BICYCLIC COMPOUNDS AS ALLOSTERIC SHP2 INHIBITORS

[0001] This application is a continuation of U.S. patent application Ser. No. 18/220,196, filed on Jul. 10, 2023, which is a divisional of U.S. patent application Ser. No. 16/518,798, filed Jul. 22, 2019, now U.S. Pat. No. 11,739,093, which is a continuation of International Patent Application No. PCT/US2018/013023, filed Jan. 9, 2018, which claims the benefit of U.S. Provisional Application No. 62/449,530, filed Jan. 23, 2017, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to inhibitors of protein tyrosine phosphatase SHP2 useful in the treatment of diseases or disorders. Specifically, this disclosure is concerned with compounds and compositions inhibiting SHP2, methods of treating diseases associated with SHP2, and methods of synthesizing these compounds.

[0003] SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.

[0004] SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, self-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.

[0005] Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases. The compounds of the present disclosure fulfill the need for small molecules to that inhibit the activity of SHP2.

[0006] The present disclosure relates to compounds capable of inhibiting the activity of SHP2. The disclosure further provides a process for the preparation of compounds disclosed herein, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.

[0007] One aspect of the disclosure relates to compounds of Formula I′:

• • [0008] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0009] R⁴ is H or

• • [0010] A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • [0011] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0012] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, halogen, —NO₂, —CN, —NR⁵R⁶,
  • [0013] —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0014] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0015] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0016] Y¹ is —S—, a direct bond, —NH—, —S(O)₂—, —S(O)₂—NH—, —C(═CH₂)—, —CH—, or —S(O)—;
  • [0017] X¹ is N or C;
  • [0018] X² is N or CH;
  • [0019] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • [0020] R² is —H, —OR^b, —NR⁵R⁶, —CN, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0021] —C₂-C₆alkynyl, —NH₂, halogen, —C(O)OR^b, —C₃-C₈cycloalkyl, 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(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶,
  • [0022] —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
  • [0023] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0024] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0025] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0026] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0027] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or
  • [0028] —C₁-C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more
  • [0029] —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;
  • [0030] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0031] —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,
  • [0032] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0033] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0034] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0035] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0036] 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 —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —COOR^b, —CONHR^b, —CONH(CH₂)_nCOOR^b,
  • [0037] —NHCOOR^b, —CF₃, —CHF₂, or —CH₂F;
  • [0038] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0039] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0040] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0041] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0042] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0043] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0044] Another aspect of the disclosure relates to compounds of Formula I:

• • [0045] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0046] A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • [0047] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0048] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, halogen, —NO₂, —CN, —NR⁵R⁶,
  • [0049] —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0050] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen,
  • [0051] —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0052] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0053] Y¹ is —S—, a direct bond, —NH—, —S(O)₂—, —S(O)₂—NH—, —C(═CH₂)—, —CH—, or —S(O)—;
  • [0054] X¹ is N or C;
  • [0055] X² is N or CH;
  • [0056] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • [0057] R² is —H, —OR^b, —NR⁵R⁶, —CN, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0058] —C₂-C₆alkynyl, —NH₂, halogen, —C(O)OR^b, —C₃-C₈cycloalkyl, 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(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶,
  • [0059] —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
  • [0060] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0061] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0062] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0063] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0064] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or
  • [0065] —C₁-C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more
  • [0066] —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;
  • [0067] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0068] —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,
  • [0069] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0070] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0071] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0072] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0073] 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 —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —COOR^b, —CONHR^b, —CONH(CH₂)_nCOOR^b,
  • [0074] —NHCOOR^b, —CF₃, —CHF₂, or —CH₂F;
  • [0075] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0076] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0077] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0078] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0079] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0080] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0081] Another aspect of the disclosure relates to compounds of Formula II:

• • [0082] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0083] A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • [0084] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0085] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, halogen, —NO₂, —CN, —NR⁵R⁶,
  • [0086] —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0087] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0088] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0089] X¹ is N or C;
  • [0090] X² is N or CH;
  • [0091] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • [0092] R² is —H, —OR^b, —NR⁵R⁶, —CN, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0093] —C₂-C₆alkynyl, —NH₂, halogen, —C(O)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, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵,
  • [0094] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0095] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
  • [0096] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—
  • [0097] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0098] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0099] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0100] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or
  • [0101] —C₁-C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more
  • [0102] —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;
  • [0103] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0104] —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,
  • [0105] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0106] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0107] R³ is, at each occurrence, selected from the group consisting of —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more
  • [0108] —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0109] 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 —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —COOR^b, —CONHR^b, —CONH(CH₂)_nCOOR^b,
  • [0110] —NHCOOR^b, —CF₃, —CHF₂, or —CH₂F;
  • [0111] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0112] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0113] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0114] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0115] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0116] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0117] Another aspect of the disclosure relates to compounds of Formula III:

• • [0118] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0119] A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • [0120] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0121] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, halogen, —NO₂, —CN, —NR⁵R⁶,
  • [0122] —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0123] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0124] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0125] X¹ is N or C;
  • [0126] X² is N or CH;
  • [0127] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • [0128] R² is —H, —OR^b, —NR⁵R⁶, —CN, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0129] —C₂-C₆alkynyl, —NH₂, halogen, —C(O)OR^b, —C₃-C₈cycloalkyl, 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(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶,
  • [0130] —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
  • [0131] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0132] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0133] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0134] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0135] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or
  • [0136] —C₁-C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more
  • [0137] —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;
  • [0138] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0139] —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,
  • [0140] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0141] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0142] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0143] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0144] 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 —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —COOR^b, —CONHR^b, —CONH(CH₂)_nCOOR^b,
  • [0145] —NHCOOR^b, —CF₃, —CHF₂, or —CH₂F;
  • [0146] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0147] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0148] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0149] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0150] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0151] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0152] One aspect of the disclosure relates to compounds of Formula IV:

• • [0153] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0154] R⁴ is H or

• • [0155] A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the heteroaryl is not

• • [0156] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0157] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, —OR⁵, halogen, —NO₂, —CN,
  • [0158] —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶,
  • [0159] —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen,
  • [0160] —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0161] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0162] Y¹ is —S—, a direct bond, —NH—, —S(O)₂—, —S(O)₂—NH—, —C(═CH₂)—, —CH—, or —S(O)—;
  • [0163] X¹ is N or C;
  • [0164] X² is N or CH;
  • [0165] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl, wherein each heterocycle or heteroaryl is optionally substituted with one or more
  • [0166] —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃,
  • [0167] —CHF₂, or —CH₂F;
  • [0168] R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0169] —C₂-C₆alkynyl, —NH₂, halogen, —C₃-C₈cycloalkyl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more
  • [0170] —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵,
  • [0171] —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl is not attached via a nitrogen atom;
  • [0172] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0173] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0174] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0175] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0176] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or —C₁-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;
  • [0177] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0178] —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,
  • [0179] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0180] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0181] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0182] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0183] 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 —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that the heterocycle formed by the combination of R³ and R^a is not an optionally substituted piperazinyl;
  • [0184] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0185] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0186] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0187] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0188] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0189] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0190] One aspect of the disclosure relates to compounds of Formula IV that are compounds of Formula IV-Q:

• • [0191] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0192] R⁴ is H or

• • [0193] A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl, provided that the heteroaryl is not

• • [0194] R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or
  • [0195] —NR⁵R⁶;
  • [0196] Y¹ is —S— or a direct bond;
  • [0197] X¹ is N or C;
  • [0198] X is N or CH;
  • [0199] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl, wherein each heterocycle or heteroaryl is optionally substituted with one or more
  • [0200] —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0201] R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶;
  • [0202] Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0203] 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 —C₁-C₆alkyl, —OH, —NH₂,
  • [0204] —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that the heterocycle formed by the combination of R³ and R^a is not an optionally substituted piperazinyl;
  • [0205] R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl;
  • [0206] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0207] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0208] Another aspect of the disclosure relates to methods of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).

