oxo-1,3,3a,7- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide tetraaza-7-indenyl]acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl](6-ethyl-5-{4-[(5-hydroxy- phenyl](6-ethyl-5-{4-[(5-hydroxy- (trifluoromethyl)phenyl][2-(3,3- 6-methyl-4-pyrimidinyl)carbonyl]- 6-methyl-4-pyrimidinyl)carbonyl]- difluoro-5-indanyl)-6-ethyl-5-{4- 1-piperazinyl}-4-oxo-7H- 1-piperazinyl}-2-(2-methyl-2H- [(5-hydroxy-6-methyl-4- 1,1',3,3a,7,7a'-hexaaza-2,5'- indazol-6-yl)-4-oxo-1,3,3a,7- pyrimidinyl)carbonyl]-1- biindenyl-7-yl)acetamide tetraaza-7-indenyl)acetamide piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl]acetamide

[0005] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(2,2- (trifluoromethyl)phenyl)-2-(2-(3,4- (trifluoromethyl)phenyl]-2-{5- difluorobenzo[d][1,3]dioxol-5-yl)- dihydro-1H-pyrano[3,4-c]pyridin- ethyl-6-[4-(5-hydroxy-6- 5-ethyl-6-(4-(5-hydroxy-6- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-[(2R)-2- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- methoxy-2,3-dihydro-1H-inden-5- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyri midin- yl]-7-oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide 4(7H)-yl)acetamide a]pyrimidin-4-yl}acetamide N-[2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(2-(5,6- (trifluoromethyl)phenyl]-2-{5- ethyl-6-[4-(5-hydroxy-6- dihydro-4H-pyrrolo[1,2-b]pyrazol- ethyl-6-[4-(5-hydroxy-6-methyl methylpyrimidine-4- 2-yl)-5-ethyl-6-(4-(5-hydroxy-6- pyrimidine-4-carbonyl)piperazin-1- carbonyl)piperazin-1-yl]-2-[( methylpyrimidine-4- yl]-7-oxo-2-{4H,5H,6H,7H- carbonyl)piperazin-1-yl)-7-oxo- pyrazolo[1,5-a]pyridin-2-yl}- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo [1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl][2-(1,1- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- difluoro-5-indanyl)-6-ethyl-5-{4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- [(5-hydroxy-6-methyl-4- piperazinyl}-2-(2-methyl-1-oxo-5- piperazinyl}-2-(2-methyl-3-oxo-5- pyrimidinyl)carbonyl]-1- isoindolinyl)-4-oxo-1,3,3a,7- isoindolinyl)-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl)acetamide tetraaza-7-indenyl)acetamide tetraaza-7-indenyl]acetamide

[0006] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- {4-[(5-hydroxy-6-methyl-4- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- methylpyrimidine-4- piperazinyl}-4-oxo-2-(3-oxo-5- carbonyl)piperazin-1-yl]-2-[(3S)-3- carbonyl)piperazin-1-yl]-2-[(3R)-3- isoindolinyl)-1,3,3a,7-tetraaza-7- methyl-1,3-dihydro-2-benzofuran- methyl-1,3-dihydro-2-benzofuran- indenyl)acetamide 5-yl]-7-oxo-[1,2,4]triazolo[1,5- 5-yl]-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl}acetamide a]pyrimidin-4-yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl][2-(3,3- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- dimethyl-2,3-dihydro-1- methylpyrimidine-4- methylpyrimidine-4- benzofuran-5-yl)-6-ethyl-5-{4-[(5- carbonyl)piperazin-1-yl]-2-[(1R)-1- carbonyl)piperazin-1-yl]-2-[(1S)-1- hydroxy-6-methyl-4- methyl-1,3-dihydro-2-benzofuran- methyl-1,3-dihydro-2-benzofuran- pyrimidinyl)carbonyl]-1- 5-yl]-7-oxo-[1,2,4]triazolo[1,5- 5-yl]-7-oxo-[1,2,4]triazolo[1,5- piperazinyl}-4-oxo-1,3,3a,7- a]pyrimidin-4-yl}acetamide a]pyrimidin-4-yl}acetamide tetraaza-7-indenyl]acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- (trifluoromethyl)phenyl][2-(2,2- phenyl] [2-(1,1-dimethyl-6- (trifluoromethyl)phenyl]-2-{5- dimethyl-2,3-dihydro-1- isochromanyl)-6-ethyl-5-{4-[(5- ethyl-6-[4-(5-hydroxy-6- benzofuran-5-yl)-6-ethyl-5-{4-[(5- hydroxy-6-methyl-4- methylpyrimi dine-4- hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- carbonyl)pipera zin-1-yl]-2-(4- pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-1,3,3a,7- methyl-1,3-dihydro-2-benzofuran- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl]acetamide 5-yl)-7-oxo-[1,2,4]triazolo[1,5- tetraaza-7-indenyl]acetamide a]pyr imidin-4-yl}acetamide

[0007] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-2-(2-methyl-5- piperazinyl}-2-(4-methyl-3-oxo- piperazinyl}-2-(1-methyl-5- isoindolinyl)-4-oxo-1,3,3a,7- 2,4-dihydro-1,4-benzoxazin-6-yl)- indolinyl)-4-oxo-1,3,3a,7-tetraaza- tetraaza-7-indenyl)acetamide 4-oxo-1,3,3a,7-tetraaza-7- 7-indenyl)acetamide indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[5-ethyl- (trifluoromethyl)phenyl]-2-[5-ethyl- (trifluoromethyl)phenyl]-2-[5-ethyl- 2-(4-fluoro-1,3-dihydro-2- 2-(6-fluoro-1,3-dihydro-2- 2-(7-fluoro-1,3-dihydro-2- benzofuran-5-yl)-6-[4-(5-hydroxy- benzofuran-5-yl)-6-[4-(5-hydroxy- benzofuran-5-yl)-6-[4-(5-hydroxy- 6-methylpyrimidine-4- 6-methylpyrimidine-4- 6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide yl]acetamide N-[2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl][2-(4- ethyl-6-[4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- difluoromethylene-1-piperidyl)-6- methylpyrimidine-4- methylpyrimidine-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- carbonyl)piperazin-1-yl]-2-(6- carbonyl)piperazin-1-yl)-2-(1H- pyrimidinyl)carbonyl]-1- methyl-1,3-dihydro-2-benzofuran- inden-6-yl)-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- tetraaza-7-indenyl]acetamide a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide

[0008] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- (S)-N-(2-chloro-4- (R)-N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- ethyl-6-[4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-(7- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-2-(1- methyl-1,3-dihydro-2-benzofuran- methoxy-2,3-dihydro-1H-inden-5- methoxy-2,3-dihydro-1H-inden-5- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl}acetamide a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl]-2-(2- (trifluoromethyl)phenyl]-2-[5-ethyl- 6-(4-(5-hydroxy-6- {4H,5H,6H- 2-(6-fluoro-1,1-dimethyl-3H-2- methylpyrimidine-4- cyclopenta[d][1,3]thiazol-2-yl}-5- benzofuran-5-yl)-6-[4-(5-hydroxy- carbonyl)piperazin-1-yl)-2-(1- ethyl-6-[4-(5-hydroxy-6- 6-methylpyrimidine-4- methyl-3'H-spiro[azetidine-3,1'- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- isobenzofuran]-5'-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide 4(7H)-yl)acetamide yl)acetamide

[0009] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-(2-chloro-4- phenyl]-2-[5-ethyl-2-(7-fluoro-1,1- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- dimethyl-3H-2-benzofuran-5-yl)-6- ethyl-6-[4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- [4-(5-hydroxy-6-methylpyrimidine- methylpyrimidine-4- methylpyrimidine-4- 4-carbonyl) piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl)-7-oxo-2- [1,2,4] triazolo[1,5-a] pyrimidin-4- (1,1,6-trimethyl-3H-2-benzofuran- (1,1,4-trimethyl-1,3- yl] acetamide 5-yl)-[1,2,4]triazolo[1,5- dihydroisobenzofuran-5-yl)- a]pyrimidin-4-yl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-[5-ethyl- (trifluoromethyl)phenyl]-2-[5-ethyl- ethyl-6-[4-(5-hydroxy-6- 2-(4-fluoro-1,1-dimethyl-3H-2- 2-(5-fluoro-3,4-dihydro-1H-2- methylpyrimidine-4- benzofuran-5-yl)-6-[4-(5-hydroxy- benzopyran-6-yl)-6-[4-(5-hydroxy- carbonyl)piperazin-1-yl]-7-oxo-2- 6-methylpyrimidine-4- 6-methylpyrimidine-4- {3H-spiro[2-benzofuran-1,1'- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- cyclobutan]-5-yl}- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide yl}acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) phenyl](6-ethyl-5-{4-[(5-hydroxy- phenyl](6-ethyl-5-{4-[(5-hydroxy- phenyl] (6-ethyl-5-{4-[(5-hydroxy- 6-methyl-4-pyrimidinyl)carbonyl]- 6-methyl-4-pyrimidinyl)carbonyl]- 6-methyl-4-pyrimidinyl) carbonyl]- 1-piperazinyl}-1'-methyl-4-oxo-7H- 1-piperazinyl}-4-oxo-7H- 1-piperazinyl}-4-oxo-7H- 1,2',3,3a,7,7a'-hexaaza-2,5'- 1,2',3,3a,7,7a'-hexaaza-2,5'- 1,1',3,3',3a,7,7a'-heptaaza-2,5'- biindenyl-7-yl)acetamide biindenyl-7-yl)acetamide biindenyl-7-yl) acetamide

[0010] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl]-2-[2-(3,3- (trifluoromethyl)phenyl]-2-[2-(3,3- 6-(4-(5-hydroxy-6- dimethyl-1,4-dihydro-2- dimethyl-1,4-dihydro-2- methylpyrimidine-4- benzopyran-8-yl)-5-ethyl-6-[4-(5- benzopyran-8-yl)-5-ethyl-6-[4-(5- carbonyl)piperazin-1-yl)-7-oxo-2- hydroxy-6-methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- (1,1,7-trimethyl-1,3- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- dihydroisobenzofuran-5-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide yl]acetamide 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- (R)-N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[2-(2,2- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(2-(1- difluoro-1,3-dihydroinden-5-yl)-5- ethyl-6-[4-(5-hydroxy-6- (difluoromethoxy)-2,3-dihydro-1H- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- inden-5-yl)-5-ethyl-6-(4-(5- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-(3- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methyl-2-oxo-1,3-benzoxazol-5- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl)-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide N-[2-chloro-4- (R)-N-(2-chloro-4- (S)-N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{2-[1- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- (difluoromethoxy)-2,3-dihydro-1H- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- inden-5-yl]-5-ethyl-6-[4-(5- methylpyrimidine-4- methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl]-7-oxo- methylisochroman-6-yl)-7-oxo- methylisochroman-6-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- yl}acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 (S)-N-(2-chloro-4- (R)-N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(2-(2,2- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- difluorobenzo[d][1,3]dioxol-4-yl)- methylpyrimidine-4- methylpyrimidine-4- 5-ethyl-6-(4-(5-hydroxy-6- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl)-2-(2- methylpyrimidine-4- methyl-2,3-dihydrobenzofuran-5- methyl-2,3-dihydrobenzofuran-5- carbonyl)piperazin-1-yl)-7-oxo- yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4] triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide 4(7H)-yl)acetamide N-(2-chloro-4- 2-(2-(benzo[c][1,2,5]oxadiazol-5- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- yl)-5-ethyl-6-(4-(5-hydroxy-6- (trifluoromethyl)phenyl)-2-(5-ethyl- 6-(4-(5-hydroxy-6- methylpyrimidine-4- 6-(4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(3- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-2-(2- methyl-2-oxo-2,3- 4(7H)-yl)-N-(2-chloro-4- methyl-2H-indazol-5-yl)-7-oxo- dihydrobenzo[d]oxazol-6-yl)-7- (trifluoromethyl)phenyl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- oxo-[1,2,4] triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl]-2-{5- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl]-2-(4- methyl-1H-benzo[d]imidazol-6-yl)- methylbenzo[d]oxazol-6-yl)-7-oxo- methyl-2,3-dihydro-1-benzofuran- 7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide 4(7H)-yl)acetamide a]pyrimidin-4-yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-(5-ethyl- ethyl-6-[4-(5-hydroxy-6-methyl ethyl-6-[4-(5-hydroxy-6- 2-{4-fluoropyrazolo[1,5-a]pyridin- pyrimidine-4-carbonyl)piperazin-1- methylpyrimidine-4-carbonyl) 5-yl}-6-[4-(5-hydroxy-6- yl]-2-{4-methylpyrazolo[1,5- piperazin-1-yl]-2-{7- methylpyrimidine-4- a]pyridin-5-yl}-7-oxo- methylpyrazolo[1,5-a]pyridin-5- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide a]pyrimidin-4-yl}acetamide yl)acetamide N-(2-chloro-4- N-[2-chloro-4- (S)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- 2-(6-fluoropyrazolo[1,5-a]pyridin- ethyl-6-[4-(5-hydroxy-6- 2-(6-fluoro-1-methoxy-2,3-dihydro- 5-yl)-6-(4-(5-hydroxy-6- methylpyrimidine-4- 1H-inden-5-yl)-6-(4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-{6- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- methylpyrazolo[1,5-a]pyridin-5- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- yl}-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide (R)-N-(2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(5-ethyl- phenyl] (6-ethyl-5-{4-[(5-hydroxy- phenyl] (6-ethyl-5-{4-[(5-hydroxy- 2-(6-fluoro-1-methoxy-2,3-dihydro- 6-methyl-4-pyrimidinyl) carbonyl]- 6-methyl-4-pyrimidinyl) carbonyl]- 1H-inden-5-yl)-6-(4-(5-hydroxy-6- 1-piperazinyl}-1'-methyl-4-oxo-7H- 1-piperazinyl}-2'-methyl-4-oxo-7H- methylpyrimidine-4- 1,2',3,3',3a,7,7a'-heptaaza-2,5'- 1,1',3,3a,7,7a'-hexaaza-2,5'- carbonyl)piperazin-1-yl)-7-oxo- biindenyl-7-yl) acetamide biindenyl-7-yl) acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide

[0011] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-[2-chloro-4- phenyl] {2-[2-(difluoromethyl)-2H- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- indazol-5-yl]-6-ethyl-5-{4-[(5- ethyl-2-[(2S)-6-fluoro-2-methyl- ethyl-2-[(2R)-6-fluoro-2-methyl- hydroxy-6-methyl-4-pyrimidinyl) 2,3-dihydro-1-benzofuran-5-yl]-6- 2,3-dihydro-1-benzofuran-5-yl]-6- carbonyl]-1-piperazinyl}-4-oxo- [4-(5-hydroxy-6-methylpyrimidine- [4-(5-hydroxy-6-methylpyrimidine- 1,3,3a,7-tetraaza-7-indenyl} 4-carbonyl)piperazin-1-yl]-7-oxo- 4-carbonyl)piperazin-1-yl]-7-oxo- acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-(5-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- 2-{2-fluoropyrazolo[1,5-a]pyridin- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- 5-yl}-6-[4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-1'-methyl-4-oxo- piperazinyl}-4-oxo-7H- carbonyl)piperazin-1-yl]-7-oxo- 7H,1'H-1,1',3,3a,7,7'-hexaaza-2,5'- 1,3,3',3a,3a',7-hexaaza-2,5'- [1,2,4]triazolo[1,5-a]pyrimidin-4- biindenyl-7-yl)acetamide biindenyl-7-yl)acetamide yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- phenyl] [6-ethyl-2-(6-fluoro-2- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- methyl-2H-indazol-5-yl)-5-{4-[(5- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- hydroxy-6-methyl-4-pyrimidinyl) piperazinyl}-2-(1-methyl-1H-1,3- piperazinyl}-2'-methyl-4-oxo-7H- carbonyl]-1-piperazinyl}-4-oxo- benzimidazol-5-yl)-4-oxo-1,3,3a,7- 1,1',3,3a,3a',7-hexaaza-2,5'- 1,3,3a,7-tetraaza-7- tetraaza-7-indenyl)acetamide biindenyl-7-yl)acetamide indenyl]acetamide

[0012] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- N-(2-chloro-4- phenyl] [2-(1,3-dihydro-2- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- benzothiophen-5-yl)-6-ethyl-5-{4- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- [(5-hydroxy-6-methyl-4- methylpyrimidine-4- methylpyrimidine-4- pyrimidinyl) carbonyl]-1- carbonyl)piperazin-1-yl)-2-(2H- carbonyl)piperazin-1-yl)-2-(3- piperazinyl}-4-oxo-1,3,3a,7- indazol-5-yl)-7-oxo- methyl-4-oxo-3,4- tetraaza-7-indenyl] acetamide [1,2,4]triazolo[1,5-a]pyrimidin- dihydroquinazolin-6-yl)-7-oxo- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- 2-(7-fluoro-3,4-dihydro-1H-2- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- benzopyran-6-yl)-6-[4-(5-hydroxy- methylpyrimidine-4- methylpyrimidine-4- 6-methylpyrimidine-4-carbonyl) carbonyl)piperazin-1-yl)-7-oxo-2- carbonyl)piperazin-1-yl)-2-(2- piperazin-1-yl]-7-oxo- (1,1,2-trimethylisoindolin-5-yl)- isopropyl-2H-indazol-5-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-[2-chloro-4- phenyl] (6-ethyl-5-{4-[(5-hydroxy- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl][2-(2,1- 6-methyl-4-pyrimidinyl) carbonyl]- {4-[(5-hydroxy-6-methyl-4- benzisoxazol-6-yl)-6-ethyl-5-{4- 1-piperazinyl}-4-oxo-2-(6- pyrimidinyl)carbonyl]-1- [(5-hydroxy-6-methyl-4- quinazolinyl)-1,3,3a,7-tetraaza-7- piperazinyl}-4-oxo-2-(6-quinolyl)- pyrimidinyl)carbonyl]-1- indenyl) acetamide 1,3,3a,7-tetraaza-7- piperazinyl}-4-oxo-1,3,3a,7- indenyl)acetamide tetraaza-7-indenyl]acetamide

[0013] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl][2-(2,1- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- benzisothiazol-5-yl)-6-ethyl-5-{4- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- [(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-2-{p-[(1- piperazinyl}-4-oxo-2-(3,4,5- piperazinyl}-4-oxo-1,3,3a,7- pyrrolidinyl)carbonyl]phenyl}- trimethoxyphenyl)-1,3,3a,7- tetraaza-7-indenyl]acetamide 1,3,3a,7-tetraaza-7- tetraaza-7-indenyl)acetamide indenyl)acetamide N-cyclopropylp-(7-{[N-2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenylcarbamoyl] (trifluoromethyl)phenyl]{2-[p-(1- (trifluoromethyl)phenyl)-2-(5-ethyl- methyl}-6-ethyl-5-{4-[(5-hydroxy- azetidinylsulfonyl)phenyl]-6-ethyl- 6-(4-(5-hydroxy-6- 6-methyl-4-pyrimidinyl)carbonyl]- 5-{4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- 1-piperazinyl}-4-oxo-1,3,3a,7- pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl)-2-(1- tetraaza-2-indenyl)benzamide piperazinyl}-4-oxo-1,3,3a,7- methyl-2-oxoindolin-5-yl)-7-oxo- tetraaza-7-indenyl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-(5-ethyl- (trifluoromethyl)phenyl]-2-{5- ethyl-6-[4-(5-hydroxy-6- 2-{6'-fluoro-1-methyl-3'H- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- spiro[azetidine-3,1'-[2]benzofuran]- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-{3- 5'-yl}-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo-2- methylpyrazolo[1,5-a]pyridin-5- methylpyrimidine-4- [(1R)-1-(trifluoromethyl)-1,3- yl}-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- dihydro-2-benzofuran-5-yl]- a]pyrimidin-4-yl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl)acetamide yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl]-7-oxo-2- [(3S)-3-(trifluoromethyl)-1,3- [(1S)-1-(trifluoromethyl)-1,3- [(3R)-3-(trifluoromethyl)-1,3- dihydro-2-benzofuran-5-yl]- dihydro-2-benzofuran-5-yl]- dihydro-2-benzofuran-5-yl]- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide yl}acetamide yl}acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- ethyl-6-[4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-7-oxo-2- {3H-spiro[2-benzofuran-1,3'- methyl-2,2-dioxido-1,3- (quinoxalin-6-yl)- oxetan]-5-yl}-[1,2,4]triazolo[1,5- dihydrobenzo[c]isothiazol-5-yl)-7- [1,2,4]triazolo[1,5-a]pyrimidin- a]pyrimidin-4-yl}acetamide oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) phenyl] [2-(3,4-dihydro-2H-1,4- (trifluoromethyl)phenyl](6-ethyl-5- phenyl] [2-(1-benzofuran-5-yl)-6- benzoxazin-7-yl)-6-ethyl-5-{4-[(5- {4-[(5-hydroxy-6-methyl-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- hydroxy-6-methyl-4-pyrimidinyl) pyrimidinyl)carbonyl]-1- pyrimidinyl) carbonyl]-1- carbonyl]-1-piperazinyl}-4-oxo- piperazinyl}-2'-methyl-4-oxo-7H- piperazinyl}-4-oxo-1,3,3a,7- 1,3,3a,7-tetraaza-7-indenyl] 3'-oxa-1,1',3,3a,7,7'-hexaaza-2,5'- tetraaza-7-indenyl] acetamide acetamide biindenyl-7-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-(2-(2-aminobenzo[d]oxazol-6-yl)- N-[2-chloro-4- N-[2-chloro-4- 5-ethyl-6-(4-(5-hydroxy-6- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- methylpyrimidine-4- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- carbonyl)piperazin-1-yl)-7-oxo- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- [1,2,4]triazolo[1,5-a]pyrimidin- piperazinyl}-2-(2-methyl-1,3- piperazinyl}-2-(7-methoxy-2- 4(7H)-yl)-N-(2-chloro-4- benzothiazol-6-yl)-4-oxo-1,3,3a,7- methyl-2H-indazol-5-yl)-4-oxo- (trifluoromethyl)phenyl)acetamide tetraaza-7-indenyl)acetamide 1,3,3a,7-tetraaza-7- indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- (trifluoromethyl)phenyl][6-ethyl-2- phenyl] [2-(1,3-benzothiazol-5-yl)- (trifluoromethyl)phenyl)-2-(5-ethyl- (7-fluoro-2-methyl-2H-indazol-5- 6-ethyl-5-{4-[(5-hydroxy-6-methyl- 6-(4-(5-hydroxy-6- yl)-5-{4-[(5-hydroxy-6-methyl-4- 4-pyrimidinyl) carbonyl]-1- methylpyrimidine-4- pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-1,3,3a,7- carbonyl)piperazin-1-yl)-7-oxo-2- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl] acetamide (2',3',5',6'-tetrahydro-3H- tetraaza-7-indenyl]acetamide spiro[isobenzofuran-1,4'-pyran]-5- yl)-[1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[5-ethyl- (trifluoromethyl)phenyl)-2-(2-(2- (trifluoromethyl)phenyl)-2-(2-(2- 2-(3-fluoro-2-methylindazol-5-yl)- (difluoromethyl)-6-fluoro-2H- (2,2-difluoroethyl)-2H-indazol-5- 6-[4-(5-hydroxy-6- indazol-5-yl)-5-ethyl-6-(4-(5- yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(1- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- (2,2-difluoroethyl)-1H-indazol-5- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- yl)-5-ethyl-6-(4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-2-(2-methyl-1,2,3,4- piperazinyl}-2-(2-methyl-4-methyl- carbonyl)piperazin-1-yl)-7-oxo- tetrahydro-6-isoquinolyl)-4-oxo- 2H-indazol-5-yl)-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin- 1,3,3a,7-tetraaza-7- tetraaza-7-indenyl)acetamide 4(7H)-yl)acetamide indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl][2-(1- (trifluoromethyl)phenyl][6-ethyl-2- (trifluoromethyl)phenyl](6-ethyl-5- acetyl-2,2-dimethyl-5-indolinyl)-6- (4-fluoro-2-methyl-1,3-benzoxazol- {4-[(5-hydroxy-6-methyl-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- 6-yl)-5-{4-[(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-2-(2-methyl-3-methyl- piperazinyl}-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- 2H-indazol-5-yl)-4-oxo-1,3,3a,7- tetraaza-7-indenyl]acetamide tetraaza-7-indenyl]acetamide tetraaza-7-indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl)-2-(5-ethyl- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- 6-(4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-2-(2-methyl-7-methyl- piperazinyl}-2'-methyl-4-oxo- carbonyl)piperazin-1-yl)-2-(2- 2H-indazol-5-yl)-4-oxo-1,3,3a,7- 7H,2'H-1,2',3,3',3a,7,7'-heptaaza- methyl-2H-benzo[d][1,2,3]triazol- tetraaza-7-indenyl)acetamide 2,5'-biindenyl-7-yl)acetamide 5-yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide

[0014] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(2-(2- (trifluoromethyl)phenyl](6-ethyl-5- 6-(4-(5-hydroxy-6- ((2,2- {4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- difluoroethyl)amino)benzo[d]oxazo pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl)-7-oxo-2- l-6-yl)-5-ethyl-6-(4-(5-hydroxy-6- piperazinyl}-3'-methyl-4-oxo- (2-propyl-2H-indazol-5-yl)- methylpyrimidine-4- 7H,3'H-1,3,3',3a,7,7'-hexaaza-2,5'- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-7-oxo- biindenyl-7-yl)acetamide 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl)-2-(5-ethyl- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- 6-(4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-4-oxo-7H- piperazinyl}-2-(1-methyl-5-methyl- carbonyl)piperazin-1-yl)-2-(2- 1,1',3,3a,3a',7,7'-heptaaza-2,5'- 1H-indazol-6-yl)-4-oxo-1,3,3a,7- (methylamino)benzo[d]oxazol-6- biindenyl-7-yl)acetamide tetraaza-7-indenyl)acetamide yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl](6-ethyl-5- phenyl] (6-ethyl-5-{4-[(5-hydroxy- phenyl] (6-ethyl-5-{4-[(5-hydroxy- {4-[(5-hydroxy-6-methyl-4- 6-methyl-4-pyrimidinyl) carbonyl]- 6-methyl-4-pyrimidinyl) carbonyl]- pyrimidinyl)carbonyl]-1- 1-piperazinyl}-4-oxo-2-(2-oxo-6- 1-piperazinyl}-4-oxo-7H-1'-thia- piperazinyl}-2-(2-methyl-1,2,3,4- indolinyl)-1,3,3a,7-tetraaza-7- 1,3,3a,7,7'-pentaaza-2,5'-biindenyl- tetrahydro-7-isoquinolyl)-4-oxo- indenyl) acetamide 7-yl) acetamide 1,3,3a,7-tetraaza-7- indenyl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl](6-ethyl-5- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-2-(1-methyl-6-methyl- piperazinyl}-2-(1-methyl-3-methyl- piperazinyl}-2'-methyl-4-oxo- 1H-indazol-5-yl)-4-oxo-1,3,3a,7- 1H-indazol-5-yl)-4-oxo-1,3,3a,7- 7H,2'H-1,1',2',3,3a,7,7'-heptaaza- tetraaza-7-indenyl)acetamide tetraaza-7-indenyl)acetamide 2,5'-biindenyl-7-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl-5- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl]-2-{5- {4-[(5-hydroxy-6-methyl-4- 6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- methylpyrimidine-4- piperazinyl}-2-(1-methyl-1H-1,2,3- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl]-7-oxo-2- benzotriazol-5-yl)-4-oxo-1,3,3a,7- morpholinobenzo[d]oxazol-6-yl)-7- (1,2,2-trimethyl-3H-indol-5-yl)- tetraaza-7-indenyl)acetamide oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyrimidin-4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{2-[7- phenyl] (6-ethyl-5-{4-[(5-hydroxy- (trifluoromethyl)phenyl)-2-(5-ethyl- (difluoromethoxy)-4- 6-methyl-4-pyrimidinyl) carbonyl]- 2-(2-ethyl-2H-indazol-5-yl)-6-(4- fluoropyrazolo[1,5-a]pyridin-5-yl]- 1-piperazinyl}-4-oxo-2-(2-oxo-6- (5-hydroxy-6-methylpyrimidine-4- 5-ethyl-6-[4-(5-hydroxy-6- quinolyl)-1,3,3a,7-tetraaza-7- carbonyl)piperazin-1-yl)-7-oxo- methylpyrimidine-4- indenyl) acetamide [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl]-7-oxo- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(5,8- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(5-ethyl- difluoroquinolin-6-yl)-5-ethyl-6-(4- 6-(4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- (5-hydroxy-6-methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-7-oxo-2- [1,2,4]triazolo[1,5-a]pyrimidin- methyl-1H-indazol-5-yl)-7-oxo- (8-(trifluoromethyl)quinolin-6-yl)- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide 4(7H)-yl)acetamide N-(2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(5-ethyl- phenyl] (6-ethyl-5-{4-[(5-hydroxy- phenyl] (6-ethyl-5-{4-[(5-hydroxy- 6-(4-(5-hydroxy-6- 6-methyl-4-pyrimidinyl) carbonyl]- 6-methyl-4-pyrimidinyl) carbonyl]- methylpyrimidine-4- 1-piperazinyl}-2-(1-methyl-2-oxo- 1-piperazinyl}-4-oxo-2-(2-oxo-5- carbonyl)piperazin-1-yl)-2-(2- 3,4-dihydro-6-quinolyl)-4-oxo- indolinyl)-1,3,3a,7-tetraaza-7- methylquinolin-6-yl)-7-oxo- 1,3,3a,7-tetraaza-7-indenyl) indenyl) acetamide [1,2,4]triazolo[1,5-a]pyrimidin- acetamide 4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl] (6-ethyl-3'-fluoro-5-{4-[(5- phenyl] [2-(1-benzofuran-3-yl)-6- (trifluoromethyl)phenyl](3'-chloro- hydroxy-6-methyl-4-pyrimidinyl) ethyl-5-{4-[(5-hydroxy-6-methyl-4- 6-ethyl-5-{4-[(5-hydroxy-6-methyl- carbonyl]-1-piperazinyl}-4-oxo- pyrimidinyl) carbonyl]-1- 4-pyrimidinyl)carbonyl]-1- 7H-1,1',3,3a,7,7a'-hexaaza-2,5'- piperazinyl}-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-7H,1'H- biindenyl-7-yl) acetamide tetraaza-7-indenyl] acetamide 1,1',3,3a,7,7'-hexaaza-2,5'- biindenyl-7-yl)acetamide

[0015] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- [p-(7-{[N-2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]{2-[p- (trifluoromethyl)phenylcarbamoyl] (trifluoromethyl)phenyl](6-ethyl-5- (aminosulfonylamino)phenyl]-6- methyl}-6-ethyl-5-{4-[(5-hydroxy- {4-[(5-hydroxy-6-methyl-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- 6-methyl-4-pyrimidinyl)carbonyl]- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- 1-piperazinyl}-4-oxo-1,3,3a,7- piperazinyl}-2-[p-(3- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-2-indenyl)phenoxy]acetic methylureido)phenyl]-4-oxo- tetraaza-7-indenyl}acetamide acid 1,3,3a,7-tetraaza-7- indenyl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- phenyl] (6-ethyl-5-{4-[(5-hydroxy- phenyl] (6-ethyl-5-{4-[(5-hydroxy- (trifluoromethyl)phenyl)-2-(2-(2- 6-methyl-4-pyrimidinyl) carbonyl]- 6-methyl-4-pyrimidinyl) carbonyl]- (difluoromethoxy)-4- 1-piperazinyl}-2-[2-(3-oxetanyl)- 1-piperazinyl}-2-[p- fluoropyrazolo[1,5-a]pyridin-5-yl)- 2H-indazol-5-yl]-4-oxo-1,3,3a,7- (methylsulfinyl) phenyl]-4-oxo- 5-ethyl-6-(4-(5-hydroxy-6- tetraaza-7-indenyl) acetamide 1,3,3a,7-tetraaza-7-indenyl) methylpyrimidine-4- acetamide carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide

[0016] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{2-[1- (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl)-2-(2-(4,4- (difluoromethyl)-4-fluoro-2- 6-(4-(5-hydroxy-6- dimethyl-1,4-azasilinan-1-yl)-5- oxopyrazolo[1,5-a]pyridin-5-yl]-5- methylpyrimidine-4- ethyl-6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl)-2-(8- methylpyrimidine-4- methylpyrimidine-4- methylquinolin-6-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide 4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-(1-(4-(2-((2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-(3,6- (trifluoromethyl)phenyl)amino)-2- (trifluoromethyl)phenyl]-2-[2-(3,6- dihydro-2H-pyran-4-yl)-5-ethyl-6- oxoethyl)-2-(3,6-dihydro-2H- dihydro-2H-pyran-4-yl)-5-ethyl-6- {5-methyl-6-oxo-4H,7H- pyran-4-yl)-5-ethyl-7-oxo-4,7- [4-(5-hydroxy-6-methylpyrimidine- pyrazolo[1,5-a]pyrazin-2-yl}-7- dihydro-[1,2,4]triazolo[1,5- 4-carbonyl)-1,4-diazepan-1-yl]-7- oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)pyrrolidin-3-yl)-5- oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl]acetamide hydroxy-N,6-dimethylpyrimidine- a]pyrimidin-4-yl]acetamide 4-carboxamide

[0017] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[2-(3,6- (trifluoromethyl)phenyl]-2-[2-(3,6- (trifluoromethyl)phenyl)-2-(2-(3,6- dihydro-2H-pyran-4-yl)-5-ethyl-6- dihydro-2H-pyran-4-yl)-5-ethyl-6- dihydro-2H-pyran-4-yl)-5-ethyl-6- [(5S)-4-(5-hydroxy-6- [(5R)-4-(5-hydroxy-6- (3-(5-hydroxy-6-methylpyrimidine- methylpyrimidine-4-carbonyl)-5- methylpyrimidine-4-carbonyl)-5- 4-carbonyl)-3,7- methyl-1,4-diazepan-1-yl]-7-oxo- methyl-1,4-diazepan-1-yl]-7-oxo- diazabicyclo[4.2.0]octan-7-yl)-7- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- oxo-[1,2,4]triazolo[1,5- yl]acetamide yl]acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl](5-{4-[(E)-4-(p- phenyl)-2-(2-(3,6-dihydro-2H- (trifluoromethyl)phenyl]-2-[2-(3,6- methoxyphenyl)-4-oxo-2- pyran-4-yl)-5-ethyl-6-(1-(5- dihydro-2H-pyran-4-yl)-5-ethyl-6- butenoyl]-1-piperazinyl}-2-(3,6- hydroxy-6-methylpyrimidine-4- [3-(5-hydroxy-6-methylpyrimidine- dihydro-2H-pyran-4-yl)-6-ethyl-4- carbonyl)octahydro-4H- 4-carbonyl)-3,8- oxo-1,3,3a,7-tetraaza-7- pyrrolo[3,2-b]pyridin-4-yl)-7-oxo- diazabicyclo[4.2.0]octan-8-yl]-7- indenyl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4-yl]acetamide

[0018] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- (trifluoromethyl)phenyl]-2-[2-(3,6- (trifluoromethyl)phenyl]-2-[2-(2,3- 5-ethyl-6-[4-(5-hydroxy-6- dihydro-2H-pyran-4-yl)-5-ethyl-6- dihydro-1-benzofuran-4-yl)-5- methylpyrimidine-4- [4-(5-hydroxy-6-methylpyrimidine- ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo- 4-carbonyl)-hexahydro-2H- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- pyrrolo[3,2-b]pyridin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-[4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- (trifluoromethyl)bicyclo[2.2.2] yl]acetamide yl]acetamide octan-1-yl]acetamide N-(6,6- N-(4,4-difluorocyclohexyl)-2-[2- N-{3- difluorobicyclo[3.1.0]hexan-3-yl)- (3,6-dihydro-2H-pyran-4-yl)-5- cyclobutylbicyclo[1.1.1]pentan-1- 2-(2-(3,6-dihydro-2H-pyran-4-yl)- ethyl-6-[4-(5-hydroxy-6- yl}-2-[2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- yl)-5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl] acetamide

[0019] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-[2-(3,6-dihydro-2H-pyran-4-yl)- N-{3-[3-(1,1- N-(2-chloro-4- 5-ethyl-6-[4-(5-hydroxy-6- difluoroethyl)bicyclo[1.1.1]pentan- (chlorodifluoromethoxy)phenyl)-2- methylpyrimidine-4- 1-yl]bicyclo[1.1.1]pentan-1-yl}-2- (2-(3,6-dihydro-2H-pyran-4-yl)-5- carbonyl)piperazin-1-yl]-7-oxo- [2-(3,6-dihydro-2H-pyran-4-yl)-5- ethyl-6-(4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- yl]-N-[3-(4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- fluorophenyl)bicyclo[1.1.1]pentan- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- 1-yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl]acetamide 2-[2-(3,6-dihydro-2H-pyran-4-yl)- N-{6,6-difluorospiro[3.3]heptan-2- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[4-(5-hydroxy-6- yl}-2-[2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- yl)-5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]-N-{4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]-N-[1-(trifluoromethyl)-2- [(trifluoromethyl)sulfanyl]phenyl} yl]acetamide oxabicyclo[2.2.2]octan-4- acetamide yl]acetamide

[0020] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-{3- 2-(2-(3,6-dihydro-2H-pyran-4-yl)- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- cyclopropylbicyclo[1.1.1]pentan-1- 5-ethyl-6-(4-(5-hydroxy-6- 5-ethyl-6-[4-(5-hydroxy-6- yl}-2-[2-(3,6-dihydro-2H-pyran-4- methylpyrimidine-4- methylpyrimidine-4- yl)-5-ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- 4(7H)-yl)-N-(5- yl]-N-[3-(3,3,3- [1,2,4]triazolo[1,5-a]pyrimidin-4- (trifluoromethyl)quinolin-8- trifluoropropyl)bicyclo yl]acetamide yl)acetamide [1.1.1]pentan-1-yl]acetamide 2-[2-(3,6-dihydro-2H-pyran-4-yl)- 2-(2-(3,6-dihydro-2H-pyran-4-yl)- N-{2-chloro-4- 5-ethyl-6-[4-(5-hydroxy-6- 5-ethyl-6-(4-(5-hydroxy-6- [(trifluoromethyl)sulfanyl]phenyl}- methylpyrimidine-4- methylpyrimidine-4- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- 5-ethyl-6-[4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- methylpyrimidine-4- yl]-N-[4- 4(7H)-yl)-N-(5- carbonyl)piperazin-1-yl]-7-oxo- (trifluoromethyl)bicyclo[2.2.1] (trifluoromethyl)pyridin-2- [1,2,4]triazolo[1,5-a]pyrimidin-4- heptan-1-yl]acetamide yl)acetamide yl]acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)- N-(1,1-difluorospiro[2.3]hexan-5- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-(4-(5-hydroxy-6- yl)-2-(2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)-N-(5- [1,2,4]triazolo[1,5-a]pyrimidin- yl]-N-[1-meth yl-2-oxo-6- (trifluoromethyl)quinolin-8- 4(7H)-yl)acetamide (trifluoromethyl)pyridin-3- yl)acetamide yl]acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-(2-(3,6-dihydro-2H-pyran-4-yl)- N-(4-difluoromethoxy-2- N-(2-chloro-4- 5-ethyl-6-(4-(5-hydroxy-6- fluorophenyl) [2-(3,6-dihydro-2H- difluoromethoxyphenyl) [2-(3,6- methylpyrimidine-4- pyran-4-yl)-6-ethyl-5-{4-[(5- dihydro-2H-pyran-4-yl)-6-ethyl-5- carbonyl)piperazin-1-yl)-7-oxo- hydroxy-6-methyl-4-pyrimidinyl) {4-[(5-hydroxy-6-methyl-4- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl]-1-piperazinyl}-4-oxo- pyrimidinyl) carbonyl]-1- 4(7H)-yl)-N-(7- 1,3,3a,7-tetraaza-7- piperazinyl}-4-oxo-1,3,3a,7- (trifluoromethyl)benzo[d]thiazol-4- indenyl]acetamide tetraaza-7-indenyl] acetamide yl)acetamide N-{2,2-difluoro-3- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- N-(5-chloro-7- methylbicyclo[1.1.1]pentan-1-yl}- 5-ethyl-6-[4-(5-hydroxy-6- (trifluoromethyl)benzo[d]thiazol-4- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- methylpyrimidine-4- yl)-2-(2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo- yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-{6-fluorospiro[3.3]heptan-2- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- 2-[2-(1,3-dihydro-2-benzofuran-5- (trifluoromethyl)phenyl]-2-[2-(3,6- (trifluoromethyl)phenyl)-2-(5- yl)-5-ethyl-6-[4-(5-hydroxy-6- dihydro-2H-pyran-4-yl)-7-ethyl-6- (difluoromethoxy)-2-(1,3- methylpyrimidine-4- [4-(5-hydroxy-6-methylpyrimidine- dihydroisobenzofuran-5-yl)-6-(4- carbonyl)piperazin-1-yl]-7-oxo- 4-carbonyl)piperazin-1-yl]- (5-hydroxy-6-methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyridin-8- carbonyl)piperazin-1-yl)-7-oxo- yl]-N-[5- yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin- (trifluoromethyl)bicyclo[4.2.0]octa- 4(7H)-yl)acetamide 1(6),2,4-trien-2-yl]acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-[2-(azetidin-1-yl)-5-ethyl-6-[4-(5- N-(2-chloro-4- N-(2-chloro-4- hydroxy-6-methylpyrimidine-4- (trifluoromethyl)phenyl)-2-(2-(2,3- (trifluoromethyl)phenyl)-2-(6-(4-(2- carbonyl)piperazin-1-yl]-7-oxo- dihydrobenzo[b][1,4]dioxin-5-yl)- (cyclopropanesulfonamido)benzoyl [1,2,4]triazolo[1,5-a]pyrimidin-4- 5-ethyl-6-(4-(2- )piperazin-1-yl)-2-(2,3- yl]-N-[5- (methylsulfonamido)benzoyl)pipera dihydrobenzo[b][1,4]dioxin-5-yl)- (trifluoromethyl)bicyclo[4.2.0]octa- zin-1-yl)-7-oxo-[1,2,4]triazolo[1,5- 5-ethyl-7-oxo-[1,2,4]triazolo[1,5- 1(6),2,4-trien-2-yl]acetamide a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide 2-(2-(benzo[d][1,3]dioxol-5-yl)-5- N-[3-chloro-5- 2-{5-ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- (trifluoromethyl)bicyclo[4.2.0]octa- methylpyrimidine-4- methylpyrimidine-4- 1(6),2,4-trien-2-yl]-2-[2-(2,3- carbonyl)piperazin-1-yl]-2-{3- carbonyl)piperazin-1-yl)-7-oxo- dihydro-1-benzofuran-6-yl)-5- oxabicyclo[3.1.0]hexan-6-yl}-7- [1,2,4]triazolo[1,5-a]pyrimidin- ethyl-6-[4-(5-hydroxy-6- oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)-N-(3-chloro-5- methylpyrimidine-4- a]pyrimidin-4-yl}-N-[5- (trifluoromethyl)bicyclo[4.2.0]octa- carbonyl)piperazin-1-yl]-7-oxo- (trifluoromethyl)bicyclo[4.2.0]octa- 1(6),2,4-trien-2-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 1(6),2,4-trien-2-yl]acetamide yl]acetamide

[0021] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[3-chloro-5- N-[3-chloro-5- 2-[2-(2H-1,3-benzodioxol-4-yl)-5- (trifluoromethyl)bicyclo[4.2.0]octa- (trifluoromethyl)bicyclo[4.2.0]octa- ethyl-6-[4-(5-hydroxy-6- 1(6),2,4-trien-2-yl]-2-[2-(2,3- 1(6),2,4-trien-2-yl]-2-[2-(1,3- methylpyrimidine-4- dihydro-1-benzofuran-5-yl)-5- dihydro-2-benzofuran-5-yl)-5- carbonyl)piperazin-1-yl]-7-oxo- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- methylpyrimidine-4- methylpyrimidine-4- yl]-N-[3-chloro-5- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- (trifluoromethyl)bicyclo[4.2.0]octa- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- 1(6),2,4-trien-2-yl]acetamide) yl]acetamide yl]acetamide) N-[3-chloro-5- N-[3-chloro-5- N-[3-chloro-5- (trifluoromethyl)bicyclo[4.2.0]octa- (trifluoromethyl)bicyclo[4.2.0]octa- (trifluoromethyl)bicyclo[4.2.0]octa- 1(6),2,4-trien-2-yl]-2-[2-(1,3- 1(6),2,4-trien-2-yl]-2-[2- 1(6),2,4-trien-2-yl]-2-[2-(2,3- dihydro-2-benzofuran-4-yl)-5- (dimethylamino)-5-ethyl-6-[4-(5- dihydro-1,4-benzodioxin-5-yl)-5- ethyl-6-[4-(5-hydroxy-6- hydroxy-6-methylpyrimidine-4- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide

[0022] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(3-chloro-5- N-(3-chloro-5- 2-[2-(azetidin-1-yl)-5-ethyl-6-[4-(5- (trifluoromethyl)bicyclo[4.2.0]octa- (trifluoromethyl)bicyclo[4.2.0]octa- hydroxy-6-methylpyrimidine-4- 1(6),2,4-trien-2-yl)-2-(5-ethyl-6-(4- 1(6),2,4-trien-2-yl)-2-(5-ethyl-6-(4- carbonyl)piperazin-1-yl]-7-oxo- (5-hydroxy-6-methylpyrimidine-4- (5-hydroxy-6-methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl)-2- carbonyl)piperazin-1-yl)-2- yl]-N-[3-chloro-5- (isochroman-5-yl)-7-oxo- (isochroman-8-yl)-7-oxo- (trifluoromethyl)bicyclo[4.2.0]octa- [1,2,4]triazolo [1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- 1(6),2,4-trien-2-yl]acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide 2-[2-(dimethylamino)-5-ethyl-6-[4- 2-(5-ethyl-6-(4-(5-hydroxy-6- 2-[2-(2H-1,3-benzodioxol-4-yl)-5- (5-hydroxy-6-methylpyrimidine-4- methylpyrimidine-4-carbonyl) ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo- piperazin-1-yl)-2-(isochroman-6- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl)-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-{4- a]pyrimidin-4(7H)-yl)-N-(4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [(trifluoromethyl)sulfanyl]phenyl}a ((trifluoromethyl)thio) yl]-N-{4- cetamide phenyl)acetamide [(trifluoromethyl)sulfanyl]phenyl}a cetamide N-{2-chloro-4- N-{2-chloro-4- N-p- [(trifluoromethyl)sulfanyl]phenyl}- [(trifluoromethyl)sulfanyl]phenyl}- chlorodifluoromethoxyphenyl[2- 2-[2-(3,4-dihydro-1H-2- 2-[2-(dimethylamino)-5-ethyl-6-[4- (2,3-dihydro-1-benzofuran-5-yl)-6- benzopyran-6-yl)-5-ethyl-6-[4-(5- (5-hydroxy-6-methylpyrimidine-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- pyrimidinyl) carbonyl]-1- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- piperazinyl}-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide tetraaza-7-indenyl]acetamide yl]acetamide

[0023] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-p- N-{2-chloro-4- 2-[2-(2H-1,3-benzodioxol-4-yl)-5- chlorodifluoromethoxyphenyl[2- [(trifluoromethyl)sulfanyl]phenyl}- ethyl-6-[4-(5-hydroxy-6- (2,3-dihydro-1-benzofuran-5-yl)-6- 2-[2-(2,3-dihydro-1,4-benzodioxin- methylpyrimidine-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- 5-yl)-5-ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo- pyrimidinyl) carbonyl]-1- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- piperazinyl}-4-oxo-1,3,3a,7- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-{2-chloro-4- tetraaza-7-indenyl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [(trifluoromethyl)sulfanyl]phenyl}a yl]acetamide cetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2-(3,4- (trifluoromethyl)phenyl]-2-(6-{4- (dimethylamino)-5-ethyl-6-[4-(5- dihydro-1H-2-benzopyran-6-yl)-5- [6-(difluoromethyl)-5- hydroxy-6-methylpyrimidine-4- ethyl-6-[4-(5-hydroxy-6- hydroxypyrimidine-4- carbonyl) piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-(2,3- [1,2,4]triazolo[1,5-a]pyrimidin -4- carbonyl)piperazin-1-yl]-7-oxo- dihydro-1,4-benzodioxin-5-yl)-5- yl]-2,2-difluoroacetamide [1,2,4]triazolo[1,5-] pyri midin-4- ethyl-7-oxo-[1,2,4]triazolo[1,5- yl]-2,2-difluoroacetamide a]pyrimidin-4-yl)acetamide 2-[2-(2H-1,3-benzodioxol-4-yl)-6- N-(2-chloro-4- N-(2-chloro-4- {4-[6-(difluoromethyl)-5- chlorodifluoromethoxyphenyl) [2- chlorodifluoromethoxyphenyl) (6- hydroxypyrimidine-4- (2,3-dihydro-1-benzofuran-5-yl)-6- ethyl-5-{4-[(5-hydroxy-6-methyl-4- carbonyl]piperazin-1-yl}-5-ethyl-7- ethyl-5-{4-[(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- oxo-[1,2,4]triazolo[1,5- pyrimidinyl) carbonyl]-1- piperazinyl}-2-(6-isochromanyl)-4- a]pyrimidin-4-yl]-N-[2-chloro-4- piperazinyl}-4-oxo-1,3,3a,7- oxo-1,3,3a,7-tetraaza-7- (trifluoromethyl)phenyl]acetamide tetraaza-7-indenyl]acetamide indenyl)acetamide

