WO2020012337A1 - 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases - Google Patents

3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases Download PDF

Info

Publication number
WO2020012337A1
WO2020012337A1 PCT/IB2019/055807 IB2019055807W WO2020012337A1 WO 2020012337 A1 WO2020012337 A1 WO 2020012337A1 IB 2019055807 W IB2019055807 W IB 2019055807W WO 2020012337 A1 WO2020012337 A1 WO 2020012337A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
dione
methyl
piperidine
cyclohexyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2019/055807
Other languages
English (en)
French (fr)
Inventor
Rohan Eric John Beckwith
Simone BONAZZI
Artiom CERNIJENKO
Fupeng Ma
Nathaniel F. WARE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Priority to KR1020217003431A priority Critical patent/KR20210031923A/ko
Priority to ES19782692T priority patent/ES2963695T3/es
Priority to BR122022012745-2A priority patent/BR122022012745B1/pt
Priority to EP19782692.8A priority patent/EP3820574B1/en
Priority to MX2021000310A priority patent/MX2021000310A/es
Priority to CA3103674A priority patent/CA3103674A1/en
Priority to AU2019301947A priority patent/AU2019301947B2/en
Priority to JP2021500409A priority patent/JP7462606B2/ja
Priority to CN201980041638.0A priority patent/CN112334194B/zh
Priority to BR112021000049-6A priority patent/BR112021000049B1/pt
Publication of WO2020012337A1 publication Critical patent/WO2020012337A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present disclosure relates to 3-(5-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione compounds and compositions and their use for the treatment of IKAROS Family Zinc Finger 2 (IKZF2)-dependent diseases or disorders or where reduction of IKZF2 or IKZF4 protein levels can ameliorate a disease or disorder.
  • IKAROS Family Zinc Finger 2 IKZF2
  • IKZF4 protein levels can ameliorate a disease or disorder.
  • IKAROS Family Zinc Finger 2 (also known as Helios) is one of the five members of the Ikaros family of transcription factors found in mammals.
  • IKZF2 contains four zinc finger domains near the N-terminus which are involved in DNA binding and two zinc finger domains at the C-terminus which are involved in protein dimerization.
  • IKZF2 is about 50% identical with Ikaros family members, Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4) with highest homology in the zinc finger regions (80%+ identity).
  • IKZF1 Ikaros
  • IKZF3 Aiolos
  • Eos IKZF4
  • IKZF5 The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds a different DNA site than other Ikaros family members and does not readily heterodimerize with the other Ikaros family proteins.
  • IKZF2, IKZF1 and IKZF3 are expressed mainly in hematopoietic cells while IKZF4 and IKZF5 are expressed in a wide variety of tissues.
  • IKZF2 is believed to have an important role in the function and stability of regulatory T cells (Tregs). IKZF2 is highly expressed at the mRNA and protein level by regulatory T-cell populations. Knockdown of IKZF2 by siRNA has been shown to result in downregulation of FoxP3 and to impair the ability of isolated human CD4+ CD25+ Tregs to block T-cell activation in vitro. Moreover, overexpression of IKZF2 in isolated murine Tregs has been shown to increase expression of Treg related markers such as CD103 and GITR and the IKZF2 overexpressing cells showed increased suppression of responder T-cells. IKZF2 has also been found to bind the promoter of FoxP3, the defining transcription factor of the regulatory T-cell lineage, and to affect FoxP3 expression.
  • IKZF2 knockout mutant mice develop autoimmune disease by 6-8 months of age, with increased numbers of activated CD4 and CD8 T cells, follicular helper T cells, and germinal center B cells. This observed effect is believed to be cell intrinsic, as Rag2-/- mice given bone marrow from IKZF2 knockout mice, but not bone marrow from IKZF2+/+ develop autoimmune disease.
  • IKZF2 affects regulatory T-cell function
  • mice in which IKZF2 was deleted only in FoxP3 expressing cells FoxP3-YFP-Cre Heliosfl/fl.
  • the results showed that the mice also develop autoimmune disease with similar features as observed in the whole animal IKZF2 knockout.
  • pathway analysis of a CHIP-SEQ experiment has also suggested that IKZF2 is affecting expression of genes in the STAT5/IL-2Ra pathway in regulatory T-cells.
  • Ikaros isoforms which lack the DNA binding regions have been shown to be associated with multiple human haematological malignancies. Recently, mutations in the IKZF2 gene, which lead to abnormal splicing variants, have been identified in adult T-cell leukemias and low hypodiploid acute lymphoblastic leukemia. It has been proposed that these isoforms, which are capable of dimerization, have a dominant negative effect on Ikaros family transcription factors which primes the development of lymphomas. IKZF2 knockout mutants that survive into adulthood do not develop lymphomas, supporting this hypothesis (Asanuma, S., et al., (2013), Cancer Sci. 104: 1097-1106; Zhang, Z., et al., (2007), Blood 109:2190-2197; Kataoka, D., et al., (2015), Nature Genetics 47: 1304-1315.)
  • CTLA4 Anti-CTLA4 antibodies are used in the clinic to target Tregs in tumors.
  • targeting CTLA4 often causes systemic activation of T-effector cells, resulting in excessive toxicity and limiting therapeutic utility.
  • CTCAE Common Terminology for Adverse Events
  • An IKZF2-specific degrader has the potential to focus the enhanced immune response to areas within or near tumors providing a potentially more tolerable and less toxic therapeutic agent for the treatment of cancer.
  • the compounds of the disclosure have use as therapeutic agents, particularly for cancers and related diseases.
  • the compounds of the disclosure have IKZF2 degrader activity, preferably having such activity at or below the 50 mM level, and more preferably having such activity at or below the 10 pM level.
  • the compounds of the disclosure have degrader activity for IKZF2 that is selective over one or more of IKZF1, IKZF3, IKZF4, and/or IKZF5.
  • the compounds of the disclosure have degrader activity for both IKZF2 and IKZF4.
  • the compounds of the disclosure have usefulness in treating cancer and other diseases for which such degrader activity would be beneficial for the patient.
  • the present disclosure provides novel IKZF2 degraders useful for the treatment of cancer and other diseases.
  • a first aspect of the present disclosure relates to compounds of Formula (G)
  • Xi and X2 are each independently H, (Ci-Cijalkyl, (Ci-C 6 )alkoxy, (Ci-Cijhaloalkyl,
  • R x is H or D
  • R2 is H, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, or (C3-C6)cycloalkyl; or
  • R2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • each R 3 is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy,
  • R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S; or
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, and -NH 2 ;
  • each R 4 is (Ci-C 6 )alkyl, (Ci-Ce)alkoxy, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, halogen, -OH, or
  • R5 is -ORe or -NR7R7’;
  • Re is H, (Ci-C 6 )alk l, (Ci-C 6 )haloalkyl, -C(0)(Ci-C 6 )alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • R7 and Rr are each independently H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6- membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn; or
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9 ; or
  • R2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (G-G)alkyl.
  • each Rs is -C(0)OH, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Ri 0 ;
  • each R9 is independently at each occurrence (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkyl, (Ci- C6)haloalkoxy, halogen, -OH, CN, -NR12R13, or -NH 2 , wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, and 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; or
  • each Rio is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-Ce)alkoxy, (Ci-C 6 )haloalkoxy, halogen, -OH, CN, or -NH 2 ; or
  • each Rn is independently at each occurrence (G-G)alkyl.
  • R12 and R13 are each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S;
  • n and ml are each independently 0, 1 or 2;
  • nl 0, 1, 2, or 3;
  • n2 and n3 are each independently 1 or 2;
  • each s and n is independently 1, 2, or 3, wherein s + n is ⁇ 4;
  • the present disclosure relates to compounds of Formula (G) having the structure of Formula (I):
  • R2 is H, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, or (C3-C6)cycloalkyl; or
  • R2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • each R 3 is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy,
  • R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S; or
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, -OH, CN, and -NH 2 ;
  • each R 4 is (Ci-C 6 )alkyl, (Ci-Ce)alkoxy, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, halogen, -OH, or -NH 2 ;
  • R 6 is H, (Ci-C 6 )alk l, (Ci-C 6 )haloalkyl, -C(0)(Ci-C 6 )alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • R7 and R7 ’ are each independently H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6- membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs; or
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9 ; or
  • R 2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, -OH, CN, and -NH 2 ;
  • each Rs is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Ri 0 ;
  • each Rs is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 ; or
  • each Rio is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 ; or
  • n and ml are each independently 0, 1 or 2;
  • nl 0, 1, 2, or 3;
  • each s and n is independently 1, 2, or 3, wherein s + n is ⁇ 4; or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the hydrogens in the compound of Formula (G) or Formula (I) are present in their normal isotopic abundances.
  • the hydrogens are isotopically enriched in deuterium (D), and in a particularly preferred aspect of the invention the hydrogen at position R x is enriched in D, as discussed in more detail concerning isotopes and isotopic enrichment below.
  • compositions comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is useful in the treatment of IKZF2- dependent diseases or disorders.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the pharmaceutical composition is useful in the treatment of IKZF2-dependent diseases or disorders.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • compositions comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is useful in the treatment of diseases or disorders affected by the reduction of IKZF2 protein levels.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of a disease or disorder affected by the reduction of IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • the present disclosure relates to a method of degrading IKZF2.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method of modulating IKZF2 protein levels.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method of reducing IKZF2 protein levels.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method of decreasing IKZF2 protein levels.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method of reducing the proliferation of a cell.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and reducing IKZF2 protein levels.
  • the present disclosure relates to a method of reducing IKZF2 protein levels.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method of treating cancer.
  • the method comprises administering to the patient in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma Ewing’s sar
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple -negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of an IKZF2 -dependent disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient in the manufacture of a medicament for treating of an IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a method for treating an IKZF2-dependent disease or disorder comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure relates to a method for treating an IKZF2-dependent disease or disorder comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating an IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a method for treating a disease or disorder that is affected by the modulation of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method for treating a disease or disorder that is affected by a decrease in IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method for treating a disease or disorder that is affected by the reduction of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the modulation of IKZF2 protein levels.
  • a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment of a disease or disorder that is affected by the reduction of IKZF2 protein levels.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by a decrease in IKZF2 protein levels.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the modulation of IKZF2 protein levels.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of IKZF2 protein levels.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by a decrease in IKZF2 protein levels.
  • the present disclosure relates to a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with the modulation of IKZF2 protein levels.
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma soft tissue s
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to the use of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the modulation of IKZF2 protein levels.
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma soft tissue s
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with the reduction of IKZF2 protein levels.
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma soft tissue s
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of IKZF2 protein levels.
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma soft tissue s
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • Another aspect of the present disclosure relates to a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with a decrease in IKZF2 protein levels.
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma soft tissue s
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with a decrease in IKZF2 protein levels.
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Ewing’s sarcoma soft tissue s
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • Another aspect of the present disclosure relates to a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triplenegative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triplenegative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • GIST gastrointestinal stromal tumor
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triplenegative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of cancer, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triplenegative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triplenegative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • GIST gastrointestinal stromal tumor
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triplenegative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating cancer, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).
  • the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyos
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • Another aspect of the present disclosure relates to a method of treating a disease or disorder that is affected by the reduction of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosar
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to a method of treating a disease or disorder that is affected by a decrease of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyos
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the modulation of IKZF2 protein levels
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcom
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of IKZF2 protein levels
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by a decrease of IKZF2 protein levels
  • the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcom
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the modulation of IKZF2 levels, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcom
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • Another aspect of the present disclosure relates to the use of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of IKZF2 protein levels, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcom
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by a decrease in IKZF2 protein levels, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sar
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • carcinoid acute myelogenous leukemia
  • GIST gastrointestinal stromal tumor
  • the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (ms
  • the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to a method of treating a disease or disorder that is affected by the reduction of IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to a method of treating a disease or disorder that is affected by a decrease in IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the modulation of IKZF2 protein levels, wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of IKZF2 protein levels, wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by a decrease in IKZF2 protein levels, wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the modulation of IKZF2 protein levels wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of IKZF2 protein levels wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by a decrease in IKZF2 protein levels wherein the disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a cancer for which the immune response is deficient or an immunogenic cancer.
  • Another aspect of the present disclosure relates to a method of treating an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to a method of treating an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a method of treating an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a method of treating an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to a method of treating an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a method of treating an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels wherein the decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a method of treating a disease or disorder by reducing IKZF2 protein levels comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a method of treating a disease or disorder by reducing IKZF2 protein levels comprising the step of administering to a subject in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a method of treating a disease or disorder by modulating IKZF2 protein levels comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a method of treating a disease or disorder by modulating IKZF2 protein levels comprising the step of administering to a subject in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a method of treating a disease or disorder by decreasing IKZF2 protein levels comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a method of treating a disease or disorder by decreasing IKZF2 protein levels comprising the step of administering to a subject in need thereof a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels wherein decreasing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels wherein decreasing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by decreasing IKZF2 protein levels, wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by decreasing IKZF2 protein levels wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a IKZF2-dependent disease or disorder by reducing IKZF2 protein levels, wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a IKZF2-dependent disease or disorder by reducing IKZF2 protein levels, wherein reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a IKZF2-dependent disease or disorder by modulating IKZF2 protein levels, wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a IKZF2-dependent disease or disorder by modulating IKZF2 protein levels, wherein modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels, wherein decreasing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a IKZF2-dependent disease or disorder by decreasing IKZF2 protein levels, wherein decreasing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by reducing IKZF2 protein levels, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by reducing IKZF2 protein levels, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by modulating IKZF2 protein levels, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by modulating IKZF2 protein levels, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by decreasing IKZF2 protein levels, wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder by decreasing IKZF2 protein levels, wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by reducing IKZF2 protein levels wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by modulating IKZF2 protein levels wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by decreasing IKZF2 protein levels wherein decreasing IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein reduction of IKZF2 protein levels treats the disease or disorder.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein modulation of IKZF2 protein levels treats the disease or disorder.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder by decreasing IKZF2 protein levels, wherein decreasing of IKZF2 protein levels treats the disease or disorder.
  • the compounds according to the disclosure are formulated into pharmaceutical compositions comprising an effective amount, preferably a pharmaceutically effective amount, of a compound according to the disclosure or salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient or carrier.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating an IKZF2-dependent disease or disorder.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with modulating IKZF2 protein levels.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with the modulation of IKZF2 protein levels.
  • the administration of the compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is performed orally, parentally, subcutaneously, by injection, or by infusion.
  • the present disclosure provides degraders of IKZF2 that are therapeutic agents in the treatment of diseases such as cancer and metastasis, in the treatment of diseases affected by the modulation of IKZF2 protein levels, and in the treatment IKZF2-dependent diseases or disorders.
  • the disease or disorder that can be treated by the compounds of the present disclosure is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • the disease or disorder that can be treated by the compounds of the present disclosure is selected from nonsmall cell lung cancer (NSCLC), melanoma, triple -negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC nonsmall cell lung cancer
  • TNBC triple -negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).
  • GIST gastrointestinal stromal tumor
  • the disease or disorder that can be treated by the compounds of the present disclosure is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • the IKZF2-dependent disease or disorder is a cancer for which the immune response is deficient or an immunogenic cancer.
  • the present disclosure provides agents with novel mechanisms of action toward IKZF2 proteins in the treatment of various types of diseases including cancer and metastasis, in the treatment of diseases affected by the modulation of IKZF2 protein levels, and in the treatment IKZF2-dependent diseases or disorders.
  • the present disclosure provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with IKZF2 proteins. DETAILED DESCRIPTION OF THE DISCLOSURE