[0209] Another aspect of the disclosure relates to methods of inhibiting SHP2. The method comprises administering to a patient in need thereof, an effective amount of one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).

[0210] Another aspect of the disclosure is directed to pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, diluent, or surfactant. The pharmaceutical composition can be effective for treating a disease associated with SHP2 modulation in a subject in need thereof.

[0211] Another aspect of the disclosure relates to methods 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 comprising one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).

[0212] Another aspect of the disclosure relates to methods of inhibiting SHP2 comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).

[0213] Another aspect of the disclosure relates to one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use in treating or preventing a disease associated with SHP2 modulation. One aspect of the disclosure relates to pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), and a pharmaceutically acceptable carrier, for use in treating of preventing a disease associated with SHP2 modulation.

[0214] Another aspect of the disclosure relates to the use of one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), in the manufacture of a medicament for treating or preventing a disease associated with SHP2 modulation. Another aspect of the disclosure relates to the use of pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating or preventing a disease associated with SHP2 modulation.

[0215] Another aspect of the disclosure relates to one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament. Another aspect of the disclosure relates to pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I′, I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament. In some embodiments, the medicament is used for treating or preventing a disease associated with SHP2 modulation.

[0216] The present disclosure also provides compounds and pharmaceutical compositions that are useful in inhibiting SHP2.

[0217] In a first aspect, compounds of Formula I′ are described:

• • [0218] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein B, X¹, X², R², R³, R⁴, and Y² are described as above.

[0219] In another aspect, compounds of the Formula I are described:

• • [0220] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X¹, X², R¹, R², R³, Y¹, Y², and n are described as above.

[0221] In another aspect, compounds of the Formula II are described:

• • [0222] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X¹, X², R¹, R², R³, Y², and n are described as above.

[0223] In another aspect, compounds of the Formula III are described:

• • [0224] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X¹, X², R¹, R², R³, Y², and n are described as above.

[0225] In a first aspect, compounds of Formula IV are described:

• • [0226] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein B, X¹, X², R², R³, R⁴, and Y² are described as above.

[0227] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0228] The articles “a” and “an” are used in this disclosure and may refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element.

[0229] The term “and/or” is used in this disclosure to possibly mean either “and” or “or” unless indicated otherwise.

[0230] As used herein, “optional” or “optionally,” may mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” may encompass both “aryl” and “substituted aryl” as defined herein. It will be understood by those ordinarily skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable.

[0231] The term “optionally substituted” is understood to possibly mean that a given chemical moiety (e.g. an alkyl group) can (but is not required to) be bonded other substituents (e.g. heteroatoms). For instance, an alkyl group that is optionally substituted may be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents different from hydrogen. For instance, it can, at any point along the chain be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” may mean that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.

[0232] The term “aryl” may refer to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen, —O—C₁-C₆alkyl, —C₁-C₆alkyl, —OC₂-C₆alkenyl, —OC₂-C₆alkynyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and —S(O)N(C₁-C₆alkyl)₂. The substituents can themselves be optionally substituted.

[0233] Unless otherwise specifically defined, “heteroaryl” may mean a monovalent or multivalent monocyclic aromatic radical or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, S, P, and O, the remaining ring atoms being C. Heteroaryl as herein defined also may mean a bicyclic heteroaromatic group wherein the heteroatom is selected from N, S, P, and O. The term may also include multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. The term may also include multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1, 2, 3, 4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7, 8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen). The heteroaromatic radical may by optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyrazinyl, indazolyl, 1-methyl-1H-indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, isoindolin-1-one, indolin-2-one, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, benzo[d]isoxazolyl, benzo[d]oxazolyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, 2-methylbenzo[d]oxazolyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidyl, 2,3-dihydrobenzofuranyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl, 1-methyl-1H-benzo[d][1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, quinoxalinyl, benzo[c][1,2,5]oxadiazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, benzo[d][1,3]dioxolyl, pyrazolo[1,5-a]pyridinyl, and derivatives of any of the foregoing.

[0234] “Alkyl” may refer to a straight or branched chain saturated hydrocarbon. C₁-C₆alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkyl group may include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

[0235] The term “alkenyl” may mean an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl groups may have about 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups may include, but are not limited to, ethenyl, propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.

[0236] The term “alkynyl” may mean an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups may have about 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups may include, but are not limited to, ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆ alkynyl group is an alkynyl group containing between 2 and 6 carbon atoms.

[0237] The term “cycloalkyl” may mean monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups may include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group may be fused (e.g., decalin) or bridged (e.g., norbornane).

[0238] The term “cycloalkenyl” may mean monocyclic, non-aromatic unsaturated carbon rings containing 4-18 carbon atoms. Examples of cycloalkenyl groups may include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. A C₄-C₈ cycloalkenyl is a cycloalkenyl group containing between 4 and 8 carbon atoms.

[0239] In some embodiments, the terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” may refer to monocyclic or polycyclic 3 to 24-membered rings containing carbon and heteroatoms selected from oxygen, phosphorus, nitrogen, and sulfur and wherein there are no delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms. Heterocyclyl rings may include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl. A heterocyclyl or heterocycloalkyl ring may also be fused or bridged, e.g., can be a bicyclic ring.

[0240] In some embodiments “heterocyclyl” or “heterocycloalkyl” or “heterocycle” may be a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-24 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ring sulfur atom may be optionally oxidised to form the S-oxides. “Heterocyclyl” may be a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ring sulfur atom may be optionally oxidised to form S-oxide(s). Non-limiting examples and suitable values of the term “heterocyclyl” may include thiazolidinyl, pyrrolidinyl, pyrrolidin-2-one, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydro thienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydro uracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1-isoquinolonyl.

[0241] As used herein, the term “halo” or “halogen” may mean a fluoro, chloro, bromo, or iodo group.

[0242] The term “carbonyl” may refer to a functional group comprising a carbon atom double-bonded to an oxygen atom. It can be abbreviated herein as “oxo,” as C(O), or as C═O.

[0243] “Spirocycle” or “spirocyclic” may mean carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples may include, but are not limited to, spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A C₅-C₁₂ spirocycle is a spirocycle containing between 5 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

[0244] The term “spirocyclic heterocycle,” “spiroheterocyclyl,” or “spiroheterocycle” is understood to possibly mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl). A spirocyclic heterocycle can contain between 5 and 12 atoms, at least one of which is a heteroatom selected from N, O, S and P.

[0245] The disclosure also includes pharmaceutical compositions comprising an effective amount of one or more disclosed compounds and a pharmaceutically acceptable carrier. As used herein “pharmaceutically acceptable carrier, diluent or excipient” may include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0246] The disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein. Representative “pharmaceutically acceptable salts” may include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, 1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0247] “Pharmaceutically acceptable salt” also includes both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” may refer to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which may be formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0248] “Pharmaceutically acceptable base addition salt” may refer to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. For example, inorganic salts may include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

[0249] The term “tautomers” may refer to a set of compounds that have the same number and type of atoms, but differ in bond connectivity and are in equilibrium with one another. A “tautomer” is a single member of this set of compounds. Typically a single tautomer is drawn but it may be understood that this single structure may represent all possible tautomers that might exist. Examples include enol-ketone tautomerism. When a ketone is drawn it may be understood that both the enol and ketone forms are part of the disclosure.

[0250] For example, compounds of the Present disclosure can exist in tautomeric form. In some embodiments of Formula I, II, III, or IV, R² can be —OH and tautomers of the compounds can exist in equilibrium:

[0251] The disclosure may include prodrugs of the compounds described herein. The term “prodrug,” as used in this disclosure, may mean a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. Furthermore, as used herein a prodrug may be a drug which is inactive in the body, but may be transformed in the body typically either during absorption or after absorption from the gastrointestinal tract into the active compound. The conversion of the prodrug into the active compound in the body may be done chemically or biologically (i.e., using an enzyme).

