Inhibitors of bunyaviruses

Abstract

The present invention is related to the development of therapeutics and prophylactics for the treatment and / or prevention of bunyavirus infection in humans and other mammals. A new class of small molecules is disclosed that inhibits the bunyavirus endonucleases. Also disclosed are methods of using the small molecule inhibitors in the treatment / prevention of bunyavirus infection.

Description

[0001] INHIBITORS OF BUNYA VIRUSES

[0002] Cross-Reference to Related Applications

[0003] The present application claims the benefit under 35 U. S. C. 119(e) of U. S. Provisional Patent Application No. 63 / 747,195, inventors Gai Liu et al., filed January 20, 2025, the disclosure of which is incorporated herein by reference.

[0004] Statement Regarding Federally Sponsored Research

[0005] This invention was made with government support under grant 1R41AI165102-01A1 awarded by NIH. The United States government has certain rights in the invention.

[0006] Field of the Invention

[0007] This invention is in the field of therapeutic and prophylactic drugs to treat bunyavirus infections and disease. In particular, the invention describes a novel spiro-piperidine pyrido pyrimidine series of compounds that inhibit bunyaviral endonuclease activity and are effective for the treatment or prevention of bunyaviral infections, including Rift Valley Fever Virus (RVFV).

[0008] Background of the Invention

[0009] In mammals, 5’ cap recognition is widely used by cytosolic innate immune proteins to determine whether an mRNA transcript is self or non-self. To avoid activating host innate responses and ensure translation of viral genes, viruses must “make it or break it,” i.e., synthesize a host-like 5’ cap or break off existing 5’ caps from host transcripts. The latter occurs via a process called cap-snatching, which is performed by many viruses of medical importance. This process not only facilitates the generation of viral mRNAs, but also leads to the downregulation of host mRNA. This dual function can further limit host innate immune responses (1). Cap-snatching was first described and is best understood in the context of Influenza A virus (IAV), a member of the family Orthomyxoviridae. The influenza PA protein contains an N-terminal endonuclease (EN) domain which chelates divalent metal cations, particularly manganese (Mn2+) and magnesium (Mg2+), to perform its cap-snatching action. A C-terminal cap-binding domain captures the 5’ cap so it can be used as the initiation site for viral transcription by the RNA-dependent RNA polymerase (RdRp) domain, resulting in a host-capped viral transcript capable of evading recognition by host innate immune proteins (1, 2).The cap-snatching mechanism is not unique to influenza and can be found in other orthomyxoviruses, some arenaviruses, and many members of family Bunyaviridae. Bunyaviruses including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), Rift Valley fever vims (RVFV) and Heartland vims (HRTV), are predominantly arthropod-borne, segmented negative-sense viruses (sNSVs) with tripartite RNA genomes, wide geographic distributions, and a history of severe human disease (3). Epizootic outbreaks of RVFV have occurred in livestock in Africa and the Middle East since the first reported outbreak in Kenya’s Rift Valley in 1931 (World Health Organization, 2018). These outbreaks cause spontaneous abortion rates of up to 100% in pregnant animals and fatality rates greater than 90% in young animals, causing significant socioeconomic impact (4)(World Health Organization, 2018). Zoonotic RVFV outbreaks occur in humans through mosquito-vectored transmission or direct contact with the blood of infected animals, with severe cases progressing to ocular, hemorrhagic fever, or meningoencephalitis forms (World Health Organization, 2018). Closely related to RVFV, SFTSV is an emerging tick-borne vims that causes severe fever with thrombocytopenia syndrome (SFTS). Though the syndrome was first identified in the mral Hubei and Henan provinces of China in 2009 and the causative agent found to be SFTSV in 2011, the vims has since spread to other Chinese provinces and to Japan, South Korea, Vietnam, Myanmar, Thailand, and Taiwan, with case fatality rates as high as 45.7% (5, 6, 7). While most human SFTSV cases are zoonotic, either from infected ticks or direct contact with infected livestock, retroactive sera analyses revealed that person-to-person transmission of SFTSV through blood contact has occurred since at least 2006 (6). HRTV, another tick-borne bunyavims, was discovered in 2009 in the US with symptoms similar to those of SFTSV. There have been over 60 human cases reported in thirteen states in the US with a case fatality rate -12% (8, 9). No reservoir host has been identified, however, wildlife animals such as deer, raccoon and moose are positive for antibodies to HRTV (10).

[0010] These bunyavimses have no specific medical countermeasures, with no human prophylactic or therapeutic treatments available. Scientists seek to fill this significant gap in part by high-throughput screens (HTSs) aimed at identifying novel or existing compounds which can be used as antivirals. Like IAV-PA, SFTSV-L and RVFV-L have N-terminal EN domains with metal-dependent RNase activity which are responsible for cleaving 5’ caps from captured mRNAs. Available crystal structures and sequence alignments of these EN domains reveal key residues within this pocket are highly conserved across cap-snatching sNSVs (2, 11, 12, 13, 14). This is especially significant because the FDA-approved antiviralpro-drug, baloxavir marboxil (BXM), effectively reduces IAV replication by targeting this conserved interface (14, 15). Therefore, endonuclease inhibitors can make excellent antivirals.

[0011] Previous literature presents EN activity assays which are not practical for a high-throughput screen due to costly materials, lack of time course readouts, or poor scalability (12, 16, 17, 18, 19). Our group previously adapted a fluorescence resonance energy transfer (FRET)-based IAV-PA activity assay to monitor activity of purified SFTSV-EN (14).

[0012] Therefore, currently there is a need for safe and effective methods for the treatment and prevention of bunyaviral infections, including RVFV.

[0013] Summary of the Invention

[0014] The present invention is directed to the identification, isolation, and characterization of small molecule inhibitors of bunyavirus infections for use in the treatment and / or prevention of bunyavirus infections in mammals, and in particular the treatment and / or prevention of bunyavirus infections in humans. In a preferred embodiment, the present invention is directed to the isolation of compounds suitable for the treatment or prevention of Rift Valley Fever Virus (RVFV).

[0015] Herein, we describe a scalable high-throughput FRET-based bunyaviral endonuclease activity assay which, in conjunction with established cellular and biochemical techniques, identifies novel bunyaviral endonuclease inhibitors which show promise for use in anti-bunyaviral therapies.

[0016] As a result, a novel spiro-piperidine pyrido pyrimidine series of compounds that inhibit bunyaviral endonuclease activity were identified. This novel series of compounds are exemplified by the following compounds:

[0017] MBX# Structure

[0018]

[0019]

[0020] Therefore, the present invention is related to the discovery of novel small molecule bunyavirus endonuclease inhibitors. The inhibitors described herein are suitable for the treatment and / or prevention of bunyavirus infections in mammals. More particularly, the inhibitors described herein are suitable for the treatment and / or prevention of bunyavirus infections in humans.

[0021] In another embodiment, the present invention is directed to a composition for treating or preventing bunyavirus infection, the composition comprising a novel small moleculebunyavirus endonuclease inhibitor. The compositions described herein are suitable for the treatment or prevention of bunyavirus infections in mammals, and in particular, humans.

[0022] In another embodiment, the present invention is directed to a method for treating or preventing bunyavirus infections in a mammal by administration of the novel bunyavirus inhibitors of the present invention. In a preferred embodiment, the mammal is a human.

[0023] In another embodiment, the present invention is directed to the use of the bunyavirus inhibitors described herein in the manufacture of a medicament for use in the treatment or prevention of a bunyavims infection in a mammal. In a preferred embodiment, the mammal is a human.

[0024] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a novel bunyavirus inhibitor compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions are suitable for use in the disclosed methods for treating or preventing bunyavirus infections in a mammal. The pharmaceutical compositions may be formulated for both parenteral and / or non-parenteral administration to a subject or patient in need thereof.

[0025] More particularly, the invention is related to the identification of small molecule inhibitors for treating and / or preventing bunyavirus infections, preferably an infection caused by Rift Valley Fever virus (RVFV), thrombocytopenia syndrome virus (SFTSV) or heartland virus (HRTV). More particularly, the present invention is directed to the identification and characterization of small molecule bunyavirus inhibitors suitable for the treatment and / or prevention of an infection caused by Rift Valley Fever vims.

[0026] In another embodiment, the small molecule inhibitors of the present invention may be administered to a subject in need thereof optionally in combination with one or more known additional antiviral agents.

[0027] In another embodiment, the small molecules of the present invention are formulated into a pharmaceutically acceptable carrier and are applied / administered to a subject in need thereof by an injection, including, without limitation, intradermal, transdermal, intramuscular, intraperitoneal and intravenous. According to another embodiment of the invention, the administration is oral, and the compound may be presented, for example, in the form of a tablet or encased in a gelatin capsule or a microcapsule, which simplifies oral application. The production of these forms of administration is within the general knowledge of a technical expert. Multiple routes of administration are envisioned for these drug-like molecules, and highly cost-effective production strategies can be easily achieved.In a preferred embodiment, the bunyavims inhibitor compounds of the present invention exhibit an inhibitory concentration of <10pM against bunyavirus endonuclease and a cytotoxicity (CC50) of >100pM.

[0028] In one embodiment, a bunyavirus inhibitor compound of the present invention comprises a compound selected from the following:

[0029] A compound of Formula I:

[0030] Formula I

[0031]

[0032] or a pharmaceutically acceptable salt, polymorphs, racemic mixtures, enantiomers, diastereomers, tautomers and combinations thereof, wherein:

[0033] Ri and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(0)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0034] R1and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 memberedcycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(Ci4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0035] K is selected from N or CH;

[0036] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are

[0037]

[0038] independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(C1-3alkyl or branched alkyl), -S(C1-3alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI_4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and

[0039] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, - S(O)2NH-;

[0040] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituentsselected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0041] X is independently selected from the group consisting of N, O, S, -NH-, N(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0042] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0043] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.A compound of general Formula II

[0044] Formula II

[0045]

[0046] Wherein Ri and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, - NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(0)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(0)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0047] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl,heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C 1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(Cy alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0048] P is selected from NH, CH2, O, S, S(O)2and B is fused to ring A and directly fused to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- and may also include E / Z isomers of substituents W;

[0049] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl), -C(O)NHS(O)2(Ci.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are

[0050]

[0051] independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(Ci.3alkyl or branched alkyl), -S(C]_3alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(Ci_4 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and

[0052] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0053] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0054] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0055] The compound wherein ring C can be asymmetric and and is comprised independently of isomers of Formula III or Formula IV,F

[0056]

[0057] ormula III

[0058] wherein, ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0059]

[0060] The compound with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,

[0061]

[0062] -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;R1and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0063] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine: and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0064] Ring B - wherein K = N or CH can be fused to ring A and consisting of R3 substitutions as defined below and directly connected to ring C in a spirocyclic manner and can be connected to ring D through X and W.