  • the present disclosure relates to compounds and compositions that are capable of modulating IKZF2 protein levels.
  • the disclosure features methods of treating, preventing, or ameliorating a disease or disorder in which IKZF2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the methods of the present disclosure can be used in the treatment of a variety of IKZF2-dependent diseases and disorders by modulating IKZF2 protein levels. Modulation of IKZF2 protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metathesis, and other IKZF2-dependent diseases or disorders.
  • the compounds of the disclosure have use as therapeutic agents, particularly for cancers and related diseases.
  • the compounds of the disclosure have IKZF2 degradation activity, preferably having such activity at or below the 50 mM level, and more preferably having such activity at or below the 10 mM level.
  • the compounds of the disclosure have degrader activity for IKZF2 that is selective over one or more of IKZF1, IKZF3, IKZF4, and/or IKZF5.
  • the compounds of the disclosure have degrader activity for both IKZF2 and IKZF4. The compounds of the disclosure have usefulness in treating cancer and other diseases for which such degradation activity would be beneficial for the patient.
  • the present disclosure provides novel IKZF2 degraders useful for the treatment of cancer and other diseases.
  • R a , R b , R x , Ri, R , Xi, and X are as described herein above.
  • (Ci-Cio)alkyl means an alkyl group or radical having 1 to 10 carbon atoms.
  • the last named group is the radical attachment point, for example,“alkylaryl” means a monovalent radical of the formula alkyl-aryl-, while “arylalkyl” means a monovalent radical of the formula aryl-alkyl-.
  • “alkylaryl” means a monovalent radical of the formula alkyl-aryl-
  • arylalkyl means a monovalent radical of the formula aryl-alkyl-.
  • designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have 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.
  • the term“optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH 2 CN, -0-(Ci-C 6 )alkyl, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, -0-(C 2 -C 6 )alkenyl, -0-(C 2 -C 6 )alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, - 0P(0)(0H) 2 , -0C(0)(Ci-C 6 )alkyl, -C(0)(Ci-C 6 )alkyl, -0C(0)0(Ci-C 6 )alkyl, -NH 2 , -NH((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 cycloalkyl may 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” means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic orbicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group is 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, -CN, -0-(Ci-C 6 )alkyl, (Ci-C 6 )alkyl, -0-(C 2 -C 6 )alkenyl, -0-(C 2 -C 6 )alkynyl, (C2-C 6 )alkenyl, (C2-C 6 )alkynyl, -OH, -0P(0)(0H) 2 , -0C(0)(Ci-C 6 )alkyl, -C(0)(Ci-C 6 )alkyl, -C(0)(Ci-C 6 )alkyl, -
  • Exemplary ring systems of these aryl 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 aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S.
  • 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- c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]
  • the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring.
  • exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro- IH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.
  • Halogen or“halo” mean fluorine, chlorine, bromine, or iodine.
  • Alkyl means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms.
  • Examples of a (Ci-C 6 )alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • Alkoxy means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal“O” in the chain, e.g., -O(alkyl).
  • alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • Alkenyl means 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, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted and may be straight or branched.
  • Alkynyl means 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, isobutynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • Cycloalkyl or“carbocyclyl” means a monocyclic or polycyclic saturated carbon ring containing 3-18 carbon atoms.
  • Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof.
  • a (CVCx)cvcloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
  • a cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbomane).
  • Heterocyclyl or“heterocycloalkyl” means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S) and wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms.
  • the heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl
  • Haloalkyl means an alkyl group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • Haloalkoxy means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • “Cyano” means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g.,
  • Amino means a substituent containing at least one nitrogen atom (e.g., -NH 2 ).
  • Prodrug or“prodrug derivative” mean a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
  • prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds.
  • the prodmg is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
  • Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5:“Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp.
  • “Pharmaceutically acceptable prodmg” as used herein means a prodmg of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
  • Salt means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound.
  • Salts of the compounds of the present disclosure can be synthesized from the parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • “Pharmaceutically acceptable salt” means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use.
  • the term includes pharmaceutically -acceptable acid addition salts and pharmaceutically-acceptable base addition salts.
  • the compounds of the present disclosure are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sch, 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.
  • “Pharmaceutically-acceptable acid addition salt” means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fum
  • “Pharmaceutically-acceptable base addition salt” means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium
  • Solvate means a complex of variable stoichiometry formed by a solute, for example, a compound of Formula (G) or Formula (I)) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • “Hydrate” means a solvate wherein the solvent molecule(s) is/are water.
  • the compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and prodrugs and may include oxidized sulfur atoms or quatemized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmaceutically acceptable forms thereof. Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.
  • “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.
  • the term includes stereoisomers and geometric isomers.
  • Stepoisomer or“optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure, which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof.
  • the compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.
  • stereoisomers can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
  • individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art. “Enantiomers” means a pair of stereoisomers that are non-superimposable mirror images of each other.
  • Diastereoisomers or“diastereomers” mean optical isomers, which are not mirror images of each other.
  • Racemic mixture or“racemate” mean a mixture containing equal parts of individual enantiomers.
  • Non-racemic mixture means a mixture containing unequal parts of individual enantiomers.
  • Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.
  • enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like.
  • one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer.
  • one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.
  • racemic form of dmg may be used, it is often less effective than administering an equal amount of enantiomerically pure dmg; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent.
  • ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the dmg is less than that of the pure S-isomer).
  • the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic.
  • one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.
  • Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization.
  • A“patient” or“subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus.
  • the subject is a primate.
  • the subject is a human.
  • an“effective amount” or“therapeutically effective amount” when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • “pharmaceutically effective amount” or“therapeutically effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician.
  • the amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.
  • the term“pharmaceutical composition” refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
  • Carried encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • a subject is“in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).
  • the term“inhibit”, “inhibition”, or“inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term“treat”,“treating”, or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • the term“prevent”,“preventing”, or“prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • disorder means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administering means 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.
  • solvates and hydrates are generally considered compositions.
  • the compounds of the disclosure and the formulas designating the compounds of the disclosure are understood to only include the stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
  • “Stable compound” or“stable structure” means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent.
  • a compound, which would have a“dangling valency” or is a carbanion is not a compound contemplated by the disclosure.
  • the term“about” or“approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
  • Cancer means any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, and the like.
  • cancers include, but are not limited to, mesothelioma, leukemias, and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T- cell lymphotrophic vims (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin’s lymphoma, Burkitt lymphoma, adult T- cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma.
  • CCL cutaneous T-cell
  • myelodisplastic syndrome childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms’ tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal, and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non-small cell), breast cancer (e.g., triple-negative breast cancer (TNBC)), pancreatic cancer, melanoma, and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin’s syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer.
  • childhood solid tumors such as brain tumors, neuroblastoma, retinoblasto
  • Additional exemplary forms of cancer which may be treated by the subject compounds include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.
  • cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retin
  • “Simultaneously” or“simultaneous” when referring to a method of treating or a therapeutic use means with a combination of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time.
  • “Separately” or“separate” when referring to a method of treating or a therapeutic use means with a combination of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time.
  • therapeutic administration“over a period of time” means, when referring to a method of treating or a therapeutic use with a combination of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times.
  • the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins.
  • a one of the active ingredients i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)
  • a one of the active ingredients i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)
  • Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and the one or more second agents the therapeutic administration over a period of time could be such that a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is administered once a day and the one or more second agent(s) is administered once every four weeks.
  • the compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • IKZF2-dependent disease or disorder means any disease or disorder which is directly or indirectly affected by the modulation of IKZF2 protein levels.
  • IKZF4-dependent disease or disorder means any disease or disorder which is directly or indirectly affected by the modulation of IKZF4 protein levels.
  • the present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of modulating IKZF2 protein levels, which are useful for the treatment of diseases and disorders associated with modulation of IKZF2 protein levels.
  • the disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for reducing or decreasing IKZF2 protein levels.
  • the compounds of Formula (G) or Formula (I) have the structure of Formula (la) or Formula (la-1):
  • the compounds of Formula (G) or Formula (I) have the structure of Formula (lb) or Formula (Ib-1):
  • the compounds of Formula (F) have the structure of Formula (la-2) or Formula
  • the compounds of Formula (F) have the structure of Formula (Ib-2) or Formula (Ib-3):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (lc) or Formula (lc-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Id) or Formula (Id-1):
  • the compounds of Formula (G) or Formula (I) have the structure of Formula (Ie) or Formula (Ie-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (If) or Formula (If-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Ig) or Formula (Ig-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Ih) or Formula (Ih- 1 ) :
  • the compounds of Formula (G) or Formula (I) have the structure of Formula (Ii) or Formula (Ii-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Ij) or Formula (Ij-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Ik) or Formula (Ik-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (II) or Formula (11-1):
  • the compounds of Formula (G) or Formula (I) have the structure of Formula (Im) or Formula (Im-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (In) or Formula (In-1):
  • the compounds of Formula (F) or Formula (I) have the stmcture of Formula (Io) or Formula (Io-l):
  • the compounds of Formula (F) or Formula (I) have the stmcture of Formula (Ip) or Formula (Ip-1):
  • the compounds of Formula (G) or Formula (I) have the structure of Formula (Iq) or Formula (Iq-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Ir) or Formula (Ir-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (Is) or Formula (Is-1):
  • the compounds of Formula (F) or Formula (I) have the structure of Formula (It) or Formula (It-1):
  • Ri is
  • Xi is H, (Ci-C3)alkyl, (Ci-C 6 )alkoxy, (Ci- C3)haloalkyl, (Ci-C 6 )haloalkoxy, (C3-C7)cycloalkyl, halogen, CN, -OH, or -NH 2 .
  • Xi is H, (Ci-C3)alkyl, (Ci-Ce)alkoxy, (Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, halogen, CN, -OH, or -NH 2 .
  • Xi is H, (G-G)alkvl.
  • Xi is H, (G-G)alkvl. (G-G)alkoxy. (G-G)haloalkyl, (Ci-Ci/haloalkoxy, or halogen.
  • Xi is H, halogen, CN, -OH, or -NH 2 .
  • Xi is H, (G-G)alkyl, (G-G)haloalkvl. halogen, CN, -OH, or -NH 2 .
  • Xi is H, (G-G)alkyl, (G-G)haloalkyl, halogen, -OH, or -NH 2 .
  • Xi is H, (Ci-Ci/alkyl, halogen, -OH, or -NH 2 .
  • Xi is H, halogen, -OH, or -NH 2 .
  • Xi is H.
  • X 2 is H, (Ci-C 3 )alkyl, (Ci-G,)alkoxy. (G- C 3 )haloalkyl, (Ci-C 6 )haloalkoxy, (C 3 -C 7 )cycloalkyl, halogen, CN, -OH, or -NH 2 .
  • X 2 is H, (Ci-C 3 )alkyl, (Ci-G,)alkoxy.
  • X 2 is H, (Ci-C 4 )alkyl, (G-G)alkoxy. (Ci-C 4 )haloalkyl, (Ci-C 4 )haloalkoxy, (G- C 7 )cycloalkyl, or halogen.
  • X 2 is H, (Ci-C 4 )alkyl, (G-G)alkoxy. (Ci-C 4 )haloalkyl, (Ci-C 4 )haloalkoxy, or halogen.
  • X 2 is H, halogen, CN, -OH, or -NH 2 .
  • X 2 is H, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, halogen, CN, -OH, or -NH 2 .
  • X 2 is H, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, halogen, -OH, or -NH 2 .
  • X 2 is H, (Ci-C 4 )alkyl, halogen, -OH, or -NH 2 .
  • X 2 is H, halogen, -OH, or -NH 2 .
  • X 2 is H.
  • Xi is H and X 2 is (Ci-C3)alkyl, (G-G)alkoxy.
  • Xi is (Ci-C 3 )alkyl, (G-G)alkoxy.
  • R x is D. In another embodiment, R x is H.
  • R 2 is H, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, or (G- C 6 )cycloalkyl.
  • R 2 is (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, or (C 3 -C 6 )cycloalkyl.
  • R 2 is H, (Ci-C 3 )alkyl, or (C 3 -C 6 )cycloalkyl.
  • R 2 is H, (G- C 3 )alkyl, or (Ci-C 3 )haloalkyl.
  • R 2 is H or (Ci-C 3 )alkyl. In another embodiment, R 2 is H, methyl, ethyl, n-propyl, or isopropyl. In yet another embodiment, R 2 is H, methyl, or ethyl. In another embodiment, R 2 is H or methyl.
  • R 2 and R 7 together with the nitrogen atoms to which they are attached form a 7-membered heterocycloalkyl ring. In another embodiment, R 2 and R 7 together with the nitrogen atoms to which they are attached form a 6-membered heterocycloalkyl ring.
  • each R 3 is independently at each occurrence (G- C 3 )alkyl, (Ci-C 3 )alkoxy, (G-C 3 )haloalkyl, (G-G)haloalkoxy, halogen, CN, -OH, or -NH 2 .
  • R3 is independently at each occurrence (Ci-C3)alkyl, (Ci-G)alkoxy, (G-G)haloalkyl, (G- C 3 )haloalkoxy, or halogen.
  • R 3 is independently at each occurrence halogen, CN, -OH, or -NH 2 .
  • R 3 is independently at each occurrence (G-C 3 )alkyl, (G- G)alkoxy, (G-G)haloalkyl, or (G-G)haloalkoxy.
  • R3 is independently at each occurrence (Ci-C3)alkyl, (Ci-C3)haloalkyl, halogen, CN, -OH, or -NH 2 .
  • R3 is independently at each occurrence (Ci-C3)alkyl, (Ci-C3)haloalkyl, halogen, or CN.
  • R3 is independently at each occurrence (Ci-C3)alkyl, halogen, or CN.
  • R3 is independently at each occurrence (Ci-C3)alkyl or (Ci-C3)haloalkyl. In yet another embodiment, R3 is independently at each occurrence (Ci-C3)alkyl or CN. In another embodiment, R3 is independently at each occurrence (Ci-C3)alkyl. In yet another embodiment, R3 is independently at each occurrence methyl, ethyl, n-propyl, or isopropyl.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3- C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 5- or 6-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C4-C7)cycloalkyl or a 5- or 6-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S .
  • two R3 together with the carbon atoms to which they are attached form a (C5-C7)cycloalkyl or a 5- or 6-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl.
  • two R3 together with the carbon atoms to which they are attached form a (C4-C7)cycloalkyl.
  • two R3 together with the carbon atoms to which they are attached form a (C5-C7)cycloalkyl.
  • two R3 together with the carbon atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together when on adjacent carbon atoms form a phenyl or a 5-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together when on adjacent carbon atoms form a phenyl or a 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together when on adjacent carbon atoms form a phenyl.
  • two R3 together when on adjacent carbon atoms form a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R3 together when on adjacent carbon atoms form a 5-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, two R3 together when on adjacent carbon atoms form a 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl, or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3- C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or two R3 together when on adjacent carbon atoms form a phenyl.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7- membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or two R3 together when on adjacent carbon atoms form a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalky 1 or two R3 together when on adjacent carbon atoms form a phenyl.
  • two R3 together with the carbon atoms to which they are attached form a (C4-C7)cycloalkyl or two R3 together when on adjacent carbon atoms form a phenyl.
  • two R3 together with the carbon atoms to which they are attached form a (C5-C7)cycloalkyl or two R3 together when on adjacent carbon atoms form a phenyl.
  • two R3 together with the carbon atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S or two R3 together when on adjacent carbon atoms form a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S or two R3 together when on adjacent carbon atoms form a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S or two R3 together when on adjacent carbon atoms form a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together when attached to the same carbon atom form a (C3- C7)spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 when on adjacent carbon atoms form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R3 together with the carbon atoms to which they are attached form a bridged (C3- C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, and halogen.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, and halogen.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S.
  • each R 4 is (Ci-C 6 )alkyl, (Ci-C3)alkoxy, (Ci- C3)haloalkyl, (Ci-C3)haloalkoxy, halogen, -OH, or -NH 2 .
  • R 4 is (Ci-C 6 )alkyl, (Ci- C3)alkoxy, (Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, or halogen.
  • R is (Ci-Ce)alkyl, (Ci-C3)alkoxy, (Ci-C3)haloalkyl, or (Ci-C3)haloalkoxy.
  • R 4 is (Ci-Ci/alkyl, (Ci- C3)haloalkyl, or halogen.
  • R t is halogen, -OH, or -NH 2 .
  • R 4 is (Ci-C 6 )alkyl, (Ci-C3)haloalkyl, halogen, -OH, or -NH 2 .
  • R 4 is (Ci-Ci/alkyl, (Ci- C3)haloalkyl, halogen, or -OH.
  • R 4 is (Ci-C 6 )alkyl or (Ci-C3)haloalkyl.
  • R 4 is (Ci-C 6 )alkyl.
  • R 5 is -ORe. In another embodiment, R 5 is -NR 7 R 7’ .
  • Rr is H, (Ci-C3)alkyl, (Ci-C3)haloalkyl, -C(0)(Ci- C3)alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is (Ci-C3)alkyl, (Ci-C3)haloalkyl, -C(0)(Ci-C 3 )alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (G,-C
  • s is H, (Ci-C3)alkyl, (Ci-C3)haloalkyl, -C(0)(Ci-C 3 )alkyl, (C3- C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C6-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alk l is substituted with one to three substituents each independently selected from (C 6 -Cio)ary 1 and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is (Ci-C3)alkyl, (Ci-C3)haloalkyl, -C(0)(Ci-C 3 )alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-G ⁇ i )aryl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Re is H, (Ci-C3)alkyl, (Ci-C3)haloalkyl, or -C(0)(Ci-C 3 )alkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is (Ci-C 6 )alkyl, (Ci-C3)haloalkyl, or -C(0)(Ci-C 3 )alkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (G-Gn)arvl and 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is H, (Ci-C3)alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (G-Gn)arvl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is H, (Ci- C3)alkyl, (C3-C7)cycloalkyl, or 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (G-Gn)arvl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is H, (Ci-C3)alkyl, (G-Gn)arvl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Re is H, (Ci-C3)alkyl, (C3-C7)cycloalkyl, or (C 6 -Cio)aryl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is H, (Ci-C3)alkyl, (C3-C7)cycloalkyl, or (G-Gn)arvl. wherein the alkyl is optionally substituted with one to three (C 6 -Cio)aryl.
  • Rr is H, (Ci-C3)alkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S , wherein the alkyl is optionally substituted with one to three substituents each independently selected from (G-Gn)arvl and 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • Rr is H, (Ci-C3)alkyl, (C3-C7)cycloalkyl, or (G-Gn)arvl. wherein the alkyl is optionally substituted with one to three (C 6 -Cio)aryl.