[0252] The disclosure may include solvates of the compounds described herein. The term “solvate” may refer to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents may include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates may include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0253] The disclosure may include isomers of the compounds described herein. The term “isomer” may refer to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of present disclosure may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0254] The disclosure may include stereoisomers of the compounds described herein. The term “stereoisomers” may refer to the set of compounds which have the same number and type of atoms and share the same bond connectivity between those atoms, but differ in three dimensional structure. The term “stereoisomer” may refer to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer.

[0255] In addition, the present disclosure may embrace all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

[0256] The term “enantiomers” may refer to a pair of stereoisomers which are non-superimposable mirror images of one another. The term “enantiomer” may refer to a single member of this pair of stereoisomers. The term “racemic” may refer to a 1:1 mixture of a pair of enantiomers. The disclosure may include enantiomers of the compounds described herein. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. In some embodiments the compounds may be the (S)-enantiomer. In other embodiments the compounds may be the (R)-enantiomer. In yet other embodiments, the compounds may be the (+) or (−) enantiomers.

[0257] In some embodiments, compounds and compositions of the disclosure may be enriched to provide predominantly one enantiomer of a compound described herein. An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5 or even 100 mol percent. In some embodiments, the compound described herein enriched in one enantiomer may be substantially free of the other enantiomer, wherein substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2 mol percent of the second enantiomer.

[0258] The term “diastereomers” may refer to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans-double bonds, endo- and exo-substitution on bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations may be considered to be diastereomers. The term “diastereomer” may refer to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. The disclosure may include diastereomers of the compounds described herein.

[0259] In some embodiments, the compounds and compositions of the disclosure may be enriched to provide predominantly one diastereomer of a compound disclosed herein. A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 99, 95, 96, 97, 98, 99, or even 100 mol percent.

[0260] The compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds. An “isotopically” or “radio-labeled” compound may be a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in some embodiments, in the compounds described herein hydrogen atoms are replaced or substituted by one or more deuterium or tritium. Certain isotopically labeled compounds of this disclosure, for example, those incorporating a radioactive isotope, may be useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., ³H, and carbon 14, i.e., ¹⁴C, may be particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Suitable isotopes that may be incorporated in compounds described herein include but are not limited to ²H (also written as D for deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, can be useful in Positron Emission Topography (PET) studies.

[0261] An “effective amount” when used in connection with a compound may be an amount effective for treating or preventing a disease in a subject as described herein.

[0262] The term “carrier,” as used in this disclosure, may encompass carriers, excipients, and diluents and may mean a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0263] The term “treating” with regard to a subject, may refer to improving at least one symptom of the subject's disorder. Treating may include curing, improving, or at least partially ameliorating the disorder.

[0264] The term “prevent” or “preventing” with regard to a subject may refer to keeping a disease or disorder from afflicting the subject. Preventing may include prophylactic treatment. For instance, preventing can include administering to the subject one or more compounds disclosed herein before a subject is afflicted with a disease and the administration will keep the subject from being afflicted with the disease.

[0265] The term “disorder” is used in this disclosure and may be used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0266] The term “administer,” “administering,” or “administration” as used in this disclosure refers to either directly administering one or more disclosed compounds or a pharmaceutically acceptable salt of the one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject, or administering a prodrug derivative or analog of the one or more disclosed compounds or pharmaceutically acceptable salts of the one or more disclosed compounds or compositions to the subject, which may form an equivalent amount of active compound within the subject's body.

[0267] A “patient” or “subject” may be a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

[0268] Compounds of the disclosure include compounds of Formula I′ I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers of any of the foregoing.

[0269] In one or more embodiments of the compounds of Formula I, the compound is of the Formula I-A:

• • [0270] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0271] A is aryl;
  • [0272] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0273] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, halogen, —NO₂, —CN, —NR⁵R⁶,
  • [0274] —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0275] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen,
  • [0276] —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0277] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0278] Y¹ is —S—, a direct bond, —NH—, —S(O)₂—, —S(O)₂—NH—, —C(═CH₂)—, —CH—, or —S(O)—;
  • [0279] X¹ is N or C;
  • [0280] X² is N or CH;
  • [0281] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • [0282] R² is —H, —OR^b, —NR⁵R⁶, —CN, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0283] —C₂-C₆alkynyl, —NH₂, halogen, —C(O)OR^b, —C₃-C₈cycloalkyl, 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(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶,
  • [0284] —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
  • [0285] Y²—NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0286] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0287] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0288] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0289] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or
  • [0290] —C₁-C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more
  • [0291] —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;
  • [0292] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0293] —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,
  • [0294] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0295] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0296] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0297] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0298] 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 —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —COOR^b, —CONHR^b, —CONH(CH₂)_nCOOR^b,
  • [0299] —NHCOOR^b, —CF₃, —CHF₂, or —CH₂F;
  • [0300] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0301] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0302] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0303] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0304] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0305] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0306] In one or more embodiments of the compounds of Formula I, the compound is of the Formula I-B:

• • [0307] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0308] A is heteroaryl;
  • [0309] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0310] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, halogen, —NO₂, —CN, —NR⁵R⁶,
  • [0311] —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0312] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0313] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0314] Y¹ is —S—, a direct bond, —NH—, —S(O)₂—, —S(O)₂—NH—, —C(═CH₂)—, —CH—, or —S(O)—;
  • [0315] X¹ is N or C;
  • [0316] X² is N or CH;
  • [0317] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • [0318] R² is —H, —OR^b, —NR⁵R⁶, —CN, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0319] —C₂-C₆alkynyl, —NH₂, halogen, —C(O)OR^b, —C₃-C₈cycloalkyl, 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(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶,
  • [0320] —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
  • [0321] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0322] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0323] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—, —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0324] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or —C₁-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;
  • [0325] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0326] —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,
  • [0327] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0328] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0329] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0330] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0331] 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 —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —COOR^b, —CONHR^b, —CONH(CH₂)_nCOOR^b,
  • [0332] —NHCOOR^b, —CF₃, —CHF₂, or —CH₂F;
  • [0333] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0334] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0335] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0336] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0337] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0338] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0339] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-A:

• • [0340] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0341] In one or more embodiments of the compounds of the Formula II-A, the compound is of the Formula II-A1:

• • [0342] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0343] C forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the nitrogen atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, or —NH₂.

[0344] In one or more embodiments of the compounds of Formula II-A, the compound is of the Formula II-A2:

• • [0345] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0346] In one or more embodiments of the compounds of Formula II-A, the compound is of the Formula II-A3:

• • [0347] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0348] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-B:

• • [0349] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0350] In one or more embodiments of the compounds of Formula II-B, the compound is of the Formula II-B1:

• • [0351] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0352] C forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the carbon atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, or —NH₂.

[0353] In one or more embodiments of the compounds of Formula II-B, the compound is of the Formula II-B2:

• • [0354] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0355] In one or more embodiments of the compounds of Formula II-B, the compound is of the Formula II-B3:

• • [0356] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0357] In one or more embodiments of the compounds of Formula II-B, the compound is of the Formula II-B4:

• • [0358] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0359] In one or more embodiments of the compounds of Formula II-B, the compound is of the Formula II-B5:

• • [0360] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0361] In one or more embodiments of the compounds of Formula II-B, the compound is of the Formula II-B6:

• • [0362] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0363] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-C:

• • [0364] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0365] C forms a 3- to 12-membered monocyclic or polycyclic heterocycle, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, or —NH₂.

[0366] In one or more embodiments of the compounds of Formula II-C, the compound is of the Formula II-C1:

• • [0367] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0368] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-D:

• • [0369] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0370] C forms a 3- to 12-membered monocyclic or polycyclic heterocycle, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, or —NH₂.

