WO2023107696A2 - Inhibitors of menin-mll interaction - Google Patents

Inhibitors of menin-mll interaction Download PDF

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Publication number
WO2023107696A2
WO2023107696A2 PCT/US2022/052404 US2022052404W WO2023107696A2 WO 2023107696 A2 WO2023107696 A2 WO 2023107696A2 US 2022052404 W US2022052404 W US 2022052404W WO 2023107696 A2 WO2023107696 A2 WO 2023107696A2
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compound
pharmaceutically acceptable
solvate
acceptable salt
stereoisomer
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French (fr)
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WO2023107696A3 (en
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Ruben Abagyan
Vladislav Zenonovich Parchinsky
Nikolay Savchuk
Alexandre Vasilievich IVACHTCHENKO
Alexander Khvat
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Bala Therapeutics Inc
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Bala Therapeutics Inc
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Priority to EP22905177.6A priority Critical patent/EP4444300A4/en
Priority to JP2024534648A priority patent/JP2024545184A/ja
Priority to CN202280090933.7A priority patent/CN118647378A/zh
Priority to KR1020257029621A priority patent/KR20250135350A/ko
Priority to US18/717,973 priority patent/US20250163061A1/en
Priority to AU2022405438A priority patent/AU2022405438A1/en
Priority to KR1020247022800A priority patent/KR20240117133A/ko
Priority to CA3240074A priority patent/CA3240074A1/en
Application filed by Bala Therapeutics Inc filed Critical Bala Therapeutics Inc
Priority to MX2024007069A priority patent/MX2024007069A/es
Publication of WO2023107696A2 publication Critical patent/WO2023107696A2/en
Publication of WO2023107696A3 publication Critical patent/WO2023107696A3/en
Priority to MX2025012108A priority patent/MX2025012108A/es
Anticipated expiration legal-status Critical
Priority to JOJO/P/2024/0130A priority patent/JOP20240130A1/ar
Priority to JP2025137487A priority patent/JP2025170331A/ja
Priority to AU2025230651A priority patent/AU2025230651A1/en
Priority to US19/334,801 priority patent/US20260022120A1/en
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    • 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
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07D487/10—Spiro-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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 is directed to inhibitors of the interaction of menin and MLL,.
  • the inhibitors described herein can be useful in the treatment of diseases or disorders associated with menin-MLL interaction, such as cancer.
  • the disclosure is concerned with compounds and pharmaceutical compositions inhibiting/blocking menin-MLL interaction, methods of treating diseases or disorders associated with menin-MLL interaction, and methods of synthesizing these compounds.
  • MLL mixed lineage leukemia
  • Menin is an essential co-factor of oncogenic MLL fusion proteins and the menin-MLL interaction is critical for development of acute leukemia in vivo.
  • Targeting the menin-MLL interaction with small molecules represents an attractive strategy to develop new anticancer agents.
  • Recent developments, including determination of menin crystal structure and development of potent small molecule and peptidomimetic inhibitors, demonstrate feasibility of targeting the menin-MLL interaction.
  • biochemical and structural studies revealed that MLL binds to rnenin in a complex bivalent mode engaging two MLL motifs, and therefore inhibition of this protein-protein interaction represents a challenge,
  • chromosome band 1 lq23 Chromosomal rearrangements of the MLL gene located at chromosome band 1 lq23 are found in patients with de novo acute myeloid (AML) and acute lymphoblastic (ALL) leukemias, and in therapy related leukemias or myelodysplastic syndrome (MDS).
  • AML de novo acute myeloid
  • ALL acute lymphoblastic
  • MDS myelodysplastic syndrome
  • the MLL gene is fused with one of over 60 different protein partners, such as the most frequent AF4, AF9, ENL, AF6, ELL, and AF10.
  • Disruption of MLL by gene fusions upregulates expression of HOXA9 axidMEISl genes that are critical to leukemogenesis.
  • M H() ⁇ .4 genes in leukemic transformation has been verified in both, in vitro and in vivo models, demonstrating that MLL fusion protein mediated upregulation of HOXA9 and MEIS J genes results in enhanced proliferation and blockage of hematopoietic differentiation, ultimately leading to acute leukemia.
  • Patients with leukemias harboring MLL translocations have very unfavorable prognosis (20% event free survival at 3 years) and respond poorly to available treatments, demonstrating a clear need for new therapies.
  • the oncogenic function of MLL fusion proteins is critically dependent on their direct interaction with menin.
  • Menin is a 67 kDa protein encoded by the MEN1 (Multiple Endocrine Neoplasia I) gene localized on chromosome 11 ql 3. Menin is a ubiquitously expressed protein, predominantly localized in the nucleus. Menin directly binds to the A’-terminus of MLL that is retained in all MLL fusion proteins and plays an important role in recruitment of MLL and MLL fusions to target genes, including HOXA9. Loss of menin binding by MLL fusion proteins abolishes their oncogenic properties in vitro and in vivo.
  • MEN1 Multiple Endocrine Neoplasia I
  • MLL -ENL oncoprotein Mutations within the A'-terminus of MLL -ENL oncoprotein, resulting in protein unable to associate with menin, abolish its potential to upregulate Hox gene expression and induce leukemia in mice.
  • Expression of a dominant-negative inhibitor composed of the amino terminal MLL sequence inhibits growth of the MLL-AF9 transformed bone marrow cells and blocks leukemogenic transformation.
  • KMT2A histone methyltransferase MLL1
  • a first aspect of the disclosure relates to compounds of Formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein
  • X 1 , X 2 , X 3 , X 4 , X 3 , and X 6 are each independently selected from CH or N; and at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is N;
  • W is -CN; or W and ring B together with the atoms to which they are attached and any intervening atoms, form a 5-10 membered heterocycle; each R 1 is independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Cj-Ce alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, NHz, NHCH3, and N(CH?,)2 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroary l is optionally substituted with one or more substituents independently selected from halogen, OH, NR 9 R 10 , CI-C 6 alkyl, Ci-C 6 alkoxy, C3-C10 cycloalkyl, C2-C5 alkenyl, C 2 -C 6 alkynyl, heterocycle,
  • L is selected from (CRxOq, (CR 5 2.)qO, (CR 5 2) q S(O) s and (CR 5 2 ) q C(O);
  • R 5 is selected from hydrogen, deuterium, Ci-Cs alkyl, C3-C10 cycloalkyd, heterocyclyl, ary l, heteroaryl and L 4 ; wherein,
  • L 5 is selected from (CR 5 2 )q, (CR 5 2 )qO, (CR 5 2 ) q S(O) s and (CR 5 2 ) q C(O);
  • Ring B is selected from C3-C14 cycloalkyl, 3- to 10-membered heterocycle, aryl, and heteroaryl, wherein cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO?, oxo, OH, NR 9 R i0 , Ci-Ce alkyl, Ci-Ce alkoxy, cycloalkyl, heterocycle, aiyl, and heteroaryl:
  • R 4 is selected from H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ci- C6 alkyl-Ci-Ce alkoxy, C(O)R Z , heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl rs optionally substituted with one or more substituents independently selected from halogen, OH, NH2, Ci-Ce alkyl, and Ci-Ce alkoxy: each R 5 IS independently selected from H, halogen, CN, OH, Cj-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl;
  • R 6 is selected from H, Ci-C 6 alkyl, -C(O)R 7 , -NHC(O)R 7 , S(O) s R n , -NHStOMV ’, - s
  • R 7 is selected from R 8 , OR 8 , NR 9 R 10 ,
  • R 8 is selected from H, Ci-Cs alkyl, Cz-Ce alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyd rs optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, NR 9 R s0 ; each R 9 and R i0 is independently H, C1-C6 alkyl, C2-C6 alkenyl, Cz-Ce alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocycle, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NH?, Ci-Cr, alkyl, and alkoxy; or R 9 and R
  • R 11 is selected from Ci-Ce alkyl, C3-C10 cycloalkyl, Ci-Ce alkoxy, and NR 9 R 10 ; m and n are each an integer independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; r is an integer selected from 0, 1, 2 and 3; q is an integer selected from 0, 1, 2, 3 and 4; s is an integer selected from 0, 1, and 2; wherein, cycloalkyl is a mono or polycyclic saturated carbon rings containing 3-18 carbon atoms; and is a cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the disclosure relates to a method of treating a disease or disorder associated with interaction of menin and MLL.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with interaction of menin and MLL an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the disclosure is directed to a method of inhibiting of interaction of menin and MLL.
  • Hie method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hy drate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof
  • Another aspect of the present disclosure relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting interaction of menin and MLL.
  • Another aspect of the present disclosure relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting of interaction of menin and MLL.
  • Another aspect of the present disclosure relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the disclosure is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present disclos ure relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • the present disclosure further provides methods of treating a disease or disorder associated with interaction of menin and MU., comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (1), or a pharmaceutically acceptable salt, hydrate, solvate, prodnig, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present disclosure provides inhibitors of interaction of menin and MLL that are therapeutic agents in the treatment of diseases and disorders.
  • the present disclosure further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of menin and MLL interaction.
  • the present disclosure also provides agents with novel mechanisms of action toward interaction of menin and MLL in the treatment of various ty pes of diseases.
  • the present disclosure further provides methods of treating a disease or disorder associated with interaction of menin and MLL, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present disclosure provides inhibitors of interaction of menin and MLL that are therapeutic agents in the treatment of diseases and disorders.
  • the present disclosure further provides methods of treating a disease, disorder, or condition selected from cancer, acute myeloid (AML) and acute lymphoblastic (ALL) leukemias, or myelodysplastic syndrome (MDS), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a disease, disorder, or condition selected from cancer, acute myeloid (AML) and acute lymphoblastic (ALL) leukemias, or myelodysplastic syndrome (MDS)
  • AML acute myeloid
  • ALL acute lymphoblastic
  • MDS myelodysplastic syndrome
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure A or B).
  • the present disci osure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g, the intermediate is selected from the intermediates described in the preparation examples provided herein below).
  • the present disclosure provides a method of preparing compounds of the present disclosure.
  • the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.
