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

Abstract

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

Description

COMPOSITIONS COMPRISING WERNER SYNDROME HELICASE INHIBITORS AND METHODS OF USING THE SAMECROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 535,307, filed on August 29, 2023, and U.S. Provisional Patent Application Serial No. 63 / 665,217, filed on June 27, 2024, the contents of which are incorporated herein by reference in their entireties.TECHNICAL FIELDThe subject matter described herein relates to compositions comprising Werner Syndrome Helicase (WRN, also known as Werner Syndrome RecQ Helicase or Werner Syndrome ATP-Dependent Helicase) inhibitors and methods of using the same.BACKGROUNDThe WRN gene encodes a helicase that falls within the RecQ DNA helicase subfamily and is directly involved in DNA damage repair. While WRN has previously been shown to exhibit tumor suppressive activity, an activity that correlates well with its activity in DNA damage repair, certain cancer cells have been shown to be dependent on the presence of WRN. For example, certain cancers associated with deficient DNA mismatch repair (dMMR), which often exhibit high levels of microsatellite instability (microsatellite instability-high or MSI-H cancers), depend on WRN activity for continued survival. In view of WRN’ s essential role in such cancers, there remains a need in the art to identify WRN inhibitors for use in the treatment of such dMMR and / or MSI-H cancers.SUMMARY OF THE INVENTIONIn certain aspects, the compositions and methods described herein relate to compositions comprising WRN helicase inhibitors and methods of their use in treating disease, e.g., cancer.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereofK and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6or R7can optionally join with R5to form a C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein: (A) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclylring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3alkyl, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4--membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6-membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring,wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring, and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; (B) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra and Rb are independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, - NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein thesubstituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C2-C6alkenyl, a C3-C7 cycloalkyl ring, C1-C6 hydroxyalkyl, , wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, orX is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10iswherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond; wherein whenwherein when U is N+, R15is O-, R16and R17are H, and U V is a double bond;wherein when U is C, R15 is -NR19R20,U V is a double-bond and R16, R17, R18, are independently selected from H, -CH3, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5cycloalkyl ring; wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring, and wherein R4 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring, orL and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl;wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl; wherein when6alkyl, C2-C6alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, or -C(O), R26 and R27 are independently selected from H, -OCF2Cl, or -S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen, wherein R1is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2 and R3 are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6and R7are independently selected from H or halogen;wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and wherein (A) R1 is NR30R31, aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or H; wherein when R1is aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, the said aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is optionally substituted with one or more R36, or the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is fused with a second 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8 cycloalkenyl ring, wherein R36 is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl-COOH, -C(O)-R33, -C(O)- NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; and either (B) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fusedC3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2is NR8R9and R3is H or R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C1-C6hydroxyalkyl, C2-C6alkenyl, a C3-C7cycloalkyl ring, wherein R10is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is, wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; ; wherein whenwherein when U is N+, R15is O-, R16and R17are H, and U V is a double bond; wherein when U is C, R15is -NR19R20U V is a double-bond and R16, R17, and R18are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and - S(O)R21R22, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5cycloalkyl ring, and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substitutedor unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring;, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl; wherein when6 alkyl, C2-C6 alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring;wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen, and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and wherein (A) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or - S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring, wherein when the 3-8 membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein R8and R9are independently selected from H, C1-C6alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10 is selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3- C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10is fused with a second C3-C8cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl; and either (B) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, andwherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1is C3-C7cycloalkyl ring, the said C3-C7cycloalkyl is a fully saturated ring, wherein the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group; wherein when R1is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10aryl ring, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom,wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; orĨC) R4 is selected from, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl; wherein when6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring;wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25and R29are independently selected from H, halogen, =O, or -C(O), R26and R27are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen, and wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring. 1. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S;R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6 and R7 are independently selected from H or halogen; wherein R6or R7can optionally join with R5to form a C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein (B) R4is selected from, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein R23and R24are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, a bridged or unbridged C3-C8cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whensingle or double bond; R25, R29, and R35 are independently selected from H, halogen, -OH, =O, -C(O); C1-C6 alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26 to form a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring;and either (B) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1is C3-C7cycloalkyl ring, the said C3-C7cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 memberedheteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; orthe said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring1; or (C) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2and R3join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is, wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wherein when U is N+, R15is O-, R16and R17are H, and U V is a double bond; wherein when U is C, R15 is -NR19R20 U V is a double-bond and R16, R17, and R18are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and -S(O)R21R22, R19, and R20are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 are independently selected from C1-C3alkyl, C3-C5cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring, and wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II) with the formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl, and wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II) with the formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, where formula (II) isIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R5is C1-C6alkyl, C1-C6 alkenyl, C1-C6 alkynyl or C3-C6 cycloalkyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R5 is C2 alkyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are independently selected from H or halogen. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are H. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are F. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein:R1 is NR30R31, aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or H; wherein when R1is aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3- 8 membered heterocyclyl, the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is optionally substituted with one or more R36, or the said aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is fused with a second 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8 cycloalkenyl ring, wherein R36is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl- COOH, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, - NH-C(O)-NH-R33, and wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is NR30R31, aryl, C3-C7 cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring;wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O- (C1-C6)alkyl-COOH, three C1-C6alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3alkyl, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3- C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3- C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group;wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6-membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6- membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6- membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom,wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6- membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C6alkyl, C1-C6alkenyl, C1-C6 alkynyl, or H. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C3 alkyl.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is NR30R31, R30 and R31 are -CH3. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6alkoxy, -C(O)-R33, - C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3alkyl, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is fused with a 5- or 6- membered heterocyclyl ring, wherein the said 5- or 6- membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, and wherein the said 5- or 6- membered heterocyclyl ring is optionally substituted with C1-C3alkyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the phenyl is fused with a 5-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the phenyl is fused with a 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the 5- or 6- membered heterocyclyl ring comprises carbon atoms and one or two oxygen atoms. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the 5- or 6- membered heterocyclyl ring comprises carbon atoms and one or two nitrogen atoms. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the 5- or 6- membered heterocyclyl ring comprises carbon atoms, one or two oxygen and one or two nitrogen atoms. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:,, , , , , , , , , ,, , , ,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6 alkoxy, -C(O)-NH-R33, - S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33is selected from C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: ,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 5-10 membered heteroaryl ring, wherein the said aryl and the said 5-10 membered heteroaryl ring are optionally substituted by one or more halogen, -OH, =O, - C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C8cycloalkyl; C3-C8cycloalkenyl, a second C6-C10aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:,,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a C3-C8 cycloalkyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: ,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 3-8 membered cycloalkenyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituentsdisclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 3-8 membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof wherein R1is aryl, the aryl is fused with a 3-8 membered heterocyclyl ring, wherein the said aryl and the said 3-8 membered heterocyclyl ring are optionally substituted by one or more halogen, -OH, =O, - C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or a second 3-8 membered heterocyclyl, or the said C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or the second 3-8 membered heterocyclyl is linked with the said aryl and the said first 3-8 membered heterocyclyl ring to form a spiro ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:,,. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a fully saturated C3-C7cycloalkyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the C3-C7cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH,- C(O)-C1-C6alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3- C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is substituted with C1-C4 alkoxy. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituentsIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the said 4- or 7- membered heterocyclyl ring is optionally joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6-membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring is a fully saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6halogenated alkenyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring is a fully saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom; wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof wherein R1is selected fromIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a pyridinylring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the pyridinyl ring, the second 4-, 5-, or 6-membered heterocyclyl ring, are optionally substituted by one or more H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof wherein R1 is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof wherein the said the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or - S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring, wherein when the 3-8 membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1- C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring;wherein R8 and R9 are independently selected from H, C1-C6 alkyl, and - C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10 is selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C8cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10is fused with a second C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra and Rb are independently selected from H, - OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6- membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or - S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with - C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5-membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C2-C6alkenyl, a C3-C7cycloalkyl ring, C1-C6hydroxyalkyl, , wherein R10is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 iswherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond; wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15is -NR19R20, U V is a double-bond and R16, R17, R18are independently selected from H, -CH3, R19, and R20are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 are independentlyselected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5cycloalkyl ring In certain embodiments, the compositions and methods described herein relate to a compound of formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb, R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or - C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or - S(O2)R34, wherein R34 is a C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinselected fromIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, X is N, Y is C, R2is NR8R9,and R3is H, wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6- membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, X is N, Y isIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; whereinwhen R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 is NR8R9 and R3 is H, wherein R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y areIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the said fused ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5- membered heterocyclyl ring, wherein when the 5-membered heterocyclyl ring is substituted,the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the said fused 4- or 5-membered heterocyclyl ring is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 alkyl, C1-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C3 alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is -C(O)R10, and R10is C1-C6alkyl, C2-C6alkenyl, a C3-C5cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C3 alkoxy, an optionally substituted C3- C5cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R10is C2-C6 alkenyl. In certain embodiments the compositions and methods described herein relate to a compound of fo nts disclosedherein, or a pharmaceutically acceptable salt thereof, wherein R10. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is -S(O2)R10, and R10is C1-C4alkyl, C1-C4alkenyl, a C3-C5cycloalkyl ring, a 5- or 6-membered heterocyclyl ring, wherein R10 is optionally substituted with -OH, C1- C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, -S(O2)CH3, and / or - C(O)N(CH3)2. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n=2, X is C, Y is N, R2is H, R3is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R3 is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, wherein, wherein W, P, S, T, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wwherein when T is N, R10 is, and M and Z are independently selected from N or C; and wherein when T is C, R10iwherein when N M and M Z are both single bonds, M is C(O) and Z is N or C substituted with H or C1-C3 alkyl; and when one of N M and M Z is a single-bond and one is a double-bond, M and Z are independently selected from C or N, optionally substituted with H or C1-C3alkyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from: ,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10 is, wherein A, W, T, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; R12, R13, and R14are independently selected from H, -OH, =O, C1-C3alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, a C3-C8 cycloalkyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring,, or R12and R13join together to form a fused substituted or unsubstituted 5- or 6- membered heterocyclyl ring, wherein when the said 5- or 6- membered heterocyclyl ring is substituted, the substituentsIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10are independently selected from H, -OH, or C1-C3 alkyl, or R12 and R13 join together to form a fused substituted or unsubstituted 5- or 6- membered heterocyclyl ring, wherein when the said 5- or 6- membered heterocyclyl ring is substituted, the substituents are selected from C1-C3 alkyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 alkyl, C2-C6 alkenyl, a C3-C7cycloalkyl ring, a C1-C6aryl, or a 5- or 6-membered heterocyclyl ring, wherein R10is optionally substituted with -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, and / or -C(O)N(CH3)2, wherein when R10is a C3-C7cycloalkyl ring, a C1-C6aryl, a 5-10 membered heteroaryl ring or a 5- or 6-membered heterocyclyl ring R10is optionallyfused with a second C3-C7 cycloalkyl ring, C1-C6 aryl, 5-10 membered heteroaryl, or 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3iswherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15 is -OH or -NR19R20; wherein when R15 is -OH, R16 is a carbonyl, R17 and R18 join together to form a fused 5- or 6- membered heterocyclyl ring, and U V is a single bond; wherein when R15 is NR19R20, U V is a double-bond and R16, R17, R18, R19, and R20are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5cycloalkyl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from: ,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected fromindependently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein R23and R24are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, abridged or unbridged C3-C8 cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whensingle or double bond; R25, R29, and R35 are independently selected from H, halogen, -OH, =O, -C(O); C1-C6 alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; R26and R27are independently selected from H, C1-C6alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26 to form a C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereofwherein R4is selected fromindependently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl;wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl; wherein when6alkyl, C2-C6alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinis C or O, n is 0 or 1, and R23 is C1-C4 alkyl, wherein the C1-C4 alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments the compositions and methods described herein relate to a compound of fo substituentsdisclosed herein, or a pharmaceutically acceptable salt thereof, whereinis C or O, n is 0, and R23is C1-C4alkyl, wherein the C1-C4alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinis C or O, n is 1, and R23is C1-C4alkyl, wherein the C1-C4alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinis C or O, n is 0 or 1, and R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected fromIn certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof,O, n is 1 or 2, x is 1 or 2, and R24is C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens from F or Cl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, L is C or O, n is 0, 1 or 2, x is 0, 1 or 2, the atoms in the bridge can be selected from C, N, O, or S, and R24is C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, n is 0, 1 or 2, R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, L G is a single or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, or -C(O), R26 and R27 are independently selected from H C1 C6 alkyl C1 C6 haloalkyl, - OR28, or -S(O)mor either R25or R27 join with R26 to form a C4-C7 cycloalkyl ring or a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, L G is a single or double bond; G and L are independently selected from C, N, O; R25, R29, and R35, are independently selected from H, halogen, -OH, =O, -C(O); C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl, - OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26 to form a C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:,In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:,,,,,,,, ,,,,,,,,, ,,,,,, ,,,,, ,,,,, ,,,,,,,,,,, ,, ,,, ,,, ,,, ,. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ,,, ,,,,,,, ,,,, ,,. , In certain embodiments, the compositions and methods described herein relate to a combination comprising a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, and one or more additional active agents. In certain embodiments, the compositions and methods described herein relate to a combination wherein an additional active agent is an anti-cancer agent. In certain embodiments, the compositions and methods described herein relate to a combination wherein the additional active anti- cancer agent is a chemotherapy. In certain embodiments, the compositions and methods described herein relate to a pharmaceutical composition comprising a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use as a medicament.In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) that is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the compositions and methods described herein relate to a method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of inhibiting WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of treating a disorder or disease with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of treating cancer with a WRN inhibitor in a subject, comprising administering tothe subject a therapeutically effective amount of the compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, as described herein. In certain embodiments, the compositions and methods described herein relate to a method of treating cancer with a WRN inhibitor in a subject, comprising administering a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the compositions and methods described herein relate to a method of treating a cancer wherein the cancer is characterized as microsatellite instability- high (MSI-H) and / or mismatch repair deficient (dMMR) and is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the compositions and methods described herein relate to a use of a compound, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the compositions and methods described herein relate to a use of a compound or pharmaceutically acceptable salt thereof, wherein the use is for the treatment of a cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the compositions and methods described herein relate to a process to manufacture a compound described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts the results of an in vivo efficacy assay of certain compounds of the present disclosure. Briefly, MSI-h HCT116 or MSS HT-29 tumors were established in 4–5- week-old female Crl:NU(NCr)-Foxn1nu athymic nude mice (Charles River Laboratories). Mice were housed in 5 animals per cage and food and water was provided ad libitum. All procedures were performed at the Mispro Vivarium facility in New York, NY and were conducted according to the guidelines of the Mispro Institutional Animal Care and Use Committee and Eikon Therapeutics protocol. HCT116 and HT-29 cells were sourced from ATCC and cultured in McCoy’s 5a Medium (ATCC) with 10% FBS. To establish the tumors, mice were injected with 2 x 106 HCT116 or HT-29 cells in 50% Geltrex / 50% HBSSin the right flank. Animal body weights and tumor volumes were measured twice weekly throughout the study and recorded in StudyLog. Tumor volume was calculated using the formula TV = 0.5*length*width2. Tumor Growth Inhibition (TGI) was calculated using the formula TGI = (1-((TD25- Tinitial) / (CD25-Cinitial)))*100, where T is the Test group TV and C is the Control group TV at Day 25 vs the initial TV at study commencement. Percent tumor regression was calculated using the formula % regression = 100- ((Tfinal / Tinitial)x100), where Tfinal is the latest TV measurement and Tinitial is the initial TV at study commencement. After HCT116 tumors grew to an average volume of 150-200 mm3 (7 days post-implantation), mice were randomized into treatment groups (n=8 mice / group) and received either test compounds or vehicle control daily via oral gavage at 10mL / kg body weight. Compounds were dissolved to required concentrations in an aqueous solution of 20% 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) w / v in water and pH adjusted to 7.4. Compound 13 was administered at 15, 30 or 90 mg / kg while compounds 164 and 169 were administered at 5, 15 or 30 mg / kg. Figure 2 depicts the results of an assay to validate that efficacy of WRN inhibitors is limited to MSI-h tumors. Briefly, the activity of Compound 164 was assessed in the MSS HT-29 tumor model. Very limited activity of Compound 164 was observed in the HT-29 tumor model. Figure 3 depicts the results of a pharmacodynamic assessment of WRN levels in tumor samples demonstrating the specific degradation of WRN protein upon treatment with Compound 164. Briefly, at the initial 2 h timepoint, moderate reduction in WRN relative vehicle control is observed, with a dose responsive decrease of approximately 20-35 %. At 8 h post final dose, a further reduction in WRN protein in observed, with a 40% reduction seen following 5 mg / kg Compound 164 and 50% reduction seen for both 15 and 30 mg / kg of Compound 164. A rebound in overall WRN levels is seen at the final 48 h timepoint, with WRN levels in tumors treated with 5 mg / kg Compound 164 being equivalent to vehicle control. In the higher doses, an around 20 % reduction in WRN level relative to vehicle was observed at the 48 h timepoint. Plasma concentrations of Compound 164 demonstrated clear dose dependent increase from 5 to 30 mg / kg and showed expected decrease over the time- course of the study.DETAILED DESCRIPTION The presently disclosed subject matter relates to compositions comprising WRN helicase inhibitors and methods of their use in treating cancer. For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 1. Definitions 2. Compositions of Matter 3. Methods of Use 4. Examples 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the presently disclosed subject matter. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other instances “comprising,” “consisting of”, and “consisting essentially of,” the instances or elements presented herein, whether explicitly set forth or not. For the recitation of numeric ranges herein, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, whichwill depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. As used herein, “modulate” or “modulating” refers to increasing or decreasing, e.g., modulation of the activity of an enzyme includes increasing the activity of the enzyme as well as decreasing the activity of the enzyme. As used herein, “treat” or “treating” refers to an effort to alter the natural course of a disease, including prophylaxis of the disease, alleviation of symptoms and / or ameliorating pathology associated with the disease. As used herein, “alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, C1-Cn as in “C1-Cn alkyl" is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement. For example, C1-C6, as in “C1-C6 alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl. As used herein, “alkenyl” refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, “C2-C6 alkenyl” means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. The term “alkynyl” refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non- aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, “C2-C6 alkynyl” means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl.As used herein, “heteroalkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch. As used herein, “cycloalkyl” refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle, including, but not limited to, those containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group. As used herein, the term “cycloalkenyl” refers to a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond, including, but not limited to, those having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. The group may be a terminal group or a bridging group. As used herein, the term “heterocyclyl” or “heterocyclic” refers to a mono- or poly- cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Heteroatoms include N, O, and / or S, including N- oxides, sulfur oxides, and dioxides. In certain embodiments, the ring is three to ten- membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another “heterocyclic” ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like. The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise. As used herein, “aryl” is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p- toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl,anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring. As used herein, the term “heteroaryl” refers to any stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridazine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4- dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, benzothiazolyl, thienyl, benzothienyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, tetra- hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is nonaromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. As used herein, the term “halogen” refers to F, Cl, Br, and I.As used herein, the term “haloalkyl” means an alkyl group that is substituted with one or more fluorine, chlorine, bromine or iodine atoms. Examples of such haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups. The term “substitution,” “substituted” and “substituent” refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described herein, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, and trifluorom ethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result. The compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule. Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. The compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkali earth metal salts, sodium, potassium or lithium. The term "pharmaceuticallyacceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.2. Compositions of Matter The presently disclosed subject matter relates to compositions comprising Werner Syndrome Helicase (WRN) inhibitors and methods of using the same. For example, but not by way of limitation, the present disclosure is directed to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and wherein (A) R1 is NR30R31, aryl, C3-C7 cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring;wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1is C3-C7cycloalkyl ring, the said C3-C7cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10aryl ring, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1 is a 4-membered heterocyclyl ring,the said 4--membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; orthe 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2 and R3 are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring, and wherein R4 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; (B) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra and Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, - NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring,a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or -S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2is NR8R9,and R3is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C2-C6alkenyl, a C3-C7 cycloalkyl ring, C1-C6 hydroxyalkyl, , wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 iswherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond;wherein whenwherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15is -NR19R20,U V is a double-bond and R16, R17, R18, are independently selected from H, -CH3, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5cycloalkyl ring; wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring, and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring;L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2;wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein whenC1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl; wherein when6 alkyl, C2-C6 alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25and R29are independently selected from H, halogen, or -C(O), R26and R27are independently selected from H, -OCF2Cl, or -S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25 or R27 join with R26 to form a 5- or 6-membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen; wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2 and R3 are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:whereinK and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein (A) R1is NR30R31, aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1 is aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is optionally substituted with one or more R36, or the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is fused with a second 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8 cycloalkenyl ring, wherein R36is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl-COOH, -C(O)-R33, -C(O)- NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; and either (B) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or -S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2is NR8R9and R3is H or R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2,X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is, wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; ; wherein whenwherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15is -NR19R20U V is a double-bond and R16, R17, and R18 are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and - S(O)R21R22, R19, and R20are independently selectedfrom -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5cycloalkyl ring; and wherein R4 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; orL and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl;wherein when6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25and R29are independently selected from H, halogen, =O, or -C(O), R26and R27are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring. 2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6or R7can optionally join with R5to form a C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein (A) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, orRa and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or - S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring, wherein when the 3-8 membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein R8 and R9 are independently selected from H, C1-C6 alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10is selected from C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, a C3- C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10 is fused with a second C3-C8 cycloalkyl, C3-C8cycloalkenyl, C6-C10aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl; and either (B) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or H;wherein when R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1- C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3alkyl, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8cycloalkenyl, a second C6-C10aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, orthe said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; and wherein R4 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring orL and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6alkyl;wherein when6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen; and wherein R1is H,f -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and wherein (A) R4 is selected from, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein R23 and R24 are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C6-C10aryl, 5-10 membered heteroaryl, a bridged or unbridged C3-C8 cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl;wherein whensingle or double bond; R25, R29, and R35are independently selected from H, halogen, -OH, =O, -C(O); C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6haloalkyl, C2-C6haloalkenyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; wherein R25or R27join with R26to form a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; and either (B) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl;C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclylring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2 and R3 are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring; or(C) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2is NR8R9,and R3is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2and R3join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected froma 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is, wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15 is -NR19R20 U V is a double-bond and R16, R17, and R18 are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and -S(O)R21R22, R19, and R20are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5cycloalkyl ring; and wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound of formula (II) with the formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, K and J are independently selected from C, N, O,or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl, wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring. 3. In certain embodiments, the compositions described herein relate to a compound of formula (II) with the formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, where formula (II) is ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R5 is C1-C6 alkyl, C1-C6 alkenyl, C1- C6alkynyl or C3-C6cycloalkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R5is C2alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are independently selected from H or halogen.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are H. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are F. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is NR30R31, aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or H; wherein when R1 is aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3- 8 membered heterocyclyl, the said aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is optionally substituted with one or more R36, or the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is fused with a second 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8 cycloalkenyl ring, wherein R36 is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl- COOH, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, - NH-C(O)-NH-R33, and wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy,C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein: R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or H; wherein when R1 is aryl, the aryl is substituted by one or more -O- (C1-C6)alkyl-COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3- C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl;wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7cycloalkyl ring is optionally linked with a second C3- C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4 is a substituted phenyl group; wherein when R1is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6-membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6- membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- memberedheterocyclyl ring to form a spiro ring, or the said 5- or 6- membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6- membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is NR30R31, R30and R31areindependently selected from optionally substituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, or H. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is NR30R31, R30and R31are independently selected from optionally substituted C1-C3 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is NR30R31, R30and R31are -CH3. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, - S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6- membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 5- or 6- membered heterocyclyl ring, wherein the said 5- or 6- membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, andwherein the said 5- or 6- membered heterocyclyl ring is optionally substituted with C1-C3 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the phenyl is fused with a 5- membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the phenyl is fused with a 6- membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heterocyclyl ring comprises carbon atoms and one or two oxygen atoms. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heterocyclyl ring comprises carbon atoms and one or two nitrogen atoms. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heterocyclyl ring comprises carbon atoms, one or two oxygen and one or two nitrogen atoms. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from: ,, , , , , , ,,,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl-COOH, three C1-C6 alkoxy, -C(O)-NH-R33, -S(O)R33, - S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33is selected from C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from: ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 5- 10 membered heteroaryl ring, wherein the said aryl and the said 5-10 membered heteroaryl ring are optionally substituted by one or more halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: , , ,, , , , ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a C3- C8 cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein,or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, the aryl is fused with a 3- 8 membered cycloalkenyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is aryl, the aryl is fused with a 3- 8 membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof wherein R1 is aryl, the aryl is fused with a 3-8 membered heterocyclyl ring, wherein the said aryl and the said 3-8 membered heterocyclyl ring are optionally substituted by one or more halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or a second 3-8 membered heterocyclyl, or the said C3-C8cycloalkyl, C3-C8cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or the second 3-8 membered heterocyclyl is linked with the said aryl and the said first 3-8 membered heterocyclyl ring to form a spiro ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from: , ,, , , , ,,. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a fully saturated C3-C7cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5- 10 membered heteroaryl to form a spiro ring, or the said C3-C7cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH,-C(O)-C1-C6alkyl, or -O-(C1-C6)alkyl-COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein,or a pharmaceutically acceptable salt thereof, wherein R1is selected from, , , , , ,. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is substituted with C1-C4alkoxy.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the said 4- or 7-membered heterocyclyl ring is optionally joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6-membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring is a fully saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6- membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a 5- or 6-membered heterocyclylring, wherein the 5- or 6-membered heterocyclyl ring is a fully saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6- membered heterocyclyl ring is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom; wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereofwherein R1is selected fromIn certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1 is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the pyridinyl ring, the second 4-, 5-, or 6-membered heterocyclyl ring, are optionally substituted by one or more H, halogen, - OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereofwherein R1 is selected from:,,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereofwherein the said the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R1is. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or - S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; orR2 and R3 join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring, wherein when the 3-8 membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1- C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein R8 and R9 are independently selected from H, C1-C6 alkyl, and - C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10is selected from C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10 is fused with a second C3-C8cycloalkyl, C3-C8cycloalkenyl, C6-C10aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra and Rb are independently selected from H, - OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6- membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclylring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or - S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2is NR8R9and R3is H or R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with - C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5-membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C2-C6alkenyl, a C3-C7 cycloalkyl ring, C1-C6 hydroxyalkyl, , wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 iswherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond;wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15is -NR19R20, U V is a double-bond and R16, R17, R18are independently selected from H, -CH3, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 are independently selected from C1-C3alkyl, C3-C5cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring 4. In certain embodiments, the compositions described herein relate to a compound of formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb, R2and R3are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or - C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or - S(O2)R34, wherein R34is a C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring.5. In certain embodiments, the compositions described herein relate to a compound of formula (II) with the formula further defined by the substituents disclosed herein, or aIn certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, X is N, Y is C, R2is NR8R9,and R3 is H, wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1- C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinand R3 is H.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 is NR8R9 and R3is H, wherein R8and R9are independently selected from H, C1-C4alkyl, and - C(O)R11, wherein R11 is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2 is. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 1, X and Y are C, R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2is NR8R9, R8and R9are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the said fused ring.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5-membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the said fused 4- or 5-membered heterocyclyl ring is selected from:In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is - C(O)R10, or -S(O2)R10, and R10is C1-C6alkyl, C1-C6alkenyl, a C3-C7cycloalkyl ring, wherein R10is optionally substituted with -OH, C1-C3alkoxy, an optionally substituted C3- C5 cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is - C(O)R10, and R10 is C1-C6 alkyl, C2-C6 alkenyl, a C3-C5 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C3alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from:In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10 is C2-C6 alkenyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) with the formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is - S(O2)R10, and R10is C1-C4alkyl, C1-C4alkenyl, a C3-C5cycloalkyl ring, a 5- or 6-membered heterocyclyl ring, wherein R10 is optionally substituted with -OH, C1-C3 alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, -S(O2)CH3, and / or -C(O)N(CH3)2. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n=2, X is C, Y is N, R2 is H, R3 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R3is . In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is - C(O)R10, or -S(O2)R10, wherein,wherein W, P, S, T, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wherein T is N or C; wherein when T is N, R10 is, and M and Z are independently selected from N or C; and wherein when T is C, R10wherein when N M and M Z are both single bonds, M is C(O) and Z is N or C substituted with H or C1-C3 alkyl; and when one of N M and M Z is a single-bond and one is a double-bond, M and Z are independently selected from C or N, optionally substituted with H or C1-C3alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from: ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10, wherein A, W, T, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; R12, R13, and R14are independently selected from H, -OH, =O, C1-C3alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, a C3-C8 cycloalkyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroarylring,, or R12 and R13 join together to form a fused substituted or unsubstituted 5- or 6- membered heterocyclyl ring, wherein when the said 5- or 6- membered heterocyclyl ring is substituted, the substituents are selected from C1-C3 alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is - C(O)R10, or -S(O2)R10, and R10are independently selected from H, -OH, or C1-C3 alkyl, or R12 and R13 join together to form a fused substituted or unsubstituted 5- or 6- membered heterocyclyl ring, wherein when the said 5- or 6- membered heterocyclyl ring is substituted, the substituents are selected from C1-C3alkyl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from:In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2is H, R3is - C(O)R10, or -S(O2)R10, and R10 is C1-C6 alkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, a C1- C6 aryl, or a 5- or 6-membered heterocyclyl ring, wherein R10 is optionally substituted with -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, and / or -C(O)N(CH3)2,wherein when R10 is a C3-C7 cycloalkyl ring, a C1-C6 aryl, a 5-10 membered heteroaryl ring, or a 5- or 6-membered heterocyclyl ring, R10is optionally fused with a second C3-C7 cycloalkyl ring, C1-C6 aryl, 5-10 membered heteroaryl, or 5- or 6-membered heterocyclyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10 is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein,or a pharmaceutically acceptable salt thereof, wherein n is 2, X is C, Y is N, R2 is H, R3 is -wherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15 is -OH or -NR19R20; wherein when R15 is -OH, R16 is a carbonyl, R17 and R18 join together to form a fused 5- or 6- membered heterocyclyl ring, and U V is a single bond; wherein when R15 is NR19R20, U V is a double-bond and R16, R17, R18, R19, and R20are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21and R22are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5cycloalkyl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein R23 and R24 are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C6-C10aryl, 5-10 membered heteroaryl, a bridged or unbridged C3-C8 cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein whensingle or double bond; R25, R29, and R35 are independently selected from H, halogen, -OH, =O, -C(O); C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; R26and R27are independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C2-C6haloalkenyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28 is C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl; wherein R25or R27join with R26to form a C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereofwherein R4 is selected fromare independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected fromF or Cl, or R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein whenC1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R24is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl; wherein when6alkyl, C2-C6alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinor 1, and R23 is C1-C4 alkyl, wherein the C1-C4 alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, and R23is C1-C4alkyl, wherein the C1-C4alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, and R23is C1-C4alkyl, wherein the C1-C4alkyl is alkyl is optionally substituted with halogens selected from F or Cl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinor 1, and R23 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl,C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected fromIn certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof,1 or 2, and R24 is C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens from F or Cl. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein, 1 or 2, x is 0, 1 or 2, the atoms in the bridge can be selected from C, N, O, or S, and R24is C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected fromIn certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4is. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinsingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, or -C(O), R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, -OR28, or -S(O)mR28 wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27join with R26to form a C4-C7 cycloalkyl ring or a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen.In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from: ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, whereinsingle or double bond; G and L are independently selected from C, N, O; R25, R29, and R35, are independently selected from H, halogen, -OH, =O, -C(O); C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; R26and R27are independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26to form a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from: ,, , , , , ,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:,In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:,,,,,,,, ,,,,,,,,, ,,,,,, ,,,,, ,,,,, ,,,,,,,,,,, ,, ,,, ,,, ,,, ,. In certain embodiments, the compositions described herein relate to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ,,, ,,,,,,, ,,,, ,,. , 3. Methods of Use In certain embodiments, the present disclosure is directed to a compound of formula (I) or formula (II), with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof: and one or more additional active agents. For example, but not by way of limitation, the present disclosure is directed to compounds of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or pharmaceutically acceptable salts thereof, wherein the additional active agent is an anti-cancer agent. In certain embodiments, the active anti-cancer agent is a chemotherapy. In certain embodiments, the additional active agent is a cytotoxic agent, a cytostatic agent, a hormone treatment, or a checkpoint inhibitor. In certain embodiments, the additional active agent is an immunotherapy. In certain embodiments, the present disclosure is directed to a compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, where the compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or apharmaceutically acceptable salt thereof is formulated in a composition comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the present disclosure is directed to a compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof is for use as a medicament. For example, but not by way of limitation, wherein the use is for the treatment of a disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the present disclosure is directed to a method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of inhibiting WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating a disorder or disease with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating cancer with a WRN inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the cancer is characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR). In certain embodiments, the cancer characterized as microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) is selected from colorectal, gastric, bladder, endometrial, adrenocortical, uterine, cervical, esophageal, central nervous system, head and neck, breast, kidney, liver, lung, skin, prostate and ovarian cancer. In certain embodiments, the present disclosure is directed to a process to manufacture a compound of formula (I) or formula (II) with either formula further defined by the substituents disclosed herein, or a pharmaceutically acceptable salt thereof. 4. Examples The following Examples are presented by way of illustration, not limitation. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products. Abbreviations UsedPreparation of Intermediates Intermediate A Synthesis of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid. Intermediate AStep 1: Preparation of 5-(benzyloxy)-4,6-dichloropyrimidine. Intermediate A1A mixture of 4,6-dichloropyrimidin-5-ol (5.0 g, 30.3 mmol), K2CO3(7.1 g, 51.5 mmol) and benzyl bromide (5.7 g, 33.0 mmol) in DMF (25 mL) was stirred at 25 °C for 16 hours. The mixture was quenched with H2O (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 12% EtOAc in petroleum ether) to afford (6.0 g, 77.6% yield) of 5-(benzyloxy)-4,6-dichloropyrimidine as a colorless solid. LCMS observed m / z = 255.0 [M+H]+. Step 2: Preparation of 5-(benzyloxy)-4-chloro-6-methylpyrimidine. Intermediate A2A mixture of 5-(benzyloxy)-4,6-dichloropyrimidine (30.2 g, 118.3 mmol), Pd(dppf)Cl2.CH2Cl2(4.8 g, 6.6 mmol), K3PO4(75.3 g, 355.1 mmol) in toluene (300 mL) and H2O (90 mL) was stirred under N2 at 105 °C. To the mixture was added dropwise a solution of methylboronic acid (8.5 g, 142.0 mmol) in dioxane (400 mL). The resulting mixture was stirred at 105 °C for 18 hours. To the mixture was added a second batch solution of methylboronic acid (8.5 g, 142.0 mmol) in dioxane (300 mL) and stirred at 105 °C for an additional 8 hours under N2. To the mixture was added a third batch solution of methylboronic acid (8.5 g, 142.0 mmol) in dioxane (300 mL) and stirred at 105 °C for an additional 8 hours under N2. The resulting mixture was cooled to 25 °C, quenched with H2O (500 mL), filtered and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was extracted with EtOAc (3 x 250 mL), washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 17% EtOAc in petroleum ether) to afford (18.7 g, 67.3% yield) of 5-(benzyloxy)-4-chloro-6-methylpyrimidine as a light yellow oil. LCMS observed m / z = 235.1 [M+H]+.Step 3: Preparation of methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate. Intermediate A3A mixture of 5-(benzyloxy)-4-chloro-6-methylpyrimidine (5.0 g, 21.3 mmol) in MeOH (20 mL) was added Pd(dppf)Cl2.CH2Cl2 (0.7 g, 1.0 mmol) in a pressure tank. The mixture was purged with N2for 5 minutes and then was charged with carbon monoxide (5 atm.) three times at 25 °C. The resulting mixture was heated to 50 °C and stirred at 50 °C for 48 hours. The mixture was cooled to 25 °C, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, (eluent: with 50% EtOAc in petroleum ether) to afford (4.0 g, 72.6% yield) of methyl 5-(benzyloxy)-6- methylpyrimidine-4-carboxylate as a colorless oil. LCMS observed m / z = 259.1 [M+H]+. Step 4: Preparation of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid. Intermediate AA mixture of methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate (10.0 g, 38.7 mmol) in THF (20 mL) and MeOH (20 mL) was added dropwise a solution of NaOH (3.8 g, 97.1 mmol) in H2O (20 mL). The mixture was stirred at 25 °C for 10 minutes. Then the resulting mixture was concentrated in vacuo to remove THF and MeOH. The mixture was acidified to pH 3 with HCl (6 M in H2O) aqueous solution. The precipitated solids were collected by filtration and washed with H2O (3 x 5 mL) to afford (2.0 g, 21% yield) of 5- (benzyloxy)-6-methylpyrimidine-4-carboxylic acid as a white solid.1H NMR (400MHz, DMSO-d6) δ 14.13 (s, 1H), 8.86 (s, 1H), 7.49 – 7.36 (m, 5H), 5.05 (s, 2H), 2.49 (s, 3H). LCMS observed m / z = 245.10 [M+H]+. Intermediate B Synthesis of 3-bromo-1H-1,2,4-triazol-5-amine. Intermediate BA mixture of 5-amino-1H-1,2,4-triazole (50.0 g, 594.6 mmol), NaBr (152.9 g, 1486.6 mmol) and H2SO4 (145.8 g, 1486.6 mmol) in H2O (450 mL) was stirred at 25 °C for 10 minutes. To the mixture was added dropwise a solution of sodium bromate (44.8 g, 297.3 mmol) in H2O (150 mL) over 1 hour at 55-60 °C. The mixture was stirred at 55-60 °C for an additional 20 hours. The mixture was cooled to 0 °C and quenched with saturated sodium hyposulfite aqueous solution at 0 °C. The mixture was adjusted to pH 6 with 20% NaOH aqueous solution. The resulting mixture was concentrated in vacuo. The residue was washed by n-BuOH (750 mL) and EtOAc (1.5 L) in order. Then the solid was purified by trituration with dioxane (300 mL) at 80 °C. After filtration, the filter cake was vacuum-dried at 50-60 °C for 12 hours to afford (8.5 g, 8% yield) of 5-bromo-2H-1,2,4-triazol-3-amine as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 6.29 (s, 2H). LCMS observed m / z = 163.05 [M+H]+. Intermediate C Synthesis of tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1- carboxylate. Intermediate CA mixture of tert-butyl piperazine-1-carboxylate (120.0 g, 644.2 mmol) and methyl 2-chloro-3-oxopentanoate (106.0 g, 644.2 mmol) in MeCN (500 mL) was added NEt3 (268.6 mL, 1932.8 mmol) in one portion at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 16 hours. The mixture was cooled to 25 °C and concentrated in vacuo. The residue was diluted with H2O (300 mL) and extracted with CH2Cl2 (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 20% EtOAc in petroleum ether) to afford (30.5 g, 14% yield) of tert-butyl 4- (1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate as a light-yellow semi-solid.1H NMR (400 MHz, CDCl3) δ 4.10 (s, 1H), 3.79 (d, J = 8.2 Hz, 3H), 3.51 (s, 3H), 3.09 – 3.05 (m, 1H), 2.89 (s, 1H), 2.75 (s, 3H), 2.70 – 2.55 (m, 2H), 1.48 (d, J = 7.2 Hz, 9H), 1.15 – 1.11 (m, 3H). LCMS observed m / z = 313.2 [M+H]+.Intermediate D Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide. Intermediate DStep 1: Preparation of 2-chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide. Intermediate D1To a mixture of 2-chloro-4-(trifluoromethyl)aniline (100.0 g, 511.3 mmol) in CH2Cl2 (500 mL) was added NEt3 (155.2 g, 1534.0 mmol) at 25 °C. To the mixture was added dropwise 2-chloroacetyl chloride (121.3 g, 1073.8 mmol) over 5 minutes at 0 °C. The mixture was stirred at 25 °C for 12 hours. Then the mixture was quenched by the addition of H2O at 25 °C and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column (eluent: with 8% EtOAc in petroleum ether) to afford (56.0 g, 40.2% yield) of 2-chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide as a white solid. LCMS observed m / z = 270.0 [M+H]+. Preparation of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide. Intermediate DA mixture of 2-chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (56.0 g, 205.8 mmol) in acetone (100 mL) was treated with KI (102.5 g, 617.5 mmol) at 60 °C for 5 hours. The mixture was filtered to remove solid and the filtrate was concentrated in vacuo to afford (71.0 g, 95% yield) of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide as a white solid. The crude product was used in other reactions without further purification. LCMS observed m / z = 362.0 [M+H]+. Intermediate E Synthesis of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate EA mixture of tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1- carboxylate (14.5 g, 46.2 mmol, Intermediate C) and 5-bromo-2H-1,2,4-triazol-3-amine (7.6 g, 46.3 mmol, Intermediate B) in EtOH (45 mL) was treated with H3PO4 (4.5 g, 46.3 mmol) at 80 °C under N2 for 16 hours. Then the mixture was cooled to 25 °C and adjusted to pH 8 with saturated Na2CO3aqueous solution. The resulting mixture was concentrated in vacuo. The residue was diluted with EtOH (100 mL) and stirred at 25 °C for 30 minutes. The resulting mixture was filtered, and the filter cake was washed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 8% MeOH in CH2Cl2) to afford (4.0 g, 20% yield) of tert-butyl 4-{2-bromo- 5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}piperazine-1-carboxylate as a light- yellow solid. LCMS observed m / z = 362.0 [M+H]+. Intermediate F Synthesis of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate FA mixture of tert-butyl 4-{2-bromo-5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}piperazine-1-carboxylate (30.0 g, 70.2 mmol, Intermediate E) and DIPEA (27.2 g, 210.6 mmol) in DMF (30 mL) was treated with N-[2-chloro-4- (trifluoromethyl)phenyl]-2-iodoacetamide (28.0 g, 77.2 mmol, Intermediate D) at 90 °C under N2for 3.5 hours. The mixture was quenched with H2O (100 mL) at 25 °C and was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatography (eluent: with 50% EtOAc in petroleum ether) to afford (10.0 g, 21% yield) of tert-butyl 4-[2-bromo-4-({[2- chloro-4-(trifluoromethyl)phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]piperazine-1-carboxylate as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.7, 2.1 Hz, 1H), 5.32 (s, 2H), 3.96 – 3.93 (m, 2H), 3.39 (dd, J = 4.7, 2.2 Hz, 2H), 2.98 – 2.95 (m, 4H), 2.66 (d, J = 11.2 Hz, 2H), 1.44 (s, 9H), 1.17 (t, J = 7.4 Hz, 3H). LCMS observed m / z = 662.0 [M+H]+. Intermediate G Synthesis of 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide. Intermediate GA mixture of tert-butyl 4-[2-bromo-4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]piperazine-1-carboxylate (4.8 g, 7.2 mmol, Intermediate F) in TFA (24 mL) and CH2Cl2(24 mL) was stirred at 25 °C under N2for 30 minutes. The mixture was concentrated in vacuo to afford (4.5 g crude) of 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1- yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide as the crude mixture and was used directly in the next step without further purification. LCMS observed m / z = 562.0 [M+H]+. Intermediate H Synthesis of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide. Intermediate HA mixture of 2-[2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (1.5 g, 2.6 mmol, Intermediate G), HATU (1.5 g, 3.9 mmol) and DIPEA (1.7 g, 13.3 mmol) in DMF (15 mL) was stirred at 25 °C under N2for 2.5 hours. The mixture was quenched with H2O (200 mL) at 25 °C and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 10% petroleum ether in EtOAc) to afford (749 mg, 33% yield) of 2-(6-{4-[5- (benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-bromo-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide as a white solid.1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.84 (s, 1H), 8.49 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.59 – 7.55 (m, 1H), 7.50 – 7.39 (m, 5H), 5.22 – 5.19 (m, 1H), 5.16 – 5.06 (m, 3H), 4.81 – 4.79 (m, 1H), 3.80 – 3.76 (m, 2H), 3.44 – 3.29 (m, 2H), 3.15 (q, J = 7.5 Hz, 2H), 3.07 – 3.05 (m, 1H), 2.88 – 2.83 (m, 1H), 2.65 (m, 1H), 2.48 (s, 3H), 1.32 (t, J = 7.7 Hz, 3H). LCMS observed m / z = 788.40 [M+H]+. Intermediate I Synthesis of tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7- dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate ITo a mixture of tert-butyl 4-{2-bromo-5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}piperazine-1-carboxylate (1.2 g, 3.0 mmol, Intermediate E) and 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (954 mg, 4.5 mmol) in dioxane (15 mL) and H2O (5 mL) were added Pd(dppf)Cl2.CH2Cl2 (247 mg, 0.3 mmol) andNa2CO3 (641 mg, 6.0 mmol) in one portion at 25 °C under N2. The mixture was heated to 100 °C and stirred for 16 hours at 100 °C under N2. The resulting mixture was cooled to 25 °C, filtered and the filter cake was washed with EtOAc (30 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 9% MeOH in CH2Cl2) to afford (1.1 g, 84% yield) of tert-butyl 4-[2-(3,6- dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine- 1-carboxylate as a light-yellow solid. LCMS observed m / z = 429.2 [M+H]+. Intermediate J Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate JTo a mixture of tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4H- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (775 mg, 1.8 mmol, Intermediate I) and N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (719 mg, 1.9 mmol, Intermediate D) in DMF (9 mL) was treated with DIPEA (698 mg, 5.4 mmol) at 45 °C under N2for 3.5 hours. The mixture was concentrated in vacuo and the residue was purified by reversed phase C18 silica gel column chromatography (mobile phase: 10-100% MeCN in H2O) to afford (525 mg, 44% yield) of tert-butyl 4-[4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7- oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate as a brown solid. LCMS observed m / z = 664.2 [M-H]-. Intermediate K Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran- 4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetamide. Intermediate Kof tert-butyl 4-[4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7- oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (50 mg, 0.07 mmol, Intermediate J) in TFA (10 mL) was stirred at 25 ℃ for 2 hours. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (eluent: 17% EtOAc in petroleum ether) to afford (10.7 mg, 25% yield) of N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1- yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.58 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 7.00 – 6.95 (m, 1H), 5.41 (s, 2H), 4.34 (q, J = 2.8 Hz, 2H), 4.03 – 3.81 (m, 4H), 3.38 – 3.34 (m, 2H), 3.24 – 3.14 (m, 2H), 3.09 (q, J = 7.5 Hz, 2H), 2.94 (d, J = 9.9 Hz, 2H), 2.67 – 2.63 (m, 2H), 1.36 – 1.22 (t, J = 7.3 Hz, 3H). LCMS observed m / z = 566.30 [M+H]+. Intermediate L Synthesis of 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine- 2-carboxylic acid. Intermediate LStep 1: Preparation of amino(methyl)aluminum chloride. Intermediate L1A mixture of NH4Cl (3.4 g, 64.4 mmol) in toluene (50 mL) was added dropwise a solution of trimethylaluminum (65 mL, 0.9 mmol, 1 M in toluene) at 0 °C under N2. The resulting mixture was used directly in the next step without work up or further purification. Intermediate L2Step-2: A mixture of ethyl 2-(benzyloxy) acetate (2.8 g, 14.4 mmol), NaH (0.4 g, 15.9 mmol, 60% purity) and ethyl oxalate (2.1 g, 14.4 mmol) in THF (50 mL) and EtOH (8.37 uL, 0.1 mmol) was stirred at 25 °C under N2 for 18 hours. Then the mixture was quenched with H2O and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford (3.5 g crude) of diethyl 2-(benzyloxy)-3- oxosuccinate as the crude product and was used directly in the next step without further purification. LCMS observed m / z = 295.3 [M+H]+. [M+H]+. Step 3: Preparation of 2-(2-(methylthio)ethoxy)acetic acid. Intermediate L3A mixture of NaH (0.9 g, 39.8 mmol, 60% purity) in THF (60 mL) were added 2- (methylthio)-ethanol (1.0 g, 10.9 mmol) at 25 °C. After 20 minutes, a solution of 2- bromoacetic acid (1.5 g, 10.8 mmol) in THF (25 mL) was added dropwise to the mixture at 25 °C under N2 and stirred at 70 °C under N2 for 6 hours. Then the mixture was cooled to 25 °C, adjusted to pH 3 with HCl (1 M in H2O) aqueous solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford (1.4 g crude) of 2-(2-(methylthio)ethoxy)acetic acid as a yellow oil and was used directly in the next step without further purification.1HNMR (400 MHz, CDCl3) δ 4.20 (s, 2H), 3.79 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.19 (s, 3H). Step 4: Preparation of methyl 2-(2-(methylthio)ethoxy)acetate. Intermediate L4A mixture of 2-(2-(methylthio)ethoxy)acetic acid (1.4 g, 9.3 mmol) and oxalyl chloride (2.3 g, 18.6 mmol) in CH2Cl2 (50 mL) was stirred at 25 °C under N2 for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (50 mL) and to the mixture was added MeOH (6.0 mL, 148.2 mmol) and pyridine (10 mL, 126.