[0371] In one or more embodiments of the compounds of Formula II-D, the compound is of the Formula II-D1:

• • [0372] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0373] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-E:

• • [0374] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0375] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-F:

• • [0376] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0377] In one or more embodiments of the compounds of Formula II, the compound is of the Formula II-G:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein R² is an aryl or heteroaryl.

[0378] In one or more embodiments of the compounds of Formula III, the compound is of the Formula III-A:

• • [0379] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0380] In one or more embodiments of the compounds of Formula III-A, the compound is of the Formula III-A1:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein

• • [0381] C forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the nitrogen atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, or —NH₂.

[0382] In one or more embodiments of the compounds of Formula III-A, the compound is of the Formula III-A2:

• • [0383] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0384] In one or more embodiments of the compounds of Formula III-A, the compound is of the Formula III-A3:

• • [0385] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0386] In some embodiments, the compounds of the disclosure are compounds of Formula IV:

• • [0387] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • [0388] R⁴ is H or

• • [0389] A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the heteroaryl is not

• • [0390] R¹ is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0391] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —OH, —OR⁵, halogen, —NO₂, —CN,
  • [0392] —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶,
  • [0393] —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, —C(O)R⁵, or —CO₂R⁵, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, halogen,
  • [0394] —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶,
  • [0395] —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl;
  • [0396] Y¹ is —S—, a direct bond, —NH—, —S(O)₂—, —S(O)₂—NH—, —C(═CH₂)—, —CH—, or —S(O)—;
  • [0397] X¹ is N or C;
  • [0398] X² is N or CH;
  • [0399] B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl, wherein each heterocycle or heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0400] R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,
  • [0401] —C₂-C₆alkynyl, —NH₂, halogen, —C₃-C₈cycloalkyl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more
  • [0402] —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR⁵, —NR⁵R⁶, —SR⁵, —S(O)₂NR⁵R⁶, —S(O)₂R⁵,
  • [0403] —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵, —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl is not attached via a nitrogen atom;
  • [0404] Y² is —NR^a—, —(CR^a₂)_m—, —C(O)—, —C(R^a)₂NH—, —(CR^a₂)_mO—, —C(O)N(R^a)—,
  • [0405] —N(R^a)C(O)—, —S(O)₂N(R^a)—, —N(R^a)S(O)₂—, —N(R^a)C(O)N(R^a)—, —N(R^a)C(S)N(R^a)—,
  • [0406] —C(O)O—, —OC(O)—, —OC(O)N(R^a)—, —N(R^a)C(O)O—, —C(O)N(R^a)O—, —N(R^a)C(S)—,
  • [0407] —C(S)N(R^a)—, or —OC(O)O—; wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0408] R^a is independently, at each occurrence, —H, -D, —OH, —C₃-C₈cycloalkyl, or
  • [0409] —C₁-C₆alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more
  • [0410] —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;
  • [0411] R^b is independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₃-C₈cycloalkyl,
  • [0412] —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,
  • [0413] —S(O)₂NR⁵R⁶, —S(O)₂R⁵, —NR⁵S(O)₂NR⁵R⁶, —NR⁵S(O)₂R⁶, —S(O)NR⁵R⁶, —S(O)R⁵,
  • [0414] —NR⁵S(O)NR⁵R⁶, —NR⁵S(O)R⁶, heterocycle, aryl, heteroaryl, —(CH₂)_nOH, —C₁-C₆alkyl, —CF₃, —CHF₂, or —CH₂F;
  • [0415] R³ is —H, —C₁-C₆alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle,
  • [0416] —C₃-C₈cycloalkyl, or —(CH₂)_n—R^b, wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —OR^b, —NHR^b, —(CH₂)_nOH, heterocyclyl, or spiroheterocyclyl; or
  • [0417] 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 —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that the heterocycle formed by the combination of R³ and R^a is not an optionally substituted piperazinyl;
  • [0418] R⁵ and R⁶ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0419] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR⁷, —SR⁷, halogen, —NR⁷R⁸, —NO₂, or —CN;
  • [0420] R⁷ and R⁸ are independently, at each occurrence, —H, -D, —C₁-C₆alkyl, —C₂-C₆alkenyl,
  • [0421] —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, 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, —NH₂, —NO₂, or —CN;
  • [0422] m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • [0423] n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0424] In one or more embodiments of Formula IV, R⁴ is H.

[0425] In one or more embodiments of Formula IV, R⁴ is

In certain such embodiments, Y¹ is —S— or a direct bond. In one or more embodiments of Formula IV, Y¹ is —S—. In one or more embodiments of Formula IV, Y¹ is a direct bond.

[0426] In one or more embodiments of the compounds of Formula IV, Y² is —(CR^a₂)_m—. In one or more embodiments of the compounds of Formula IV, Y² is —NR^a—.

[0427] In one or more embodiments of Formula IV, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV, A is phenyl. In one or more embodiments of Formula IV, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV, A is pyridinyl. In one or more embodiments of Formula IV, A is indazolyl. In one or more embodiments of Formula IV, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.

[0428] In one or more embodiments of Formula IV, n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV, n is independently, at each occurrence, 1 or 2.

[0429] In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or —NR⁵R⁶. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H, —OR⁵ or halogen. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H or —OR⁵. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H or halogen. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H or —NR⁵R⁶. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H, —OR⁵ or —NR⁵R⁶. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H, halogen or —NR⁵R⁶. In certain such embodiments, R⁵ and R⁶ are both —H. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H, methyl, fluoro, chloro, or —NH₂. In one or more embodiments of Formula IV, R¹ is independently, at each occurrence, —H, —CN or halogen.

[0430] In one or more embodiments of Formula IV, R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl. In one or more embodiments of Formula IV, R⁵ and R⁶ are independently, at each occurrence, —H. In one or more embodiments of Formula IV, R⁵ and R⁶ are independently, at each occurrence, —C₁-C₆alkyl.

[0431] In one or more embodiments of Formula IV, R² is —H. In one or more embodiments of Formula IV, R² is —C₁-C₆alkyl, wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In certain such embodiments, R² is methyl. In one or more embodiments of Formula IV, R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In one or more embodiments of Formula IV, R² is —OH. In one or more embodiments of Formula IV, R² is —NR⁵R⁶. In one or more embodiments of Formula IV, R² is —NH₂.

[0432] In one or more embodiments of Formula IV, R^a is —H.

[0433] In one or more embodiments of Formula IV, R³ is an optionally substituted —C₁-C₆alkyl. In one or more embodiments of Formula IV, R³ is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV, R³ is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV, R³ is an optionally substituted 5- to 12-membered polycyclic heterocycle.

[0434] In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0435] In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0436] In one or more embodiments of Formula IV, R³ 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV, R³ 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV, R³ 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0437] In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0438] In one or more embodiments of Formula IV, X¹ is N and X² is N. In one or more embodiments of Formula IV, X¹ is C and X² is CH. In one or more embodiments of Formula IV, X¹ is C and X² is N. In one or more embodiments of Formula IV, X¹ is N and X² is CH.

[0439] In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12-membered heterocycle. In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heterocycle. In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.

[0440] In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV, the heterocyclyl ring is bridged.

[0441] In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heteroaryl. In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.

[0442] In one or more embodiments of Formula IV, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula IV, the polycyclic heteroaryl is a multiple condensed ring as described above. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.

