WO2018136265A1 - Bicyclic compounds as allosteric shp2 inhibitors - Google Patents

Bicyclic compounds as allosteric shp2 inhibitors Download PDF

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WO2018136265A1
WO2018136265A1 PCT/US2018/013023 US2018013023W WO2018136265A1 WO 2018136265 A1 WO2018136265 A1 WO 2018136265A1 US 2018013023 W US2018013023 W US 2018013023W WO 2018136265 A1 WO2018136265 A1 WO 2018136265A1
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formula
optionally substituted
compound
heterocycle
membered
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English (en)
French (fr)
Inventor
Brian R. BLANK
Jennifer PITZEN
Gang Wang
Walter S. Won
Christos TZITZILONIS
Jie Jack Li
Elena S. Koltun
Naing Aay
Andreas BUCKL
Kevin MELLEM
Christopher Semko
Ash JOGALEKAR
Gert KISS
Adrian Gill
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Revolution Medicines Inc
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Revolution Medicines Inc
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Priority to SG11201906209SA priority Critical patent/SG11201906209SA/en
Priority to CN201880018606.4A priority patent/CN110446709B/zh
Priority to KR1020197024604A priority patent/KR102665763B1/ko
Priority to CA3051206A priority patent/CA3051206A1/en
Priority to IL296456A priority patent/IL296456A/en
Priority to RU2019126456A priority patent/RU2776846C2/ru
Priority to CN202311080113.2A priority patent/CN117327075A/zh
Priority to MX2019008695A priority patent/MX2019008695A/es
Priority to BR112019015075-7A priority patent/BR112019015075A2/pt
Priority to JP2019539774A priority patent/JP7240319B2/ja
Priority to EP18701883.3A priority patent/EP3571199A1/en
Priority to AU2018210770A priority patent/AU2018210770B2/en
Application filed by Revolution Medicines Inc filed Critical Revolution Medicines Inc
Publication of WO2018136265A1 publication Critical patent/WO2018136265A1/en
Priority to IL268030A priority patent/IL268030B2/en
Priority to US16/518,798 priority patent/US11739093B2/en
Anticipated expiration legal-status Critical
Priority to AU2022204275A priority patent/AU2022204275A1/en
Priority to JP2022187881A priority patent/JP2023018095A/ja
Priority to US18/220,196 priority patent/US12365688B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • One aspect of the disclosure relates to compounds of Formula ⁇ :
  • A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -Ci-Cealkynyl, -C 3 -C 8 cycloalkyl, -OH, halogen, -NO2, -CN, - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0)NR 5 R 6 , - R 5 S(0)R 6 , -C(0)R 5 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted
  • X 1 is N or C;
  • X 2 is N or CH
  • 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;
  • R 2 is -H, -OR b , -NR 5 R 6 ,-CN, -Ci-Cealkyl, -C 2 -C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -NH 2 , halogen, -C(0)OR b , -C 3 -C 8 cycloalkyl, 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, -R 5 , -OR 5 , - R 5 R
  • Y 2 is - R a - -(CR3 ⁇ 4)m- -C(O)-, -C(R a ) 2 NH- -(CR a 2 )mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C 3 -C 8 cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more - H 2 , wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C3-C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R 3 is -H, -C i-C 6 alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, -C 3 -C 8 cycloalkyl, or -(CH 2 )n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , -NHR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -COOR b , -CONHR b , -CONH(CH 2 )nCOOR b ,
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN; R and R are independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycl
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 , -NR 5 S(0)NR 5 R 6 , -NR 5 S(0)R 6 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is
  • X 1 is N or C;
  • X 2 is N or CH
  • 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;
  • R 2 is -H, -OR b , -NR 5 R 6 ,-CN, -Ci-Cealkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -NH2, halogen, -C(0)OR b , -C 3 -C 8 cycloalkyl, 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, -R 5 , -OR 5 , - R 5 R 6 ,
  • Y 2 is - R a - -(CR3 ⁇ 4)m- -C(O)-, -C(R a ) 2 NH- -(CR a 2 )mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C 3 -C 8 cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more - H 2 , wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C3-C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R 3 is -H, -Ci-C 6 alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -C 3 -C 8 cycloalkyl, or -(CH 2 )n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , -NHR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -COOR b , -CONHR b , -CONH(CH 2 )nCOOR b ,
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 , -NR 5 S(0)NR 5 R 6 , -NR 5 S(0)R 6 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is
  • X 1 is N or C
  • X 2 is N or CH
  • B is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • R 2 is -H, -OR b , - R 5 R 6 ,-CN, -Ci-Cealkyl, -Ci-Cealkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, - H2, halogen, -C(0)OR b , -C3-C 8 cycloalkyl, 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, wherein each alkyl, alkeny
  • Y 2 is - R a - -(CR a 2)m- -C(O)-, -C(R a ) 2 H-, -(CR a 2 )mO- -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C3-C 8 cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more - H2, wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C3-C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R 3 is, at each occurrence, selected from the group consisting of -H, -Ci-C 6 alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, C 3 -C 8 cycloalkyl, or -(CH2)n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH2, -OR b , -NHR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, -NH2, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -COOR b , -CONHR b , -CONH(CH 2 )nCOOR b ,
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 , -NR 5 S(0)NR 5 R 6 , -NR 5 S(0)R 6 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is
  • X 1 is N or C
  • X 2 is N or CH
  • B is a monocyclic or polycyclic 5- to 12-membered heterocycle or a monocyclic or polycyclic 5- to 12-membered heteroaryl;
  • R 2 is -H, -OR b , - R 5 R 6 ,-CN, -Ci-Cealkyl, -Ci-Cealkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, - H2, halogen, -C(0)OR b , -C3-C 8 cycloalkyl, 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
  • Y 2 is - R a - -(CR3 ⁇ 4)m-, -C(O)-, -C(R a ) 2 H-, -(CR a 2 )mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C3-C 8 cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more - H2, wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C3-C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R 3 is -H, -Ci-C 6 alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, -C 3 -C 8 cycloalkyl, or -(CH2)n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH2, -OR b , -NHR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, -NH2, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -COOR b , -CONHR b , -CONH(CH 2 )nCOOR b ,
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C3-C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • A is a 5- to 12-membered monocyclic or olycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the heteroaryl is not
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, -OH, -OR 5 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 , -NR 5 S(0)NR 5 R 6 , -NR 5 S(0)R 6 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or
  • X 1 is N or C;
  • X 2 is N or CH
  • B 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
  • -Ci-Cealkyl -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F;
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-Cealkyl, -C 2 -C 6 alkenyl, -C 4 -C 8 cycloalkenyl,
  • each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0) 2 R 5 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0)R 6 , heterocycle, aryl, or heteroaryl;
  • Y 2 is - R a - -(CR3 ⁇ 4)m- -C(O)-, -C(R a ) 2 H-, -(CR a 2 )mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C 3 -C 8 cycloalkyl, or -Ci- C 6 alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more - H2, wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C 3 -C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R 3 is -H, -Ci-C 6 alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -C 3 -C 8 cycloalkyl, or -(CH 2 )n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , - HR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C6alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F, provided that the heterocycle formed by the combination of R 3 and R a is not an optionally substituted piperazinyl;
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH 2 , -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • One aspect of the disclosure relates to compounds of Formula IV that are compounds of Formula IV-Q:
  • A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl, provided that R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 ;
  • Y 1 is -S- or a direct bond
  • X 1 is N or C
  • X 2 is N or CH
  • B 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
  • -Ci-Cealkyl -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F;
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-Cealkyl, or - H 2 ; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 ;
  • Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;
  • R 3 is combined with R a to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, - H 2 , -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F, provided that the heterocycle formed by the combination of R 3 and R a is not an optionally substituted piperazinyl;
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl
  • n is independently, at each occurrence, 1, 2, 3, 4, 5 or 6;
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • 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, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).
  • compounds disclosed herein e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • 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, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).
  • Another aspect of the disclosure is directed to pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula ⁇ , 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.
  • composition can be effective for treating a disease associated with SHP2 modulation in a subject in need thereof.
  • 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, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).
  • a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).
  • 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, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).
  • a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof).
  • Another aspect of the disclosure relates to one or more compounds disclosed herein (e.g., compounds of Formula ⁇ , 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, 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.
  • Another aspect of the disclosure relates to the use of one or more compounds disclosed herein (e.g., compounds of Formula ⁇ , 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.
  • compounds disclosed herein e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof
  • 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, 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.
  • compounds disclosed herein e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof
  • a pharmaceutically acceptable carrier in the manufacture of a medicament for treating or preventing a disease associated with SHP2 modulation.
  • Another aspect of the disclosure relates to one or more compounds disclosed herein (e.g., compounds of Formula ⁇ , 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, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • the medicament is used for treating or preventing a disease associated with SHP2 modulation.
  • the present disclosure also provides compounds and pharmaceutical compositions that are useful in inhibiting SHP2.
  • an alkyl group that is optionally substituted may be a fully saturated alkyl chain (i.e. a pure hydrocarbon).
  • 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.
  • 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,
  • 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.
  • heteroaryls to form for example a naphthyridinyl such as 1,8-naphthyridinyl
  • heterocycles to form for example a 1, 2, 3, 4-tetrahydronaphthyrid
  • 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.
  • substituents 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[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2- a] pyridinyl, imidazo[l,5-a]pyrazinyl, indazolyl
  • Alkyl may refer to a straight or branched chain saturated hydrocarbon.
  • Ci- C 6 alkyl groups contain 1 to 6 carbon atoms. Examples of a Ci-C 6 alkyl group may include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
  • 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.
  • 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.
  • 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).
  • 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 C 4 - C 8 cycloalkenyl is a cycloalkenyl group containing between 4 and 8 carbon atoms.