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. Then the mixture was quenched with H2O (30 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with HCl (15 mL, 1 M in H2O) aqueous solution, saturated NaHCO3 aqueous solution (25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford (1.4 g, 91% yield) of methyl 2-(2- (methylthio)ethoxy)acetate as a yellow oil.1HNMR (400 MHz, DMSO-d6) δ 4.15 (s, 2H), 3.65 (d, J = 8.6 Hz, 5H), 2.65 (t, J = 6.8 Hz, 2H), 2.09 (s, 3H). Step 5: Preparation of 2-(2-(methylthio)ethoxy)acetimidamide. Intermediate L5To a mixture of methyl 2-(2-(methylthio)ethoxy)acetate (1.4 g, 8.5 mmol) was added dropwise the solution of amino(methyl)aluminum chloride in toluene at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 18 hours. The mixture was cooled to 0 °C and quenched with MeOH (100 mL) at 0 °C. The mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated in vacuo and the residue was purified by trituration with IPA (160 mL) and acetone (40 mL). The precipitated solids were collected by filtration and washed with IPA (2 x 10 mL) to afford (1.2 g crude) of 2- (2-(methylthio)ethoxy)acetimidamide as the HCl salt and was used directly in the next step without further purification. LCMS observed m / z = 149.1 [M+H]+. Step 6: Preparation of ethyl 5-(benzyloxy)-2-{[2-(methylsulfanyl)ethoxy]methyl}- 6-oxo-1H-pyrimidine-4-carboxylate. Intermediate L6To a mixture of EtONa (138 mg, 2.0 mmol) in EtOH (50 mL), 2-(2- (methylthio)ethoxy)acetimidamide (1.2 g crude, HCl salt) and 1,4-diethyl 2-(benzyloxy)-3- oxobutanedioate (1.2 g, 4.0 mmol) was added to a 100 mL round-bottom flask at 25 °C. The mixture was stirred at 60 °C for 3 hours. The mixture was cooled to 25 °C, quenched with acetic acid (2 mL) and concentrated in vacuo to remove EtOH. The mixture was diluted with EtOAc (150 mL) and washed with saturated NaHCO3 aqueous solution, brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 50% EtOAc in petroleum ether) to afford (100 mg, 5% yield) of ethyl 5-(benzyloxy)-2-{[2- (methylsulfanyl)ethoxy]methyl}-6-oxo-1H-pyrimidine-4-carboxylate as a yellow oil. LCMS observed m / z = 379.1 [M+H]+. Step 7: Preparation of (2-((5-(benzyloxy)-4-(ethoxycarbonyl)-6-oxo-1,6- dihydropyrimidin-2-yl)methoxy)ethyl)dimethylsulfonium Intermediate L7A mixture ethyl 5-(benzyloxy)-2-{[2-(methylsulfanyl)ethoxy]methyl}-6-oxo-1H- pyrimidine-4-carboxylate (100 mg, 0.3 mmol) and MeI (4.1 mL, 66.8 mmol) in CH2Cl2(5 mL) was stirred at 25 °C under N2for 8 days. Then the mixture was concentrated in vacuo to afford (130 mg, 95% yield) of (2-{[5-(benzyloxy)-4-(ethoxycarbonyl)-6-oxo-1H- pyrimidin-2-yl]methoxy}ethyl)dimethylsulfanium iodide as the crude product and was used directly in the next step without further purification. LCMS observed m / z = 394.1 [M+H]+. Step 8: Preparation of ethyl 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1- c][1,4]oxazine-2-carboxylate. Intermediate L8A mixture of (2-((5-(benzyloxy)-4-(ethoxycarbonyl )-6–oxo-1,6-dihydropyrimidin– 2-yl)methoxy)ethyl) dimethylsulfonium (130 mg, 0.3 mmol) and K2CO3(913.2 mg, 6.6 mmol) in DMF (5 mL) was stirred at 25 °C under N2 for 2 days. Then the solid was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc (30 mL), washed with HCl (0.1 M in H2O) aqueous solution, saturated Na2CO3aqueous solution (25 mL) and dried over MgSO4. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography on silica column (eluent: with 40% EtOAc in petroleum ether) to afford (80 mg, 73% yield) of ethyl 3-(benzyloxy)-4-oxo-6H,7H,9H-pyrimido[2,1- c][1,4]oxazine-2-carboxylate as a white solid. LCMS observed m / z = 331.3 [M+H]+. Step 9: Preparation of 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1- c][1,4]oxazine-2-carboxylic acid. Intermediate LA mixture of ethyl 3-(benzyloxy)-4-oxo-6H,7H,9H-pyrimido[2,1-c][1,4]oxazine-2- carboxylate (80 mg, 0.2 mmol) and NaOH (32 mg, 0.8 mmol) in EtOH (20 mL) was stirred at 25 °C under N2 for 30 minutes. The mixture was quenched with HCl (4 M in H2O, 10 mL) aqueous solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4and concentrated in vacuo to afford (60 mg, 82% yield) of 3-(benzyloxy)-4-oxo-6H,7H,9H-pyrimido[2,1- c][1,4]oxazine-2-carboxylic acid as a white solid and the crude product was used directly in the next step without further purification. LCMS observed m / z = 303.09 [M+H]+. Intermediate M Synthesis of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(dimethylamino)-5- ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid. Intermediate MStep 1: Preparation of tert-butyl 4-(2-bromo-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7- oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate M1A mixture of tert-butyl 4-{2-bromo-5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}piperazine-1-carboxylate (10.0 g, 23.4 mmol, Intermediate E) and ethyl bromoacetate (5.9 g, 35.1 mmol) in DMF (40 mL) was added DIPEA (9.1 g, 70.2 mmol) at 25 °C under N2. The mixture was heated to 90 ℃ and stirred at 90 ℃ under N2for 5 hours. The mixture was cooled to 25 ℃, quenched with H2O (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 33% EtOAc in petroleum ether) to afford (6.0 g, 50% yield) of tert-butyl 4-[2-bromo-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7- oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate as a yellow solid. LCMS observed m / z = 513.1 [M+H]+. Step 2: Preparation of tert-butyl 4-(2-(dimethylamino)-4-(2-ethoxy-2-oxoethyl)-5- ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate M2A mixture of tert-butyl 4-[2-bromo-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (3.0 g, 5.8 mmol) and KOAc (1.1 g, 11.7 mmol) in a mixed solvent of DMF (5 mL) and DMSO (5 mL) was added dimethylamine (2 M in THF, 11.7 mL, 23.4 mmol) solution at 25 °C under N2. The reaction mixture was heated to 120 ℃ and stirred at 120 ℃ under N2for 3 hours. The reaction mixture was cooled to 25 ℃, quenched with H2O (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 17% EtOAc in petroleum ether) to afford (1.6 g, 57% yield) of tert-butyl 4-[2-(dimethylamino)-4-(2-ethoxy-2-oxoethyl)-5- ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate as a light yellow solid. LCMS observed m / z = 478.3 [M+H]+. Step 3: Preparation of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- (dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid. Intermediate MA mixture of tert-butyl 4-[2-(dimethylamino)-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7- oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (1.5 g, 3.1 mmol) in a mixed solvent of THF (10 mL) and H2O (10 mL) was added LiOH.H2O (150 mg, 6.3 mmol) in portions at 25 °C. The mixture stirred at 25 °C for 2 hours. The mixture was quenched with saturated NH4Cl aqueous solution and concentrated in vacuo. The residue was dissolved in H2O (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford (1.3 g, 92% yield) of {6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2-(dimethylamino)-5-ethyl-7- oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetic acid as a yellow oil and the crude product was used directly in the next step without further purification. LCMS observed m / z = 450.25 [M+H]+. Intermediate NSynthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-5-ethyl- 7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Intermediate NStep 1: Preparation of tert-butyl 4-[4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-2-(dimethylamino)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate. Intermediate N1A mixture of {6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2-(dimethylamino)-5- ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetic acid (1.3 g, 2.9 mmol, Intermediate M), 2-chloro-4-(trifluoromethyl)aniline (848 mg, 4.3 mmol) and NEt3 (2.2 g, 21.4 mmol) in EtOAc (3 mL) was added T3P (25 mL) at 25 °C under N2 for 3 hours. Then the mixture was concentrated in vacuo. The residue was purified by reversed phase C18 silica gel column chromatography (mobile phase: 10-50% MeCN in H2O) to afford (580 mg, 32% yield) of tert-butyl 4-[4-({[2-chloro-4-(trifluoromethyl)phenyl]carbamoyl}methyl)-2- (dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1- carboxylate as a yellow solid. LCMS observed m / z = 626.2 [M+H]+. Step 2: Preparation of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2- (dimethylamino)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide. Intermediate NA mixture of tert-butyl 4-[4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-2-(dimethylamino)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (580 mg, 0.9 mmol) in CH2Cl2(5 mL) was added TFA (5 mL) and stirred at 25 °C under N2for 3 hours. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (10-34% MeCN in H2O) to afford (320 mg, 66% yield) of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2- (dimethylamino)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4- yl]acetamide as a white solid. LCMS observed m / z = 526.2 [M+H]+. Intermediate O Synthesis of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-(dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid. Intermediate OStep 1: Preparation of ethyl 2-(2-(dimethylamino)-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate. Intermediate O1A mixture of tert-butyl 4-[2-(dimethylamino)-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7- oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (600 mg, 1.2 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL) and stirred at 25 °C under N2 for 3 hours. The mixture was concentrated in vacuo to afford (426 mg, crude) of ethyl 2-[2-(dimethylamino)- 5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetate as a yellow solid and the crude product was used directly in the next step without further purification. LCMS observed m / z = 378.2 [M+H]+. Step 2: Preparation of ethyl 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetate. Intermediate O2A mixture of ethyl 2-[2-(dimethylamino)-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetate (275 mg, 0.7 mmol), 5-(benzyloxy)-6- methylpyrimidine-4-carboxylic acid (195 mg, 0.8 mmol) and DIPEA (188 mg, 1.4 mmol) in DMF (10 mL) was added HATU (332 mg, 0.8 mmol) and stirred at 25 °C under N2 for 3 hours. The mixture was quenched by the addition of H2O (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 17% EtOAc in petroleum ether) to afford (197 mg, 44% yield) of ethyl 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-(dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl)acetate as a light yellow solid. LCMS observed m / z = 604.3 [M+H]+. Step 3: Preparation of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetic acid. Intermediate OA mixture of ethyl 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-(dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl)acetate (192 mg, 0.3 mmol) in THF (6 mL) and H2O (3 mL) was added LiOH.H2O (15 mg, 0.6 mmol) and was stirred at 25 °C under N2for 3 hours. The mixture was adjusted to pH 6 with HCl (1 M in H2O) aqueous solution and concentrated in vacuo. The residue was purified by reversed phase C18 silica gel column chromatography (mobile phase: 0-50% MeCN in H2O) to afford (97 mg, 52% yield) of (6-{4-[5-(benzyloxy)-6- methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-(dimethylamino)-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetic acid as a white solid. LCMS observed m / z = 576.26 [M+H]+. Intermediate P Synthesis of 5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine. Intermediate PStep 1: Preparation of 2-bromo-5-iodobicyclo[4.2.0]octa-1,3,5-triene. Intermediate P1A mixture of 2,5-dibromobicyclo[4.2.0]octa-1(6),2,4-triene (5.2 g, 19.6 mmol) in THF (60 mL) was added n-BuLi (2.5 M in hexane, 9.4 mL, 23.6 mmol, 1.2 equiv.) solution dropwise at -78 ℃ under N2. The mixture was stirred for 30 minutes at -78 ℃. To the mixture was added a solution of I2 (6.0 g, 23.6 mmol) in THF (60 mL) dropwise at -78 ℃. The mixture was stirred for additional 25 minutes at -78 ℃. The mixture was warmed to 25 ℃ and stirred at 25 ℃ for 50 minutes. The mixture was quenched with saturatedNa2S2O3 aqueous solution (20 mL) at 0 ℃, extracted with EtOAc (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 100% petroleum ether) to afford (5.4 g, 90% yield) of 2-bromo-5-iodobicyclo[4.2.0]octa-1(6),2,4-triene as a white solid. LCMS observed m / z = 308.9 [M+H]+. Step 2: Preparation of 2-bromo-5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4- triene. Intermediate P2A mixture of 2-bromo-5-iodobicyclo[4.2.0]octa-1(6),2,4-triene (5.4 g, 17.5 mmol) and methyl 2,2-difluoro-2-sulfoacetate (16.8 g, 87.4 mmol) in NMP (30 mL) was treated with CuI (5.0 g, 26.2 mmol) in one portion at 25 ℃. The mixture was heated to 80 ℃ and stirred at 80 ℃ for 16 hours under N2. The mixture was cooled to 25 ℃, quenched with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 100% petroleum ether) to afford (4.1 g, 93% yield) of 2- bromo-5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-triene as a colorless oil. LCMS observed m / z = 250.9 [M+H]+. Step 3: Preparation of 5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine. Intermediate PA mixture of 2-bromo-5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-triene (3.9 g, 15.7 mmol) and Cu(acac)2 (4.1 g, 15.7 mmol) in DMF (40 mL) was treated with NH3.H2O (40 mL) in one portion at 25 ℃. The mixture was heated to 90 ℃ and stirred at 90 ℃ for 16 hours. The mixture was cooled to 25 ℃, quenched by the addition of H2O (65 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: with 2% EtOAc in petroleum ether) to afford (1.9 g, 65% yield) of 5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine as a brown yellow oil. LCMS observed m / z = 188.1 [M+H]+. Intermediate Q Synthesis of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)amino)ethyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate QStep 1: Preparation of tert-butyl 4-{2-bromo-4-[2-(tert-butoxy)-2-oxoethyl]-5-ethyl- 7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}piperazine-1-carboxylate. Intermediate Q1A mixture of tert-butyl 4-{2-bromo-5-ethyl-7-oxo-4H-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}piperazine-1-carboxylate (5.0 g, 11.7 mmol, Intermediate E) and tert- butyl 2-bromoacetate (2.4 g, 12.3 mmol) in DMF (8 mL) was treated with DIPEA (4.5 g, 35.1 mmol) in one portion at 25 ℃. The mixture was heated to 45 ℃ and stirred at 45 ℃ for 16 hours under N2. The mixture was cooled to 25 ℃. The precipitated solids were collected by filtration and washed with DMF (2 x 2 mL) to afford (2.5 g, 39% yield) of tert- butyl 4-{2-bromo-4-[2-(tert-butoxy)-2-oxoethyl]-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}piperazine-1-carboxylate as a white solid. LCMS observed m / z = 539.1 [M+H]+. Step 2: Preparation of {2-bromo-6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-5-ethyl- 7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetic acid.Intermediate Q2A mixture of tert-butyl 4-{2-bromo-4-[2-(tert-butoxy)-2-oxoethyl]-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl}piperazine-1-carboxylate (2.3 g, 4.2 mmol) in THF (150 mL) and MeOH (15 mL) was treated with NaOH (340 mg, 8.5 mmol) in H2O (20 mL) in one portion at 25 ℃. The mixture was stirred at 25 ℃ for 2 hours. The mixture was acidified to pH 6~7 with HCl (0.1 M in H2O) aqueous solution and concentrated in vacuo. The aqueous layer was extracted with CH2Cl2(3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford (1.8 g) of {2-bromo-6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl}acetic acid as a brown yellow solid. The crude product was used directly in the next step without further purification. LCMS observed m / z = 487.1 [M+H]+. Step 3: Preparation of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)amino)ethyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate QA mixture of {2-bromo-6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-5-ethyl-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetic acid (1.3 g, 2.7 mmol) and 5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine (467 mg, 2.5 mmol, Intermediate P) in DMF (20 mL) was treated with TCFH (898 mg, 3.2 mmol) and NMI (1.1 g, 13.4 mmol) in one portion at 25 ℃. The mixture was heated to 40 ℃ and stirred at 40 ℃ for 36 hours. The mixture was cooled to 25 ℃, quenched with H2O (120 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washedwith brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by reversed phase C18 silica gel column chromatography to afford (1.0 g, 55% yield) of tert-butyl 4-[2-bromo-5-ethyl-7-oxo-4-({[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]carbamoyl}methyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate as a white solid.1H NMR (400 MHz, Methanol-d4) δ 7.42 (q, J = 8.8 Hz, 2H), 5.23 (s, 2H), 4.11 – 4.05 (m, 2H), 3.57 – 3.53 (m, 2H), 3.37 (s, 2H), 3.24 (t, J = 4.3 Hz, 2H), 3.09 – 3.03 (m, 4H), 2.79 – 2.75 (m, 2H), 1.51 (s, 9H), 1.29 (t, J = 7.5 Hz, 3H). LCMS observed m / z = 654.25 [M+H]+. Intermediate R Synthesis of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)amino)ethyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate R6. Step 1: Preparation of 2-[2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4- trien-2-yl]acetamide. Intermediate R1A mixture of tert-butyl 4-[2-bromo-5-ethyl-7-oxo-4-({[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]carbamoyl}methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (1.5 g, 2.3 mmol, Intermediate Q) in HCl (4 M in 1,4-dioxane, 20 mL) solution was stirred for 30 minutes at 25 ℃. The mixture was concentrated in vacuo to afford (1.3 g crude) of 2-[2-bromo-5- ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide. The crude product was used directly in the next step without further purification. LCMS observed m / z = 554.0 [M+H]+. Step 2: Preparation of 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N- [5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide. Intermediate RA mixture of 2-[2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide (1.3 g, 2.3 mmol) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (560 mg, 2.3 mmol, Intermediate A) in DMF (10 mL) was treated with HATU (1.1 g, 2.8 mmol) and DIPEA (1.5 g, 11.5 mmol) in one portion at 25 ℃ and stirred at 25 ℃ for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by reversed phase C18 silica gel column chromatography (mobile phase: 50-99% MeOH in H2O) to afford (1.0 g, 53% yield) of 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine- 4-carbonyl]piperazin-1-yl}-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)- N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]acetamide as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.87 (s, 1H), 7.55 – 7.48 (m, 3H), 7.48 – 7.38 (m, 4H), 5.22 – 5.06 (m, 4H), 4.57 (m, 1H), 3.48 (m, 2H), 3.37 (s, 1H), 3.27 (dd, J = 5.5,2.9 Hz, 2H), 3.19 (q, J = 4.7, 4.2 Hz, 2H), 3.02 – 2.98 (m, 3H), 2.87 – 2.85 (m, 1H), 2.66 – 2.64 (m, 1H), 2.49 (s, 3H), 1.16 (t, J = 7.4 Hz, 