[0443] In one or more embodiments of Formula IV, B is substituted with one or more —(CH₂)_nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV, B is substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV, B is substituted with one or more oxo. In one or more embodiments of Formula IV, B is substituted with one or more —C₁-C₆alkyl. In one or more embodiments of Formula IV, B is substituted with one or more —OH. In one or more embodiments of Formula IV, B is substituted with one or more —NH₂. In one or more embodiments of Formula IV, B is substituted with one or more —CF₃. In one or more embodiments of Formula IV, B is substituted with one or more —CHF₂. In one or more embodiments of Formula IV, B is substituted with one or more —CH₂F. In one or more embodiments of Formula IV, B is substituted with one or more —(CH₂)_nNH₂. In certain such embodiments, n is 1.

[0444] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0445] a) R⁴ is H;
  • [0446] b) X¹ is C and X² is CH;
  • [0447] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0448] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0449] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0450] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0451] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0452] a) R⁴ is H;
  • [0453] b) X¹ is N and X² is N;
  • [0454] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0455] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0456] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0457] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0458] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0459] a) R⁴ is H;
  • [0460] b) X¹ is C and X² is N;
  • [0461] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0462] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0463] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0464] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0465] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0466] a) R⁴ is H;
  • [0467] b) X¹ is N and X² is CH;
  • [0468] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0469] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0470] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0471] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0472] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0473] a) R⁴ is H;
  • [0474] b) X¹ is C and X² is CH;
  • [0475] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0476] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0477] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0478] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0479] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0480] a) R⁴ is H;
  • [0481] b) X¹ is N and X² is N;
  • [0482] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0483] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0484] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0485] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0486] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0487] a) R⁴ is H;
  • [0488] b) X¹ is C and X² is N;
  • [0489] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0490] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0491] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0492] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0493] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0494] a) R⁴ is H;
  • [0495] b) X¹ is N and X² is CH;
  • [0496] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0497] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0498] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0499] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0500] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0501] a) R⁴ is H;
  • [0502] b) X¹ is C and X² is CH;
  • [0503] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0504] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0505] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0506] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0507] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0508] a) R⁴ is H;
  • [0509] b) X¹ is N and X² is N;
  • [0510] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0511] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0512] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0513] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0514] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0515] a) R⁴ is H;
  • [0516] b) X¹ is C and X² is N;
  • [0517] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0518] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0519] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0520] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0521] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0522] a) R⁴ is H;
  • [0523] b) X¹ is N and X² is CH;
  • [0524] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0525] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0526] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0527] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0528] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0529] a) R⁴ is H;
  • [0530] b) X¹ is C and X² is CH;
  • [0531] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0532] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0533] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0534] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0535] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0536] a) R⁴ is H;
  • [0537] b) X¹ is N and X² is N;
  • [0538] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0539] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0540] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0541] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0542] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0543] a) R⁴ is H;
  • [0544] b) X¹ is C and X² is N;
  • [0545] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0546] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0547] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0548] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0549] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0550] a) R⁴ is H;
  • [0551] b) X¹ is N and X² is CH;
  • [0552] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0553] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0554] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0555] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0556] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0557] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0558] b) X¹ is C and X² is CH;
  • [0559] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0560] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0561] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0562] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0563] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0564] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0565] b) X¹ is N and X² is N;
  • [0566] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0567] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0568] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0569] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0570] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0571] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0572] b) X¹ is C and X² is N;
  • [0573] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0574] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0575] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0576] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0577] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0578] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0579] b) X¹ is N and X² is CH;
  • [0580] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0581] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0582] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0583] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0584] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0585] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0586] b) X¹ is C and X² is CH;
  • [0587] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0588] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0589] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0590] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0591] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0592] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0593] b) X¹ is N and X² is N;
  • [0594] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0595] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0596] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0597] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0598] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0599] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0600] b) X¹ is C and X² is N;
  • [0601] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0602] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0603] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0604] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0605] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0606] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0607] b) X¹ is N and X² is CH;
  • [0608] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0609] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0610] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0611] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0612] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0613] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0614] b) X¹ is C and X² is CH;
  • [0615] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0616] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0617] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0618] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0619] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0620] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0621] b) X¹ is N and X² is N;
  • [0622] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0623] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0624] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0625] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0626] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0627] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0628] b) X¹ is C and X² is N;
  • [0629] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0630] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0631] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0632] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0633] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0634] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0635] b) X¹ is N and X² is CH;
  • [0636] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0637] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0638] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0639] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0640] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0641] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0642] b) X¹ is C and X² is CH;
  • [0643] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0644] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0645] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0646] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0647] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0648] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0649] b) X¹ is N and X² is N;
  • [0650] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0651] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0652] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0653] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0654] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0655] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0656] b) X¹ is C and X² is N;
  • [0657] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0658] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0659] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0660] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0661] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0662] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is —S—;
  • [0663] b) X¹ is N and X² is CH;
  • [0664] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0665] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0666] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0667] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0668] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0669] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0670] b) X¹ is C and X² is CH;
  • [0671] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0672] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0673] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0674] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0675] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0676] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0677] b) X¹ is N and X² is N;
  • [0678] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0679] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0680] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0681] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0682] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0683] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0684] b) X¹ is C and X² is N;
  • [0685] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0686] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0687] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0688] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0689] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0690] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0691] b) X¹ is N and X² is CH;
  • [0692] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0693] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0694] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0695] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0696] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0697] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0698] b) X¹ is C and X² is CH;
  • [0699] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0700] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0701] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0702] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0703] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0704] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0705] b) X¹ is N and X² is N;
  • [0706] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0707] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0708] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0709] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0710] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0711] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0712] b) X¹ is C and X² is N;
  • [0713] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0714] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0715] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0716] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0717] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0718] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0719] b) X¹ is N and X² is CH;
  • [0720] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0721] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0722] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0723] f) R³ is combined with R^a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0724] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0725] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0726] b) X¹ is C and X² is CH;
  • [0727] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0728] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0729] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0730] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0731] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0732] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0733] b) X¹ is N and X² is N;
  • [0734] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0735] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0736] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0737] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0738] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0739] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0740] b) X¹ is C and X² is N;
  • [0741] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0742] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0743] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0744] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0745] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0746] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0747] b) X¹ is N and X² is CH;
  • [0748] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0749] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0750] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0751] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0752] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0753] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0754] b) X¹ is C and X² is CH;
  • [0755] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0756] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0757] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0758] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0759] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0760] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0761] b) X¹ is N and X² is N;
  • [0762] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0763] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0764] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0765] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0766] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0767] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0768] b) X¹ is C and X² is N;
  • [0769] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0770] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0771] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0772] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0773] In some embodiments, the compounds of the disclosure compounds of Formula IV, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, have one, two, or three or more of the following features:

• • [0774] a) R⁴ is

• •  A is a monocyclic or polycyclic aryl or pyridinyl, and Y¹ is a direct bond;
  • [0775] b) X¹ is N and X² is CH;
  • [0776] c) B, including the atoms at the points of attachment, is a monocyclic 5- to 12-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F;
  • [0777] d) R² is —H, —C₁-C₆alkyl, or —NH₂;
  • [0778] e) Y² is —NR^a—, wherein the bond on the left side of Y², as drawn, is bound to the ring and the bond on the right side of the Y² moiety, as drawn, is bound to R³;
  • [0779] f) R³ is combined with R^a to form a 5- to 12-membered spiroheterocycle, wherein the spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0780] In certain embodiments of Formula IV, the compound is of Formula IV-A:

• • [0781] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein X^B1 is N, NR⁹, CR⁹, S, or O; X^B2 is N, NR⁹, CR⁹, S, or O; and X^B3 is N, NR⁹, CR⁹, S, or O, wherein R⁹ is independently, at each occurrence, —H, —C₁-C₆alkyl,
  • [0782] —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that if X¹ is C, at least one of X^B1, X^B2, and X^B3 is not CR⁹, or provided that if each of X^B1, X^B2, and X^B3 are CR⁹, X¹ must be N.