  • the present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which associated with the inhibition of the interaction of menin and MLL1 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, OH, -CN, COOH, -CH2CN, -O-(Ci-Ce) alkyl, (Ci-C 6 ) alkyl, (C 3 -C 6 ) alkoxy, (Ci-C 6 ) haloalkyl, (Ci-C 6 ) haloalkoxy, -O-(C 2 -C 6 ) alkenyl, -O-(C2-Ce) alkynyl, (C2-C6) alkenyl, (C 2 -Ce) alkynyl, -OH, -OP(O)(OH) 2 , - OC(O)(Ci-C 6 ) alkyl, -C(O)(Ci-C 6 ) alkyl, -C(O)(Ci-C 6
  • substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
  • an aryl substituted with a cycloalkyd may 7 indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • unsubstituted means that the specified group bears no substituents.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 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 aryi group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryi group may be optionally substituted by one or more substituents, e.g, 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, -H, -halogen, -O-(Ci-C 6 )alkyl, (C f -C 6 )alkyl, -O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 - Cejalkenyl, (C ? ⁇ Ce jalkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(Ci-C6)alkyl, -C(O)(Ci-Ce) alkyl, - OC(O)O(Ci-C6)alkyl, M b.
  • Exemplary ring systems of these aryi groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • heteroaryl means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • a polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like.
  • fused means two rings sharing two ring atoms.
  • spiro-fused means two rings sharing one ring atom.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group w- herein the heteroatom is selected from N, O, S, P, or B.
  • Heteroary l as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B.
  • Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B.
  • the aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3- cjpyridinyl, imidazo[l,2-a]pyridinyl, mdazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2- cfpyridinyl, pyrazolo[3,4-
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring.
  • a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo.
  • Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH— isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1 ,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyndo[3,2- bjpyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridiny
  • Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.
  • Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (Ci-Ce) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, teo-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, neo-pentyl, and zso-hexyl.
  • Alkoxy refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl).
  • alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2- 12 carbon atoms.
  • the “alkenyl” group contains at least one double bond in the chain.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups include ethenyl, propeny l, n-butenyl, /so-butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • Alkenyl, as herein defined may be straight or branched.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2- 12 carbon atoms.
  • the “alkynyl” group contains at least one triple bond in the chain.
  • alkenyl groups include ethynyl, propargyl, .n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • alkylene or “alkylenyl” refers to a divalent alkyl radical. Any of the above- mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a Ci-Cr, alkylene. An alkylene may further be a C1-C4 alkylene.
  • Typical alkylene groups include, but are not limited to, -CH2- , -CH(CH 3 )-, -C(CHJ)2-, -CH2CH2-, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 )2-> -CH2CH2CH2-, - CH2CEI2CH2CH2-, and the like.
  • Cycloalkyl means mono or polycyclic saturated or partially unsaturated carbon rings containing 3-18 carbon atoms.
  • Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl.
  • a polycyclic cycloalkyl comprises at least one non-aromatic ring.
  • cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbomyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-lH-indenyl, spiro]3.5]nonyl, spiro [5.5]undecyl, bicyclo[l .1.1 Jpentanyl, bicyclo[2.2.2]octanyl, or bicyclo] 2.2.2]octenyl.
  • Heterocyclyl mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic.
  • the heterocycloalkyl ring structure may be substituted by one or more substituents.
  • a polycyclic heterocycloalkyl comprises at least one non-aromatic ring.
  • Polycyclic heterocycles may be bridged, fused, or spiro-fused.
  • the substituents can themselves be optionally substituted.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyi, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepmyl, tropanyl, oxazolidinonyi, homotropanyi, 2-oxa-5-azabicyclo[2.2.2]octane, and 2,6- di azaspiro [3.3] heptany 1.
  • aromatic means a planar ring having 4n -r 2 electrons in a conjugated system.
  • conjugated system means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted with one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, tri chloromethoxy, etc.
  • “Spirocycloalkyd” or “spirocyclyl” means 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 include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g, O, N, S, or P).
  • a (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • One or more of the carbon atoms can be substituted with a heteroatom,
  • spiroheterocycloalkyd is understood to 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 piperidinyl).
  • solvate refers to a complex of variable stoichiometry' formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, w'ater, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • alkyl-aryl refers to a chemical moiety comprising an alkyl group covalently attached to an aryl group, wherein the linkage to the rest of the molecule is on the first group recited, i.e., the alkyl group.
  • alkyl-alkoxy refers to a chemical moiety comprising an alkyl group covalently attached to an alkoxy group wherein the linkage to the rest of the molecule is on the alkyd group. This nomenclature may also be used for, e.g., alkenyl-aryl, alkenyl-heteroaryl, alkynyl- aryl, alkynyl-heteroaryl.
  • Cj alkyl-phenyl refers to ;
  • C-2 alkenyl-furanyl refers to
  • Q alkyl-C2 alkoxy refers to , and so on.
  • the term "isomer” refers to compounds that have die 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 Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • the present disclosure also contemplates isotopically labelled compounds of Formula I (e.g., those labeled with ? H and !4 C).
  • Deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable earner.
  • pharmaceutically acceptable salts include, e.g., water-soluble and waterinsoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate.
  • a "patient” or “subject” is 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.
  • an "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • treating refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound
  • salt refers to pharmaceutically acceptable salts
  • pharmaceutically acceptable salt also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • Menin/MLL interaction inhibitor refer to compounds of Formula I and/or compositions comprising a compound of Formula I which inhibits the interaction of menin and MLL.
  • the amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose.
  • therapeutic agents e.g., compounds or compositions of Formula I (and/or additional agents) described herein
  • the therapeutic agents are given at a pharmacologically effective dose.
  • a “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease.
  • An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g. , slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease.
  • administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g, a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival.
  • Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
  • inhibitors of menin-MLL interaction comprise compounds having a structure represented by Formula (I):
  • X 1 , X 2 , X J , X 4 , X 5 , and X 6 are each independently selected from CH or N; and at least one of X ! , X 2 , X 3 , X 4 , X s , and X° is N;
  • W is -CN; or W and ring B together with the atoms to which they are attached and any intervening atoms, form a 5-10 membered heterocycle; each R 3 is independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, NH2, NHCH3, and N(CH3>2 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NR 9 R 10 , Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl
  • L is selected from (CR 5 2)q, (CR 5 2)qO, (CR 5 2)qS(O) s and (CR 5 2)qC(O);
  • R 3 is selected from hydrogen, deuterium, Cj-Ce alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 ; wherein,
  • 1/ is selected from (CR'hlq, (CR 5 2)qO, (CR 5 2) q S(O) s and (CR 5 2) q C(O);
  • Ring B is selected from C3-C14 cycloalkyl, 3- to 10-membered heterocycle, aryl, and heteroaryl, wherein cycloalkyl, heterocycle, and, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 10 , Ci-Ce alkyl, C-.-Cf, alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl;
  • R 4 is selected from H, Ci-Cf, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ci-Cs alkyl-Ci-Ce alkoxy, C(O)R', heterocyclyl, aryl, or heteroaiyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, Cj-Ce alkyl, and Ci-Ce alkoxy; each R 3 is independently selected from H, halogen, CN, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl;
  • R 6 is selected from H, Ci-C 6 alkyl, -C(O)R 7 , -NHC(O)R 7 , S(O) s R n , -NHS(O) s R n , -
  • R' is selected from R s , OR 8 , NR 9 R W ,
  • R 8 is selected from H, Ci-Ce alkyl, Cr-Ce alkenyl, C2-C6 alkynyl, C3-C10 cy cloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO?., NR 9 R !0 ; each R 9 and R 10 is independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocycle, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, Ci-Cg alkyl, and Ci-Ce alkoxy; or R 9 and R
  • R“ is selected from Ci-Ce alkyl, Cs-Cio cycloalkyl, Ci-Cg alkoxy, and NR 9 R 10 ;
  • m and 11 are each an integer independently selected from 1, 2, and 3;
  • p is an integer selected from 0, 1, and 2;
  • r is an integer selected from 0, 1, 2 and 3;
  • q is an integer selected from 0, 1, 2, 3 and 4;
  • s is an integer selected from 0, 1, and 2;
  • cycloalkyl is a mono or polycyclic saturated carbon rings containing 3-18 carbon atoms; aryl is a cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; and heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • the present disclosure provides compounds of Formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: wherein R 1 , R 2 , R 3 , R 4 , X 3 , X r , X 2 , X 3 , X 4 , X 3 , X°, Y, L, m, n, p, and r are as described herein. [0073] It is understood that, for a compound of Formula (I), R ⁇ , R 2 , R ; . R 4 , R ⁇ R 6 , R 7 , R 8 , R 9 , R 10 , R !!
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from CH or N; and at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is N;
  • W is -CN; or W and ring B together with the atoms to which they are attached and any intervening atoms, form a 5-10 membered heterocycle; each R 3 is independently selected from halogen, Ci-Ce alkyl, Ci-Cs alkoxy, C3-C10 cycloalkyl, Cj-Ce alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl -aryl, Ci-Cs alkyl-heteroaryl, C2-C6 alkenyl-aryl, Ci-Cf.
  • L is selected from (CR 5 2)q, (CRblqO, (CR 5 2)qS(O) s and (CR 5 2)qC(O);
  • R 3 is selected from hydrogen, deuterium, Ci-Ce alkyl, C3-C10 cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 ; wherein.
  • L 5 is selected from (CR 5 2)q, (CR 5 2)qO, (CR 3 2)qS(O) s and (CR 3 2)qC(O);
  • Ring B is selected from C3-C14 cycloalkyl, 3- to 10-membered heterocycle, aiyl, and heteroaryl, wherein cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently’ selected from halogen, CN, NO?., oxo, OH, NR 9 R !0 , Ci-Ce alkyl, Ci-Ce alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl;
  • R 4 is selected fromH, Ci-Ce alkyl, C2-C6 alkenyl, (b-Ce alkynyl, C3-C10 cycloalkyl, Ci- Ce alkyl -Ci-Cf, alkoxy, C(O)R', heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, Nib, Ci-Ce alkyl, and Ci-Ce alkoxy; each R s is independently selected fromH, halogen, CN, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ⁇ , ⁇ Cw cycloalkyl;
  • R 6 is selected from H, Ci-Ce alkyl, ⁇ C(O)R', -NHC(O)R 7 , S(O) 3 R n , -NHS(O) s R u , -
  • R 7 is selected from R 8 , OR 8 , NR 9 R 10 .