3H). LCMS observed m / z = 780.30 [M+H]+. Intermediate S Synthesis of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetic acid. Intermediate SStep 1: Preparation of ethyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6- (piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate. Intermediate S1A mixture of tert-butyl 4-[2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethoxy-2-oxoethyl)- 5-ethyl-7-oxo-[1,2,4] triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (2.4 g, 4.6 mmol) in mixed solvent of CH2Cl2 (25 mL) and TFA (14 mL) was stirred at 25 °C for 40 minutes. The mixture was concentrated in vacuo to afford (1.9 g, crude) of ethyl 2-(2-(3,6- dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4] triazolo [1,5-a]pyrimidin- 4(7H)-yl)acetate. The crude product was used directly in the next step without further purification. LCMS observed m / z = 417.1 [M+H]+. Step 2: Preparation of ethyl 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetate. Intermediate S2A mixture of ethyl 2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1- yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetate (1.9 g, 4.5 mmol), 5-(benzyloxy)-6- methylpyrimidine-4-carboxylic acid (1.2 g, 5.0 mmol, Intermediate A), DIPEA (2.9 g, 22.8 mmol) and HATU (2.6 g, 6.8 mmol) in DMF (25 mL) was stirred at 25 °C for 4 hours. The mixture was quenched with H2O (30 mL) at 25°C and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 5% MeOH in CH2Cl2) to afford (1.8 g, 61% yield) of ethyl 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin-1-yl}-2-(3,6- dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetate as a brown yellow oil. LCMS observed m / z = 643.1 [M+H]+. Step 3: Preparation of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetic acid. Intermediate SA mixture of ethyl 2-(6-{4-[5-(benzyloxy)-6-methylpyrimidine-4- carbonyl]piperazin-1-yl}-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-4-yl)acetate (1.8 g, 5.3 mmol) and LiOH.H2O (380 mg, 15.9 mmol) in THF (20 mL) and H2O (4 mL) was stirred at 40 °C for 6 hours. The mixture was concentrated invacuo. The residue was purified by preparatory HPLC (column: XBridge BEH C18 OBD Prep Column 130, 5 m, 30 mm * 150 mm; mobile phase: 12-35% MeCN in H2O) to afford (911 mg, 50% yield) of (6-{4-[5-(benzyloxy)-6-methylpyrimidine-4-carbonyl]piperazin-1- yl}-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4- yl)acetic acid as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.82 (s, 1H), 7.54 – 7.38 (m, 5H), 6.97 – 6.93 (m, 1H), 5.21 – 5.12 (m, 2H), 4.95 (d, J = 3.6 Hz, 2H), 4.70 – 4.67 (m, 1H), 4.34 (q, J = 2.8 Hz, 2H), 3.93 – 3.90 (m, 2H), 3.78 – 3.69 (m, 2H), 3.47 – 3.34 (m, 2H), 3.16 – 2.92 (m, 4H), 2.77 – 7.74 (m, 1H), 2.69 – 2.63 (m, 2H), 2.49 (s, 3H), 1.30 – 1.26 (m, 3H). LCMS observed m / z = 615.40 [M+H]+. Intermediate T Synthesis of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetic acid. Intermediate TStep 1: Preparation of tert-butyl 4-(2-(benzo[d][1,3]dioxol-5-yl)-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate T1A mixture of tert-butyl 4-[2-bromo-4-({[2-chloro-4-(trifluoromethyl) phenyl]carbamoyl} methyl)-5-ethyl-7-oxo-[1,2,4]triazolo [1,5-a]pyrimidin-6-yl] piperazine-1-carboxylate (2.0 g, 3.0 mmol, Intermediate F) and 2-(2H-1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 4.5 mmol) in dioxane (60 mL) and H2O (20 mL) were added Na2CO3(960 mg, 9.1 mmol) and Pd(dppf)Cl2.CH2Cl2(246 mg, 0.3 mmol) in portions at 25 °C. The mixture was heated to 100 °C and stirred at 100°C for 3 hours under N2. The mixture was cooled to 25 °C and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 17% EtOAc in petroleum ether) to afford (1.2 g, 56% yield) of tert-butyl 4-[2-(2H-1,3-benzodioxol-5-yl)-4-({[2- chloro-4-(trifluoromethyl)phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]piperazine-1-carboxylate as a white solid. LCMS observed m / z = 704.21 [M+H]+. Step 2: Preparation of 2-[2-(2H-1,3-benzodioxol-5-yl)-5-ethyl-7-oxo-6-(piperazin- 1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[2-chloro-4- (trifluoromethyl)phenyl]acetamide. Intermediate TA mixture of tert-butyl 4-[2-(2H-1,3-benzodioxol-5-yl)-4- ({[2-chloro-4- (trifluoromethyl) phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]piperazine-1-carboxylate (1.4 g, 2.0 mmol) and TFA (1.1 g, 1.0 mmol) in CH2Cl2(10 mL) was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo, diluted with H2O (10 mL), basified to pH 8 with saturated NaHCO3aqueous solution and extracted with CH2Cl2 (5 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by trituration with EtOAc to afford (530.4 mg, 44% yield) of 2-[2-(2H-1,3-benzodioxol-5-yl)- 5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[2-chloro-4- (trifluoromethyl)phenyl]acetamide as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 8.6 Hz, 1H), 7.85 – 7.76 (m, 2H), 7.66 – 7.60 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.04 (s, 2H), 5.47 (s, 2H), 3.96- 3.91 (m, 2H), 3.39 – 3.34 (m, 2H), 3.26 – 3.21 (m, 2H), 3.13 – 3.10 (m, 2H), 3.04 – 2.97 (m, 2H), 1.33 (t, J = 7.5 Hz, 3H). LCMS observed m / z = 604.25 [M+H]+.Intermediate U Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(isochroman-6- yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide. Intermediate UStep 1: Preparation of tert-butyl 4-(2-(benzo[d][1,3]dioxol-5-yl)-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate U1A mixture of tert-butyl 4-[2-bromo-4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]piperazine-1-carboxylate (700 mg, 1.0 mmol, Intermediate F) and 2-(3,4- dihydro-1H-2-benzopyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (329 mg, 1.2 mmol) in dioxane (10 mL) and H2O (3 mL) were added K2CO3 (364 mg, 2.6 mmol) and Pd(dppf)Cl2.CH2Cl2 (77 mg, 0.1 mmol) in portions at 25 °C under N2. The mixture was heated to 90 °C and stirred at 90 °C for 4 hours under N2. The mixture was cooled to 25 °C and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 50% EtOAc in petroleum ether) to afford (500 mg, 66% yield) of tert-butyl 4- [4-({[2-chloro-4-(trifluoromethyl)phenyl]carbamoyl}methyl)-2-(3,4-dihydro-1H-2- benzopyran-6-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1- carboxylate as a white solid. LCMS observed m / z = 716.2 [M+H]+.Step 2: Preparation of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-(3,4-dihydro- 1H-2-benzopyran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin- 4-yl]acetamide. Intermediate UA mixture of tert-butyl 4-[4-({[2-chloro-4- (trifluoromethyl)phenyl]carbamoyl}methyl)-2-(3,4-dihydro-1H-2-benzopyran-6-yl)-5- ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate (100 mg, 0.1 mmol) in a mixed solvent of TFA (3 mL) and CH2Cl2(3 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 50% EtOAc in petroleum ether) to afford (50 mg, 58% yield) of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-(3,4-dihydro-1H-2-benzopyran-6-yl)-5- ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.06 (s, 1H), 8.61 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.90 (dt, J = 4.2, 2.0 Hz, 2H), 7.73 (dd, J = 8.7, 2.1 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 5.42 (s, 2H), 4.74 (s, 2H), 3.92 (t, J = 5.7 Hz, 2H), 3.83 – 3.73 (m, 2H), 3.18 (s, 3H), 3.05-2.95 (m, 2H), 2.92 – 2.83 (m, 4H), 1.25-1.15 (m, 3H). LCMS observed m / z = 616.20 [M+H]+. Intermediate V Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(2- (cyclopropanesulfonamido)benzoyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((3aR,6aS)- tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetamide. Intermediate VStep 1: Preparation of tert-butyl 4-(4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-((3aR,6aS)-tetrahydro-1H- furo[3,4-c]pyrrol-5(3H)-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1- carboxylate. Intermediate V1To a solution of tert-butyl 4-[2-bromo-4-({[2-chloro-4-(trifluoromethyl) phenyl] carbamoyl} methyl)-5-ethyl-7-oxo- [1,2,4] triazolo[1,5-a] pyrimidin-6-yl] piperazine-1- carboxylate (400 mg, 0.6 mmol, Intermediate F) and (3aR,6aS)-hexahydro-1H-furo[3,4-c] pyrrole (137 mg, 1.2 mmol) in IPA (4 mL) was added NEt3(244 mg, 2.4 mmol) in one portion at 25 °C. The mixture was stirred at 100 °C under N2 for 48 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: with 50% EtOAc in petroleum ether) to afford (331 mg, 79% yield) of tert-butyl 4- {2-[(3aR,6aS)-hexahydrofuro[3,4-c] pyrrol-5-yl]-4-({[2-chloro-4-(trifluoromethyl) phenyl] carbamoyl} methyl)-5-ethyl-7-oxo- [1,2,4] triazolo[1,5-a] pyrimidin-6-yl} piperazine-1- carboxylate as a white solid. LCMS observed m / z = 695.30 [M+H]+. Step 2: Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(2- (cyclopropanesulfonamido)benzoyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((3aR,6aS)- tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetamide. Intermediate VA mixture of tert-butyl 4-{2-[(3aR,6aS)-hexahydrofuro[3,4-c] pyrrol-5-yl]-4-({[2- chloro-4-(trifluoromethyl) phenyl] carbamoyl} methyl)-5-ethyl-7-oxo- [1,2,4] triazolo[1,5- a] pyrimidin-6-yl} piperazine-1-carboxylate (196 mg, 0.3 mmol) in CH2Cl2(5 mL) was added TFA (1 mL) in portions at 0 °C under N2. The mixture was stirred at 0 °C under N2for 30 minutes. The mixture was quenched with H2O (10 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (6-(4-(2-(cyclopropanesulfonamido)benzoyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((3aR,6aS)- tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetamide as a crude product. The crude product was used directly in the next step without further purification. LCMS observed m / z = 595.20 [M+H]+. Intermediate W Synthesis of 2-[2-(dimethylamino)-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4- trien-2-yl]acetamide. Intermediate WStep 1: Preparation of tert-butyl 4-[2-(dimethylamino)-5-ethyl-7-oxo-4-({[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]carbamoyl}methyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate.Intermediate W1To a stirred mixture of {6-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2- (dimethylamino)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}acetic acid (200 mg, 0.4 mmol, Intermediate M) and 5-(trifluoromethyl) bicyclo[4.2.0]octa-1(6),2,4-trien-2- amine (83 mg, 0.4 mmol, Intermediate P) in MeCN (2 mL) were added NMI (109 mg, 1.3 mmol) and TCFH (124 mg, 0.4 mmol) in portions at 25 °C under N2. The mixture was heated to 50 °C and stirred at 50 °C for 2 hours under N2. The mixture was cooled to 25 °C. The mixture was quenched with H2O (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by reversed phase C18 silica gel column chromatography (mobile phase: with 60-75% MeCN in H2O) to afford (234 mg, 85% yield) of tert-butyl 4-[2-(dimethylamino)-5-ethyl-7-oxo-4-({[5- (trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]carb amoyl}methyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate as a yellow solid. LCMS observed m / z = 619.6 [M+H]+. Step 2: Preparation of 2-[2-(dimethylamino)-5-ethyl-7-oxo-6-(piperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4- trien-2-yl]acetamide. Intermediate WA solution of tert-butyl 4-[2-(dimethylamino)-5-ethyl-7-oxo-4-({[5- (trifluoromethyl) bicyclo [4.2.0] octa-1(6),2,4-trien-2-yl] carbamoyl} methyl)- [1,2,4]triazolo[1,5-a] pyrimidin-6-yl] piperazine-1-carboxylate (234 mg, 0.4 mmol) and TFA (111 mg, 1.2 mmol) in CH2Cl2(5 mL) was stirred at 25 ℃ for 1 hour. The mixture was concentrated in vacuo to afford (160 mg, crude) of 2-[2-(dimethylamino)-5-ethyl-7-oxo-6- (piperazin-1-yl)- [1,2,4] triazolo[1,5-a] pyrimidin-4-yl]-N-[5-(trifluoromethyl) bicyclo [4.2.0] octa-1(6),2,4-trien-2-yl] acetamide as a yellow oil. The crude product was used directly in the next step without further purification. LCMS observed m / z = 743.2 [M+H]+. Intermediate X Synthesis of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-1,1-difluoro-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate XThe title compound can be prepared using similar procedure as Intermediate F, replacing N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (Intermediate D) with N-(2-chloro-4-(trifluoromethyl)phenyl)-2,2-difluoro-2-iodoacetamide. Intermediate Y Synthesis of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((3- (perfluoroethyl)bicyclo[1.1.1]pentan-1-yl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate YThe title compound can be prepared using similar procedure as Intermediate Q, replacing 5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine (Intermediate P) with 3-(perfluoroethyl)bicyclo[1.1.1]pentan-1-amine. Intermediate Z Synthesis of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- ((trifluoromethyl)thio)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Intermediate ZThe title compound can be prepared using similar procedure as Intermediate Q, replacing 5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine (Intermediate P) with 2-chloro-4-((trifluoromethyl)thio)aniline. Intermediate AA Synthesis of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4- ((trifluoromethyl)thio)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)piperazine-1-carboxylate. Intermediate AAThe title compound can be prepared using similar procedure as Intermediate Q, replacing 5-(trifluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine (Intermediate P) with 4-((trifluoromethyl)thio)aniline. Intermediate AB Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylic acidIntermediate ABTo a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid, Intermediate A (30.0 g, 122 mmol, 1 eq) in EtOAc (150 mL) was added Pd / C (3.00 g, 2.82 mmol, 10% purity, 2.30e-2eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2(15 Psi) at 28 °C for 4 hrs. TLC (Dichloromethane / Methanol = 5 / 1) indicated Intermediate A consumed completely and one new spot formed. The mixture was filtrated through a pad of Celite and washed with MeOH (3 times 200 mL), then was concentrated under reduced pressure to give a residue. The crude product (14.5 g, 94.0 mmol, 76.6% yield) was used into the next step without further purification and obtained as a reddish solid. LCMS observed m / z = 153.14 [M–H]–. Intermediate AC Synthesis of 2-(2-bromo-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide Intermediate ACIn a 250 mL round bottom flask equipped with a stir bar was added 5-hydroxy-6- methylpyrimidine-4-carboxylic acid, Intermediate AB (1.75 g, 11.4 mmol) and CH2Cl2 (75 mL). The mixture was allowed to stir at room temperature for 2 minutes to form a slurry, then Ghosez reagent (1.80 mL, 13.6 mmol) was added dropwise at room temperature via syringe over a period of 5 minutes. The reaction mixture was allowed to stir at room temperature. After 1.5 hours, the reaction mixture was a homogeneous brown solution. In a separate 500 mL round bottom flask equipped with a stir bar was added 2-(2-bromo-5-ethyl- 7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide, Intermediate G (4.52 g, 7.54 mmol), CH2Cl2 (60 mL), and DIPEA (7.9 mL, 45.3 mmol). The mixture was allowed to stir at room temperature for5 minutes to form a suspension, then cooled to -10 C via brine / ice bath. The reaction vessel was fitted with an addition funnel, and the reaction mixture containing above reaction mixture was transferred to the addition funnel, rinsing with CH2Cl2 (3 x 2 mL). The reaction mixture was allowed to stir at -10 C. After 1.5 hours, the reaction mixture was diluted with 1:1 H2O : saturated aqueous NH4Cl (100 mL) and the phases were partitioned. The organic layer was washed with water (1 x 100 mL), and the combined aqueous layers were further extracted with 3:1 CHCl3 : i-PrOH (3 x 200 mL). The combined organic extracts were washed with saturated aqueous NaHCO3(1 x 200 mL), brine (1 x 200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The combined crude residue was purified by column chromatography (SiO2, 1% to 10% MeOH in CH2Cl2) affording Intermediate AC (5.01 g, 96% yield). LCMS observed m / z = 698.10 [M+H]+. Intermediate AD Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate Intermediate ADTo a solution of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate F (77.6 g, 117 mmol, 1 eq) and the corresponding boronate ester (30.2 g, 122 mmol, 1.05 eq) in dioxane (776 mL) and H2O (115 mL) was added K3PO4(74.5 g, 351 mmol, 3 eq) and Pd(dppf)Cl2(4.28 g, 5.85 mmol, 0.05 eq) under N2. The mixture was stirred at 80 °C for 16 hrs under N2. The residue was diluted with water (1200 mL) and extracted with ethyl acetate (1200 mL * 4). The combined organic layers were washed with aq. NaCl (1200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. TLC (Petroleum ether: Ethyl acetate = 1: 1, Rf / product = 0.40). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, CH2Cl2) attwice. The product was dissolved with CH2Cl2 (1.5 L). The mixture was added Pd scavenger (70.0 g) and stirred at 38 °C for 30 mins, filtered and concentrated under the reduced pressure to give tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (67.0 g, 95.4 mmol, 81.5% yield) as a white solid. LCMS: m / z = 646.4 [M-56+1]+. Intermediate AE Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3- dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide Intermediate AETo a solution of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate AD (74.6 g, 106 mmol, 1 eq) was added HCl / dioxane (2 M, 746 mL, 14.04 eq) in portions. The mixture was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,3- dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)acetamide (68.1 g, crude, HCl) was obtained as a white solid. LCMS: m / z = 602.2 [M+1]+. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate Intermediate AFTo a solution of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Intermediate F (10.0 g, 15.1 mmol, 1 eq) and the corresponding boronic acid (2.9 g, 15.1 mmol, 1.0 eq) in dioxane (50 mL) and H2O (15 mL) was added K3PO4(9.61 g, 45.3 mmol, 3 eq) and Pd(dppf)Cl2(616 mg, 0.754 mmol, 0.05 eq) under N2. The mixture was stirred at 80 °C for 16 hrs under N2. The residue was diluted with water (120 mL) and extracted with ethyl acetate (120 mL * 4). The combined organic layers were washed with aq. NaCl (120 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. TLC (Petroleum ether: Ethyl acetate = 1: 1, Rf / product = 0.40). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, CH2Cl2). The product was dissolved with CH2Cl2(1.5 L). The mixture was added Pd scavenger (10.0 g) and stirred at 38 °C for 30 mins, filtered and concentrated under the reduced pressure to givetert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(1,1-dimethyl-1,3- dihydroisobenzofuran-5-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)piperazine-1-carboxylate (8.33 g, 11.4 mmol, 75.6% yield) as a white solid. LCMS: m / z = 674.2 [M-56+1]+. Intermediate AG Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(1,1...