  • 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 ⁇ electrons (aromaticity) shared among the ring carbon or
  • 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 heteroycyclyl or heterocycloalkyl ring may also be fused or bridged, e.g., can be a bicyclic ring.
  • 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).
  • 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-l,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, benzothien
  • 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.
  • 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.
  • 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.
  • compositions comprising an effective amount of one or more disclosed compounds and a pharmaceutically acceptable carrier.
  • 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.
  • the disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein.
  • 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,
  • “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-l,2-d
  • “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,
  • tromethamine purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • 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.
  • compounds of the Present disclosure can exist in tautomeric form.
  • R 2 can be -OH and tautomers of the compounds can exist in equilibrium:
  • the disclosure may include prodrugs of the compounds described herein.
  • 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.
  • 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).
  • the disclosure may include solvates of the compounds described herein.
  • solvate may refer to a complex of variable stoichiometry formed by a solute and solvent.
  • solvents for the purpose of the disclosure may not interfere with the biological activity of the solute.
  • 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.
  • 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. [0054] The disclosure may include stereoisomers of the compounds described herein.
  • 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.
  • stereoisomer may refer to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer.
  • the present disclosure may embrace all geometric and positional isomers.
  • 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.
  • the substituent may be in the E or Z configuration.
  • the cycloalkyl substituent may have a cis or trans configuration.
  • 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.
  • the compounds may be the ( ⁇ -enantiomer.
  • the compounds may be the (R)-enantiomer.
  • the compounds may be the (+) or (-) enantiomers.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the synthetic route may produce a single diastereomer or a mixture of diastereomers.
  • the disclosure may include diastereomers of the compounds described herein.
  • 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.
  • 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).
  • 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.
  • radioactive isotopes tritium, i.e., 3 H, and carbon 14, i.e., 14 C 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., 2 H, 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 2 H (also written as D for deuterium), 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 C1 , 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 I.
  • 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.
  • 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.
  • 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.
  • 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.
  • disorder is used in this disclosure and may be used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer 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.
  • 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.
  • Compounds of the disclosure include compounds of Formula ⁇ I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers of any of the foregoing.
  • the compound is of the Formula I-A:
  • A is aryl
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -Ci-Cealkynyl, -C 3 -C 8 cycloalkyl, -OH, halogen, -NO2, -CN, - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 5 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , -NR 5 S(0) R 5 R 6 , - R 5 S(0)R 6 , -C(0)R 5 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally
  • X 1 is N or C;
  • X 2 is N or CH
  • 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;
  • R 2 is -H, -OR b , -NR 5 R 6 , -CN, -Ci-Cealkyl, -C 2 -C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -NH 2 , halogen, -C(0)OR b , -C 3 -C 8 cycloalkyl, 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, -R 5 , -OR 5 , -NR 5
  • R a is independently, at each occurrence, -H, -D, -OH, -C3-C8cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more - H 2 , wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C 3 -C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , -S(0)R 5 ,
  • R 3 is -H, -Ci-C 6 alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, -C 3 -C 8 cycloalkyl, or -(CH 2 )n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , - HR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -COOR b , -CO HR b , -CO H(CH 2 )nCOOR b ,
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH 2 , -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • A is heteroaryl
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -Ci-Cealkynyl, -Cs-Cscycloalkyl, -OH, halogen, -NO2, -CN, - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0)NR 5 R 6 , - R 5 S(0)R 6 , -C(0)R 5 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one
  • X 1 is N or C;
  • X 2 is N or CH
  • 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;
  • R 2 is -H, -OR b , -NR 5 R 6 , -CN, -Ci-Cealkyl, -C 2 -C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -C2-C 6 alkynyl, -NH 2 , halogen, -C(0)OR b , -C3-C 8 cycloalkyl, 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, -R 5 , -OR 5 , -NR 5 R
  • Y 2 is -NR a -, -(CR3 ⁇ 4)m-, -C(O)-, -C(R a ) 2 H-, -(CR3 ⁇ 4)mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C3-C8cycloalkyl, or -Ci- C 6 alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more - H 2 , wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C 3 -C 8 cycloalkyl, -C 2 -C 6 alkenyl, 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, -R 5 , -OR 5 , - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , -S(0)R 5 ,
  • R 3 is -H, -Ci-C 6 alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, -C 3 -C 8 cycloalkyl, or -(CH 2 )n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , - HR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -COOR b , -CO HR b , -CO H(CH 2 )nCOOR b ,
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH 2 , -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the compound is of the Formula II- A:
  • the compound is of the Formula II-A1 :
  • 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 -Ci-C6alkyl, -OH, or - H 2 .
  • the compound is of the Formula II- A2:
  • the compound is of the Formula II- A3 :
  • the compound is the Formula II-B:
  • the compound is of the Formula II-B 1 :
  • 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 -Ci-C6alkyl, -OH,
  • the compound is of the Formula II-B2:
  • the compound is of the Formula II-B3 :
  • the compound is of the Formula II-B4:
  • the compound is of the Formula II-B 5:
  • the compound is of the Formula II-B6:
  • ⁇ - ⁇ 6 and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is the Formula II-C:
  • C forms a 3- to 12-membered monocyclic or poly cyclic heterocycle, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C6alkyl, -OH, or - H 2
  • the compound is of the Formula II-C 1 :
  • the compound is the Formula II-D:
  • C forms a 3- to 12-membered monocyclic or poly cyclic heterocycle, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C6alkyl, -OH, or - H 2
  • the compound is of the Formula II-D 1 :
  • the compound is the Formula II-E:
  • the compound is the Formula II-F:
  • the compound is the Formula II-G:
  • R 2 is an aryl or heteroaryl.
  • the compound is of the Formula III- A:
  • the compound is of the Formula III-A 1 :
  • 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 -Ci-C6alkyl, -OH,
  • the compound is of the Formula III- A2:
  • the compound is of the Formula III- A3 :
  • III-A3 and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compounds of the disclosure are compounds of Formula IV:
  • A is a 5- to 12-membered monocyclic or olycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the heteroaryl is not
  • R 1 is independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl,
  • each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , halogen, -NO2, -CN, - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0) R 5 R 6 , -C(0)R 5 , or -C0 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN,
  • X 1 is N or C;
  • X 2 is N or CH
  • B 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 -Ci- Cealkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F;
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-Cealkyl, -C 2 -C 6 alkenyl, -C 4 -C 8 cycloalkenyl,
  • each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0) 2 R 5 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0)R 6 , heterocycle, aryl, or heteroaryl;
  • Y 2 is - R a - -(CR3 ⁇ 4)m- -C(O)-, -C(R a ) 2 H-, -(CR a 2 )mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C 3 -C 8 cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more - H 2 , wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C 3 -C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R is -H, -Ci-C6alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, -C3-C8cycloalkyl, or -(CH2)n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , - HR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F, provided that the heterocycle formed by the combination of R 3 and R a is not an optionally substituted piperazinyl;
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, - H2, -NO2, or -CN; m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 4 is H.
  • R 4 is .
  • Y 1 is -S- or a direct bond.
  • Y 1 is -S-.
  • Y 1 is a direct bond.
  • Y 2 is -(CR a 2 )m- In one or more embodiments of the compounds of Formula IV, Y 2 is -NR a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV, A is a monocyclic or poly cyclic 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 poly cyclic aryl or heteroaryl.
  • 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.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 . In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NFh. In one or more embodiments of Formula IV, R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H.
  • R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In one or more embodiments of Formula IV, R 2 is -OH. In one or more embodiments of Formula IV, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV, R 2
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula IV, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 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 -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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
  • -Ci-Cealkyl -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or - H2.
  • n is 1.
  • R and R a together with the atoms to which they are attached combine to form a 5- to 12- membered spiroheterocycle, which is optionally substituted with one or more -Ci-C6alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV, X 1 is C and X 2 is N. In one or more embodiments of Formula IV, X 1 is N and X 2 is CH.
  • 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.
  • B including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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. [00112] 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.
  • 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.
  • 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 -Ci-Cealkyl, -OH, - Fh, oxo, -(CH2)n H2,
  • B is substituted with one or more oxo. In one or more embodiments of Formula IV, B is substituted with one or more -Ci-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 - H2. 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.
  • 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: a) R 4 is H; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F; d) R 2 is -H, -Ci-Cealkyl, or - H2; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound
  • 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: a) R 4 is H; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y
  • 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: a) R 4 is H; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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: a) R 4 is H; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of
  • 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:
  • A is a monocyclic or polycyclic aryl or pyridinyl
  • X 1 is C and X 2 is CH;
  • 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ; f) R is combined with R a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optionally
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H2; e) Y 2 is - R a -, wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • A is a monocyclic or polycyclic aryl or pyridinyl
  • X 1 is N and X 2 is CH;
  • 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ; f) R 3 is combined with R a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle is optional
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R
  • 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:
  • A is a monocyclic or polycyclic aryl or pyridinyl
  • X 1 is N and X 2 is N;
  • 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ; f) R 3 is combined with R a to form a 3- to 12-membered monocyclic heterocycle, wherein the heterocycle
  • 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: a) R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or -
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H2; e) Y 2 is - R a -, wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • A is a monocyclic or polycyclic aryl or pyridinyl
  • X 1 is C and X 2 is CH;
  • 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ; f) R 3 is combined with R a to form a 5- to 12-membered spiroheterocycle, wherein
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • 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:
  • A is a monocyclic or polycyclic aryl or pyridinyl
  • X 1 is C and X 2 is N;
  • 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ; f) R 3 is combined with R a to form a 5- to 12-membered spiroheterocycle, wherein
  • 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: a) R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is -S-; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or -
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H2; e) Y 2 is - R a -, wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R
  • 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:
  • R is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn,
  • 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: a) R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl,
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H2; e) Y 2 is - R a -, wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is C and X 2 is N; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • 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:
  • R 4 is , A is a monocyclic or polycyclic aryl or pyridinyl, and Y 1 is a direct bond; b) X 1 is N and X 2 is CH; 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 -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F; d) R 2 is -H, -Ci-Cealkyl, or - H 2 ; e) Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn
  • the compound is of Formula IV-A:
  • X B1 is N, R 9 , CR 9 , S, or O
  • X B2 is N, R 9 , CR 9 , S, or O
  • X B3 is N, NR 9 , CR 9 , S, or O
  • R 9 is independently, at each occurrence, -H, -Ci-C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F, provided that if X 1 is C, at least one of X B1 , X B2 , and X B3 is not CR 9 , or provided that if each of X B1 , X B2 , and X B3 are
  • X B1 is N or NR 9 .