  • R 8 is selected from H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, ON, NO2, NR 9 R 10 ; each R 9 and R 10 is independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, or heterocycle, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, Ci-Ce alkyl,
  • R n is selected from Ci-Ce alkyl, C3-C10 cycloalkyl, Ci-Ce alkoxy, NR 9 R 10 ; m and n are each an integer independently selected from 1, 2, and 3; p is an integer selected from 0, 1 , and 2; r is an integer selected from 0, 1 , 2 and 3; q is an integer selected from 0, 1, 2, 3 and 4; s is an integer selected from 0, 1, and 2.
  • each from X 1 , X 2 , X J , X 4 , X 5 , and X 6 is independently selected from CH or N; and at least one of X ! , X 2 , X 3 , X 4 , X', and X° is N,
  • each from X 1 , X 2 , X 3 , X 4 , X s , and X b is independently selected from CH or N; and at least two of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are N,
  • each from X ! , X 2 , X X 4 , X 5 , and X 6 is independently selected from CH or N; and at least three of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are N.
  • each from X ! , X 2 , X', X 4 , X 5 , and X 6 is independently selected from CH or N; and at least four from X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are N,
  • X 1 is CH or N.
  • X 1 is CH, wherein H is optionally replaced with R 1 .
  • X 1 is CH.
  • X 1 is CR 1 .
  • X ! is N.
  • X 2 is CH orN.
  • X 2 is CH, wherein H is optionally replaced with R 1 .
  • X 2 is CH.
  • X 2 is CR’ ! .
  • X 2 is N.
  • X 3 is CH or N. [0090] In some embodiments, X 3 is CH, wherein H is optionally replaced with R 1 .
  • X J is CH.
  • X J is CR 1 .
  • X 3 is N.
  • X' is CH or N.
  • X‘ : is CH, wherein H is optionally replaced with R l .
  • X 4 is CH.
  • X 4 is CR 1 .
  • X 4 is N.
  • X 5 is CH or N.
  • X 5 is CH, wherein H is optionally replaced with R 1 .
  • X 5 is CR 1 .
  • X 5 is N.
  • X° is CH orN.
  • X b is CH, wherein H is optionally replaced with R 1 .
  • X b is CH.
  • X 6 is CR 1 .
  • X 6 is N.
  • each from X 1 and X 6 is N.
  • each from X 1 and X b is N and each from X 2 , X J , X 4 and X 5 is CH, wherein each H is optionally replaced with R ⁇
  • each from X 1 and X 6 is N and each from X 2 , X 3 , X 4 and X 5 is CH.
  • each from X 1 and X 6 is N; each from .X 2 , X 4 and .X 5 is CH; and X 3 is CR 1 .
  • each from X 1 and X 6 is N; each from X 2 , X 4 and X s is CH, and X J is CF.
  • each from X 1 and X b is N; each from X 2 , X 3 and X 5 is CH, and X 4 is CR 1 .
  • each from X 1 and X b is N; each from X 2 , X J and X 5 is CH, and X 4 is CF.
  • each from X 5 and X 6 is N.
  • each from X 5 and X 6 is N and each from X 1 , X 2 , X 3 and X 4 is CH, wherein each H is optionally replaced by R l .
  • each from X s and X 6 is N and each of X 1 , X 2 , X 3 and X 4 is CH.
  • each from X 1 and X 5 is N.
  • each from X 1 and X 5 is N and each from X 2 , X 3 , X 4 and X° is CH, wherein each H is optionally replaced by R j .
  • each from X 1 and X s is N and each of X 2 , X 3 , X 4 and X 6 is CH. [0121] In some embodiments, each from X 1 , X 4 and X 6 is N.
  • each from X 1 , X 4 and X 6 is N and each from X 2 , X 3 and X 5 is CH, wherein each H is optionally replaced by R 1 .
  • each from X 1 , X 4 and X 6 is N and each of X 2 , X 3 and X 5 is CH. [0124] In some embodiments, each from X 3 , X 3 and X" is N.
  • each from X 1 , X 3 and X 6 is N and each from X 2 , X 4 and X 5 is CH, wherein each H is optionally replaced by R 1 .
  • each from X 1 , X J and X 6 is N and each of X 2 , X 4 and X 5 is CH. [0127] In some embodiments, each from X ! , X 2 and X 6 is N.
  • each from X 3 , X 2 and X 6 is N and each from X 3 , X 4 and X 5 is CH, wherein each II is optionally replaced by R 1 .
  • each from X f , X 2 and X 6 is N and each of X 3 , X 4 and X 5 is CH. [0130] In some embodiments, each from X f , X 2 , X 4 and X 6 is N.
  • each from X 1 , X 2 , X 4 and X° is N and each from X 3 and X s is CH, wherein each H is optionally replaced by R l .
  • each from X ! , X 2 , X 4 and X° is N and each of X ’ and X s is CH.
  • each R 1 is independently selected from halogen, Ci-Ce alkyl, Ci-Cf, alkoxy, C3-C10 cycloalkyl, Cz-Ce alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, Ci-Cb alkyl-aryl, C1-C6 alkyl-heteroaryl, Cz-Ce alkenyl-aryl, Cz-Ce alkenyl-heteroaryl, Cz-Cs alkynyl-aryl, Cz-Ce alkynyl-heteroaryl, andNR s R 10 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or
  • R 1 is halogen
  • R 1 is F. In some embodiments, R ! is Cl. In some embodiments, R ⁇ is Br. In some embodiments, R 3 is I.
  • R’ ! is F.
  • each R 1 is independently selected from C3-C10 cycloalkyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, Ci-Ce alkyl-heteroaryl, Cz-Cs alkenyl-aryl, Cz- Cb alkenyl-heteroaryl, C2-C6 alkynyl-aryl, and C2-C6 alkynyl-heteroaryl.
  • each R 1 is independently selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl.
  • each R f is independently selected from Ci-Ce alkyd and Ci-Ce alkoxy.
  • each R 1 is independently selected from C3-C10 cycloalkyl and aryl.
  • each R’ 1 is independently selected from heterocycle and heteroaryl.
  • R ⁇ is Ci-Ce alkyl.
  • R ! is methyl. In some embodiments, R ! is ethyl. In some embodiments, R ! is propyl. In some embodiments, R 1 is n-propyl. In some embodiments, R 1 is iso-propyl. In some embodiments, R ! is butyl. In some embodiments, R 1 is ra-butyl. In some embodiments, R 1 is /so-butyl. In some embodiments, R ! is sec-butyl. In some embodiments, R ! is tert-butyl. In some embodiments, R 1 is pentyd. In some embodiments, R 1 is hexyl.
  • R 1 is C1-C6 alkoxy.
  • R 1 is methoxy. In some embodiments, R ⁇ is ethoxy. In some embodiments, R 1 is propoxy. In some embodiments, R 1 is butoxy. In some embodiments, R ! is pentoxy. In some embodiments, one R 1 is hexoxy.
  • R ! is Cs-Cw cycloalkyl.
  • R f is a monocyclic C3-C10 cycloalkyl.
  • R 1 is a polycyclic C3-C10 cycloalkyl.
  • R 1 is C5-C6 cycloalkyl.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.
  • R 1 is cyclopropyl.
  • R 1 is cyclobutyl.
  • R ! is cyclopentyl.
  • R 1 is cyclohexyl.
  • R 1 is cycloheptyl.
  • R ! is cyclooctyd.
  • R’ ! is cyclononyl.
  • R 1 is cyclodecyl.
  • R ! is a fused polycyclic C3-C10 cycloalkyl.
  • R 1 is a bridged polycyclic C3-C10 cycloalkyl.
  • R ! is a C3- C10 spirocycloalkyl
  • R? is C2-C6 alkenyl.
  • R 1 is C2 alkenyl. In some embodiments, R 1 is C3 alkenyl. In some embodiments, R 1 is (ri alkenyl. In some embodiments, R*is CS alkenyl. In some embodiments, R 1 is Ce alkenyl.
  • R 1 is C2-C6 alkynyl.
  • R 1 is C2 alkynyl. In some embodiments, R 1 is C3 alkynyl. In some embodiments, R 1 is C4 alkynyl. In some embodiments, R l is Cs alkynyl. In some embodiments, R ! is Ce alkynyl.
  • R 1 is heterocycle. In some embodiments, R 1 is 3-10 membered heterocycle. In some embodiments, R 1 is heterocycle comprising one, two, or three heteroatonis. In some embodiments, R 1 is 3-10 membered heterocycle comprising one, two, or three heteroatoms.
  • R 1 is a monocyclic heterocycle. In some embodiments, R 1 is a polycyclic heterocycle.
  • R ⁇ is 3-membered heterocycle. In some embodiments, R 1 is 4- membered heterocycle. In some embodiments, R 1 is 5-membered heterocycle. In some embodiments, R 1 is 6-membered heterocycle. In some embodiments, R 1 is 7-membered heterocycle. In some embodiments, R ⁇ is 8-membered heterocycle. In some embodiments, R 1 is 9-membered heterocycle. In some embodiments, R 1 is 10-membered heterocycle.
  • R ! is 5- to 6-membered heterocycle.
  • R ! is aryl
  • R ! is Ce aryl (e.g., phenyl).
  • R 1 is heteroaryl. In some embodiments, R 1 is 5- to 6-membered heteroaryk
  • R ⁇ is Ci-Ce alkyl-aryl.
  • R 1 is methyl-aryl. In some embodiments, R 1 is ethyl-aryl. In some embodiments, R 1 is propyl-aryl. In some embodiments, R 1 is n-propyl-aryl. In some embodiments, R 1 is iso-propyl-aiyl. In some embodiments, R 1 is butyl-aryl. In some embodiments, R 1 is 77-butyl-aryl. In some embodiments, R 1 is isobutyl-aryl. In some embodiments, R 1 is sec-butyl-aryl. In some embodiments, R 1 is tert-butyl-aryl. In some embodiments, R 1 is pentyl-aryl. In some embodiments, R ! is hexyl-aryl. [0163] In some embodiments, R 1 is Ci-Ce alkyl-heteroaryl.