  • R7 is H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R 7 is H, (Ci- Ce)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Gn)arvl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R 11 .
  • R 7 is (Ci-C 6 )alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-G ⁇ i) aryl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R 7 is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3- C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R7 is H, (Ci-Ci/alkyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6- membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 is (Ci- C 6 )alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (Ce-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aiyl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs.
  • R7 is (Ci-C6)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R7 is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • R7 is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, or 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, and heterocycloalkyl are optionally substituted with one to four Rn.
  • R7 is H, (Ci-Ci/alkyl, (G,-C
  • heteroaryl comprising 1-3 heteroatoms selected from O, N, and S , wherein the alkyl is optionally substituted with one to three Rs and wherein the aryl and heteroaryl are optionally substituted with one to four Rn.
  • R7 is (Ci-C6)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs.
  • R 7 is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, or 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 is H, (Ci-Ci/alkyl, (C 6 -Cio)aryl, or 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S , wherein the alkyl is optionally substituted with one to three Rs.
  • R7 is H, (Ci-Ci/alkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the heterocycloalkyl and heteroaryl are optionally substituted with one to four Rn.
  • R7 is H, (Ci-C6)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, or (G-Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, or (C 6 - Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl and aryl are optionally substituted with one to four Rn.
  • R7 is H, (Ci-Ci/alkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, or (C 6 -Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 is H, (Ci-Ci/alkyl, (C3- C7)cycloalkyl, or (C6-Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 ' is H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R 7' is H, (Ci- Ce)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Gn)arvl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R 11 .
  • R 7' is (Ci-C 6 )alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-G ⁇ i) aryl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R 7' is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3- C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R 7 ⁇ is H, (Ci-Ci/alkyl, (Ci-C 6 )haloalkyl, (C3-C7)cycloalkyl, 5- or 6- membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 ’ is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 ’ is (Ci- Ce)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Gn)arvl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 ’ is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-G ⁇ i) aryl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs.
  • R 7' is (Ci-C 6 )alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn.
  • R 7' is H, (G-G)alkyl.
  • R7 ' is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, or 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, and heterocycloalkyl are optionally substituted with one to four Rn.
  • R7 ' is H, (Ci-Ci/alkyl, (C6-Cio)aryl, or 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S , wherein the alkyl is optionally substituted with one to three Rs and wherein the aryl and heteroaryl are optionally substituted with one to four Rn.
  • R7 ’ is (Ci-C6)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • R 7 ⁇ is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 ⁇ is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, or 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 ’ is H, (Ci-Ci/alkyl, (C 6 -Cio)aryl, or 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S , wherein the alkyl is optionally substituted with one to three Rs.
  • R7 ' is H, (Ci-Ci/alkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the heterocycloalkyl and heteroaryl are optionally substituted with one to four Rn.
  • R7 ' is H, (Ci-C6)alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, or (G-Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs.
  • R 7 ' is H, (Ci-Ci/alkyl, (C3-C7)cycloalkyl, or (C 6 - Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl and aryl are optionally substituted with one to four Rn.
  • R7 ’ is H, (Ci-Ci/alkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs.
  • R7 ’ is H, (Ci-Ci/alkyl, (Ci-C3)haloalkyl, (C3-C7)cycloalkyl, or (G-Cio)aryl, wherein the alkyl is optionally substituted with one to three Rs.
  • R7’ is H, (G-G)alkyl.
  • R 7 ’ is H or (Ci-Ci/alkyl, wherein the alkyl is optionally substituted with one to three Rs.
  • Rr is H or (Ci-Ci/alkyl, wherein the alkyl is substituted with one to three Rs.
  • R7 ’ is H or (Ci-C6)alkyl.
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ⁇ together with the nitrogen atom to which they are attached form a 6- or 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 5-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 7- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 .
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, and halogen.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, and halogen.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, and halogen.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, and halogen.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (G-G)alkyl. (Ci-C6)haloalkyl, and halogen.
  • R 3 and R 7 together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, substituted with one to four substituents each independently selected from (G-G)alkyl.
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S.
  • each R 8 is -C(0)OH, (C3-C7)cycloalkyl, 4- to 7- membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is -C(0)OH, (C3-C7)cycloalkyl or 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three Rio.
  • each R 8 is -C(0)OH, (G,-C
  • each R 8 is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is (C3- C7)cycloalkyl or 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three Rio.
  • each R 8 is (G-Go)aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is -C(0)0H, (C3-C7)cycloalkyl or (G-Go)aryl.
  • each R 8 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is -C(0)OH, (C3-C7)cycloalkyl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is -C(0)0H, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or (G,-C
  • each R 8 is (C3-C7)cycloalkyl or (G-Go)aryl, wherein the cycloalkyl and aryl are optionally substituted with one to three Rio.
  • each R 8 is 4- to 7- membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is (C3- C7)cycloalkyl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heteroaryl are optionally substituted with one to three Rio.
  • each R 8 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or (C 6 -Cio)aryl, wherein the heterocycloalkyl and aryl are optionally substituted with one to three Rio.
  • each R 8 is -C(0)OH, or (C3-C7)cycloalkyl optionally substituted with one to three Rio. In yet another embodiment, each R 8 is (C3-C7)cycloalkyl substituted with one to three Rio. In another embodiment, each R 8 is -C(0)0H, or (C3-C7)cycloalkyl. In yet another embodiment, each R 8 is (C 6 -Cio)aryl optionally substituted with one to three Rio. In another embodiment, each R 8 is -C(0)0H, or (C 6 -Cio)aryl substituted with one to three Rio. In yet another embodiment, each R 8 is -C(0)0H, or (C 6 - Cio)aryl. In another embodiment, each R 8 is -C(0)0H.
  • each R 8 is (C3-C7)cycloalkyl optionally substituted with one to three Rio. In yet another embodiment, each R 8 is (C3-C7)cycloalkyl substituted with one to three Rio. In another embodiment, each R 8 is (C3-C7)cycloalkyl. In yet another embodiment, each R 8 is (G-Go)aryl optionally substituted with one to three Rio. In another embodiment, each R 8 is (G-Go)aryl substituted with one to three Rio. In yet another embodiment, each R 8 is (C 6 -Cio)aryl.
  • each R 8 is -C(0)0H, or 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three Rio.
  • each R 8 is -C(0)0H, or 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, substituted with one to three Rio.
  • each R 8 is -C(0)0H, or 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 8 is -C(0)0H, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three Rio. In another embodiment, each R 8 is -C(0)0H, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, substituted with one to three Rio. In yet another embodiment, each R 8 is -C(0)0H, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 8 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three Rio. In yet another embodiment, each R 8 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, substituted with one to three Rio. In another embodiment, each R 8 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 8 is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three Rio.
  • each R 8 is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, substituted with one to three Rio. In yet another embodiment, each R 8 is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 9 is independently at each occurrence halogen, (Ci-Ci/alkyl, (G-Gialkoxv. (G-Gihaloalkvl. (G-Gihaloalkoxv.
  • each R 9 is independently at each occurrence halogen, (G-Gialkvl.
  • each R is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkyl, (Ci- C4)haloalkoxy, CN, -NR I2 R I3 , or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (G-G )aiyl. and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, CN, or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkyl, (Ci- C4)haloalkoxy, halogen, CN, -NR I2 R I3 , or -OH, wherein the alkoxy is optionally substituted with (C3- C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, and (C 6 -Cio)aryl.
  • each R 9 is independently at each occurrence halogen, (Ci- Ci/alkyl, (Ci-Ci/alkoxy, (Ci-Ci/haloalkyl, (Ci-Ci/haloalkoxy, halogen, CN, or -OH, wherein the alkoxy is optionally substituted with (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, and (C 6 -Cio)aryl.
  • each R 9 is independently at each occurrence halogen, (Ci -Chalky 1.
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkyl, (Ci- C4)haloalkoxy, halogen, CN, or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl, (CV,-C
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, CN, or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, CN, or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl and 4- to 7- membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, CN, or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (CV,-C
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, CN, or -OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • each R 9 is independently at each occurrence halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, CN, or - OH, wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl and (Ce-Cio/aiyl.
  • eachR 9 is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C3)haloalkyl, halogen, CN, -OH, or -NH 2 .
  • each R 9 is independently at each occurrence (Ci- C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, or -NH 2 .
  • each R 9 is independently at each occurrence (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, or halogen.
  • each R 9 is independently at each occurrence (Ci-Ci/alkyl, (Ci-C 6 )haloalkyl, halogen, or -OH. In yet another embodiment, each R 9 is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, or -NH 2 In another embodiment, each R 9 is independently at each occurrence halogen, -OH, or -NH 2 In yet another embodiment, each R 9 is independently at each occurrence (Ci-C3)alkyl, (Ci-C3)haloalkyl, or halogen. In another embodiment, each R 9 is independently at each occurrence (Ci-C 6 )alkyl or halogen. In yet another embodiment, each R 9 is independently at each occurrence halogen.
  • two R 9 together with the atoms to which they are attached form a (C5-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together with the atoms to which they are attached form a (C5-C7)cycloalkyl.
  • two R 9 together with the atoms to which they are attached form a (CVG,)cycloalkyl.
  • two R 9 together with the atoms to which they are attached form a (C6-C7)cycloalkyl.
  • two R 9 together with the atoms to which they are attached form a (C ⁇ )cycloalkyl. In another embodiment, two R 9 together with the atoms to which they are attached form a (C 6 )cycloalkyl. In yet another embodiment, two R 9 together with the atoms to which they are attached form a (C7)cycloalkyl.
  • two R 9 together with the atoms to which they are attached form a 5- to 7- membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together with the atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two R 9 together when attached to the same carbon atom form a (C5- C7)spirocycloalkyl or a 5- to 7-membered spiroheterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R 9 when on adjacent carbon atoms form a (C5-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • two R 9 together with the carbon atoms to which they are attached form a bridged (C5- C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • each Rio is independently at each occurrence (Ci- Cejalkyl, (Ci-C 6 )haloalkyl, (Ci-Ce)alkoxy, (Ci-C 6 )haloalkoxy, halogen, -OH, CN, or -NH 2 .
  • each Rio is independently at each occurrence (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, halogen, or CN.
  • each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 6 )alkoxy, halogen, or CN.
  • each Rio is independently at each occurrence halogen, -OH, CN, or -NH 2 .
  • each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )haloalkoxy, or halogen.
  • each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci- C 3 )haloalkyl, (Ci-C 6 )alkoxy, or halogen. In another embodiment, each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, or halogen. In yet another embodiment, each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, or CN. In another embodiment, each Rio is independently at each occurrence (Ci-C 3 )alkyl or (Ci-C 3 )haloalkyl.
  • each Rio is independently at each occurrence halogen or CN. In another embodiment, each Rio is independently at each occurrence (Ci-C 3 )alkyl or halogen. In yet another embodiment, each Rio is independently at each occurrence (Ci-C 3 )haloalkyl.
  • each Rio is independently at each occurrence (Ci-C 6 )alkyl, (Ci- C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 .
  • each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, halogen, or CN.
  • each Rio is independently at each occurrence halogen, -OH, CN, or -NH 2 .
  • each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, or halogen.
  • each Rio is independently at each occurrence (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, or CN. In another embodiment, each Rio is independently at each occurrence (Ci-C3)alkyl or (Ci-C3)haloalkyl. In yet another embodiment, each Rio is independently at each occurrence halogen or CN. In another embodiment, each Rio is independently at each occurrence (Ci-C 3 )alkyl or halogen. In yet another embodiment, each Rio is independently at each occurrence (Ci-C 3 )haloalkyl.
  • two Rio together with the atoms to which they are attached form a (C 5 -C 7 )cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S, optionally substituted with one to three substituents each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 .
  • two Rio together with the atoms to which they are attached form a (C 5 -C 7 )cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together with the atoms to which they are attached form a (C 5 -C 7 )cycloalkyl.
  • two Rio together with the atoms to which they are attached form a (CVG,)cycloalkyl.
  • two Rio together with the atoms to which they are attached form a (C 6 -C 7 )cycloalkyl.
  • two Rio together with the atoms to which they are attached form a (C ⁇ )cycloalkyl.
  • two Rio together with the atoms to which they are attached form a (G cycloalkyl.
  • two Rio together with the atoms to which they are attached form a (C 7 )cycloalkyl.
  • two Rio together with the atoms to which they are attached form a 5- to 7- membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together with the atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together with the atoms to which they are attached form a 7-membered heterocycloalkyl ring comprising 1-2 heteroatoms selected from O, N, and S.
  • two Rio together when attached to the same carbon atom form a (C5- C7)spirocycloalkyl or a 5- to 7-membered spiroheterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three substituents each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 .
  • two Rio when on adjacent carbon atoms form a (C5-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three substituents each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 .
  • two Rio together with the carbon atoms to which they are attached form a bridged (C5- C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three substituents each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 .
  • each Rn is independently at each occurrence (Ci- C’rialkyl. (Ci-Cijhaloalkyl, halogen, -OH, CN, or -NH 2 .
  • each Rn is independently at each occurrence (Ci-C-Oalkyl. (Ci-Cijhaloalkyl, or halogen.
  • each Rn is independently at each occurrence halogen, -OH, CN, or -NH 2 .
  • each Rn is independently at each occurrence (Ci-Cijalkyl, (Ci-Cijhaloalkyl, halogen, -OH, or -NH 2 .
  • each Rn is independently at each occurrence (Ci-C-Oalkyl. halogen, -OH, CN, or -NH 2 . In another embodiment, each Rn is independently at each occurrence (Ci-C-Oalkyl. or halogen. In another embodiment, each Rn is independently at each occurrence (Ci-Cijhaloalkyl or halogen. In another embodiment, each Rn is independently at each occurrence halogen.
  • each Rn is independently at each occurrence (Ci-C’rialkyl. (Ci- C’rihaloalkyl. (Ci-G,)alkoxy. (Ci-C 6 )haloalkoxy, halogen, -OH, CN, or -NH 2 .
  • each Rn is independently at each occurrence (Ci-C’rialkvl. (Ci-Cijhaloalkyl, (Ci-C’rialkoxv. (Ci-Cijhaloalkoxy, halogen, -OH, CN, or - NH 2 .
  • each Rn is independently at each occurrence (Ci-C-Oalkyl.
  • each Rn is independently at each occurrence (Ci-C’rialkyl. (Ci-Cijhaloalkyl, or halogen. In another embodiment, each Rn is independently at each occurrence halogen, -OH, CN, or -NH 2 . In another embodiment, each Rn is independently at each occurrence (Ci-C-Oalkyl. (Ci-Cijhaloalkyl, halogen, -OH, or -NH 2 .
  • each Rn is independently at each occurrence (Ci-Cijalkyl, halogen, -OH, CN, or -NH 2 .
  • each R 11 is independently at each occurrence (Ci-C-Oalkyl. or halogen.
  • each Rn is independently at each occurrence (Ci-Ci/haloalkyl or halogen.
  • each Rn is independently at each occurrence halogen.
  • R12 is selected from selected from (Ci-C 6 )alkyl and (Ci-C 6 )haloalkyl.
  • R12 is selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, and (C 6 -Cio)aryl.
  • R12 is selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R12 is selected from (C3-C7)cycloalkyl, (G,-C
  • R12 is selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • R12 is selected from (C3-C7)cycloalkyl and 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • R12 is selected from (C6-Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R12 is selected from (C3-C7)cycloalkyl and (C 6 -Cio)aryl.
  • R12 is selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R12 is selected from (C3-C7)cycloalkyl and 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R12 is selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S and (C 6 -Cio)aryl.
  • R12 is (C3-C7)cycloalkyl.
  • R12 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • R12 is (C 6 -Cio)aryl.
  • R12 is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from selected from (Ci-C6)alkyl and (Ci-C 6 )haloalkyl.
  • R13 is selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, and (C 6 -Cio)aryl.
  • R13 is selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from (C3-C7)cycloalkyl, (G-Gn)arvl. and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from (C3-C7)cycloalkyl and 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from (G,-C
  • R13 is selected from (C3-C7)cycloalkyl and (C 6 -Cio)aryl.
  • R13 is selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from (C3-C7)cycloalkyl and 5- or 6- membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is selected from 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S and (C 6 -Cio)aryl.
  • R13 is (C3-C7)cycloalkyl.
  • R13 is 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S.
  • R13 is (C 6 -Cio)aryl.
  • R13 is 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • m is 0, 1, or 2. In another embodiment, m is 0 or 1. In yet another embodiment, m is 1 or 2. In another embodiment, m is 0. In yet another embodiment, m is 1. In another embodiment, m is 2.
  • ml is 0, 1, or 2. In another embodiment, ml is 0 or 1. In yet another embodiment, ml is 1 or 2. In another embodiment, ml is 0. In yet another embodiment, ml is 1. In another embodiment, ml is 2.
  • nl is 0, 1, or 2. In another embodiment, nl is 1, 2, or 3. In another embodiment, nl is 0 or 1. In another embodiment, nl is 1 or 2. In another embodiment, nl is 2 or 3. In another embodiment, nl is 0. In another embodiment, nl is 1. In another embodiment, nl is 2. In another embodiment, nl is 3.
  • n2 is 1. In another embodiment, n2 is 2.
  • n3 is 1. In another embodiment, n3 is 2.
  • n2 is 1 and n3 is 1. In another embodiment, n2 is 2 and n3 is 1. In yet another embodiment, n2 is 1 and n3 is 2. In another embodiment, n2 is 1 or 2 and n3 is 1. In yet another embodiment, n2 is 1 or 2 and n3 is 2. In another embodiment, n2 is 1 and n3 is 1 or 2. In yet another embodiment, n2 is 2 and n3 is 1 or 2.
  • each s and n is independently 1, 2, or 3, wherein s + n is ⁇ 4. In another embodiment, each s and n is independently 1 or 2, wherein s + n is ⁇ 4. In another embodiment, each s and n is independently 2 or 3, wherein s + n is ⁇ 4. In another embodiment, s is 1 and n is 1. In another embodiment, s is 2 and n is 2. In another embodiment, s is 1 and n is 2. In another embodiment, s is 2 and n is 1. In another embodiment, s is 3 and n is 1. In another embodiment, s is 1 and n is 3.
  • methyl, and R5 is -NR7R7’.
  • R5 is -OR6.
  • R 5 is -ORi,.
  • Xi is H, and X2 is H.
  • R 5 is -ORr,. and Xi is H.
  • R 5 is -ORr,. and X 2 is H.
  • R5 is -NR7R7 ’ .
  • R5 is -NR7R7 ’
  • Xi is H
  • X 2 is H.
  • R 5 is -NR7R7 ’
  • Xi is H.
  • R 5 is -NR7R7 ’
  • X 2 is H.
  • nl is 1 or 2 and R 2 is H or methyl.
  • nl is 1 or 2
  • R 2 is H or methyl
  • R 5 is -ORr
  • nl is 1 or 2
  • R 2 is H or methyl
  • R 5 is -NR 7 R 7’ .
  • nl is 1 or 2 and R5 is -OR6.
  • nl is 1 or 2 and R 5 is -NR 7 R 7’ . In some embodiments of the formulae above,
  • R5 is -OR 6 .
  • R5 is -NR7R7 ’ .
  • R 2 is H or methyl and R 5 is -NR 7 R 7’ .
  • R 2 is H or methyl and R5 is -ORe.
  • ml is 0 and R 5 is -NR 7 R 7’ .
  • ml is 0 and R 5 is -ORi.
  • R 2 is H or methyl.
  • R 5 is -ORi.
  • R5 is -NR7R7’.
  • methyl, and R5 is -NR7R7’.
  • nl is 1 or 2 and ml is 0.
  • nl is 1 or 2
  • ml is 0, and R 5 is -ORe.
  • nl is 1 or 2
  • ml is 0, and R 5 is -NR 7 R 7’ .
  • nl is 1 or 2
  • ml is 0, and R 2 is H or methyl.
  • nl is 1 or 2
  • ml is 0,
  • R 2 is H or methyl, and
  • R 5 is - OR 6 .
  • nl is 1 or 2
  • ml is 0,
  • R 2 is H or methyl, and