  • X B1 is CR 9 . 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 NR 9 . In certain embodiments of Formula IV-A, X B2 is CR 9 . 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 NR 9 . In certain embodiments of Formula IV-A, X B3 is CR 9 . In certain embodiments of Formula IV-A, X B3 is S.
  • X B3 is O.
  • X B1 is N, NR 9 , or CR 9 ;
  • X B2 is N, R 9 , or CR 9 ; and
  • X B3 is N, NR 9 , or CR 9 .
  • X B1 is N or NR 9 .
  • X B1 is CR 9 .
  • X B2 is N or NR 9 .
  • X B2 is CR 9 .
  • X B3 is N or NR 9 .
  • X B3 is CR 9 .
  • R 9 is -( ⁇ 3 ⁇ 4) ⁇ 0 ⁇ and n is 1. In some embodiments of Formula IV-A, R 9 is H.
  • R 4 is H.
  • R 4 is In certain such embodiments, Y 1 is -S- or a direct bond. In one or more embodiments of Formula IV-A, Y 1 is -S-. In one or more embodiments of Formula IV-A, Y 1 is a direct bond.
  • Y 2 is
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-A, A is a monocyclic or poly cyclic 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.
  • 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.
  • 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.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-A, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-A, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-A, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-A, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-A, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl. In one or more embodiments of Formula IV-A, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- A, R 5 and R 6 are independently, at each occurrence, -Ci-C 6 alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-A, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-A, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV- A, R 2 is -OH. In one or more embodiments of Formula IV- A, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-A, R 2 is - H2.
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C6alkyl. In one or more embodiments of Formula IV-A, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-A, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-A, R 3 is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, [00179]
  • R and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -Ci-Cealkyl, -NFh, -OH, -(CFh ⁇ Fh, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 is optionally substituted with one or more -Ci-Cealkyl, -NFh, -OH, -(CFh ⁇
  • spiroheterocycle which is optionally substituted with one or more -Ci-C6alkyl, -(CH2)nNH2, or -NFh.
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or - H2.
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV- A, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV- A, X 1 is C and X 2 is N. In one or more embodiments of Formula IV- A, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-B:
  • IV-B and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof wherein X B4 is N or CR 9 ; X B5 is N or CR 9 ; X B6 is N or CR 9 ; and X B7 is N or CR 9 , wherein R 9 is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, - H 2 , heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F, provided that if X 1 is C, at least one of X B4 , X B5 , X B6 , and X B7 is not CR 9 , or provided that if each of X B4 , X B5 , X B6 , and X B7 are CR 9 , where
  • X B4 is N. In certain embodiments of Formula IV-B, X B4 is CR 9 . In certain embodiments of Formula IV-B, X B5 is N. In certain embodiments of Formula IV-B, X B5 is CR 9 . In certain embodiments of Formula IV-B, X B6 is N. In certain embodiments of Formula IV-B, X B6 is CR 9 . In certain embodiments of
  • Formula IV-B, X B7 is N. In certain embodiments of Formula IV-B, X B7 is CR 9 . In certain embodiments of Formula IV-B, X B4 is N, X B5 is CR 9 , X B6 is N, and X B7 is CR 9 . In certain such embodiments, R 9 is independently, at each occurrence, -H.
  • R 9 is -(CH 2 ) n OH and n is 1. In some embodiments of Formula IV-B, R 9 is H.
  • R 4 is H.
  • R 4 is In certain such embodiments, Y 1 is -S- or a direct bond. In one or more embodiments of Formula IV-B, Y 1 is -S-. In one or more embodiments of Formula IV-B, Y 1 is a direct bond.
  • Y 2 is -(CR3 ⁇ 4)m-. In one or more embodiments of the compounds of Formula IV-B, Y 2 is - R a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-B, A is a monocyclic or poly cyclic 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.
  • A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3.
  • n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-B, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-B, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-B, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-B, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-B, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV-B, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- B, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-B, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-B, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In one or more embodiments of Formula IV-B, R 2 is -OH. In one or more embodiments of Formula IV-B, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV-B, R 2 is -NH2.
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula IV-B, R 3 is an optionally substituted 3- to 12-membered monocyclic or poly cyclic heterocycle. In one or more embodiments of Formula IV-B, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-B, R is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or - H2.
  • n is 1.
  • R 3 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 -Ci-C6alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-C 6 alkyl, -(CH 2 ) n NH 2 , or - H 2 .
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-B, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-B, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-B, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-C:
  • IV-C and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
  • R 4 is H.
  • R 4 is .
  • Y 1 is -S- or a direct bond.
  • Y 1 is -S-.
  • Y 1 is a direct bond.
  • A is a monocyclic or poly cyclic cycloalkyl.
  • A is a monocyclic or poly cyclic heterocycloalkyl.
  • A is a monocyclic or polycyclic aryl.
  • 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.
  • 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.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-C, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-C, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-C, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-C, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-C, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl. In one or more embodiments of Formula IV-C, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- C, R 5 and R 6 are independently, at each occurrence, -Ci-C 6 alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-C, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-C, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-C, R 2 is -OH. In one or more embodiments of Formula IV-C, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-C, R 2 is -NHz.
  • R 3 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 -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, -NHz, oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, -NH2, -OH, -(CH2)nNH2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or -NH2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, -NH2, oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)nNH2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or -NH2.
  • n is 1.
  • R 3 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 -Ci-C6alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-C6alkyl, -(CH 2 ) n NH 2 , or - H 2 .
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-C, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-C, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-C, X 1 is N and X 2 is CH.
  • 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.
  • B including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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. [00216] 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.
  • 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.
  • 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 -Ci-Cealkyl, -OH, - H2, 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 -Ci-C6alkyl.
  • B is substituted with one or more -OH. In one or more embodiments of Formula IV-C, B is substituted with one or more - H2. 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.
  • the compound is of Formula IV-D:
  • IV-D and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein:
  • 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CFIF2, or -CH2F.
  • the C ring is optionally substituted with one or more -Ci-Cealkyl, - H2, -OH, -(CH 2 )n H2, -(CH 2 )nOH, -CF3, -CHF2, or -CH2F.
  • n is 1.
  • the C ring is optionally substituted with one or more -Ci-C6alkyl, -(CH2)nNH2, or - H2. In certain such embodiments, n is 1.
  • the C ring, along with the nitrogen atom to which it is attached, is an optionally substituted 3- to 12-membered monocyclic
  • the C ring, along with the nitrogen atom to which it is attached, is an optionally substituted 3-to 12-membered polycyclic heterocycle.
  • the nitrogen atom to which it is attached is an optionally substituted 5- to 12-membered spiroheterocycle.
  • Formula IV-D C ring, along with the nitrogen atom to which it is attached, is an optionally substituted — .
  • the nitrogen atom to which it is attached is an optionally substituted — .
  • R 4 is H.
  • R 4 is .
  • Y 1 is -S- or a direct bond.
  • Y 1 is -S-.
  • Y 1 is a direct bond.
  • 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 poly cyclic aryl or heteroaryl.
  • 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.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-D, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-D, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-D, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-D, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-D, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV-D, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- D, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-D, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-D, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In one or more embodiments of Formula IV-D, R 2 is -OH. In one or more embodiments of Formula IV-D, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV-D, R 2 is -NH2.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-D, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-D, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-D, X 1 is N and X 2 is CH.
  • 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.
  • B including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • 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 -Ci-Cealkyl, -OH, -NH 2 , oxo,
  • B is substituted with one or more oxo. In one or more embodiments of Formula IV-D, B is substituted with one or more -Ci-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 - H2. In one or more embodiments of Formula IV-D, B is substituted with one or more -CF 3 . In one or more embodiments of Formula IV-D, B is substituted with one or more -CHF2.
  • 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.
  • the compound is of Formula IV-E:
  • IV-E and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein X B1 is N, NR 9 , CR 9 , S, or O; X B2 is N, R 9 , CR 9 , S, or O; and X B3 is N, NR 9 , CR 9 , S, or O, wherein R 9 is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, -NH2, heteroaryl, heterocyclyl, -(CH 2 )nNH2, -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F, provided that if X 1 is C, at least one of X B1 , X B2 , and X B3 is not CR 9 , or provided that if each of X B1 , X B2 , and X B3 are CR 9 , X 1
  • X B1 is N or NR 9 .
  • X B1 is CR 9 . 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 NR 9 . In certain embodiments of Formula IV-E, X B2 is CR 9 . 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 NR 9 . In certain embodiments of Formula IV-E, X B3 is CR 9 . In certain embodiments of Formula IV-E, X B3 is S. In certain embodiments of Formula IV-E, X B3 is O.
  • X B1 is N or NR 9 .
  • X B1 is CR 9 .
  • X B2 is N or NR 9 .
  • X B2 is CR 9 .
  • X B3 is N or NR 9 .
  • X B3 is CR 9 .
  • R 9 is -( ⁇ 3 ⁇ 4) ⁇ 0 ⁇ and n is 1.