  • R 1 is methyl-heteroaryl. In some embodiments, R 1 is ethyl- heteroaryl. In some embodiments, R 1 is propyl-heteroaryl. In some embodiments, R 1 is n- propyl-heteroaryl. In some embodiments, R ⁇ is isopropyl-heteroaryl. In some embodiments, R 1 is butyl-heteroaiyl. In some embodiments, R 1 is rt-butyl-heteroaiyl. In some embodiments, R 1 is iso-butyl-heteroaryl. In some embodiments, R ! is sec-butyl -heteroaryl. In some embodiments, R f is te/7-butyl-heteroaryl. In some embodiments, R 1 is pentyl-heteroaryl. In some embodiments, R 1 is hexyl-heteroaryl.
  • R ! is Cj-Ce alkenyl-aryl.
  • R 1 is C? alkenyl -aryl. In some embodiments, R 1 is Co alkenylaryl. In some embodiments, R 1 is C4 alkenyl-aryl. In some embodiments, R ! IS Cs alkenyl-aryl. In some embodiments, R 1 is Cs alkenyl-aryl.
  • R 1 is C2-C6 alkenyl-heteroaryl.
  • R ! is C?. alkenyl-heteroaryl. In some embodiments, R 1 is C3 alkenyl-heteroaryl. In some embodiments, R ! is C4 alkenyl-heteroaryl. In some embodiments, R‘is C5 alkenyl-heteroaryl. In some embodiments, R 1 is G, alkenyl-heteroaryl.
  • R ! is Cj-Ce alkynyl-aryl.
  • R* is C2 alkynyl-aryl.
  • R ⁇ is C3 alkynyl- aryl.
  • R 1 is C4 alkynyl-aryl.
  • R 1 is C5 alkynyl-aryl.
  • R l is G. alkynyl-aryl.
  • R* is and C2-C6 alkynyl-heteroaryl.
  • R 1 is C2 alkynyl-heteroaryl. In some embodiments, R ! is C3 alkynyl-heteroaryl. In some embodiments, R 1 is C4 alkynyl-heteroaryl. In some embodiments, R 1 is C5 alkynyl-heteroaryl. In some embodiments, R l is Ce alkynyl-heteroaryl.
  • R ! is NR 9 R 10 . In some embodiments, R ! is NHR 10 . In some embodiments, R 1 is NHCH3.
  • R 1 is ⁇ R‘'R
  • p is 2, one R 1 is NHCHs, and the other R 1 is Ci-Ce alkyl optionally substituted with one or more halogen. In some embodiments, p is 2, one R 1 is NHCH3, and the other R 1 is Ci-Cg alkyl optionally substituted with one or more fluoro. In some embodiments, one R 1 is NHCH3, and the other R* is CH2CF3.
  • R 1 is Ci-Cs alkyl substituted with one or more halogen.
  • R l is Ci-Ck, alkyl substituted with one or more F.
  • R 1 is Ci-Ce alkyl substituted with one or more Cl.
  • R’ ! is Ci-Ce alkyl substituted with one or more Br.
  • R 1 is Ci-Ce alkyl substituted with one or more I.
  • R 1 is C-.-Ce alkyl substituted with one or more OH.
  • R 1 is Ci-Cs alkyl substituted with one or more NH2.
  • R 1 is Ci-Ce alkyl substituted with one or more Ci-Ce alkyl. In some embodiments, R 1 is Ci-Ce alkyl substituted with one or more O.-Ce alkoxy. In some embodiments, R 1 is O.-Ce alkyl substituted with one or more NR 9 R 10 . In some embodiments, R 1 is Ci-Ce alkyl substituted with one or more C3-C10 cycloalkyl. In some embodiments, R 1 is Ci-Cb alkyd substituted with one or more C2-C6 alkenyl. In some embodiments, R 1 is Ci-Ce alkyl substituted with one or more C2-C6 alkynyl.
  • R 1 is Cj-Ce alkyl substituted with one or more heterocycle. In some embodiments, R 1 is Ci-Ce alkyl subs tituted with one or more aryl. In some embodiments, R 1 is Ci-Ce allyl substituted with one or more heteroaryl.
  • R 1 is Ci-Ce alkyl substituted with one or more F substituted with one or more F. In some embodiments, R 1 is methyl substituted with one or more F. In some embodiments, R ! is ethyl substituted with one or more F. In some embodiments, R 1 is propyl substituted with one or more F. In some embodiments, R 1 is n-propyl substituted with one or more F. In some embodiments, R ! is iso-propyl substituted with one or more F. In some embodiments, R ! is butyl substituted with one or more F. In some embodiments, R l is .u-butyl substituted with one or more F.
  • R 1 is iso-butyl substituted with one or more F. In some embodiments, R 1 is sec-butyl substituted with one or more F. In some embodiments, R 1 is tert-butyl substituted with one or more F. In some embodiments, R 1 is pentyl substituted with one or more F. In some embodiments, R f is hexyl substituted with one or more F.
  • R 1 is (CFFOo-sCF?. In some embodiments, R ! is CF3. In some embodiments, R 1 is CH2CF3.
  • R’ ! is -CH2CF3. In some embodiments, R ! is -CF2CF3.
  • p is 1 and R 1 is (CFFOo-sCF?. In some embodiments, p is I and R ! is CF3. In some embodiments, p is 1 and R l is CH2CF3. [0181] In some embodiments, p is 2 and at ieast one and R 1 is (CH2)o-5CF3. In some embodiments, p is 2 and at least one and R 1 is CFs. In some embodiments, p is 2 and at least one and R 1 is CH2CF3.
  • R 1 is Cj-Cc, alkoxy substituted with one or more halogen.
  • R l is Ci-Ce alkoxy substituted with one or more F.
  • R* is Ci-Ce alkoxy substituted with one or more Cl.
  • R ! is Ci-Ce alkoxy substituted with one or more Br.
  • R 1 is Ci-Ce alkoxy substituted with one or more I.
  • R 1 is Ci-Ce alkoxy substituted with one or more OH.
  • R 1 is Ci-Cf, alkoxy substituted with one or more NH2.
  • R 1 is Ci-Ce alkoxy substituted with one or more Ci-Ce alkyl. In some embodiments, R 1 is Ci-Ce alkoxy substituted with one or more Ci-Ce alkoxy. In some embodiments, R ! is Ci-Cs alkoxy substituted with one or more N R f 2 R*3. In some embodiments, R 1 is Ci-Ce alkoxy substituted with one or more C3-C10 cycloalkyl. In some embodiments, R 1 is Ci-Ce alkoxy substituted with one or more C2-C6 alkenyl. In some embodiments, R ! is C-.-Ce alkoxy substituted with one or more C2-C0 alkynyl.
  • R 1 is C1-C6 alkoxy substituted with one or more heterocycle. In some embodiments, R 1 is Ci-Ce alkoxy substituted with one or more aryl. In some embodiments, R 1 is Cj-Cc, alkoxy substituted with one or more heteroaryl.
  • R ! is C3-C10 cycloalkyl substituted with one or more halogen.
  • R’ ! is C3-C10 cycioalkyl substituted with one or more F.
  • R ! is C3-C10 cycloalkyl substituted with one or more Cl.
  • R ! is C3-C10 cycioalkyl substituted with one or more Br.
  • R 1 is C3-C10 cycioalkyl substituted with one or more I.
  • R ! is C3-C10 cycioalkyl substituted with one or more OH.
  • R f is C3-C10 cycioalkyl substituted with one or more NH2.
  • R 1 is C3-C10 cycioalkyl substituted with one or more Ci-Ce alkyl .
  • R 1 is C3-C10 cycioalkyl substituted with one or more Ci-Ce alkoxy.
  • R’ ! is C3-C10 cycioalkyl substituted with one or more NR 12 R 13 .
  • R ! is Ch-Cio cycioalkyl substituted with one or more C3-C10 cycloalkyl.
  • R 1 is C3-C10 cycloalkyl substituted with one or more C2-C0 alkenyl.
  • R 3 is cycloalkyl substituted with one or more Cz-Cc, alkynyl.
  • R 1 is C3-C10 cycloalkyl substituted with one or more heterocycle.
  • R l is C3-C10 cycloalkyl substituted with one or more aryl.
  • R 1 is C3-C10 cycloalkyl substituted with one or more heteroaryl.
  • R 3 is Cz-Cc, alkenyl substituted with one or more halogen. In some embodiments, R 3 is C2-C6 alkenyl substituted with one or more F. In some embodiments, R ! IS C2-C6 alkenyl substituted with one or more CL In some embodiments, R 1 is C2-C6 alkenyl substituted with one or more Br. In some embodiments, R 1 is C2-C6 alkenyl substituted with one or more I. In some embodiments, R 3 is Cz-Ce alkenyl substituted with one or more OH. In some embodiments, R 1 is C2-C6 alkenyl substituted with one or more NH2.
  • R 1 is C2-C6 alkenyl substituted with one or more Ci-Ce alkyl.
  • R 3 is Cz-Cb alkenyl substituted with one or more Ci-Ce alkoxy.
  • R 3 is Cz-Ce alkenyl substituted with one or more NR 12 R 13 .
  • R 3 is C2-C6 alkenyl substituted with one or more C3-C10 cycloalkyl.
  • R 1 is C2-C6 alkenyl substituted with one or more aryl.
  • R 1 is C2-C6 alkenyl substituted with one or more heteroaryl.
  • R 3 is Cz-Ce alkynyl substituted with one or more halogen. In some embodiments, R 3 is C2-C6 alkynyl substituted with one or more heteroaryl.
  • R 1 is heterocycle substituted with one or more halogen.
  • R 3 is heterocycle substituted with one or more heteroaiyl.
  • R 1 is aryl substituted with one or more halogen. In some embodiments, R 1 is aryl substituted with one or more heteroaryl.
  • R 3 is heteroaryl substituted with one or more halogen. In some embodiments, R 3 is heteroaryl substituted with one or more heteroaiyl.
  • R 3 is Ci-Ce alkyl-aryl substituted with one or more halogen. In some embodiments, R 3 is Cj-Ce alkyl-aryl substituted with one or more heteroaiy l.
  • R 3 is C1-C6 alkyl-heteroaiyl substituted with one or more halogen.
  • R 1 is Ci-Ce alkyl-heteroaryl substituted with one or more heteroaryl.
  • R 1 is Cj-Ce alkenyl-aryl substituted with one or more halogen.
  • R 3 is C2-C6 alkenyl-aryl substituted with one or more heteroaryl.
  • R f is C2-C6 alkenyl-heteroaryl substituted with one or more halogen.