[0783] In certain embodiments of Formula IV-A, X^B1 is N or NR⁹. In certain embodiments of Formula IV-A, X^B1 is CR⁹. In certain embodiments of Formula IV-A, X^B1 is S. In certain embodiments of Formula IV-A, X^B1 is O. In certain embodiments of Formula IV-A, X^B2 is N or NR⁹. In certain embodiments of Formula IV-A, X^B2 is CR⁹. In certain embodiments of Formula IV-A, X^B2 is S. In certain embodiments of Formula IV-A, X^B2 is O. In certain embodiments of Formula IV-A, X^B3 is N or NR⁹. In certain embodiments of Formula IV-A, X^B3 is CR⁹. In certain embodiments of Formula IV-A, X^B3 is S. In certain embodiments of Formula IV-A, X^B3 is O.

[0784] In certain embodiments of Formula IV-A, X^B1 is N, NR⁹, or CR⁹; X^B2 is N, NR⁹, or CR⁹; and X^B3 is N, NR⁹, or CR⁹. In certain embodiments of Formula IV-A, X^B1 is N or NR⁹. In certain embodiments of Formula IV-A, X^B1 is CR⁹. In certain embodiments of Formula IV-A, X^B2 is N or NR⁹. In certain embodiments of Formula IV-A, X^B2 is CR⁹. In certain embodiments of Formula IV-A, X^B3 is N or NR⁹. In certain embodiments of Formula IV-A, X^B3 is CR⁹.

[0785] In some embodiments of Formula IV-A, R⁹ is —(CH₂)_nOH and n is 1. In some embodiments of Formula IV-A, R⁹ is H.

[0786] In certain embodiments of Formula IV-A,

wherein is a single bond or double bond to satisfy valency rules, is

[0787] In one or more embodiments of Formula IV-A, R⁴ is H.

[0788] In one or more embodiments of Formula IV-A, R⁴ is

In certain such embodiments, Y¹ is —S— or a direct bond. In one or more embodiments of Formula IV-A, Y¹ is —S—. In one or more embodiments of Formula IV-A, Y¹ is a direct bond.

[0789] In one or more embodiments of the compounds of Formula IV-A, Y² is —(CR^a₂)_m—. In one or more embodiments of the compounds of Formula IV-A, Y² is —NR^a—.

[0790] In one or more embodiments of Formula IV-A, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-A, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-A, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-A, A is phenyl. In one or more embodiments of Formula IV-A, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-A, A is pyridinyl. In one or more embodiments of Formula IV-A, A is indazolyl. In one or more embodiments of Formula IV-A, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.

[0791] In one or more embodiments of Formula IV-A, n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-A, n is independently, at each occurrence, 1 or 2.

[0792] In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or —NR⁵R⁶. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H, —OR⁵ or halogen. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H or —OR⁵. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H or halogen. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H or —NR⁵R⁶. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H, —OR⁵ or —NR⁵R⁶. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H, halogen or —NR⁵R⁶. In certain such embodiments, R⁵ and R⁶ are both —H. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H, methyl, fluoro, chloro, or —NH₂. In one or more embodiments of Formula IV-A, R¹ is independently, at each occurrence, —H, —CN or halogen.

[0793] In one or more embodiments of Formula IV-A, R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl. In one or more embodiments of Formula IV-A, R⁵ and R⁶ are independently, at each occurrence, —H. In one or more embodiments of Formula IV-A, R⁵ and R⁶ are independently, at each occurrence, —C₁-C₆alkyl.

[0794] In one or more embodiments of Formula IV-A, R² is —H. In one or more embodiments of Formula IV-A, R² is —C₁-C₆alkyl, wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In certain such embodiments, R² is methyl. In one or more embodiments of Formula IV-A, R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In one or more embodiments of Formula IV-A, R² is —OH. In one or more embodiments of Formula IV-A, R² is —NR⁵R⁶. In one or more embodiments of Formula IV-A, R² is —NH₂.

[0795] In one or more embodiments of Formula IV-A, R^a is —H.

[0796] In one or more embodiments of Formula IV-A, R³ is an optionally substituted —C₁-C₆alkyl. In one or more embodiments of Formula IV-A, R³ is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-A, R³ is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-A, R³ is an optionally substituted 5- to 12-membered polycyclic heterocycle.

[0797] In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0798] In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-A, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-A, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0799] In one or more embodiments of Formula IV-A, R³ 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-A, R³ 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-A, R³ 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0800] In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-A, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0801] In one or more embodiments of Formula IV-A, X¹ is N and X² is N. In one or more embodiments of Formula IV-A, X¹ is C and X² is CH. In one or more embodiments of Formula IV-A, X¹ is C and X² is N. In one or more embodiments of Formula IV-A, X¹ is N and X² is CH.

[0802] In certain embodiments of Formula IV, the compound is of Formula IV-B:

• • [0803] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, wherein R⁹ is independently, at each occurrence, —H, —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that if X¹ is C, at least one of X^B4, X^B5, X^B6, and X^B7 is not CR⁹, or provided that if each of X^B4, X^B5, X^B6, and X^B7 are CR⁹, X¹ must be N.

[0804] In certain embodiments of Formula IV-B, X^B4 is N. In certain embodiments of Formula IV-B, X^B4 is CR⁹. In certain embodiments of Formula IV-B, X^B5 is N. In certain embodiments of Formula IV-B, X^B5 is CR⁹. In certain embodiments of Formula IV-B, X^B6 is N. In certain embodiments of Formula IV-B, X^B6 is CR⁹. In certain embodiments of Formula IV-B, X^B7 is N. In certain embodiments of Formula IV-B, X^B7 is CR⁹. In certain embodiments of Formula IV-B, X^B4 is N, X^B5 is CR⁹, X^B6 is N, and X^B7 is CR⁹. In certain such embodiments, R⁹ is independently, at each occurrence, —H.

[0805] In some embodiments of Formula IV-B, R⁹ is —(CH₂)_nOH and n is 1. In some embodiments of Formula IV-B, R⁹ is H.

[0806] In one or more embodiments of Formula IV-B, R⁴ is H.

[0807] In one or more embodiments of Formula IV-B, R⁴ is

In certain such embodiments, Y¹ is —S— or a direct bond. In one or more embodiments of Formula IV-B, Y¹ is —S—. In one or more embodiments of Formula IV-B, Y¹ is a direct bond.

[0808] In one or more embodiments of the compounds of Formula IV-B, Y² is —(CR^a₂)_m—. In one or more embodiments of the compounds of Formula IV-B, Y² is —NR^a—.

[0809] In one or more embodiments of Formula IV-B, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-B, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-B, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-B, A is phenyl. In one or more embodiments of Formula IV-B, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-B, A is pyridinyl. In one or more embodiments of Formula IV-B, A is indazolyl. In one or more embodiments of Formula IV-B, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.

[0810] In one or more embodiments of Formula IV-B, n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-B, n is independently, at each occurrence, 1 or 2.

[0811] In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or —NR⁵R⁶. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H, —OR⁵ or halogen. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H or —OR⁵. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H or halogen. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H or —NR⁵R⁶. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H, —OR⁵ or —NR⁵R⁶. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H, halogen or —NR⁵R⁶. In certain such embodiments, R⁵ and R⁶ are both —H. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H, methyl, fluoro, chloro, or —NH₂. In one or more embodiments of Formula IV-B, R¹ is independently, at each occurrence, —H, —CN or halogen.

[0812] In one or more embodiments of Formula IV-B, R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl. In one or more embodiments of Formula IV-B, R⁵ and R⁶ are independently, at each occurrence, —H. In one or more embodiments of Formula IV-B, R⁵ and R⁶ are independently, at each occurrence, —C₁-C₆alkyl.

[0813] In one or more embodiments of Formula IV-B, R² is —H. In one or more embodiments of Formula IV-B, R² is —C₁-C₆alkyl, wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In certain such embodiments, R² is methyl. In one or more embodiments of Formula IV-B, R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In one or more embodiments of Formula IV-B, R² is —OH. In one or more embodiments of Formula IV-B, R² is —NR⁵R⁶. In one or more embodiments of Formula IV-B, R² is —NH₂.