  • R 9 is H.
  • Y 2 is -(CR3 ⁇ 4)m-. In one or more embodiments of the compounds of Formula IV-E, Y 2 is - R a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-E, A is a monocyclic or poly cyclic 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.
  • 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.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-E, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-E, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-E, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-E, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-E, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV-E, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV-E, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-E, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally
  • R 2 is methyl.
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-C 6 alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 .
  • R 2 is -OH.
  • R 2 is - R 5 R 6 .
  • R 2 is - H2.
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula IV-E, R 3 is an optionally substituted 3- to 12-membered monocyclic or poly cyclic heterocycle. In one or more embodiments of Formula IV-E, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-E, R 3 is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-C6alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H2, -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-E, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-E, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-E, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-F:
  • IV-F and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof wherein X B4 is N or CR 9 ; X B5 is N or CR 9 ; X B6 is N or CR 9 ; and X B7 is N or CR 9 , wherein R 9 is independently, at each occurrence, -H, -Ci-C 6 alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F, provided that if X 1 is C, at least one of X B4 , X B5 , X B6 , and X B7 is not CR 9 , or provided that if each of X B4 , X B5 , X B6 , and X B7 are CR 9 , X 1 must be N.
  • X B4 is N. In certain embodiments of Formula IV-F, X B4 is CR 9 . In certain embodiments of Formula IV-F, X B5 is N. In certain embodiments of Formula IV-F, X B5 is CR 9 . In certain embodiments of Formula IV-F, X B6 is N. In certain embodiments of Formula IV-F, X B6 is CR 9 . In certain embodiments of Formula IV-F, X B7 is N. In certain embodiments of Formula IV-F, X B7 is CR 9 . In certain
  • X B4 is N
  • X B5 is CR 9
  • X B6 is N
  • X B7 is CR 9 .
  • R 9 is independently, at each occurrence, -H.
  • R 9 is -( ⁇ 3 ⁇ 4) ⁇ 0 ⁇ and n is 1.
  • R 9 is H.
  • Y 2 is -(CR3 ⁇ 4)m-. In one or more embodiments of the compounds of Formula IV-F, Y 2 is -NR a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-F, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-F, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-F, A is phenyl. In one or more embodiments of Formula IV-F, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-F, A is pyridinyl. In one or more embodiments of Formula IV- F, A is indazolyl. In one or more embodiments of Formula IV-F, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-F, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-F, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-F, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-F, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-F, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-F, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl. In one or more embodiments of Formula IV-F, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV-F, R 5 and R 6 are independently, at each occurrence, -Ci-C 6 alkyl. [00260] In one or more embodiments of Formula IV-F, R 2 is -H.
  • R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-F, R 2 is -H, -OH, - R 5 R 6 , -Ci-C6alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-F, R 2 is -OH. In one or more embodiments of Formula IV-F, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV-
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula IV-F, R 3 is an optionally substituted 3- to 12-membered monocyclic or poly cyclic heterocycle. In one or more embodiments of Formula IV-F, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-F, R 3 is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-F, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-F, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-F, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-G:
  • IV-G and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-G, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-G, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-G, A is phenyl. In one or more embodiments of Formula IV-G, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-G, A is pyridinyl. In one or more embodiments of Formula IV- G, A is indazolyl. In one or more embodiments of Formula IV-G, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-G, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-G, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-G, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-G, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-G, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-G, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV-G, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- G, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-G, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-G, R 2 is -H, -OH, - R 5 R 6 , -Ci-C 6 alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-G, R 2 is -OH. In one or more embodiments of Formula IV-G, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-G, R 2 is - H2.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-G, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-G, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-G, X 1 is N and X 2 is CH.
  • Formula IV-G is an optionally substituted monocyclic or polycyclic 5- to 12- membered heterocycle. In one or more embodiments of Formula IV-G, 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-G, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle. [00280] In one or more embodiments of Formula IV-G, B, including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl. In certain embodiments, the heteroycyclyl ring is fused. In one or more embodiments of Formula IV-G, the heterocyclyl ring is bridged.
  • Formula IV-G 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-G, 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-G, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-G, B is substituted with one or more -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F. In one or more embodiments of Formula IV-G, B is substituted with one or more oxo. In one or more embodiments of Formula IV-G, B is substituted with one or more -Ci-C6alkyl.
  • B is substituted with one or more -OH. In one or more embodiments of Formula IV-G, B is substituted with one or more - H2. In one or more embodiments of Formula IV-G, B is substituted with one or more -CF3. In one or more embodiments of Formula IV-G, B is substituted with one or more -CHF2. In one or more embodiments of Formula IV-G, B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-G, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • the compound is of Formula IV-H:
  • IV-H and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein:
  • 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • the C ring is optionally substituted with one or more -Ci-Cealkyl, - H2, -OH, -(CH 2 )n H2, -(CH 2 )nOH, -CF3, -CHF2, or -CH2F.
  • n is 1.
  • the C ring is optionally substituted with one or more -Ci-C6alkyl, -(CH2)nNH2, or - H2. In certain such embodiments, n is 1.
  • the C ring, along with the nitrogen atom to which it is attached is an optionally substituted 3- to 12-membered monocyclic heterocycle.
  • the C ring, along with the nitrogen atom to which it is attached is an optionally substituted 3-to 12-membered polycyclic heterocycle.
  • the nitrogen atom to which it is attached is an optionally substituted 5- to 12-membered spiroheterocycle.
  • nitrogen atom to which it is attached is an optionally sub
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-H, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-H, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-H, A is phenyl. In one or more embodiments of Formula IV-H, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-H, A is pyridinyl. In one or more embodiments of Formula IV- H, A is indazolyl. In one or more embodiments of Formula IV-H, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-H, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-H, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-H, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-H, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-H, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-H, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl. In one or more embodiments of Formula IV-H, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- H, R 5 and R 6 are independently, at each occurrence, -Ci-C 6 alkyl. [00291] In one or more embodiments of Formula IV-H, R 2 is -H.
  • R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-H, R 2 is -H, -OH, - R 5 R 6 , -Ci-C6alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-H, R 2 is -OH. In one or more embodiments of Formula IV-H, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-H, R 2 is - H2.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-H, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-H, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-H, X 1 is N and X 2 is CH.
  • Formula IV-H is an optionally substituted monocyclic or polycyclic 5- to 12- membered heterocycle. In one or more embodiments of Formula IV-H, 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-H, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • Formula IV-H is an optionally substituted monocyclic or polycyclic 5- to 12- membered heteroaryl. In one or more embodiments of Formula IV-H, 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-H, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-H, B is substituted with one or more -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH2)n H2,
  • B is substituted with one or more oxo. In one or more embodiments of Formula IV-H, B is substituted with one or more -Ci-C6alkyl. In one or more embodiments of Formula IV-H, B is substituted with one or more -OH. In one or more embodiments of Formula IV-H, B is substituted with one or more - H2. In one or more embodiments of Formula IV-H, B is substituted with one or more -CF3. In one or more embodiments of Formula IV-H, B is substituted with one or more -CHF2.
  • B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-H, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • the compound is of Formula IV-I:
  • X B1 is N, NR 9 , CR 9 , S, or O
  • X B2 is N, R 9 , CR 9 , S, or O
  • X B3 is N, NR 9 , CR 9 , S, or O
  • R 9 is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, -NH2, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F, provided that if X 1 is C, at least one of X B1 , X B2 , and X B3 is not CR 9 , or provided that if each of X B1 , X B2 , and X B3 are CR 9 , X
  • X B1 is N or NR 9 . In certain embodiments of Formula IV-I, X B1 is CR 9 . In certain embodiments of Formula IV-I, X B1 is S. In certain embodiments of Formula IV-I, X B1 is O. In certain embodiments of Formula IV-I, X B2 is N or NR 9 . In certain embodiments of Formula IV-I, X B2 is CR 9 . In certain embodiments of Formula IV-I, X is S. In certain embodiments of Formula IV-I, X is O. In certain embodiments of Formula IV-I, X B3 is N or R 9 . In certain embodiments of Formula IV-I, X B3 is CR 9 . In certain embodiments of Formula IV-I, X B3 is S. In certain embodiments of Formula IV-I, X B3 is O.
  • X B1 is N or NR 9 .
  • X B1 is CR 9 .
  • X B2 is N or NR 9 .
  • X B2 is CR 9 .
  • X B3 is N or NR 9 .
  • X B3 is CR 9 .
  • R 9 is -( ⁇ 3 ⁇ 4) ⁇ 0 ⁇ and n is 1. In some embodiments of Formula IV-I, R 9 is H.
  • Y 2 is -(CR3 ⁇ 4)m In one or more embodiments of the compounds of Formula IV-I, Y 2 is -NR a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-I, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-I, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-I, A is phenyl. In one or more embodiments of Formula IV-I, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-I, A is pyridinyl. In one or more embodiments of Formula IV-I, A is indazolyl. In one or more embodiments of Formula IV-I, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-I, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-I, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-I, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-I, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-I, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-I, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV-I, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV-I, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-I, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-I, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 .
  • R 2 is -OH. In one or more embodiments of Formula IV-I, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV-I, [00309] In one or more embodiments of Formula IV-I, R a is -H.