  • R 1 is C2-C6 alkenyl-heteroaryl substituted with one or more heteroaryl.
  • R 1 is C2-C6 alkyiiyl-aryl substituted with one or more halogen.
  • R 3 is C2-C6 alkynyl-aryl substituted with one or more heteroaryl.
  • R 1 is C2-C6 alkynyl-heteroaryl substituted with one or more halogen. In some embodiments, R 1 is C2-C6 alkynyl-heteroaryl substituted with one or more heteroaryl.
  • R 1 is unsubstituted Ci-Ce alkyd. In some embodiments, R 1 is unsubstituted Ci-Ce alkoxy. In some embodiments, R 1 is unsubstituted C3-C10 cycloalkyl. In some embodiments, R 1 is unsubstituted Ci-Ce alkenyl. In some embodiments, R 1 is unsubstituted C2-C6 alkynyl. In some embodiments, R j is unsubstituted heterocycle. In some embodiments, R 1 is unsubstituted aryl. In some embodiments, R 1 is unsubstituted heteroaryl.
  • R 1 is unsubstituted Cj-Ce alkyl-aryl. In some embodiments, R 1 is unsubstituted Ci-Ce alkyl-heteroaryl. In some embodiments, R 1 is unsubstituted C2-C6 alkenylaryl. In some embodiments, R ! is unsubstituted C2-C6 alkenyl-heteroaryl. In some embodiments, R 1 is unsubstituted C2-C6 alkynyl-aryl. In some embodiments, R 1 is unsubstituted C?-Ce alkynyl-heteroary l.
  • R ⁇ is -OH.
  • R 1 is -NH2.
  • R ! is -NIICH3.
  • R’ ! is -X(CI hb
  • L is selected from (CRXlq, (CR 5 2)qO, (CR 3 2)e.S(O) s and (CR 5 2 )qC(O).
  • s is an integer selected from 0, 1, and 2.
  • s is 0,
  • s is 1.
  • s is 2.
  • s is 0 and L is (CR 5 2.)qS.
  • s is 1 and L is (CR 5 2)qS(O).
  • s is 2 and L is (CR 5 2)qS(O)2.
  • L is (CR 5 2 )qC(O).
  • L is (CR 5 2)q and the compound is of Formula 1-1: wherein s is an integer selected from 0, 1 or 2 for the different oxidation stages of the sulfur atom.
  • L is (CR 5 2)qS(O)2 and the compound is of Formula 1-3’:
  • q is an integer selected from 0, 1, 2, 3 and 4.
  • q is 0.
  • q is 1. [0233] In some embodiments, q is 2.
  • q is 3.
  • q is 4.
  • q is 0 and L is bond. [0237] In some embodiments, q is 0 and L is S(O)?.
  • q is 0 and L is C(O).
  • each R 5 is independently selected from H, halogen, CN, OH, Cj- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyd.
  • R is H.
  • R 5 is C1-C6 alkyl.
  • R 5 is methyl
  • q is 1 and L is C(R , )2.
  • q is 1 and L is CH?.
  • q is 1 and L is C(R 5 )2O.
  • q is 1 and L is CH2O.
  • q is 1 and L is C(R 5 )2 ⁇ .
  • q is 1 and L is CH2S.
  • q is 1 and L is C(R')?S(O).
  • q is 1 and L is CFbSCO).
  • q is 1 and L is C(R 5 )2S(O)2.
  • q is 1 and L is CH?S(O)2.
  • q is 1 and L is C(R 5 )2C(O).
  • q is 1 and L is CIHCCO).
  • q is 1 and L is C( R ( R'j 2.
  • q is 1 and L is CH2CH2.
  • q is 1 and L is C(R’)2C(R 5 )2O.
  • q is 1 and L is CH2CH2O.
  • q is 1 and L is C(R > )2C(R 5 )2S.
  • q is 1 and L is CH2CH2S.
  • q is 1 and L is C(R 5 )2C(R 5 )2S(O).
  • q is 1 and L is CFbCHiSCO).
  • q is 1 and L is C(R')2C(R 5 )2S(O)2.
  • q is 1 and L is CH2CH2S(O)2.
  • q is 1 and L is C(R s )2C(R y )2C(O).
  • q is 1 and L is CH 2CH2C 1(0).
  • q is 1 and L is ((’( R'bh.
  • q is 1 and L is CH2CH2CH2.
  • q is 1 and L is (( ( R'bbO [0270] In some embodiments, q is 1 and L is CH2CH2CH2O.
  • q is 1 and L is (C(R S )2)3S.
  • q is 1 and L is CH2CH2CH2S.
  • q is 1 and L is (C(R 5 )2)3S(O).
  • q is 1 and L is ClbClbClhStO).
  • q is 1 and L is (C(R 5 )2)3S(O)2.
  • q is 1 and L is CH2CH2CH2S(O)2.
  • q is 1 and L is (C(R’)2)3C(O).
  • q is 1 and L is CH ⁇ CI-bCHjCIO).
  • q is 1 and L is (C(R > )2)4.
  • q is 1 and L is CH2CH2CH2CH2.
  • q is 1 and L is (C(R 5 )2)4O.
  • q is 1 and L is CH2CH2CH2CH2O.
  • q is 1 and L is (C(R')?,)4S.
  • q is 1 and L is CH2CH2CH2CH2S.
  • q is 1 and L is (C(R S )2)4S(O).
  • q is 1 and L is CH?.CH2CH2CH2S(O).
  • q is 1 and L is (C(R 5 )2)4S(O)2.
  • q is 1 and L is ClbClbClhClhSCOh.
  • q is 1 and L is (C(R 5 )2)4C(O).
  • q is 1 and L is CH2CH2CH2CH2C(O).
  • L is CH2.
  • L is Cl 1 -CH >
  • L is C(O).
  • L is CH2CH2O.
  • each R 2 is independently selected from halogen, OH, CN, Ci- C'e alkyl, Ci-Cf, alkoxy, NR 9 R i0 , C3-C10 cycloalkyd, and, heterocyclyl, heteroaryl.
  • R 2 halogen
  • R 2 is F.
  • R 2 is Cl
  • R 2 is Br
  • R 2 is I.
  • R 2 is OH
  • R 2 is CN. [0303] In some embodiments, R 2 is Ci-Ce alkyl.
  • R 2 is methyl
  • R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is zz-propyl. In some embodiments, R 2 is iso-propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is w-butyl. In some embodiments, R 2 is zso-butyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is /erf-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl.
  • R 2 is Ci-Ce alkoxy.
  • R 2 is methoxy
  • R 2 is ethoxy
  • R 2 is propoxy
  • R 2 is butoxy
  • R 2 is pentoxy
  • R 2 is hexoxy
  • R 2 is NR 9 R 10 .
  • R 2 is NH?.
  • R 2 is NHCH3.
  • R 2 is N(CHJ)2.
  • R 2 is Cj-Cw cycloalkyl.
  • R 2 is cyclopropyl
  • R 2 is cyclobutyl
  • R 2 is cyclopentyl
  • R 2 is aryl
  • R 2 is phenyl.
  • R 3 is selected from hydrogen, deuterium, Ci-Ce alkyl, C3-C10 cycloalkyl, and L 4 .
  • R 3 is H
  • R 3 is Ci-Ce alkyl.
  • R 3 is methyl
  • R 3 is C3-C10 cycloalkyl.
  • R 3 is cyclopropyi.
  • R 3 is L 4 .
  • L 5 is selected from (CR'Ojg, (CR 5 2 )qO, (CR 5 2 ) q S(O) s and (CR 5 2 )qC(O).
  • I? is (CR 5 2 )q.
  • 1? is (CR 5 ?)qO.
  • 1/ is (CR 5 2 ) q S(O) s .
  • s is an integer selected from 0, 1, and 2.
  • s is 0,
  • s is 1.
  • s is 2.
  • s is 0 and L is (CR 5 2 )qS.
  • s is 1 and L is (CR 5 2 )qS(O).
  • s is 2 and L is (CR 5 2 )qS(O) 2 .
  • L? is (CR > 2 ) q C(O).
  • L 5 is (CR 5 2 )q and the compound is of Formula I- 11 :
  • L 5 is (CR 5 2)qO and the compound is of Formula 1-12:
  • L 5 is (CR 5 2)qS(O)2 and the compound is of Formula 1-13:
  • 1? is (CR 5 2.)qS(O)?. and the compound is of Formula 1-14:
  • q is an integer selected from 0, 1, 2, 3 and 4.
  • q is 0.
  • q is 1.
  • q is 2.
  • q is 3. [0357] In some embodiments, q is 4.
  • q is 0 and L 5 is bond.
  • q is 0 and L 5 is S(O)?..
  • q is 0 and 1? is C(O).
  • each R 5 is independently selected from H, halogen, CN, OH, Ci- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl.
  • R 5 is H.
  • R 5 is Ci-Ce alkyl.
  • R 5 is methyl
  • q is 1 and L 5 is C(R 5 )2.
  • q is 1 and I? is CH2.
  • q is 1 and L? is C(R 5 )2O.
  • q is 1 and L 5 is CH2O.
  • q is 1 and L 5 is C(R')?,S.
  • q is 1 and L 5 is CH2S.
  • q is 1 and L 5 is C(R 5 )2S(O).
  • q is 1 and L 1 is CH 28(G).
  • q is 1 and 1? is C(R 5 )2S(O)2.
  • q is 1 and I? is CH2S(O)2.
  • q is 1 and L 5 is C(R 3 )2C(O).
  • q is 1 and L 5 is CH2C(O).
  • q is 1 and L 5 is C(R’)2C(R 5 )2.
  • q is 1 and L 5 is CH2CH2.
  • q is 1 and L 5 is C(R > )2C(R 5 )?.O.
  • q is 1 and L'’ is CH2CH2O.
  • q is 1 and I? is C(R 5 )2C(R-)2S.
  • q is 1 and L 5 is CH2CH2S.
  • q is 1 and L 5 is C(R 3 )2C(R 5 )2S(O).
  • q is 1 and L 5 is CFbCI-bSCO).
  • q is 1 and L 5 is C(R 5 )2C(R 5 )2S(O)2.
  • q is 1 and I? is CH2CH2.S(O)2.
  • q is 1 and 1? is C(R 5 )2C(R 3 )2C(O).