  • R 5 is -
  • ml is 0 and R 2 is H or methyl.
  • ml is 0, R 2 is H or methyl, and R 5 is -ORe.
  • ml is 0, R 2 is H or methyl, and R 5 is -NR 7 R 7 ’. In some embodiments of the formulae above,
  • R5 is -OR 6 .
  • R5 is -NR7R7’.
  • nl is 1 or 2 and ml is 2.
  • nl is 1 or 2
  • ml is 2
  • R 5 is -OR 6 .
  • nl is 1 or 2
  • ml is 2
  • R 5 is -NR 7 R 7 ’.
  • ml is 2 and R 5 is -OR 6 .
  • ml is 2 and R 5 is -NR 7 R 7 ’.
  • R2 is H or methyl
  • R2 is H or methyl
  • R5 is -ORi.
  • R 2 is H or methyl
  • R 5 is -NR 7 R 7 ’.
  • R5 is -OR6.
  • m is 0 or 1.
  • R 5 is -OR 6 .
  • R5 is -NR7R7 ’ .
  • n is 2, s is 1 or 2, and m is 0 or 1.
  • n is 2, s is 1 or 2, m is 0 or 1, and R 2 is H or methyl. In some embodiments of the formulae above, n is 2, s is 1 or 2, m is 0 or 1, and R 5 is -OR 6 .
  • n is 2, s is 1 or 2, m is 0 or 1, and R 5 is -NR 7 R 7 ’. In some embodiments of the formulae above, n is 2, s is 1 or 2, m is 0 or 1, R 2 is H or methyl, and R5 is -OR 6 .
  • n is 2, s is 1 or 2, m is 0 or 1, R 2 is H or methyl, and R 5 is -NR 7 R 7’ .
  • n is 2, s is 1 or 2 and R 2 is H or methyl.
  • n is 2, s is 1 or 2 and R 5 is -ORi.
  • n is 2, s is 1 or 2 and R 5 is -NR 7 R 7’ .
  • n is 2, s is 1 or 2, R 2 is H or methyl, and R 5 is -ORi. In some embodiments of the formulae above, n is 2, s is 1 or 2, R 2 is H or methyl, and R 5 is -NR 7 R 7’ . In some embodiments of the formulae above, m is 0 or 1 and R 2 is H or methyl.
  • m is 0 or 1
  • R 2 is H or methyl
  • R 5 is -ORi
  • m is 0 or 1
  • R 2 is H or methyl
  • R 5 is -NR 7 R 7’ .
  • m is 0 or 1 and R 5 is -ORi.
  • m is 0 or 1 and R 5 is -NR 7 R 7’ .
  • R 2 is H, ml is 0, R 5 is -ORr,. and Ri is H or (Ci-Ci/alkyl optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3
  • heteroatoms selected from O, N, and S.
  • R 5 is -ORe
  • Ri is H or (Ci-C 6 )alkyl optionally substituted with one to three (C 6 -Cio)aryl.
  • substituents each independently selected from (G,-C
  • Ri is H or (G-Gdalkyl optionally substituted with one to three (C 6 -Cio)aryl, and nl is 2.
  • R 5 is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci-
  • R 5 is -NR7R7 ’
  • R7 is H or (G-G alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (G-G)alkyl optionally substituted with one to three Rs
  • Rs is (G-Gn)arvl optionally substituted with one or two Rio.
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G-Gn)aiyl optionally substituted with one or two Rio
  • nl is 1 or 2.
  • optionally substituted with one to three Rs, R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (C6-Cio)aryl optionally substituted with one or two Rio, and nl is 1.
  • Ri is
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (C 6 -Cio)aryl optionally substituted with one or two Rio, and nl is 2.
  • C6)alkyl optionally substituted with one to three Rs, R7 ’ is H or (G-G)alkyl optionally substituted with one
  • Ri is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • Ri is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • nl is 1 or 2.
  • Ri is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (C 6 -Cio)aryl, and nl is 1.
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (C 6 -Cio)aryl, and nl is 1.
  • Ce)alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (G-Ce)alkyl optionally substituted with one to three Rg
  • Rs is (Ce-Go)aryl
  • nl is 2.
  • methyl, and ml is 0.
  • Ri is
  • Ri is methyl, ml is 0, and R5 is -ORi. In another embodiment, Ri is
  • Ri is H or (Ci-C 6 )alkyl optionally substituted with one to three substituents each independently selected from (G,-C
  • Ri is
  • R 5 is -ORr,.
  • R 6 is H or (G-Ci/alkyl optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, and nl is 1 or 2.
  • Ri is
  • Ri is H or (G-G)alkyl optionally substituted with one to three substituents each independently selected from (C6-Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, and nl is 1.
  • Ri is methyl, ml is 0, R 5 is -ORr,.
  • R 6 is H or (Ci-C 6 )alkyl optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, and nl is 2.
  • Ri is H or (Ci-C 6 )alkyl optionally substituted with one to three (C 6 -Cio)aryl. In another embodiment, Ri is
  • R 5 is -ORr,.
  • R 6 is H or (Ci-C 6 )alkyl optionally substituted with
  • nl is 1 or 2.
  • methyl ml is 0, R5 is -ORi,.
  • Ri is H or (C i-CV,)alk> l optionally substituted with one to three (C6-Cio)aryl, and nl is
  • methyl, ml is 0, R 5 is -ORi, 5 is H or (Ci- Ce)alkyl optionally substituted with one to three (G,-C
  • methyl, ml is 0, and R 5 is -NR 7 R 7’ .
  • methyl, ml is 0, R 5 is -NR 7 R 7’ , and R 7 is H or (Ci-
  • Ri is methyl, ml is 0, R5 is -NR7R7 ’ , R7 is H or (Ci-C6)alkyl optionally substituted with one to three Rs, and R7 ’ is H or (Ci-C6)alk l optionally substituted with one to three Rs.
  • Ri is
  • R 5 is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (X
  • Cio aryl optionally substituted with one or two Rio.
  • Cio aryl optionally substituted with one or two Rio.
  • R 5 is -NR7R7 ’
  • R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (C i-CV,)alkyl optionally substituted with one to three Rs
  • Rs is (CVC in)aiyl optionally substituted with
  • nl is 1 or 2.
  • methyl is 0,
  • R 5 is -NR 7 R 7’
  • R 7 is H or (Ci-C 6 )alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • nl is 1.
  • methyl ml is 0, R 5 is -NR 7 R 7 , R 7 is
  • R7 is H or (Ci-C6)alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (CVC ii )aiyl optionally substituted with one or two Rio
  • nl is 2.
  • R5 is -NR7R7 ’
  • R7 is H or (Ci-C 6 )alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with
  • R 5 is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci- Ce)alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • R 5 is -NR7R7 ’
  • R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three
  • R 5 is -NR7R7 ’
  • R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • methyl, ml is 0, R 5 is -ORi,. and Ri is H or (Ci-
  • Ce)alkyl optionally substituted with one to three substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • substituents each independently selected from (C 6 -Cio)aryl and 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.
  • methyl, ml is 0, R 5 is -ORi, and Ri is H or (Ci-Ci/alkyl
  • Ri is H or (C i -CV,)alkyl optionally substituted with one to three (C6-
  • Cio aryl
  • nl is 1 or 2.
  • methyl ml is 0, R 5 is -ORe, Ri is H or (Ci-Ci/alkyl optionally substituted with one to three (C6-Cio)aryl, and nl is 1.
  • Ri is H or (Ci-Ci/alkyl optionally substituted with one to three (C6-Cio)aryl, and nl is 1.
  • methyl, ml is 0, R 5 is -ORi, Ri is H or (Ci-Ci/alkyl optionally substituted with one to three (C6-Cio)aryl, and nl is 2.
  • R5 is -NR7R7 ’ .
  • r methyl, ml is 0,
  • R 5 is - NR 7 R 7’ , and
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs.
  • Ri is -NR7R7 ’ .
  • R 5 is -NR 7 R 7’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (C i-Co)alkyl optionally substituted with one to three Rs.
  • methyl, ml is 0, R 5 is -NR 7 R 7’ , R 7 is H or (Ci- C6)alkyl optionally substituted with one to three Rs, and Rs is (C6-Cio)aryl optionally substituted with one or two Rio.
  • nl is 1 or 2.
  • methyl ml is 0,
  • R 5 is -NR 7 R 7 ’,
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (C6-Cio)aryl optionally substituted with one or two Rio, and nl is 1.
  • R 5 is -NR 7 R 7 ’
  • R 7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (C6-Cio)aryl optionally substituted with one or two Rio
  • nl is 1.
  • R2 is H or methyl, ml is 0, R 5 is -NR7R7 ’ , R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Re is (C 6 -Cio)aryl optionally substituted with one or two Rio, and nl is 2.
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, and Rs is (C 6 -Cio)aryl.
  • R 5 is -NR7R7 ’
  • R7 is H or (Ci-C 6 )alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted
  • R2 is H or methyl, ml is 0, R5 is -NR7R7 ’ , R7 is H or (Ci-C6)alkyl optionally substituted with one to three Rs, R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (G,-C
  • R5 is -NR7R7 ’
  • R7 is H or (Ci-C6)alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (G,-C
  • methyl, ml is 0, R5 is -NR7R7 ’ , R7 is H or (Ci- C 6 )alkyl optionally substituted with one to three Rs, R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, Rs is (Ce-Cio)aryl, and nl is 2.
  • R5 is -NR7R7 ’
  • R7 is H or (Ci- C 6 )alkyl optionally substituted with one to three Rs
  • R 7’ is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • Rs is (Ce-Cio)aryl
  • nl is 2.
  • methyl, m is 0, n
  • R5 is -OR6.
  • methyl m is 0, n is 1, s is 1,
  • R5 is -OR 6
  • Ri is H or (Ci-Ci/alkyl optionally substituted with one to three (C6-Cio)aryl.
  • n 0, n is 1, s is 1, R5 is -NR7R7 ’ , R7 is H or (Ci-G,)alkyl optionally substituted with one to three Rs, R7 ’ is H or (Ci-C 6 )alkyl optionally substituted with one to three Rs, and Rs is (C 6 -Cio)aryl.
  • R5 is -NR7R7 ’
  • R7 is H or (Ci-G,)alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-C 6 )alkyl optionally substituted with one to three Rs
  • Rs is (C 6 -Cio)aryl.
  • methyl methyl
  • m 0, n
  • R5 is -OR6.
  • methyl m is 0, n is 2, s is 1,
  • R5 is -OR 6
  • Ri is H or (Ci-Ci/alkyl optionally substituted with one to three (C6-Cio)aryl.
  • methyl, m is 0, n is 2, s is 1, R 5 is -NR 7 R 7’ , R 7 is
  • n 0, n is 2, s is 1, R5 is -NR7R7 ’ , R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs, R7 ’ is H or (Ci-G,)alkyl optionally substituted with one to three Rs, and Rs is (C6-Cio)aryl.
  • R5 is -NR7R7 ’
  • R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-G,)alkyl optionally substituted with one to three Rs
  • Rs is (C6-Cio)aryl.
  • methyl methyl
  • m 0, n
  • R5 is -OR6.
  • methyl m is 0, n is 2, s is 2,
  • R5 is -OR 6
  • Ri is H or (Ci-Ci/alkyl optionally substituted with one to three (C6-Cio)aryl.
  • R 5 is -NR7R7 ’
  • R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rs
  • R7 ’ is H or (Ci-G,)alkyl optionally substituted with one to three Rs
  • Rs is (C 6 -Cio)aryl.
  • methyl, m is 0, n
  • R5 is -NR7R7 ’ .
  • methyl m is 0, n is 2, s is 1 or 2, R 5 is -NR7R7 ’ , and R7 is H or (Ci-Ci/alkyl optionally substituted with one to three
  • Rg In another embodiment, methyl, m is 0, n is 2, s is 1 or 2, R 5 is -
  • R7 is H or (Ci-C 6 )alkyl optionally substituted with one to three Rg, and R7 ⁇ is H or (Ci-Ci/alkyl
  • R 5 is -NR7R7 ’
  • R7 is H or (Ci-Ci/alkyl optionally substituted with one to three Rg
  • R7 ⁇ is H or (Ci-Ci/alkyl optionally substituted with one to three Rg
  • Rg is (C 6 -Cio)aryl.
  • 3 )alkyl, and ml is 0. In another embodiment, 3)alkyl, ml is 0, and R5 is -NR7R7 ’ . In another embodiment,
  • 3)alkyl, ml is 0, and R5 is -NR7R7 ’ .
  • ml is 0, and R5 is -NR7R7 ’ .
  • nl is 1 or 2.
  • -NR7R7 ’ , R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9, and nl is 1.
  • nl is 1.
  • R2 is H, ml is 0, R 5 is -NR7R7 ’ , R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9 and nl is 2.
  • Embodiment 1 A compound of Formula (G), wherein:
  • Xi and X2 are each independently H, (G-G)alkvl. (Ci-G,)alkoxy. (Ci-Cijhaloalkyl,
  • R x is H or D
  • R2 is H, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, or (C3-C6)cycloalkyl; or
  • R 2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • each R 3 is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy,
  • R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S; or
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, -OH, CN, and -NH 2 ;
  • each R is (G-G)alkvl. (G-G)alkoxy. (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, halogen, -OH, or
  • R5 is -ORe or -NR7R7’
  • Ri is H, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -C(0)(Ci-C 6 )alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-G ( ) aiyl. or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents each independently selected from (G,-C
  • R7 and Rr are each independently H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6- membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Rn; or
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9 ; or
  • R2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (G-G)alkyl.
  • each Rs is -C(0)OH, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Ri 0 ;
  • each R9 is independently at each occurrence (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkyl, (G- C6)haloalkoxy, halogen, -OH, CN, -NR12R13, or -NH 2 , wherein the alkoxy is optionally substituted with one to three substituents independently selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • each Rio is independently at each occurrence (G-C 6 )alkyl, (G-C 6 )haloalkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )haloalkoxy, halogen, -OH, CN, or -NH 2 ; or
  • each Rn is independently at each occurrence (G-G)alkyl.
  • R I2 and R13 are each independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (G,-C
  • n and ml are each independently 0, 1 or 2;
  • nl 0, 1, 2, or 3;
  • n2 and n3 are each independently 1 or 2;
  • each s and n is independently 1, 2, or 3, wherein s + n is ⁇ 4;
  • Embodiment 2 The compound of embodiment 1, having a Formula (I), wherein:
  • R x is H or D
  • R 2 is H, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, or (C3-C6)cycloalkyl; or
  • R 2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • each R 3 is independently at each occurrence (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, halogen, CN, -OH, or -NH 2 ; or
  • R3 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or two R3 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S; or
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, -OH, CN, and -NH 2 ;
  • each R 4 is (Ci-C 6 )alkyl, (Ci-Ce)alkoxy, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, halogen, -OH, or
  • R5 is -ORe or -NR7R7’
  • R 6 is H, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -C(0)(Ci-C 6 )alkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S, (G-G»)aryl.
  • R7 and R7 ’ are each independently H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6- membered heterocycloalkyl comprising 1-3 heteroatoms selected from O, N, and S,
  • (C 6 -Cio)aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three Rs; or
  • R7 and R7 ’ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four R 9 ; or
  • R2 and R7 together with the nitrogen atoms to which they are attached form a 6- or 7-membered heterocycloalkyl ring;
  • R3 and R7 together with the nitrogen and carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl ring optionally comprising 1 to 2 additional heteroatoms selected from O, N, and S, optionally substituted with one to four substituents each independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, -OH, CN, and -NH 2 ;
  • each Rs is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from O, N, and S, (C 6 -Cio)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four Ri 0 ;
  • each Rs is independently at each occurrence (Ci-Ce)alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 ; or
  • each Rio is independently at each occurrence (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, halogen, -OH, CN, or -NH 2 ; or
  • n and ml are each independently 0, 1, or 2;
  • nl 0, 1, 2, or 3;
  • each s and n is independently 1, 2, or 3, wherein s + n is ⁇ 4;
  • Embodiment 3 The compound of Embodiment 1 or 2, wherein
  • Embodiment 4 The compound of any one of Embodiments 1-3, wherein nl is 1 or 2.
  • Embodiment 5 The compound of any one of Embodiments 1-4, wherein ml is 0.
  • Embodiment 6 The compound of any one of Embodiments 1-5, wherein ml is 2.
  • Embodiment 7 The compound of Embodiment 1, wherein
  • Embodiment 8 The compound of Embodiment 7, wherein n is 2 and s is 1 or 2.
  • Embodiment 9 The compound of Embodiment 7 or 8, wherein m is 0 or 1.
  • Embodiment 10 The compound of Embodiment 1 or 2, having a Formula (la), Formula (lb), Formula (la-1) or Formula (Ib-1); or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Embodiment 11 The compound of Embodiment 1 or 2, having a Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ic- 1), Formula (Id-1), Formula (Ie-1), Formula (If-1), Formula (Ig-1), Formula (Ih-1), Formula (Ii-1), or Formula (Ij-1); or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Embodiment 12 The compound of Embodiment 1 or 2, having a Formula (Ik), Formula (II), Formula (Im), Formula (In), Formula (Io), Formula (Ip), Formula (Ik-1), Formula (11-1), Formula (Im-1), Formula (In-1), Formula (Io-l), or Formula (Ip-1), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Embodiment 13 The compound of any one of Embodiments 1-12, wherein R 5 is -OR 6 .
  • Embodiment 14 The compound of any one of Embodiments 1-12, wherein R 5 is -NR 7 R 7’ .
  • Embodiment 15 The compound of Embodiment 1 or 2, having a Formula (Iq), Formula (Ir), Formula (Is), Formula (It), Formula (Iq-1), Formula (Ir-1), Formula (Is-1), or Formula (It- 1 ) ; or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Embodiment 16 The compound of any one of Embodiments 1-15, wherein R 2 is H or methyl.
  • Embodiment 17 The compound of Embodiment 1 selected from:
  • Embodiment 18 A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the Embodiments 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Embodiment 19 The pharmaceutical composition of Embodiment 18 further comprising at least one additional pharmaceutical agent.
  • Embodiment 20 The pharmaceutical composition of Embodiment 18 or Embodiment 19 for use in the treatment of a disease or disorder that is affected by the reduction of IKZF2 protein levels.
  • Embodiment 21 A method of degrading IKZF2 comprising administering to the patient in need thereof a compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Embodiment 22 A method of treating a disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Embodiment 23 A method of modulating IKZF2 protein levels comprising administering to the patient in need thereof a compound of any one of Embodiments 1 - 17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Embodiment 24 A method of reducing the proliferation of a cell the method comprising, contacting the cell with a compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
  • Embodiment 25 A method of treating cancer comprising administering to the patient in need thereof a compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Embodiment 26 The method of Embodiment 25, wherein the cancer is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancers
  • Embodiment 27 The method of Embodiment 25, wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
  • Embodiment 28 A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the Embodiments 1-17, or a pharmaceutically acceptable salt.
  • Embodiment 29 The method of any one of Embodiment 21-28, wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion.
  • Embodiment 30 A compound according to any one of the Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of IKZF2 protein levels.
  • Embodiment 31 Use of a compound according to any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of IKZF2 protein levels.
  • Embodiment 32 A compound according to any one of the Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with the reduction of IKZF2 protein levels.
  • Embodiment 33 The compound of Embodiment 32, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancer
  • Embodiment 34 Use of a compound according to any one of Embodiments 1-17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of IKZF2 protein levels.
  • Embodiment 35 The use of Embodiment 34, wherein the disease or disorder is selected from prostate cancer, breast carcinoma, lymphomas, leukaemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, and Ewing’s sarcoma.
  • RMS rhabdomyosarcoma
  • synovial sarcoma synovial sarcoma
  • osteosarcoma rhabdoid cancer
  • Embodiment 36 The method of Embodiment 25, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).
  • GIST gastrointestinal stromal tumor
  • Embodiment 37 The compound of Embodiment 32, wherein the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).
  • GIST gastrointestinal stromal tumor
  • Embodiment 38 The use of Embodiment 34, wherein the disease or disorder is selected from nonsmall cell lung cancer (NSCLC), melanoma, triple -negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • NSCLC nonsmall cell lung cancer
  • TNBC triple -negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma carcinoid
  • acute myelogenous leukemia and gastrointestinal stromal tumor (GIST).
  • GIST gastrointestinal stromal tumor
  • the compounds of the present disclosure are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments, the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of the present disclosure may be (+) or (-) enantiomers.
  • the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.
  • the compounds of the disclosure may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.
  • the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure.
  • Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
  • the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
  • the assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure.
  • Enantiomers can also
  • the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure and chemical structures and names. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.
  • All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds including those of the salts, solvates, esters, and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)- form.
  • the compounds of the disclosure may form salts, which are also within the scope of this disclosure.
  • Reference to a compound of the Formula herein is generally understood to include reference to salts thereof, unless otherwise indicated.
  • the compounds and intermediates may be isolated and used as the compound per se. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and, such as 2 H, 3 ⁇ 4, n C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, respectively.
  • the disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C, are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F, n C, or labeled compound may be particularly desirable for PET or SPECT studies.
  • substitution with heavier isotopes may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent) or an improvement in therapeutic index.
  • substitution with deuterium may modulate undesirable side effects of the undeuterated compound, such as competitive CYP450 inhibition, time dependent CYP450 inactivation, etc.
  • deuterium in this context is regarded as a substituent in compounds of the present disclosure.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by carrying out the procedures disclosed in the schemes or in the examples and preparations described below using an appropriate isotopically -labeled reagent in place of the non-isotopically labeled reagent.
  • solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D 2 0, di-acetone, d 6 -DMSO.
  • the present disclosure relates to compounds, which are modulators of IKZF2 protein levels.
  • the compounds of the present disclosure decrease IKZF2 protein levels.
  • the compounds of the present disclosure reduce IKZF2 protein levels.
  • the compounds of the present disclosure are degraders of IKZF2.
  • the present disclosure relates to compounds, which are modulators of IKZF2 and IKZF4 protein levels.
  • the compounds of the present disclosure decrease IKZF2 and IKZF4 protein levels.
  • the compounds of the present disclosure reduce IKZF2 and IKZF4 protein levels.
  • the compounds of the present disclosure are degraders of IKZF2.
  • the compounds of the disclosure are selective over other proteins.