  • R 3 is an optionally substituted -Ci-C6alkyl. In one or more embodiments of Formula IV-I, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-I, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-I, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 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 -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H2, -(CH 2 )nOH, -CF 3 , -CHF2, or -CFI2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-I, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-I, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-I, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-J:
  • X B4 is N or CR 9 ;
  • X B5 is N or CR 9 ;
  • X B6 is N or CR 9 ;
  • X B7 is N or CR 9 , wherein R 9 is independently, at each occurrence, -H, -Ci-C 6 alkyl, -OH, - H2, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F, provided that if X 1 is C, at least one of X B4 , X B5 , X B6 , and X B7 is not CR 9 , or provided that if each of X B4 , X B5 , X B6 , and X B7 are CR 9 , X 1
  • X B4 is N. In certain embodiments of Formula IV-J, X B4 is CR 9 . In certain embodiments of Formula IV-J, X B5 is N. In certain embodiments of Formula IV-J, X B5 is CR 9 . In certain embodiments of Formula IV-J, X B6 is N. In certain embodiments of Formula IV-J, X B6 is CR 9 . In certain embodiments of Formula IV-J, X B7 is N. In certain embodiments of Formula IV-J, X B7 is CR 9 . In certain
  • X B4 is N
  • X B5 is CR 9
  • X B6 is N
  • X B7 is CR 9
  • R 9 is independently, at each occurrence, -H.
  • R 9 is -(CH 2 ) n OH and n is 1. In some embodiments of Formula IV-J, R 9 is H.
  • Y 2 is -(CR3 ⁇ 4)m-. In one or more embodiments of the compounds of Formula IV-J, Y 2 is - R a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-J, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-J, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-J, A is phenyl. In one or more embodiments of Formula IV-J, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-J, A is pyridinyl. In one or more embodiments of Formula IV-J, A is indazolyl. In one or more embodiments of Formula IV-J, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-J, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-J, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-J, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-J, R 1 is independently, at each occurrence, -H or halogen.
  • R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-J, R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 . In one or more embodiments of Formula IV- J, R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula IV- J, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2. In one or more embodiments of Formula IV- J, R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV- J, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- J, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV- J, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV- J, R 2 is -H, -OH, - R 5 R 6 , -Ci-C 6 alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV- J, R 2 is -OH. In one or more embodiments of Formula IV- J, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV- J,
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula IV- J, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-J, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-J, R 3 is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered poly cyclic heterocycle, which is optionally substituted with one or more -Ci-C6alkyl, - H 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 )nOH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-C 6 alkyl, -(CH 2 )n H 2 , or - H 2 .
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-C 6 alkyl, -(CH 2 ) n NH 2 , or - H 2 .
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-C 6 alkyl, -(CH 2 ) n NH 2 , or - H 2 .
  • n is 1.
  • R 3 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 -Ci-C6alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV- J, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV- J, X 1 is C and X 2 is N. In one or more embodiments of Formula IV- J, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-K:
  • IV-K and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-K, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-K, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-K, A is phenyl. In one or more embodiments of Formula IV-K, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-K, A is pyridinyl. In one or more embodiments of Formula IV- K, A is indazolyl. In one or more embodiments of Formula IV-K, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-K, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C 6 alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-K, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-K, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-K, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-K, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-K, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula IV-K, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV- K, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-K, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-K, R 2 is -H, -OH, - R 5 R 6 , -Ci-C 6 alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-K, R 2 is -OH. In one or more embodiments of Formula IV-K, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-K, R 2 is - H2.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered poly cyclic heterocycle, which is optionally substituted with one or more -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CFIF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or - H2.
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or - H2.
  • n is 1.
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-K, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-K, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-K, X 1 is N and X 2 is CH.
  • B including the atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5- to 12- membered heterocycle.
  • 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-K, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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-K, 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-K, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-K, B is substituted with one or more -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH2)n H2,
  • B is substituted with one or more oxo. In one or more embodiments of Formula IV-K, B is substituted with one or more -Ci-C6alkyl. In one or more embodiments of Formula IV-K, B is substituted with one or more -OH. In one or more embodiments of Formula IV-K, B is substituted with one or more - H2. In one or more embodiments of Formula IV-K, B is substituted with one or more -CF3. In one or more embodiments of Formula IV-K, B is substituted with one or more -CHF2.
  • B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-K, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • the compound is of Formula IV-L:
  • IV-L and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein:
  • C forms a 3- to 12-membered monocyclic heterocycle, 3- to 12-membered poly cyclic 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(C h Fh, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • the C ring is optionally substituted with one or more -Ci-Cealkyl, - H2, -OH, -(CH 2 )n H2, -(CH 2 )nOH, -CF3, -CHF2, or -CH2F.
  • n is 1.
  • the C ring is optionally substituted with one or more -Ci-C6alkyl, -(CH2)n H2, or - H2. In certain such embodiments, n is 1.
  • the C ring, along with the nitrogen atom to which it is attached is an optionally substituted 3- to 12-membered monocyclic heterocycle.
  • the C ring, along with the nitrogen atom to which it is attached is an optionally substituted 3-to 12-membered polycyclic heterocycle.
  • the nitrogen atom to which it is attached is an optionally substituted 5- to 12-membered spiroheterocycle.
  • nitrogen atom to which it is attached is an optionally sub
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula IV-L, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula IV-L, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-L, A is phenyl. In one or more embodiments of Formula IV-L, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-L, A is pyridinyl. In one or more embodiments of Formula IV- L, A is indazolyl. In one or more embodiments of Formula IV-L, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-L, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula IV-L, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-L, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV-L, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-L, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-L, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl. In one or more embodiments of Formula IV-L, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV-L, R 5 and R 6 are independently, at each occurrence, -Ci-C 6 alkyl. [00355] In one or more embodiments of Formula IV-L, R 2 is -H.
  • R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl.
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-C6alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 .
  • R 2 is -OH.
  • R 2 is - R 5 R 6 .
  • R 2 is - H2.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-L, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-L, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-L, X 1 is N and X 2 is CH.
  • 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-L, 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-L, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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-L, 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-L, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-L, B is substituted with one or more -Ci-Cealkyl, -OH, - H2, oxo, -(CH2)nNH2,
  • B is substituted with one or more oxo. In one or more embodiments of Formula IV-L, B is substituted with one or more -Ci-C6alkyl. In one or more embodiments of Formula IV-L, B is substituted with one or more -OH. In one or more embodiments of Formula IV-L, B is substituted with one or more - H2. In one or more embodiments of Formula IV-L, B is substituted with one or more -CF3. In one or more embodiments of Formula IV-L, B is substituted with one or more -CHF2.
  • B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-L, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • the compound is of Formula IV-M:
  • IV-M and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof wherein X B1 is N, NR 9 , CR 9 , S, or O; X B2 is N, R 9 , CR 9 , S, or O; and X B3 is N, NR 9 , CR 9 , S, or O, wherein R 9 is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, -NH2, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F, provided that if X 1 is C, at least one of X B1 , X B2 , and X B3 is not CR 9 , or provided that if each of X B1 , X B2 , and X B3 are CR 9 , X
  • X B1 is N or NR 9 .
  • X B1 is CR 9 . In certain embodiments of Formula IV-M, X B1 is S. In certain embodiments of Formula IV-M, X B1 is O. In certain embodiments of Formula IV-M, X B2 is N or NR 9 . In certain embodiments of Formula IV-M, X B2 is CR 9 . In certain embodiments of Formula IV-M, X is S. In certain embodiments of Formula IV-M, X B2 is O. In certain embodiments of Formula IV-M, X B3 is N or R 9 . In certain
  • X B3 is CR 9 . In certain embodiments of Formula IV-M, X B3 is S. In certain embodiments of Formula IV-M, X B3 is O.
  • X B1 is N or NR 9 .
  • X B1 is CR 9 .
  • X B2 is N or NR 9 .
  • X B2 is CR 9 .
  • X B3 is N or NR 9 .
  • X B3 is CR 9 .
  • R 9 is -( ⁇ 3 ⁇ 4) ⁇ 0 ⁇ and n is 1. In some embodiments of Formula IV-M, R 9 is H.
  • Y 2 is
  • Y 2 is -NR a -
  • R 2 is -H. In one or more embodiments of Formula IV-M, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-M, R 2 is -H, -OH, - R 5 R 6 , -Ci-C6alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-M, R 2 is -OH. In one or more embodiments of Formula IV-M, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-M, R 2 is - H2.
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C6alkyl. In one or more embodiments of Formula IV-M, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-M, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-M, R 3 is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-M, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-M, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-M, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-N:
  • X B4 is N or CR 9 ;
  • X B5 is N or CR 9 ;
  • X B6 is N or CR 9 ;
  • X B7 is N or CR 9 , wherein R 9 is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 )nNH2, -(CH 2 )nOH, -CF 3 , -CHF 2 , or -CH 2 F, provided that if X 1 is C, at least one of X B4 , X B5 , X B6 , and X B7 is not CR 9 , or provided that if each of X B4 , X B5 , X B6 , and X B7 are CR 9 , X 1 must be
  • X B4 is N. In certain embodiments of Formula IV-N, X B4 is CR 9 . In certain embodiments of Formula IV-N, X B5 is N. In certain embodiments of Formula IV-N, X B5 is CR 9 . In certain embodiments of Formula IV-N, X B6 is N. In certain embodiments of Formula IV-N, X B6 is CR 9 . In certain embodiments of Formula IV-N, X B7 is N. In certain embodiments of Formula IV-N, X B7 is CR 9 .
  • X B4 is N
  • X B5 is CR 9
  • X B6 is N
  • X B7 is CR 9
  • R 9 is independently, at each occurrence, -H.
  • R 9 is -(CH 2 )nOH and n is 1. In some embodiments of Formula IV-N, R 9 is H.
  • Y 2 is
  • Y 2 is -NR a -
  • R 2 is -H. In one or more embodiments of Formula IV-N, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-N, R 2 is -H, -OH, -NR 5 R 6 ,
  • R 2 is -OH. In one or more embodiments of Formula IV-N, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV-N, R 2 is -NH 2 . [00381] In one or more embodiments of Formula IV-N, R a is -H.
