received by the International Bureau on 15 February 2018 (15.02.2018)

Claims:

1. A compound of Formula I-W:

I-W or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, and isomer thereof, wherein:

A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl,

heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12- membered polycyclic;

Y¹ is -S-, a direct bond, -NH-, -S(0)₂- -S(0)₂-NH- -C(=CH₂) -, -CH-, or -S(O)-;

Y² is -NR^a-, -(CR¾)m- -C(O)-, -C(R^a)₂NH- -(CR^a₂)mO- -C(0)N(R^a)-,

-N(R^a)C(0)-, -S(0)₂N(R^a)-, -N(R^a)S(0)₂-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(S)N(R^a)-, -C(0)0-, -OC(O)-, -OC(0)N(R^a)-, -N(R^a)C(0)0- -C(0)N(R^a)0-, -N(R^a)C(S)-, -C(S)N(R^a)-, or -OC(0)0-; wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;

R¹ is independently, at each occurrence, -H, -D, -Ci-C₆alkyl, -C₂-C₆alkenyl, -C₄-C₈cycloalkenyl, -C₂-C₆alkynyl, -C₃-C₈cycloalkyl, -OH, -OR⁶, halogen, -NO2, -CN, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, -C(0)R⁵,-C0₂R⁵, -C(0)NR⁵R⁶, - R⁵C(0)R⁶, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more -OH, -NO2, oxo, =0, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl;

R² is independently -OH, -CN, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, F, Br, I, -C₃-C₈cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5

heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, - R⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R^a is independently, at each occurrence, -H, -D, -OH, -C3-C8cycloalkyl, -Ci- C₆alkyl, 3- to 12-membered heterocyclyl, or -(CH₂)n-aryl, wherein each alkyl or cycloalkyl is optionally substituted with one or more - H2, or wherein 2 R^a, together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;

R^b is independently, at each occurrence, -H, -D, -OH, -Ci-C₆alkyl, -C3- Cscycloalkyl, -C2-C₆alkenyl, -(CH₂)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or -(CH₂)n-aryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵,

-NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, -C(0)NR⁵R⁶, -NR⁵C(0)R⁶, heterocycle, aryl, heteroaryl, -(CH₂)nOH, -Ci-Cealkyl, -CF₃,

R³ is independently -H, -Ci-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C₃-C₈cycloalkyl, or -(CH₂)n-R^b, wherein each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH₂, -OR^b, -NHR^b, -(CH₂)nOH, heterocyclyl, or

spiroheterocyclyl; or

R³ can combine with R^a to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C₆alkyl, halogen, -OH, -OR^b, -NH₂, -NHR^b, heteroaryl, heterocyclyl, -(CH₂)nNH₂, -(CH₂)nOH, -COOR^b,

-CONHR^b, -CONH(CH₂)nCOOR^b, -NHCOOR^b, -CF₃, -CHF2, -CH2F, or =0;

R⁴ is independently -H, -D, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -Ci-C₆hydroxyalkyl, -CF2OH, -CHFOH, -NH-NHR⁵, -NH-OR⁵, -0-NR⁵R⁶, -NHC(0)R⁵,

-NHC(0)NHR⁵, -NHS(0)₂R⁵, -NHS(0)₂NHR⁵, -S(0)₂OH, -C(0)OR⁵, -NH(CH₂)nOH, -C(0)NH(CH₂)nOH, -C(0)NH(CH₂)nR^b, -C(0)R^b, -NH₂, -OH, -CN, -C(0)NR⁵R⁶, -S(0)₂NR⁵R⁶, C₃-C₈cycloalkyl, aryl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more -OH, -NH2, -OR^b, halogen, or oxo; wherein each aryl is optionally substituted with one or more -OH, - H2, or halogen; or

R^a and R⁴, together with the atom or atoms to which they are attached, can combine to form a monocyclic or poly cyclic C3-Ci2cycloalkyl or a monocyclic or poly cyclic 3- to 12- membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo; wherein the heterocycle optionally comprises -S(0)2- in the heterocycle;

R⁵ is independently -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, - R⁷R⁸, -NO2, -CF3, or -CN;

R⁶ is independently -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, halogen, - R⁷R⁸, -NO2, -CF3, or -CN;

R⁷ and R⁸ are independently, at each occurrence, -H, -D, -Ci-C₆alkyl,

-C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, -C3-C₈cycloalkyl, -OR^b, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN;

m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound of claim 1 wherein the compound is Formula I:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, wherein:

A is 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Y¹ is -S- or a direct bond;

Y² is -NR^a- -(CR¾)m- -C(O)-, -C(R^a)₂NH- -(CR^a₂)mO- -C(0)N(R^a)-,

-N(R^a)C(0)-, -S(0)₂N(R^a)-, -N(R^a)S(0)₂- -N(R^a)C(0)N(R^a)-, -N(R^a)C(S)N(R^a)-, -C(0)0- -OC(O)-, -OC(0)N(R^a)-, -N(R^a)C(0)0-, -C(0)N(R^a)0-, -N(R^a)C(S)-, -C(S)N(R^a)-, or -OC(0)0-; wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety is bound to R³;

R¹ is independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C₆alkenyl, -C₄-C₈cycloalkenyl, -Ci-Cealkynyl, -C₃-C₈cycloalkyl, -OH, halogen, -NO2, -CN, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, - R⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, -C(0)R⁵, or -C0₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more -OH, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶,

-NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl;

R² is independently -OH, -CN, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, -C₃-C₈cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl,

cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R^a is independently, at each occurrence, -H, -D, -OH, -C₃-C₈cycloalkyl, or -Ci- C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more -NH₂, wherein 2 R^a, together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;

R^b is independently, at each occurrence, -H, -D, -Ci-C₆alkyl, -C₃-C₈cycloalkyl, -C2-C₆alkenyl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, or heterocycle is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, - NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl;

R³ is independently -Ci-C₆alkyl or a 3- to 12-membered monocyclic or polycyclic heterocycle, wherein each alkyl or heterocycle is optionally substituted with one or more -Ci- Cealkyl, -OH, or -NH₂; or R can combine with R^a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with -Ci-C6alkyl, -OH, or - H2;

R⁴ is independently -H, -D, or -Ci-C₆alkyl, wherein each alkyl is optionally substituted with one or more -OH, -NH2, halogen, or oxo; or

R^a and R⁴, together with the atom or atoms to which they are attached, can combine to form a monocyclic or poly cyclic C3-Ci2cycloalkyl or a monocyclic or poly cyclic 3- to 12- membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo;

R⁵ is independently -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, - R⁷R⁸, -NO2, or -CN;

R⁶ is independently -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, halogen, - R⁷R⁸, -NO2, or -CN;

R⁷ and R⁸ are independently, at each occurrence, -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, -C3-C₈cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

3. The compound of claim 1 wherein the compound is Formula I-W6:

I-W6

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer,

thereof, wherein:

A is a 5- to 12-membered monocyclic or polycyclic heteroaryl;

Y¹ is -S-; Y² is - R^a-; wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;

R³ is combined with R^a to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C6alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH₂)n H₂, -COOR^b, -CO HR^b, -CO H(CH₂)_nCOOR^b,

- HCOOR^b, -CF3, -CHF₂, or -CH₂F;

R¹ is independently, at each occurrence, -H, -Ci-C₆alkyl, -OH, halogen, -N0₂, -CN, - R⁵R⁶, -SR⁵, -C(0)R⁵, or -C0₂R⁵;

R² is -Ci-Cealkyl;

R^b is independently, at each occurrence, -H or -Ci-C₆alkyl;

R⁴ is -H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Ci-Cehydroxyalkyl, -CF₂OH, -CHFOH, -C(0) H(CH₂)nOH, -C(0) H(CH₂)_nR^b, -C(0)R^b,-C(0) R⁵R⁶, -OH, or -CN, wherein alkyl is optionally substituted with one or more -OH, -NH₂, halogen, or oxo; or

R⁵ and R⁶ are each independently, at each occurrence, -H or -Ci-C₆alkyl; and n is independently, at each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The compound of claim 1 wherein the compound is Formula I-W7:

I-W7

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, wherein:

A is a 5- to 12-membered monocyclic or polycyclic heteroaryl;

Y¹ is a direct bond;

Y² is -NR^a-; wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;

R³ is combined with R^a to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C₆alkyl, -OH, -NH₂, heteroaryl, heterocyclyl, -(CH₂)n H₂, -COOR^b, -CO HR^b, -CO H(CH₂)nCOOR^b,

- HCOOR^b, -CF₃, -CHF₂, or -CH₂F;

R¹ is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, halogen, -N0₂, -CN, - R⁵R⁶, -SR⁵, -C(0)R⁵, or -COzR⁵;

R² is -Ci-Cealkyl;

R^b is independently, at each occurrence, -H or -Ci-C₆alkyl;