  • “selective modulator”, “selective degrader”, or“selective compound” means, for example, a compound of the disclosure, that effectively modulates, decreases, or reduces the levels of a specific protein or degrades a specific protein to a greater extent than any other protein.
  • A“selective modulator”,“selective degrader”, or“selective compound” can be identified, for example, by comparing the ability of a compound to modulate, decrease, or reduce the levels of or to degrade a specific protein to its ability to modulate, decrease, or reduce the levels of or to degrade other proteins.
  • the selectivity can be identified by measuring the EC50 or IC50 of the compounds.
  • the compounds of the present application are selective IKZF2 modulators.
  • selective IKZF2 modulator “selective IKZF2 degrader”, or“selective IKZF2 compound” refers to a compound of the application, for example, that effectively modulates, decrease, or reduces the levels of IKZF2 protein or degrades IKZF2 protein to a greater extent than any other protein, particularly any protein (transcription factor) from the Ikaros protein family (e.g., IKZF1, IKZF3, IKZF4, and IKZF5).
  • IKZF1, IKZF3, IKZF4, and IKZF5 any protein (transcription factor) from the Ikaros protein family
  • A“selective IKZF2 modulator”,“selective IKZF2 degrader”, or“selective IKZF2 compound” can be identified, for example, by comparing the ability of a compound to modulate IKZF2 protein levels to its ability to modulate levels of other members of the Ikaros protein family or other proteins. For example, a substance may be assayed for its ability to modulate IKZF2 protein levels, as well as IKZF1, IKZF3, IKZF4, IKZF5, and other proteins.
  • the selectivity can be identified by measuring the EC50 of the compounds.
  • a selective IKZF2 degrader is identified by comparing the ability of a compound to degrade IKZF2 to its ability to degrade other members of the Ikaros protein family or other proteins.
  • the compounds of the application are IKZF2 degraders that exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over other proteins (e.g., IKZF1, IKZF3, IKZF4,and IKZF5). In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over other proteins.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over the other members of the Ikaros protein family (e.g., IKZF1, IKZF3, IKZF4, and IKZF5). In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over the other members of the Ikaros protein family (e.g., IKZF1, IKZF3, IKZF4, and IKZF5).
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over IKZF1. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over IKZF1.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over IKZF3. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over IKZF3.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold or 100-fold selectivity for the degradation of IKZF2 over IKZF4. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over IKZF4.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over IKZF5. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over IKZF5.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 and IKZF4 over the other members of the Ikaros protein family (e.g., IKZF1, IKZF3, and IKZF5). In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 and IKZF4 over the other members of the Ikaros protein family (e.g., IKZF1, IKZF3, and IKZF5).
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 and IKZF4 over IKZF1. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 and IKZF4 over IKZF1.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 and IKZF4 over IKZF3. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 and IKZF4 over IKZF3.
  • the compounds of the application exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 and IKZF4 over IKZF5. In various embodiments, the compounds of the application exhibit up to 1000-fold selectivity for the degradation of IKZF2 and IKZF4 over IKZF5.
  • the degradation of IKZF2 is measured by EC 50 .
  • Potency of can be determined by EC50 value.
  • a compound with a lower EC50 value, as determined under substantially similar degradation conditions, is a more potent degrader relative to a compound with a higher EC50 value.
  • the substantially similar conditions comprise determining degradation of protein levels in cells expressing the specific protein, or a fragment of any thereof.
  • the disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.
  • the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • the compounds of the present disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (F) or Formula (I).
  • the present disclosure includes all possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example,“Stereochemistry of Organic Compounds” by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • Preferred methods include but are not limited to those methods described below.
  • R a , Ri,. R x , R2, R3, R 7 , Rs, Xi, X2, ml, and nl are as defined in Formula (G).
  • compounds of Formula (G) where Rr is an alkyl optionally substituted with R 8 can be obtained by alkylation of (G) wherein R 7 ⁇ is H with an alkyl halide, tosylate or mesylate I-c in the presence of a base (e.g., Et3N, /-P ⁇ NEt, CS2CO3, etc.), in a solvent (e.g., MeCN, N,N-dimethylforamide (DMF), etc.), and optionally at elevated temperature.
  • a base e.g., Et3N, /-P ⁇ NEt, CS2CO3, etc.
  • a solvent e.g., MeCN, N,N-dimethylforamide (DMF), etc.
  • R a , Ri,. R x , R2, R4, R7, Rs, Xi, X 2 , m, s, and n are as defined in Formula (G).
  • R 8 is an alkyl optionally substituted with R 8 can be obtained by alkylation of (G) wherein R 7 ⁇ is H with an alkyl halide, tosylate or mesylate I-c in the presence of a base (e.g., Et3N, /-Pr 2 NEt, CS2CO3, etc.), in a solvent (e.g., MeCN, N,N-dimethylformamide (DMF), etc.), and optionally at elevated temperature.
  • a base e.g., Et3N, /-Pr 2 NEt, CS2CO3, etc.
  • a solvent e.g., MeCN, N,N-dimethylformamide (DMF), etc.
  • Compounds of Formula (G) where Ri, is a H can be obtained by hydrogenation of (G) wherein R 6 is benzyl in the presence of a suitable catalyst (e.g., Pd/C or Pt(3 ⁇ 4), in a solvent (e.g., DMF or EtOH), and under an atmosphere of hydrogen gas.
  • a suitable catalyst e.g., Pd/C or Pt(3 ⁇ 4)
  • a solvent e.g., DMF or EtOH
  • R 7 ⁇ is H I d wherein R 7 ⁇ is aiky! substituted with R s wherein R x , R 2 , R 3 , R 7 , Rs, Xi, X2, ml, and nl are as defined in Formula (G).
  • optionally substituted alkyl (optionally substituted with one or more Rs) can be prepared by using intermediates I-b, I-c, I-d, IV-a, IV-b, IV-c, and IV-d is outlined in General Scheme IV. Alkylation of IV- a with dimethylformamide (DMF) in the presence of a base (e.g., LiTMP, LDA, TMPMgCFLiCl etc.), in a solvent (e.g., tetrahydrofuran (THF), etc.), and optionally at low temperature provides IV-b.
  • a base e.g., LiTMP, LDA, TMPMgCFLiCl etc.
  • solvent e.g., tetrahydrofuran (THF), etc.
  • Reaction of IV-b and IV-c in the presence of a reducing agent e.g., sodium triacetoxyborohydride (NaB(OAc)3H), sodium cyanoborohydride (NaBFFCN), etc.
  • a reducing agent e.g., sodium triacetoxyborohydride (NaB(OAc)3H), sodium cyanoborohydride (NaBFFCN), etc.
  • a solvent e.g., DMF, THF, etc.
  • compounds of Formula (G) where Rr is an alkyl optionally substituted with R 8 can be obtained by alkylation of (G) wherein R 7 ⁇ is H with an alkyl halide, tosylate or mesylate I-c in the presence of a base (e.g., Et 3 N, /-Pr 2 NEt, Cs 2 C0 3 , etc.), in a solvent (e.g., MeCN, N,N-dimethylformamide (DMF), etc.), and optionally at elevated temperature.
  • a base e.g., Et 3 N, /-Pr 2 NEt, Cs 2 C0 3 , etc.
  • a solvent e.g., MeCN, N,N-dimethylformamide (DMF), etc.
  • R x , R 2 , R 3 , R 7 , Rs, Xi, X 2 , ml, and nl are as defined in Formula (G).
  • mild base e.g., KOAc
  • solvent e.g. HOAc
  • Coupling of V-b with 1,2- diamine V-c, protected with appropriate amine protecting group if necessary can be achieved using a base (e.g., /-Pr 2 NEt) in a solvent (e.g., N-methyl-2-pyrrolidone (NMP), isopropanol (/- PrOH), optionally at elevated temperature to afford the V-d wherein R 7 ⁇ is H.
  • a base e.g., /-Pr 2 NEt
  • a solvent e.g., N-methyl-2-pyrrolidone (NMP), isopropanol (/- PrOH
  • such coupling can be performed using a catalyst (e.g., Cul or RuPhos Palladacycle), a base (e.g., cesium carbonate (CS 2 CO 3 ) or sodium tert-butoxide (/-BuONa)), in a solvent, (e.g., N,N-dimethylformamide (DMF) or 1,4- dioxane), optionally at elevated temperature.
  • a catalyst e.g., Cul or RuPhos Palladacycle
  • a base e.g., cesium carbonate (CS 2 CO 3 ) or sodium tert-butoxide (/-BuONa
  • a solvent e.g., N,N-dimethylformamide (DMF) or 1,4- dioxane
  • a strong acid e.g. HC1 or trifluoroacetic acid (TFA)
  • THF tetrahydrofuran
  • solvent e.g., tetrahydrofuran (TH
  • compounds of Formula (G) where R 7 ⁇ is an alkyl optionally substituted with R 8 can be obtained by alkylation of (G) wherein R 7 ⁇ is H with an alkyl halide, tosylate or mesylate I-c in the presence of a base (e.g., Et3N, /-Pr 2 NEt, CS2CO3, etc.), in a solvent (e.g., MeCN, N,N-dimethylforamide (DMF), etc.), and optionally at elevated temperature.
  • a base e.g., Et3N, /-Pr 2 NEt, CS2CO3, etc.
  • a solvent e.g., MeCN, N,N-dimethylforamide (DMF), etc.
  • a mixture of enantiomers, diastereomers, and cis/trans isomers resulting from the process described above can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation.
  • Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid.
  • Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with modulation of IKZF2 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of IKZF2 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by the modulation of IKZF2 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders affected by the modulation of IKZF2 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by the reduction of IKZF2 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders affected by the reduction of IKZF2 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by a decrease in IKZF2 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders affected by the reduction or decrease of IKZF2 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is affected by the modulation of IKZF2 protein levels.
  • the disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is affected by the reduction of or a decrease in IKZF2 protein levels.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by the modulation of IKZF2 protein levels.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by the reduction of or a decrease in IKZF2 protein levels.
  • the present disclosure is directed to a method of modulating IKZF2 protein levels.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • IKZF2 protein levels are modulated through degradation of the IKZF2 protein.
  • IKZF2 protein levels are modulated through degradation of the IKZF2 protein mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the reduction of or decrease in IKZF2 protein levels, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure also relates to the use of a degrader of IKZF2 for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a IKZF2-dependent disease or disorder, wherein the medicament comprises a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method for treating, preventing, inhibiting, or eliminating a IKZF2-dependent disease or disorder, wherein the medicament comprises a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a IKZF2-dependent disease or disorder mediated, wherein the medicament comprises a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with the modulation of IKZF2 protein levels.
  • IKZF2 levels are modulated through degradation of the IKZF2 protein.
  • IKZF2 protein levels are modulated through degradation of the IKZF2 protein mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease associated with the modulation of IKZF2 protein levels.
  • IKZF2 levels are modulated through degradation of the IKZF2 protein.
  • IKZF2 protein levels are modulated through degradation of the IKZF2 protein mediated by an E3 ligase.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with the modulation of IKZF2 protein levels.
  • IKZF2 protein levels are modulated through degradation of the IKZF2 protein.
  • IKZF2 protein levels are modulated through degradation of the IKZF2 protein mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with the reduction of IKZF2 protein levels.
  • IKZF2 levels are reduced through degradation of the IKZF2 protein.
  • IKZF2 levels are reduced through degradation of the IKZF2 protein mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease associated with the reduction of IKZF2 protein levels.
  • IKZF2 levels are reduced through degradation of the IKZF2 protein.
  • IKZF2 levels are reduced through degradation of the IKZF2 protein mediated by an E3 ligase.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with the reduction of IKZF2 protein levels.
  • IKZF2 protein levels are reduced through degradation of the IKZF2 protein.
  • IKZF2 levels are reduced through degradation of the IKZF2 protein mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with a decrease in IKZF2 protein levels.
  • IKZF2 levels are decreased through degradation of the IKZF2 protein.
  • IKZF2 protein levels are decreased through degradation of the IKZF2 protein mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease associated with a decrease in IKZF2 protein levels.
  • IKZF2 levels are decreased through degradation of the IKZF2 protein.
  • IKZF2 protein levels are decreased through degradation of the IKZF2 protein mediated by an E3 ligase.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with a decrease in IKZF2 protein levels.
  • IKZF2 protein levels are reduced through degradation of the IKZF2 protein.
  • IKZF2 protein levels are decreased through degradation of the IKZF2 protein mediated by an E3 ligase.
  • the present disclosure relates to a method of inhibiting IKZF2 activity through degradation of IKZF2.
  • IKZF2 and IKZF4 protein degradation is mediated by an E3 ligase.
  • Another aspect of the disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for inhibiting IKZF2 activity through degradation of IKZF2.
  • IKZF2 protein degradation is mediated by an E3 ligase.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for use in the inhibition of IKZF2 activity through degradation of IKZF2.
  • IKZF2 protein degradation is mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for inhibiting IKZF2 activity through degradation of IKZF2.
  • IKZF2 protein degradation is mediated by an E3 ligase.
  • the present disclosure relates to a method of inhibiting IKZF2 and IKZF4 activity through degradation of IKZF2 and IKZF4.
  • IKZF2 and IKZF4 protein degradation is mediated by an E3 ligase.
  • Another aspect of the disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for inhibiting IKZF2 and IKZF4 activity through degradation of IKZF2 and IKZF4.
  • IKZF2 and IKZF4 protein degradation is mediated by an E3 ligase.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for use in the inhibition of IKZF2 and IKZF4 activity through degradation of IKZF2 and IKZF4.
  • IKZF2 and IKZF4 protein degradation is mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for inhibiting IKZF2 and IKZF4 activity through degradation of IKZF2 and IKZF4.
  • IKZF2 and IKZF4 protein degradation is mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for inhibiting IKZF2 and IKZF4 activity through degradation of IKZF2 and IKZF4.
  • IKZF2 and IKZF4 protein degradation is mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of IKZF2 and IKZF4 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of IKZF2 and IKZF4 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure is directed to a method of modulating IKZF2 and IKZF4 protein levels.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of, reduction of, or a decrease in IKZF4 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of, reduction of, or decrease in IKZF4 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 proteins. In some embodiments, IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 protein mediated by an E3 ligase.
  • the present disclosure is directed to a method of modulating, reducing or decreasing IKZF4 protein levels.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 proteins.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 protein mediated by an E3 ligase.
  • Another aspect of the disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of, reduction of, or a decrease in IKZF4 protein levels.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 proteins.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 protein mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of, reduction of, or a decrease in IKZF4 protein levels.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 proteins. In some embodiments, IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 protein mediated by an E3 ligase.
  • the present disclosure is directed to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of, reduction of, or a decrease in IKZF4 protein levels.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 proteins.
  • IKZF4 protein levels are modulated, reduced, or decreased through degradation of the IKZF4 protein mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with the reduction of IKZF2 and IKZF4 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with reduction of IKZF2 and IKZF4 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure is directed to a method of reducing IKZF2 and IKZF4 protein levels.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • IKZF2 and IKZF4 protein levels are reduced through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are reduced through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with a decrease in IKZF2 and IKZF4 protein levels.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with a decrease of IKZF2 and IKZF4 protein levels an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure is directed to a method of decreasing IKZF2 and IKZF4 protein levels.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • IKZF2 and IKZF4 protein levels are decreased through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are decreased through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the modulation of IKZF2 and IKZF4 protein levels, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disease or disorder is selected from the group consisting of cancer and metastasis.
  • the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the reduction of IKZF2 and IKZF4 protein levels, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disease or disorder is selected from the group consisting of cancer and metastasis.
  • Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with a decrease in IKZF2 and IKZF4 protein levels, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disease or disorder is selected from the group consisting of cancer and metastasis.
  • the present disclosure also relates to the use of a modulator of IKZF2 and IKZF4 protein levels for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a IKZF2 and IKZF4-dependent disease or disorder, wherein the medicament comprises a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a IKZF2 and IKZF4-dependent disease or disorder, wherein the medicament comprises a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with the modulation of IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease associated with the modulation of IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with the reduction of IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 protein levels are reduced through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are reduced through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease associated with the reduction of IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 are reduced through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are reduced through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • Another aspect of the present disclosure relates to a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with a decrease in IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 protein levels are decreased through degradation of the IKZF2 and IKZF4 proteins. In some embodiments, IKZF2 and IKZF4 protein levels are decreased through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease associated with a decrease in IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 are decreased through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are decreased through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with the modulation of IKZF2 and IKZF4 protein levels.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins.
  • IKZF2 and IKZF4 protein levels are modulated through degradation of the IKZF2 and IKZF4 proteins mediated by an E3 ligase.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent disease or disorder by reducing or decreasing IKZF2 protein levels, wherein reduction or decrease of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2-dependent disease or disorder by reducing or decreasing IKZF2 protein levels wherein reduction of or decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • the present disclosure the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating an IKZF2-dependent disease or disorder by reducing or decreasing IKZF2 protein levels wherein reduction of or decrease in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2 and IKZF4-dependent disease or disorder by reducing or decreasing IKZF2 and IKZF4 protein levels wherein the reduction of or decrease in IKZF2 and IKZF4 protein levels treats the IKZF2 and IKZF4-dependent disease or disorder.
  • the present disclosure the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of an IKZF2 and IKZF4- dependent disease or disorder by reducing or decreasing IKZF2 and IKZF4 protein levels wherein the reduction of or decrease in IKZF2 and IKZF4 protein levels treats the IKZF2 and IKZF4-dependent disease or disorder.
  • the present disclosure the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating an IKZF2 and IKZF4-dependent disease or disorder by reducing or decreasing IKZF2 and IKZF4 protein levels wherein the reduction of or decrease in IKZF2 and IKZF4 protein levels treats the IKZF2 and IKZF4-dependent disease or disorder.
  • Another aspect of the disclosure relates to a method of treating cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of treating cancer.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating cancer.
  • the present disclosure relates to a compound of Formula (G) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of cancer.
  • Another aspect of the disclosure relates to a method of treating an IKZF2-dependent cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, in the treatment of treating an IKZF2- dependent cancer.
  • Another aspect of the disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an IKZF2-dependent cancer.
  • the present disclosure relates to a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, for use in the treatment of an IKZF2-dependent cancer.
  • Another aspect of the disclosure relates to a method of treating an IKZF2-dependent and IKZF4- dependent cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof.
  • the present disclosure relates to the use of a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, or a composition comprising a compound of Formula (F) or Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodmg, stereoisomer, or tautomer thereof, in the treatment of treating an IKZF2- dependent and IKZF4-dependent cancer.