  • R 3 is an optionally substituted -Ci-C6alkyl. In one or more embodiments of Formula IV-N, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-N, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula IV-N, R 3 is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C6alkyl, -NFh, -OH, -(CH2)nNH2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)nNH2, or -NFh.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, -NH2, oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, -NH2, -OH, -(CH2)nNH2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)nNH2, or -NH2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, -NH2, oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)nNH2, -(CH2)nOH, -CF 3 , -CHF 2 , or -CH2F.
  • R and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C6alkyl, -OH, -NH2, oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)nNH2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, -NH2, oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-N, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-N, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-N, X 1 is N and X 2 is CH.
  • the compound is of Formula IV-O:
  • R 2 is -H.
  • R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl.
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-C6alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 .
  • R 2 is -OH.
  • R 2 is - R 5 R 6 .
  • R 2 is - H2.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF 2 , or -CH2F.
  • R and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C6alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H2, -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-O, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-O, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-O, X 1 is N and X 2 is CH.
  • 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-O, 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-O, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • B, including the atoms at the points of attachment is an optionally substituted monocyclic or polycyclic 5- to 12- membered heteroaryl.
  • B, including the atoms at the points of attachment is an optionally substituted monocyclic 5 to 6-membered heteroaryl.
  • B, including the atoms at the points of attachment is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-O, B is substituted with one or more -Ci-Cealkyl, -OH, - H 2 , oxo, -(CH2)n H2, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F. In one or more embodiments of Formula IV-O, B is substituted with one or more oxo. In one or more embodiments of Formula IV-O, B is substituted with one or more -Ci-C6alkyl.
  • B is substituted with one or more -OH. In one or more embodiments of Formula IV-O, B is substituted with one or more - H2. In one or more embodiments of Formula IV-O, B is substituted with one or more -CF3. In one or more embodiments of Formula IV-O, B is substituted with one or more -CHF2. In one or more embodiments of Formula IV-O, B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-O, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • the compound is of Formula IV-P:
  • IV-P and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, wherein:
  • 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(03 ⁇ 4) ⁇ ⁇ 2, -( ⁇ 3 ⁇ 4) ⁇ 0 ⁇ , -CF 3 , -CHF2, or -CH2F.
  • the C ring is optionally substituted with one or more -Ci-Cealkyl, - H2, -OH, -(CH 2 )n H2, -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F.
  • n is 1.
  • the C ring is optionally substituted with one or more -Ci-C6alkyl, -(CH2)n H2, or - H2. In certain such embodiments, n is 1.
  • the C ring, along with the nitrogen atom to which it is attached, is an optionally substituted 3- to 12-membered monocyclic
  • the C ring, along with the nitrogen atom to which it is attached, is an optionally substituted 3-to 12-membered polycyclic heterocycle.
  • the nitrogen atom to which it is attached is an optionally substituted 5- to 12-membered spiroheterocycle.
  • Formula I -P, C ring, along with the nitrogen atom to which it is attached, is an optionally substituted in certain embodiments of Formula IV-P, C ring, along with the
  • nitrogen atom to which it is attached is an optionally substituted
  • R 2 is -H. In one or more embodiments of Formula IV-P, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-P, R 2 is -H, -OH, - R 5 R 6 , -Ci-C 6 alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula IV-P, R 2 is -OH. In one or more embodiments of Formula IV-P, R 2 is -NR 5 R 6 . In one or more embodiments of Formula IV- P, R 2 is -NHz.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-P, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-P, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-P, X 1 is N and X 2 is CH.
  • 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-P, 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-P, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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-P, 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-P, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-P, B is substituted with one or more -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H2, -(CH2)nOH, -CF 3 , -CFIF2, or -CH2F. In one or more embodiments of Formula IV-P, B is substituted with one or more oxo. In one or more embodiments of Formula IV-P, B is substituted with one or more -Ci-C6alkyl.
  • B is substituted with one or more -OH. In one or more embodiments of Formula IV-P, B is substituted with one or more - H2. In one or more embodiments of Formula IV-P, B is substituted with one or more -CF3. In one or more embodiments of Formula IV-P, B is substituted with one or more -CHF2. In one or more embodiments of Formula IV-P, B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-P, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • the compound is of Formula IV-Q:
  • A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl, provided that
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 ;
  • Y 1 is -S- or a direct bond
  • X 1 is N or C
  • X 2 is N or CH
  • B 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
  • R 2 is -H, -OH, - R 5 R 6 , -Ci-Cealkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 ;
  • Y 2 is - R a - wherein the bond on the left side of Y 2 , as drawn, is bound to the ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;
  • R 3 is combined with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C6alkyl, -OH, - H2, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, -CHF 2 , or -CH 2 F, provided that the heterocycle formed by the combination of R 3 and R a is not an optionally substituted piperazinyl;
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl
  • n is independently, at each occurrence, 1, 2, 3, 4, 5 or 6;
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • Y 1 is -S-. In one or more embodiments of Formula IV-Q, Y 1 is a direct bond.
  • A is a monocyclic or poly cyclic aryl. In one or more embodiments of Formula IV-Q, A is phenyl. In one or more
  • A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-Q, A is pyridinyl. In one or more embodiments of Formula IV- Q, A is indazolyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula IV-Q, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula IV-Q, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula IV- Q, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula IV-Q, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula IV-Q, R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula IV-Q, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2. In one or more embodiments of Formula IV-Q, R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula IV-Q, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula IV-Q, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula IV-Q, R 2 is -OH. In one or more embodiments of Formula IV-Q, R 2 is - R 5 R 6 . In one or more embodiments of Formula IV-
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered poly cyclic heterocycle, which is optionally substituted with one or more -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 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 -Ci-Cealkyl, -NFh, -OH, -(CFh ⁇ Fh, -(CH2)nOH, -CF 3 , -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • n 1
  • X 1 is N and X 2 is N. In one or more embodiments of Formula IV-Q, X 1 is C and X 2 is CH. In one or more embodiments of Formula IV-Q, X 1 is C and X 2 is N. In one or more embodiments of Formula IV-Q, X 1 is N and X 2 is CH.
  • 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-Q, 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-Q, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • 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-Q, 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-Q, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula IV-Q, B is substituted with one or more oxo. In one or more embodiments of Formula IV-Q, B is substituted with one or more -Ci-C6alkyl. In one or more embodiments of Formula IV- Q, B is substituted with one or more -OH. In one or more embodiments of Formula IV-Q, B is substituted with one or more - H 2 . In one or more embodiments of Formula IV-Q, B is substituted with one or more -CF 3 .
  • B is substituted with one or more -CHF2. In one or more embodiments of Formula IV-Q, B is substituted with one or more -CH2F. In one or more embodiments of Formula IV-Q, B is substituted with one or more -(CH2)nNH2. In certain such embodiments, n is 1.
  • a compound of the present disclosure e.g., a compound of Formula ⁇ , I, II, III, or IV
  • a compound of Formula ⁇ , I, II, III, or IV can be selected from:
  • the compounds of the disclosure are compounds of Formula V:
  • A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the heteroaryl is not R 1 is independently, at each occurrence, -H, -D, -Ci-C6alkyl, -C2-C 6 alkenyl, -C 4 -C 8 cycloalkenyl, -Ci-Cealkynyl, -C 3 -C 8 cycloalkyl, -OH, -OR 5 , halogen, -NO2, -CN, - R 5 R 6 , -SR 5 , -S(0) 2 R 5 R 6 , -S(0) 2 R 5 , - R 5 S(0) 2 R 5 R 6 , - R 5 S(0) 2 R 6 , -S(0) R 5 R 6 , -S(0)R 5 , - R 5 S(0)R 6 , -C 5 S(0)R 6 , -C
  • B 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 -Ci- Cealkyl, -OH, -NH 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or
  • R 2 is -H, -OH, -NR 5 R 6 , -Ci-Cealkyl, -C 2 -C 6 alkenyl, -C 4 -C 8 cycloalkenyl,
  • Y 2 is -NR a - -(CR3 ⁇ 4)m- -C(O)-, -C(R a ) 2 NH-, -(CR a 2 )mO-, -C(0)N(R a )-,
  • R a is independently, at each occurrence, -H, -D, -OH, -C 3 -C 8 cycloalkyl, or
  • each alkyl or cycloalkyl is optionally substituted with one or more -NH2, wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
  • R b is independently, at each occurrence, -H, -D,-Ci-C 6 alkyl, -C 3 -C 8 cycloalkyl, -C2-C 6 alkenyl, 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, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(0) 2 NR 5 R 6 , -S(0) 2 R 5 , -NR 5 S(0) 2 NR 5 R 6 , -NR 5 S(0) 2 R 6 , -S(0)NR 5 R 6 , -S(0)R 5 ,
  • R 3 is -H, -Ci-C6alkyl, a 3- to 12-membered monocyclic or poly cyclic heterocycle, -C 3 -C8cycloalkyl, or -(CH 2 )n-R b , wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more -Ci-Cealkyl, -OH, -NH 2 , -OR b , -NHR b , -(CH 2 )nOH, heterocyclyl, or spiroheterocyclyl; or
  • R 3 can combine with R a to form a 3- to 12-membered monocyclic or poly cyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more -Ci-C 6 alkyl, -OH, -NH 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 )nNH 2 , -(CH 2 )nOH, -CF 3 , -CHF2, or -CH2F, provided that the heterocycle formed by the combination of R 3 and R a is not an optionally substituted piperazinyl;
  • R 5 and R 6 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, a monocyclic or poly cyclic 3- to 12- membered heterocycle, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2, or -CN;
  • R 7 and R 8 are independently, at each occurrence, -H, -D, -Ci-C 6 alkyl, -C2-C 6 alkenyl, -C4-C 8 cycloalkenyl, -C2-C 6 alkynyl, -C 3 -C 8 cycloalkyl, or a monocyclic or poly cyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH 2 , -NO2, or -CN;
  • R 10 is -H or -Ci-Cealkyl
  • n is independently, at each occurrence, 1, 2, 3, 4, 5 or 6;
  • n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 4 is H.