[0065] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0066] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0067] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0068] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0069] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0070] The compound wherein ring C can be asymmetric and is comprised independently of isomers of Formula V and Formula VI,

[0071]

[0072] wherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0073]

[0074] The compound with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,

[0075] R4 R4 A, cx) Ac A., G A, c rv )

[0076]

[0077] \ \x—z\ ~Q> -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -0(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl oraryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0078] Ri and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0079] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl )2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0080] Ring B wherein P can be substituted with NH, CH2, O, S, S(O)2and fused to ring A and consisting of R3 substitutions as defined below and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formula II and in case of Formula II can also include E / Z isomers of substituents W;

[0081] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1 -6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0082] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0083] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0084] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-. -S(O)2-, -S(O)2NH-;

[0085] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0086] In another embodiment, the compound has the general Formula VII

[0087] R3

[0088] Formula VII

[0089] N X

[0090] W,

[0091]

[0092] D

[0093] Wherein

[0094] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted withone or two heteroatoms consisting of -O-, -S-, -Nil-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(0)NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-

[0095] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0096] Ring B can be a dihydropyrazine fused to ring A and can be connected to spirocyclc ring C and can be connected to ring D through X and W;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(C1-3alkyl or

[0097]

[0098] b

[0099]

[0100] ranched alkyl), -S(Ci.3alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(CWalkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI_4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(CMalkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CWalkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and

[0101] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl orheteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0102] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0103] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0104] X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0105] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0106] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkylor cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0107] In another embodiment, compound has the general Formula VIII

[0108]

[0109] Formula VIII

[0110] Wherein

[0111] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CMalkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.

[0112] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0113] Ring B can be a 1,2, 3, 4 tetrahydropyrazine fused to ring A and consisting of R3 substitutions and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formula II and in case of Formula II can also include E / Z isomers of substituents W

[0114]

[0115] Rs - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(0)NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0116] Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused andeach of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(Ci-3 alkyl or branched alkyl), -S(Ci-3 alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and W linker connecting ring C and ring E can be selected independently from a group consisting of alkyl carbon chains of 1-8 carbon length which can be a straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0117] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0118] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0119] The compound of Claim 7 wherein ring C can be asymmetric and is comprised independently of isomers of Formula IX and X

[0120]

[0121] wherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0122]

[0123] The compound with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,

[0124]

[0125] -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0126] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heleroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heleroaryl), -C(0)N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C]_4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C^ alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.

[0127] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0128] Ring B can be a dihydropyrazine fused to ring A and can be connected to spirocycle ring C and can be connected to ring D through X and W;

[0129] R3- is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl orheteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0130] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0131] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0132] X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0133] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0134] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1 -6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkylor cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0135] The compound of Claim 8 wherein ring C can be asymmetric and is comprised independently of isomers of Formula XI and XII

[0136]

[0137] Formula XII

[0138] wherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0139]

[0140] The compound with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(0)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI_4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl), -NHS(O)2(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl) or -S(0)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2:

[0141] 10

[0142]

[0143] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.

[0144] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0145] Ring B can be a 1,2, 3, 4 tetrahydropyrazine fused to ring A and consisting of R3 substitutions and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formulae XI and XII and in case of Formulae XI and XII can also include E / Z isomers of substituents W

[0146] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(0)20II; -0(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(0)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0147] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NII-, -S(O)2-, -S(O)2NH-;

[0148] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or hctcroaryl)2;

[0149] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0150] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heleroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkylor cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NIIS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0151] In another embodiment, the compound has the general Formula XIII

[0152] Formula XIII

[0153]

[0154] wherein

[0155] Ring A can be a pyridine

[0156] Ring B can be a tetrahydropyrazine fused to ring A and connected to spirocyclic piperidine ring C

[0157] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; Ring Ring E can be selected from a group consisting of aryl or heteroaryl and can be substituted with alkyl, halogen, and alkoxy;

[0158] Ring D can be selected from a group consisting of cycloalkyl;

[0159] In another embodiment, the compound has the general Formula XIV

[0160] Formula XIV

[0161]

[0162] Ring A can be a pyridine

[0163] Ring B can be a piperazine fused to ring A and connected to spirocyclic piperidine ring C Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0164] Ring E can be selected from a group consisting of aryl or heteroaryl and can be substituted with alkyl, halogen, and alkoxy;

[0165] Ring D can be selected from a group consisting of cycloalkyl;

[0166] In another embodiment, the present invention is directed to a composition for preventing or treating a bunyavirus infection, the composition comprising at least one compound according to Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV formulated into a pharmaceutically acceptable earner or excipient for parenteral and / or nonparenteral administration.

[0167] In yet another embodiment, the present invention is directed to a method for treating or preventing bunyavirus infections in a mammal by administration of a composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV. In a preferred embodiment of such method, the mammal is a human.

[0168] A fluorescence resonance energy transfer (FRET) assay was used to identify the novel inhibitors described herein. This FRET assay was designed to be specific against the recently characterized enzymatic activity of RVFV endonuclease.

[0169] Definitions

[0170] A composition or method described herein as "comprising" (or "comprises") one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising" one or more named elements or steps also describes the corresponding, more limited, composition or method "consisting essentially of" (or "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consistingessentially of" one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method "consisting of" (or "consists of") the named elements or steps to the exclusion of any other element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step, respectively.

[0171] As used herein, the term 'subject' can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. A 'patient' or 'subject in need thereof refers to a mammal afflicted with a disease or disorder. The term 'patient' includes human and veterinary subjects.

[0172] Terms such as 'parenteral', 'parenterally', and the like, refer to routes or modes of administration of a compound or composition to an individual other than along the alimentary canal. Examples of parenteral routes of administration include, without limitation, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intra-arterial (i.a.), intraperitoneal (i.p.), transdermal (absor tion through the skin or dermal layers), nasal ('intranasal'; absorption across nasal mucosa), or pulmonary (e.g., inhalation for absorption across the lung tissue), vaginal, direct injections or infusions into body cavities or organs other than those of the alimentary canal, as well as by implantation of any of a variety of devices into the body (e.g., of a composition, depot, or device that permits active or passive release of a compound or composition into the body).

[0173] The terms 'non-parenteral', 'non-parenterally', 'enteral', 'enterally', 'oral', 'orally', and the like, refer to administration of a compound or composition to an individual by a route or mode along the alimentary canal. Examples of enteral routes of administration include, without limitation, oral, as in swallowing solid (e.g., tablet) or liquid (e.g., syrup) dosage forms, sublingual (absorption through the mucosal membranes lining the floor of the mouth, e.g., under the tongue), buccal (absorption through the mucosal membranes lining the cheeks), nasojejunal or gastrostomy tubes (delivery into the stomach), intraduodenal administration, as well as rectal administration (e.g., suppositories for release of a drug composition into and absorption by the lower intestinal tract of the alimentary canal).

[0174] In the present description, in a structural formula allowing for one or more substituents at a given position and listing suitable substituents, it will be understood that substituents may be "stacked" or combined to form compound substituents. For example, a listing of suitable substituents including alkyl and aryl substituents, aralkyl and alkaryl substituents are also contemplated.

[0175] The term 'hydrogen' is intended to mean a hydrogen radical.The term 'halo' or 'halogen' means fluorine, chlorine, bromine, or iodine.

[0176] The term 'alkyl' as used herein is intended to mean a branched, straight-chain, or cyclic saturated hydrocarbon group of 1 to 24 carbon atoms, preferably 1-10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, v-bulyl, / -butyl, n-pentyl, isopentyl,.s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the "substituted alkyl" group denotes an alkyl group substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or amido groups.

[0177] The term 'sulfonyl' is intended to mean a sulfur radical that is doubly bound to two oxygens (-SO2-). A sulfonyl group may be linked via the sulfur atom with an amino, alkylamino, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety to produce a monovalent radical.

[0178] The term 'sulfinyl' is intended to mean a sulfur radical that is doubly bound to one oxygen (-S(O)-), and the sulfur atom may be substituted with an amino, alkylamino, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety to produce a monovalent radical.

[0179] The term 'hydroxyl' or 'hydroxy' is intended to mean the radical -OH.

[0180] The term 'alkoxy' is intended to mean the radical -OR, where R is an alkyl or cycloalkyl group.

[0181] The term 'haloalkyl' is intended to mean an alkyl moiety wherein one or more hydrogen atoms is replaced with the same or different halogen atoms, e.g., -CH2C1, -CF3, -CH2CF3, -CH2CCI3, and the like.

[0182] The term 'haloalkoxy’ is intended to mean an alkoxy radical wherein one or more hydrogen atoms are replaced with the same or different halogen atoms, e.g. -OCHF2, -OCF3, -OCH2CF3, -OCH2CCI3, and the like.

[0183] The term 'alkenyl' is intended to mean a straight-chain, branched, or cyclic hydrocarbon radical having from 2-8 carbon atoms and at least one double bond, e.g., ethenyl, 3-buten-l-yl, 3-hexen-l-yl, cyclopent- l-en-3-yl, and the like. The alkenyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, amido, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, hydroxy, ketone, or thiol.The tern 'alkynyl' is intended to mean a straight-chain or branched hydrocarbon radical having from 2-8 carbon atoms an at least one triple bond, e.g., ethynyl, 3-butyn-l-yl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, amido, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, hydroxy, ketone, azide, nitro, or thiol, as described herein.