Landscapes

  • 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)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/IB2019/055807 2018-07-10 2019-07-08 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases Ceased WO2020012337A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
KR1020217003431A KR20210031923A (ko) 2018-07-10 2019-07-08 3-(5-아미노-1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체 및 ikaros 패밀리 아연 핑거 2(ikzf2) 의존성 질환의 치료에서 이들의 용도
ES19782692T ES2963695T3 (es) 2018-07-10 2019-07-08 Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidin-2,6-diona y su uso en el tratamiento de enfermedades dependientes de la proteína con dedos de zinc 2 de la familia ikaros (ikzf2)
BR122022012745-2A BR122022012745B1 (pt) 2018-07-10 2019-07-08 Usos de derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona, e kit
EP19782692.8A EP3820574B1 (en) 2018-07-10 2019-07-08 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases
MX2021000310A MX2021000310A (es) 2018-07-10 2019-07-08 Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidin-2,6-diona y su uso en el tratamiento de las enfermedades que dependen de la familia de dedo de zinc ikaros (ikzf2).
CA3103674A CA3103674A1 (en) 2018-07-10 2019-07-08 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
AU2019301947A AU2019301947B2 (en) 2018-07-10 2019-07-08 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of I KAROS Family Zinc Finger 2 (IKZF2)-dependent diseases
JP2021500409A JP7462606B2 (ja) 2018-07-10 2019-07-08 ３－（５－アミノ－１－オキソイソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びＩｋａｒｏｓファミリージンクフィンガー２（ＩＫＺＦ２）依存性疾患の治療におけるその使用
CN201980041638.0A CN112334194B (zh) 2018-07-10 2019-07-08 3-(5-氨基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其在治疗i karos家族锌指2(ikzf2)依赖性疾病中的用途
BR112021000049-6A BR112021000049B1 (pt) 2018-07-10 2019-07-08 Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6- diona, e composição farmacêutica

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862695922P 2018-07-10 2018-07-10
US62/695,922 2018-07-10

Publications (1)

Publication Number Publication Date
WO2020012337A1 true WO2020012337A1 (en) 2020-01-16

Family

ID=68136442

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2019/055807 Ceased WO2020012337A1 (en) 2018-07-10 2019-07-08 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases

Country Status (15)

Country Link
US (2) US11185537B2 (https=)
EP (1) EP3820574B1 (https=)
JP (1) JP7462606B2 (https=)
KR (1) KR20210031923A (https=)
CN (1) CN112334194B (https=)
AR (1) AR116109A1 (https=)
AU (1) AU2019301947B2 (https=)
BR (2) BR112021000049B1 (https=)
CA (1) CA3103674A1 (https=)
ES (1) ES2963695T3 (https=)
MX (1) MX2021000310A (https=)
PY (1) PY1954554A (https=)
TW (1) TWI830747B (https=)
UY (1) UY38296A (https=)
WO (1) WO2020012337A1 (https=)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020128972A1 (en) * 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2021194914A1 (en) * 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Substituted oxoisoindoline compounds for the treatment of cancer
WO2021260528A1 (en) * 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2022270994A1 (ko) 2021-06-25 2022-12-29 한국화학연구원 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도
WO2023283430A1 (en) * 2021-07-09 2023-01-12 Plexium, Inc. Cycloalkyl compounds and pharmaceutical compositions that modulate ikzf2
WO2023283425A1 (en) * 2021-07-09 2023-01-12 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate ikzf2
WO2023283428A1 (en) * 2021-07-09 2023-01-12 Plexium, Inc. Heterocycloalkyl and heteroaryl compounds and pharmaceutical compositions that modulate ikzf2
US11718601B2 (en) 2021-04-06 2023-08-08 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds
CN116783180A (zh) * 2020-10-14 2023-09-19 C4医药公司 用于降解ikzf2或ikzf4的三环配体
JP2023545509A (ja) * 2020-10-14 2023-10-30 シーフォー セラピューティクス， インコーポレイテッド 医学的療法のための、ネオ基質を分解する三環式化合物
US11897862B2 (en) 2022-03-17 2024-02-13 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof
JP2024517772A (ja) * 2021-04-29 2024-04-23 ネオモルフ インコーポレイテッド 置換された２－（２，６－ジオキソピペリジン－３－イル）－５－（１－ピペリジン－４－イル）イソインドリン－１，３－ジオン誘導体及びその使用
US12122764B2 (en) 2021-12-22 2024-10-22 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof
EP4329746A4 (en) * 2021-04-29 2025-03-19 Dana-Farber Cancer Institute, Inc. Phthalimido cereblon complex binders and transcription factor degraders and methods of use

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY35468A (es) 2013-03-16 2014-10-31 Novartis Ag Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19
AU2015244039B2 (en) * 2014-04-07 2021-10-21 Novartis Ag Treatment of cancer using anti-CD19 chimeric antigen receptor
DK3820573T3 (da) 2018-07-10 2023-10-23 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6-dion-derivativer og anvendelse deraf ved behandling af ikaros family zinc finger 2 (ikzf2)-afhængige sygdomme
WO2020102226A1 (en) * 2018-11-13 2020-05-22 Nantcell, Inc Combination therapies for multiple myeloma
CN113490528B (zh) * 2019-02-15 2024-12-03 诺华股份有限公司 3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途
AU2020387392B2 (en) 2019-11-19 2025-09-11 Bristol-Myers Squibb Company Compounds useful as inhibitors of Helios protein
CN116669769A (zh) * 2020-10-16 2023-08-29 达纳－法伯癌症研究所公司 Helios的哌啶基小分子降解剂和使用方法
UY39671A (es) * 2021-03-15 2022-10-31 Novartis Ag Derivados de pirazolopiridina y sus usos.
US20250066325A1 (en) * 2021-11-04 2025-02-27 The Brigham And Women's Hospital, Inc. Directed degron molecules and applications thereof
CN116640122A (zh) * 2022-02-16 2023-08-25 苏州国匡医药科技有限公司 Ikzf2降解剂及包含其的药物组合物和用途
CN114853754B (zh) 2022-05-23 2023-04-18 云白药征武科技(上海)有限公司 一种硫代酰胺衍生物及其制备方法和应用