R⁴ is -H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Ci-Cehydroxyalkyl, -CF₂OH, -CHFOH, -C(0) H(CH₂)nOH, -C(0) H(CH₂)_nR^b, -C(0)R^b,-C(0) R⁵R⁶, -OH, or -CN, wherein alkyl is optionally substituted with one or more -OH, -NH₂, halogen, or oxo; or

R⁵ and R⁶ are each independently, at each occurrence, -H or -Ci-C₆alkyl; and n is independently, at each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. A compound of Formula I-Vl :

I- VI

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or thereof, wherein:

A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl,

heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12 membered polycyclic;

Y¹ is -S-, a direct bond, -NH-, -S(0)₂- -S(0)₂-NH- -C(=CH₂) -, -CH-, or -S(O)-;

Y² is -NR^a-, wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;

R^a and R⁴, together with the atom or atoms to which they are attached, are combined to form a monocyclic or polycyclic C₃-Ci₂cycloalkyl or a monocyclic or polycyclic 3- to 12- membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo; wherein the heterocycle optionally comprises -S(0)₂- in the heterocycle;

R¹ is independently, at each occurrence, -H, -D, -Ci-C₆alkyl, -C₂-C₆alkenyl, -C₄-C₈cycloalkenyl, -C₂-C₆alkynyl, -C₃-C₈cycloalkyl, -OH, -OR⁶, halogen, -NO2, -CN, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, -C(0)R⁵ ,-C0₂R⁵, -C(0)NR⁵R⁶, - R⁵C(0)R⁶, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more -OH, -N0₂, oxo, =0, -CN, -R⁵, -OR⁵, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, - R⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, heterocycle, aryl, or heteroaryl;

R² is independently - H₂, -OH, -CN, -Ci-Cealkyl, -C₂-C₆alkenyl, -C₄- Cscycloalkenyl, -C₂-C₆alkynyl, F, Br, I, -C3-C₈cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1- 5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R^b is independently, at each occurrence, -H, -D, -OH, -Ci-C₆alkyl, -C3- C₈cycloalkyl, -C2-C₆alkenyl, -(CH₂)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or -(CH₂)n-aryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵,

-NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, -C(0)NR⁵R⁶, -NR⁵C(0)R⁶, heterocycle, aryl, heteroaryl, -(CH₂)nOH, -Ci-Cealkyl, -CF₃,

R³ is independently -H, -Ci-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C₃-C₈cycloalkyl, or -(CH₂)n-R^b, wherein each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH₂, -OR^b, -NHR^b, -(CH₂)nOH, heterocyclyl, or

spiroheterocyclyl;

R⁵ is independently -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, -NR⁷R⁸, -NO2, -CF₃, or -CN; R⁶ is independently -H, -D, -Ci-C6alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, halogen, - R⁷R⁸, -NO2, -CF₃, or -CN;

R⁷ and R⁸ are independently, at each occurrence, -H, -D, -Ci-C₆alkyl,

-C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, -C₃-C₈cycloalkyl, -OR^b, or a monocyclic or polycyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, - H2, -NO2, or -CN; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

6. A compound of Formula I-V2:

I-V2 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, and thereof, wherein:

A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12- membered polycyclic;

Y¹ is -S-, a direct bond, -NH-, -S(0)₂- -S(0)₂-NH- -C(=CH₂) -, -CH-, or -S(O)-;

Y² is -NR^a-, wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;

R³ is combined with R^a to form a 3- to 12-membered polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -C i-Cealkyl, halogen, -OH, -OR^b, -NH2, -NHR^b, heteroaryl, heterocyclyl, -(CH₂)nNH₂, -(CH₂)nOH, -COOR^b, -CONHR^b, -CONH(CH₂)nCOOR^b, -NHCOOR^b, -CF₃, -CHF2, -CH2F, or =0;

R¹ is independently, at each occurrence, -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C₄-C₈cycloalkenyl, -C2-C₆alkynyl, -C₃-C₈cycloalkyl, -OH, -OR⁶, halogen, -NO2, -CN, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, -C(0)R⁵ -CO2R⁵, -C(0)NR⁵R⁶, - R⁵C(0)R⁶, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more -OH, -NO2, oxo, =0, -CN, -R⁵, -OR⁵, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, - R⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, heterocycle, aryl, or heteroaryl;