[0184] The term "carbon substituent" is intended to refer to substituent groups wherein the first atom of the substituent bound at the site of attachment is carbon, e.g., as in -CH3(methyl), -COOII (carboxyl), -Cells (phenyl), -ON (cyano), etc., which may contrasted with "nitrogen substituents" such as -NH2(amino), -NO2(nitro), etc., wherein the first atom bound at the site of attachment is nitrogen.

[0185] The tern 'cycloalkyl' is intended to mean a non-aromatic monovalent cyclic or polycyclic hydrocarbon radical having from 3-12 carbon atoms. 'Substituted cycloalkyl' groups, e.g., substituted cyclopentyl, cyclohexyl, decalinyl, may be substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or amido cycloalkyl, alkoxy, amino, ether, hydroxy, or thiol as described herein.

[0186] The term 'heterocycloalkyl' is intended to mean a non-aromatic monovalent monocyclic or polycyclic radical having from 2-12 carbon atoms, and 1-5 heteroatoms selected from nitrogen (N), oxygen (O), or sulfur (S). 'Substituted heterocycloalkyl' groups, e.g., substituted pyrrolodinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxiranyl groups, and the like, may be substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or amido, cycloalkyl, alkoxy, amino, ether, hydroxy, or thiol as described herein.

[0187] The term 'aryl' is intended to mean an aromatic, monovalent monocyclic or polycyclic radical comprising from 5 and 18 carbon ring members, e.g., phenyl, biphenyl, naphthyl, phenanthryl, and the like. A 'substituted aryl' group is an aryl group substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or amido, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, carboxylic acid, ester, ether, hydroxy, ketone, or thiol as described herein. In addition, the aryl group can be asingle ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.

[0188] The term 'heteroaryl' is intended to mean an aromatic, monovalent monocyclic or polycyclic radical comprising from 3 and 18 carbon ring members and at least 1 heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), e.g., pyridyl, pyrazinyl, pyridizinyl, pyrimidinyl, furanyl, thienyl, triazolyl, quinolinyl, imidazolinyl, benzimidazolinyl, indolyl, and the like. 'Substituted heteroaryl' is a heteroaryl group substituted with one or more groups including, but not limited to, alkyl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, amido, cycloalkyl, amino, ether, hydroxy, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems.

[0189] The term 'aryloxy' is intended to mean the radical -OAr where Ar is an aryl group. The term 'heteroaryloxy' is intended to mean the radical -O(heteroAr) where heteroAr is a heteroaryl group.

[0190] The term 'acyl' is intended to mean a -C(O)R radical, where R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, e.g. acetyl, benzoyl, and the like.

[0191] The term 'alkoxycarbonyl' is intended to mean a RO-C(O)- radical where R is alkyl or cycloalkyl.

[0192] The term 'alkylcarbonyl' refers to a RC(O)- radical where R is alkyl or cycloalkyl. The term 'aryloxycarbonyl' is intended to mean a RO-C(O)- radical where R is aryl; 'heteroaryloxycarbonyf refers to a radical of the same structure RO-C(O)- where R is heteroaryl.

[0193] The term 'amino' is intended to mean the radical -NH2.

[0194] The term 'alkylamino' is intended to mean the radical -NHR where R is an alkyl group, or -NRR', where R and R’ are each independently, hydrogen or alkyl. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentylamino, isopentylamino, (tert-pentyl)amino, hexylamino, dimethylamino, methylethylamino, diethylamino, methylpentylamino, and the like.

[0195] The term 'acylamino' is intended to mean the radical -NHC(O)R, where R is a monovalent organic radical such as, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.The term 'amido' in intended to mean the radical -C(O)NRR’ where R and R' are, independently, hydrogen, or monovalent organic radicals, such as, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.

[0196] The term 'alkyl sulfonyl' is intended to mean the radical -SO2R where R is a monovalent organic radical such as, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.

[0197] The term 'sulfonylamino' is intended to mean the radical -NHSO2R where R is a monvalent organic radical such as, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.

[0198] The term 'aminosulfonyf is intended to mean the radical -SO2NRR' where R and R' are, independently, hydrogen, or a monovalent organic radical such as, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, or heterocycloalkyl.

[0199] The term 'sulfhydryl' or 'mercapto' is intended to mean the radical -SH.

[0200] The term 'alkylthio' is intended to mean the radical -SR where R is an alkyl or cycloalkyl group.

[0201] The term 'arylthio' is intended to mean the radical -SAr where Ar is an aryl group.

[0202] Brief Description of the Drawings

[0203] FIGS. 1A through IF: Hit compound MBXC-4522 inhibits RVFV-EN activity in biochemical assays. (FIG. 1A) Line drawing of the chemical structure of hit compound MBXC-4522. (FIG. IB) Pilot HTS assay shows that MBXC-4522 has a dose-dependent impact on RVFV-EN activity with or without an additional 5 mM of MnCl2. (FIG. 1C) Cytotoxicity of MBXC-4522 in HcLa cells via the CcllTitcr Gio 2.0 viability assay, plotted against compound concentration, showing the concentration of compound necessary to reduce cell viability. (FIG. ID) Cell-free endonuclease activity assay with second-generation TexasRed probe shows bunyaviral endonuclease activity at the 6h timepoint is reduced with increasing concentration of MBXC-4522 in the reaction. Notably, the compound is more inhibitory for RVFV-EN than for SFTSV-EN. (FIG. IE) Cell-free protein thermal shift assay (PTSA) shows the thermostability of endonucleases in the presence of increasing compound concentration is differentially impacted by MBXC-4522; namely, the compound is stabilizing for RVFV-EN and destabilizing for SFTSV-EN. (FIG. IF) In vitro ADME data reveal that MBXC-4522 has very low stability in mouse liver microsomes, but good serum stability. MMS, mouse microsome stability. SB, serum binding. SS, serum stability.FIGS. 2A through 2F: Analog compounds MBXC-4523, -4524, -4554, and -4555 have differential impacts on RVFV-EN activity and cytotoxicity compared to parent compound MBXC-4522. (FIGS. 2A through 2D) Line drawings of the chemical structures of analogs MBXC-4523, -4524, -4554, and -4555. (FIG. 2E) The FRET assay shows that the analog compounds have differing inhibitory impacts on RVFV-EN activity (FIG. 2F) Cytotoxicity of analogs in HEK293 cells was determined via the CellTiter Gio 2.0 viability assay, plotted against compound concentration, and fitted with a nonlinear regression to calculate the CC50 values.

[0204] FIGS. 3A through 3H: Analogs MBXC-4520, -4521, -4523, and -4524 variably impact the activity' and thermostability of bunyaviral endonucleases. Graphs in the left column (FIGS.

[0205] 3A, 3C, 3E, 3G) show the impact of each compound on the FRET-based activity of SFTSV-EN or RVFV-EN. Graphs in the right column (FIGS. 3B, 3D, 3F, 3H) are PTS A data showing the impact of each compound on the thermostability of SFTSV-EN or RVFV-EN. Error was calculated for each point but only displayed when the height of the error bars would exceed the height of the data symbol.

[0206] FIGS. 4A through 4M: Compound MBXC-4522 significantly inhibits RVFV-MP12GFPinfection of BV2 cells in a dose-dependent fashion. (FIGS. 4A through 4J) Bright field and GFP fluorescence images of the 50 pM condition of each compound as well as untreated and DMSO-only control BV2 cells were imaged at lOx magnification. Compound MBXC-4522 shows significant visual inhibition of infection. (FIGS.4K, 4L and 4M) Flow cytometry was used to quantify the percentage of BV2 cells infected at each tested concentration of the five assayed compounds. Because DMSO treatment resulted in a statistically significant reduction in infectivity, the significance of each compound dose was calculated as compared to the DMSO condition. From this, it can be appreciated that MBXC-4520 has significant inhibition at 10 and 50 pM concentrations, while MBXC-4522 has significant dose-dependent inhibition at all tested concentrations. *, p < 0.0332. **, p < 0.0021. ***, p < 0.0002. ****, p < 0.0001.

[0207] FIGS. 5A and 5B: 4522 exhibits pan-bunyaviral infection inhibition in viral plaque assays. Quantification of viral titer in plaque -forming units (PFU) per mL. Cells were pre -treated with DMSO or increasing concentrations of 4522 prior to infection with SFTSV (FIG. 5A), or HRTV (FIG. 5B) at an MOI of 1 under BSL3 conditions. Infections were overlaid with agar pucks and incubated upside-down until plaques formed. Cells were then fixed with 4%paraformaldehyde and stained with crystal violet. Plaques were counted and PFU / mL quantified for each virus. The assay finds that 4522 inhibits plaque formation for all three viruses. NTC, non-treated control. Dotted line, limit of detection. The significance of each compound dose was calculated as compared to the DMSO condition. ****, p < 0.0001.

[0208] FIGS. 6A and 6B: Cytotoxicity of hit compound MBXC-4522 in additional immortalized human cell lines. Cell cytotoxicity of hit compound MBXC-4522 was assessed in two additional cell types, the human hepatocyte line HepG2 (FIGS. 6A) and the HEK293T human cell line. (FIG. 6B). Cell viability was determined by the CellTiter Gio 2.0 viability assay, plotted against compound concentration, and fitted with a nonlinear regression to determine the concentration of MBXC-4522 necessary to reduce cell viability by 50% (CC50) is 73.82 pM in HepG2 cells (FIG. 6A) and 30.08 pM in HeLa cells (FIG. 6B). Error was calculated for each point but only displayed when the error bar exceeded the height of the symbol.

[0209] Detailed Description of the Invention

[0210] Herein is described the identification of new inhibitory chemical scaffolds isolated through the application of a biochemical homogeneous FRET assay against the recently characterized enzymatic activity of RVFV endonuclease and secondary cellular infectious assays. The RVFV endonuclease is an innovative drug target, as it has never been used for hemorrhagic fever virus inhibitor screening, and it is critical for viral replication. An additional innovation of targeting RVFV endonuclease is that the core structure and the catalytic triad are highly conserved among bunyaviruses, which makes it feasible to develop broad-spectrum antivirals by targeting the viral endonuclease.