[0024] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-{2-chloro-4- chlorodifluoromethoxyphenyl) [2- (trifluoromethyl)phenyl)-2-(2-(1,3- [(trifluoromethyl)sulfanyl]phenyl}- (1,3-dihydro-5-isobenzofuranyl)-6- dihydroisobenzofuran-5-yl)-6-(4- 2-[2-(1,3-dihydro-2-benzofuran-5- ethyl-5-{4-[(5-hydroxy-6-methyl-4- (2,4-dihydroxy-5-isopropylbenzoyl) yl)-5-ethyl-6-[4-(5-hydroxy-6- pyrimidinyl) carbonyl]-1- piperazin-1-yl)-5-ethyl-7-oxo- methylpyrimidine-4- piperazinyl}-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl]-7-oxo- tetraaza-7-indenyl] acetamide 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide N-(2-chloro-4- 2-[2-(2,3-dihydro-1,4-benzodioxin- N-(2-chloro-4- ((trifluoromethyl)thio)phenyl)-2-(2- 5-yl)-5-ethyl-6-[4-(5-hydroxy-6- (trifluoromethyl)phenyl)-2-(6-(4-(6- (2,3-dihydrobenzofuran-5-yl)-5- methylpyrimidine-4- (3,3-difluoroazetidin-1-yl)-5- ethyl-6-(4-(5-hydroxy-6-methyl carbonyl)piperazin-1-yl]-7-oxo- hydroxypyrimidine-4- pyrimidine-4-carbonyl)piperazin-1- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl)-2-(1,3- yl)-7-oxo-[1,2,4]triazolo[1,5- yl]-N-{4- dihydroisobenzofuran-5-yl)-5- a]pyrimidin-4(7H)-yl)acetamide [(trifluoromethyl)sulfanyl]phenyl}a ethyl-7-oxo-[1,2,4]triazolo[1,5- cetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-6-cyclopropoxy-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl)-2-(2-(1,3- dihydro-2-benzofuran-5-yl)-6-[4- dihydro-2-benzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-5- (2,4-dihydroxy-5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6-(3- methylbenzoyl)piperazin-1-yl]-5- methylpyrimidine-4- methoxyazetidin-1-yl)pyrimidine-4- ethyl-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- a]pyrimidin-4-yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide

[0025] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-cyclopropoxy-4- N-[2-chloro-4- N-[2-chloro-5-cyclopropyl-4- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl]-2-[2-(1,3- dihydro-2-benzofuran-5-yl)-5- dihydro-2-benzofuran-5-yl)-5- dihydro-2-benzofuran-5-yl)-5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-{3-hydroxy-5H,6H,7H- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- cyclopenta[b]pyridine-2- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- carbonyl}piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide yl]acetamide N-[2-chloro-4-(3,3,3-trifluoroprop- N-(2-chloro-4-(1- N-[2-chloro-4-(2,2- 1-en-2-yl)phenyl]-2-[2-(1,3- (trifluoromethyl)cyclopropyl)pheny difluoroethenyl)phenyl]-2-[2-(1,3- dihydro-2-benzofuran-5-yl)-5- l)-2-(2-(1,3-dihydroisobenzofuran- dihydro-2-benzofuran-5-yl)-5- ethyl-6-[4-(5-hydroxy-6- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a] pyrimidin-4- yl]acetamide 4(7H)-yl)acetamide yl]acetamide

[0026] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-(2-chloro-4- N-(5-chloro-7- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl)-2-(2-(1,3- (trifluoromethyl)benzo[d]thiazol-4- dihydro-2-benzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-5- yl)-2-(2-(1,3-dihydroisobenzofuran- ethyl-6-(4-{3-hydroxy-4-oxo- ethyl-6-(4-(3-hydroxy-5,6,7,8- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- 6H,7H,8H-pyrrolo[1,2- tetrahydroquinoline-2- methylpyrimidine-4- a]pyrimidine-2-carbonyl}piperazin- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- 1-yl)-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- a]pyrimidin-4-yl]acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide N-(2-chloro-4-(trifluoromethyl) N-(2-chloro-4- N-[2-chloro-4- phenyl)-2-(1,3- (trifluoromethyl)phenyl)-2-(2-(1,3- (trifluoromethyl)phenyl]-2-[2-(1,3- dihydroisobenzofuran-5-yl)-6-(4- dihydroisobenzofuran-5-yl)-6-(4- dihydro-2-benzofuran-5-yl)-5- (2,2-dioxido-3,4-dihydro-1H- (2,2-dioxido-1H- ethyl-6-(4-{3-hydroxy-4-oxo- benzo[c][1,2] thiazine-8- benzo[c][1,2]thiazine-8- 6H,7H,8H,9H-pyrido[1,2- carbonyl)piperazin-1-yl)-5-ethyl-7- carbonyl)piperazin-1-yl)-5-ethyl-7- a]pyrimidine-2-carbonyl}piperazin- oxo-[1,2,4]triazolo[1,5- oxo-[1,2,4]triazolo[1,5- 1-yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4-yl]acetamide N-(5-chloro-7- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)benzo[d]thiazol-4- (trifluoromethyl)phenyl)-2-(2-(1,3- (trifluoromethyl)phenyl)-2-(6-(4- yl)-2-(2-(2,3-dihydrobenzofuran-5- dihydroisobenzofuran-5-yl)-5- (3,6-dihydro-2H-pyran-4- yl)-5-ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(6-methoxy-1-methyl- carbonyl)piperazin-1-yl)-5-ethyl-2- methylpyrimidine-4- 1H-benzo[d][1,2,3]triazole-5- (2-hydroxypyrimidin-4-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4] triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(5-ethyl- (trifluoromethyl)phenyl]-2-[2-(1,3- phenyl] [2-(1,3-dihydro-5- 2-(2-hydroxypyrimidin-4-yl)-7- dihydro-2-benzofuran-5-yl)-5- isobenzofuranyl)-6-ethyl-5-{4-[(6- oxo-6-(4-(tetrahydro-2H-pyran-4- ethyl-6-(4-{7-hydroxy-2H,3H,4H- hydroxy-1-methyl-1H-1,2,3- carbonyl)piperazin-1-yl)- pyrano[3,2-b]pyridine-6- benzotriazol-5-yl) carbonyl]-1- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl}piperazin-1-yl)-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- tetraaza-7-indenyl] acetamide yl]acetamide 2-(6-(4-acetylpiperazin-1-yl)-5- N-[2-chloro-4- N-(2-chloro-4- ethyl-2-(5-hydroxypyrimidin-2-yl)- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl)-2-(6-(4- 7-oxo-[1,2,4]triazolo[1,5- dihydro-2-benzofuran-5-yl)-5- (3,6-dihydro-2H-pyran-4- a]pyrimidin-4(7H)-yl)-N-(2-chloro- ethyl-6-(4-{6-hydroxy-2H,3H- carbonyl)piperazin-1-yl)-5-ethyl-2- 4- furo[3,2-b]pyridine-5- (5-hydroxypyrimidin-2-yl)-7-oxo- (trifluoromethyl)phenyl)acetamide carbonyl}piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl]acetamide 2-{6-[(3aS,7aS)-4-(5-hydroxy-6- 2-{6-[(3aR,7aS)-4-(5-hydroxy-6- N-(2-chloro-4- methylpyrimidine-4-carbonyl)- methylpyrimidine-4-carbonyl)- (trifluoromethyl)phenyl)-2-(2-(1,3- hexahydro-2H-pyrrolo[3,2- hexahydro-2H-pyrrolo[3,2- dihydroisobenzofuran-5-yl)-5- b]pyridin-1-yl]-2-(1,3-dihydro-2- b]pyridin-1-yl]-2-(1,3-dihydro-2- ethyl-6-(4-(4-hydroxyisoxazole-3- benzofuran-5-yl)-5-ethyl-7-oxo- benzofuran-5-yl)-5-ethyl-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- yl}-N-[2-chloro-4- yl}-N-[2-chloro-4- 4(7H)-yl)acetamide (trifluoromethyl)phenyl]acetamide (trifluoromethyl)phenyl]acetamide

[0027] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[6-chloro-4-(trifluoromethyl)- (trifluoromethyl)phenyl][2-(1,3- (trifluoromethyl)phenyl][2-(1,3- 2,3-dihydro-1-benzofuran-7-yl]-2- dihydro-5-isobenzofuranyl)-6- dihydro-5-isobenzofuranyl)-6- [2-(1,3-dihydro-2-benzofuran-5-yl)- ethyl-5-{4-[(3-hydroxy-7,8- ethyl-5-{4-[(3-hydroxy-6,8- 5-ethyl-6-[4-(5-hydroxy-6- dihydro-5H-6-oxa-1-azanaphth-2- dihydro-5H-7-oxa-1-azanaphth-2- methylpyrimidine-4-carbonyl) yl)carbonyl]-1-piperazinyl}-4-oxo- yl)carbonyl]-1-piperazinyl}-4-oxo- piperazin-1-yl]-7-oxo- [1,2,4] 1,3,3a,7-tetraaza-7- 1,3,3a,7-tetraaza-7- triazolo[1,5-a] pyrimidin-4-yl] indenyl]acetamide indenyl]acetamide acetamide N-(2-chloro-4- 2-(6-(4-(5H-pyrrolo[3,2- N-(2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(2-(1,3- d]pyrimidine-4-carbonyl)piperazin- phenyl)-2-(2-(1,3- dihydroisobenzofuran-5-yl)-5- 1-yl)-2-(1,3-dihydroisobenzofuran- dihydroisobenzofuran-5-yl)-5- ethyl-6-(4-(4-hydroxy-5-(4- 5-yl)-5-ethyl-7-oxo- ethyl-6-(4-(4-hydroxy-5- methylpiperazin-1-yl)isothiazole-3- [1,2,4]triazolo[1,5-a]pyrimidin- morpholinoisothiazole-3- carbonyl)piperazin-1-yl)-7-oxo- 4(7H)-yl)-N-(2-chloro-4- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- (trifluoromethyl)phenyl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide 4(7H)-yl)acetamide N-(2-chloro-4-(trifluoromethyl) N-[6-chloro-4-(trifluoromethyl)-1- N-[2-chloro-4- phenyl)-2-(2-(1,3- benzofuran-7-yl]-2-[2-(1,3-dihydro- (trifluoromethyl)phenyl][2-(1,3- dihydroisobenzofuran-5-yl)-5- 2-benzofuran-5-yl)-5-ethyl-6-[4-(5- dihydro-5-isobenzofuranyl)-6- ethyl-6-(4-(4-hydroxyisoxazole-3- hydroxy-6-methylpyrimidine-4- ethyl-5-(4-{[4-hydroxy-5-(4- carbonyl) piperazin-1-yl)-7-oxo- carbonyl) piperazin-1-yl]-7-oxo- pyridyl)-3-isothiazolyl]carbonyl}- [1,2,4] triazolo[1,5-a] pyrimidin- [1,2,4] triazolo[1,5-a] pyrimidin-4- 1-piperazinyl)-4-oxo-1,3,3a,7- 4(7H)-yl)acetamide yl] acetamide tetraaza-7-indenyl]acetamide

[0028] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{6-[4- (trifluoromethyl)phenyl]-2-[2-(1,3- (trifluoromethyl)phenyl)-2-(2-(1,3- (5-cyano-3-hydroxy-2- dihydro-2-benzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-7- methylpyridine-4- ethyl-6-{4-[3-hydroxy-2-methyl-6- ethyl-6-(4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-2-(1,3- (4-methylpiperazin-1-yl)pyridine-4- methylpyrimidine-4- dihydro-2-benzofuran-5-yl)-5- carbonyl]piperazin-1-yl}-7-oxo- carbonyl)piperazin-1-yl)-3-methyl- ethyl-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- 5-oxoimidazo[1,2-a]pyrimidin- a]pyrimidin-4-yl}acetamide yl]acetamide 8(5H)-yl)acetamide N-(2-chloro-4- (S)-N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(2-(1,3- (trifluoromethyl)phenyl]-2-[2-(1,1- phenyl] (5-{4-[(1H-1,6-diazainden- dihydroisobenzofuran-5-yl)-7- dimethyl-3H-2-benzofuran-5-yl)-5- 7-yl) carbonyl]-1-piperazinyl}-2- ethyl-6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- (1,1-dimethyl-1,3-dihydro-5- methylpyrimidine-4- methylpyrimidine-4-carbonyl)-2- isobenzofuranyl)-6-ethyl-4-oxo- carbonyl)piperazin-1-yl)-3- methylpiperazin-1-yl]-7-oxo- 1,3,3a,7-tetraaza-7-indenyl) (hydroxymethyl)-5- [1,2,4]triazolo[1,5-a]pyrimidin-4- acetamide oxoimidazo[1,2-a]pyrimidin-8(5H)- yl]acetamide yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl] {2-(1,1-dimethyl-1,3- phenyl] [2-(1,1-dimethyl-1,3- (trifluoromethyl)phenyl]-2-[2-(1,1- dihydro-5-isobenzofuranyl)-6- dihydro-5-isobenzofuranyl)-6- dimethyl-3H-2-benzofuran-5-yl)-5- ethyl-5-[4-(3-hydroxy-2-methyl- ethyl-4-oxo-5-{4-[(3H-1,3,5- ethyl-6-[(3R)-4-(5-hydroxy-6- isonicotinoyl)-1-piperazinyl]-4- triazainden-4-yl) carbonyl]-1- methylpyrimidine-4-carbonyl)-3- oxo-1,3,3a,7-tetraaza-7-indenyl} piperazinyl}-1,3,3a,7-tetraaza-7- methylpiperazin-1-yl]-7-oxo- acetamide indenyl] acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide

[0029] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(1,1- (trifluoromethyl)phenyl)-2-(2-(1,1- (trifluoromethyl)phenyl)-2-(2-(1,1- dimethyl-1,3- dimethyl-1,3- dimethyl-1,3- dihydroisobenzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-5- ethyl-6-((1S,6S)-5-(5-hydroxy-6- ethyl-6-((1S,6R)-5-(5-hydroxy-6- ethyl-6-((1R,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5- methylpyrimidine-4-carbonyl)-2,5- methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-7- diazabicyclo[4.2.0]octan-2-yl)-7- diazabicyclo[4.2.0]octan-2-yl)-7- oxo-[1,2,4]triazolo[1,5- oxo-[1,2,4]triazolo[1,5- oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide. a]pyrimidin-4(7H)-yl)acetamide (R)-N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(1,1- (trifluoromethyl)phenyl][2-(1,1- (trifluoromethyl)phenyl][2-(1,1- dimethyl-1,3- dimethyl-1,3-dihydro-5- dimethyl-1,3-dihydro-5- dihydroisobenzofuran-5-yl)-5- isobenzofuranyl)-6-ethyl-5-[4-(3- isobenzofuranyl)-6-ethyl-5-{4-[(3- ethyl-6-(4-(5-hydroxy-6- hydroxy-4-oxo-7-oxa-1,4a-diaza- hydroxy-7-oxa-1-aza-5,8-dihydro- methylpyrimidine-4-carbonyl)-5- 4,5,6,8-tetrahydro-2-naphthoyl)-1- 6H-naphth-2-yl)carbonyl]-1- methyl-1,4-diazepan-1-yl)-7-oxo- piperazinyl]-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin- tetraaza-4,7-dihydro-7- tetraaza-4,7-dihydro-7- 4(7H)-yl)acetamide indenyl]acetamide indenyl]acetamide N-[2-chloro-4- (10R,12R)-N-[2-chloro-4- (10S,12R)-N-[2-chloro-4- (trifluoromethyl)phenyl][2-(1,1- (trifluoromethyl)phenyl]-4-(1,1- (trifluoromethyl)phenyl]-4-(1,1- dimethyl-1,3-dihydro-5- dimethyl-3H-2-benzofuran-5-yl)-8- dimethyl-3H-2-benzofuran-5-yl)-8- isobenzofuranyl)-6-ethyl-5-[4-({3- [(1S,6S)-5-(5-hydroxy-6- [(1S,6S)-5-(5-hydroxy-6- [(p-methoxyphenyl)methoxy]-6- methylpyrimidine-4-carbonyl)-2,5- methylpyrimidine-4-carbonyl)-2,5- oxa-1-aza-7,8-dihydro-5H-naphth- diazabicyclo[4.2.0]octan-2-yl]-10- diazabicyclo[4.2.0]octan-2-yl]-10- 2-yl}carbonyl)-1-piperazinyl]-4- methyl-7-oxo-1,3,5,6- methyl-7-oxo-1,3,5,6- oxo-1,3,3a,7-tetraaza-4,7-dihydro- tetraazatricyclo[7.3.0.0^{2,6}]dode tetraazatricyclo[7.3.0.0^{2,6}]dode 7-indenyl]acetamide ca-2,4,8-triene-12-carboxamide ca-2,4,8-triene-12-carboxamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 (10R,12S)-N-[2-chloro-4- (10S,12S)-N-[2-chloro-4- (7R,9S)-N-(2-chloro-4- (trifluoromethyl)phenyl]-4-(1,1- (trifluoromethyl)phenyl]-4-(1,1- (trifluoromethyl)phenyl)-2-(1,1- dimethyl-3H-2-benzofuran-5-yl)-8- dimethyl-3H-2-benzofuran-5-yl)-8- dimethyl-1,3- [(1S,6S)-5-(5-hydroxy-6- [(1S,6S)-5-(5-hydroxy-6- dihydroisobenzofuran-5-yl)-6-(4- methylpyrimidine-4-carbonyl)-2,5- methylpyrimidine-4-carbonyl)-2,5- (5-hydroxy-6-methylpyrimidine-4- diazabicyclo[4.2.0]octan-2-yl]-10- diazabicyclo[4.2.0]octan-2-yl]-10- carbonyl)piperazin-1-yl)-7-methyl- methyl-7-oxo-1,3,5,6- methyl-7-oxo-1,3,5,6- 5-oxo-5,7,8,9-tetrahydropy tetraazatricyclo[7.3.0.0^{2,6}]dode tetraazatricyclo[7.3.0.0^{2,6}]dode rrolo[1,2-c][1,2,4]triazolo[1,5- ca-2,4,8-triene-12-carboxamide ca-2,4,8-triene-12-carboxamide a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4- (7S,9S)-N-(2-chloro-4- (7S,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(1,1- (trifluoromethyl)phenyl)-2-(1,1- (trifluoromethyl)phenyl)-2-(1,1- dimethyl-1,3- dimethyl-1,3- dimethyl-1,3- dihydroisobenzofuran-5-yl)-6-(4- dihydroisobenzofuran-5-yl)-6-(4- dihydroisobenzofuran-5-yl)-6-(4- (5-hydroxy-6-methylpyrimidine-4- (5-hydroxy-6-methylpyrimidine-4- (5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-methyl- carbonyl)piperazin-1-yl)-7-methyl- carbonyl)piperazin-1-yl)-7-methyl- 5-oxo-5,7,8,9- 5-oxo-5,7,8,9- 5-oxo-5,7,8,9- tetrahydropyrrolo[1,2- tetrahydropyrrolo[1,2- tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidine- c][1,2,4]triazolo[1,5-a]pyrimidine- c][1,2,4]triazolo[1,5-a]pyrimidine- 9-carboxamide 9-carboxamide 9-carboxamide In certain embodiments, the compositions and methods described herein relate to a combination comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more additional active agents. In certain embodiments, the compositions and methods described herein relate to a combination wherein an additional active agent is an anti-cancer agent. In certain embodiments, the compositions and methods described herein relate to a combination wherein the additional active anti- cancer agent is a chemotherapy. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions and methods described herein relate to a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In certain embodiments, the compositions and methods described herein relate to a compound as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament. In certain embodiments, the compositions and methods described herein relate to a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease. In certain embodiments, the compositions and methods described herein relate to a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In certain embodiments, the compositions and methods described herein relate to a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the compositions and methods described herein relate to a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) that is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the compositions and methods described herein relate to a method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of inhibiting WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of treating a disorder or disease with a WRN inhibitor in a subject, comprising ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 administering to the subject a therapeutically effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of treating cancer with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of treating cancer with a WRN inhibitor in a subject, comprising administering a compound as described herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the compositions and methods described herein relate to a method of treating a cancer wherein the cancer is characterized as microsatellite instability- high (MSI-H) and / or mismatch repair deficient (dMMR) and is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the compositions and methods described herein relate to a use of a compound, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the compositions and methods described herein relate to a use of a compound or pharmaceutically acceptable salt thereof, wherein the use is for the treatment of a cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the compositions and methods described herein relate to a process to manufacture a compound described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts the results of an in vivo efficacy assay of certain compounds of the present disclosure. Briefly, MSI-h HCT116 or MSS HT-29 tumors were established in 4–5- week-old female Crl:NU(NCr)-Foxn1nu athymic nude mice (Charles River Laboratories). Mice were housed in 5 animals per cage and food and water was provided ad libitum. All procedures were performed at the Mispro Vivarium facility in New York, NY and were ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 conducted according to the guidelines of the Mispro Institutional Animal Care and Use Committee and Eikon Therapeutics protocol. HCT116 and HT-29 cells were sourced from ATCC and cultured in McCoy’s 5a Medium (ATCC) with 10% FBS. To establish the tumors, mice were injected with 2 x 106 HCT116 or HT-29 cells in 50% Geltrex / 50% HBSS in the right flank. Animal body weights and tumor volumes were measured twice weekly throughout the study and recorded in StudyLog. Tumor volume was calculated using the formula TV = 0.5*length*width2. Tumor Growth Inhibition (TGI) was calculated using the formula TGI = (1-((TD25- Tinitial) / (CD25-Cinitial)))*100, where T is the Test group TV and C is the Control group TV at Day 25 vs the initial TV at study commencement. Percent tumor regression was calculated using the formula % regression = 100-((Tfinal / Tinitial)x100), where Tfinal is the latest TV measurement and Tinitial is the initial TV at study commencement. After HCT116 tumors grew to an average volume of 150-200 mm3 (7 days post-implantation), mice were randomized into treatment groups (n=8 mice / group) and received either test compounds or vehicle control daily via oral gavage at 10mL / kg body weight. Compounds were dissolved to required concentrations in an aqueous solution of 20% 2-hydroxypropyl-beta-cyclodextrin"=E&t&89# f(e X] fPcTa P]S _= PSYdbcTS c^ 0'-' 8^\_^d]S *, fPb PS\X]XbcTaTS Pc *.% ,) ^a90 mg / kg while compounds 164 and 169 were administered at 5, 15 or 30 mg / kg. Figure 2 depicts the results of an assay to validate that efficacy of WRN inhibitors is limited to MSI-h tumors. Briefly, the activity of Compound 164 was assessed in the MSS HT- 29 tumor model. Very limited activity of Compound 164 was observed in the HT-29 tumor model. Figure 3 depicts the results of a pharmacodynamic assessment of WRN levels in tumor samples demonstrating the specific degradation of WRN protein upon treatment with Compound 164. Briefly, at the initial 2 h timepoint, moderate reduction in WRN relative vehicle control is observed, with a dose responsive decrease of approximately 20-35 %. At 8 h post final dose, a further reduction in WRN protein in observed, with a 40% reduction seen following 5 mg / kg Compound 164 and 50% reduction seen for both 15 and 30 mg / kg of Compound 164. A rebound in overall WRN levels is seen at the final 48 h timepoint, with WRN levels in tumors treated with 5 mg / kg Compound 164 being equivalent to vehicle control. In the higher doses, an around 20 % reduction in WRN level relative to vehicle was observed at the 48 h timepoint. Plasma concentrations of Compound 164 demonstrated clear dose dependent increase from 5 to 30 mg / kg and showed expected decrease over the time-course of the study. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Figure 4 depicts the anti-tumor efficacy of Compound 164 and body weight in RKO tumor-bearing mice. Tumor volume and body weight measurements are an average of 8 mice per group + / - standard error of the mean (SEM) except Group 4 where 8 mice received 270 mg / kg QDx1; 3 / 8 mice were euthanized leaving 5 mice that received 180 mg / kg QDx15. Figure 5 depicts the anti-tumor efficacy of Compound 164 and body weight in IGROV-1 tumor-bearing mice. Tumor volume and body weight measurements are an average of 8 mice per group + / - standard error of the mean (SEM) except Group 4 where 8 mice received 270 mg / kg QDx1; 5 / 8 mice were died leaving 3 mice that received 180 mg / kg QDx20. Figure 6 depicts the anti-tumor efficacy of Compound 164 in HCT116 tumor-bearing mice. Tumor volume and body weight measurements are an average of 8 mice per group + / - standard error of the mean (SEM). Figure 7 depicts that Compound 164 leads to dose-dependent WRN degradation in HCT116 tumor xenografts following administration of different dose levels to mice. Relative WRN levels and Compound 164 plasma concentrations are an average of 3-5 mice per group ± standard deviation. QD = quaque die, once daily. PO = per os, orally. Figure 8 depicts Compound 164 mediated degradation of WRN protein and induction of gamma-H2AX in HCT116 tumors. Figure 9 depicts that Compound 164 leads to WRN degradation in HCT116 tumor xenografts following administration of different dose levels to mice. Relative WRN levels and EIK1005 plasma concentrations are an average of 3-5 mice per group ± standard deviation, n = 4-5. QD = quaque die, once daily. PO = per os, orally. DETAILED DESCRIPTION The presently disclosed subject matter relates to compositions comprising WRN helicase inhibitors and methods of their use in treating cancer. For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 1. Definitions 2. Compositions of Matter 3. Methods of Use 4. Examples ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the presently disclosed subject matter. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other instances “comprising,” “consisting of”, and “consisting essentially of,” the instances or elements presented herein, whether explicitly set forth or not. For the recitation of numeric ranges herein, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2- fold, of a value. As used herein, “modulate” or “modulating” refers to increasing or decreasing, e.g., modulation of the activity of an enzyme includes increasing the activity of the enzyme as well as decreasing the activity of the enzyme. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 As used herein, “treat” or “treating” refers to an effort to alter the natural course of a disease, including prophylaxis of the disease, alleviation of symptoms and / or ameliorating pathology associated with the disease. As used herein, “alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, C1-Cnas in “C1-Cnalkyl" is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement. For example, C1-C6, as in “C1-C6 alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl. As used herein, “alkenyl” refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, “C2-C6alkenyl” means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. The term “alkynyl” refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, “C2- C6 alkynyl” means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As used herein, “heteroalkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch. As used herein, “cycloalkyl” refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle, including, but not limited to, those containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 As used herein, the term “cycloalkenyl” refers to a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond, including, but not limited to, those having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. The group may be a terminal group or a bridging group. As used herein, the term “heterocyclyl” or “heterocyclic” refers to a mono- or poly- cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. In certain embodiments, the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another “heterocyclic” ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like. The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise. As used herein, “aryl” is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. As used herein, the term “heteroaryl” refers to any stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridazine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4- dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, benzothiazolyl, thienyl, benzothienyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is nonaromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. As used herein, the term “halogen” refers to F, Cl, Br, and I. As used herein, the term “haloalkyl” means an alkyl group that is substituted with one or more fluorine, chlorine, bromine or iodine atoms. Examples of such haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups. The term “substitution,” “substituted” and “substituent” refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described herein, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, and trifluorom ethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result. The compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms. In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule. Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. The compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkali earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co- administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. 2. Compositions of Matter The presently disclosed subject matter relates to compositions comprising Werner Syndrome Helicase (WRN) inhibitors and methods of using the same. For example, but not by way of limitation, the present disclosure is directed to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6 and R7 are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 memberedheterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and whereinR1 is NR30R31, aryl, C3-C7 cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6-memberedheterocyclyl ring; wherein when R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, - NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33is selected from C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclylring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl; C3-C8cycloalkenyl, a second C6-C10aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, aC6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 memberedheterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring, the said 4--membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7- membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Raand Rbare independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6- membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6- membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1- C4alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6- membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2and R3join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C2-C6 alkenyl, a C3-C7cycloalkyl ring, C1-C6hydroxyalkyl, , wherein R10is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond; wherein when R10 wherein when U is N+, R15 is O-, R16 and R17 are H, and U Vis a double bond; wherein when U is C, R15 is -NR19R20,U V is adouble-bond and R16, R17, R18, are independently selected from H, -CH3, R19, and R20are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1- C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring; or are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein when R4 is , L is C or O, n is 0 or 1, and R23 is C1-C4 alkyl, whereinthe C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl; wherein when alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 memberedheteroaryl or the said R24 is a spiro ring or a fused ring; wherein when single or double bond; wherein whenL G is a double bond, G and L are independently selected from C or N, R25 and R29are independently selected from H, halogen, or -C(O), R26 and R27 are independently selected from H, -OCF2Cl, or -S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6 and R7 are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 memberedheterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and whereinR1 is NR30R31, aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 memberedheterocyclyl; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or H; wherein when R1 is aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 memberedheterocyclyl, the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8membered heterocyclyl is optionally substituted with one or more R36, or the said aryl, ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is linkedwith a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is fused with a second 5-10membered heteroaryl, a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8cycloalkenyl ring, wherein R36 is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl-COOH, -C(O)-R33, -C(O)- NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; and n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6- membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2is NR8R9and R3is H or R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4- membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1- C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6- membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C1-C6hydroxyalkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is , wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; ; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when R10 wherein when U is N+, R15 is O-, R16 and R17 are H, and U Vis a double bond; wherein when U is C, R15 is -NR19R20 U V is adouble-bond and R16, R17, and R18are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and - S(O)R21R22, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 andR22 are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring; or are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein when R4 is , L is C or O, n is 0 or 1, and R23 is C1-C4 alkyl, whereinthe C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl; wherein when alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 memberedheteroaryl or the said R24is a spiro ring or a fused ring; wherein when single or double bond; wherein whenL G is a double bond, G and L are independently selected from C or N, R25 and R29are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or -S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6 and R7 are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 memberedheterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3- C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5- 10 membered heteroaryl ring is substituted by -C(O)R34or -S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring, wherein when the 3-8 membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6- membered heterocyclyl ring; wherein R8 and R9 are independently selected from H, C1-C6 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10 is selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C8cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10is fused with a second C3-C8cycloalkyl, C3-C8cycloalkenyl, C6-C10aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl; andR1 is NR30R31, aryl, C3-C7 cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6-memberedheterocyclyl ring; wherein when R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, - NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3alkyl, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl; C3-C8cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1is C3-C7cycloalkyl ring, the said C3-C7cycloalkyl is a fully saturated ring, wherein the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, aC6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 memberedheterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7- ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 or are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein when R4 is , L is C or O, n is 0 or 1, and R23 is C1-C4 alkyl, whereinthe C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein when C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl; wherein when alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 memberedheteroaryl or the said R24is a spiro ring or a fused ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when single or double bond; wherein whenL G is a double bond, G and L are independently selected from C or N, R25 and R29are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or -S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: wherein K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6 and R7 are independently selected from H or halogen; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 memberedheterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and whereinR4 is selected from G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein R23 and R24 are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, a bridged or unbridged C3-C8cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein when single or double bond; R25, R29, and R35are independently selected from H, halogen, -OH, =O, -C(O); C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; R26and R27are independently selected from H, C1-C6alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26 to form a C3- C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; andR1 is NR30R31, aryl, C3-C7 cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6-memberedheterocyclyl ring; wherein when R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, - NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33is selected from C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1is C3-C7cycloalkyl ring, the said C3-C7cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, aC6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 memberedheterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7- membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; or n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6- membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4- membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1- C4alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6- membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2and R3join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is , wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is adouble bond; wherein when U is C, R15 is -NR19R20 U V is a double-bond and R16,R17, and R18 are independently selected from H, -CH3, -C(O)R21, - S(O2)R21, and -S(O)R21R22, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 areindependently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)- C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl, wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 memberedheterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, where formula (II) is , In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R5 is C1-C6 alkyl, C1- C6 alkenyl, C1-C6 alkynyl or C3-C6 cycloalkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R5is C2alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R6and R7are independently selected from H or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are H. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is NR30R31, aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 memberedheterocyclyl; wherein when R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8membered heterocyclyl, the said aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is optionally substituted with one ormore R36, or the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8membered heterocyclyl is linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8membered heterocyclyl is fused with a second 5-10 membered heteroaryl, a C3- C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8 cycloalkenyl ring, wherein R36 is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl- COOH, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH- C(O)-NH-R33, and wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 memberedheteroaryl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is NR30R31, aryl, C3-C7 cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6-membered heterocyclyl ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, the aryl is substituted by one or more -O-(C1- C6)alkyl-COOH, three C1-C6alkoxy, -C(O)-R33, -C(O)-NH-R33, - S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, or the aryl isfused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3- C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1- C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3- C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5- 10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10aryl ring, a C3-C8cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 memberedheterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5- , or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is NR30R31, R30and R31 are independently selected from optionally substituted C1-C6 alkyl, C1-C6 alkenyl, C1- C6 alkynyl, or H. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C3 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is NR30R31, R30and R31are -CH3. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 and at least one oxygen and / or at least one nitrogen atom, , wherein R33 is selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl,halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is fused with a 5- or 6- membered heterocyclyl ring, wherein the said 5- or 6- membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, and wherein the said 5- or 6- membered heterocyclyl ring is optionally substituted with C1-C3alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the phenyl is fused with a 5-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the phenyl is fused with a 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heterocyclyl ring comprises carbon atoms and one or two oxygen atoms. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heterocyclyl ring comprises carbon atoms and one or two nitrogen atoms. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heterocyclyl ring comprises carbon atoms, one or two oxygen and one or two nitrogen atoms. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6alkoxy, -C(O)-NH-R33, - S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl,halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or5-10 membered heteroaryl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 fused with a 5-10 membered heteroaryl ring, wherein the said aryl and the said 5-10 membered heteroaryl ring are optionally substituted by one or more halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C8cycloalkyl; C3-C8cycloalkenyl, a second C6-C10aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is fused with a C3-C8cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: , , In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 3-8 membered cycloalkenyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl isfused with a 3-8 membered heterocyclyl ring.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein R1 is aryl, the aryl is fused with a 3-8 membered heterocyclyl ring, wherein the said aryl and the said 3-8 membered ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 heterocyclyl ring are optionally substituted by one or more halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or a second 3-8 membered heterocyclyl, or the said C3-C8cycloalkyl, C3-C8cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or the second 3-8 membered heterocyclyl is linked with the said aryl and the said first 3-8 membered heterocyclyl ring to form a spiro ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is a fully saturated C3-C7cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the C3-C7cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6- C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is a 5-10 ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH,- C(O)-C1-C6alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10aryl ring, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, or 4-8 membered heterocyclyl ring.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is selected from In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the said 4- or 7- membered heterocyclyl ring is optionally joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring is a fully saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1is a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring is a fully saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6- membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom; wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereofwherein R1is selected from In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the pyridinyl ring, the second 4-, 5-, or 6-membered heterocyclyl ring, are optionally substituted by one or more H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereofwherein R1 is selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the said the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R1 is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, - NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5- 10 membered heteroaryl ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3- C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5- 10 membered heteroaryl ring is substituted by -C(O)R34or -S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring, wherein when the 3-8 membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1- C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein R8and R9are independently selected from H, C1-C6alkyl, and - C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10is selected from C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10 is fused with a second C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Raand Rbare independently selected from H, - OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3- C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5- 10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2is NR8R9,and R3is H; wherein when n is 1, X and Y are C, R2is NR8R9and R3is H or R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5-membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C2-C6alkenyl, a C3- C7cycloalkyl ring, C1-C6hydroxyalkyl, , wherein R10is optionally substituted with - OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond; wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond;wherein when U is C, R15 is -NR19R20, U V is a double-bond and R16, R17, R18 areindependently selected from H, -CH3, R19, and R20are independently selected from - C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3alkyl, C3-C5cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5cycloalkyl ring In certain embodiments, the compositions described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb, R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2- C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3- C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5- 10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein selected from In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 0, X is N, Y is C, R2is NR8R9,and R3is H, wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6- membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with - C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 C, R2 is NR8R9 and R3 is H, wherein R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted 5- or 6- membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5-membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 alkyl, C1-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10is optionally substituted with -OH, C1-C3alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -C(O)R10, and R10 is C1-C6 alkyl, C2-C6 alkenyl, a C3-C5 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R3 is: , . ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10is C2-C6alkenyl. In certain embodiments, the compositions described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R10is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is -S(O2)R10, and R10is C1-C4alkyl, C1-C4alkenyl, a C3-C5cycloalkyl ring, a 5- or 6-membered heterocyclyl ring, wherein R10is optionally substituted with -OH, C1-C3alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n=2, X is C, Y is N, R2 is H, R3 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, wherein R10 wherein W, P, S, T, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wherein T is N or C; wherein when T is N, R10is , and M and Z are independently selected from N or C; and wherein when T is C, R10 ; wherein when N M and MZ are both single bonds, M is C(O) and Z is N or C substituted with Hor C1-C3 alkyl; and when one of N M and M Z is a single-bond ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 and one is a double-bond, M and Z are independently selected from C or N, optionally substituted with H or C1-C3alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10is selected from: In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10 , wherein A, W, T, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; R12, R13, and R14are independently selected from H, -OH, =O, C1-C3alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, a C3-C8cycloalkyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring,, or R12 and R13 join together to form a fused substituted or unsubstituted 5- or 6- membered heterocyclyl ring, wherein when the said 5- or 6- membered heterocyclyl ring is substituted, the substituents are selected from C1-C3 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10 are independently selected from H, -OH, or C1-C3 alkyl, or R12 and R13 join together to form a fused substituted or unsubstituted 5- or 6- membered heterocyclyl ring, wherein when the said 5- or 6- membered heterocyclyl ring is substituted, the substituents are selected from C1-C3 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10 is selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 alkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, a C1-C6 aryl, or a 5- or 6-membered heterocyclyl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, and / or -C(O)N(CH3)2, wherein when R10is a C3-C7cycloalkyl ring, a C1-C6aryl, a 5-10 membered heteroaryl ring, or a 5- or 6-membered heterocyclyl ring, R10is optionally fused with a second C3-C7cycloalkyl ring, C1-C6aryl, 5-10 membered heteroaryl, or 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10 is selected from: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N,R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a doublebond; wherein when U is C, R15 is -OH or -NR19R20; wherein when R15 is -OH, R16 is a carbonyl, R17 and R18 join together to form a fused 5- or 6- membered heterocyclyl ring, and U V is asingle bond; wherein when R15 is NR19R20, U V is a double-bond and R16, R17,R18, R19, and R20are independently selected from H, -CH3, -C(O)R21, - S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3alkyl, C3-C5cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10 is selected from: In certain embodiments, the compositions described herein relate to a compound offormula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein R23 and R24 are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, C1-C6hydroxyalkyl, C6-C10aryl, 5-10 membered heteroaryl, a bridged or unbridged C3-C8cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein when R4 is , L G is a single or double bond; R25, R29, and R35are independently selected from H, halogen, -OH, =O, -C(O); C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; R26and R27are independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C2-C6haloalkenyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26 to form a C3- C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound offormula (I) or (II), or a pharmaceutically acceptable salt thereofwherein R4 is selected from independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein when R4isR23, L is C or O, n is 0 or 1, and R23is C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein when C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl; wherein when alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 memberedheteroaryl or the said R24 is a spiro ring or a fused ring; wherein when single or double bond; wherein whenL G is a double bond, G and L are independently selected from C or N, R25 and R29are independently selected from H, halogen, =O, or -C(O), R26and R27are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or -S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4isR23Lis C or O, n is 0 or 1, and R23 is C1-C4 alkyl, wherein the C1-C4 alkyl is alkyl is optionally substituted with halogens selected from F or Cl. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 isR23Lis C or O, n is 0, and R23 is C1-C4 alkyl, wherein the C1-C4 alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 isR23Lis C or O, n is 1, and R23 is C1-C4 alkyl, wherein the C1-C4 alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4isR23Lis C or O, n is 0 or 1, and R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from In certain embodiments, the compositions described herein relate to a compound offormula (I) or (II), or a pharmaceutically acceptable salt thereof, O, n is 1 or 2, x is 1 or 2, and R24is C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens from F or Cl. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 is . In certain embodiments, the compositions described herein relate to a compound offormula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein is C or O, n is 0, 1 or 2, x is 0, 1 or 2, the atoms in the bridge can be selected from C, N, O, or S, and R24 is C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 memberedheterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4is selected from In certain embodiments, the compositions described herein relate to a compound offormula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein is 0, 1 or 2, R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring,C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 is or . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein L G is a single or double bond; wherein when L G is a double bond, G and L areindependently selected from C or N, R25 and R29 are independently selected from H, halogen, or -C(O), R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, -OR28, or -S(O)mR28wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27join with R26to form a C4-C7cycloalkyl ring or a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4is selected from: In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4 is ,L G is a single or double bond; G and L are independently selected from C, N, O; R25, R29,and R35, are independently selected from H, halogen, -OH, =O, -C(O); C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl, -OR28, or -S(O)mR28, ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 wherein m is 0-2, R28 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; wherein R25or R27join with R26to form a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R4is selected from: In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: N-(2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5-ethyl- (5,6-dihydro-8H-imidazo[2,1- ethyl-6-[4-(5-hydroxy-6- 6-(4-(5-hydroxy-6- c][1,4]oxazin-2-yl)-5-ethyl-6-(4- methylpyrimidine-4- methylpyrimidine-4- (5-hydroxy-6-methylpyrimidine- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl)-2-(2- 4-carbonyl)piperazin-1-yl)-7-oxo- {4H,6H,7H-pyrazolo[3,2- methylbenzo[d]oxazol-4-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- c][1,4]oxazin-2-yl}- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-(5- (trifluoromethyl)phenyl]-2-[2-(2,3- ethyl-6-[4-(5-hydroxy-6- ethyl-2-{2H,3H-furo[2,3- dihydro-1-benzofuran-7-yl)-5-ethyl- methylpyrimidine-4- b]pyridin-5-yl}-6-[4-(5-hydroxy- 6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-2-(2- 6-methylpyrimidine-4- methylpyrimidine-4- methyl-1,3-benzothiazol-4-yl)-7- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyrimidin-4-yl}acetamide yl)acetamide yl]acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-{5- (3,4-dihydro-2H-1-benzopyran-5- (3,4-dihydro-2H-1-benzopyran-8- ethyl-6-[4-(5-hydroxy-6-methylpyri yl)-5-ethyl-6-[4-(5-hydroxy-6- yl)-5-ethyl-6-[4-(5-hydroxy-6- midine-4-carbonyl)piperazin-1-yl]- methylpyrimidine-4- methylpyrimidine-4- 7-oxo-2-{1H,3H,4H-pyrano[4,3- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- c]pyridin-8-yl}-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyri midin-4-yl}acetamide yl]acetamide yl]acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(2-(1,1- ethyl-6-[4-(5-hydroxy-6- (3,4-dihydro-1H-pyrano[3,4- dimethyl-1,3-dihydroisobenzofuran- methylpyrimidine-4- c]pyridin-5-yl)-5-ethyl-6-(4-(5- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo-2- hydroxy-6-methylpyrimidine-4- methylpyrimidine-4- {5H,6H,8H-pyrano[3,4-b]pyridin- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- 3-yl}-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyri midin- [1,2,4]triazolo[1,5-a]pyrimidin- a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide

[0030] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- N-(2-chloro-4- phenyl] [2-(3,3-dimethyl-1,3- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(5-ethyl- dihydro-5-isobenzofuranyl)-6- (5,6-dihydro-4H-pyrrolo[1,2- 6-(4-(5-hydroxy-6- ethyl-5-{4-[(5-hydroxy-6-methyl- b]pyrazol-3-yl)-5-ethyl-6-(4-(5- methylpyrimidine-4- 4-pyrimidinyl) carbonyl]-1- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-2- piperazinyl}-4-oxo-1,3,3a,7- carbonyl)piperazin-1-yl)-7-oxo- (4,5,6,7-tetrahydropyrazolo[1,5- tetraaza-7-indenyl] acetamide [1,2,4]triazolo[1,5-a]pyrimidin- a]pyridin-3-yl)-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl][6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- ethyl-6-[4-(5-hydroxy-6- 2-(6-fluoro-2,3-dihydro-1- {4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- benzofuran-5-yl)-5-{4-[(5- pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl]-2-(2- hydroxy-6-methyl-4- piperazinyl}-2-(3-methyl-2,3- methyl-2,3-dihydro-1-benzofuran- pyrimidinyl)carbonyl]-1- dihydro-1-benzofuran-5-yl)-4-oxo- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- piperazinyl}-4-oxo-1,3,3a,7- 1,3,3a,7-tetraaza-7- a]pyrimidin-4-yl}acetamide tetraaza-7-indenyl] indenyl)acetamide

[0031] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl](6-ethyl- ethyl-6-(4-(5-hydroxy-6- 5-{4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl)-2-(7- piperazinyl}-4-oxo-2-(1,1,3,3- methyl-2,3-dihydrobenzofuran-5- tetramethyl-1,3-dihydro-5- yl)-7-oxo-[1,2,4]triazolo[1,5- isobenzofuranyl)-1,3,3a,7- a]pyrimidin-4(7H)-yl)acetamide tetraaza-7-indenyl)acetamide N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl][2-(1,3- ethyl-2-(7-fluoro-2,3- ethyl-6-(4-(5-hydroxy-6- dimethyl-2-oxo-1,3-dihydro-1,3- dihydrobenzofuran-5-yl)-6-(4-(5- methylpyrimidine-4- benzimidazol-5-yl)-6-ethyl-5-{4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(6- [(5-hydroxy-6-methyl-4- carbonyl)piperazin-1-yl)-7-oxo- methyl-2,3-dihydrobenzofuran-5- pyrimidinyl)carbonyl]-1- [1,2,4]triazolo[1,5-a]pyrimidin- yl)-7-oxo-[1,2,4] triazolo[1,5- piperazinyl}-4-oxo-1,3,3a,7- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide tetraaza-7-indenyl]acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl](6-ethyl-5-{4-[(5-hydroxy- phenyl](6-ethyl-5-{4-[(5-hydroxy- (trifluoromethyl)phenyl][2-(3,3- 6-methyl-4- 6-methyl-4-pyrimidinyl)carbonyl]- difluoro-5-indanyl)-6-ethyl-5-{4- pyrimidinyl)carbonyl]-1- 1-piperazinyl}-2-(2-methyl-2H- [(5-hydroxy-6-methyl-4- piperazinyl}-4-oxo-7H- indazol-6-yl)-4-oxo-1,3,3a,7- pyrimidinyl)carbonyl]-1- 1,1',3,3a,7,7a'-hexaaza-2,5'- tetraaza-7-indenyl)acetamide piperazinyl}-4-oxo-1,3,3a,7- biindenyl-7-yl)acetamide tetraaza-7-indenyl]acetamide

[0032] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl]-2-{5- (2,2-difluorobenzo[d][1,3]dioxol- (3,4-dihydro-1H-pyrano[3,4- ethyl-6-[4-(5-hydroxy-6- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- c]pyridin-5-yl)-5-ethyl-6-(4-(5- methylpyrimidine-4- methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-[(2R)-2- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- methoxy-2,3-dihydro-1H-inden-5- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyri midin- yl]-7-oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide 4(7H)-yl)acetamide a]pyrimidin-4-yl}acetamide N-[2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl]-2-{5- ethyl-6-[4-(5-hydroxy-6- (5,6-dihydro-4H-pyrrolo[1,2- ethyl-6-[4-(5-hydroxy-6-methyl methylpyrimidine-4- b]pyrazol-2-yl)-5-ethyl-6-(4-(5- pyrimidine-4-carbonyl)piperazin-1- carbonyl)piperazin-1-yl]-2-[( hydroxy-6-methylpyrimidine-4- yl]-7-oxo-2-{4H,5H,6H,7H- carbonyl)piperazin-1-yl)-7-oxo- pyrazolo[1,5-a]pyridin-2-yl}- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo [1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl][2-(1,1- 5-{4-[(5-hydroxy-6-methyl-4- 5-{4-[(5-hydroxy-6-methyl-4- difluoro-5-indanyl)-6-ethyl-5-{4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- [(5-hydroxy-6-methyl-4- piperazinyl}-2-(2-methyl-1-oxo-5- piperazinyl}-2-(2-methyl-3-oxo-5- pyrimidinyl)carbonyl]-1- isoindolinyl)-4-oxo-1,3,3a,7- isoindolinyl)-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl)acetamide tetraaza-7-indenyl)acetamide tetraaza-7-indenyl]acetamide

[0033] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- 5-{4-[(5-hydroxy-6-methyl-4- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- methylpyrimidine-4- piperazinyl}-4-oxo-2-(3-oxo-5- carbonyl)piperazin-1-yl]-2-[(3S)- carbonyl)piperazin-1-yl]-2-[(3R)-3- isoindolinyl)-1,3,3a,7-tetraaza-7- 3-methyl-1,3-dihydro-2- methyl-1,3-dihydro-2-benzofuran- indenyl)acetamide benzofuran-5-yl]-7-oxo- 5-yl]-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyrimidin-4-yl}acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl][2-(3,3- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- dimethyl-2,3-dihydro-1- methylpyrimidine-4- methylpyrimidine-4- benzofuran-5-yl)-6-ethyl-5-{4-[(5- carbonyl)piperazin-1-yl]-2-[(1R)- carbonyl)piperazin-1-yl]-2-[(1S)- hydroxy-6-methyl-4- 1-methyl-1,3-dihydro-2- 1-methyl-1,3-dihydro-2- pyrimidinyl)carbonyl]-1- benzofuran-5-yl]-7-oxo- benzofuran-5-yl]-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- tetraaza-7-indenyl]acetamide yl}acetamide yl}acetamide