R² is independently - H2, -OH, -CN, -Ci-Cealkyl, -C₂-C₆alkenyl, -C₄- Cscycloalkenyl, -C2-C₆alkynyl, F, Br, I, -C3-C₈cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1- 5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R^b is independently, at each occurrence, -H, -D, -OH, -Ci-C₆alkyl, -C3- C₈cycloalkyl, -C2-C₆alkenyl, -(CH₂)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or -(CH₂)n-aryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵,

-NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, -C(0)NR⁵R⁶, -NR⁵C(0)R⁶, heterocycle, aryl, heteroaryl, -(CH₂)nOH, -Ci-Cealkyl, -CF₃,

R⁴ is independently -H, -D, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -Ci-C₆hydroxyalkyl, -CF2OH, -CHFOH, -NH-NHR⁵, -NH-OR⁵, -0-NR⁵R⁶, -NHC(0)R⁵,

-NHC(0)NHR⁵, -NHS(0)₂R⁵, -NHS(0)₂NHR⁵, -S(0)₂OH, -C(0)OR⁵, -NH(CH₂)nOH, -C(0)NH(CH₂)nOH, -C(0)NH(CH₂)nR^b, -C(0)R^b, -NH₂, -OH, -CN, -C(0)NR⁵R⁶, -S(0)₂NR⁵R⁶, C₃-C₈cycloalkyl, aryl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more -OH, -NH₂, -OR^b, halogen, or oxo; wherein each aryl is optionally substituted with one or more -OH, -NH₂, or halogen;

500 R⁵ is independently -H, -D, -Ci-C6alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷ - R⁷R⁸, -NO2, -CF3, or -CN;

R⁶ is independently -H, -D, -Ci-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2- C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, halogen, - R⁷R⁸, -NO2, -CF₃, or -CN;

R⁷ and R⁸ are independently, at each occurrence, -H, -D, -Ci-C₆alkyl,

-C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, -C₃-C₈cycloalkyl, -OR^b, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. The compound of claim 5 or 6, wherein R² is -NH2.

8. The compound of any one of claims 1-2 and 5-7, wherein A is cycloalkyl.

9. The compound of any one of claims 1-2 and 5-7, wherein A is heterocycloalkyl.

10. The compound of any one of claims 1-2 and 5-7, wherein A is aryl.

11. The compound of any one of claims 1-2 and 5-7, wherein A is heteroaryl.

12. The compound of any one of claims 1-7, wherein A is pyridinyl.

13. The compound of any one of claims 1-12, wherein n is 1 or 2.

14. The compound of any one of claims 1-13, wherein R¹ is independently, at each occurrence, -Ci-C₆alkyl, halogen, or -NR⁵R⁶.

15. The compound of any one of claims 1-13, wherein R¹ is independently selected from methyl, fluoro, chloro, and -NH2.

501

16. The compound of any one of claims 1-2 and 5-15, wherein Y¹ is -S-.

17. The compound of any one of claims 1-2 and 5-15, wherein Y¹ is a direct bond.

18. The compound of any of one of claims 1-6 and 8-17, wherein R² is -OH.

19. The compound of claim 18, wherein R^b is -H.

20. The compound of claim 18, wherein R^b is -Ci-C6alkyl.

21. The compound of any of one of claims 1-6 and 8-17, wherein R² is -CN.

22. The compound of any of one of claims 1-6 and 8-17, wherein R² is -Ci-C6alkyl.

23. The compound of any of claim 22, wherein R² is methyl.

24. The compound of any of one of claims 1-6 and 8-17, wherein R² is -C2-C6alkenyl.

25. The compound of any of one of claims 1-6 and 8-17, wherein R² is -C2-C₆alkynyl.

26. The compound of any one of claims 1-4 and 6-25, wherein R⁴ is -Ci-C₆alkyl, which is optionally substituted with one or more -OH, -NH2, halogen, or oxo.

27. The compound of claim 26, wherein R⁴ is -Ci-C₆alkyl, which is substituted with -OH.

28. The compound of claim 26, wherein R⁴ is -CH2-OH.

29. The compound of any one of claims 1-4 and 6-25, wherein R⁴ is -H.

30. The compound of any one of claims 1-4 and 6-25, wherein R⁴ is -CN.

31. The compound of any one of claims 1-4 and 6-25, wherein R⁴ is -CF2OH or

-CHFOH.

502

32. The compound of any one of claims 1-2 and 7-31, wherein Y² is - R^a-

33. The compound of any one of claims 1-2 and 7-31, wherein Y² is -(CR¾)m-.

34. The compound of any one of claims 1-2, 5, and 7-33, wherein R³ is -Ci-C6alkyl, which is optionally substituted with one or more -Ci-C6alkyl, -OH, - H2, -OR^b, - HR^b, - (CH2)nOH, heterocyclyl, or spiroheterocyclyl.