[0814] In one or more embodiments of Formula IV-B, R^a is —H.

[0815] In one or more embodiments of Formula IV-B, R³ is an optionally substituted —C₁-C₆alkyl. In one or more embodiments of Formula IV-B, R³ is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-B, R³ is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-B, R³ is an optionally substituted 5- to 12-membered polycyclic heterocycle.

[0816] In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0817] In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-B, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-B, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0818] In one or more embodiments of Formula IV-B, R³ 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-B, R³ 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-B, R³ 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0819] In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-B, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0820] In one or more embodiments of Formula IV-B, X¹ is N and X² is N. In one or more embodiments of Formula IV-B, X¹ is C and X² is CH. In one or more embodiments of Formula IV-B, X¹ is C and X² is N. In one or more embodiments of Formula IV-B, X¹ is N and X² is CH.

[0821] In certain embodiments of Formula IV, the compound is of Formula IV-C:

• • [0822] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.

[0823] In one or more embodiments of Formula IV-C, R⁴ is H.

[0824] In one or more embodiments of Formula IV-C, R⁴ is

In certain such embodiments, Y¹ is —S— or a direct bond. In one or more embodiments of Formula IV-C, Y¹ is —S—. In one or more embodiments of Formula IV-C, Y¹ is a direct bond.

[0825] In one or more embodiments of Formula IV-C, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-C, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-C, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-C, A is phenyl. In one or more embodiments of Formula IV-C, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-C, A is pyridinyl. In one or more embodiments of Formula IV-C, A is indazolyl. In one or more embodiments of Formula IV-C, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.

[0826] In one or more embodiments of Formula IV-C, n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-C, n is independently, at each occurrence, 1 or 2.

[0827] In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or —NR⁵R⁶. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H, —OR⁵ or halogen. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H or —OR⁵. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H or halogen. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H or —NR⁵R⁶. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H, —OR⁵ or —NR⁵R⁶. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H, halogen or —NR⁵R⁶. In certain such embodiments, R⁵ and R⁶ are both —H. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H, methyl, fluoro, chloro, or —NH₂. In one or more embodiments of Formula IV-C, R¹ is independently, at each occurrence, —H, —CN or halogen.

[0828] In one or more embodiments of Formula IV-C, R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl. In one or more embodiments of Formula IV-C, R⁵ and R⁶ are independently, at each occurrence, —H. In one or more embodiments of Formula IV-C, R⁵ and R⁶ are independently, at each occurrence, —C₁-C₆alkyl.

[0829] In one or more embodiments of Formula IV-C, R² is —H. In one or more embodiments of Formula IV-C, R² is —C₁-C₆alkyl, wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In certain such embodiments, R² is methyl. In one or more embodiments of Formula IV-C, R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In one or more embodiments of Formula IV-C, R² is —OH. In one or more embodiments of Formula IV-C, R² is —NR⁵R⁶. In one or more embodiments of Formula IV-C, R² is —NH₂.

[0830] In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0831] In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-C, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-C, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0832] In one or more embodiments of Formula IV-C, R³ 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-C, R³ 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-C, R³ 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0833] In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-C, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0834] In one or more embodiments of Formula IV-C, X¹ is N and X² is N. In one or more embodiments of Formula IV-C, X¹ is C and X² is CH. In one or more embodiments of Formula IV-C, X¹ is C and X² is N. In one or more embodiments of Formula IV-C, X¹ is N and X² is CH.

[0835] In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12-membered heterocycle. In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heterocycle. In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.

[0836] In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-C, the heterocyclyl ring is bridged.

[0837] In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heteroaryl. In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.

[0838] In one or more embodiments of Formula IV-C, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula IV-C, the polycyclic heteroaryl is a multiple condensed ring as described above. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.

[0839] In one or more embodiments of Formula IV-C, B is substituted with one or more —(CH₂)_nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-C, B is substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-C, B is substituted with one or more oxo. In one or more embodiments of Formula IV-C, B is substituted with one or more —C₁-C₆alkyl. In one or more embodiments of Formula IV-C, B is substituted with one or more —OH. In one or more embodiments of Formula IV-C, B is substituted with one or more —NH₂. In one or more embodiments of Formula IV-C, B is substituted with one or more —CF₃. In one or more embodiments of Formula IV-C, B is substituted with one or more —CHF₂. In one or more embodiments of Formula IV-C, B is substituted with one or more —CH₂F. In one or more embodiments of Formula IV-C, B is substituted with one or more —(CH₂)_nNH₂. In certain such embodiments, n is 1.

[0840] In certain embodiments of Formula IV, the compound is of Formula IV-D:

• • [0841] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein:
  • [0842] C forms a 3- to 12-membered monocyclic heterocycle, 3- to 12-membered polycyclic heterocycle, or a 5- to 12-membered spiroheterocycle, along with the nitrogen atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH,
  • [0843] —CF₃, —CHF₂, or —CH₂F. In some embodiments of Formula IV-D, the C ring is optionally substituted with one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃,
  • [0844] —CHF₂, or —CH₂F. In certain such embodiments, n is 1. In some embodiments of Formula IV-D, the C ring is optionally substituted with one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or
  • [0845] —NH₂. In certain such embodiments, n is 1.

[0846] In certain embodiments of Formula IV-D, the C ring, along with the nitrogen atom to which it is attached, is an optionally substituted 3- to 12-membered monocyclic heterocycle. In certain embodiments of Formula IV-D, the C ring, along with the nitrogen atom to which it is attached, is an optionally substituted 3- to 12-membered polycyclic heterocycle. In certain embodiments of Formula IV-D, along with the nitrogen atom to which it is attached, is an optionally substituted 5- to 12-membered spiroheterocycle.

[0847] In certain embodiments of Formula IV-D, C ring, along with the nitrogen atom to which it is attached, is an optionally substituted

In certain embodiments of Formula IV-D, C ring, along with the nitrogen atom to which it is attached, is an optionally substituted

In certain embodiments of Formula IV-D, C ring, along with the nitrogen atom to which it is attached, is an optionally substituted

[0848] In one or more embodiments of Formula IV-D, R⁴ is H.

[0849] In one or more embodiments of Formula IV-D, R⁴ is

In certain such embodiments, Y¹ is —S— or a direct bond. In one or more embodiments of Formula IV-D, Y¹ is —S—. In one or more embodiments of Formula IV-D, Y¹ is a direct bond.

[0850] In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-D, A is phenyl. In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-D, A is pyridinyl. In one or more embodiments of Formula IV-D, A is indazolyl. In one or more embodiments of Formula IV-D, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.

[0851] In one or more embodiments of Formula IV-D, n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-D, n is independently, at each occurrence, 1 or 2.

[0852] In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or —NR⁵R⁶. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H, —OR⁵ or halogen. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H or —OR⁵. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H or halogen. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H or —NR⁵R⁶. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H, —OR⁵ or —NR⁵R⁶. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H, halogen or —NR⁵R⁶. In certain such embodiments, R⁵ and R⁶ are both —H. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H, methyl, fluoro, chloro, or —NH₂. In one or more embodiments of Formula IV-D, R¹ is independently, at each occurrence, —H, —CN or halogen.

[0853] In one or more embodiments of Formula IV-D, R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl. In one or more embodiments of Formula IV-D, R⁵ and R⁶ are independently, at each occurrence, —H. In one or more embodiments of Formula IV-D, R⁵ and R⁶ are independently, at each occurrence, —C₁-C₆alkyl.