  • q is 1 and I? is ClbCIbQO).
  • q is 1 and L 5 is (C( R' ⁇ > r. [0390] In some embodiments, q is 1 and L 5 is CH2CH2CH2.
  • q is 1 and L 5 is (C(R 5 ) 2 hO.
  • I? is and the compound is of Formula 1-21
  • Ring B is aryl, heteroaryl, 3- to 8-membered heterocycle, or C3- C14 cycloalkyl, wherein aryl, heteroaryl, heterocycle or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R i0 , Ci-Ce alkyl, Ci-C-6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is aryl wherein aryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 1u , Ci-Cs alkyl, Ci-Ce alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is phenyl wherein phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, NO?, oxo, OH, NR 9 R i0 , Ci-Ce alkyl, Ci-Ce alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is benzenediyl wherein benzenediyl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 10 , Ci-Ce alkyl, Ci-Ce alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is benzenediyl- 1,4 wherein benzenediyl- 1,4 is optionally substituted with one or more substituents independently selected from halogen, CN, NO?, oxo, OH, NR 9 R 10 , Ci-Ce alkyl, Cj-Ce alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is benzenediyl- 1,3 wherein benzenediyl- 1,3 is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 30 , Ci-Ce alkyl, Ci-Ce alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is benzenediyl- 1,2 wherein benzenediyl- 1,2 is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is phenyl
  • Ring B is benzenediyl.
  • Ring B is benzenediyl -1,4.
  • Ring B is benzenediyl-1,3.
  • Ring B is benzenediyl-1,2.
  • Ring B is heteroaiyl, wherein heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 3u , Ci-Cs alkyl, Ci-Ce alkoxy, aryl, heteroaiyl, cycloalkyl, and heterocycle.
  • Ring B is heteroaiyl
  • Ring B is monocyclic 5-membered heteroaryl.
  • Ring B is monocyclic 5-membered heteroaiyl containing one N as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is monocyclic 5-membered heteroaiyl containing two N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is monocyclic 5-membered heteroaiyl containing one N and one 0 as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is monocyclic 5-membered heteroaryl containing one O as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is monocyclic 5-membered heteroaiyl containing one S as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is monocyclic 6-membered heteroaryl .
  • Ring B is monocyclic 6-membered heteroaiyl containing one N as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is monocyclic 6-membered heteroaryl containing two N as the ring heteroatoms, the remaining ring atoms being C,
  • Ring B is monocyclic 6-membered heteroaiyl containing three N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is bicyclic 9-membered heteroaiyl.
  • Ring B is bicyclic 9-membered heteroaryl containing one N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is bicyclic 9-membered heteroaryl containing two N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is bicyclic 9-membered heteroaryl containing three N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is bicyclic 9-membered heteroaryl containing one O as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is bicyclic 9-membered heteroaryl containing one S as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is bicyclic 10-membered heteroaryl.
  • Ring B is bicyclic 10-membered heteroaryl containing one N as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is bicyclic 10-membered heteroaryl containing two N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is bicyclic 10-membered heteroaryl containing three N as the ring heteroatoms, the remaining ring atoms being C,
  • Ring B is 3- to 8-membered heterocycle, wherein heterocycle is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 10 , Ci-Ce alkyl, Ci-Cr, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is 3- to 8-membered heterocycle.
  • Ring B is 3-membered heterocycle.
  • Ring B is 3-membered heterocycle containing one N as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is 4-membered heterocycle.
  • Ring B is 4-membered heterocycle containing one N as the ring heteroatoni, the remaining ring atoms being C.
  • Ring B is 5-membered heterocycle.
  • Ring B is 5-membered heterocycle containing one N as the ring heteroatom, the remaining ring atoms being C. [0467] In some embodiments, Ring
  • Ring B is 5 -membered heterocycle containing two N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is O
  • Ring B is 5-membered heterocycle containing one O as the ring heteroatoni, the remaining ring atoms being C.
  • Ring B is 5-membered heterocycle containing one S as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is 6-membered heterocycle.
  • Ring B is 6-membered heterocycle containing one N as the ring heteroatom, the remaining ring atoms being C.
  • Ring B is 6-membered heterocycle containing one N as the ring heteroatom, the remaining ring atoms being C substituted with aryl.
  • Ring B is 6-membered heterocycle containing two N as the ring heteroatoms, the remaining ring atoms being C, [0480] In some embodiments. Ring B is
  • Ring B is a member of [0481] in some embodiments.
  • Ring ⁇ [0482] In some embodiments, Ring ⁇
  • Ring ⁇ [0483] In some embodiments, Ring ⁇
  • Ring B is 6-membered heterocycle containing one N and one O as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is
  • Ring [0489] In some embodiments. Ring
  • Ring B is 6-membered heterocycle containing one N, one S and one O as the ring heteroatoms, the remaining ring atoms being C. [0491] In some embodiments.
  • Ring B is 7 -membered heterocycle.
  • Ring B is monocyclic 7-membered heterocycle.
  • Ring B is monocyclic 7-membered heterocycle containing one N as the ring heteroatom, the remaining ring atoms being C.
  • Ring ⁇ [0495] In some embodiments, Ring ⁇
  • Ring B is monocyclic 7-membered heterocycle containing two N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is
  • Ring B is monocyclic 7-membered heterocycle containing one N and one O as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is
  • Ring B is bicyclic 7-membered heterocycle.
  • Ring B is bicyclic 7 -membered heterocycle containing two N as the ring heteroatoms, the remaining ring atoms being C.
  • Ring B is
  • Ring B is C3-C14 cycloalkyl, wherein cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR y R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.
  • Ring B is monocyclic cycloalkyl.
  • Ring B is fused bicyclic cycioalkyl.
  • Ring B is bridged bicyclic cycloalkyl. [0508] In some embodiments. Ring B is spiro bicyclic cycloalkyl.
  • Ring B is 3-membered cycloalkyl.
  • Ring B is 4-membered cycloalkyl.
  • Ring B is 5-membered cycloalkyd.
  • Ring B is monocyclic 5-membered cycloalkyl.
  • Ring B is bridged bicyclic 5-membered cycloalkyl.
  • Ring B is
  • Ring B is
  • Ring B is 6-membered cycloalkyl.
  • Ring B is monocyclic 6-membered cycloalkyd.
  • Ring B is
  • Ring B is 7-membered cycloalkyl.
  • Ring B is monocyclic 7-membered cycloalkyl.
  • Ring B is
  • R 6 is selected from H, Ci-Ce alkyl, -C(O)R Z , -NHC(O)R',
  • R 6 is H.
  • R° is Ci-Cg alkyl, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NR 9 R 10 , cycloalkyl, heterocvclyl, aryl, heteroarvl.
  • R 6 is Ci-Ce alkyl.
  • R 6 is CII3.
  • R 6 is Ci-Ce alkanediyl aryl optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NR 9 R 10 , Ci-Ce alkyl, Ci-Cb alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • R° is Ci-Cs alkanediyl and optionally substituted with one Ci-
  • R 1, is C2H5.
  • R 1, is propyl
  • R 6 is 7?-propyl.
  • R 6 is /-propyl
  • R 6 is butyl
  • R 6 is u-butyf
  • R° is /-butyl
  • R 6 is tert-butyl
  • R 6 is pentyl
  • R° is hexyl
  • R 1 is ⁇ C(O)R' .
  • R z is selected from R 8 , OR 8 , NR 9 R KJ .
  • R 7 is R 8 .
  • R ? is OR 8 .
  • R 7 is NR 9 R i0 .
  • R 8 is selected from H, Cj-Ce alky l, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, NR 9 R j0 .
  • R s is H.
  • R 8 is Ci-Ce alkyl, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, NR 9 R 10 .
  • R 8 is Ci-Ce alkyl.
  • R 8 is -CHj. In some embodiments, R 8 is -C2H5. In some embodiments, R 8 is -CH2CH2CH3. In some embodiments, R 8 is -C H(( H ; ⁇ > In some embodiments, R 8 is -CH2CH2CH2CH3. In some embodiments, R 8 is -CH2CH(CH-,)2. In some embodiments, R 8 is pentyl, in some embodiments, R 8 is hexyl.
  • R 8 is C2-C6 alkenyl, wherein alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO?., NR 9 R 10 .
  • R 8 is C2-C6 alkenyl.
  • R 8 is -CIRCH2.
  • R 8 is -CH-CH-CH?.
  • R 8 is C2-C6 alkynyl, wherein alkynyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, NR 9 R 10 .
  • R 8 is C3-C10 cycloalkyl, wherein cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO? stamp NR 9 R W .
  • R 6 is -NHC(O)R 7 .
  • R z is selected from R 5 , OR 5 , NR 9 R 30
  • R z is NR 9 R !0 .
  • R z is NH?
  • R z is NHCH3.
  • R ? is R 8 .
  • R 8 is selected fromH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, NR 9 R i0 .
  • R 8 is H.
  • R 8 is Ci-Ce alkyl, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, NO2, NR 9 R 10 .
  • R 8 is C1-C6 alkyl.
  • R 8 methyl
  • R 6 is S(C)) s R n .
  • s is an integer selected from 0, 1, and 2.
  • s is 0.
  • s is 1.
  • s is 2.
  • R 6 is -SR ! .
  • R 6 is -S(O)R n .
  • R" is -SfCfhR 11 .
  • R n is selected from Ci-Cs alkyl, C3-C10 cycloalkyl, Ci-Ce alkoxy, NR 9 R i0 .
  • R n is Ci-Ce alkyl
  • R n is methyl
  • R !i is ethyl
  • R 11 is propyl
  • R“ is 77-propyl.
  • R 1 1 is z-propyl.
  • R !! is butyl
  • R 1! is zz-butyk
  • R n is /-buty l.
  • R 11 is Zer/-butyl.
  • R 11 is pentyl. In some embodiments, R 11 is hexyl.
  • R“ is C3-C10 cycloalkyl.
  • R 1 1 is monocynch C3-C10 cycloalkyl.
  • R !! is cyclopropyl
  • R n is cyclobutyl
  • R !! is cyclopentyl
  • R 11 is cyclohexyl
  • R 11 is cycloheptyl
  • R“ is bicyclic C5-C10 cycloalkyl.
  • R 1 1 is bicyclic fused C5-C10 cycloalkyl.
  • R 11 is bicyclic bridged C5-C10 cycloalkyl.