[0034] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- (trifluoromethyl)phenyl][2-(2,2- phenyl] [2-(1,1-dimethyl-6- (trifluoromethyl)phenyl]-2-{5- dimethyl-2,3-dihydro-1- isochromanyl)-6-ethyl-5-{4-[(5- ethyl-6-[4-(5-hydroxy-6- benzofuran-5-yl)-6-ethyl-5-{4-[(5- hydroxy-6-methyl-4- methylpyrimi dine-4- hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- carbonyl)pipera zin-1-yl]-2-(4- pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-1,3,3a,7- methyl-1,3-dihydro-2-benzofuran- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl]acetamide 5-yl)-7-oxo-[1,2,4]triazolo[1,5- tetraaza-7-indenyl]acetamide a]pyr imidin-4-yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- 5-{4-[(5-hydroxy-6-methyl-4- 5-{4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-2-(2-methyl-5- piperazinyl}-2-(4-methyl-3-oxo- piperazinyl}-2-(1-methyl-5- isoindolinyl)-4-oxo-1,3,3a,7- 2,4-dihydro-1,4-benzoxazin-6-yl)- indolinyl)-4-oxo-1,3,3a,7-tetraaza- tetraaza-7-indenyl)acetamide 4-oxo-1,3,3a,7-tetraaza-7- 7-indenyl)acetamide indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[5- (trifluoromethyl)phenyl]-2-[5- (trifluoromethyl)phenyl]-2-[5- ethyl-2-(4-fluoro-1,3-dihydro-2- ethyl-2-(6-fluoro-1,3-dihydro-2- ethyl-2-(7-fluoro-1,3-dihydro-2- benzofuran-5-yl)-6-[4-(5- benzofuran-5-yl)-6-[4-(5-hydroxy- benzofuran-5-yl)-6-[4-(5-hydroxy- hydroxy-6-methylpyrimidine-4- 6-methylpyrimidine-4- 6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide yl]acetamide

[0035] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl][2-(4- ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- difluoromethylene-1-piperidyl)-6- methylpyrimidine-4- methylpyrimidine-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- carbonyl)piperazin-1-yl]-2-(6- carbonyl)piperazin-1-yl)-2-(1H- pyrimidinyl)carbonyl]-1- methyl-1,3-dihydro-2-benzofuran- inden-6-yl)-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- tetraaza-7-indenyl]acetamide a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide N-[2-chloro-4- (S)-N-(2-chloro-4- (R)-N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-(7- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-2-(1- methyl-1,3-dihydro-2-benzofuran- methoxy-2,3-dihydro-1H-inden-5- methoxy-2,3-dihydro-1H-inden-5- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl}acetamide a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl]-2-(2- (trifluoromethyl)phenyl]-2-[5- ethyl-6-(4-(5-hydroxy-6- {4H,5H,6H- ethyl-2-(6-fluoro-1,1-dimethyl-3H- methylpyrimidine-4- cyclopenta[d][1,3]thiazol-2-yl}-5- 2-benzofuran-5-yl)-6-[4-(5- carbonyl)piperazin-1-yl)-2-(1- ethyl-6-[4-(5-hydroxy-6- hydroxy-6-methylpyrimidine-4- methyl-3'H-spiro[azetidine-3,1'- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- isobenzofuran]-5'-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide 4(7H)-yl)acetamide yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-(2-chloro-4- phenyl]-2-[5-ethyl-2-(7-fluoro- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5- 1,1-dimethyl-3H-2-benzofuran-5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- yl)-6-[4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4-carbonyl) carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl)-7-oxo-2- piperazin-1-yl]-7-oxo- [1,2,4] (1,1,6-trimethyl-3H-2-benzofuran- (1,1,4-trimethyl-1,3- triazolo[1,5-a] pyrimidin-4-yl] 5-yl)-[1,2,4]triazolo[1,5- dihydroisobenzofuran-5-yl)- acetamide a]pyrimidin-4-yl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-[5- (trifluoromethyl)phenyl]-2-[5- ethyl-6-[4-(5-hydroxy-6- ethyl-2-(4-fluoro-1,1-dimethyl- ethyl-2-(5-fluoro-3,4-dihydro-1H- methylpyrimidine-4- 3H-2-benzofuran-5-yl)-6-[4-(5- 2-benzopyran-6-yl)-6-[4-(5- carbonyl)piperazin-1-yl]-7-oxo-2- hydroxy-6-methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- {3H-spiro[2-benzofuran-1,1'- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- cyclobutan]-5-yl}- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide yl}acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) phenyl](6-ethyl-5-{4-[(5-hydroxy- phenyl](6-ethyl-5-{4-[(5-hydroxy- phenyl] (6-ethyl-5-{4-[(5-hydroxy- 6-methyl-4- 6-methyl-4-pyrimidinyl)carbonyl]- 6-methyl-4-pyrimidinyl) carbonyl]- pyrimidinyl)carbonyl]-1- 1-piperazinyl}-4-oxo-7H- 1-piperazinyl}-4-oxo-7H- piperazinyl}-1'-methyl-4-oxo-7H- 1,2',3,3a,7,7a'-hexaaza-2,5'- 1,1',3,3',3a,7,7a'-heptaaza-2,5'- 1,2',3,3a,7,7a'-hexaaza-2,5'- biindenyl-7-yl)acetamide biindenyl-7-yl) acetamide biindenyl-7-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2-(3,3- ethyl-6-(4-(5-hydroxy-6- (3,3-dimethyl-1,4-dihydro-2- dimethyl-1,4-dihydro-2- methylpyrimidine-4- benzopyran-8-yl)-5-ethyl-6-[4-(5- benzopyran-8-yl)-5-ethyl-6-[4-(5- carbonyl)piperazin-1-yl)-7-oxo-2- hydroxy-6-methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- (1,1,7-trimethyl-1,3- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- dihydroisobenzofuran-5-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide yl]acetamide 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- (R)-N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(2-(1- (2,2-difluoro-1,3-dihydroinden-5- ethyl-6-[4-(5-hydroxy-6- (difluoromethoxy)-2,3-dihydro-1H- yl)-5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- inden-5-yl)-5-ethyl-6-(4-(5- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-(3- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methyl-2-oxo-1,3-benzoxazol-5- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl)-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide N-[2-chloro-4- (R)-N-(2-chloro-4- (S)-N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{2-[1- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- (difluoromethoxy)-2,3-dihydro- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- 1H-inden-5-yl]-5-ethyl-6-[4-(5- methylpyrimidine-4- methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl]-7-oxo- methylisochroman-6-yl)-7-oxo- methylisochroman-6-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- yl}acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 (S)-N-(2-chloro-4- (R)-N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(2-(2,2- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- difluorobenzo[d][1,3]dioxol-4-yl)- methylpyrimidine-4- methylpyrimidine-4- 5-ethyl-6-(4-(5-hydroxy-6- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl)-2-(2- methylpyrimidine-4- methyl-2,3-dihydrobenzofuran-5- methyl-2,3-dihydrobenzofuran-5- carbonyl)piperazin-1-yl)-7-oxo- yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4] triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide 4(7H)-yl)acetamide N-(2-chloro-4- 2-(2-(benzo[c][1,2,5]oxadiazol-5- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(5- yl)-5-ethyl-6-(4-(5-hydroxy-6- (trifluoromethyl)phenyl)-2-(5- ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(3- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-2-(2- methyl-2-oxo-2,3- 4(7H)-yl)-N-(2-chloro-4- methyl-2H-indazol-5-yl)-7-oxo- dihydrobenzo[d]oxazol-6-yl)-7- (trifluoromethyl)phenyl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- oxo-[1,2,4] triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl]-2-{5- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl]-2-(4- methyl-1H-benzo[d]imidazol-6- methylbenzo[d]oxazol-6-yl)-7- methyl-2,3-dihydro-1-benzofuran- yl)-7-oxo-[1,2,4]triazolo[1,5- oxo-[1,2,4]triazolo[1,5- 5-yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4-yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-(5- ethyl-6-[4-(5-hydroxy-6-methyl ethyl-6-[4-(5-hydroxy-6- ethyl-2-{4-fluoropyrazolo[1,5- pyrimidine-4-carbonyl)piperazin- methylpyrimidine-4-carbonyl) a]pyridin-5-yl}-6-[4-(5-hydroxy-6- 1-yl]-2-{4-methylpyrazolo[1,5- piperazin-1-yl]-2-{7- methylpyrimidine-4- a]pyridin-5-yl}-7-oxo- methylpyrazolo[1,5-a]pyridin-5- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide a]pyrimidin-4-yl}acetamide yl)acetamide N-(2-chloro-4- N-[2-chloro-4- (S)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5- ethyl-2-(6-fluoropyrazolo[1,5- ethyl-6-[4-(5-hydroxy-6- ethyl-2-(6-fluoro-1-methoxy-2,3- a]pyridin-5-yl)-6-(4-(5-hydroxy- methylpyrimidine-4- dihydro-1H-inden-5-yl)-6-(4-(5- 6-methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-{6- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- methylpyrazolo[1,5-a]pyridin-5- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- yl}-7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide a]pyrimidin-4-yl}acetamide 4(7H)-yl)acetamide (R)-N-(2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(5- phenyl] (6-ethyl-5-{4-[(5- phenyl] (6-ethyl-5-{4-[(5-hydroxy- ethyl-2-(6-fluoro-1-methoxy-2,3- hydroxy-6-methyl-4-pyrimidinyl) 6-methyl-4-pyrimidinyl) carbonyl]- dihydro-1H-inden-5-yl)-6-(4-(5- carbonyl]-1-piperazinyl}-1'- 1-piperazinyl}-2'-methyl-4-oxo- hydroxy-6-methylpyrimidine-4- methyl-4-oxo-7H- 7H-1,1',3,3a,7,7a'-hexaaza-2,5'- carbonyl)piperazin-1-yl)-7-oxo- 1,2',3,3',3a,7,7a'-heptaaza-2,5'- biindenyl-7-yl) acetamide [1,2,4]triazolo[1,5-a]pyrimidin- biindenyl-7-yl) acetamide 4(7H)-yl)acetamide

[0036] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-[2-chloro-4- phenyl] {2-[2-(difluoromethyl)- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- 2H-indazol-5-yl]-6-ethyl-5-{4-[(5- ethyl-2-[(2S)-6-fluoro-2-methyl- ethyl-2-[(2R)-6-fluoro-2-methyl- hydroxy-6-methyl-4-pyrimidinyl) 2,3-dihydro-1-benzofuran-5-yl]-6- 2,3-dihydro-1-benzofuran-5-yl]-6- carbonyl]-1-piperazinyl}-4-oxo- [4-(5-hydroxy-6- [4-(5-hydroxy-6-methylpyrimidine- 1,3,3a,7-tetraaza-7-indenyl} methylpyrimidine-4- 4-carbonyl)piperazin-1-yl]-7-oxo- acetamide carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-(5- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- ethyl-2-{2-fluoropyrazolo[1,5- 5-{4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- a]pyridin-5-yl}-6-[4-(5-hydroxy- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- 6-methylpyrimidine-4- piperazinyl}-1'-methyl-4-oxo- piperazinyl}-4-oxo-7H- carbonyl)piperazin-1-yl]-7-oxo- 7H,1'H-1,1',3,3a,7,7'-hexaaza-2,5'- 1,3,3',3a,3a',7-hexaaza-2,5'- [1,2,4]triazolo[1,5-a]pyrimidin-4- biindenyl-7-yl)acetamide biindenyl-7-yl)acetamide yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl- phenyl] [6-ethyl-2-(6-fluoro-2- 5-{4-[(5-hydroxy-6-methyl-4- 5-{4-[(5-hydroxy-6-methyl-4- methyl-2H-indazol-5-yl)-5-{4-[(5- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- hydroxy-6-methyl-4-pyrimidinyl) piperazinyl}-2-(1-methyl-1H-1,3- piperazinyl}-2'-methyl-4-oxo-7H- carbonyl]-1-piperazinyl}-4-oxo- benzimidazol-5-yl)-4-oxo- 1,1',3,3a,3a',7-hexaaza-2,5'- 1,3,3a,7-tetraaza-7- 1,3,3a,7-tetraaza-7- biindenyl-7-yl)acetamide indenyl]acetamide indenyl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- N-(2-chloro-4- phenyl] [2-(1,3-dihydro-2- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- benzothiophen-5-yl)-6-ethyl-5-{4- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- [(5-hydroxy-6-methyl-4- methylpyrimidine-4- methylpyrimidine-4- pyrimidinyl) carbonyl]-1- carbonyl)piperazin-1-yl)-2-(2H- carbonyl)piperazin-1-yl)-2-(3- piperazinyl}-4-oxo-1,3,3a,7- indazol-5-yl)-7-oxo- methyl-4-oxo-3,4- tetraaza-7-indenyl] acetamide [1,2,4]triazolo[1,5-a]pyrimidin- dihydroquinazolin-6-yl)-7-oxo- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- ethyl-2-(7-fluoro-3,4-dihydro-1H- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- 2-benzopyran-6-yl)-6-[4-(5- methylpyrimidine-4- methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-2- carbonyl)piperazin-1-yl)-2-(2- carbonyl) piperazin-1-yl]-7-oxo- (1,1,2-trimethylisoindolin-5-yl)- isopropyl-2H-indazol-5-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-[2-chloro-4- phenyl] (6-ethyl-5-{4-[(5- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl][2-(2,1- hydroxy-6-methyl-4-pyrimidinyl) 5-{4-[(5-hydroxy-6-methyl-4- benzisoxazol-6-yl)-6-ethyl-5-{4- carbonyl]-1-piperazinyl}-4-oxo-2- pyrimidinyl)carbonyl]-1- [(5-hydroxy-6-methyl-4- (6-quinazolinyl)-1,3,3a,7-tetraaza- piperazinyl}-4-oxo-2-(6-quinolyl)- pyrimidinyl)carbonyl]-1- 7-indenyl) acetamide 1,3,3a,7-tetraaza-7- piperazinyl}-4-oxo-1,3,3a,7- indenyl)acetamide tetraaza-7-indenyl]acetamide

[0037] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl][2-(2,1- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- benzisothiazol-5-yl)-6-ethyl-5-{4- 5-{4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- [(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-2-{p-[(1- piperazinyl}-4-oxo-2-(3,4,5- piperazinyl}-4-oxo-1,3,3a,7- pyrrolidinyl)carbonyl]phenyl}- trimethoxyphenyl)-1,3,3a,7- tetraaza-7-indenyl]acetamide 1,3,3a,7-tetraaza-7- tetraaza-7-indenyl)acetamide indenyl)acetamide N-cyclopropylp-(7-{[N-2-chloro- N-[2-chloro-4- N-(2-chloro-4- 4- (trifluoromethyl)phenyl]{2-[p-(1- (trifluoromethyl)phenyl)-2-(5-(trifluoromethyl)phenylcarbamoyl azetidinylsulfonyl)phenyl]-6- ethyl-6-(4-(5-hydroxy-6- ]methyl}-6-ethyl-5-{4-[(5- ethyl-5-{4-[(5-hydroxy-6-methyl- methylpyrimidine-4- hydroxy-6-methyl-4- 4-pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl)-2-(1- pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-1,3,3a,7- methyl-2-oxoindolin-5-yl)-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin- tetraaza-2-indenyl)benzamide 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-(5- (trifluoromethyl)phenyl]-2-{5- ethyl-6-[4-(5-hydroxy-6- ethyl-2-{6'-fluoro-1-methyl-3'H- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- spiro[azetidine-3,1'- methylpyrimidine-4- carbonyl)piperazin-1-yl]-2-{3- [2]benzofuran]-5'-yl}-6-[4-(5- carbonyl)piperazin-1-yl]-7-oxo-2- methylpyrazolo[1,5-a]pyridin-5- hydroxy-6-methylpyrimidine-4- [(1R)-1-(trifluoromethyl)-1,3- yl}-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- dihydro-2-benzofuran-5-yl]- a]pyrimidin-4-yl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl)acetamide yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl]-2-{5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl]-7-oxo-2- [(3S)-3-(trifluoromethyl)-1,3- [(1S)-1-(trifluoromethyl)-1,3- [(3R)-3-(trifluoromethyl)-1,3- dihydro-2-benzofuran-5-yl]- dihydro-2-benzofuran-5-yl]- dihydro-2-benzofuran-5-yl]- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl}acetamide yl}acetamide yl}acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{5- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo-2- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-7-oxo-2- {3H-spiro[2-benzofuran-1,3'- methyl-2,2-dioxido-1,3- (quinoxalin-6-yl)- oxetan]-5-yl}-[1,2,4]triazolo[1,5- dihydrobenzo[c]isothiazol-5-yl)-7- [1,2,4]triazolo[1,5-a]pyrimidin- a]pyrimidin-4-yl}acetamide oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) phenyl] [2-(3,4-dihydro-2H-1,4- (trifluoromethyl)phenyl](6-ethyl- phenyl] [2-(1-benzofuran-5-yl)-6- benzoxazin-7-yl)-6-ethyl-5-{4- 5-{4-[(5-hydroxy-6-methyl-4- ethyl-5-{4-[(5-hydroxy-6-methyl-4- [(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl) carbonyl]-1- pyrimidinyl) carbonyl]-1- piperazinyl}-2'-methyl-4-oxo-7H- piperazinyl}-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- 3'-oxa-1,1',3,3a,7,7'-hexaaza-2,5'- tetraaza-7-indenyl] acetamide tetraaza-7-indenyl] acetamide biindenyl-7-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-(2-(2-aminobenzo[d]oxazol-6- N-[2-chloro-4- N-[2-chloro-4- yl)-5-ethyl-6-(4-(5-hydroxy-6- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- methylpyrimidine-4- 5-{4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- carbonyl)piperazin-1-yl)-7-oxo- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- [1,2,4]triazolo[1,5-a]pyrimidin- piperazinyl}-2-(2-methyl-1,3- piperazinyl}-2-(7-methoxy-2- 4(7H)-yl)-N-(2-chloro-4- benzothiazol-6-yl)-4-oxo-1,3,3a,7- methyl-2H-indazol-5-yl)-4-oxo- (trifluoromethyl)phenyl)acetamide tetraaza-7-indenyl)acetamide 1,3,3a,7-tetraaza-7- indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- (trifluoromethyl)phenyl][6-ethyl- phenyl] [2-(1,3-benzothiazol-5- (trifluoromethyl)phenyl)-2-(5- 2-(7-fluoro-2-methyl-2H-indazol- yl)-6-ethyl-5-{4-[(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- 5-yl)-5-{4-[(5-hydroxy-6-methyl- methyl-4-pyrimidinyl) carbonyl]- methylpyrimidine-4- 4-pyrimidinyl)carbonyl]-1- 1-piperazinyl}-4-oxo-1,3,3a,7- carbonyl)piperazin-1-yl)-7-oxo-2- piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl] acetamide (2',3',5',6'-tetrahydro-3H- tetraaza-7-indenyl]acetamide spiro[isobenzofuran-1,4'-pyran]-5- yl)-[1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[5- (trifluoromethyl)phenyl)-2-(2-(2- (trifluoromethyl)phenyl)-2-(2-(2- ethyl-2-(3-fluoro-2- (difluoromethyl)-6-fluoro-2H- (2,2-difluoroethyl)-2H-indazol-5- methylindazol-5-yl)-6-[4-(5- indazol-5-yl)-5-ethyl-6-(4-(5- yl)-5-ethyl-6-(4-(5-hydroxy-6- hydroxy-6-methylpyrimidine-4- hydroxy-6-methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(1- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- (2,2-difluoroethyl)-1H-indazol-5- 5-{4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- yl)-5-ethyl-6-(4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-2-(2-methyl-1,2,3,4- piperazinyl}-2-(2-methyl-4-methyl- carbonyl)piperazin-1-yl)-7-oxo- tetrahydro-6-isoquinolyl)-4-oxo- 2H-indazol-5-yl)-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin- 1,3,3a,7-tetraaza-7- tetraaza-7-indenyl)acetamide 4(7H)-yl)acetamide indenyl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl][2-(1- (trifluoromethyl)phenyl][6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- acetyl-2,2-dimethyl-5-indolinyl)- 2-(4-fluoro-2-methyl-1,3- {4-[(5-hydroxy-6-methyl-4- 6-ethyl-5-{4-[(5-hydroxy-6- benzoxazol-6-yl)-5-{4-[(5- pyrimidinyl)carbonyl]-1- methyl-4-pyrimidinyl)carbonyl]- hydroxy-6-methyl-4- piperazinyl}-2-(2-methyl-3-methyl- 1-piperazinyl}-4-oxo-1,3,3a,7- pyrimidinyl)carbonyl]-1- 2H-indazol-5-yl)-4-oxo-1,3,3a,7- tetraaza-7-indenyl]acetamide piperazinyl}-4-oxo-1,3,3a,7- tetraaza-7-indenyl)acetamide tetraaza-7-indenyl]acetamide N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl)-2-(5- 5-{4-[(5-hydroxy-6-methyl-4- 5-{4-[(5-hydroxy-6-methyl-4- ethyl-6-(4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-2-(2-methyl-7- piperazinyl}-2'-methyl-4-oxo- carbonyl)piperazin-1-yl)-2-(2- methyl-2H-indazol-5-yl)-4-oxo- 7H,2'H-1,2',3,3',3a,7,7'-heptaaza- methyl-2H-benzo[d][1,2,3]triazol- 1,3,3a,7-tetraaza-7- 2,5'-biindenyl-7-yl)acetamide 5-yl)-7-oxo-[1,2,4]triazolo[1,5- indenyl)acetamide a]pyrimidin-4(7H)-yl)acetamide