[0211] Segmented negative-sense, single-stranded RNA viruses (sNSVs), which include bunyaviruses, are causative agents of human diseases. Rift Valley Fever virus (RVFV) is a member of the newly identified Bunyavirus genus in the Phenuiviridae family of the Bunyavirales order according to the Vims Taxonomy 2019, released by the International Committee on Taxonomy of Viruses (ICTV) in 2019. RVFV is a mosquito-borne disease but has a widespread range of insect vectors with potential to spread to Europe, Asia and the Americas. RVFV has the potential to cause significant global health and economic impact; yet there are no safe, efficacious, and approved treatments for RVFV. Therefore, there is an urgent medical need to develop potent therapeutics for RVFV.The present invention meets this need by optimizing small molecule inhibitors targeting the enzymatic activity of the RVFV endonuclease, which is essential for replication of the virus and represents a new antiviral drug target. Similar to other bunyaviruses, RVFV does not encode an enzyme with mRNA capping activity (14), which is required for efficient translation initiation by ribosomes. In cytosols of mammalian cells, single-stranded RNA without a cap is recognized by pattern recognition receptors (PRR), which trigger innate immune responses (20, 21). To protect single- stranded viral RNA and avoid immune responses, bunyaviruses encode a conserved cap-snatching endonuclease domain at the N-terminus of the L polymerase that clips host cellular mRNA caps and uses them as primers for further RNA transcription.

[0212] Using the FRET enzymatic assay for RVFV endonuclease, we identified a novel inhibitory spiro-piperidine pyrido pyrimidine series class of compounds characterized by a common chemical scaffold. Essentially, we developed a FRET-enzymatic assay (EA) for RVFV endonuclease using purified N-tcrminal region of RVFV L based on a previous publication (22). A 21 -nt long single- stranded RNA, which contains the digestive site of RVFV L, is conjugated with Iowa Black™ FQ and 6-FAM at its 5’ and 3’ ends, respectively. When the self-quenched substrate is cleaved by endonuclease, fluorescence emission of 6-FAM can be detected at 535 nm and is used as the endonuclease enzymatic activity. Fluorescence signals increase with incubation time, as well as protein concentration. To determine the optimal concentration of endonuclease protein for the FRET-based endonuclease assay, we tested different concentrations of protein ranging from 0.125 - 2 pM. Half a micromolar endonuclease exhibited the largest dynamic range. The FRET assay was conducted in a 384- well plate format, which is suitable for high throughput screening.

[0213] Using the FRET assay, libraries FDA2, ChemDiv4, Maybridge Protein-Protein Interaction, and ChemDiv5 (partial) containing a total of 20,480 compounds were screened at 25 pM in the HTS RVFV-EN activity assay, resulting in 55 initial hits. The 55 initial hits were then down selected via cherry-pick, structure drag likeness, counter-screens for cell cytotoxicity, FRET-based assay with second- generation Texas Red probe against both RVFV-EN and closely related SFTSV-EN, and impact on thermostability of RVFV-EN and SFTSV-EN. Of the 55 initial hits, MBXC-4522 (FIG. 1A) provided promising results in both the initial HTS and subsequent counter-screens. As shown in FIG. IB, MBXC-4522 dose-dependently inhibits RVFV-EN activity, with an IC50 value of 3.1 pM. While the magnitude of this inhibition is reduced by the addition of excess cation, the compound’s inhibitory action is not disrupted by cation even after the addition of 5 mM MnCI?. Further, decrease ofRVFV-EN activity with increasing MBXC-4522 concentration occurs with and without excess cation.

[0214] To determine the suitability of MBXC-4522 to various cell-based assays, the cytopathic effect of the compound was evaluated in numerous cell types. Cell cytotoxicity assays revealed MBXC-4522 has favorable CC50values of 30 pM in HEK293 cells (FIG.

[0215] 1C), 74 pM in HepG2 cells (FIG. 5A), and 80 pM in HeLa cells (FIG. 5B). Counter-screens with second-generation FRET-based activity assay reinforced initial HTS results that MBXC-4522 dose-dependently inhibits RVFV-EN activity while also revealing a lesser but still notable inhibition of SFTSV-EN activity (FIG. ID).

[0216] An additional counter- screen in the protein thermal shift assay (PTSA), which can be used as an indirect measure of compound-protein binding, shows a differential effect of MBXC-4522 on SFTSV-EN and RVFV-EN, with dose-dependent increases to RVFV-EN thermostability and less pronounced dose-dependent reductions to SFTSV-EN thermostability (FIG. IE). This suggests stronger binding of MBXC-4522 to RVFV-EN than to SFTSV-EN, potentially explaining the different magnitudes of inhibitory action by the compound on the proteins. Next, to determine whether the compound would be suitable for in vivo studies, in vitro ADME (absorption, distribution, metabolism, and excretion) experiments were conducted. Data revealed that MBXC-4522 is not stable in mouse liver microsomes but has good serum stability (FIG. IF). Taken together, the ADME data suggest MBXC-4522 would have poor in vivo stability and therefore low efficacy in mouse models despite its other favorable biochemical characteristics.

[0217] Four analogs of MBXC-4522 (MBXC-4520, -4521, -4523, -4524) were evaluated in the RVFV-EN FRET assay and counter-screened for cytotoxicity (FIG. 2). These analog compounds maintain the core structure of 4522 while having distinct chemical modifications (FIG. 2A-2D). The FRET assay with RVFV-EN reveals that, as expected, the analogs have structure-dependent effects on the endonuclease, with IC50 values summarized in the table beneath the plot (FIG. 2E). Due to the nature of the trends, IC50 values for MBXC-4520 and MBXC-4524 in particular should be interpreted with caution and likely do not reflect true inhibitory concentrations. Cell cytotoxicity assays also show that the analogs are less cytotoxic than the parent compound, with CC50 values summarized in the table beneath the plot (FIG. 2F). Of note, MBXC-4524 did not display any impact on cell viability.

[0218] Following these initial studies, the analogs were counter-screened with the second-generation FRET-based activity assay as well as the PTSA to better characterize the nature of the interaction between compounds and proteins (FIG. 3). Although structure- activityrelationship (SAR) studies are still ongoing, initial biochemical assays identified multiple differences between the analogs and MBXC-4522. MBXC-4520 and -4521 have limited impacts on SFTSV-EN or RVFV-EN activity in the FRET-based assay, while both reduced the thermal stability of SFTSV-EN and RVFV-EN. MBXC-4523 behaves similarly to the parent compound; namely, it has a greater impact on RVFV-EN activity than on SFTSV-EN activity in the FRET-based assay (FIG. 3E), while the PTSAs reveal that MBXC-4523 stabilizes RVFV-EN and destabilizes SFTSV-EN, albeit in different magnitudes than the parent compound (FIG. 3F). MBXC-4524 reduces the activity of RVFV-EN and to a lesser extent of SFTSV-EN (FIG. 3G) but does not appear to have a clear dose-dependent impact on the thermostability of either EN (FIG. 3H).

[0219] Therefore, the present invention is related to the discovery of novel organic small molecule inhibitors against bunyavirus endonuclease. The inhibitors described herein are suitable for use in a composition for the treatment and / or prevention of bunyavirus infections in a mammal. More particularly, the inhibitors described herein are suitable for the treatment and / or prevention of bunyavirus infections in humans.

[0220] In another embodiment, the novel small molecule inhibitors described herein are suitable for use in a method for treating or preventing bunyavirus infections in a mammal by administration of the inhibitors described herein to a patient or subject in need thereof. In a preferred embodiment, the bunyavirus inhibitors described herein are suitable for use in a method for treating or preventing bunyavirus infections in humans.

[0221] More particularly the invention described herein is related to the identification and characterization of small molecules (inhibitors) that treat or prevent bunyavirus infections, especially that treat or prevent infection by thrombocytopenia syndrome virus (SFTSV) and Rift Valley Fever virus (RVFV) in a subject or patient in need thereof. In a particularly preferred embodiment, the inhibitors of the present invention are effective for the treatment or prevention of infection by Rift Valley Fever vims.

[0222] In another embodiment, the inhibitor compounds of the present invention are suitable for use in a method for treating or preventing bunyavirus infections in a mammalian subject, and in particular preventing infection by thrombocytopenia syndrome vims (SFTSV) and Rift Valley Fever vims (RVFV) in a subject or patient in need thereof. In a preferred embodiment, the mammalian subject is a human and the bunyavims inhibitor compound is administered to prevent Rift Valley Fever vims infection.Without in any way limiting the scope of the present invention, preferably, the bunyavirus inhibitors of the present invention will target, i.e., will be specific for, the bunyavirus endonuclease and more particularly the cap-snatching endonuclease domain at the N-terminus of the L polymerase that clips host cellular mRNA caps and uses them as primers for further RNA transcription.

[0223] Additionally, the bunyavirus inhibitor compounds described herein can be administered as pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include the gluconate, lactate, acetate, tartarate, citrate, phosphate, maleate, borate, nitrate, sulfate, and hydrochloride salts. The salts of the compounds described herein can be prepared, for example, by reacting the base compound with the desired acid in solution. After the reaction is complete, the salts are crystallized from solution by the addition of an appropriate amount of solvent in which the salt is insoluble. In some embodiments, the hydrochloride salt is made by passing hydrogen chloride gas into an ethanolic solution of the free base. Accordingly, in some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0224] In another embodiment, the compounds are formulated into a pharmaceutically acceptable carrier or excipient for administration to a subject in need thereof. In another embodiment, the compounds may be formulated into a pharmaceutical formulation and further comprise an additional antiviral compound. In another embodiment, the pharmaceutical formulation may be formulated to be administered orally, parenterally, or topically.