  • R n is bicyclic spiro C5-C10 cycloalkyl.
  • R n is Ci-Ce alkoxy.
  • R !i is NR 9 R 10 .
  • R 6 is -S(O)2-Ci-C6-alkyl. [0605] In some embodiments, R 6 is -S(0)2CHs.
  • R 6 is -SCOhCIbCHs.
  • R° is -S(O)2(CH2)2CHs.
  • R 1 is -SCOXCEh ⁇ CEh.
  • R 6 is -S(O) 2 CH(CEl3)2.
  • R 6 is -NHS(O) 2 R n .
  • R 6 is -NHS(O)2CEh.
  • R 6 is -NHS(O)2CH 2 CH3.
  • R 6 is -NHS(C)) 2 NR 9 R 10 .
  • R° is -NHS(O)2NH 2 .
  • L 4 is selected from the options in Table 1.
  • R 4 is selected from H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkyl-Ci-Ce alkoxy, C(O)R', aryl, heteroaryl, or heterocycle, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, ary l, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NR y R i0 , Ci-Ce alkyl, and Ci-Ce alkoxy.
  • R 4 is H
  • R 4 is Ci-Ce alkyl.
  • R 4 is methyl.
  • W is -CN.
  • the compound is of Formula 1-31:
  • the compound is of Formula 1-33: wherein R B is selected from halogen, CN, NO2, oxo, OH, NR S R 10 , Ci-Ce alkyl, Ci-Ce alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle; b is an integer selected from 0, 1, 2, 3, 4; and all other variables are as defined herein.
  • n and 11 are each an integer independently selected from 1, 2, and 3.
  • each m is 1.
  • each ni is 2.
  • each m is 3.
  • each n is 1.
  • each n is 2,
  • each n is 3.
  • the value of m and n is selected from the Table 2
  • p is an integer selected from 0, 1, and 2.
  • p is 0.
  • p is 1.
  • p is 2.
  • r is an integer selected from 0, 1, 2 and 3.
  • r is 0.
  • r is 1.
  • r is 2.
  • r is 3.
  • the compound is of Formula (I- A):
  • the compound is of Formula (I-A’): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-B’):
  • the compound is of Formula (I-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-C’): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-D): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-D’): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-I):
  • the compound is of Formula (I-F): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-IT ): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-Ill): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-IIT):
  • the compound is of Formula (I-IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-IV’):
  • the compound is of Formula (I-V): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-V’):
  • the compound is of Formula (I-VI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-VI’):
  • the compound is of Formula (I-VII): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-VII’):
  • the compound is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (T-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein ah variables are as defined herein.
  • the compound is of Formula (I-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (1-e): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-f): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein ah variables are as defined herein.
  • the compound is of Formula (I-g): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (1-h): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (I-i): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is selected from the formulae listed in Table 3 or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all variables are as defined herein. Table 3.
  • the compound is selected from Table 4 or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all variables are as defined herein.
  • the compound is of Formula (I-A-I-d-I):
  • the compound is of Formula (1-A-I-d-l-l):
  • the compound is of Formula (I-A-I-d-I-l-A):
  • the compound is of Formula (I-A-I-d-I ⁇ l ⁇ A-H):
  • the compound is of Formula (I-A-I-d-I- l-A-H-1): (I-A-I-d-I-l-A-H-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (1-B-I-d-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (1-B-I-d-I- 1):
  • the compound is of Formula (1-B-I-d-I-l-A):
  • the compound is of Formula (I-B-I-d-I-1 -A-H):
  • the compound is of Formula (I-B-I-d-I-l-A-H-1 ):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-h):
  • the compound is of Formula (I-B-I-d-I-l-A-H-1 -B):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-G):
  • each R B is independently selected from H, Ci-C& alkyl, or two R B form oxo and all other variables are as defined herein.
  • the compound is of Formula (I-B-I-d-l-l-A-H-l-B-I):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-I-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-I-a*): (I-B-I-d-I- 1 -A-H- 1 -B-I-a*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l -A-H-l-B-I-a**):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-II):
  • the compound is of Formula (I-B-I-d-I- 1 -A-H-l -B-II-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-III-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-IV-a): (I-B-I-d-I- 1 -A-H- 1 -B-IV-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-V): (I-B-I-d-I-1 -A-H- 1 -B-V), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof,
  • the compound is of Formula (I-B-I-d-l-l-A-H-l-B-V-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-V-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-1 -B-V-a**):
  • the compound is of Formula (I-B-I-d-I-l-A-f 1- 1-B-VI): (I-B-I-d-I-1 -A-H-l -B-VI), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-VI-a): (LB-I-d-1- 1 -A-H- 1 -B- VLa), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (l-B-I-d-LLA-H-l-B-Vl-a*): (LB-Ld-L 1 -A-H- 1 -B- VLa*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof,
  • the compound is of Formula (LB-I-d-l-l-A-H-l-B-VI-a**):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-Vll):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-VII-a):
  • the compound is of Formula (I-B-I-d-I- 1-A-I I-l-B-VTII): (I-B-I-d-I- 1 -A-H- 1 -B-V I II ), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-1 -B-VIII-a): (I-B-I-d-I- 1 -A-H-l -B-VIII-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I- 1 -A-H-l -B-VIII-a*): (I-B-I-d-I- 1 -A-H-l -B-VIII-a*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-VIII-a**): (I-B-I-d-I ⁇ 1 -A-H-l-B-VIII-a**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-IX): (I-B-I-d-I- 1 - A-H-1 -B-IX), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-IX-a): (I-B-I-d-I- 1 -A-H- 1 -B-IX-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l-B-IX-a*):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l-B-IX-a**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-X):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-1 -B-X- a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-X-a*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-l-l-A-H-l-B-X-a**): (I-B-I-d-I- 1 -A-H-l -B-X-a**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-X-a***):
  • the compound is of Formula (I-B-I-d-I- 1 -A-H- 1 -B-X-a****):
  • the compound is of Formula (i-B-I-d-I-l-A-H-l-B-Xl):
  • the compound is of Formula (I-B-I-d-I- 1 -A-H- 1-B-XI-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XI-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XI-a**):
  • the compound is of Formula (I-B-I-d-I-l-A-F 1- 1-B-IX):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XII-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-IX-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XII-a**):
  • the compound is of Formula (I-B-I-d-I- 1 -A-H- 1-B-XIII):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XIII-a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XlV):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l -B-XIV -a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XV):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XV-a): (I-B-I-d-I- 1 -A-H- 1 -B-XV-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I- 1- A-H- l -B-XVI):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVI-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVI-a**):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVII-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVII-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVII-a**):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-GG):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVIII):
  • the compound is of Formula (I-B-I-d-I- 1 -A-H- 1-B-XVIII-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVIII-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVIII-a**):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XVIII-a***):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l -B-XVIII- a****):
  • the compound is of Formula (I-B-l-d-I- l-A-H-l-B-XIX):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XIX-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XX):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XX-a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXI):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXI-a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXII):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXII-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXIII):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l -B-XXIII-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXIV):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXIV-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXV):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l -B-XXV -a):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l-B-GT):
  • each R 1 is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, aryl, heteroaryl.
  • the compound is of Formula (I-B-I-d-I-1 -A-H- 1-B-XX VI):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXVI-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXVII):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXVII-a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-GGG):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXVIII):
  • the compound is of Formula (I-B-I-d-I-l-A-H-l-B-XXVIII-a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXIX):
  • the compound is of Formula (I-B-I-d-I-I-A-H-l-B-XXIX-a):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXX):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l-B-XXX-a):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-l-B-XXXI):
  • the compound is of Formula (I-B-I-d-I-1 -A-H- 1-B-XXXI-a):
  • the compound is of Formula (I-B-l-d-I-l-A-H-l-B-XXXII):
  • the compound is of Formula (I-B ⁇ I ⁇ d-I-l-A-H-l-B-XXXII-a):
  • the compound is of Formula (I-B-l-d-I-l-A-H-l-B-XXXIII):
  • the compound is of Formula (1-B-I-d-I-l-A-H-l-B-XXXIII-a):
  • the compound is of Formula (I-B-I-d-I-1 -A-H-2):
  • the compound is of Formula (l-B-I-d-I-l-A-H-2-h):
  • the compound is of Formula (l-B-I-d-I-l-A-H-2-B):
  • the compound is of Formula (I-B4 ⁇ d44"A-H-2 ⁇ B ⁇ G):
  • each R B is independently selected from H, Cj-Ce alkyl, or two R B form oxo all other variables are as defined herein.
  • the compound is of Formula (I-B-I-d-I-l-A-H-2-B-I):
  • the compound is of Formula (I-B-I-d-I-l-A-H-2-B-I-a):
  • the compound is of Formula (I-B-I-d-I-l-A-H-2-B-I-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-2-B-I-a**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (l-B-I-d-I-l-A-H-3):
  • the compound is of Formula (I-B-I-d-I-l-A-H-3-h):
  • the compound is of Formula (I-B-I-d-I-l-A-H-3-B): (I-B-I-d-l-l-A-H-3-B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-3-B-I): (l-B-I-d-I-l ⁇ A-H-3-B-I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-A-H-3-B-I-a): (I-B-I-d-I-l-A-H-3-B-I-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof,
  • the compound is of Formula (I-B-I-d-l-l-A-H-3-B-I-a*):
  • the compound is of Formula (I-B-I-d-I-l-A-H-3-B-I-a**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I- 1 -B):
  • the compound is of Formula (I-B-I-d-I-l-B-H-1):
  • the compound is of Formula (I-B-I-d-I-1 -B-H-l -B):
  • the compound is of Formula (I-B-I-d-I-1 -B-H- 1-B-I):
  • the compound is of Formula (I-B-I-d-I-l-B-H-l-B-I-a):
  • the compound is of Formula (I-B-I-d-I-l-C-H-1):
  • the compound is of Formula (I-B-I-d-I-l-C-H-l-h):
  • the compound is of Formula (I-B-I-d-I-l -C-H-1 -B):
  • the compound is of Formula (I-B-l-d-I- l-C-H- l-B-I):
  • the compound is of Formula (I-B-I-d-I-l-C-H-l-B-I-a):
  • the compound is of Formula (I-B-I-d-I-l-C-H-l-B-I-a*):
  • the compound is of Formula (1-B-I-d-I-l-C-H-l-B-I-a**):
  • the compound is of Formula (I-B-I-d-I-l-D):
  • the compound is of Formula (I-B-I-d-I-l-D-H): (I-B-I-d-I-l-D-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (1-B-I-d-I-l-D-H-l): (I-B-I-d-I-l-D-H-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-D-H-1 -h): (I-B-I-d-I-l-D-H-l-h), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-D-H-l-B):
  • the compound is of Formula (1-B-I-d-I-l-D-H-l-B-G):
  • each R B is independently selected from H, Ci-C& alkyl, or two R B form oxo all other variables are as defined herein.