  • R 4 is .
  • Y 1 is -S- or a direct bond.
  • Y 1 is -S-.
  • Y 1 is a direct bond.
  • Y 2 is -(CR3 ⁇ 4)m-. In one or more embodiments of the compounds of Formula V, Y 2 is -NR a - [00432] In one or more embodiments of the compounds of Formula V, R is -H. In one or more embodiments of the compounds of Formula V, R 10 is -Ci-C6alkyl.
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula V, A is a monocyclic or poly cyclic heterocycloalkyl. In one or more embodiments of Formula V, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula V, A is phenyl. In one or more embodiments of Formula V, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula V, A is pyridinyl. In one or more embodiments of Formula V, A is indazolyl. In one or more embodiments of Formula V, A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each
  • n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C 6 alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula V, R 1 is independently, at each occurrence, -OR 5 or halogen. In one or more embodiments of Formula V, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula V, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula V, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula V, R 1 is independently, at each
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula V, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NFh. In one or more embodiments of Formula V, R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C 6 alkyl. In one or more embodiments of Formula V, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula V, R 5 and R 6 are independently, at each occurrence, -Ci-C 6 alkyl.
  • R 2 is -H.
  • R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula V, R 2 is -H, -OH, - R 5 R 6 , -Ci-C6alkyl, or - H2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula V, R 2 is -OH. In one or more
  • R 2 is - R 5 R 6 . In one or more embodiments of Formula V, R 2 is
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C6alkyl. In one or more embodiments of Formula V, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula V, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula V, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF3, -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • 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 V, 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 V, B, including the atoms at the points of attachment, is an optionally substituted monocyclic 7- to 12-membered heterocycle.
  • B including the atoms at the points of attachment, is an optionally substituted polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • B, including the atoms at the points of attachment is an optionally substituted monocyclic or polycyclic 5- to 12-membered heteroaryl.
  • B, including the atoms at the points of attachment is an optionally substituted monocyclic 5 to 6-membered heteroaryl.
  • B, including the atoms at the points of attachment is a monocyclic 7- to 12-membered heteroaryl.
  • B is an optionally substituted polycyclic 5- to 12-membered heteroaryl.
  • 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.
  • B is substituted with one or more -(CH2)nOH. In certain such embodiments, n is 1. In one or more embodiments of Formula V, B is substituted with one or more -Ci-Cealkyl, -OH, - H2, oxo, -(CH 2 )n H2, -(CH 2 )nOH, -CF3, -CHF2, or -CH2F. In one or more embodiments of Formula V, B is substituted with one or more oxo. In one or more embodiments of Formula V, B is substituted with one or more -Ci-C6alkyl.
  • B is substituted with one or more -OH. In one or more embodiments of Formula V, B is substituted with one or more - H2. In one or more embodiments of Formula V, B is substituted with one or more -CF3. In one or more embodiments of Formula V, B is substituted with one or more -CHF2. In one or more embodiments of Formula V, B is substituted with one or more -CH2F. In one or more embodiments of Formula V, B is substituted with one or more -(CH 2 )nNH 2 . In certain such embodiments, n is 1.
  • the compound is of Formula V-A:
  • V-A and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof wherein X B4 is N or CR 9 ; X B5 is N or CR 9 ; X B6 is N or CR 9 ; and X B7 is N or CR 9 , wherein R 9 is independently, at each occurrence, -H, -Ci-C6alkyl, -OH, - H 2 , heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • X B4 is N. In certain embodiments of Formula V-A, X B4 is CR 9 . In certain embodiments of Formula V-A, X B5 is N. In certain embodiments of Formula V-A, X B5 is CR 9 . In certain embodiments of Formula V-A, X B6 is N. In certain embodiments of Formula V-A, X B6 is CR 9 . In certain embodiments of Formula V-A, X B7 is N. In certain embodiments of Formula V-A, X B7 is CR 9 .
  • R 9 is -(CH 2 ) n OH and n is 1. In some embodiments of Formula V-A, R 9 is H.
  • R 10 is -H. In one or more embodiments of the compounds of Formula V-A, R 10 is -Ci-C6alkyl.
  • R 4 is H.
  • R 4 is In certain such embodiments, Y 1 is -S- or a direct bond. In one or more embodiments of Formula V-A, Y 1 is -S-. In one or more embodiments of Formula V-A, Y 1 is a direct bond.
  • Y 2 is -(CR3 ⁇ 4)m-. In one or more embodiments of the compounds of Formula V-A, Y 2 is - R a -
  • A is a monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula V-A, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula V-A, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula V-A, A is phenyl. In one or more embodiments of Formula V-A, A is a monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula V-A, A is pyridinyl. In one or more embodiments of Formula V-A, A is indazolyl.
  • A is a 5- to 12-membered monocyclic or polycyclic aryl or heteroaryl.
  • n is independently, at each occurrence, 0, 1, 2, or 3.
  • n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, -OR 5 , halogen, -Ci-C6alkyl, -CN, or - R 5 R 6 . In one or more embodiments of Formula V-A, R 1 is independently, at each occurrence, -H, -OR 5 or halogen. In one or more embodiments of Formula V-A, R 1 is independently, at each occurrence, -H or -OR 5 . In one or more embodiments of Formula V-A, R 1 is independently, at each occurrence, -H or halogen. In one or more embodiments of Formula V-A, R 1 is independently, at each occurrence, -H or - R 5 R 6 . In one or more embodiments of Formula V-A, R 1 is
  • R 1 is independently, at each occurrence, -H, -OR 5 or - R 5 R 6 .
  • R 1 is independently, at each occurrence, -H, halogen or - R 5 R 6 .
  • R 5 and R 6 are both -H.
  • R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or - H2.
  • R 1 is independently, at each occurrence, -H, -CN or halogen.
  • R 5 and R 6 are independently, at each occurrence, -H or -Ci-C6alkyl. In one or more embodiments of Formula V-A, R 5 and R 6 are independently, at each occurrence, -H. In one or more embodiments of Formula V-A, R 5 and R 6 are independently, at each occurrence, -Ci-C6alkyl.
  • R 2 is -H. In one or more embodiments of Formula V-A, R 2 is -Ci-C 6 alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In certain such embodiments, R 2 is methyl. In one or more embodiments of Formula V-A, R 2 is -H, -OH, -NR 5 R 6 , -Ci-C 6 alkyl, or -NH2; wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or -NR 5 R 6 . In one or more embodiments of Formula V-A, R 2 is -OH. In one or more embodiments of Formula V-A, R 2 is -NR 5 R 6 . In one or more embodiments of Formula V-A,
  • R a is -H.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula V-A, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula V-A, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula V-A, R is an optionally substituted 5- to 12- membered polycyclic heterocycle.
  • R 3 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 -Ci-C6alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF 2 , or -CH2F.
  • R 3 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 -Ci-C6alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-C 6 alkyl, - H2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 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 -Ci-C 6 alkyl, -(CH2)n H2, or - H2.
  • n is 1.
  • R 3 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 -Ci-Cealkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 )nOH, -CF3,
  • R 3 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 -Ci-Cealkyl, -NH2, -OH, -(CH2)n H2, -(CH2)nOH, -CF3, -CHF2, or -CH2F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered
  • R 3 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 -Ci-C6alkyl, -OH, - H2, oxo, heteroaryl, heterocyclyl, -(CH 2 )n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 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 -Ci-Cealkyl, -NH 2 , -OH, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered
  • R 3 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 -Ci-C 6 alkyl, -OH, - H 2 , oxo, heteroaryl, heterocyclyl, -(CH 2 ) n H 2 , -(CH 2 ) n OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 4 is H.
  • R 4 is
  • A is a 5- to 12- membered monocyclic or poly cyclic cycloalkyl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, A is a monocyclic or polycyclic heteroaryl.
  • Y 1 is -S-. In one or more embodiments of Formula ⁇ , I, IV, or V, Y 1 is a direct bond.
  • Y 2 is - R a - In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, Y 2 is -(CR a 2 ) m - In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, Y 2 is -C(O)-. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, Y 2 is -C(R a ) 2 H- or -(CR3 ⁇ 4)mO-. In one or more
  • Y 2 is -C(0)N(R a )-, -N(R a )C(0)-,
  • Y 2 is -N(R a )C(0)N(R a )-, -N(R a )C(S)N(R a )-, -OC(0)N(R a )-, -N(R a )C(0)0-, or -C(0)N(R a )0-.
  • Y 2 is -C(0)0- -OC(O)-, or -OC(0)0-.
  • R 2 is -OH. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 2 is -Ci-C6alkyl, wherein each alkyl is optionally substituted with one or more -OH, halogen, -OR 5 , or - R 5 R 6 . In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 2 is an optionally substituted -C2-C6alkenyl.
  • R 2 is an optionally substituted -C4-C8cycloalkenyl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 2 is an optionally substituted -C2-C 6 alkynyl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 2 is an optionally substituted -C3-C8cycloalkyl.
  • R 2 is an optionally substituted monocyclic or poly cyclic heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O.
  • R a is -H. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R a is -OH. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R a is an optionally substituted -C3-C8cycloalkyl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R a is an optionally substituted
  • R b is H. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R b is an optionally substituted
  • R b is an optionally substituted -C3-C8cycloalkyl.
  • R is an optionally substituted -C2-C 6 alkenyl.
  • R b is an optionally substituted monocyclic or polycyclic heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O.