[0225] Bunyavirus inhibitor compounds of the present invention comprise the following compounds:

[0226] A compound of Formula I:

[0227]

[0228] Formula I

[0229] or a pharmaceutically acceptable salt, polymorphs, racemic mixtures, enantiomers, diastereomers, tautomers and combinations thereof, wherein:R1and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0230] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine: and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0231] K is selected from N or CH;

[0232] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - Oil, -CN, -SII, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(Ci-3 alkyl or branched alkyl), -S(Ci-3 alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl

[0233]

[0234] or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and

[0235] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0236] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituentsselected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0237] X is independently selected from the group consisting of N, O, S, -NH-, N(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0238] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0239] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C].4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.A compound of Formula II

[0240]

[0241] Formula II

[0242] R1and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0243] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine: and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0244] P is selected from NH, CH2, O, S, S(O)2 and B is fused to ring A and directly fused to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- and may also include E / Z isomers of substituents W;

[0245] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1 -6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(0)NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from II, halogen, -CF3, - Oil, -CN, -SH, -NH2, -NO2, -O(Ci-3 alkyl or branched alkyl), -S(Ci-3 alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl

[0246]

[0247] or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(0)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and

[0248] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0249] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0250] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0251] The compound wherein ring C can be asymmetric and and is comprised independently of isomers of Formula III or Formula IV,F

[0252]

[0253] ormula III

[0254] wherein, ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0255]

[0256] The compound with asymmetric ring C with exocyclic substituents wherein, the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,

[0257]

[0258] -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;R1and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0259] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine: and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0260] Ring B - wherein K = N or CH can be fused to ring A and consisting of R3 substitutions as defined below and directly connected to ring C in a spirocyclic manner and can be connected to ring D through X and W.

[0261] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0262] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0263] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0264] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0265] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SII, -NII2, -NO2, -C(O)OH, -S(O)2OII; -O(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0266] The compound wherein ring C can be asymmetric and is comprised independently of isomers of Formula V and Formula VI,

[0267]

[0268] wherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0269]

[0270] The compound with asymmetric ring C with exocyclic substituents wherein the R4substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,

[0271] R4 R4 A, cx) Ac A., G A, c rv )

[0272]

[0273] \ \x—z\ ~Q> -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -0(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl oraryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0274] Ri and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; or

[0275] Ri and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl )2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0276] Ring B wherein P can be substituted with NH, CH2, O, S, S(O)2and fused to ring A and consisting of R3 substitutions as defined below and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formula II and in case of Formula II can also include E / Z isomers of substituents W;

[0277] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1 -6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0278] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0279] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0280] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0281] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0282] In another embodiment, the compound has the general Formula VII

[0283] Formula VII

[0284]

[0285] Wherein

[0286] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can bechosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4

[0287]

[0288] alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2

[0289]

[0290] , -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-

[0291] 4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0292] Ring B can be a dihydropyrazine fused to ring A and can be connected to spirocycle ring C and can be connected to ring D through X and W;

[0293] Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclicsubstituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(C1-3alkyl or branched alkyl), -S(C1-3alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; and

[0294] R3- is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0295] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0296] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituentsselected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0297] X is independently selected from the group consisting of N, O, S, -NH-, N(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;

[0298] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0299] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0300] In another embodiment, compound has the general Formula VIII

[0301]

[0302] Formula VIII

[0303] Wherein

[0304] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.

[0305] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B can be a 1,2, 3, 4 tetrahydropyrazine fused to ring A and consisting of Rj substitutions and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formula II and in case of Formula II can also include E / Z isomers of substituents W

[0306] R3 is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(0)NH2, -C(0)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(Ci_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from II, halogen, -CF3, - Oil, -CN, -SH, -NH2, -NO2, -O(Ci-3 alkyl or branched alkyl), -S(Ci-3 alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl

[0307] 4-10 5-8

[0308]

[0309] or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(0)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; andW linker connecting ring C and ring E can be selected independently from a group consisting of alkyl carbon chains of 1-8 carbon length which can be a straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0310] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(0)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0311] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0312] The compound wherein ring C can be asymmetric and is comprised independently of isomers of Formula IX and X

[0313]

[0314] wherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2:

[0315]

[0316] The compound with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,

[0317]

[0318] -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CMalkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI_4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0319] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(0)2(CI.

[0320] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)or -S(O)2N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0321] Ring B can be a dihydropyrazine fused to ring A and can be connected to spirocycle ring C and can be connected to ring D through X and W;

[0322] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(0)NH2, -C(0)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(0)0(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0323] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(0)-, -C(0)0-, -C(0)NH-, -S(0)2-, -S(0)2NH-;

[0324] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -N02, -C(0)0H, -S(0)20H; -O(CI-3alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl); -C(0)NH2, -C(0)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(0)0(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)NHS(0)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(0)2N(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0325] X is independently selected from the group consisting of N, O, S, -NH-, N(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0326] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0327] The compound wherein ring C can be asymmetric and is comprised independently of isomers of Formula XI and XII

[0328] Formula XII

[0329]

[0330] wherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;

[0331] The compound with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from from H, halogen, -CF3, - OH, -CN, -SH, -NH2,-N02, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(0)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(0)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0332]

[0333] Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.

[0334] 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0335] Ring B can be a 1,2, 3, 4 tetrahydropyrazine fused to ring A and consisting of R3 substitutions and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formulae XI and XII and in case of Formulae XI and XII can also include E / Z isomers of substituents W

[0336] R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or arylor heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0337] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0338] Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;

[0339] W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0340] Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl),C(O)NIIS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.

[0341] In another embodiment, the compound has the general Formula XIII

[0342] Formula XIII

[0343]

[0344] wherein

[0345] Ring A can be a pyridine

[0346] Ring B can be a tetrahydropyrazine fused to ring A and connected to spirocyclic piperidine ring C

[0347] Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; Ring Ring E can be selected from a group consisting of aryl or heteroaryl and can be substituted with alkyl, halogen, and alkoxy;

[0348] Ring D can be selected from a group consisting of cycloalkyl;

[0349] In another embodiment, the compound has the general Formula XIV

[0350] Formula XIV

[0351]

[0352] Ring A can be a pyridine

[0353] Ring B can be a piperazine fused to ring A and connected to spirocyclic piperidine ring CY is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;

[0354] Ring E can be selected from a group consisting of aryl or heteroaryl and can be substituted with alkyl, halogen, and alkoxy;

[0355] Ring D can be selected from a group consisting of cycloalkyl;

[0356] It is preferable to develop an orally active therapeutic, since that is the most convenient and rapid method to administer a drug to a large, exposed population in case of pandemic. However, it is also expected that the bunayvirus inhibitors described herein will be suitable for intravenous (i.v.) administration, because it is envisioned that in case of a natural outbreak the infected patients may require i.v. administration. Therefore, the inhibitors described herein will provide an effective, safe, and easy therapeutic option for any newly emerged pandemic strain(s).

[0357] Compositions and Methods

[0358] Unless otherwise indicated, it is understood that description of the use of a bunyavirus inhibitor compound in a composition or method also encompasses the embodiment wherein one or a combination of two or more bunyavirus inhibitor compounds are employed as the source of bunyavirus inhibitory activity in a composition or method of the invention.

[0359] Pharmaceutical compositions according to the invention comprise a bunyavirus inhibitor compound as described herein, or a pharmaceutically acceptable salt thereof, as the 'active ingredient' and a pharmaceutically acceptable carrier (or 'vehicle'), which may be a liquid, solid, or semi-solid compound.

[0360] In some embodiments, the presently disclosed subject matter is related to a method of treating or preventing a bunyavirus infection in a subject in need of treatment thereof wherein the method comprises administering to the subject an effective amount of a composition comprising a compound of one of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV. The compounds may be administered alone or optionally in combination with one or more additional antiviral agents.

[0361] The compositions and methods of the presently disclosed invention are useful for treating and / or preventing bunyavirus infections in that they inhibit the onset, growth, or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a mammalian subject, preferably a human, afflicted with, or at risk of, contracting the condition. Thus, in accordance with the presently disclosedsubject matter, the terms 'treat', 'treating', and grammatical variations thereof, as well as the phrase 'method of treating', are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing bunyavirus infection in a subject, and a method for the prophylaxis (i.e., preventing) of bunyavirus infection, such as in a subject that has been exposed to a virus as disclosed herein or that has an expectation of being exposed to the virus as disclosed herein.

[0362] In another aspect, the invention relates to pharmaceutical compositions comprising one or more compounds according to Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV herein, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, and a pharmaceutically acceptable carrier. That is, a pharmaceutical composition can be provided comprising at least one disclosed compound of the present invention, at least one product of a disclosed method, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, and a pharmaceutically acceptable carrier. In one aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable earner and at least one compound according to Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV herein, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0363] In one aspect of the invention, a pharmaceutical composition will comprise an effective amount of at least one compound according to Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV, herein or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, and a pharmaceutically acceptable carrier. In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount. In a still further aspect, the pharmaceutical composition comprises a compound that is a product of a disclosed method of making.

[0364] In a further aspect, the pharmaceutical composition is used to treat a mammal. In a yet further aspect, the mammal is a human. In a further aspect, the mammal has been diagnosed with a bunyaviral infection. In a still further aspect, the mammal has been diagnosed with a need for treatment of an RVFV infection. In an even further aspect, the mammal is human.

[0365] In a further aspect, the pharmaceutical composition is a solid dosage form selected from a capsule, a tablet, a pill, a powder, a granule, an effervescing granule, a gel, a paste, a troche, and a pastille. In a still further aspect, the pharmaceutical composition is a liquid dosage form selected from an emulsion, a solution, a suspension, a syrup, and an elixir.

[0366] In various aspects, the pharmaceutical composition of the present invention comprisesa pharmaceutically acceptable carrier; an effective amount of at least one disclosed compound of the present invention; or a pharmaceutically acceptable salt, solvate, or polymorph thereof; and further comprises a second active agent. In a further aspect, the second active agent is an antiviral agent.

[0367] In certain aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds according to Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV herein, (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0368] As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non- toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc and the like salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N, N -dibcnzylethylcncdiaminc, dicthylaminc, 2-dicthylaminocthanol, 2-dimcthylaminocthanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0369] In practice, the compounds of the invention, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.The earner can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0370] Thus, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0371] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers arc sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0372] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniquesA tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0373] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.