Claims

CLAIMS: What is claimed is:

1. A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6 and R7 are independently selected from H or halogen; wherein R6or R7can optionally join with R5to form a C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein (A) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclylring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, , wherein R33is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3alkyl, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4--membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6-membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1 is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6 alkenyl, or C2-C6 halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring,wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring, and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; (B) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra and Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, - NR8R9, -C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or -S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2is NR8R9and R3is H or R2and R3join together to form a substituted fused 4-membered heterocyclyl ring, wherein thesubstituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C2-C6alkenyl, a C3-C7 cycloalkyl ring, C1-C6 hydroxyalkyl, , wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10iswherein W, U, V, and Z are independently selected from H, C, N, S, or O and refers to a single or a double bond; wherein whenwherein when U is N+, R15is O-, R16and R17are H, and U V is a double bond; wherein when U is C, R15 is -NR19R20,U V is a double-bond and R16, R17, R18, are independentlyselected from H, -CH3, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 are independently selected from C1-C3 alkyl, C3-C5 cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring; wherein R1is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring, and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring;, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2; wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl; wherein when6 alkyl, C2-C6 alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25and R29are independently selected from H, halogen, or -C(O), R26and R27are independently selected from H, -OCF2Cl, or -S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25 or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen; wherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2 and R3 are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring.

2. A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6 alkoxy, or C3-C6 cycloalkyl; R6 and R7 are independently selected from H or halogen; wherein R6or R7can optionally join with R5to form a C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein (A) R1is NR30R31, aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, the said aryl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is optionally substituted with one or more R36, or the said aryl, C3-C7cycloalkyl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl is linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a spiro ring, or said the aryl C3-C7cycloalkyl 5-10 membered heteroaryl or 3-8 membered heterocyclylis fused with a second 5-10 membered heteroaryl, a C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl ring or a C3-C8cycloalkenyl ring, wherein R36 is independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6hydroxyalkyl, C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -O-(C1-C6)alkyl-COOH, -C(O)-R33, -C(O)- NH-R33, -S(O)R33, -S(O2)R33, -NH-S(O2)R33, -NH-C(O)-NH-R33, wherein R33is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; and either (B) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2 is NR8R9, and R3 is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein thesubstituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4 alkyl, and -C(O)R11, wherein R11 is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2 and R3 join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is C1-C6hydroxyalkyl, C2-C6 alkenyl, a C3-C7 cycloalkyl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C3alkoxy, an optionally substituted C3-C5 cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2is H, R3is -C(O)R10, or -S(O2)R10, and R10is, wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; ; wherein whenwherein when U is N+, R15 is O-, R16 and R17 are H, and U V is a double bond; wherein when U is C, R15is -NR19R20U V is a double-bond and R16, R17, and R18 are independentlyselected from H, -CH3, -C(O)R21, -S(O2)R21, and - S(O)R21R22, R19, and R20are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 are independently selected from C1-C3 alkyl, C3-C5cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21 and R22 join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring; and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring; or (C) R4is selected fromL and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2; wherein whenalkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein whenC1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl;wherein when6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25 and R29 are independently selected from H, halogen, =O, or -C(O), R26 and R27 are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28is a methyl or trihalomethyl group, or either R25or R27 join with R26 to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring.

3. A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:K and J are independently selected from C, N, O, or S; R, R0and R5are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl ring; and wherein (A) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, -OH, =O, C1-C6alkyl; R2and R3are independently selected from H, -OH, =O, C1-C6alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when Ra and R2 join together to form a fused C3-C8 cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34or - S(O2)R34, wherein R34is a C1-C6alkyl, C3-C8cycloalkyl ring, C4-C8cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2and R3join together to form an unsubstituted or substituted fused 3-8 membered heterocyclyl ring wherein when the 3-8 membered heterocyclyl ring is substituted,the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11,wherein R11is a C1-C3alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein R8 and R9 are independently selected from H, C1-C6 alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein R10 is selected from C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, a C3- C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, wherein R10is optionally substituted with -OH, C1-C6alkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, a 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or R10 is fused with a second C3-C8 cycloalkyl, C3-C8cycloalkenyl, C6-C10aryl, a 3-8 membered heterocyclyl, or a 5-10 membered heteroaryl; and either (B) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionally substituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl;C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-memberedheterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; and wherein R4is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring orL and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 1 or 2;wherein whenalkyl, wherein the C1-C4alkyl is optionally substituted with halogens selected from F or Cl, or R23is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, bridged C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl; wherein whenC1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with halogens selected from F or Cl, or R24 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring, wherein L is optionally substituted with -OH, halogen, C1-C6 alkyl; wherein when6 alkyl, C2-C6 alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl or the said R24 is a spiro ring or a fused ring; wherein whensingle or double bond; wherein when L G is a double bond, G and L are independently selected from C or N, R25and R29are independently selected from H, halogen, =O, or -C(O), R26and R27are independently selected from H, -C(F2)-C(F2Cl), -OC(F2Cl), -OC(HF2), or - S(O)mR28, wherein m is 0-2, R28 is a methyl or trihalomethyl group, or either R25 or R27join with R26to form a 5- or 6- membered heterocyclyl ring, optionally substituted with -OH, alkyl, haloalkyl, or halogen; andwherein R1 is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring.