[0854] In one or more embodiments of Formula IV-D, R² is —H. In one or more embodiments of Formula IV-D, R² is —C₁-C₆alkyl, wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In certain such embodiments, R² is methyl. In one or more embodiments of Formula IV-D, R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In one or more embodiments of Formula IV-D, R² is —OH. In one or more embodiments of Formula IV-D, R² is —NR⁵R⁶. In one or more embodiments of Formula IV-D, R² is —NH₂.

[0855] In one or more embodiments of Formula IV-D, X¹ is N and X² is N. In one or more embodiments of Formula IV-D, X¹ is C and X² is CH. In one or more embodiments of Formula IV-D, X¹ is C and X² is N. In one or more embodiments of Formula IV-D, X¹ is N and X² is CH.

[0856] In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12-membered heterocycle. In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heterocycle. In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.

[0857] In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-D, the heterocyclyl ring is bridged.

[0858] In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heteroaryl. In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.

[0859] In one or more embodiments of Formula IV-D, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula IV-D, the polycyclic heteroaryl is a multiple condensed ring as described above. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.

[0860] In one or more embodiments of Formula IV-D, B is substituted with one or more —(CH₂)_nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-D, B is substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-D, B is substituted with one or more oxo. In one or more embodiments of Formula IV-D, B is substituted with one or more —C₁-C₆alkyl. In one or more embodiments of Formula IV-D, B is substituted with one or more —OH. In one or more embodiments of Formula IV-D, B is substituted with one or more —NH₂. In one or more embodiments of Formula IV-D, B is substituted with one or more —CF₃. In one or more embodiments of Formula IV-D, B is substituted with one or more —CHF₂. In one or more embodiments of Formula IV-D, B is substituted with one or more —CH₂F. In one or more embodiments of Formula IV-D, B is substituted with one or more —(CH₂)_nNH₂. In certain such embodiments, n is 1.

[0861] In certain embodiments of Formula IV, the compound is of Formula IV-E:

• • [0862] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein X^B1 is N, NR⁹, CR⁹, S, or O; X^B2 is N, NR⁹, CR⁹, S, or O; and X^B3 is N, NR⁹, CR⁹, S, or O, wherein R⁹ is independently, at each occurrence, —H, —C₁-C₆alkyl,
  • [0863] —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that if X¹ is C, at least one of X^B1, X^B2, and X^B3 is not CR⁹, or provided that if each of X^B1, X^B2, and X^B3 are CR⁹, X¹ must be N.

[0864] In certain embodiments of Formula IV-E, X^B1 is N or NR⁹. In certain embodiments of Formula IV-E, X^B1 is CR⁹. In certain embodiments of Formula IV-E, X^B1 is S. In certain embodiments of Formula IV-E, X^B1 is O. In Certain embodiments of Formula IV-E, X^B2 is N or NR⁹. In certain embodiments of Formula IV-E, X^B2 is CR⁹. In certain embodiments of Formula IV-E, X^B2 is S. In Certain embodiments of Formula IV-E, X^B2 is O In certain embodiments of Formula IV-E, X^B3 is N or NR⁹. In certain embodiments of Formula IV-E, X^B3 is CR⁹. In certain embodiments of Formula IV-E, X^B3 is S. In Certain embodiments of Formula IV-E, X^B3 is O.

[0865] In certain embodiments of Formula IV-E, X^B1 is N, NR⁹, or CR⁹; X^B2 is N, NR⁹, or CR⁹; and X^B3 is N, NR⁹, or CR⁹. In certain embodiments of Formula IV-E, X^B1 is N or NR⁹. In certain embodiments of Formula IV-E, X^B1 is CR⁹. In certain embodiments of Formula IV-E, X^B2 is N or NR⁹. In certain embodiments of Formula IV-E, X^B2 is CR⁹. In certain embodiments of Formula IV-E, X^B3 is N or NR⁹. In certain embodiments of Formula IV-E, X^B3 is CR⁹.

[0866] In some embodiments of Formula IV-E, R⁹ is —(CH₂)_nOH and n is 1. In some embodiments of Formula IV-E, R⁹ is H.

[0867] In certain embodiments of Formula IV-E,

wherein is a single bond or double bond to satisfy valency rules, is

[0868] In one or more embodiments of the compounds of Formula IV-E, Y² is —(CR^a₂)_m—. In one or more embodiments of the compounds of Formula IV-E, Y² is —NR^a—.

[0869] In one or more embodiments of Formula IV-E, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-E, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-E, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-E, A is phenyl. In one or more embodiments of Formula IV-E, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-E, A is pyridinyl. In one or more embodiments of Formula IV-E, A is indazolyl. In one or more embodiments of Formula IV-E, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.

[0870] In one or more embodiments of Formula IV-E, n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-E, n is independently, at each occurrence, 1 or 2.

[0871] In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H, —OR⁵, halogen, —C₁-C₆alkyl, —CN, or —NR⁵R⁶. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H, —OR⁵ or halogen. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H or —OR⁵. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H or halogen. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H or —NR⁵R⁶. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H, —OR⁵ or —NR⁵R⁶. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H, halogen or —NR⁵R⁶. In certain such embodiments, R⁵ and R⁶ are both —H. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H, methyl, fluoro, chloro, or —NH₂. In one or more embodiments of Formula IV-E, R¹ is independently, at each occurrence, —H, —CN or halogen.

[0872] In one or more embodiments of Formula IV-E, R⁵ and R⁶ are independently, at each occurrence, —H or —C₁-C₆alkyl. In one or more embodiments of Formula IV-E, R⁵ and R⁶ are independently, at each occurrence, —H. In one or more embodiments of Formula IV-E, R⁵ and R⁶ are independently, at each occurrence, —C₁-C₆alkyl.

[0873] In one or more embodiments of Formula IV-E, R² is —H. In one or more embodiments of Formula IV-E, R² is —C₁-C₆alkyl, wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In certain such embodiments, R² is methyl. In one or more embodiments of Formula IV-E, R² is —H, —OH, —NR⁵R⁶, —C₁-C₆alkyl, or —NH₂; wherein each alkyl is optionally substituted with one or more —OH, halogen, —OR⁵, or —NR⁵R⁶. In one or more embodiments of Formula IV-E, R² is —OH. In one or more embodiments of Formula IV-E, R² is —NR⁵R⁶. In one or more embodiments of Formula IV-E, R² is —NH₂.

[0874] In one or more embodiments of Formula IV-E, R^a is —H.

[0875] In one or more embodiments of Formula IV-E, R³ is an optionally substituted —C₁-C₆alkyl. In one or more embodiments of Formula IV-E, R³ is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-E, R³ is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-E, R³ is an optionally substituted 5- to 12-membered polycyclic heterocycle.

[0876] In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0877] In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-E, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-E, R³ and R^a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0878] In one or more embodiments of Formula IV-E, R³ 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-E, R³ 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-E, R³ 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0879] In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —NH₂, —OH, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F. In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —(CH₂)_nNH₂, or —NH₂. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-E, 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 one or more —C₁-C₆alkyl, —OH, —NH₂, oxo, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F.

[0880] In one or more embodiments of Formula IV-E, X¹ is N and X² is N. In one or more embodiments of Formula IV-E, X¹ is C and X² is CH. In one or more embodiments of Formula IV-E, X¹ is C and X² is N. In one or more embodiments of Formula IV-E, X¹ is N and X² is CH.

[0881] In certain embodiments of Formula IV, the compound is of Formula IV-F:

• • [0882] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, wherein R⁹ is independently, at each occurrence, —H, —C₁-C₆alkyl, —OH, —NH₂, heteroaryl, heterocyclyl, —(CH₂)_nNH₂, —(CH₂)_nOH, —CF₃, —CHF₂, or —CH₂F, provided that if X¹ is C, at least one of X^B4, X^B5, X^B6, and X^B7 is not CR⁹, or provided that if each of X^B4, X^B5, X^B6, and X^B7 are CR⁹, X¹ must be N.