[0038] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(2-(2- (trifluoromethyl)phenyl](6-ethyl-5- ethyl-6-(4-(5-hydroxy-6- ((2,2- {4-[(5-hydroxy-6-methyl-4- methylpyrimidine-4- difluoroethyl)amino)benzo[d]oxaz pyrimidinyl)carbonyl]-1- carbonyl)piperazin-1-yl)-7-oxo-2- ol-6-yl)-5-ethyl-6-(4-(5-hydroxy- piperazinyl}-3'-methyl-4-oxo- (2-propyl-2H-indazol-5-yl)- 6-methylpyrimidine-4- 7H,3'H-1,3,3',3a,7,7'-hexaaza-2,5'- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-7-oxo- biindenyl-7-yl)acetamide 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl)-2-(5- 5-{4-[(5-hydroxy-6-methyl-4- 5-{4-[(5-hydroxy-6-methyl-4- ethyl-6-(4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- piperazinyl}-4-oxo-7H- piperazinyl}-2-(1-methyl-5- carbonyl)piperazin-1-yl)-2-(2- 1,1',3,3a,3a',7,7'-heptaaza-2,5'- methyl-1H-indazol-6-yl)-4-oxo- (methylamino)benzo[d]oxazol-6- biindenyl-7-yl)acetamide 1,3,3a,7-tetraaza-7- yl)-7-oxo-[1,2,4]triazolo[1,5- indenyl)acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl](6-ethyl- phenyl] (6-ethyl-5-{4-[(5- phenyl] (6-ethyl-5-{4-[(5-hydroxy- 5-{4-[(5-hydroxy-6-methyl-4- hydroxy-6-methyl-4-pyrimidinyl) 6-methyl-4-pyrimidinyl) carbonyl]- pyrimidinyl)carbonyl]-1- carbonyl]-1-piperazinyl}-4-oxo-2- 1-piperazinyl}-4-oxo-7H-1'-thia- piperazinyl}-2-(2-methyl-1,2,3,4- (2-oxo-6-indolinyl)-1,3,3a,7- 1,3,3a,7,7'-pentaaza-2,5'-biindenyl- tetrahydro-7-isoquinolyl)-4-oxo- tetraaza-7-indenyl) acetamide 7-yl) acetamide 1,3,3a,7-tetraaza-7- indenyl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl](6-ethyl-5- 5-{4-[(5-hydroxy-6-methyl-4- 5-{4-[(5-hydroxy-6-methyl-4- {4-[(5-hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-2-(1-methyl-6- piperazinyl}-2-(1-methyl-3- piperazinyl}-2'-methyl-4-oxo- methyl-1H-indazol-5-yl)-4-oxo- methyl-1H-indazol-5-yl)-4-oxo- 7H,2'H-1,1',2',3,3a,7,7'-heptaaza- 1,3,3a,7-tetraaza-7- 1,3,3a,7-tetraaza-7- 2,5'-biindenyl-7-yl)acetamide indenyl)acetamide indenyl)acetamide N-[2-chloro-4- N-(2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl](6-ethyl- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl]-2-{5- 5-{4-[(5-hydroxy-6-methyl-4- ethyl-6-(4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- pyrimidinyl)carbonyl]-1- methylpyrimidine-4- methylpyrimidine-4- piperazinyl}-2-(1-methyl-1H- carbonyl)piperazin-1-yl)-2-(2- carbonyl)piperazin-1-yl]-7-oxo-2- 1,2,3-benzotriazol-5-yl)-4-oxo- morpholinobenzo[d]oxazol-6-yl)- (1,2,2-trimethyl-3H-indol-5-yl)- 1,3,3a,7-tetraaza-7- 7-oxo-[1,2,4]triazolo[1,5- [1,2,4]triazolo[1,5-a]pyrimidin-4- indenyl)acetamide a]pyrimidin-4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{2-[7- phenyl] (6-ethyl-5-{4-[(5- (trifluoromethyl)phenyl)-2-(5- (difluoromethoxy)-4- hydroxy-6-methyl-4-pyrimidinyl) ethyl-2-(2-ethyl-2H-indazol-5-yl)- fluoropyrazolo[1,5-a]pyridin-5- carbonyl]-1-piperazinyl}-4-oxo-2- 6-(4-(5-hydroxy-6- yl]-5-ethyl-6-[4-(5-hydroxy-6- (2-oxo-6-quinolyl)-1,3,3a,7- methylpyrimidine-4- methylpyrimidine-4- tetraaza-7-indenyl) acetamide carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl}acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(5- (5,8-difluoroquinolin-6-yl)-5- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- methylpyrimidine-4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(1- carbonyl)piperazin-1-yl)-7-oxo-2- carbonyl)piperazin-1-yl)-7-oxo- methyl-1H-indazol-5-yl)-7-oxo- (8-(trifluoromethyl)quinolin-6-yl)- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide 4(7H)-yl)acetamide 4(7H)-yl)acetamide N-(2-chloro-4- N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(5- phenyl] (6-ethyl-5-{4-[(5- phenyl] (6-ethyl-5-{4-[(5-hydroxy- ethyl-6-(4-(5-hydroxy-6- hydroxy-6-methyl-4-pyrimidinyl) 6-methyl-4-pyrimidinyl) carbonyl]- methylpyrimidine-4- carbonyl]-1-piperazinyl}-2-(1- 1-piperazinyl}-4-oxo-2-(2-oxo-5- carbonyl)piperazin-1-yl)-2-(2- methyl-2-oxo-3,4-dihydro-6- indolinyl)-1,3,3a,7-tetraaza-7- methylquinolin-6-yl)-7-oxo- quinolyl)-4-oxo-1,3,3a,7-tetraaza- indenyl) acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 7-indenyl) acetamide 4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl] (6-ethyl-3'-fluoro-5-{4- phenyl] [2-(1-benzofuran-3-yl)-6- (trifluoromethyl)phenyl](3'-chloro- [(5-hydroxy-6-methyl-4- ethyl-5-{4-[(5-hydroxy-6-methyl- 6-ethyl-5-{4-[(5-hydroxy-6-methyl- pyrimidinyl) carbonyl]-1- 4-pyrimidinyl) carbonyl]-1- 4-pyrimidinyl)carbonyl]-1- piperazinyl}-4-oxo-7H- piperazinyl}-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-7H,1'H- 1,1',3,3a,7,7a'-hexaaza-2,5'- tetraaza-7-indenyl] acetamide 1,1',3,3a,7,7'-hexaaza-2,5'- biindenyl-7-yl) acetamide biindenyl-7-yl)acetamide

[0039] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- [p-(7-{[N-2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]{2-[p- (trifluoromethyl)phenylcarbamoyl (trifluoromethyl)phenyl](6-ethyl-5- (aminosulfonylamino)phenyl]-6- ]methyl}-6-ethyl-5-{4-[(5- {4-[(5-hydroxy-6-methyl-4- ethyl-5-{4-[(5-hydroxy-6-methyl- hydroxy-6-methyl-4- pyrimidinyl)carbonyl]-1- 4-pyrimidinyl)carbonyl]-1- pyrimidinyl)carbonyl]-1- piperazinyl}-2-[p-(3- piperazinyl}-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- methylureido)phenyl]-4-oxo- tetraaza-7-indenyl}acetamide tetraaza-2-indenyl)phenoxy]acetic 1,3,3a,7-tetraaza-7- acid indenyl)acetamide N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4- phenyl] (6-ethyl-5-{4-[(5- phenyl] (6-ethyl-5-{4-[(5- (trifluoromethyl)phenyl)-2-(2-(2- hydroxy-6-methyl-4-pyrimidinyl) hydroxy-6-methyl-4-pyrimidinyl) (difluoromethoxy)-4- carbonyl]-1-piperazinyl}-2-[2-(3- carbonyl]-1-piperazinyl}-2-[p- fluoropyrazolo[1,5-a]pyridin-5-yl)- oxetanyl)-2H-indazol-5-yl]-4-oxo- (methylsulfinyl) phenyl]-4-oxo- 5-ethyl-6-(4-(5-hydroxy-6- 1,3,3a,7-tetraaza-7-indenyl) 1,3,3a,7-tetraaza-7-indenyl) methylpyrimidine-4- acetamide acetamide carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide

[0040] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{2-[1- (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl)-2-(2-(4,4- (difluoromethyl)-4-fluoro-2- ethyl-6-(4-(5-hydroxy-6- dimethyl-1,4-azasilinan-1-yl)-5- oxopyrazolo[1,5-a]pyridin-5-yl]- methylpyrimidine-4- ethyl-6-(4-(5-hydroxy-6- 5-ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl)-2-(8- methylpyrimidine-4- methylpyrimidine-4- methylquinolin-6-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide 4(7H)-yl)acetamide yl}acetamide N-[2-chloro-4- N-(1-(4-(2-((2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)amino)-2- (trifluoromethyl)phenyl]-2-[2-(3,6- (3,6-dihydro-2H-pyran-4-yl)-5- oxoethyl)-2-(3,6-dihydro-2H- dihydro-2H-pyran-4-yl)-5-ethyl-6- ethyl-6-{5-methyl-6-oxo-4H,7H- pyran-4-yl)-5-ethyl-7-oxo-4,7- [4-(5-hydroxy-6-methylpyrimidine- pyrazolo[1,5-a]pyrazin-2-yl}-7- dihydro-[1,2,4]triazolo[1,5- 4-carbonyl)-1,4-diazepan-1-yl]-7- oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)pyrrolidin-3-yl)- oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl]acetamide 5-hydroxy-N,6- a]pyrimidin-4-yl]acetamide dimethylpyrimidine-4- carboxamide

[0041] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)-2-(2-(3,6- (3,6-dihydro-2H-pyran-4-yl)-5- (3,6-dihydro-2H-pyran-4-yl)-5- dihydro-2H-pyran-4-yl)-5-ethyl-6- ethyl-6-[(5S)-4-(5-hydroxy-6- ethyl-6-[(5R)-4-(5-hydroxy-6- (3-(5-hydroxy-6-methylpyrimidine- methylpyrimidine-4-carbonyl)-5- methylpyrimidine-4-carbonyl)-5- 4-carbonyl)-3,7- methyl-1,4-diazepan-1-yl]-7-oxo- methyl-1,4-diazepan-1-yl]-7-oxo- diazabicyclo[4.2.0]octan-7-yl)-7- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- oxo-[1,2,4]triazolo[1,5- yl]acetamide yl]acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4-(trifluoromethyl) N-(2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl](5-{4-[(E)-4-(p- phenyl)-2-(2-(3,6-dihydro-2H- (trifluoromethyl)phenyl]-2-[2-(3,6- methoxyphenyl)-4-oxo-2- pyran-4-yl)-5-ethyl-6-(1-(5- dihydro-2H-pyran-4-yl)-5-ethyl-6- butenoyl]-1-piperazinyl}-2-(3,6- hydroxy-6-methylpyrimidine-4- [3-(5-hydroxy-6-methylpyrimidine- dihydro-2H-pyran-4-yl)-6-ethyl-4- carbonyl)octahydro-4H- 4-carbonyl)-3,8- oxo-1,3,3a,7-tetraaza-7- pyrrolo[3,2-b]pyridin-4-yl)-7-oxo- diazabicyclo[4.2.0]octan-8-yl]-7- indenyl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4-yl]acetamide

[0042] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-[2-chloro-4- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2- 5-ethyl-6-[4-(5-hydroxy-6- (3,6-dihydro-2H-pyran-4-yl)-5- (2,3-dihydro-1-benzofuran-4-yl)- methylpyrimidine-4- ethyl-6-[4-(5-hydroxy-6- 5-ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4-carbonyl)- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- hexahydro-2H-pyrrolo[3,2- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-[4- b]pyridin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- (trifluoromethyl)bicyclo[2.2.2] [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide octan-1-yl]acetamide yl]acetamide N-(6,6- N-(4,4-difluorocyclohexyl)-2-[2- N-{3- difluorobicyclo[3.1.0]hexan-3-yl)- (3,6-dihydro-2H-pyran-4-yl)-5- cyclobutylbicyclo[1.1.1]pentan-1- 2-(2-(3,6-dihydro-2H-pyran-4-yl)- ethyl-6-[4-(5-hydroxy-6- yl}-2-[2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- yl)-5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl] acetamide

[0043] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-[2-(3,6-dihydro-2H-pyran-4-yl)- N-{3-[3-(1,1- N-(2-chloro-4- 5-ethyl-6-[4-(5-hydroxy-6- difluoroethyl)bicyclo[1.1.1]pentan (chlorodifluoromethoxy)phenyl)-2- methylpyrimidine-4- -1-yl]bicyclo[1.1.1]pentan-1-yl}- (2-(3,6-dihydro-2H-pyran-4-yl)-5- carbonyl)piperazin-1-yl]-7-oxo- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- ethyl-6-(4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- 5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- yl]-N-[3-(4- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- fluorophenyl)bicyclo[1.1.1]pentan carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- -1-yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl]acetamide 2-[2-(3,6-dihydro-2H-pyran-4-yl)- N-{6,6-difluorospiro[3.3]heptan- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[4-(5-hydroxy-6- 2-yl}-2-[2-(3,6-dihydro-2H-pyran- 5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- 4-yl)-5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]-N-{4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]-N-[1-(trifluoromethyl)-2- [(trifluoromethyl)sulfanyl]phenyl} yl]acetamide oxabicyclo[2.2.2]octan-4- acetamide yl]acetamide

[0044] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-{3- 2-(2-(3,6-dihydro-2H-pyran-4-yl)- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- cyclopropylbicyclo[1.1.1]pentan- 5-ethyl-6-(4-(5-hydroxy-6- 5-ethyl-6-[4-(5-hydroxy-6- 1-yl}-2-[2-(3,6-dihydro-2H- methylpyrimidine-4- methylpyrimidine-4- pyran-4-yl)-5-ethyl-6-[4-(5- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- hydroxy-6-methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- 4(7H)-yl)-N-(5- yl]-N-[3-(3,3,3- [1,2,4]triazolo[1,5-a]pyrimidin-4- (trifluoromethyl)quinolin-8- trifluoropropyl)bicyclo yl]acetamide yl)acetamide [1.1.1]pentan-1-yl]acetamide 2-[2-(3,6-dihydro-2H-pyran-4-yl)- 2-(2-(3,6-dihydro-2H-pyran-4-yl)- N-{2-chloro-4- 5-ethyl-6-[4-(5-hydroxy-6- 5-ethyl-6-(4-(5-hydroxy-6- [(trifluoromethyl)sulfanyl]phenyl}- methylpyrimidine-4- methylpyrimidine-4- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- 5-ethyl-6-[4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- methylpyrimidine-4- yl]-N-[4- 4(7H)-yl)-N-(5- carbonyl)piperazin-1-yl]-7-oxo- (trifluoromethyl)bicyclo[2.2.1] (trifluoromethyl)pyridin-2- [1,2,4]triazolo[1,5-a]pyrimidin-4- heptan-1-yl]acetamide yl)acetamide yl]acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)- N-(1,1-difluorospiro[2.3]hexan-5- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-(4-(5-hydroxy-6- yl)-2-(2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)-N-(5- [1,2,4]triazolo[1,5-a]pyrimidin- yl]-N-[1-meth yl-2-oxo-6- (trifluoromethyl)quinolin-8- 4(7H)-yl)acetamide (trifluoromethyl)pyridin-3- yl)acetamide yl]acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-(2-(3,6-dihydro-2H-pyran-4-yl)- N-(4-difluoromethoxy-2- N-(2-chloro-4- 5-ethyl-6-(4-(5-hydroxy-6- fluorophenyl) [2-(3,6-dihydro-2H- difluoromethoxyphenyl) [2-(3,6- methylpyrimidine-4- pyran-4-yl)-6-ethyl-5-{4-[(5- dihydro-2H-pyran-4-yl)-6-ethyl-5- carbonyl)piperazin-1-yl)-7-oxo- hydroxy-6-methyl-4-pyrimidinyl) {4-[(5-hydroxy-6-methyl-4- [1,2,4]triazolo[1,5-a]pyrimidin- carbonyl]-1-piperazinyl}-4-oxo- pyrimidinyl) carbonyl]-1- 4(7H)-yl)-N-(7- 1,3,3a,7-tetraaza-7- piperazinyl}-4-oxo-1,3,3a,7- (trifluoromethyl)benzo[d]thiazol- indenyl]acetamide tetraaza-7-indenyl] acetamide 4-yl)acetamide N-{2,2-difluoro-3- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- N-(5-chloro-7- methylbicyclo[1.1.1]pentan-1-yl}- 5-ethyl-6-[4-(5-hydroxy-6- (trifluoromethyl)benzo[d]thiazol-4- 2-[2-(3,6-dihydro-2H-pyran-4-yl)- methylpyrimidine-4- yl)-2-(2-(3,6-dihydro-2H-pyran-4- 5-ethyl-6-[4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-7-oxo- yl)-5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-{6-fluorospiro[3.3]heptan- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- 2-yl}acetamide [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide N-[2-chloro-4- N-(2-chloro-4- 2-[2-(1,3-dihydro-2-benzofuran-5- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)-2-(5- yl)-5-ethyl-6-[4-(5-hydroxy-6- (3,6-dihydro-2H-pyran-4-yl)-7- (difluoromethoxy)-2-(1,3- methylpyrimidine-4- ethyl-6-[4-(5-hydroxy-6- dihydroisobenzofuran-5-yl)-6-(4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- (5-hydroxy-6-methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]- carbonyl)piperazin-1-yl)-7-oxo- yl]-N-[5- [1,2,4]triazolo[1,5-a]pyridin-8- [1,2,4]triazolo[1,5-a]pyrimidin- (trifluoromethyl)bicyclo[4.2.0]octa- yl]acetamide 4(7H)-yl)acetamide 1(6),2,4-trien-2-yl]acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-[2-(azetidin-1-yl)-5-ethyl-6-[4- N-(2-chloro-4- N-(2-chloro-4- (5-hydroxy-6-methylpyrimidine- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(6-(4- 4-carbonyl)piperazin-1-yl]-7-oxo- (2,3-dihydrobenzo[b][1,4]dioxin- (2- [1,2,4]triazolo[1,5-a]pyrimidin-4- 5-yl)-5-ethyl-6-(4-(2- (cyclopropanesulfonamido)benzoyl yl]-N-[5- (methylsulfonamido)benzoyl)piper )piperazin-1-yl)-2-(2,3- (trifluoromethyl)bicyclo[4.2.0]oct azin-1-yl)-7-oxo- dihydrobenzo[b][1,4]dioxin-5-yl)- a-1(6),2,4-trien-2-yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin- 5-ethyl-7-oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide 2-(2-(benzo[d][1,3]dioxol-5-yl)-5- N-[3-chloro-5- 2-{5-ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6- (trifluoromethyl)bicyclo[4.2.0]oct methylpyrimidine-4- methylpyrimidine-4- a-1(6),2,4-trien-2-yl]-2-[2-(2,3- carbonyl)piperazin-1-yl]-2-{3- carbonyl)piperazin-1-yl)-7-oxo- dihydro-1-benzofuran-6-yl)-5- oxabicyclo[3.1.0]hexan-6-yl}-7- [1,2,4]triazolo[1,5-a]pyrimidin- ethyl-6-[4-(5-hydroxy-6- oxo-[1,2,4]triazolo[1,5- 4(7H)-yl)-N-(3-chloro-5- methylpyrimidine-4- a]pyrimidin-4-yl}-N-[5- (trifluoromethyl)bicyclo[4.2.0]oct carbonyl)piperazin-1-yl]-7-oxo- (trifluoromethyl)bicyclo[4.2.0]octa- a-1(6),2,4-trien-2-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- 1(6),2,4-trien-2-yl]acetamide yl]acetamide

[0045] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[3-chloro-5- N-[3-chloro-5- 2-[2-(2H-1,3-benzodioxol-4-yl)-5- (trifluoromethyl)bicyclo[4.2.0]oct (trifluoromethyl)bicyclo[4.2.0]oct ethyl-6-[4-(5-hydroxy-6- a-1(6),2,4-trien-2-yl]-2-[2-(2,3- a-1(6),2,4-trien-2-yl]-2-[2-(1,3- methylpyrimidine-4- dihydro-1-benzofuran-5-yl)-5- dihydro-2-benzofuran-5-yl)-5- carbonyl)piperazin-1-yl]-7-oxo- ethyl-6-[4-(5-hydroxy-6- ethyl-6-[4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- methylpyrimidine-4- methylpyrimidine-4- yl]-N-[3-chloro-5- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- (trifluoromethyl)bicyclo[4.2.0]octa- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- 1(6),2,4-trien-2-yl]acetamide) yl]acetamide yl]acetamide) N-[3-chloro-5- N-[3-chloro-5- N-[3-chloro-5- (trifluoromethyl)bicyclo[4.2.0]oct (trifluoromethyl)bicyclo[4.2.0]oct (trifluoromethyl)bicyclo[4.2.0]octa- a-1(6),2,4-trien-2-yl]-2-[2-(1,3- a-1(6),2,4-trien-2-yl]-2-[2- 1(6),2,4-trien-2-yl]-2-[2-(2,3- dihydro-2-benzofuran-4-yl)-5- (dimethylamino)-5-ethyl-6-[4-(5- dihydro-1,4-benzodioxin-5-yl)-5- ethyl-6-[4-(5-hydroxy-6- hydroxy-6-methylpyrimidine-4- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide

[0046] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(3-chloro-5- N-(3-chloro-5- 2-[2-(azetidin-1-yl)-5-ethyl-6-[4-(5- (trifluoromethyl)bicyclo[4.2.0]oct (trifluoromethyl)bicyclo[4.2.0]oct hydroxy-6-methylpyrimidine-4- a-1(6),2,4-trien-2-yl)-2-(5-ethyl-6- a-1(6),2,4-trien-2-yl)-2-(5-ethyl-6- carbonyl)piperazin-1-yl]-7-oxo- (4-(5-hydroxy-6- (4-(5-hydroxy-6- [1,2,4]triazolo[1,5-a]pyrimidin-4- methylpyrimidine-4- methylpyrimidine-4- yl]-N-[3-chloro-5- carbonyl)piperazin-1-yl)-2- carbonyl)piperazin-1-yl)-2- (trifluoromethyl)bicyclo[4.2.0]octa- (isochroman-5-yl)-7-oxo- (isochroman-8-yl)-7-oxo- 1(6),2,4-trien-2-yl]acetamide [1,2,4]triazolo [1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide 4(7H)-yl)acetamide 2-[2-(dimethylamino)-5-ethyl-6- 2-(5-ethyl-6-(4-(5-hydroxy-6- 2-[2-(2H-1,3-benzodioxol-4-yl)-5- [4-(5-hydroxy-6- methylpyrimidine-4-carbonyl) ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- piperazin-1-yl)-2-(isochroman-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- yl)-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- a]pyrimidin-4(7H)-yl)-N-(4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]-N-{4- ((trifluoromethyl)thio) yl]-N-{4- [(trifluoromethyl)sulfanyl]phenyl} phenyl)acetamide [(trifluoromethyl)sulfanyl]phenyl}a acetamide cetamide N-{2-chloro-4- N-{2-chloro-4- N-p- [(trifluoromethyl)sulfanyl]phenyl} [(trifluoromethyl)sulfanyl]phenyl} chlorodifluoromethoxyphenyl[2- -2-[2-(3,4-dihydro-1H-2- -2-[2-(dimethylamino)-5-ethyl-6- (2,3-dihydro-1-benzofuran-5-yl)-6- benzopyran-6-yl)-5-ethyl-6-[4-(5- [4-(5-hydroxy-6- ethyl-5-{4-[(5-hydroxy-6-methyl-4- hydroxy-6-methylpyrimidine-4- methylpyrimidine-4- pyrimidinyl) carbonyl]-1- carbonyl)piperazin-1-yl]-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- tetraaza-7-indenyl]acetamide yl]acetamide yl]acetamide

[0047] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-p- N-{2-chloro-4- 2-[2-(2H-1,3-benzodioxol-4-yl)-5- chlorodifluoromethoxyphenyl[2- [(trifluoromethyl)sulfanyl]phenyl} ethyl-6-[4-(5-hydroxy-6- (2,3-dihydro-1-benzofuran-5-yl)- -2-[2-(2,3-dihydro-1,4- methylpyrimidine-4- 6-ethyl-5-{4-[(5-hydroxy-6- benzodioxin-5-yl)-5-ethyl-6-[4-(5- carbonyl)piperazin-1-yl]-7-oxo- methyl-4-pyrimidinyl) carbonyl]- hydroxy-6-methylpyrimidine-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- 1-piperazinyl}-4-oxo-1,3,3a,7- carbonyl)piperazin-1-yl]-7-oxo- yl]-N-{2-chloro-4- tetraaza-7-indenyl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [(trifluoromethyl)sulfanyl]phenyl}a yl]acetamide cetamide N-[2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-(6-{4- (dimethylamino)-5-ethyl-6-[4-(5- (3,4-dihydro-1H-2-benzopyran-6- [6-(difluoromethyl)-5- hydroxy-6-methylpyrimidine-4- yl)-5-ethyl-6-[4-(5-hydroxy-6- hydroxypyrimidine-4- carbonyl) piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-(2,3- [1,2,4]triazolo[1,5-a]pyrimidin -4- carbonyl)piperazin-1-yl]-7-oxo- dihydro-1,4-benzodioxin-5-yl)-5- yl]-2,2-difluoroacetamide [1,2,4]triazolo[1,5-] pyri midin-4- ethyl-7-oxo-[1,2,4]triazolo[1,5- yl]-2,2-difluoroacetamide a]pyrimidin-4-yl)acetamide 2-[2-(2H-1,3-benzodioxol-4-yl)-6- N-(2-chloro-4- N-(2-chloro-4- {4-[6-(difluoromethyl)-5- chlorodifluoromethoxyphenyl) [2- chlorodifluoromethoxyphenyl) (6- hydroxypyrimidine-4- (2,3-dihydro-1-benzofuran-5-yl)- ethyl-5-{4-[(5-hydroxy-6-methyl-4- carbonyl]piperazin-1-yl}-5-ethyl- 6-ethyl-5-{4-[(5-hydroxy-6- pyrimidinyl)carbonyl]-1- 7-oxo-[1,2,4]triazolo[1,5- methyl-4-pyrimidinyl) carbonyl]- piperazinyl}-2-(6-isochromanyl)-4- a]pyrimidin-4-yl]-N-[2-chloro-4- 1-piperazinyl}-4-oxo-1,3,3a,7- oxo-1,3,3a,7-tetraaza-7- (trifluoromethyl)phenyl]acetamide tetraaza-7-indenyl]acetamide indenyl)acetamide