[0374] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0375] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0376] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointmenthaving a desired consistency.

[0377] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0378] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0379] The present invention is further directed to a method for the manufacture of a medicament for treatment of bunyavirus infection in mammals (e.g., humans) comprising combining one or more disclosed compounds of the present invention, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound according to the present invention or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0380] Also provided is a method of use of a disclosed compound, composition, or medicament, or manufacture of a medicament, comprising at least one compound of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV herein. In a further aspect, the disclosed compounds of the present invention can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned infections for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound of the present invention. When a disclosed compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound of the present invention is preferred. However, combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosedcompound of the present invention can be more efficacious than either as a single agent. In one aspect, the invention relates to a kit comprising at least one compound according to Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII-XIV herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof; and one or more of:

[0381] a) at least one agent known to inhibit bunyavirus endonuclease; b) optionally at least one additional agent known to have antiviral activity; c) instructions for treating a bunyavirus related disease;

[0382] d) instructions for administering the compound in connection with treating a bunyavirus infection; or

[0383] e) instructions for administering the compound with at least one agent known to treat a bunyavirus related disease.

[0384] The kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound of the present invention and / or product and another component for delivery to a patient.

[0385] In a further aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an amount of the compound and the agent known to have antiviral activity. In another aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the agent known to have antiviral activity.

[0386] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[0387] EXAMPLES

[0388] The following Examples have been included to illustrate modes of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter.

[0389] Example 1. Materials and Methods

[0390] CloningThe N-terminal region (aa 1-231) of SFTSV-L protein (PDB: 6ntv) was cloned at the Ndel and Hindlll sites into a modified pET28a vector (in-house) containing an N-terminal 6xHis tag and a kanamycin resistance gene. Similarly, the N-terminal region (aa 1-226) of RVFV-L protein was cloned at Ndel and BamHI sites into the pET15b vector (in-house) containing an N-terminal 6xHis tag and an ampicillin resistance gene. 1 pg of empty pET28a or pET15b vector was digested with the respective enzymes in rCutSmart buffer (New England Biolabs, Ipswich, MA, USA) for 1 hour at 37°C, with the addition of calf intestinal phosphatase (GIF; New England Biolabs) for the final 30 minutes. Digestion products were visualized on a 1% agarose gel and target bands extracted with the Wizard SV Gel and PGR Clean-Up System (Promega, Madison, WI, USA). Inserts were generated via PGR with appropriate primers (IDT, Coralville, IA, USA) in KOD polymerase reaction mix (Millipore-Sigma, Burlington, MA, USA) with respective full-length L protein as the template. PGR products were visualized on a 1% agarose gel, and target bands were extracted and cleaned prior to digestion with respective enzymes and a second round of gel extraction. Prepared inserts were ligated into their respective vectors with the T4 DNA Ligase kit (Thermo-Fisher Scientific, Waltham, MA, USA) and transformed into DH5a cells (ATCC, Manassas, VA, USA) for miniprep with Wizard Plus SV Minipreps DNA Purification System (Promega). Minipreps were Sanger sequenced (Azenta, Burlington, MA, USA), and stocks of correct clones were prepared via maxiprep (Qiagen, Hilden, Germany) for storage at -20°C.

[0391] Protein Expression and Purification

[0392] SFTSV-EN and RVFV-EN were expressed and purified with the same protocol. Expression plasmids were transformed into BL21 cells (ATCC). Cells were grown at 37°C in Miller LB Broth (Fisher Scientific, Hampton, NH, USA) and respective antibiotic (kanamycin or ampicillin; Gold Biotechnology, Olivette, MO, USA) until the optical density of 1 mL culture at 600 nm reached 0.8 as measured by a DU-700 spectrophotometer (Beckman Coulter, Brea, CA, USA). Protein expression was induced with 0.5 mM IPTG (Gold Biotechnology) for 16 hours in an 18°C Innova44 shaking incubator (Eppendorf, Hamburg, Germany). Following induction, cells were pelleted at 6,800 RPM for 15 minutes in an Avanti J26-XPI centrifuge with a JLA-8.1000 fixed-angle rotor (Beckman Coulter). Supernatant was decanted and cell pellets resuspended in 50 mL of lysis buffer (20 mM Tris [pH 8.0], 1 M NaCl, 20 mM imidazole [pH 7.0], 5 mM P-mercaptoethanol |[>-Me|, and 1 ug / mL each of antipain, pepstatin, benzamidine, and leupepsin) per 2 L of outgrowth. Resuspended pellets were snap-frozen in liquid nitrogen and stored at -80°C. Protein expression was visualized via Coomassie stain of an SDS-PAGE gel. Notably, SFTSV-EN expression cannot be clearlyvisualized until elution off the first purification column (data not shown), while RVFV-EN expresses with a clear band in the post-induction sample (data not shown).

[0393] For purification, pellets were thawed, then lysed in fresh lysis buffer using four passes through an EmulsiFlex-05 cell homogenizer (Avestin, Ottawa, ON, Canada). Whole-cell lysates (WCL) were clarified by centrifugation at 24,000 RPM for 40 minutes in an Avanti J26-XPI centrifuge with a JA-25.50 fixed-angle rotor (Beckman Coulter). Supernatants (S) were decanted from pellets (P) and syringe-filtered through a 1.2 pm membrane (Sartorius, Gottingen, Germany) for liquid chromatography on an AKTA Purifier (Cytiva, Marlborough, MA, USA). Filtered supernatants (L) were bound to a 20 mL Nickel Sepharose Fast Flow (NiFF) column (Cytiva) with Nickel Buffer Al (20 mM Tris [pll 8.0], 1 M NaCl, 20 mM imidazole [pH 7.0], 5 mM [3-mercaptoethanol [P-Me]). The column was washed with Nickel Buffer A2 (20 mM Tris [pH 8.0], 50 mM NaCl, 20 mM imidazole [pH 7.0], 5 mM -Me), and the proteins were eluted with 3 column volumes (CV) of 60% Nickel Buffer B (20 mM Tris [pH 8.0], 50 mM NaCl, 500 mM imidazole [pH 7.0], 5 mM P-Me). Proteins were visualized on an SDS-PAGE gel and Coomassie-stained (data not shown). The eluted proteins were collected and diluted 1:4 with 20 mM Tris (pH 8.0) to reduce conductivity. Diluted eluates were bound to an 8 mF S15Q ion column (Cytiva) with Q Buffer A (20 mM Tris [pH 8.0], 50 mM NaCl, 5 mM P-Me) and eluted in 4 mL fractions on a gradient from 0-60% Q Buffer B (20 mM Tris [pH 8.0], 1 M NaCl, 5 mM P-Me) over 15 CV. Select fractions were sampled and loaded onto an SDS-PAGE gel for visualization via Coomassie stain (data not shown) before desired fractions were concentrated down to approximately 5 mL using an Amicon 10 kDa exclusion membrane (Millipore-Sigma). The concentrated fractions were ran on a preparatory SD200 column (Cytiva) using SEC Buffer (20 mM HEPES [pH 7.0], 250 mM NaCl, 2 mM TCEP) and fractionated in 2 mL fractions over 0.8 CV. Fraction contents were again visualized via Coomassie stain of an SDS-PAGE gel (data not shown) before clean fractions were pooled, concentrated to approximately 1 mL, aliquoted, snap-frozen in liquid nitrogen, and stored at -80°C. To assess protein purity, final products were visualized via Coomassie staining of an SDS-PAGE gel (data not shown). All gel images were taken with a ChemiDoc MP imager (Bio-Rad, Hercules, CA, USA). Readouts for all chromatograms are the absorbance at 280 nm plotted against the volume in mL that has gone through the column.

[0394] Hit Identification by FRET-Based HTS

[0395] Aliquots of purified RVFV-EN were diluted to a final concentration of 1 pM in reaction buffer containing 50 mM HEPES pH 7.8, 150 mM KC1, 1 mM Mn CL anddistributed to all wells of 384-well microplates by a Multidrop Combi microplate dispenser (Thermo-Fisher Scientific). 0.2 pL of screening compounds were added using robot, with BXA as positive control and DMSO as negative control. Following an incubation of 30 minutes at room temperature, the self-quenched ssRNA substrate (first-generation 5’-6-FAM-2 liner ssRNA-IowaBlack-3', synthesized and HPLC purified by IDT) was added to all wells to a final concentration of 0.5 pM. Fluorescence signals of 6-FAM were measured with excitation at 485 nm and emission at 535 nm using an Envision 2102 Multilabel HTS Counter (PerkinElmer, Waltham, MA, USA). Z’-factor was calculated from the positive and negative controls for each plate as described in Data Analysis. Compounds with >70% inhibition were identified as initial hits.

[0396] Cell Cytotoxicity Assays

[0397] The cytotoxicity of compounds was tested to determine the safety in multiple mammalian cell lines, including HEK293 (ATCC), Vero (ATCC), and HepG2 (ATCC), using CellTiter Gio 2.0 (Promega) according to the manufacturer’s manual. Cells were seeded at 4,000 cells / well in a 96-well plate. On the following day, cells were treated with initial hits in serially diluted doses from 100 to 0.1 pM. An internally acquired cytotoxic compound (Microbiotix, proprietary) was used as positive control and DMSO was used as the negative control. After 72 hours at 37°C, 5% CO2, cell viability was determined by adding CellTiter Gio 2.0 to cells, incubating for 15 minutes at room temperature, and measuring luminescence on a SpectraMax (Molecular Devices, San Jose, CA, USA). The percentage of cell viability was normalized to the DMSO control and plotted against hit compound concentration. Plots were fitted and the concentration of drug which reduces cell viability by 50% compared to the control (CC50) calculated using GraphPad Prism.

[0398] In Vitro ADME Assays

[0399] Selected compounds were evaluated for adsorption, distribution, metabolism, and excretion (ADME) in the presence of mouse liver microsome preparations (XenoTech, Kansas City, KS, USA). Compounds at a final concentration of 1 pM were incubated at 37°C in mouse liver microsomes in a buffer containing 150 mM sodium phosphate and 0.25 mM MgCl2(pH 7.4) with or without NADPH. Reaction aliquots were taken at 0, 5, 10, 15, and 30 minutes after compound addition. Compounds were extracted from reaction aliquots for EC / MS analysis using a custom LC / MS method to determine the compound half-life.