35. The compound of any one of claims 1-34, wherein R^a is -H.

36. The compound of any one of claims 1-2, 5, 7-33, and 35, wherein R³ is 3- to 12- membered monocyclic or polycyclic heterocycle.

37. The compound of any one of claims 1-2, 5, 7-33, and 35, wherein R³ is a 3- to 12- membered monocyclic heterocycle.

38. The compound of any one of claims 1-2, 5-33, and 35, wherein R³ is a 3- to 12- membered polycyclic heterocycle.

39. The compound of any one of claims 1-4 and 7-33, wherein R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with -Ci-C₆alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH₂)n H₂, -COOR^b, -CO HR^b, -CO H(CH₂)nCOOR^b, - HCOOR^b, -CF₃,

40. The compound of any one of claims 1-4 and 6-33, wherein R³ and R^a together with the atoms to which they are attached combine to form a 3 - to 12-membered polycyclic heterocycle, which is optionally substituted with -Ci-C₆alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH₂)n H₂, -COOR^b, -CO HR^b, -CO H(CH₂)nCOOR^b, - HCOOR^b, -CF₃,

503

41. The compound of any one of claims 1-4 and 6-33, wherein R and R^a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with -Ci-C6alkyl, -OH, - H2, heteroaryl, heterocyclyl,

-(CH₂)n H₂, -COOR^b, -CO HR^b, -CO H(CH₂)_nCOOR^b, - HCOOR^b, -CF₃, -CHF₂, or

-CHzF.

42. The compound of claim 41, wherein R³ and R^a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with -Ci-Cealkyl, -OH, - H₂, heteroaryl, heterocyclyl, -(CH₂)_n H₂, -COOR^b, -CO HR^b, -CO H(CH₂)nCOOR^b, - HCOOR^b, -CF₃, -CHF₂, or -CH₂F.

43. The compound of any of claims 1-2, 7-25, 32-34, and 36-38, wherein R^a and R⁴ together with the atom to which they are attached combine to form a monocyclic or poly cyclic 3- to 12-membered cycloalkyl.

44. The compound of any of claims 1-2, 7-25, 32-34, and 36-38, wherein R^a and R⁴ together with the atom to which they are attached combine to form a monocyclic or polycyclic 3- to 12-membered heterocycle.

45. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of:

3 4

504

505

506

46. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of:

507

508

509

510

511

A-24

A-25

A-26

A-27

512

513 A-32

A-33

A-34

A-35

A-36

514

515 A-42

A-43

A-44

A-45

A-46

516

517

518

519

520

521

522

523 A-81

A-82

A-83

A-84

A-85

524

525

526

527

528

529

530

531 A-119

A- 120

A-121

A- 122

532

533

534

535

536

47. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of:

537

538

539

540

541

542

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565 ; and

48. A compound of Formula I-W:

I-W

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, wherein:

A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12- membered polycyclic;

Y¹ is -S-, a direct bond, -NH-, -S(0)₂- -S(0)₂- H- -C(=CH₂) -, -CH-, or -S(O)-;

Y² is - R^a- -(CR¾)m- -C(O)-, -C(R^a)₂ H-, -(CR^a₂)mO-, -C(0)N(R^a)-, -N(R^a)C(0)-, -S(0)₂N(R^a)-, -N(R^a)S(0)₂-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(S)N(R^a)-, -C(0)0-, -OC(O)-, -OC(0)N(R^a)-, -N(R^a)C(0)0-, -C(0)N(R^a)0- -N(R^a)C(S)-, -C(S)N(R^a)-, or -OC(0)0-; wherein the bond on the left side of Y², as drawn, is bound to the pyrazine ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;

566 R¹ is independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C₆alkenyl, -C₄-C₈cycloalkenyl, -Ci-Cealkynyl, -C₃-C₈cycloalkyl, -OH, -OR⁶, halogen, -NO2, -CN, - R⁵R⁶, -SR⁵, -S(0)₂ R⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂ R⁵R⁶, - R⁵S(0)₂R⁶, -S(0) R⁵R⁶, -S(0)R⁵, - R⁵S(0) R⁵R⁶, - R⁵S(0)R⁶, -C(0)R⁵,-C0₂R⁵, -C(0)NR⁵R⁶, - R⁵C(0)R⁶, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, =0, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl;