Citations (362)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
US2779780A (en) 1955-03-01 1957-01-29 Du Pont 1, 4-diamino-2, 3-dicyano-1, 4-bis (substituted mercapto) butadienes and their preparation
US4261989A (en) 1979-02-19 1981-04-14 Kaken Chemical Co. Ltd. Geldanamycin derivatives and antitumor drug
US4433059A (en) 1981-09-08 1984-02-21 Ortho Diagnostic Systems Inc. Double antibody conjugate
US4444878A (en) 1981-12-21 1984-04-24 Boston Biomedical Research Institute, Inc. Bispecific antibody determinants
US4818541A (en) 1987-08-19 1989-04-04 Schering Corporation Transdermal delivery of enantiomers of phenylpropanolamine
US4851332A (en) 1985-04-01 1989-07-25 Sloan-Kettering Institute For Cancer Research Choriocarcinoma monoclonal antibodies and antibody panels
EP0346087A2 (en) 1988-06-09 1989-12-13 Snow Brand Milk Products Co., Ltd. Hybrid antibody and process for the production thereof
WO1991003493A1 (en) 1989-08-29 1991-03-21 The University Of Southampton Bi-or trispecific (fab)3 or (fab)4 conjugates
US5114946A (en) 1987-06-12 1992-05-19 American Cyanamid Company Transdermal delivery of pharmaceuticals
US5262564A (en) 1992-10-30 1993-11-16 Octamer, Inc. Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents
WO1993023537A1 (en) 1992-05-08 1993-11-25 Creative Biomolecules Chimeric multivalent protein analogues and methods of use thereof
US5273743A (en) 1990-03-09 1993-12-28 Hybritech Incorporated Trifunctional antibody-like compounds as a combined diagnostic and therapeutic agent
WO1994009131A1 (en) 1992-10-15 1994-04-28 Scotgen Limited Recombinant specific binding protein
WO1994012625A2 (en) 1992-11-23 1994-06-09 Zeneca Limited LIGAND BINDING VARIABLE DOMAIN (V-MIN) COMPRISING A FRAMEWORK REGION WITH A CYCLICALLY PERMUTED CENTRAL β-BARREL
WO1995009917A1 (en) 1993-10-07 1995-04-13 The Regents Of The University Of California Genetically engineered bispecific tetravalent antibodies
US5534254A (en) 1992-02-06 1996-07-09 Chiron Corporation Biosynthetic binding proteins for immuno-targeting
WO1996037621A2 (en) 1995-05-23 1996-11-28 Morphosys Gesellschaft Für Proteinoptimierung Mbh Multimeric proteins
US5582996A (en) 1990-12-04 1996-12-10 The Wistar Institute Of Anatomy & Biology Bifunctional antibodies and method of preparing same
US5591828A (en) 1989-06-22 1997-01-07 Behringwerke Aktiengesellschaft Bispecific and oligospecific mono-and oligovalent receptors, the preparation and use thereof
EP0754230A1 (en) 1994-04-04 1997-01-22 Genentech, Inc. Agonist antibodies against the flk2/flt3 receptor and uses thereof
US5635602A (en) 1993-08-13 1997-06-03 The Regents Of The University Of California Design and synthesis of bispecific DNA-antibody conjugates
US5637481A (en) 1993-02-01 1997-06-10 Bristol-Myers Squibb Company Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
WO1997025068A2 (en) 1996-01-05 1997-07-17 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Mesothelin antigen and methods and kits for targeting it
EP0805871A1 (en) 1995-01-18 1997-11-12 Roche Diagnostics GmbH Anti-cd 30 antibodies preventing proteolytic cleavage and release of membrane-bound cd 30 antigen
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US5777084A (en) 1996-03-07 1998-07-07 Eberhard-Karls-Universitat Tubingen Antibody BV10A4H2 specific for human FLT3/FLK2 receptor and mybridoma
US5786464A (en) 1994-09-19 1998-07-28 The General Hospital Corporation Overexpression of mammalian and viral proteins
US5837242A (en) 1992-12-04 1998-11-17 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US5837821A (en) 1992-11-04 1998-11-17 City Of Hope Antibody construct
US5843674A (en) 1993-11-16 1998-12-01 Pola Chemical Industries Inc. Anti-human tyrosinase monoclonal antibody
US5844094A (en) 1992-09-25 1998-12-01 Commonwealth Scientific And Industrial Research Organization Target binding polypeptide
US5864019A (en) 1990-06-11 1999-01-26 Celltech Limited Multivalent antigen-binding proteins
US5869620A (en) 1986-09-02 1999-02-09 Enzon, Inc. Multivalent antigen-binding proteins
US5910573A (en) 1992-01-23 1999-06-08 Merck Patent Gesellschaft Mit Beschrankter Haftung Monomeric and dimeric antibody-fragment fusion proteins
WO1999028471A2 (en) 1997-12-01 1999-06-10 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services ANTIBODIES, INCLUDING Fv MOLECULES, AND IMMUNOCONJUGATES HAVING HIGH BINDING AFFINITY FOR MESOTHELIN AND METHODS FOR THEIR USE
US5932448A (en) 1991-11-29 1999-08-03 Protein Design Labs., Inc. Bispecific antibody heterodimers
US5952484A (en) 1994-03-08 1999-09-14 Sloan-Kettering Cancer Center Recombinant human anti-LK26 antibodies
US5959083A (en) 1991-06-03 1999-09-28 Behringwerke Aktiengellschaft Tetravalent bispecific receptors, the preparation and use thereof
US5989830A (en) 1995-10-16 1999-11-23 Unilever Patent Holdings Bv Bifunctional or bivalent antibody fragment analogue
WO1999064460A1 (en) 1998-06-10 1999-12-16 Celltech Therapeutics Limited Divalent antibody fragments
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
WO2000006605A2 (en) 1998-07-28 2000-02-10 Micromet Ag Heterominibodies
WO2000035436A2 (en) 1998-12-16 2000-06-22 Warner-Lambert Company Treatment of arthritis with mek inhibitors
EP1013761A2 (en) 1991-09-18 2000-06-28 Kyowa Hakko Kogyo Co., Ltd. Humanized chimeric antibody directed against ganglioside GD3
US6114148A (en) 1996-09-20 2000-09-05 The General Hospital Corporation High level expression of proteins
WO2001012812A2 (en) 1999-08-17 2001-02-22 Biogen, Inc. Baff receptor (bcma), an immunoregulatory agent
US6239259B1 (en) 1996-04-04 2001-05-29 Unilever Patent Holdings B.V. Multivalent and multispecific antigen-binding protein
WO2001038490A2 (en) 1999-11-29 2001-05-31 The Trustees Of Columbia University In The City Of New York ISOLATION OF FIVE NOVEL GENES CODING FOR NEW Fc RECEPTORS-TYPE MELANOMA INVOLVED IN THE PATHOGENESIS OF LYMPHOMA/MELANOMA
WO2001051056A1 (en) 2000-01-10 2001-07-19 Astrazeneca Ab Fulvestrant formulation
WO2001066139A1 (en) 2000-03-06 2001-09-13 University Of Kentucky Research Foundation Use of a compound that selectively binds to cd123 to impair hematologic cancer progenitor cell
US6294353B1 (en) 1994-10-20 2001-09-25 Morphosys Ag Targeted hetero-association of recombinant proteins to multi-functional complexes
US6333396B1 (en) 1998-10-20 2001-12-25 Enzon, Inc. Method for targeted delivery of nucleic acids
US20020004587A1 (en) 2000-04-11 2002-01-10 Genentech, Inc. Multivalent antibodies and uses therefor
WO2002006213A2 (en) 2000-07-19 2002-01-24 Warner-Lambert Company Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
WO2002016436A2 (en) 2000-08-22 2002-02-28 Novartis Ag ANTIBODIES TO HUMAN IL-1$g(b)
US20020076406A1 (en) 2000-07-25 2002-06-20 Leung Shui-On Multivalent target binding protein
US20020103345A1 (en) 2000-05-24 2002-08-01 Zhenping Zhu Bispecific immunoglobulin-like antigen binding proteins and method of production
WO2002066470A1 (en) 2001-01-12 2002-08-29 Amgen Inc. Substituted alkylamine derivatives and methods of use
WO2002072635A2 (en) 2001-03-13 2002-09-19 University College London Specific binding members
US6476198B1 (en) 1993-07-13 2002-11-05 The Scripps Research Institute Multispecific and multivalent antigen-binding polypeptide molecules
US6511663B1 (en) 1991-06-11 2003-01-28 Celltech R&D Limited Tri- and tetra-valent monospecific antigen-binding proteins
US6528481B1 (en) 1999-02-16 2003-03-04 The Burnam Institute NG2/HM proteoglycan-binding peptides that home to angiogenic vasculature and related methods
WO2003062401A2 (en) 2002-01-22 2003-07-31 Corixa Corporation Compositions and methods for the detection, diagnosis and therapy of hematological malignancies
WO2003064383A2 (en) 2002-02-01 2003-08-07 Ariad Gene Therapeutics, Inc. Phosphorus-containing compounds & uses thereof
WO2003076424A1 (en) 2002-03-08 2003-09-18 Eisai Co. Ltd. Macrocyclic compounds useful as pharmaceuticals
WO2003077914A1 (en) 2002-03-13 2003-09-25 Array Biopharma, Inc N3 alkylated benzimidazole derivatives as mek inhibitors
US20030207346A1 (en) 1997-05-02 2003-11-06 William R. Arathoon Method for making multispecific antibodies having heteromultimeric and common components
US20030211078A1 (en) 2001-12-07 2003-11-13 Heavner George A. Pseudo-antibody constructs
US6670453B2 (en) 1997-10-27 2003-12-30 Unilever Patent Holdings B.V. Multivalent antigen-binding proteins
WO2004005284A1 (en) 2002-07-09 2004-01-15 Astrazeneca Ab Substituted 3-cyanoquinolines as mek inhibitors
WO2004007529A2 (en) 2002-07-15 2004-01-22 The Trustees Of Princeton University Iap binding compounds
US6743896B2 (en) 1997-04-30 2004-06-01 Enzon, Inc. Single-chain antigen-binding proteins capable of glycosylation, production and uses thereof
WO2004045532A2 (en) 2002-11-15 2004-06-03 Chiron Corporation Methods for preventing and treating cancer metastasis and bone loss associated with cancer metastasis
US6770622B2 (en) 2001-06-08 2004-08-03 Gary A. Jarvis N-terminally truncated galectin-3 for use in treating cancer
US6780996B2 (en) 2002-04-30 2004-08-24 Wyeth Holdings Corporation Process for the preparation of 7-substituted-3 quinolinecarbonitriles
WO2004081051A1 (en) 2003-03-12 2004-09-23 The University Of Birmingham Bispecific antibodies
WO2004087758A2 (en) 2003-03-26 2004-10-14 Neopharm, Inc. Il 13 receptor alpha 2 antibody and methods of use
US6809185B1 (en) 1998-01-23 2004-10-26 Vlaams Interuniversitair Instituut Voor Biotechnologie Multipurpose antibody derivatives
US20040219643A1 (en) 2001-06-28 2004-11-04 Greg Winter Dual-specific ligand
US20040220388A1 (en) 2000-06-30 2004-11-04 Nico Mertens Novel heterodimeric fusion proteins
US20040242847A1 (en) 2000-10-20 2004-12-02 Naoshi Fukushima Degraded agonist antibody
US6833441B2 (en) 2001-08-01 2004-12-21 Abmaxis, Inc. Compositions and methods for generating chimeric heteromultimers
US20050003403A1 (en) 2003-04-22 2005-01-06 Rossi Edmund A. Polyvalent protein complex
US20050004352A1 (en) 1998-04-09 2005-01-06 Roland Kontermann Single-chain multiple antigen-binding molecule, its preparation and use
US6846911B2 (en) 1996-10-25 2005-01-25 The United States Of America As Represented By The Department Of Health And Human Services Methods and compositions for inhibiting inflammation and angiogenesis comprising a mammalian CD97 α subunit
WO2005014652A1 (en) 2003-08-05 2005-02-17 Morphotek, Inc. A variant cell surface molecule associated with cancer
WO2005028443A2 (en) 2003-09-15 2005-03-31 Wyeth A Corporation Of The State Of Delaware, Usa Protein tyrosine kinase enzyme inhibitors
US20050069552A1 (en) 2003-07-28 2005-03-31 Bleck Gregory T. Fusion antibodies
US20050079170A1 (en) 2001-09-14 2005-04-14 Fabrice Le Gall Dimeric and multimeric antigen binding structure
WO2005035577A1 (ja) 2003-10-08 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. ガングリオシドｇｄ３に特異的に結合する抗体組成物
US20050100543A1 (en) 2003-07-01 2005-05-12 Immunomedics, Inc. Multivalent carriers of bi-specific antibodies
US20050129701A1 (en) 2001-12-04 2005-06-16 Marasco Wayne A. Antibody to latent membrane proteins and uses thereof
US20050136051A1 (en) 2003-12-22 2005-06-23 Bernard Scallon Methods for generating multimeric molecules
US20050136049A1 (en) 2001-01-17 2005-06-23 Ledbetter Jeffrey A. Binding constructs and methods for use thereof
US20050163782A1 (en) 2003-06-27 2005-07-28 Biogen Idec Ma Inc. Modified binding molecules comprising connecting peptides
WO2005068503A2 (en) 2004-01-07 2005-07-28 Chiron Corporation M-csf-specific monoclonal antibody and uses thereof
WO2005069888A2 (en) 2004-01-16 2005-08-04 The Regents Of The University Of Michigan Smac peptidomimetics and the uses thereof
WO2005069894A2 (en) 2004-01-16 2005-08-04 The Regents Of The University Of Michigan Conformationally constrained smac mimetics and the uses thereof
US20050175606A1 (en) 2001-04-11 2005-08-11 Hua-Liang Huang Cyclic single-chain trispecific antibody
WO2005094818A1 (en) 2004-03-23 2005-10-13 Genentech, Inc. Azabicyclo-octane inhibitors of iap
WO2005097791A1 (en) 2004-04-07 2005-10-20 Novartis Ag Inhibitors of iap
US20050266425A1 (en) 2003-12-31 2005-12-01 Vaccinex, Inc. Methods for producing and identifying multispecific antibodies
WO2005117986A2 (en) 2004-06-01 2005-12-15 Genentech, Inc. Antibody drug conjugates and methods
WO2005121142A1 (en) 2004-06-11 2005-12-22 Japan Tobacco Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido’2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer
US20060014700A1 (en) 2004-07-02 2006-01-19 Genentech, Inc. Inhibitors of IAP
WO2006010118A2 (en) 2004-07-09 2006-01-26 The Regents Of The University Of Michigan Conformationally constrained smac mimetics and the uses thereof
US20060025347A1 (en) 2004-07-15 2006-02-02 Condon Stephen M IAP binding compounds
WO2006017295A2 (en) 2004-07-12 2006-02-16 Idun Pharmaceuticals, Inc. Tetrapeptide analogs
WO2006020258A2 (en) 2004-07-17 2006-02-23 Imclone Systems Incorporated Novel tetravalent bispecific antibody
WO2006039238A2 (en) 2004-09-30 2006-04-13 The Goverment Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Irta2 antibodies and methods of use
US20060083747A1 (en) 2002-12-27 2006-04-20 Domantis Limited Fc fusion
US20060120960A1 (en) 2004-01-30 2006-06-08 Sergey Deyev Multivalent complexes, their production and method of use
WO2006069063A1 (en) 2004-12-20 2006-06-29 Genentech, Inc. Pyrrolidine inhibitors of iap
WO2006076691A2 (en) 2005-01-12 2006-07-20 Medarex, Inc. Irta-2 antibodies and their uses
US7090843B1 (en) 2000-11-28 2006-08-15 Seattle Genetics, Inc. Recombinant anti-CD30 antibodies and uses thereof
WO2006086469A2 (en) 2005-02-08 2006-08-17 Genzyme Corporation Antibodies to tgfbeta
US20060204493A1 (en) 2004-09-02 2006-09-14 Genentech, Inc. Heteromultimeric molecules
WO2006099141A2 (en) 2005-03-10 2006-09-21 Morphotek, Inc. Anti-mesothelin antibodies
WO2006105021A2 (en) 2005-03-25 2006-10-05 Tolerrx, Inc. Gitr binding molecules and uses therefor
WO2006106905A1 (ja) 2005-03-31 2006-10-12 Chugai Seiyaku Kabushiki Kaisha 会合制御によるポリペプチド製造方法
US7129330B1 (en) 1998-05-05 2006-10-31 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Multivalent antibody constructs
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
US20060263367A1 (en) 2005-05-23 2006-11-23 Fey Georg H Bispecific antibody devoid of Fc region and method of treatment using same
WO2006125481A1 (en) 2005-05-27 2006-11-30 Universitätsklinikum Freiburg Monoclonal antibodies and single chain antibody fragments against cell-surface prostate specific membrane antigen
WO2006138315A2 (en) 2005-06-15 2006-12-28 Schering Corporation Anti-igf1r antibody formulations
US20070004909A1 (en) 2005-04-15 2007-01-04 Macrogenics, Inc. Covalent diabodies and uses thereof
WO2007004415A1 (ja) 2005-07-01 2007-01-11 Murata Manufacturing Co., Ltd. 多層セラミック基板およびその製造方法ならびに多層セラミック基板作製用複合グリーンシート
WO2007004606A1 (ja) 2005-07-04 2007-01-11 Nikon Vision Co., Ltd. 測距装置
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
WO2007014011A2 (en) 2005-07-21 2007-02-01 Ardea Biosciences, Inc. N-(arylamino)-sulfonamide inhibitors of mek
US7183076B2 (en) 1997-05-02 2007-02-27 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
WO2007024715A2 (en) 2005-08-19 2007-03-01 Abbott Laboratories Dual variable domain immunoglobin and uses thereof
US20070087381A1 (en) 2002-04-15 2007-04-19 Tetsuo Kojima Methods for constructing scdb libraries
WO2007044887A2 (en) 2005-10-11 2007-04-19 Transtarget, Inc. Method for producing a population of homogenous tetravalent bispecific antibodies
US20070128150A1 (en) 2003-12-23 2007-06-07 Norman Timothy J Branched molecular scaffolds for linking polymer residues to biologically active moieties
WO2007067992A2 (en) 2005-12-08 2007-06-14 Medarex, Inc. Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1
US20070141049A1 (en) 2005-08-26 2007-06-21 Reinhard Bredehorst Bivalent IgY antibody constructs for diagnostic and therapeutic applications
US20070154901A1 (en) 1997-06-11 2007-07-05 Protein Engineering Technology Aps Trimerising module
WO2007084342A2 (en) 2006-01-13 2007-07-26 The Government Of The United States, As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Codon optimi zed il- 15 and il- 15r-alpha genes for expression in mammalian cells
US7253263B1 (en) 1999-09-30 2007-08-07 Kyowa Hakko Kogyo Co., Ltd. Complementarity determining region-grafted antibody against ganglioside GD3 and derivative of antibody against ganglioside GD3
WO2007095338A2 (en) 2006-02-15 2007-08-23 Imclone Systems Incorporated Functional antibodies
WO2007110205A2 (en) 2006-03-24 2007-10-04 Merck Patent Gmbh Engineered heterodimeric protein domains
WO2007121484A2 (en) 2006-04-19 2007-10-25 Novartis Ag 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting csf-1r signaling
US20070274985A1 (en) 2006-05-26 2007-11-29 Stefan Dubel Antibody
WO2007137760A2 (en) 2006-05-25 2007-12-06 Bayer Schering Pharma Aktiengesellschaft Dimeric molecular complexes
WO2008024725A1 (en) 2006-08-21 2008-02-28 Genentech, Inc. Aza-benzofuranyl compounds and methods of use
US20080050370A1 (en) 2006-03-17 2008-02-28 Scott Glaser Stabilized polypeptide compositions
US20080069820A1 (en) 2006-08-30 2008-03-20 Genentech, Inc. Multispecific antibodies
WO2008062026A1 (en) 2006-11-23 2008-05-29 Novartis Ag 5-sulfanylmethyl-pyrazolo [1,5-a] pyrimidin-7-ol derivatives as cxcr2 antagonists
WO2008061740A1 (en) 2006-11-23 2008-05-29 Novartis Ag Pyrimidines and their use as cxcr2 receptor antagonists
WO2008061741A1 (en) 2006-11-23 2008-05-29 Novartis Ag 5-sulfanylmethyl-[1,2,4] triazol[1, 5-a] pyrimidin-7-ol derivatives as cxcr2 antagonists
US20080152645A1 (en) 2006-08-18 2008-06-26 Armagen Technologies, Inc. Genetically Encoded Multifunctional Compositions Bidrectionally Transported Between Peripheral Blood and the CNS
US7410640B2 (en) 1998-07-22 2008-08-12 Vanderbilt University GBS toxin receptor antibodies
US20080241884A1 (en) 2003-10-08 2008-10-02 Kenya Shitara Fused Protein Composition
WO2008119353A1 (en) 2007-03-29 2008-10-09 Genmab A/S Bispecific antibodies and methods for production thereof
US20080254512A1 (en) 2006-11-02 2008-10-16 Capon Daniel J Hybrid immunoglobulins with moving parts
US20080260738A1 (en) 2007-04-18 2008-10-23 Moore Margaret D Single chain fc, methods of making and methods of treatment
US7446190B2 (en) 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
WO2008132601A1 (en) 2007-04-30 2008-11-06 Immutep Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2008134679A1 (en) 2007-04-30 2008-11-06 Genentech, Inc. Inhibitors of iap
WO2008143794A1 (en) 2007-05-11 2008-11-27 Altor Bioscience Corporation Fusion molecules and il-15 variants
WO2008146911A1 (ja) 2007-06-01 2008-12-04 Sapporo Medical University IL13Ra2に対する抗体およびこれを含む診断・治療薬
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
WO2009021754A2 (en) 2007-08-15 2009-02-19 Bayer Schering Pharma Aktiengesellschaft Monospecific and multispecific antibodies and method of use
WO2009036082A2 (en) 2007-09-12 2009-03-19 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use