[0400] Protein Thermal Shift Assays (PTSAs)

[0401] Analogs were received from Microbiotix already reconstituted in DMSO to a final concentration of 10 mM (MBXC-4521) or 20 mM (MBXC-4520, MBXC-4522, MBXC-4523, MBXC-4524) and stored at 4°C. Purified bunyaviral endonuclease proteins (SFTSV-EN, RVFV-EN; in-house) were diluted on ice to a working concentration of 25 pM in reaction buffer containing 50 mM HEPES (pH 7.0), 150 mM KC1, and 1 mM MnCE. 5000x SYPRO Orange Protein Gel Stain (Invitrogen, div. Thermo-Fisher Scientific) was diluted to 50x in reaction buffer and kept on ice. Hit compounds were thawed briefly at room temperature and condition- specific master mixes containing final concentrations of 5 pM protein, 5x SYPRO Orange, and hit compound in 2% DMSO were assembled on ice. For dose response experiments, compounds underwent two-fold serial dilutions in DMSO (Acros Organics, div. Thermo-Fisher Scientific). The final amount of DMSO in the reactions was kept at 2% regardless of compound concentration except in DMSO-free controls. 25 pL of master mix per well was plated in triplicate in a MicroAmp EnduraPlate Optical 96-Well Clear 0.1 mL Reaction Plate (Applied Biosystems, div. Thermo-Fisher Scientific) and sealed with MicroAmp Optical Adhesive Film (Applied Biosystems). The reaction plate was centrifuged 1 min at 1200 RPM, 4°C in an Allegra X-30R Centrifuge fitted with an S6096 rotor (Beckman Coulter) before being loaded into a QuantStudio5 qRT-PCR machine fitted with a fixed 0.1 mL block (Applied Biosystems). A QuantStudio5 software protocol was generated such that the block cooled to 20°C at 3.1 °C / s, held at 20°C for 1 min, then ramped up to 95 °C at a rate of 0.05 °C / s. To reduce background, the heated lid function was disabled and the QuantStudio5 powered off until immediately before use.

[0402] FRET-Based Activity Assays

[0403] Second-generation assay probe WWJ174, consisting of a 5’ Texas Red fluorophore and a 3’ Iowa Black quencher linked by 21mer nonspecific ssRNA, was synthesized and HPLC -purified by IDT. Upon receipt, probe was reconstituted in DMSO to a stock concentration of 100 pM and frozen at -20°C in single-use aliquots. Purified EN proteins were diluted to a final concentration of 1 pM, 5 pM, or 20 pM in reaction buffer containing 50 mM HEPES (pH 7.0), 150 mM KC1, and 1 mM MnCh. Master mixes were assembled for each condition. Triplicate reactions for each condition were loaded onto a black 384-well microplate (Corning #3575; Coming, Corning, NY, USA) and read at 25°C with a Cytation 5 plate reader operating Gen5 software (BioTek, Winooski, VT, USA). Total volume per well was 100 pL for initial experiments and 25 pL for scaled-up experiments. Fluorescent signal was read using excitation and emission wavelengths of 584 and 625 nm, respectively, a bandwidth of 20 nm each, a read height of 10.5 mm, 10 reads per time point, and extended gain. An automatic read protocol was developed in Gen5 such that measurements were taken every three or four minutes following a three-second dual-orbital shake.Reproducibility Characterization for FRET-Based Activity Assay

[0404] Fluorescent signals for 32 positive and 32 negative control reactions were measured in the FRET-based activity assay using the read parameters described above. Descriptive statistics at 1 or 6 hours were calculated in GraphPad Prism 10 (Dotmatics, Boston, MA, USA). All reactions used 100 nM probe and were conducted in buffer containing 50 mM HEPES (pH 7.0), 150 mM KC1, and 1 mM MnCl2with a total volume of 25 pL per well. Z’ values were calculated using Equation 1 (J.-H. Zhang et al., 1999), while the signal-to-noise ratio (SNR) was calculated according to Equation 2 (X. D. Zhang, 2011).

[0405] Data Analysis

[0406] Averaging and normalization of PTSA results, as well as calculations of percent activity values for FRET-based assays, were performed in Excel (Microsoft). Graphs, fit lines, and statistics for all experiments were visualized and calculated in GraphPad Prism 10 (Dotmatics), with data fitted and IC50 or CC50values calculated according to four-parameter non-linear regression unless otherwise specified. The Z’ factor was calculated using Equation 1, where <r+and <y. are the standard deviation of the positive and negative controls, respectively, and p+and p. are the average fluorescence value of the positive and negative controls, respectively.

[0407] (1) r =

[0408]

[0409] The SNR was calculated using Equation 2, where p+and p. are the average fluorescence value of the positive and negative controls, respectively, and a. is the standard deviation of the negative controls.

[0410] (2) SVR =

[0411]

[0412] Cells and Viruses

[0413] Wild-type (WT) BV2 cells (ATCC) were maintained by serial passage in a maintenance media of DMEM + 10% FBS with 10 mM HEPES (pH 7) and 1% sodium pyruvate. HEK293 (ATCC), Vero6 (ATCC), HeEa (ATCC), HepG2 (ATCC). All cells were grown at 37°C, 5% CO2. MP12 (Safder / Farheen), RVFV-Del / DelZSG (Amy / Maris), OROV (Amy / Maris), LACV (Amy / Maris).

[0414] RVFV-MP12GFPInfectivity Inhibition Assays

[0415] 0.07 million BV2 WT cells were seeded in a 24-well plate (Coming) and allowed to reach X confluency at 37°C, 5% CO2. Working concentrations of compounds at 5, 10, 25, and 50 pM were made in 1 mL of BV2 infection media (DMEM + 2% FBS with 10 mM HEPES and 1% sodium pyruvate) as well as media-only and DMSO controls. 10% of the cellmaintenance media was replaced with 250 pl. of BV2 infection media containing DMSO or compound dilutions and incubated at 37°C, 5% CO2for 15 mins. Following incubation, fluorescent attenuated RVFV-MP12GFPvirus (in-house) was thawed and added to each well at an MOI of 1 under BSL2 conditions. The reaction plate was further incubated at 37°C, 5% CO2for 1 hour with rocking every 15 minutes to prevent cell drying. Then, the remaining volume of infection media dilutions were added to the respective wells and incubated at 37°C, 5% CO2 for 16 hours. The following day, cells were trypsinized with 0.05% Trypsin-EDTA (Life Technologies, div. Thermo-Fisher Scientific) and washed with PBS prior to fixation with 4% paraformaldehyde. Fixed cells were imaged at lOx magnification on a light microscope as well as processed by flow cytometry.

[0416] Example 2. Activity of Exemplary RVFV Endonuclease Inhibitor Compounds

[0417] The activity of MBX compounds were evaluated for their activity in the FRET assay. Aliquots of purified RVFV-EN were diluted to a final concentration of 1 pM in reaction buffer containing 50 mM HEPES pH 7.8, 150 mM KC1, 1 mM Mn('l2and distributed to all wells of 384-well microplates by a Multidrop Combi microplate dispenser (Thermo-Fisher Scientific). 0.2 pL of screening compounds were added using robot, with BXA as positive control and DMSO as negative control. Following an incubation of 30 minutes at room temperature, the self-quenched ssRNA substrate (first-generation 5’-6-FAM-21mer ssRNA-IowaBlack-3’, synthesized and HPLC purified by IDT) was added to a final concentration of 0.5 pM. Fluorescence signals of 6-FAM were measured with excitation at 485 nm and emission at 535 nm using an Envision 2102 Multilabcl HTS Counter (PcrkinElmcr, Waltham, MA, USA). Z’-factor was calculated from the positive and negative controls for each plate as described in Data Analysis. The fluorescence signals were plotted vs compound concentrations in GraphPad Prism 10. Graphs were fitted using four-parameter non-linear regression, and IC50 calculated (Table 1).

[0418] Table 1. Activity of NPC-1 inhibitors with varying alkylpiperidine substituents.

[0419] MBX# IC50(pM) C-4522 2.8 C-4523 109.3

[0420]

[0421] MBX # IC50(pM) C-4524 200.0 C-4554 84.2 C-4555 49

[0422]

[0423] Example 3. Additional MBXC-4522 Analogs

[0424] We will infer that rings D & E and to a lesser extent ring C could be more susceptible to oxidative metabolism relative to the other rings, contributing to low microsomal stability. Alternatives to the cyclopentyl E ring, as depicted in Table 2, utilize acyclic substituents E.l & E.2, unsubstituted and heteroatom substituted small rings - E.3 & E.4 substituted aromatic E.5 and heteroaromatic E.6 & E.7 along with fused bicyclic rings E.8. Although variations of E.l and E.3 can undergo oxidative reactions, these analogs will provide insights into the influence of sterics in maintaining potency. Similarly, the aromatic ring D can be a putative site for oxidative metabolism which can be averted with D.l substituted aromatics of -F, -Cl, -CF3that can block the site of metabolism, lowering of logP with substituted heteroaromatics D.2-D.3 and conformationally restricted bicyclic phenyl isosteres D.4-D.8 (23). Since the sp3hybridized carbons of the spirocyclic piperidine ring C can also undergo phase-I metabolism, we designed analogs of smaller ring size - C.l- C.2, bicyclic bioisostere of piperidine - C.3 and fused bicyclic analogs C.4- C.5. The aforementioned analogs, apart from reducing clearance in mouse liver microsomes will also contribute towards improving solubility and gain understanding of its binding affinity. Pyridine ring A variations include non-aromatic rings A.l, phenyl ring A.2, six and five membered heteroaromatics A.3-A.4. These chemical motifs will enable us to understand the effect of n-n interactions and the influence of electron density on potency. Finally, linkers or spacers between the rings play a pivotal role in orienting the molecule. In addition to spatial orientation, they serve as electronic conduits determining the donating and accepting power at the linker ends.