[0048] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-(2-chloro-4- N-{2-chloro-4- chlorodifluoromethoxyphenyl) [2- (trifluoromethyl)phenyl)-2-(2- [(trifluoromethyl)sulfanyl]phenyl}- (1,3-dihydro-5-isobenzofuranyl)- (1,3-dihydroisobenzofuran-5-yl)- 2-[2-(1,3-dihydro-2-benzofuran-5- 6-ethyl-5-{4-[(5-hydroxy-6- 6-(4-(2,4-dihydroxy-5- yl)-5-ethyl-6-[4-(5-hydroxy-6- methyl-4-pyrimidinyl) carbonyl]- isopropylbenzoyl) piperazin-1-yl)- methylpyrimidine-4- 1-piperazinyl}-4-oxo-1,3,3a,7- 5-ethyl-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- tetraaza-7-indenyl] acetamide a]pyrimidin-4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide N-(2-chloro-4- 2-[2-(2,3-dihydro-1,4- N-(2-chloro-4- ((trifluoromethyl)thio)phenyl)-2- benzodioxin-5-yl)-5-ethyl-6-[4-(5- (trifluoromethyl)phenyl)-2-(6-(4- (2-(2,3-dihydrobenzofuran-5-yl)- hydroxy-6-methylpyrimidine-4- (6-(3,3-difluoroazetidin-1-yl)-5- 5-ethyl-6-(4-(5-hydroxy-6-methyl carbonyl)piperazin-1-yl]-7-oxo- hydroxypyrimidine-4- pyrimidine-4-carbonyl)piperazin- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl)-2-(1,3- 1-yl)-7-oxo-[1,2,4]triazolo[1,5- yl]-N-{4- dihydroisobenzofuran-5-yl)-5- a]pyrimidin-4(7H)-yl)acetamide [(trifluoromethyl)sulfanyl]phenyl} ethyl-7-oxo-[1,2,4]triazolo[1,5- acetamide a]pyrimidin-4(7H)-yl)acetamide N-[2-chloro-4- N-[2-chloro-6-cyclopropoxy-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)-2-(2-(1,3- (1,3-dihydro-2-benzofuran-5-yl)- (1,3-dihydro-2-benzofuran-5-yl)- dihydroisobenzofuran-5-yl)-5- 6-[4-(2,4-dihydroxy-5- 5-ethyl-6-[4-(5-hydroxy-6- ethyl-6-(4-(5-hydroxy-6-(3- methylbenzoyl)piperazin-1-yl]-5- methylpyrimidine-4- methoxyazetidin-1-yl)pyrimidine- ethyl-7-oxo-[1,2,4]triazolo[1,5- carbonyl)piperazin-1-yl]-7-oxo- 4-carbonyl)piperazin-1-yl)-7-oxo- a]pyrimidin-4-yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide

[0049] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-cyclopropoxy-4- N-[2-chloro-4- N-[2-chloro-5-cyclopropyl-4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl]-2-[2-(1,3- (1,3-dihydro-2-benzofuran-5-yl)- (1,3-dihydro-2-benzofuran-5-yl)- dihydro-2-benzofuran-5-yl)-5- 5-ethyl-6-[4-(5-hydroxy-6- 5-ethyl-6-(4-{3-hydroxy- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- 5H,6H,7H-cyclopenta[b]pyridine- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- 2-carbonyl}piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide yl]acetamide yl]acetamide N-[2-chloro-4-(3,3,3- N-(2-chloro-4-(1- N-[2-chloro-4-(2,2- trifluoroprop-1-en-2-yl)phenyl]-2- (trifluoromethyl)cyclopropyl)phen difluoroethenyl)phenyl]-2-[2-(1,3- [2-(1,3-dihydro-2-benzofuran-5- yl)-2-(2-(1,3- dihydro-2-benzofuran-5-yl)-5- yl)-5-ethyl-6-[4-(5-hydroxy-6- dihydroisobenzofuran-5-yl)-5- ethyl-6-[4-(5-hydroxy-6- methylpyrimidine-4- ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- methylpyrimidine-4- carbonyl)piperazin-1-yl]-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a] pyrimidin-4- yl]acetamide [1,2,4]triazolo[1,5-a]pyrimidin- yl]acetamide 4(7H)-yl)acetamide

[0050] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- N-(2-chloro-4- N-(5-chloro-7- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)benzo[d]thiazol-4- (1,3-dihydro-2-benzofuran-5-yl)- (1,3-dihydroisobenzofuran-5-yl)- yl)-2-(2-(1,3-dihydroisobenzofuran- 5-ethyl-6-(4-{3-hydroxy-4-oxo- 5-ethyl-6-(4-(3-hydroxy-5,6,7,8- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6- 6H,7H,8H-pyrrolo[1,2- tetrahydroquinoline-2- methylpyrimidine-4- a]pyrimidine-2- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- carbonyl}piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide 4(7H)-yl)acetamide yl]acetamide N-(2-chloro-4-(trifluoromethyl) N-(2-chloro-4- N-[2-chloro-4- phenyl)-2-(1,3- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl]-2-[2-(1,3- dihydroisobenzofuran-5-yl)-6-(4- (1,3-dihydroisobenzofuran-5-yl)- dihydro-2-benzofuran-5-yl)-5- (2,2-dioxido-3,4-dihydro-1H- 6-(4-(2,2-dioxido-1H- ethyl-6-(4-{3-hydroxy-4-oxo- benzo[c][1,2] thiazine-8- benzo[c][1,2]thiazine-8- 6H,7H,8H,9H-pyrido[1,2- carbonyl)piperazin-1-yl)-5-ethyl- carbonyl)piperazin-1-yl)-5-ethyl- a]pyrimidine-2-carbonyl}piperazin- 7-oxo-[1,2,4]triazolo[1,5- 7-oxo-[1,2,4]triazolo[1,5- 1-yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4-yl]acetamide N-(5-chloro-7- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)benzo[d]thiazol- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(6-(4- 4-yl)-2-(2-(2,3- (1,3-dihydroisobenzofuran-5-yl)- (3,6-dihydro-2H-pyran-4- dihydrobenzofuran-5-yl)-5-ethyl- 5-ethyl-6-(4-(6-methoxy-1- carbonyl)piperazin-1-yl)-5-ethyl-2- 6-(4-(5-hydroxy-6- methyl-1H- (2-hydroxypyrimidin-4-yl)-7-oxo- methylpyrimidine-4- benzo[d][1,2,3]triazole-5- [1,2,4] triazolo[1,5-a]pyrimidin- carbonyl)piperazin-1-yl)-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide 4(7H)-yl)acetamide ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(5- (trifluoromethyl)phenyl]-2-[2- phenyl] [2-(1,3-dihydro-5- ethyl-2-(2-hydroxypyrimidin-4- (1,3-dihydro-2-benzofuran-5-yl)- isobenzofuranyl)-6-ethyl-5-{4-[(6- yl)-7-oxo-6-(4-(tetrahydro-2H- 5-ethyl-6-(4-{7-hydroxy- hydroxy-1-methyl-1H-1,2,3- pyran-4-carbonyl)piperazin-1-yl)- 2H,3H,4H-pyrano[3,2-b]pyridine- benzotriazol-5-yl) carbonyl]-1- [1,2,4]triazolo[1,5-a]pyrimidin- 6-carbonyl}piperazin-1-yl)-7-oxo- piperazinyl}-4-oxo-1,3,3a,7- 4(7H)-yl)acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- tetraaza-7-indenyl] acetamide yl]acetamide 2-(6-(4-acetylpiperazin-1-yl)-5- N-[2-chloro-4- N-(2-chloro-4- ethyl-2-(5-hydroxypyrimidin-2- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)-2-(6-(4- yl)-7-oxo-[1,2,4]triazolo[1,5- (1,3-dihydro-2-benzofuran-5-yl)- (3,6-dihydro-2H-pyran-4- a]pyrimidin-4(7H)-yl)-N-(2- 5-ethyl-6-(4-{6-hydroxy-2H,3H- carbonyl)piperazin-1-yl)-5-ethyl-2- chloro-4- furo[3,2-b]pyridine-5- (5-hydroxypyrimidin-2-yl)-7-oxo- (trifluoromethyl)phenyl)acetamide carbonyl}piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- [1,2,4]triazolo[1,5-a]pyrimidin-4- 4(7H)-yl)acetamide yl]acetamide

[0051] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 2-{6-[(3aS,7aS)-4-(5-hydroxy-6- 2-{6-[(3aR,7aS)-4-(5-hydroxy-6- N-(2-chloro-4- methylpyrimidine-4-carbonyl)- methylpyrimidine-4-carbonyl)- (trifluoromethyl)phenyl)-2-(2-(1,3- hexahydro-2H-pyrrolo[3,2- hexahydro-2H-pyrrolo[3,2- dihydroisobenzofuran-5-yl)-5- b]pyridin-1-yl]-2-(1,3-dihydro-2- b]pyridin-1-yl]-2-(1,3-dihydro-2- ethyl-6-(4-(4-hydroxyisoxazole-3- benzofuran-5-yl)-5-ethyl-7-oxo- benzofuran-5-yl)-5-ethyl-7-oxo- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin-4- [1,2,4]triazolo[1,5-a]pyrimidin- yl}-N-[2-chloro-4- yl}-N-[2-chloro-4- 4(7H)-yl)acetamide (trifluoromethyl)phenyl]acetamide (trifluoromethyl)phenyl]acetamide N-[2-chloro-4- N-[2-chloro-4- N-[6-chloro-4-(trifluoromethyl)- (trifluoromethyl)phenyl][2-(1,3- (trifluoromethyl)phenyl][2-(1,3- 2,3-dihydro-1-benzofuran-7-yl]-2- dihydro-5-isobenzofuranyl)-6- dihydro-5-isobenzofuranyl)-6- [2-(1,3-dihydro-2-benzofuran-5-yl)- ethyl-5-{4-[(3-hydroxy-7,8- ethyl-5-{4-[(3-hydroxy-6,8- 5-ethyl-6-[4-(5-hydroxy-6- dihydro-5H-6-oxa-1-azanaphth-2- dihydro-5H-7-oxa-1-azanaphth-2- methylpyrimidine-4-carbonyl) yl)carbonyl]-1-piperazinyl}-4- yl)carbonyl]-1-piperazinyl}-4- piperazin-1-yl]-7-oxo- [1,2,4] oxo-1,3,3a,7-tetraaza-7- oxo-1,3,3a,7-tetraaza-7- triazolo[1,5-a] pyrimidin-4-yl] indenyl]acetamide indenyl]acetamide acetamide N-(2-chloro-4- 2-(6-(4-(5H-pyrrolo[3,2- N-(2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(2- d]pyrimidine-4- phenyl)-2-(2-(1,3- (1,3-dihydroisobenzofuran-5-yl)- carbonyl)piperazin-1-yl)-2-(1,3- dihydroisobenzofuran-5-yl)-5- 5-ethyl-6-(4-(4-hydroxy-5-(4- dihydroisobenzofuran-5-yl)-5- ethyl-6-(4-(4-hydroxy-5- methylpiperazin-1-yl)isothiazole- ethyl-7-oxo-[1,2,4]triazolo[1,5- morpholinoisothiazole-3- 3-carbonyl)piperazin-1-yl)-7-oxo- a]pyrimidin-4(7H)-yl)-N-(2- carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin- chloro-4- [1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide (trifluoromethyl)phenyl)acetamide 4(7H)-yl)acetamide

[0052] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-(2-chloro-4-(trifluoromethyl) N-[6-chloro-4-(trifluoromethyl)-1- N-[2-chloro-4- phenyl)-2-(2-(1,3- benzofuran-7-yl]-2-[2-(1,3- (trifluoromethyl)phenyl][2-(1,3- dihydroisobenzofuran-5-yl)-5- dihydro-2-benzofuran-5-yl)-5- dihydro-5-isobenzofuranyl)-6- ethyl-6-(4-(4-hydroxyisoxazole-3- ethyl-6-[4-(5-hydroxy-6- ethyl-5-(4-{[4-hydroxy-5-(4- carbonyl) piperazin-1-yl)-7-oxo- methylpyrimidine-4-carbonyl) pyridyl)-3-isothiazolyl]carbonyl}- [1,2,4] triazolo[1,5-a] pyrimidin- piperazin-1-yl]-7-oxo- [1,2,4] 1-piperazinyl)-4-oxo-1,3,3a,7- 4(7H)-yl)acetamide triazolo[1,5-a] pyrimidin-4-yl] tetraaza-7-indenyl]acetamide acetamide N-[2-chloro-4- N-[2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl]-2-{6-[4- (trifluoromethyl)phenyl]-2-[2- (trifluoromethyl)phenyl)-2-(2-(1,3- (5-cyano-3-hydroxy-2- (1,3-dihydro-2-benzofuran-5-yl)- dihydroisobenzofuran-5-yl)-7- methylpyridine-4- 5-ethyl-6-{4-[3-hydroxy-2- ethyl-6-(4-(5-hydroxy-6- carbonyl)piperazin-1-yl]-2-(1,3- methyl-6-(4-methylpiperazin-1- methylpyrimidine-4- dihydro-2-benzofuran-5-yl)-5- yl)pyridine-4-carbonyl]piperazin- carbonyl)piperazin-1-yl)-3-methyl- ethyl-7-oxo-[1,2,4]triazolo[1,5- 1-yl}-7-oxo-[1,2,4]triazolo[1,5- 5-oxoimidazo[1,2-a]pyrimidin- a]pyrimidin-4-yl}acetamide a]pyrimidin-4-yl]acetamide 8(5H)-yl)acetamide N-(2-chloro-4- (S)-N-[2-chloro-4- N-[2-chloro-4-(trifluoromethyl) (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl]-2-[2- phenyl] (5-{4-[(1H-1,6-diazainden- (1,3-dihydroisobenzofuran-5-yl)- (1,1-dimethyl-3H-2-benzofuran-5- 7-yl) carbonyl]-1-piperazinyl}-2- 7-ethyl-6-(4-(5-hydroxy-6- yl)-5-ethyl-6-[4-(5-hydroxy-6- (1,1-dimethyl-1,3-dihydro-5- methylpyrimidine-4- methylpyrimidine-4-carbonyl)-2- isobenzofuranyl)-6-ethyl-4-oxo- carbonyl)piperazin-1-yl)-3- methylpiperazin-1-yl]-7-oxo- 1,3,3a,7-tetraaza-7-indenyl) (hydroxymethyl)-5- [1,2,4]triazolo[1,5-a]pyrimidin-4- acetamide oxoimidazo[1,2-a]pyrimidin- yl]acetamide 8(5H)-yl)acetamide

[0053] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4-(trifluoromethyl) N-[2-chloro-4- phenyl] {2-(1,1-dimethyl-1,3- phenyl] [2-(1,1-dimethyl-1,3- (trifluoromethyl)phenyl]-2-[2-(1,1- dihydro-5-isobenzofuranyl)-6- dihydro-5-isobenzofuranyl)-6- dimethyl-3H-2-benzofuran-5-yl)-5- ethyl-5-[4-(3-hydroxy-2-methyl- ethyl-4-oxo-5-{4-[(3H-1,3,5- ethyl-6-[(3R)-4-(5-hydroxy-6- isonicotinoyl)-1-piperazinyl]-4- triazainden-4-yl) carbonyl]-1- methylpyrimidine-4-carbonyl)-3- oxo-1,3,3a,7-tetraaza-7-indenyl} piperazinyl}-1,3,3a,7-tetraaza-7- methylpiperazin-1-yl]-7-oxo- acetamide indenyl] acetamide [1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide N-(2-chloro-4- N-(2-chloro-4- N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl)-2-(2-(1,1- (1,1-dimethyl-1,3- (1,1-dimethyl-1,3- dimethyl-1,3- dihydroisobenzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-5- dihydroisobenzofuran-5-yl)-5- ethyl-6-((1S,6S)-5-(5-hydroxy-6- ethyl-6-((1S,6R)-5-(5-hydroxy-6- ethyl-6-((1R,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)- methylpyrimidine-4-carbonyl)- methylpyrimidine-4-carbonyl)-2,5- 2,5-diazabicyclo[4.2.0]octan-2- 2,5-diazabicyclo[4.2.0]octan-2- diazabicyclo[4.2.0]octan-2-yl)-7- yl)-7-oxo-[1,2,4]triazolo[1,5- yl)-7-oxo-[1,2,4]triazolo[1,5- oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide a]pyrimidin-4(7H)-yl)acetamide. a]pyrimidin-4(7H)-yl)acetamide (R)-N-(2-chloro-4- N-[2-chloro-4- N-[2-chloro-4- (trifluoromethyl)phenyl)-2-(2- (trifluoromethyl)phenyl][2-(1,1- (trifluoromethyl)phenyl][2-(1,1- (1,1-dimethyl-1,3- dimethyl-1,3-dihydro-5- dimethyl-1,3-dihydro-5- dihydroisobenzofuran-5-yl)-5- isobenzofuranyl)-6-ethyl-5-[4-(3- isobenzofuranyl)-6-ethyl-5-{4-[(3- ethyl-6-(4-(5-hydroxy-6- hydroxy-4-oxo-7-oxa-1,4a-diaza- hydroxy-7-oxa-1-aza-5,8-dihydro- methylpyrimidine-4-carbonyl)-5- 4,5,6,8-tetrahydro-2-naphthoyl)-1- 6H-naphth-2-yl)carbonyl]-1- methyl-1,4-diazepan-1-yl)-7-oxo- piperazinyl]-4-oxo-1,3,3a,7- piperazinyl}-4-oxo-1,3,3a,7- [1,2,4]triazolo[1,5-a]pyrimidin- tetraaza-4,7-dihydro-7- tetraaza-4,7-dihydro-7- 4(7H)-yl)acetamide indenyl]acetamide indenyl]acetamide

[0054] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N-[2-chloro-4- (10R,12R)-N-[2-chloro-4- (10S,12R)-N-[2-chloro-4- (trifluoromethyl)phenyl][2-(1,1- (trifluoromethyl)phenyl]-4-(1,1- (trifluoromethyl)phenyl]-4-(1,1- dimethyl-1,3-dihydro-5- dimethyl-3H-2-benzofuran-5-yl)- dimethyl-3H-2-benzofuran-5-yl)-8- isobenzofuranyl)-6-ethyl-5-[4-({3- 8-[(1S,6S)-5-(5-hydroxy-6- [(1S,6S)-5-(5-hydroxy-6- [(p-methoxyphenyl)methoxy]-6- methylpyrimidine-4-carbonyl)- methylpyrimidine-4-carbonyl)-2,5- oxa-1-aza-7,8-dihydro-5H-naphth- 2,5-diazabicyclo[4.2.0]octan-2- diazabicyclo[4.2.0]octan-2-yl]-10- 2-yl}carbonyl)-1-piperazinyl]-4- yl]-10-methyl-7-oxo-1,3,5,6- methyl-7-oxo-1,3,5,6- oxo-1,3,3a,7-tetraaza-4,7-dihydro- tetraazatricyclo[7.3.0.0^{2,6}]dod tetraazatricyclo[7.3.0.0^{2,6}]dode 7-indenyl]acetamide eca-2,4,8-triene-12-carboxamide ca-2,4,8-triene-12-carboxamide (10R,12S)-N-[2-chloro-4- (10S,12S)-N-[2-chloro-4- (7R,9S)-N-(2-chloro-4- (trifluoromethyl)phenyl]-4-(1,1- (trifluoromethyl)phenyl]-4-(1,1- (trifluoromethyl)phenyl)-2-(1,1- dimethyl-3H-2-benzofuran-5-yl)- dimethyl-3H-2-benzofuran-5-yl)- dimethyl-1,3- 8-[(1S,6S)-5-(5-hydroxy-6- 8-[(1S,6S)-5-(5-hydroxy-6- dihydroisobenzofuran-5-yl)-6-(4- methylpyrimidine-4-carbonyl)- methylpyrimidine-4-carbonyl)- (5-hydroxy-6-methylpyrimidine-4- 2,5-diazabicyclo[4.2.0]octan-2- 2,5-diazabicyclo[4.2.0]octan-2- carbonyl)piperazin-1-yl)-7-methyl- yl]-10-methyl-7-oxo-1,3,5,6- yl]-10-methyl-7-oxo-1,3,5,6- 5-oxo-5,7,8,9-tetrahydropy tetraazatricyclo[7.3.0.0^{2,6}]dod tetraazatricyclo[7.3.0.0^{2,6}]dod rrolo[1,2-c][1,2,4]triazolo[1,5- eca-2,4,8-triene-12-carboxamide eca-2,4,8-triene-12-carboxamide a]pyrimidine-9-carboxamide