  • R 3 is an optionally substituted -Ci-C 6 alkyl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 3 is an optionally substituted 3- to 12- membered monocyclic heterocycle. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atom to which they are attached combine to form an optionally substituted 3- to 12- membered monocyclic heterocycle.
  • R 3 and R a together with the atoms to which they are attached combine to form an optionally substituted 3- to 12-membered polycyclic heterocycle.
  • X 1 is N. In one or more embodiments of Formula ⁇ , I, II, III, or IV, X 1 is C.
  • X 2 is N. In one or more embodiments of Formula ⁇ , I, II, III, or IV, X 2 is CH.
  • X 1 is N and X 2 is N. In one or more embodiments of Formula ⁇ , I, II, III, or IV, X 1 is N and X 2 is CH. In one or more embodiments of Formula ⁇ , I, II, III, or IV, X 1 is C and X 2 is N. In one or more embodiments of Formula ⁇ , I, II, III, or IV, X 1 is C and X 2 is CH.
  • Formula ⁇ , I, II, III, IV, or V, B including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heterocycle. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, B, including the atoms at the points of attachment, is a monocyclic 5 to 6-membered heterocycle. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heterocycle.
  • Formula ⁇ , I, II, III, IV, or V, B including the atoms at the points of attachment, is a polycyclic 5- to 12-membered heterocyclyl.
  • the heteroycyclyl ring is fused.
  • the heterocyclyl ring is bridged.
  • Formula ⁇ , I, II, III, IV, or V, B including the atoms at the points of attachment, is a monocyclic or polycyclic 5- to 12-membered heteroaryl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, B, including the atoms at the points of attachment, is a monocyclic 5 to 6-membered heteroaryl. In one or more embodiments of Formula ⁇ , I, II, III, IV, or V, B, including the atoms at the points of attachment, is a monocyclic 7- to 12-membered heteroaryl.
  • 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.
  • R 2 is an optionally substituted -Ci-C6alkyl and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heteroaryl.
  • R 2 is an optionally substituted -Ci-C6alkyl and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5-membered heteroaryl.
  • R 2 is an optionally substituted -Ci-C 6 alkyl and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 6- membered heteroaryl.
  • R 2 is -OH and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5 to 6-membered heteroaryl.
  • R 2 is -OH and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 5-membered heteroaryl.
  • R 2 is -OH and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 6-membered heteroaryl.
  • Y 1 is -S- and A is an optionally substituted 5- to 12-membered monocyclic or polycyclic cycloalkyl.
  • Y 1 is -S- and A is an optionally substituted monocyclic or polycyclic heterocycloalkyl.
  • Y 1 is -S- and A is an optionally substituted monocyclic or polycyclic aryl.
  • Y 1 is S and A is an optionally substituted monocyclic or polycyclic heteroaryl.
  • Y 1 is a direct bond and A is an optionally substituted 5- to 12-membered monocyclic or polycyclic cycloalkyl.
  • Y 1 is a direct bond and A is an optionally substituted monocyclic or polycyclic heterocycloalkyl.
  • Y 1 is a direct bond and A is an optionally substituted monocyclic or polycyclic aryl.
  • Y 1 is a direct bond and A is an optionally substituted monocyclic or polycyclic heteroaryl.
  • the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.
  • the compounds of any of the formulae described herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes and examples.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of the present disclosure.
  • the present disclosure may include both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods include but are not limited to those methods described below.
  • the resulting intermediate can be coupled to a substituted aryl- or heteroaryl-thiol in the presence of a copper catalyst (e.g., Cul) or under SNAr conditions, alternatively, the resulting intermediate can be coupled to an appropriately substituted aryl or heteroaryl boronic acid in the presence of Pd catalyst. Additional deprotection and/or functionalization steps can be required to produce the final compound.
  • Another aspect of the disclosure relates to methods of treating a disease associated with SHP2 modulation in a subject in need thereof.
  • the methods may involve administering to a patient in need of treatment for diseases or disorders associated with SHP2 modulation an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula ⁇ I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), or of one or more pharmaceutical compositions of the present disclosure.
  • compounds of the present disclosure e.g., compounds of Formula ⁇ I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the disease can be, but is not limited to Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
  • SHP2 is an important downstream signaling molecule for a variety of receptor tyrosine kinases, including the receptors of platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth factor (EGF-R).
  • PDGF-R platelet-derived growth factor
  • FGF-R fibroblast growth factor
  • EGF-R epidermal growth factor
  • SHP2 is also an important downstream signaling molecule for the activation of the mitogen activated protein (MAP) kinase pathway which can lead to cell transformation, a prerequisite for the development of cancer.
  • MAP mitogen activated protein
  • SHP2 significantly inhibited cell growth of lung cancer cell lines with SHP2 mutation or EML4/ALK translocations as well as EGFR amplified breast cancers and esophageal cancers.
  • SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma.
  • SHP2 plays a role in transducing signals originating from immune checkpoint molecules, including but not limited to programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • CTL-4 cytotoxic T-lymphocyte-associated protein 4
  • modulation of SHP2 function can lead to immune activation, specifically anti-cancer immune responses.
  • Another aspect of the disclosure is directed to a method of inhibiting SHP2.
  • the method involves administering to a patient in need thereof an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula ⁇ I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), or of one or more pharmaceutical compositions of the present disclosure.
  • the present disclosure relates to compounds or compositions disclosed herein that are capable of modulating the activity of (e.g., inhibiting) SHP2.
  • the present disclosure also relates to the therapeutic use of such compounds and compositions.
  • One or more disclosed compounds or compositions can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • SHP2 is inhibited after treatment with less than 1000 nM of a compound of the disclosure.
  • SHP2 is inhibited after treatment with about 1 nM to about 10 nM of a compound of the disclosure.
  • SHP2 is inhibited after treatment with less than about 1 nM of a compound of the disclosure.
  • SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the disclosure.
  • SHP2 is inhibited after treatment with about 100 nM to about 10 ⁇ of a compound of the disclosure.
  • Another aspect of the present disclosure relates to a one or more compounds of the present disclosure (e.g., compounds of Formula ⁇ I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), or one or more compositions of the present disclosure, for use in treating or preventing a disease associated with SHP2 modulation.
  • the disease is Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
  • SHP2 is an important downstream signaling molecule for a variety of receptor tyrosine kinases, including the receptors of platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth factor (EGF-R).
  • SFIP2 is also an important downstream signaling molecule for the activation of the mitogen activated protein (MAP) kinase pathway which can lead to cell transformation, a prerequisite for the development of cancer. Knock-down of SFIP2 significantly inhibited cell growth of lung cancer cell lines with SFIP2 mutation or
  • EML4/ALK translocations as well as EGFR amplified breast cancers and esophageal cancers.
  • SFIP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma.
  • the present disclosure relates to the use of one or more compounds of the present disclosure (e.g., compounds of Formula ⁇ , 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.
  • the disease is associated with SHP2 modulation.
  • the present disclosure relates to one or more compounds of the present disclosure (e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • the medicament is used for treating or preventing a disease associated with SHP2 modulation.
  • the present disclosure relates to one or more compositions comprising one or more compounds of the present disclosure (e.g., compounds of Formula ⁇ , I, II, III, IV, or V, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • the medicament is used for treating or preventing a disease associated with SHP2 modulation.
  • compositions comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant.
  • compositions of the disclosure can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20%) of one or more of the disclosed compounds by weight or volume.
  • modes may include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be
  • Illustrative pharmaceutical compositions may include tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/
  • polyvinylpyrrolidone if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl- cyclodextrin, PEG400, PEG200.
  • a disintegrant e.g., starches, agar, methyl cellulose, bentonite
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • one or more of the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • One or more of the disclosed compounds or compositions can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • One or more disclosed compounds or compositions can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of
  • phospholipids containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described for instance in U.S. Pat. No. 5,262,564, the contents of which are hereby incorporated by reference.
  • One or more disclosed compounds or compositions can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer,
  • the one or more disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans,

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EP18701883.3A EP3571199A1 (en) 2017-01-23 2018-01-09 Bicyclic compounds as allosteric shp2 inhibitors
KR1020197024604A KR102665763B1 (ko) 2017-01-23 2018-01-09 알로스테릭 shp2 억제제로서의 이환 화합물
CA3051206A CA3051206A1 (en) 2017-01-23 2018-01-09 Bicyclic compounds as allosteric shp2 inhibitors
IL296456A IL296456A (en) 2017-01-23 2018-01-09 Bicyclics as allosteric shp2 inhibitors
RU2019126456A RU2776846C2 (ru) 2017-01-23 2018-01-09 Бициклические соединения в качестве аллостерических ингибиторов shp2
CN202311080113.2A CN117327075A (zh) 2017-01-23 2018-01-09 作为变构shp2抑制剂的二环化合物
MX2019008695A MX2019008695A (es) 2017-01-23 2018-01-09 Compuestos biciclicos como inhibidores alostericos de shp2.
BR112019015075-7A BR112019015075A2 (pt) 2017-01-23 2018-01-09 Compostos bicíclicos como inibidores de shp2 alostéricos
JP2019539774A JP7240319B2 (ja) 2017-01-23 2018-01-09 アロステリックｓｈｐ２阻害剤としての二環式化合物
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CN201880018606.4A CN110446709B (zh) 2017-01-23 2018-01-09 作为变构shp2抑制剂的二环化合物
AU2018210770A AU2018210770B2 (en) 2017-01-23 2018-01-09 Bicyclic compounds as allosteric SHP2 inhibitors
IL268030A IL268030B2 (en) 2017-01-23 2019-07-14 Bicyclic compounds as allosteric shp2 inhibitors
US16/518,798 US11739093B2 (en) 2017-01-23 2019-07-22 Substituted pyrazolopyrazines, imidazopyrazines and [1,2,4]triazolopyrazines as allosteric SHP2 inhibitors
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