  • the compound is of Formula (I-B-I-d-l-l-D-H-l-B-I):
  • the compound is of Formula (I-B-I-d-I-l-D-H-l-B-I-a):
  • the compound is of Formula (I-B-I-d-I-l-D-H-l-B-I-a*): (I-B-I-d-I- 1 -D-H- 1 -B-I-a*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-D-H-l-B-I-a**):
  • the compound is of Formula (I-B-I-d-I-l-E):
  • the compound is of Formula (1-B-I-d-I-l-E-H-l):
  • the compound is of Formula (1-B-I-d-I-l-E-H-l-h):
  • the compound is of Formula (I-B-I-d-I-l-E-H-l-B):
  • the compound is of Formula (1-B-I-d-I-l-E-H-l-B-G):
  • each R B is independently selected from H, Cj-Ce alkyl, or two R B form oxo all other variables are as defined herein.
  • the compound is of Formula (1-B-I-d-I-l-E-H-l-B-l):
  • the compound is of Formula (I-B-I-d-I-l-E-II-l-B-I-a):
  • the compound is of Formula (I-B-I-d-I-l-E-H-l-B-I-a*):
  • the compound is of Formula (I-B-I-d-I- 1 -E-H-l -B-I-a**):
  • the compound is of Formula (I-B-I-d-I- 1 -E-H- 1 -B-II): (I-B-I-d-I-l-E-H-l-B-II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof,
  • the compound is of Formula (I-B-I-d-I- 1 -E-H- 1-B-II-a): (I-B-I-d-I- 1-E-H-l-B-lI-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (1-B-I-d-I-l-E-H-l-B-lI-a*): (i-B-I-d-I- 1 -E-H- 1 -B-II-a* ), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-l-E-H-l-B-II-a**):
  • the compound is of Formula (I-B-I-d-I-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-2- A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-I-d-I-2- A-H): (I-B-I-d-I-2-A-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (l-B-I-d-I-2-A-H-l):
  • the compound is of Formula (I-B-I-d-I-2-A-H-l-h):
  • the compound is of Formula (I-B-I-d-I-2-A-H-l-B):
  • the compound is of Formula (I-B-I-d-I-2-A-H- l-B-I):
  • the compound is of Formula (l-B-I-d-I-2-A-H-l-B-I-a):
  • the compound is of Formula (I-B-l-d-I-2-A-H-l-B-I-a**):
  • the compound is of Formula (I-B-II-d-I-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-II-d-I-1 -A):
  • the compound is of Formula (I-B-II-d-I-l-A-H-l ):
  • the compound is of Formula (I-B-II-d-I-l-A-H-l-B):
  • the compound is of Formula (1-B-II-d-I-l-A-H-l-B-I):
  • the compound is of Formula (I-B-II-d-I-l-A-H-l-B-I-a):
  • the compound is of Formula (I-B-II-d-I-l-A-H-l-B-I-a*):
  • the compound is of Formula (I-B-ll-d-I-l-A-H-l-B-I-a**):
  • the compound is of Formula (I-B ⁇ III-d-I-l):
  • the compound is of Formula (I-B-III-d-I-l-A):
  • the compound is of Formula (I-B-III-d-I- l-A-H):
  • the compound is of Formula (I-B-III-d-I-l-A-H-1): (I-B-III-d-I-l-A-H-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-111-d-I- l-A-H-l-B):
  • the compound is of Formula (I-B-III-d-I-l-A-H-l-B-I):
  • the compound is of Formula (I-B-III-d-I-l-A-H-l-B-I-a): (I-B-III-d-I- 1 - A-H- 1 -B-I-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-III-d-I-l-A-H-l-B-I-a*):
  • the compound is of Formula (I-B-III-d-l-l-A-H-l-B-I-a**):
  • the compound is of Formula (1-B-IV-d-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-IV-d-I-1):
  • the compound is of Formula (I-B-IV-d-I-l-A):
  • the compound is of Formula (I-B-IV-d-I-I ⁇ A-H);
  • the compound is of Formula (I-B ⁇ IV-d-I ⁇ l-A-H-l):
  • the compound is of Formula (I-B-IV-d-I-l-A-H-l-B-I-a):
  • the compound is of Formula (1-B-IV-d-I-l-A-H-l-B-I-a*):
  • the compound is of Formula (I-B-IV-d-I-l-A-H-l-B-I-a**):
  • the compound is of Formula (I-B-V-d-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-V-d-I-1):
  • the compound is of Formula (1-B-V-d-l-l-A):
  • the compound is of Formula (I-B-V-d-I-1 -A-H):
  • the compound is of Formula (I-B-V-d-I-1 -A-H- 1):
  • the compound is of Formula (I-B-V-d-I-1 -A-H- 1-B):
  • the compound is of Formula (I-B-V-d-I-1 -A-H- 1-B-I):
  • the compound is of Formula (I-B-V-d-I-1 -A-H- 1 -B-I-a):
  • the compound is of Formula (I-B-V-d-I-l-A-H-l-B-I-a*):
  • the compound is of Formula (I-B-V-d-I-l-A-H-l-B-I-a**):
  • the compound is of Formula (I-B-VI-d-I):
  • the compound is of Formula (I-B-VI-d-I- 1):
  • the compound is of Formula (I-B-VI-d-I- 1 -A):

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/US2022/052404 2021-12-09 2022-12-09 Inhibitors of menin-mll interaction Ceased WO2023107696A2 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
CA3240074A CA3240074A1 (en) 2021-12-09 2022-12-09 Inhibitors of menin-mll interaction
JP2024534648A JP2024545184A (ja) 2021-12-09 2022-12-09 メニン－ｍｌｌ相互作用の阻害剤
MX2024007069A MX2024007069A (es) 2021-12-09 2022-12-09 Inhibidores de la interacción menina-mll.
KR1020257029621A KR20250135350A (ko) 2021-12-09 2022-12-09 메닌-mll 상호작용의 저해제
US18/717,973 US20250163061A1 (en) 2021-12-09 2022-12-09 Inhibitors of menin-mll interaction
AU2022405438A AU2022405438A1 (en) 2021-12-09 2022-12-09 Inhibitors of menin-mll interaction
KR1020247022800A KR20240117133A (ko) 2021-12-09 2022-12-09 메닌-mll 상호작용의 저해제
EP22905177.6A EP4444300A4 (en) 2021-12-09 2022-12-09 MENINO-MLL INTERACTION INHIBITORS
CN202280090933.7A CN118647378A (zh) 2021-12-09 2022-12-09 梅嫩蛋白与mll相互作用的抑制剂
MX2025012108A MX2025012108A (es) 2021-12-09 2024-06-07 Inhibidores de la interaccion menina-mll
JOJO/P/2024/0130A JOP20240130A1 (ar) 2021-12-09 2024-06-10 مثبطات تفاعل منين-mll
JP2025137487A JP2025170331A (ja) 2021-12-09 2025-08-21 メニン－ｍｌｌ相互作用の阻害剤
AU2025230651A AU2025230651A1 (en) 2021-12-09 2025-09-09 Inhibitors of menin-mll interaction
US19/334,801 US20260022120A1 (en) 2021-12-09 2025-09-19 Inhibitors of MENIN-MLL Interaction

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163287716P 2021-12-09 2021-12-09
US63/287,716 2021-12-09
US202263306399P 2022-02-03 2022-02-03
US63/306,399 2022-02-03
US202263397322P 2022-08-11 2022-08-11
US63/397,322 2022-08-11

Related Child Applications (2)

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US18/717,973 A-371-Of-International US20250163061A1 (en) 2021-12-09 2022-12-09 Inhibitors of menin-mll interaction
US19/334,801 Division US20260022120A1 (en) 2021-12-09 2025-09-19 Inhibitors of MENIN-MLL Interaction

Publications (2)

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WO2023107696A2 true WO2023107696A2 (en) 2023-06-15
WO2023107696A3 WO2023107696A3 (en) 2023-07-27

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EP (1) EP4444300A4 (https=)
JP (2) JP2024545184A (https=)
KR (2) KR20250135350A (https=)
AU (2) AU2022405438A1 (https=)
CA (1) CA3240074A1 (https=)
JO (1) JOP20240130A1 (https=)
MX (2) MX2024007069A (https=)
TW (2) TW202529770A (https=)
WO (1) WO2023107696A2 (https=)

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Publication number Priority date Publication date Assignee Title
HK1246593A1 (zh) * 2015-06-04 2018-09-14 Kura Oncology, Inc. 用於抑制menin蛋白与mll蛋白的相互作用的方法及组合物
AU2016378579A1 (en) * 2015-12-22 2018-06-14 Vitae Pharmaceuticals, Inc. Inhibitors of the menin-MLL interaction
EP3684361A4 (en) * 2017-09-20 2021-09-08 Kura Oncology, Inc. SUBSTITUTED INHIBITORS OF MENIN-MLL AND METHOD OF USING

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JP2024545184A (ja) 2024-12-05
JP2025170331A (ja) 2025-11-18
KR20240117133A (ko) 2024-07-31
US20260022120A1 (en) 2026-01-22
MX2024007069A (es) 2024-08-22
EP4444300A4 (en) 2026-03-18
AU2025230651A1 (en) 2025-09-25
JOP20240130A1 (ar) 2024-06-10
TW202529770A (zh) 2025-08-01
MX2025012108A (es) 2025-11-03
US20250163061A1 (en) 2025-05-22
TW202337435A (zh) 2023-10-01
CA3240074A1 (en) 2023-06-15
EP4444300A2 (en) 2024-10-16
KR20250135350A (ko) 2025-09-12
WO2023107696A3 (en) 2023-07-27
AU2022405438A1 (en) 2024-06-20

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