R² is independently -OH, -CN, -C i-C₆alkyl, -C2-C₆alkenyl, -C4-C₈cycloalkenyl, -C2-C₆alkynyl, F, Br, I, -C(0)OR^b, -C₃-C₈cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1- 5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, -NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R^a is independently, at each occurrence, -H, -D, -OH, -C₃-C₈cycloalkyl, -Ci- C₆alkyl, 3- to 12-membered heterocyclyl, or -(CH₂)n-aryl, wherein each alkyl or cycloalkyl is optionally substituted with one or more -NH₂, or wherein 2 R^a, together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;

R^b is independently, at each occurrence, -H, -D, -OH, -Ci-C₆alkyl, -C₃- C₈cycloalkyl, -C2-C₆alkenyl, -(CH₂)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or -(CH₂)n-aryl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(0)₂NR⁵R⁶, -S(0)₂R⁵, - NR⁵S(0)₂NR⁵R⁶, -NR⁵S(0)₂R⁶, -S(0)NR⁵R⁶, -S(0)R⁵, -NR⁵S(0)NR⁵R⁶, -NR⁵S(0)R⁶, -C(0)NR⁵R⁶, -NR⁵C(0)R⁶, heterocycle, aryl, heteroaryl, -(CH₂)nOH, -C i-Cealkyl, -CF₃,

R³ is combined with R^a to form a 3- to 12-membered polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally

567 substituted with one or more -Ci-Cealkyl, halogen, -OH, -OR^b, - H2, - HR^b, heteroaryl, heterocyclyl, -(CH₂)n H₂, -(CH₂)_nOH, -COOR^b, -CO HR^b, -CO H(CH₂)_nCOOR^b, - HCOOR^b, -CF3, -CHF₂, -CH₂F, or =0;

R⁴ is independently -H, -D, -Ci-C6alkyl, -Ci-C6haloalkyl, -Ci-C₆hydroxyalkyl, -CF₂OH, -CHFOH, - H- HR⁵, - H-OR⁵, -0- R⁵R⁶, - HC(0)R⁵, - HC(0) HR⁵, - HS(0)₂R⁵, - HS(0)₂ HR⁵, -S(0)₂OH, -C(0)OR⁵, - H(CH₂)_nOH, -C(0) H(CH₂)_nOH, -C(0) H(CH₂)_nR^b, -C(0)R^b, - H₂, -OH, -CN, -C(0) R⁵R⁶, -S(0)₂ R⁵R⁶, C3- Cscycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more -OH, -NH₂, -OR^b, halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more -OH, - H₂, or halogen; or

R^a and R⁴, together with the atom or atoms to which they are attached, can combine to form a monocyclic or poly cyclic C3-Ci₂cycloalkyl or a monocyclic or poly cyclic 3- to 12- membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo; wherein the heterocycle optionally comprises -S(0)₂- in the heterocycle;

R⁵ and R⁶ are independently, at each occurrence, -H, -D, -Ci-C₆alkyl,

-C₂-C₆alkenyl, -C4-C₈cycloalkenyl, -C₂-C₆alkynyl, -C3-C₈cycloalkyl, a monocyclic or poly cyclic 3- to 12-membered heterocycle, -OR⁷, -SR⁷, halogen, - R⁷R⁸, -N0₂, -CF3, or -CN;

R⁷ and R⁸ are independently, at each occurrence, -H, -D, -Ci-C₆alkyl,

-C₂-C₆alkenyl, -C4-C₈cycloalkenyl, -C₂-C₆alkynyl, -C3-C₈cycloalkyl, -OR^b, or a

monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH₂, -NO2, or -CN;

m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

49. A pharmaceutical composition comprising a compound of any one of claims 1-48, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, and a pharmaceutically acceptable carrier.

568

50. A method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-48, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof.

51. The method of claim 50, wherein the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.

52. A compound of any one of claims 1-48, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, for use as a medicament.

53. A compound of any one of claims 1-48, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, for use in treating or preventing a disease associated with SHP2 modulation.

54. Use of a compound of any one of claims 1-48, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, in the manufacture of a medicament for treating or preventing a disease associated with SHP2 modulation.

55. A method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition of claim 49.

56. The method of claim 55, wherein the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.

57. A pharmaceutical composition of claim 49 for use as a medicament.

58. A pharmaceutical composition of claim 49 for use in treating or preventing a disease associated with SHP2 modulation.

569

58. Use of a pharmaceutical composition of claim 49 in the manufacture of a medicament for treating or preventing a disease associated with SHP2 modulation.

570