[0425] Table 2. Synthesis plan for additional MBXC-4522 analog inhibitors of RVFV endonucleaseScreening Hit - MBXC-4522: Representative synthetic scheme for MBXC-4522 and its analogs

[0426] Analogs

[0427]

[0428] References

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Claims

CLAIMS:Claim 1: A compound of Formula I:QD)Formula Ior a pharmaceutically acceptable salt, polymorphs, racemic mixtures, enantiomers, diastereomers, tautomers and combinations thereof, wherein:Ri and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl), -NHS(O)2(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C].4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; orRi and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-,and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;K is selected from N or CH:R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused andeach of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(Ci-3 alkyl or branched alkyl), -S(Ci-3 alkyl or branched alkyl), -C(O)OH, -C(O)NH2. -C(O)Nl 1(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NII(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl orbranched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; andY is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CM alkyl orbranched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NI I(C 1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;X is independently selected from the group consisting of N, O, S, -NH-, N(Ci.? alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or hctcroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or heteroaryl)2.Claim 2: A compound of general Formula IIR3Z; / Formula IIJ / / ( A Jj TRI and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkylor cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; orRi and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(Ci_4 alkyl orbranched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(0)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;P is selected from NH, CH2, O, S, S(O)2and B is fused to ring A and directly fused to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- and may also include E / Z isomers of substituents W;Rs - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NII2, -C(0)NII(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(0)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from II, halogen, -CF3, - Oil, -CN, -SH, -NH2, -NO2, -O(Ci-3 alkyl or branched alkyl), -S(Ci-3 alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4 alkylor branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(0)2(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -SlO OH, -SlO NI KC' 1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; andW is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 3. The compound of Claim 1 wherein ring C can be asymmetric and and is comprised independently of isomers of Formula III or Formula IV,Formula IIIwherein, ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), SCOT;Claim 4. The compound of Claim 3 with asymmetric ring C with exocyclic substituents wherein, the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, - SH,-NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(0)0(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;R1and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; orRi and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine: and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B - wherein K = N or CH can be fused to ring A and consisting of R3 substitutions as defined below and directly connected to ring C in a spirocyclic manner and can be connected to ring D through X and W.R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 5. The compound of claim 2 wherein ring C can be asymmetric and is comprised independently of isomers of Formula V and Formula VI,Formula V Formula VIwherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;Claim 6. The compound of Claim 5 with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from H, halogen, -CF3, - OH, -CN, -SH,-NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C]_3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl oraryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ri and R2are independently selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; orRi and R2may be linked to form cyclic ring A which can be fused to ring B and the cyclic rings may be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings comprise 4-8 carbons, and the heterocycloalkyl rings comprise 4-8 carbons that may be substituted with one or two heteroatoms selected from -O-, -S-, -NH-, -NR4-, -S(O)2-O-, and wherein R4 may be selected independently from substituents selected from a C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, and the heteroaryl rings may be selected independently from a 5-membered heteroaryl independently substituted with furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, 6-membered heteroaryls independently substituted with pyridine, pyrimidine, pyridazine, pyrazine; and any of the rings can be substituted independently with substituents selected from H, halogen, -CF3, -OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl )2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B wherein P can be substituted with NH, CH2, O, S, S(O)2and fused to ring A and consisting of R3 substitutions as defined below and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formula II and in case of Formula II can also include E / Z isomers of substituents W;R3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1 -6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-. -S(O)2-, -S(O)2NH-;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 7: A compound of general Formula VIIWhereinRing A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can bechosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci_ 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B can be a dihydropyrazine fused to ring A and can be connected to spirocycle ring C and can be connected to ring D through X and W;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the groupconsisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(Ci_3alkyl or branched alkyl), -S(Ci-3alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl), -S(O)2OH, -S(O)2NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; andR3- is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or arylor heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branchedalkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(CI-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 8: A compound of general Formula VIIIFormula VIIIWhereinRing A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heteroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(0)NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CMalkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(O)(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B can be a 1,2, 3, 4 tetrahydropyrazine fused to ring A and consisting of R3 substitutions and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in Formula II and in case of Formula II can also include E / Z isomers of substituents WR3 - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring C is independently selected from a mono- bi- or tricyclic 4 to 14 membered cycloalkyl, cycloalkylene, or heterocycloalkyl ring, wherein the heteroatoms are independently selected from N, O, S, B, Si, and P, and in the case of a bicyclic or tricyclic substituents, the arrangement of rings can be in any combination of a spirocycle or fused and each of the spirocycles connected to C ring may be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the group consisting of N, O, S, and in case of fused rings can be a cycloalkyl or cycloalkylene or heterocycloalkyl, wherein the heteroatoms are independently selected from the groupAcCP) s-0 0M 5-8 \ U 5-8consisting of N, O, S, or aryl or heteroaryl which can be substituted independently with substituents selected from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, -O(C1-3alkyl or branched alkyl), -S(C1-3alkyl or branched alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(Ci 4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2; andW linker connecting ring C and ring E can be selected independently from a group consisting of alkyl carbon chains of 1-8 carbon length which can be a straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C].3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 9: The compound of Claim 7 wherein ring C can be asymmetric and is comprised independently of isomers of Formula IX and XFormula Xwherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;Claim 10: The compound of Claim 9 with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from H, halogen, -CF3, -OH, -CN, -SH,-NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(Cu alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(CI_4 alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heleroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substituted independently of substituents consisting of H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci.3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci_3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(CI.4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heleroaryl), -C(0)N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C]_4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(C^ alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or hctcroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B can be a dihydropyrazine fused to ring A and can be connected to spirocycle ring C and can be connected to ring D through X and W;R3- is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or arylor heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;X is independently selected from the group consisting of N, O, S, -NH-, N(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)-;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branchedalkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(CI-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 11: The compound of Claim 8 wherein ring C can be asymmetric and is comprised independently of isomers of formula XI and XIIFormula XIIwherein ring C has an asymmetric arrangement of ring atoms wherein the G heteroatoms are selected independently from N, O, S, S(O), S(O)2;Claim 12: The compound of Claim 11 with asymmetric ring C with exocyclic substituents wherein the R4 substituents are selected independently from from H, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(Ci-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(Ci.4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(CI_4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or hctcroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or heteroaryl), -NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, - S(O)2NH(C1-4alkyl or branched alkyl or cycloalkyl orheterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring A can be a cyclic ring which can be fused to B and the cyclic rings can be independently chosen from cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl and cycloalkenyl rings can be selected from a ring consisting of 4-8 carbons; and of the heterocycloalkyl rings consisting of 4-8 carbons that can substituted with one or two heteroatoms consisting of -O-, -S-, -NH-, -NR4-, -S(O)2-O-, wherein R4 can be chosen independently from substituents consisting of C1-C5 straight chain alkyl, 4-6 membered cycloalkyls, cycloheteroaryl, heteroaryls, -C(O)-, C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; and of the heleroaryl rings can be chosen independently from the list comprising of 5-membered heteroaryls of isomers wherever applicable of furan, thiophene, pyrrole, oxazole, imidazole, pyrazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole,R4R4R4triazole, and 6-membered heteroaryls consisting of isomers wherever applicable of pyridine, pyrimidine, pyridazine, pyrazine; and any of the aforementioned rings can be substitutedindependently of substituents consisting of II, halogen, -CF3, - OH, -CN, -SH, -NH2, -NO2, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -O(C1-3alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(Ci-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)OH, -C(O)NH2, -C(O)NH(Ci^ alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(0)N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), N(Ci alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -NHC(0)(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -NHS(O)2(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2OH, -S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Ring B can be a 1,2, 3, 4 tetrahydropyrazine fused to ring A and consisting of R3 substitutions and directly connected to ring C in a spirocyclic manner and can be connected to ring D through -C(N)- and -W- as in formulae (XI and XII) and in case of formulae (XI and XII) can also include E / Z isomers of substituents WRs - is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, a 1-6 carbon alkyl chain, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl independently substituted with -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(CI-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or hctcroaryl); -C(O)NH2, -C(O)NH(C alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), - S(O)2NH(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CI-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the rings can be independently substituted with substituentsselected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, -CF3, -OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)NHS(O)2(C1-4alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2;W is a linker connecting ring C and ring E and is selected independently from the group consisting of a 1-8 carbon alkyl chain which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring D is selected independently from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl attached directly to X or attached to X through linker W, wherein each of the rings can be independently substituted with substituents selected from H, alkyl, cycloalkyl, heterocycloalkyl, branched alkyl, aryl, heteroaryl, and a 1-6 carbon alkyl chain, -CF3, - OH, -CN, -SH, -NH2, -NO2, -C(O)OH, -S(O)2OH; -O(C1-3 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl); -C(O)NH2, -C(O)NH(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), -C(O)N(Cu alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2, -C(O)O(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl), C(O)NHS(O)2(CI-4 alkyl or branched alkyl or cycloalkyl or hctcrocycloalkyl or aryl or heteroaryl), - S(O)2NH(Ci-4 alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl) or -S(O)2N(CM alkyl or branched alkyl or cycloalkyl or heterocycloalkyl or aryl or heteroaryl)2.Claim 13: A compound of general formula XIIIFormula XIIIwhereinRing A can be a pyridineRing B can be a tetrahydropyrazine fused to ring A and connected to spirocyclic piperidine ring CY is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-; Ring Ring E can be selected from a group consisting of aryl or heteroaryl and can be substituted with alkyl, halogen, and alkoxy;Ring D can be selected from a group consisting of cycloalkyl;Claim 14: A compound of general formula XIVFormula XIVRing A can be a pyridineRing B can be a piperazine fused to ring A and connected to spirocyclic piperidine ring C Y is a linker connecting ring C and ring E and is selected independently from a 1-8 carbon alkyl which can be straight chain or branched, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-;Ring E can be selected from a group consisting of aryl or heteroaryl and can be substituted with alkyl, halogen, and alkoxy;Ring D can be selected from a group consisting of cycloalkyl.

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