4. A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:wherein K and J are independently selected from C, N, O, or S; R, R0 and R5 are independently selected from H, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6alkoxy, or C3-C6cycloalkyl; R6and R7are independently selected from H or halogen; wherein R6 or R7 can optionally join with R5 to form a C3-C8 cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl ring; and wherein (A) R4 is selected from, wherein L and G are independently selected from C, N, or O, n is 0, 1, or 2, and x is 0, 1 or 2;wherein R23 and R24 are independently selected from -OH, -COOH, -NH2, - CN, oxo, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, a bridged or unbridged C3-C8 cycloalkyl, a 3-8 membered heterocyclyl, 3-8 membered heterocyclyl ring, C6-C10aryl, or 5-10 membered heteroaryl; wherein whensingle or double bond; R25, R29, and R35are independently selected from H, halogen, -OH, =O, -C(O); C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; R26 and R27 are independently selected from H, C1-C6 alkyl, C1-C6haloalkyl, C2-C6haloalkenyl, C1-C6hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8cycloalkyl, -OR28, or -S(O)mR28, wherein m is 0-2, R28is C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, alkoxy, halogenated alkoxy, or C3-C8 cycloalkyl; wherein R25 or R27 join with R26 to form a C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; and either (B) R1is NR30R31, aryl, C3-C7cycloalkyl ring, 5-10 membered heteroaryl, or 4-, 5-, or 6- membered heterocyclyl ring; wherein when R1 is NR30R31, R30 and R31 are independently selected from optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or H; wherein when R1is aryl, the aryl is substituted by one or more -O-(C1-C6)alkyl- COOH, three C1-C6 alkoxy, -C(O)-R33, -C(O)-NH-R33, -S(O)R33, -S(O2)R33, -NH- S(O2)R33, -NH-C(O)-NH-R33, or the aryl is fused with a 5-10 membered heteroaryl, a C3-C8cycloalkyl ring, a C3-C8cycloalkenyl ring, a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen and / or at least one nitrogen atom, wherein R33 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1- C6hydroxyalkyl, halogenated C1-C6alkoxy, C3-C8cycloalkyl, 4-8 membered heterocyclyl ring, C6-C10 aryl, or 5-10 membered heteroaryl, and wherein the said aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, C3-C8cycloalkenyl ring, and 5- or 6-membered heterocyclyl ring are optionallysubstituted with one or more, C1-C3 alkyl, halogen, -OH, =O, -C(O)-C1-C6 alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6 hydroxyalkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; C3-C8 cycloalkenyl, a second C6-C10 aryl, a second 5-10 membered heteroaryl, or 3-8 membered heterocyclyl; wherein when R1 is C3-C7 cycloalkyl ring, the said C3-C7 cycloalkyl is a fully saturated ring, wherein the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl to form a spiro ring, or the said C3-C7 cycloalkyl ring is optionally linked with a second C3-C8 cycloalkyl ring, a 3-8 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl to form a fused ring, unless R4is a substituted phenyl group; wherein when R1 is a 5-10 membered heteroaryl ring, the said 5-10 membered heteroaryl ring is substituted with -OH, -C(O)-C1-C6 alkyl, or -O-(C1-C6)alkyl- COOH, or the said 5-10 heteroaryl ring is fused with a second 5-10 membered heteroaryl ring, a C6-C10 aryl ring, a C3-C8 cycloalkyl ring, a C3-C8 cycloalkenyl ring, or 4-8 membered heterocyclyl ring; wherein when R1is a 4-membered heterocyclyl ring, the said 4-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, or the said 4-membered heterocyclyl ring is optionally linked with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen or oxygen atom, wherein the said 4- or 7-membered heterocyclyl ring is linked with the said second 4-, 5-, or 6- membered heterocyclyl ring by one carbon atom to form a spiro ring or two carbon atoms to form a fused ring; wherein when R1is a 5- or 6-membered heterocyclyl ring, the said 5- or 6-membered heterocyclyl ring is a fully saturated ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein the said 5- or 6-membered heterocyclyl ring is substituted with one or more C2-C6alkenyl, or C2-C6halogenated alkenyl or is linked with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ringto form a spiro ring, or the said 5- or 6-membered heterocyclyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6-membered heterocyclyl ring to form a fused ring, wherein the said second 4-, 5-, or 6-membered heterocyclyl ring comprises carbon atoms and at least one of a nitrogen atom or oxygen atom, wherein when said 5- or 6-membered heterocyclyl ring is linked with a second 5 membered heterocyclyl ring by one carbon atom to form a spiro ring and the second 5 membered heterocyclyl ring is fully saturated, the one or more heteroatoms in the second 5 membered heterocyclyl ring is selected from N or S; wherein when said 5- or 6-membered -membered heterocyclyl ring is linked with a second 4-, 5-, or 6-membered heterocyclyl ring by two carbon atoms to form a fused ring; the second 4-, 5-, or 6-membered heterocyclyl ring is partially unsaturated or fully unsaturated; or the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one silicon atom; or the 5-membered heterocyclyl ring is a pyrazole ring, wherein the pyrazole ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring, wherein the said second 4- , 5-, or 6- membered heterocyclyl ring is a saturated ring comprising carbon atoms and at least one of a nitrogen atom or oxygen atom, or the 6-membered heterocyclyl ring is a pyridinyl ring, wherein the pyridinyl ring is joined with a second substituted or unsubstituted 4-, 5-, or 6- membered heterocyclyl ring to form a fused ring; and wherein n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rb are independently selected from H, - OH, =O, a substituted or unsubstituted alkyl or join together to form a fused cycloalkyl ring, a cycloalkenyl ring, a aryl ring, a heterocyclyl ring, or a heteroaryl ring; R2and R3are independently selected from H, -OH, =O, an substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl ring, or join together to form an unsubstituted or substituted fused heterocyclyl ring or(C) n is 0, 1, 2, or 3; refers to a single or a double bond; B, D, E, X and Y are independently selected from C or N; Ra, Rbare independently selected from H, -OH, =O, C1-C6 alkyl; R2 and R3 are independently selected from H, -OH, =O, C1-C6 alkyl, -NR8R9, - C(O)R10, -S(O2)R10, substituted or unsubstituted C2-C3 alkenyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl ring, or Raand R2join together to form a fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; or R2 and R3 join together to form an unsubstituted or substituted fused 4-, 5-, or 6-membered heterocyclyl ring, wherein when the 4-, 5-, or 6-membered heterocyclyl ring is substituted, the substituents are optionally selected from -OH, =O, C1-C6 alkyl, a 5- or 6- membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring; wherein when Raand R2join together to form a fused C3-C8cycloalkyl ring, C3-C8cycloalkenyl ring, a C6-C10 aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, the fused C3-C8 cycloalkyl ring, C3-C8 cycloalkenyl ring, a C6-C10aryl ring, a 3-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring is substituted by -C(O)R34 or -S(O2)R34, wherein R34 is a C1-C6 alkyl, C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, a C6-C10 aryl ring, a 4-8 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring; wherein when n is 0, X is N, Y is C, R2is NR8R9,and R3is H; wherein when n is 1, X and Y are C, R2 is NR8R9 and R3 is H or R2 and R3 join together to form a substituted fused 4-membered heterocyclyl ring, wherein the substituted 4-membered heterocyclyl ring is substituted with -C(O)R11, and wherein R11 is a substituted 5- or 6-membered heterocyclyl ring; wherein when R2 is NR8R9, R8 and R9 are independently selected from H, C1-C4alkyl, and -C(O)R11, wherein R11is a substituted or unsubstituted 5- or 6-membered heterocyclyl ring; wherein when n is 2, X is C, Y is N, and R2and R3join together to form an unsubstituted or substituted fused 4- or 5-membered heterocyclyl ring, wherein when the 5- membered heterocyclyl ring is substituted, the substituents are selected from a 5- or 6-membered heterocyclyl ring or -C(O)R11, wherein R11 is a C1-C3 alkyl or substituted 5- or 6-membered heterocyclyl ring, orX is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is C1-C6 hydroxyalkyl, C2-C6alkenyl, a C3-C7cycloalkyl ring, wherein R10is optionally substituted with -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C3 alkoxy, an optionally substituted C3-C5cycloalkyl ring, halogen, an optionally substituted 3-8 membered heterocyclyl, -S(O2)CH3, or -C(O)N(CH3)2, or X is C, Y is N, R2 is H, R3 is -C(O)R10, or -S(O2)R10, and R10 is, wherein W, U, V, and Z are independently selected from H, C, N, S, or O and wherein refers to a single or a double bond; wherein when U is N+, R15is O-, R16and R17are H, and U V is a double bond; wherein when U is C, R15 is -NR19R20 U V is a double-bond and R16, R17, and R18are independently selected from H, -CH3, -C(O)R21, -S(O2)R21, and -S(O)R21R22, R19, and R20 are independently selected from -C(O)R21, -S(O2)R21, and -S(O)R21R22, wherein R21 and R22 are independently selected from C1-C3alkyl, C3-C5cycloalkyl ring, or 5- or 6- membered heterocyclyl ring or R21and R22join together to form a substituted or unsubstituted C3-C5 cycloalkyl ring; and wherein R1is H, -OH, =O, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl; a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, a substituted or unsubstituted heteroaryl ring.

5. The compound of claims 1-4, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, and wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3alkyl.

6. The compound of claims 1-4, wherein n is 2; B, D, E, and X are C; Y is N; Raand Rbare H; R2 is H; and R3 is -C(O)R10, wherein R10 is a 5-10 membered heteroaryl ring, and wherein R10is optionally substituted with -OH, C1-C6alkyl.

7. The compound of claims 1-4, wherein, wherein when R4isdouble bond; wherein when L G is a double bond; R25 and R33 are H and R29 is halogen; and R26 is H and R27 is C1-C6 haloalkyl.

8. The compound of claims 1-4, wherein K and J are N; R0is H, R is =O, and R5is C1-C6alkyl; and R6 and R7 are H.

9. The compound of claim 5, wherein R1 is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, and wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3 alkyl; and wherein n is 2; B, D, E, and X are C; Y is N; Raand Rbare H; R2is H; and R3is - C(O)R10, wherein R10is a 5-10 membered heteroaryl ring, and wherein R10 is optionally substituted with -OH, C1-C6 alkyl.

10. The compound of claim 5, wherein R1 is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, and wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3 alkyl; anddouble bond; wherein when L G is a double bond; R25 and R33 are H and R29 is halogen; and R26 is H and R27 is C1-C6 haloalkyl.

11. The compound of claim 5, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, and wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3alkyl; and wherein K and J are N; R0 is H, R is =O, and R5 is C1-C6 alkyl; and R6 and R7 are H.

12. The compound of claim 6, wherein n is 2; B, D, E, and X are C; Y is N; Ra and Rb are H; R2is H; and R3is -C(O)R10, wherein R10is a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl; anddouble bond; wherein when L G is a double bond; R25and R33are H and R29is halogen; R26 is H and R27 is C1-C6 haloalkyl.

13. The compound of claim 6, wherein n is 2; B, D, E, and X are C; Y is N; Ra and Rb are H; R2is H; and R3is -C(O)R10, wherein R10is a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl; and wherein K and J are N; R0 is H, R is =O, and R5 is C1-C6 alkyl; and R6 and R7 are H.

14. The compound of claim 7, wherein, wherein when R4isdouble bond; wherein when L G is a double bond; R25 and R33are H and R29is halogen; R26 is H and R27 is C1-C6haloalkyl; and wherein K and J are N; R0 is H, R is =O, and R5 is C1-C6 alkyl; and R6 and R7 are H.

15. The compound of claim 5, wherein R1 is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3 alkyl; wherein n is 2; B, D, E, and X are C; Y is N; Ra and Rb are H; R2 is H; and R3 is - C(O)R10, wherein R10is a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl; andwherein, wherein whendouble bond; wherein when L G is a double bond; R25and R33are H and R29is halogen; R26 is H and R27 is C1-C6 haloalkyl.

16. The compound of claim 5, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3 alkyl; wherein n is 2; B, D, E, and X are C; Y is N; Raand Rbare H; R2is H; and R3is - C(O)R10, wherein R10 is a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl; and wherein K and J are N; R0is H, R is =O, and R5is C1-C6alkyl; and R6and R7are H.

17. The compound of claim 5, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3alkyl; whereindouble bond; wherein when L G is a double bond; R25and R33are H and R29is halogen; and R26is H and R27is C1-C6haloalkyl. wherein K and J are N; R0 is H, R is =O, and R5 is C1-C6 alkyl; and R6 and R7 are H.

18. The compound of claim 6, wherein n is 2; B, D, E, and X are C; Y is N; Raand Rbare H; R2is H; and R3is -C(O)R10, wherein R10is a 5-10 membered heteroaryl ring, wherein R10 is optionally substituted with -OH, C1-C6 alkyl;wherein, wherein whendouble bond; wherein when L G is a double bond; R25and R33are H and R29is halogen; and R26 is H and R27 is C1-C6 haloalkyl; and wherein K and J are N; R0is H, R is =O, and R5is C1-C6alkyl; and R6and R7are H.

19. The compound of claim 5, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, and wherein the said 5- or 6-membered heterocyclyl ring is optionally substituted with C1-C3alkyl; wherein n is 2; B, D, E, and X are C; Y is N; Ra and Rb are H; R2 is H; and R3 is - C(O)R10, wherein R10 is a 5-10 membered heteroaryl ring, and wherein R10 is optionally substituted with -OH, C1-C6 alkyl; wherein, wherein whendouble bond; wherein when L G is a double bond; R25 and R33 are H and R29 is halogen; and R26is H and R27is C1-C6haloalkyl; and wherein K and J are N; R0 is H, R is =O, and R5 is C1-C6 alkyl; and R6 and R7 are H.

20. The compound of claim 5, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen.

21. The compound of claim 5, wherein R1is aryl fused with a 5- or 6-membered heterocyclyl ring, wherein the said 5- or 6-membered heterocyclyl ring comprises carbon atoms and at least one oxygen, and wherein the said 5- or 6-membered heterocyclyl ring is substituted with C1-C3 alkyl.

22. The compound of any of the preceding claims, wherein when R1is an aryl fused with a 5- or 6-membered heterocyclyl ring, the 5- or 6-membered heterocyclyl ring is a 5- membered heterocyclyl ring.

23. The compound of any of the preceding claims, wherein when R10 is a 5-10 membered heteroaryl ring, the 5-10 membered heteroaryl ring is a 6-membered heteroaryl ring.

24. The compound of any of the preceding claims, wherein when R10 is optionally substituted with C1-C6 alkyl, the C1-C6 alkyl is C1 alkyl.

25. The compound of any of the preceding claims, wherein when R29is halogen, the halogen is Cl.

26. The compound of any of the preceding claims, wherein when R27 is C1-C6 haloalkyl, the C1-C6haloalkyl is trifluoromethyl.

27. The compound of any of the preceding claims, wherein when R5is C1-C6alkyl, the C1- C6 alkyl is C2 alkyl.

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