[0055] ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 (7R,9R)-N-(2-chloro-4- (7S,9S)-N-(2-chloro-4- (7S,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(1,1- (trifluoromethyl)phenyl)-2-(1,1- (trifluoromethyl)phenyl)-2-(1,1- dimethyl-1,3- dimethyl-1,3- dimethyl-1,3- dihydroisobenzofuran-5-yl)-6-(4- dihydroisobenzofuran-5-yl)-6-(4- dihydroisobenzofuran-5-yl)-6-(4- (5-hydroxy-6-methylpyrimidine- (5-hydroxy-6-methylpyrimidine-4- (5-hydroxy-6-methylpyrimidine-4- 4-carbonyl)piperazin-1-yl)-7- carbonyl)piperazin-1-yl)-7- carbonyl)piperazin-1-yl)-7-methyl- methyl-5-oxo-5,7,8,9- methyl-5-oxo-5,7,8,9- 5-oxo-5,7,8,9- tetrahydropyrrolo[1,2- tetrahydropyrrolo[1,2- tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidine- c][1,2,4]triazolo[1,5-a]pyrimidine- c][1,2,4]triazolo[1,5-a]pyrimidine- 9-carboxamide 9-carboxamide 9-carboxamide 3. Methods of Use In certain embodiments, the present disclosure is directed to a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof: and one or more additional active agents. For example, but not by way of limitation, the present disclosure is directed to compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, wherein the additional active agent is an anti-cancer agent. In certain embodiments, the active anti- cancer agent is a chemotherapy. In certain embodiments, the additional active agent is a cytotoxic agent, a cytostatic agent, a hormone treatment, or a checkpoint inhibitor. In certain embodiments, the additional active agent is an immunotherapy. In certain embodiments, the present disclosure is directed to a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, where the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof is formulated in a composition comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the present disclosure is directed to a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof is for use as a medicament. For example, but not by way of limitation, wherein the use is for the treatment of a disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the cancer characterized as microsatellite instability-high (MSI-H) and / or ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 mismatch repair deficient (dMMR) is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the present disclosure is directed to a method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of inhibiting WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating a disorder or disease with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating cancer with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the present disclosure is directed to a process to manufacture a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. 4. Examples The following Examples are presented by way of illustration, not limitation. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products. Abbreviations Used Abbreviation: Meaning: ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 CDCl3Deuterated chloroform CH2Cl2 Dichloromethane Cs2CO3 Cesium carbonate Cu(acac)2 Copper(II) acetylacetonate CuI Copper iodide DIPEA N,N-Diisopropylethylamine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Deuterated dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol EtONa Sodium ethoxide H2O Water H2SO4Sulfuric acid H3PO4Phosphoric acid Hexafluorophosphate azabenzotriazole tetramethyl HATU uronium HCl Hydrochloric acid I2Iodine IPA Isopropyl alcohol K2CO3 Potassium carbonate K3PO4 Potassium phosphate KI Potassium iodide KOAc Potassium acetate LiOH.H2O Lithium hydroxide monohydrate MeCN Acetonitrile MeI Methyl iodide MeOH Methanol MeOH-d4 Deuterated methanol MgSO4Magnesium sulfate ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 N2Nitrogen Na2CO3 Sodium carbonate Na2SO4 Sodium sulfate NaBr Sodium bromide NaCl Sodium chloride NaH Sodium hydride NaHCO3 Sodium bicarbonate NaOH Sodium hydroxide n-BuLi n-Butyllithium n-BuOH n-Butanol NEt3Triethylamine NH4Cl Ammonium chloride NMI 1-Methylimidazole NMP N-Methyl-2-pyrrolidone N*%*s& Pd(dppf)Cl2.CH2Cl2 Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) Pd / C Palladium on carbon Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) T3P 1-Propanephosphonic anhydride Chloro-N,N,N’,N’-tetramethylformamidinium TCFH hexafluorophosphate TFA Trifluoroacetic acid THF Tetrahydrofuran 9XRhR[^WTgh[N+s%-s% / s&caXb"_a^_P]&+&h[#N*%*s&QX_WT]h[O& XPhos 2-yl]phosphane Preparation of Intermediates Intermediate A Synthesis of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid. Intermediate A ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Step 1: Preparation of 5-(benzyloxy)-4,6-dichloropyrimidine. Intermediate A1 A mixture of 4,6-dichloropyrimidin-5-ol (5.0 g, 30.3 mmol), K2CO3 (7.1 g, 51.5 mmol) and benzyl bromide (5.7 g, 33.0 mmol) in DMF (25 mL) was stirred at 25 °C for 16 hours. The mixture was quenched with H2O (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 12% EtOAc in petroleum ether) to afford (6.0 g, 77.6% yield) of 5-(benzyloxy)-4,6-dichloropyrimidine as a colorless solid. LCMS observed m / z = 255.0 [M+H]+. Step 2: Preparation of 5-(benzyloxy)-4-chloro-6-methylpyrimidine. Intermediate A2 A mixture of 5-(benzyloxy)-4,6-dichloropyrimidine (30.2 g, 118.3 mmol), Pd(dppf)Cl2.CH2Cl2 (4.8 g, 6.6 mmol), K3PO4 (75.3 g, 355.1 mmol) in toluene (300 mL) and H2O (90 mL) was stirred under N2 at 105 °C. To the mixture was added dropwise a solution of methylboronic acid (8.5 g, 142.0 mmol) in dioxane (400 mL). The resulting mixture was stirred at 105 °C for 18 hours. To the mixture was added a second batch solution of methylboronic acid (8.5 g, 142.0 mmol) in dioxane (300 mL) and stirred at 105 °C for an additional 8 hours under N2. To the mixture was added a third batch solution of methylboronic acid (8.5 g, 142.0 mmol) in dioxane (300 mL) and stirred at 105 °C for an additional 8 hours under N2. The ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 resulting mixture was cooled to 25 °C, quenched with H2O (500 mL), filtered and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was extracted with EtOAc (3 x 250 mL), washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 17% EtOAc in petroleum ether) to afford (18.7 g, 67.3% yield) of 5-(benzyloxy)-4-chloro- 6-methylpyrimidine as a light yellow oil. LCMS observed m / z = 235.1 [M+H]+. Step 3: Preparation of methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate. Intermediate A3 A mixture of 5-(benzyloxy)-4-chloro-6-methylpyrimidine (5.0 g, 21.3 mmol) in MeOH (20 mL) was added Pd(dppf)Cl2.CH2Cl2(0.7 g, 1.0 mmol) in a pressure tank. The mixture was purged with N2 for 5 minutes and then was charged with carbon monoxide (5 atm.) three times at 25 °C. The resulting mixture was heated to 50 °C and stirred at 50 °C for 48 hours. The mixture was cooled to 25 °C, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, (eluent: with 50% EtOAc in petroleum ether) to afford (4.0 g, 72.6% yield) of methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate as a colorless oil. LCMS observed m / z = 259.1 [M+H]+. Step 4: Preparation of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid. Intermediate A A mixture of methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate (10.0 g, 38.7 mmol) in THF (20 mL) and MeOH (20 mL) was added dropwise a solution of NaOH (3.8 g, 97.1 mmol) in H2O (20 mL). The mixture was stirred at 25 °C for 10 minutes. Then the resulting mixture was concentrated in vacuo to remove THF and MeOH. The mixture was acidified to pH 3 with HCl (6 M in H2O) aqueous solution. The precipitated solids were collected by filtration and washed with H2O (3 x 5 mL) to afford (2.0 g, 21% yield) of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid as a white solid. 1H NMR (400MHz, DMSO-d6) r *-'*, ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 (s, 1H), 8.86 (s, 1H), 7.49 – 7.36 (m, 5H), 5.05 (s, 2H), 2.49 (s, 3H). LCMS observed m / z = 245.10 [M+H]+. Intermediate B Synthesis of 3-bromo-1H-1,2,4-triazol-5-amine. Intermediate B A mixture of 5-amino-1H-1,2,4-triazole (50.0 g, 594.6 mmol), NaBr (152.9 g, 1486.6 mmol) and H2SO4 (145.8 g, 1486.6 mmol) in H2O (450 mL) was stirred at 25 °C for 10 minutes. To the mixture was added dropwise a solution of sodium bromate (44.8 g, 297.3 mmol) in H2O (150 mL) over 1 hour at 55-60 °C. The mixture was stirred at 55-60 °C for an additional 20 hours. The mixture was cooled to 0 °C and quenched with saturated sodium hyposulfite aqueous solution at 0 °C. The mixture was adjusted to pH 6 with 20% NaOH aqueous solution. The resulting mixture was concentrated in vacuo. The residue was washed by n-BuOH (750 mL) and EtOAc (1.5 L) in order. Then the solid was purified by trituration with dioxane (300 mL) at 80 °C. After filtration, the filter cake was vacuum-dried at 50-60 °C for 12 hours to afford (8.5 g, 8% yield) of 5-bromo-2H-1,2,4-triazol-3-amine as a white solid.1H NMR (400MHz, DMSO-d6# r *+'+ / "b% *=#% / '+2 "b% +=#' A8BH ^QbTaeTS m / z = 163.05 [M+H]+.Intermediate F Synthesis of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)- 2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1- carboxylate. Intermediate F A mixture of tert-butyl 4-{2-bromo-5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5-a]pyrimidin- 6-yl}piperazine-1-carboxylate (30.0 g, 70.2 mmol, Intermediate E) and DIPEA (27.2 g, 210.6 mmol) in DMF (30 mL) was treated with N-[2-chloro-4-(trifluoromethyl)phenyl]-2- ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 iodoacetamide (28.0 g, 77.2 mmol, Intermediate D) at 90 °C under N2 for 3.5 hours. The mixture was quenched with H2O (100 mL) at 25 °C and was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 50% EtOAc in petroleum ether) to afford (10.0 g, 21% yield) of tert-butyl 4-[2-bromo-4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate as an off-white solid. 1H NMR (400 MHz, DMSO-d6# r *)',- "b%1H), 8.09 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.7, 2.1 Hz, 1H), 5.32 (s, 2H), 3.96 – 3.93 (m, 2H), 3.39 (dd, J = 4.7, 2.2 Hz, 2H), 2.98 – 2.95 (m, 4H), 2.66 (d, J = 11.2 Hz, 2H), 1.44 (s, 9H), 1.17 (t, J = 7.4 Hz, 3H). LCMS observed m / z = 662.0 [M+H]+. Intermediate G Synthesis of 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide. Intermediate G of tert-butyl 4-[2-bromo-4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl]piperazine-1-carboxylate (4.8 g, 7.2 mmol, Intermediate F) in TFA (24 mL) and CH2Cl2(24 mL) was stirred at 25 °C under N2for 30 minutes. The mixture was concentrated in vacuo to afford (4.5 g crude) of 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide as the crude mixture and was used directly in the next step without further purification. LCMS observed m / z = 562.0 [M+H]+. Intermediate H Synthesis of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)- 2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Intermediate H A mixture of 2-[2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (1.5 g, 2.6 mmol, Intermediate G), HATU (1.5 g, 3.9 mmol) and DIPEA (1.7 g, 13.3 mmol) in DMF (15 mL) was stirred at 25 °C under N2 for 2.5 hours. The mixture was quenched with H2O (200 mL) at 25 °C and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 10% petroleum ether in EtOAc) to afford (749 mg, 33% yield) of 2-(6-{4-[5-(benzyloxy)-6- methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide as a white solid.1H NMR(400 MHz, CDCl3# r 1'11 "b% *=#% 1'1- "b% *=#% 1'-2 "S% J = 8.7 Hz, 1H), 7.70 (d, J = 2.1 Hz,1H), 7.59 – 7.55 (m, 1H), 7.50 – 7.39 (m, 5H), 5.22 – 5.19 (m, 1H), 5.16 – 5.06 (m, 3H), 4.81 – 4.79 (m, 1H), 3.80 – 3.76 (m, 2H), 3.44 – 3.29 (m, 2H), 3.15 (q, J = 7.5 Hz, 2H), 3.07 – 3.05 (m, 1H), 2.88 – 2.83 (m, 1H), 2.65 (m, 1H), 2.48 (s, 3H), 1.32 (t, J = 7.7 Hz, 3H). LCMS observed m / z = 788.40 [M+H]+. Intermediate R Synthesis of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)amino)ethyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate R ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Step 1: Preparation of 2-[2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien- 2-yl]acetamide. Intermediate R1 A mixture of tert-butyl 4-[2-bromo-5-ethyl-7-oxo-4-({[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]carbamoyl}methyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (1.5 g, 2.3 mmol, IntermediateF# X] =8[ "- B X] *%-&SX^gP]T% +) \A# b^[dcX^] fPb bcXaaTS U^a ,) \X]dcTb Pc +. {' IWTmixture was concentrated in vacuo to afford (1.3 g crude) of 2-[2-bromo-5-ethyl-7-oxo-6- (piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide. The crude product was used directly in the next step without further purification. LCMS observed m / z = 554.0 [M+H]+. Step 2: Preparation of 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide. Intermediate R ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 A mixture of 2-[2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide (1.3 g, 2.3 mmol) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (560 mg, 2.3 mmol, Intermediate A) in DMF (10 mL) was treated with HATU (1.1 g, 2.8 mmol) and DIPEA (1.5V% **'. \\^[# X] ^]T _^acX^] Pc +. { P]S bcXaaTS Pc +. { U^a * W^da' IWT \XgcdaT fPb SX[dcTSwith H2O (100 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by reversed phase C18 silica gel column chromatography (mobile phase: 50-99% MeOH in H2O) to afford (1.0 g, 53% yield) of 2-(6- {4-[5-(benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-bromo-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide as a white solid. 1H NMR (400 MHz, DMSO-d6# r *)'0* "b% *=#% 1'10 "b% *=#%7.55 – 7.48 (m, 3H), 7.48 – 7.38 (m, 4H), 5.22 – 5.06 (m, 4H), 4.57 (m, 1H), 3.48 (m, 2H), 3.37 (s, 1H), 3.27 (dd, J = 5.5, 2.9 Hz, 2H), 3.19 (q, J = 4.7, 4.2 Hz, 2H), 3.02 – 2.98 (m, 3H), 2.87 – 2.85 (m, 1H), 2.66 – 2.64 (m, 1H), 2.49 (s, 3H), 1.16 (t, J = 7.4 Hz, 3H). LCMS observed m / z = 780.30 [M+H]+. Intermediate S Synthesis of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)- 2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid. Intermediate S ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Step 1: Preparation of ethyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6- (piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate. Intermediate S1 A mixture of tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethoxy-2-oxoethyl)-5- ethyl-7-oxo-[1,2,4] triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (2.4 g, 4.6 mmol) in mixed solvent of CH2Cl2 (25 mL) and TFA (14 mL) was stirred at 25 °C for 40 minutes. The mixture was concentrated in vacuo to afford (1.9 g, crude) of ethyl 2-(2-(3,6-dihydro-2H- pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4] triazolo [1,5-a]pyrimidin-4(7H)- yl)acetate. The crude product was used directly in the next step without further purification. LCMS observed m / z = 417.1 [M+H]+. Step 2: Preparation of ethyl 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetate. Intermediate S2 ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 A mixture of ethyl 2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetate (1.9 g, 4.5 mmol), 5-(benzyloxy)-6- methylpyrimidine-4-carboxylic acid (1.2 g, 5.0 mmol, Intermediate A), DIPEA (2.9 g, 22.8 mmol) and HATU (2.6 g, 6.8 mmol) in DMF (25 mL) was stirred at 25 °C for 4 hours. The mixture was quenched with H2O (30 mL) at 25°C and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 5% MeOH in CH2Cl2) to afford (1.8 g, 61% yield) of ethyl 2-(6- {4-[5-(benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-(3,6-dihydro-2H-pyran- 4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetate as a brown yellow oil. LCMS observed m / z = 643.1 [M+H]+. Step 3: Preparation of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetic acid. Intermediate S A mixture of ethyl 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin- 1-yl}-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4- yl)acetate (1.8 g, 5.3 mmol) and LiOH.H2O (380 mg, 15.9 mmol) in THF (20 mL) and H2O (4 mL) was stirred at 40 °C for 6 hours. The mixture was concentrated in vacuo. The residue was purified by preparatory HPLC (column: XBridge BEH C18 OBD Prep Column 130, 5 m, 30 mm * 150 mm; mobile phase: 12-35% MeCN in H2O) to afford (911 mg, 50% yield) of (6-{4- [5-(benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-(3,6-dihydro-2H-pyran-4- yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetic acid as a white solid.1H NMR(400 MHz, Methanol-d4# r 1'1+ "b% *=#% 0'.- p 0',1 "\% .=#% / '20 p / '2, "\% *=#% .'+* p .'*+(m, 2H), 4.95 (d, J = 3.6 Hz, 2H), 4.70 – 4.67 (m, 1H), 4.34 (q, J = 2.8 Hz, 2H), 3.93 – 3.90 (m, 2H), 3.78 – 3.69 (m, 2H), 3.47 – 3.34 (m, 2H), 3.16 – 2.92 (m, 4H), 2.77 – 7.74 (m, 1H), 2.69 – 2.63 (m, 2H), 2.49 (s, 3H), 1.30 – 1.26 (m, 3H). LCMS observed m / z = 615.40 [M+H]+. ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Intermediate AB Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid Intermediate AB To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid, Intermediate A (30.0 g, 122 mmol, 1 eq) in EtOAc (150 mL) was added Pd / C (3.00 g, 2.82 mmol, 10% purity, 2.30e-2eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 28 °C for 4 hrs. TLC (Dichloromethane / Methanol = 5 / 1) indicated Intermediate A consumed completely and one new spot formed. The mixture was filtrated through a pad of Celite and washed with MeOH (3 times 200 mL), then was concentrated under reduced pressure to give a residue. The crude product (14.5 g, 94.0 mmol, 76.6% yield) was used into the next step without further purification and obtained as a reddish solid. LCMS observed m / z = 153.14 [M–H]–. Intermediate AC Synthesis of 2-(2-bromo-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide Intermediate AC In a 250 mL round bottom flask equipped with a stir bar was added 5-hydroxy-6- methylpyrimidine-4-carboxylic acid, Intermediate AB (1.75 g, 11.4 mmol) and CH2Cl2(75 mL). The mixture was allowed to stir at room temperature for 2 minutes to form a slurry, then Ghosez reagent (1.80 mL, 13.6 mmol) was added dropwise at room temperature via syringe over a period of 5 minutes. The reaction mixture was allowed to stir at room temperature. After 1.5 hours, the reaction mixture was a homogeneous brown solution. In a separate 500 mL round bottom flask equipped with a stir bar was added 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)- ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide, Intermediate G (4.52 g, 7.54 mmol), CH2Cl2(60 mL), and DIPEA (7.9 mL, 45.3 mmol). The mixture was allowed to stir at room temperature for 5 minutes to form a suspension, then cooled to -10 C via brine / ice bath. The reaction vessel was fitted with an addition funnel, and the reaction mixture containing above reaction mixture was transferred to the addition funnel, rinsing with CH2Cl2(3 x 2 mL). The reaction mixture was allowed to stir at -10 C. After 1.5 hours, the reaction mixture was diluted with 1:1 H2O : saturated aqueous NH4Cl (100 mL) and the phases were partitioned. The organic layer was washed with water (1 x 100 mL), and the combined aqueous layers were further extracted with 3:1 CHCl3 : i-PrOH (3 x 200 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (1 x 200 mL), brine (1 x 200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The combined crude residue was purified by column chromatography (SiO2, 1% to 10% MeOH in CH2Cl2)affording Intermediate AC (5.01 g, 96% yield). LCMS observed m / z = 698.10 [M+H]+.Intermediate AD Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)piperazine-1-carboxylate Intermediate AD To a solution of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate F (77.6 g, 117 mmol, 1 eq) and thecorresponding boronate ester (30.2 g, 122 mmol, 1.05 eq) in dioxane (776 mL) and H2O (115 mL) was added K3PO4 (74.5 g, 351 mmol, 3 eq) and Pd(dppf)Cl2 (4.28 g, 5.85 mmol, 0.05 eq) under N2. The mixture was stirred at 80 °C for 16 hrs under N2. The residue was diluted with water (1200 mL) and extracted with ethyl acetate (1200 mL * 4). The combined organic layers were washed with aq. NaCl (1200 mL), dried over Na2SO4, filtered and concentrated under ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 reduced pressure to give a residue. TLC (Petroleum ether: Ethyl acetate = 1: 1, Rf / product = 0.40). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, CH2Cl2) at twice. The product was dissolved with CH2Cl2(1.5 L). The mixture was added Pd scavenger (70.0 g) and stirred at 38 °C for 30 mins, filtered and concentrated under the reduced pressure to give tert-butyl 4-(4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7- oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (67.0 g, 95.4 mmol, 81.5% yield) as a white solid. LCMS: m / z = 646.4 [M-56+1]+. Intermediate AE Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3-dihydroisobenzofuran- 5-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide Intermediate AE To a solution of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate AD (74.6 g, 106 mmol, 1 eq) was added HCl / dioxane (2 M, 746 mL, 14.04 eq) in portions. The mixture was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. N- (2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-6- (piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (68.1 g, crude, HCl) was obtained as a white solid. LCMS: m / z = 602.2 [M+1]+. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate Intermediate AF ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 To a solution of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate F (10.0 g, 15.1 mmol, 1 eq) and thecorresponding boronic acid (2.9 g, 15.1 mmol, 1.0 eq) in dioxane (50 mL) and H2O (15 mL) was added K3PO4 (9.61 g, 45.3 mmol, 3 eq) and Pd(dppf)Cl2 (616 mg, 0.754 mmol, 0.05 eq) under N2. The mixture was stirred at 80 °C for 16 hrs under N2. The residue was diluted with water (120 mL) and extracted with ethyl acetate (120 mL * 4). The combined organic layers were washed with aq. NaCl (120 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. TLC (Petroleum ether: Ethyl acetate = 1: 1, Rf / product = 0.40). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, CH2Cl2). The product was dissolved with CH2Cl2 (1.5 L). The mixture was added Pd scavenger (10.0 g) and stirred at 38 °C for 30 mins, filtered and concentrated under the reduced pressure to givetert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (8.33 g, 11.4 mmol, 75.6% yield) as a white solid. LCMS: m / z = 674.2 [M-56+1]+. Intermediate AG Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,1-dimethyl-1,3- dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide Intermediate AG ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 To a solution of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate AF (8.33 g, 11.4 mmol, 1 eq) was added HCl / dioxane (4 M, 21 mL, 50 eq) in portions. The mixture was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,1-dimethyl-1,3- dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin- 4(7H)-yl)acetamide (7.7 g, crude, HCl) was obtained as a white solid. LCMS: m / z = 630.2 [M+1]+. 1.1 Example 1Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Compound 1 of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide. Compound 1.1 ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 To a mixture of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)piperazine-1-carboxylate (125 mg, 0.158 mmol, Intermediate F), (2,3- dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (42.8 mg, 0.238 mmol) and Cs2CO3(33.6 mg, 0.317 mmol) in a mixture of dioxane (1.5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2.CH2Cl2 (12.9 mg, 0.0158 mmol). The mixture was stirred at 100 °C under N2 for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 and filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: 10-75% EtOAc in Hexanes) to afford (70.4 mg, 75% yield) of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide as a brown solid. LCMS observed m / z = 844.3 [M+H]+. Step 2: Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Compound 1 To a mixture of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin- ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (70.4 mg, 0.0834 mmol) in CH2Cl2(1.67 mL) was added dropwise a 1 molar solution of boron trichloride in CH2Cl2(0.5 mL, 0.5 mmol). The mixture was stirred at -40 °C under N2for 15 minutes. The mixture was quenched with MeOH (1.0 mL) and warmed to 25 °C. The mixture was concentrated in vacuo and the residue was purified by preparatory HPLC (mobile phase: 0-100% MeCN in H2O) to afford (8.2 mg, 12.% yield) of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide as a whitesolid. 1H NMR (400MHz, DMSO-d6) r *)'-) "b% *=#% 1'. / "b% *=#% 1') / "S% ? 5 1' / =i% *=#%7.96 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 5.37 (s, 2H), 4.53 (d, J = 12.5 Hz, 1H), 4.29 (s, 4H), 3.52 (q, J = 11.9 Hz, 3H), 3.24 (d, J = 12.4 Hz, 2H), 3.01 (d, J = 10.0 Hz, 3H), 2.83 (d, J = 11.3 Hz, 1H), 2.66 (d, J = 10.9 Hz, 1H), 2.44 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H). LCMS observed m / z = 754.3 [M+H]+. 1.2 EXAMPLE 3Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(isochroman-6-yl)-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide. Compound 3 The title compound was prepared using similar procedure as Example 1, replacing (2,3- dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid with 2-(isochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6# r *)'-- "b% *=#% 1'-1 "b% *=#% 1', / "b%1H), 8.06 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.90 (s, 2H), 7.72 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 5.40 (s, 2H), 4.74 (s, 2H), 4.55 (d, J = 12.6 Hz, 1H), 3.91 (t, J = 5.8 Hz, 2H), 3.53 (d, J = 12.7 Hz, 3H), 3.03 (d, J = 10.3 Hz, 3H), 2.85 (d, J = 15.4 Hz, 3H), 2.68 (s, 1H), 2.42 (s, 3H), 1.22 (t, J = 7.8 Hz, 3H). LCMS observed m / z = 752.55 [M+H]+. 1.3 EXAMPLE 11 ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2,3-dihydrobenzofuran-5- yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Compound 11 The title compound was prepared using similar procedure as Example 1, replacing (2,3- dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid with 2-(2,3-dihydro-1-benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, CDCl3# r **'1- "b% *=#% 2'+, "b%1H), 8.62 (s, 1H), 8.53 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.7, 2.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.72 – 5.68 (m, 1H), 5.18 (s, 2H), 4.85 – 4.81 (m, 1H), 4.68 (t, J = 8.7 Hz, 2H), 3.88 – 3.84 (m, 2H), 3.56 – 3.52 (m, 1H), 3.34 - 3.19 (m, 4H), 3.10 (s, 1H), 2.86 – 2.81 (m, 2H), 2.59 (s, 3H), 1.38 (t, J = 7.5 Hz, 3H). LCMS observed m / z = 738.15 [M+H]+. 1.4 EXAMPLE 13Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3-dihydroisobenzofuran- 5-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Compound 13 The title compound was prepared using similar procedure as Example 1, replacing (2,3- dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid with 2-(1,3-dihydroisobenzofuran-5-yl)- ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT24,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6# r *)',+ "b% *=#% 1'.-(s, 1H), 8.12 – 8.01 (m, 3H), 7.98 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.8, 2.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 5.40 (s, 2H), 5.07 (d, J = 5.3 Hz, 4H), 4.60 – 4.49 (m, 1H), 3.64 – 3.45 (m, 4H), 3.27 – 3.24 (m, 1H) 3.03 (d, J = 9.8 Hz, 3H), 2.88 – 2.82 (m, 1H), 2.71 – 2.65 (m, 1H), 2.44 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H). LCMS observed m / z = 738.20 [M+H]+. 1.5 EXAMPLE 32Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4- yl)-5-ethyl-6-(4-(3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2- carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Compound 32 Step 1: Preparation of 2-(6-(4-(3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1- c][1,4]oxazine-2-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide. Compound 32.1 A mixture of 3-(benzyloxy)-4-oxo-6H,7H,9H-pyrimido[2,1-c][1,4]oxazine-2- carboxylic acid (19 mg, 0.1 mmol, Intermediate L) and HATU (26 mg, 0.06 mmol) in DMF (10 mL) was added N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-(3,6-dihydro-2H-pyran-4- yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (30 mg, ATTORNEY DOCKET PATENT APPLICATION 092295.0180 CLIENT REF. EIK-0019-PCT2 0.05 mmol, Intermediate K) and the mixture was stirred at 25 °C under N2 for 2 hours. The mixture was quenched with H2O and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford (40 mg crude) of 2-(6-{4-[3-(benzyloxy)-4-oxo- 6H,7H,9H-pyrimido[2,1-c][1,4]oxazine-2-carbonyl]piperazin-1-yl}-2-(3,6-dihydro-2H- pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-4- (trifluoromethyl)ph...

Claims

CLAIMS:

1. A compound, or a pharmaceutically acceptable salt thereof, selected from:

2. A compound, or a pharmaceutically acceptable salt thereof, selected from:

3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

4. A compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

5. A compound, or a pharmaceutically acceptable salt thereof, is:

6. A compound, or a pharmaceutically acceptable salt thereof, is:

7. A combination comprising a compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, and one or more additional active agents.

8. The combination according to claim 7, wherein an additional active agent is an anticancer agent.

9. The combination according to claim 8, wherein an additional active anti- cancer agent is a chemotherapy.

10. A pharmaceutical composition comprising according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

11. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, for use as a medicament.

12. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, for use according to claim 11, wherein the use is for the treatment of a disease.

13. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, for use according to claim 11 or 12, wherein the use is for the treatment of cancer.

14. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, for use according to claim 13, wherein the cancer is characterized as microsatellite instability -high (MSI-H) and / or mismatch repair deficient (dMMR).

15. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof, for use according to claim 14 wherein the cancer characterized as microsatellite instability -high (MSI-H) and / or mismatch repair deficient (dMMR) is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer.

16. A method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof.

17. A method of inhibiting WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof.

18. A method of treating a disorder or disease with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof.

19. A method of treating cancer with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof.

20. A method of treating cancer with a WRN inhibitor in a subject, comprising administering a compound according to any of claims 1-6, or a pharmaceutically acceptablesalt thereof, wherein the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR).

21. The method according to claim 20, wherein the cancer characterized as microsatellite instability -high (MSI-H) and / or mismatch repair deficient (dMMR) is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer.

22. The use of a compound according to any of claims 1-6, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

23. The use of a compound according to any of claims 1-6, or pharmaceutically acceptable salt thereof, according to claim 22, wherein the cancer is characterized as microsatellite instability -high (MSI-H) and / or mismatch repair deficient (dMMR).

24. A process to manufacture a compound according to any of claims 1-6, or a pharmaceutically acceptable salt thereof.

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