WO2009044273A2 (en) 2007-10-05 2009-04-09 Immutep Use of recombinant lag-3 or the derivatives thereof for eliciting monocyte immune response
WO2009045957A1 (en) 2007-10-01 2009-04-09 Medarex, Inc. Human antibodies that bind mesothelin, and uses thereof
US7521056B2 (en) 2005-04-06 2009-04-21 Ibc Pharmaceuticals, Inc. Stably tethered structures of defined compositions with multiple functions or binding specificities
WO2009055730A1 (en) 2007-10-25 2009-04-30 Genentech, Inc. Process for making thienopyrimidine compounds
US7527787B2 (en) 2005-10-19 2009-05-05 Ibc Pharmaceuticals, Inc. Multivalent immunoglobulin-based bioactive assemblies
US7534866B2 (en) 2005-10-19 2009-05-19 Ibc Pharmaceuticals, Inc. Methods and compositions for generating bioactive assemblies of increased complexity and uses
US20090130106A1 (en) 2005-11-29 2009-05-21 The University Of Sydney Demibodies: dimerization-activated therapeutic agents
WO2009068204A1 (en) 2007-11-26 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin antibodies and uses therefor
WO2009068630A1 (en) 2007-11-27 2009-06-04 Ablynx N.V. Immunoglobulin constructs
US20090148905A1 (en) 2007-11-30 2009-06-11 Claire Ashman Antigen-binding constructs
US20090155275A1 (en) 2007-07-31 2009-06-18 Medimmune, Llc Multispecific epitope binding proteins and uses thereof
US20090162360A1 (en) 2007-12-21 2009-06-25 Christian Klein Bivalent, bispecific antibodies
US20090162359A1 (en) 2007-12-21 2009-06-25 Christian Klein Bivalent, bispecific antibodies
US20090175867A1 (en) 2006-06-12 2009-07-09 Trubion Pharmaceuticals, Inc. Single-Chain Multivalent Binding Proteins with Effector Function
US20090175851A1 (en) 2007-12-21 2009-07-09 Christian Klein Bivalent, bispecific antibodies
WO2009085983A1 (en) 2007-12-19 2009-07-09 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
WO2009089004A1 (en) 2008-01-07 2009-07-16 Amgen Inc. Method for making antibody fc-heterodimeric molecules using electrostatic steering effects
WO2009101611A1 (en) 2008-02-11 2009-08-20 Curetech Ltd. Monoclonal antibodies for tumor treatment
WO2009106539A1 (en) 2008-02-26 2009-09-03 Novartis Ag Heterocyclic compounds as inhibitors of cxcr2
US20090232811A1 (en) 2007-12-21 2009-09-17 Christian Klein Bivalent, bispecific antibodies
US20090234105A1 (en) 2006-03-24 2009-09-17 The Regents Of The University Of California Construction of a Multivalent SCFV Through Alkyne-Azide 1,3-Dipolar Cycloaddition
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
US20090252742A1 (en) 2007-04-13 2009-10-08 Ivan Bergstein IL3Ralpha antibody conjugates and uses thereof
US20090263392A1 (en) 2006-03-31 2009-10-22 Chugai Seiyaku Kabushiki Kaisha Methods of modifying antibodies for purification of bispecific antibodies
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
US7612114B2 (en) 2002-12-26 2009-11-03 Eisai R&D Management Co., Ltd. Selective estrogen receptor modulator
US20090274649A1 (en) 2002-03-01 2009-11-05 Immunomedics, Inc. Bispecific Antibody Point Mutations for Enhancing Rate of Clearance
US20090297529A1 (en) 2008-05-30 2009-12-03 Yiwen Li Anti-flt3 antibodies
US20090304657A1 (en) 2006-05-03 2009-12-10 The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services Chimeric t cell receptors and related materials and methods of use
US20090304718A1 (en) 2006-01-05 2009-12-10 Guenther Adolf Antibody Molecules Specific for Fibroblast Activation Protein and Immunoconjugates Containing Them
US20090311181A1 (en) 2006-03-20 2009-12-17 The Regents Of The University Of California Engineered Anti-Prostate Stem Cell Antigen (PSCA) Antibodies for Cancer Targeting
US7635753B2 (en) 2007-02-19 2009-12-22 Wisconsin Alumni Research Foundation Prostate cancer and melanoma antigens
WO2009155386A1 (en) 2008-06-20 2009-12-23 Abbott Laboratories A process for the preparation of the apoptosis promoter abt-263
WO2009156737A1 (en) 2008-06-25 2009-12-30 Vernalis (R&D) Limited Triazolo [4, 5-d] pyramidine derivatives and their use as purine receptor antagonists
WO2010015613A1 (en) 2008-08-04 2010-02-11 Novartis Ag Organic compounds
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2010020675A1 (en) 2008-08-22 2010-02-25 Novartis Ag Pyrrolopyrimidine compounds as cdk inhibitors
WO2010027827A2 (en) 2008-08-25 2010-03-11 Amplimmune, Inc. Targeted costimulatory polypeptides and methods of use to treat cancer
WO2010033866A2 (en) 2008-09-19 2010-03-25 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Monoclonal antibodies for cspg4 for the diagnosis and treatment of basal breast carcinoma
WO2010053732A1 (en) * 2008-10-29 2010-05-14 Celgene Corporation Isoindoline compounds for use in the treatment of cancer
WO2010063802A1 (en) 2008-12-05 2010-06-10 Novartis Ag 3, 4-di-substituted cyclobutene- 1, 2 -diones as cxcr2 receptor antagonists
US20100150910A1 (en) 2006-10-10 2010-06-17 Universite De Nantes Use of monoclonal antibodies specific to the o-acetylated form of gd2 ganglioside for treatment of certain cancers
US7749719B2 (en) 1994-04-22 2010-07-06 The United States Of America As Represented By The Department Of Health And Human Services Melanoma antigens and their use in diagnostic and therapeutic methods
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US7767675B2 (en) 2006-11-22 2010-08-03 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
WO2010114940A1 (en) 2009-04-01 2010-10-07 Genentech, Inc. Anti-fcrh5 antibodies and immunoconjugates and methods of use
WO2010120561A1 (en) 2009-04-01 2010-10-21 Genentech, Inc. Anti-fcrh5 antibodies and immunoconjugates and methods of use
WO2010126066A1 (ja) 2009-04-27 2010-11-04 協和発酵キリン株式会社 血液腫瘍治療を目的とした抗IL-3Rα抗体
WO2010129304A2 (en) 2009-04-27 2010-11-11 Oncomed Pharmaceuticals, Inc. Method for making heteromultimeric molecules
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
US7915391B2 (en) 2006-04-24 2011-03-29 Amgen Inc. Humanized c-Kit antibody
WO2011049677A1 (en) 2009-09-02 2011-04-28 Irm Llc Compounds and compositions as tlr activity modulators
EP2322550A1 (en) 2004-12-22 2011-05-18 Amgen, Inc Compositions comprising anti-IGF-1R Antibodies and Methods for obtaining said Antibodies
WO2011066342A2 (en) 2009-11-24 2011-06-03 Amplimmune, Inc. Simultaneous inhibition of pd-l1/pd-l2
WO2011076922A1 (en) 2009-12-23 2011-06-30 Synimmune Gmbh Anti-flt3 antibodies and methods of using the same
WO2011076786A1 (en) 2009-12-22 2011-06-30 Novartis Ag Substituted isoquinolinones and quinazolinones
WO2011095625A1 (en) 2010-02-05 2011-08-11 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
WO2011131746A2 (en) 2010-04-20 2011-10-27 Genmab A/S Heterodimeric antibody fc-containing proteins and methods for production thereof
US20110268656A1 (en) 2009-12-02 2011-11-03 David Ho J591 minibodies and cys-diabodies for targeting human prostate specific membrane antigen (psma) and methods for their use
WO2011156518A2 (en) 2010-06-10 2011-12-15 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8080650B2 (en) 2003-06-27 2011-12-20 Diadexus, Inc. Pro104 antibody compositions and methods of use
WO2011159847A2 (en) 2010-06-15 2011-12-22 The Regents Of The University Of California Receptor tyrosine kinase-like orphan receptor 1 (ror1) single chain fv antibody fragment conjugates and methods of use thereof
WO2011160119A2 (en) 2010-06-19 2011-12-22 Memorial Sloan-Kettering Cancer Center Anti-gd2 antibodies
WO2011159769A2 (en) 2010-06-17 2011-12-22 Aragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
US20120009181A1 (en) 2010-02-24 2012-01-12 Ab Olga Folate Receptor 1 Antibodies and Immunoconjugates and Uses Thereof
US8114845B2 (en) 2008-08-25 2012-02-14 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
US20120039906A1 (en) 2009-02-09 2012-02-16 INSER (Institut National de la Recherche Medicale) PD-1 Antibodies and PD-L1 Antibodies and Uses Thereof
WO2012033885A1 (en) 2010-09-08 2012-03-15 Baylor College Of Medicine Immunotherapy of cancer using genetically engineered gd2-specific t cells
WO2012037411A2 (en) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8168179B2 (en) 2002-07-03 2012-05-01 Ono Pharmaceutical Co., Ltd. Treatment method using anti-PD-L1 antibody
WO2012062713A1 (en) 2010-11-08 2012-05-18 Novartis Ag Cxcr2 binding polypeptides
WO2012079000A1 (en) 2010-12-09 2012-06-14 The Trustees Of The University Of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
US8207308B2 (en) 2007-02-16 2012-06-26 Sloan-Kettering Institute For Cancer Research Anti ganglioside GD3 antibodies and uses thereof
US8207228B2 (en) 2004-10-04 2012-06-26 Regents Of The University Of Minnesota Calixarene-based peptide conformation mimetics, methods of use, and methods of making
US8236780B2 (en) 2006-05-16 2012-08-07 Galectin Therapeutics Galactose—pronged polysaccharides in a formulation for antifibrotic therapies
US8263746B2 (en) 2004-02-06 2012-09-11 Morphosys Ag Anti-CD38 human antibodies and uses thereof
WO2012135854A2 (en) 2011-04-01 2012-10-04 Memorial Sloan-Kettering Cancer Center Antibodies to cytosolic peptides
EP2514766A2 (en) 2007-03-29 2012-10-24 Technion Research & Development Foundation Ltd. Antibodies, methods and kits for diagnosing and treating melanoma
WO2012145493A1 (en) 2011-04-20 2012-10-26 Amplimmune, Inc. Antibodies and other molecules that bind b7-h1 and pd-1
US8309693B2 (en) 2001-08-23 2012-11-13 Rsr Limited Epitope regions of a thyrotrophin (TSH) receptor, uses thereof and antibodies thereto
US20120288506A1 (en) 2011-05-12 2012-11-15 Imclone Llc C-kit antibodies and uses thereof
WO2012167143A1 (en) 2011-06-03 2012-12-06 Xoma Technology Ltd. Antibodies specific for tgf-beta
WO2012163805A1 (en) 2011-05-27 2012-12-06 Glaxo Group Limited Bcma (cd269/tnfrsf17) -binding proteins
WO2012175222A1 (en) 2011-06-24 2012-12-27 Cytune AN IL-15 AND IL-15Rα SUSHI DOMAIN BASED IMMUNOCYTOKINES
US8344112B2 (en) 2007-07-31 2013-01-01 Merck Sharp & Dohme Limited IGF-1R specific antibodies useful in the detection and diagnosis of cellular proliferative disorders
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
US8362211B2 (en) 2010-12-30 2013-01-29 Takeda Pharmaceutical Company Limited Anti-CD38 antibodies
WO2013019906A1 (en) 2011-08-01 2013-02-07 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors
WO2013030803A1 (en) 2011-09-02 2013-03-07 Novartis Ag Choline salt of an anti - inflammatory substituted cyclobutenedione compound
US8399645B2 (en) 2003-11-05 2013-03-19 St. Jude Children's Research Hospital, Inc. Chimeric receptors with 4-1BB stimulatory signaling domain
WO2013040371A2 (en) 2011-09-16 2013-03-21 Baylor College Of Medicine Targeting the tumor microenvironment using manipulated nkt cells
WO2013040557A2 (en) 2011-09-16 2013-03-21 The Trustees Of The University Of Pennsylvania Rna engineered t cells for the treatment of cancer
WO2013061273A1 (en) 2011-10-25 2013-05-02 Massimo Dominici A modified effector cell (or chimeric receptor) for treating disialoganglioside gd2 -expressing neoplasia
WO2013063419A2 (en) 2011-10-28 2013-05-02 The Trustees Of The University Of Pennsylvania A fully human, anti-mesothelin specific chimeric immune receptor for redirected mesothelin-expressing cell targeting
WO2013060867A2 (en) 2011-10-27 2013-05-02 Genmab A/S Production of heterodimeric proteins
US8440798B2 (en) 2006-10-04 2013-05-14 Københavns Universitet Generation of a cancer-specific immune response toward MUC1 and cancer specific MUC1 antibodies
WO2013074916A1 (en) 2011-11-18 2013-05-23 Board Of Regents, The University Of Texas System Car+ t cells genetically modified to eliminate expression of t- cell receptor and/or hla
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
US8460927B2 (en) 1999-11-30 2013-06-11 Mayo Foundation For Medical Education And Research B7-H1 antibodies and method of use
WO2013085552A1 (en) 2011-12-08 2013-06-13 Cleveland Clinic Foundation Glenoid vault fixation
WO2013111105A1 (en) 2012-01-26 2013-08-01 Novartis Ag Imidazopyrrolidinone compounds
US8501415B2 (en) 2002-11-26 2013-08-06 B.R.A.H.M.S. Gmbh Identification of TSH receptor autoantibodies using affinity-purified antibodies
WO2013123061A1 (en) 2012-02-13 2013-08-22 Seattle Children's Hospital D/B/A Seattle Children's Research Institute Bispecific chimeric antigen receptors and therapeutic uses thereof
WO2013126712A1 (en) 2012-02-22 2013-08-29 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer
WO2013142034A1 (en) 2012-03-23 2013-09-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-mesothelin chimeric antigen receptors
US8552154B2 (en) 2008-09-26 2013-10-08 Emory University Anti-PD-L1 antibodies and uses therefor
US8552156B2 (en) 2010-06-11 2013-10-08 Kyowa Hakko Kirin Co., Ltd Anti-TIM-3 antibody
US20130295007A1 (en) 2012-05-01 2013-11-07 Genentech, Inc. Anti-pmel17 antibodies and immunoconjugates
WO2013168108A2 (en) 2012-05-09 2013-11-14 Novartis Ag Chemokine receptor binding polypeptides
WO2013173820A2 (en) 2012-05-18 2013-11-21 Scott & White Healthcare Bispecific scfv immunofusion (bif)
WO2013179174A1 (en) 2012-05-29 2013-12-05 Koninklijke Philips N.V. Lighting arrangement
US8603466B2 (en) 2006-03-29 2013-12-10 King's College London Agonist antibodies against TSHR
WO2013192294A1 (en) 2012-06-20 2013-12-27 Boston 3T Biotechnologies, Inc. Cellular therapies for treating and preventing cancers and other immune system disorders
WO2014022758A1 (en) 2012-08-03 2014-02-06 Dana-Farber Cancer Institute, Inc. Single agent anti-pd-l1 and pd-l2 dual binding antibodies and methods of use
WO2014031687A1 (en) 2012-08-20 2014-02-27 Jensen, Michael Method and compositions for cellular immunotherapy
WO2014039960A1 (en) * 2012-09-10 2014-03-13 Celgene Corporation Methods for the treatment of locally advanced breast cancer
US20140086932A1 (en) 2012-09-17 2014-03-27 Peter G. Traber Method for enhancing specific immunotherapies in cancer treatment
WO2014055897A2 (en) 2012-10-04 2014-04-10 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-pd-l1 antibodies and methods of use
WO2014066527A2 (en) 2012-10-24 2014-05-01 Admune Therapeutics Llc Il-15r alpha forms, cells expressing il-15r alpha forms, and therapeutic uses of il-15r alpha and il-15/il-15r alpha complexes
US8735553B1 (en) 2013-09-13 2014-05-27 Beigene, Ltd. Anti-PD1 antibodies and their use as therapeutics and diagnostics
WO2014089335A2 (en) 2012-12-07 2014-06-12 Amgen Inc. Bcma antigen binding proteins
WO2014100079A1 (en) 2012-12-21 2014-06-26 Merck Sharp & Dohme Corp. Antibodies that bind to human programmed death ligand 1 (pd-l1)
US8779108B2 (en) 2009-11-24 2014-07-15 Medimmune, Limited Targeted binding agents against B7-H1
US8796284B2 (en) 2010-03-31 2014-08-05 Palobiofarma, S.L. 4-aminopyrimidine derivatives and their as as adenosine A2a receptor antagonists
WO2014122144A1 (en) 2013-02-05 2014-08-14 Engmab Ag BISPECIFIC ANTIBODIES AGAINST CD3ε AND BCMA
WO2014130657A1 (en) 2013-02-20 2014-08-28 The Trustees Of The University Of Pennsylvania Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor
WO2014130635A1 (en) 2013-02-20 2014-08-28 Novartis Ag Effective targeting of primary human leukemia using anti-cd123 chimeric antigen receptor engineered t cells
WO2014130310A1 (en) 2013-02-19 2014-08-28 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
WO2014140180A1 (en) 2013-03-15 2014-09-18 Glaxosmithkline Intellectual Property Development Limited Anti-lag-3 binding proteins
WO2014138805A1 (en) 2013-03-14 2014-09-18 Csl Limited Anti il-3r alpha agents and uses thereof
WO2014138819A1 (en) 2013-03-14 2014-09-18 Csl Limited Agents that neutralize il-3 signaling and uses thereof
WO2014144622A2 (en) 2013-03-15 2014-09-18 Stephen Forman Cd123-specific chimeric antigen receptor redirected t cells and methods of their use
WO2014140248A1 (en) 2013-03-15 2014-09-18 Amgen Research (Munich) Gmbh Binding molecules for bcma and cd3
US8841418B2 (en) 2011-07-01 2014-09-23 Cellerant Therapeutics, Inc. Antibodies that specifically bind to TIM3
WO2014153270A1 (en) 2013-03-16 2014-09-25 Novartis Ag Treatment of cancer using humanized anti-cd19 chimeric antigen receptor
WO2014165707A2 (en) 2013-04-03 2014-10-09 Memorial Sloan-Kettering Cancer Center Effective generation of tumor-targeted t-cells derived from pluripotent stem cells
WO2014179664A2 (en) 2013-05-02 2014-11-06 Anaptysbio, Inc. Antibodies directed against programmed death-1 (pd-1)
WO2014194302A2 (en) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-1
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
WO2014210064A1 (en) 2013-06-24 2014-12-31 Genentech, Inc. Anti-fcrh5 antibodies
WO2014209804A1 (en) 2013-06-24 2014-12-31 Biomed Valley Discoveries, Inc. Bispecific antibodies
US8927697B2 (en) 2008-09-12 2015-01-06 Isis Innovation Limited PD-1 specific antibodies and uses thereof
WO2015026684A1 (en) 2013-08-20 2015-02-26 Merck Sharp & Dohme Corp. Modulation of tumor immunity
WO2015031667A2 (en) 2013-08-30 2015-03-05 Amgen Inc. Gitr antigen binding proteins
US8993731B2 (en) 2010-03-11 2015-03-31 Ucb Biopharma Sprl PD-1 antibody
WO2015061668A1 (en) 2013-10-25 2015-04-30 Dana-Farber Cancer Institute, Inc. Anti-pd-l1 monoclonal antibodies and fragments thereof
US9029393B2 (en) 2009-01-26 2015-05-12 Kaldi Pharma, Sas Adenosine receptor ligands and uses thereof
WO2015081158A1 (en) 2013-11-26 2015-06-04 Bristol-Myers Squibb Company Method of treating hiv by disrupting pd-1/pd-l1 signaling
WO2015085847A1 (zh) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Pd-1抗体、其抗原结合片段及其医药用途
WO2015090230A1 (en) 2013-12-19 2015-06-25 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
WO2015109124A2 (en) 2014-01-15 2015-07-23 Kadmon Corporation, Llc Immunomodulatory agents
US20150210769A1 (en) 2014-01-24 2015-07-30 Novartis Ag Antibody molecules to pd-1 and uses thereof
WO2015112805A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
WO2015112800A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-1
US20150218274A1 (en) 2014-01-31 2015-08-06 Novartis Ag Antibody molecules to tim-3 and uses thereof
WO2015116539A1 (en) 2014-01-28 2015-08-06 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
US9133197B2 (en) 2009-03-20 2015-09-15 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Oxidated derivatives of triazolylpurines useful as ligands of the adenosine A2A receptor and their use as medicaments
US20150259420A1 (en) 2014-03-14 2015-09-17 Novartis Ag Antibody molecules to lag-3 and uses thereof
WO2015136017A1 (en) 2014-03-13 2015-09-17 F. Hoffmann-La Roche Ag Methods and compositions for modulating estrogen receptor mutants
WO2015142675A2 (en) 2014-03-15 2015-09-24 Novartis Ag Treatment of cancer using chimeric antigen receptor
US9163087B2 (en) 2010-06-18 2015-10-20 The Brigham And Women's Hospital, Inc. Bi-specific antibodies against TIM-3 and PD-1 for immunotherapy in chronic immune conditions
US9175082B2 (en) 2012-05-31 2015-11-03 Sorrento Therapeutics, Inc. Antigen binding proteins that bind PD-L1
WO2015181342A1 (en) 2014-05-29 2015-12-03 Spring Bioscience Corporation Pd-l1 antibodies and uses thereof
WO2015184099A1 (en) 2014-05-28 2015-12-03 4-Antibody Ag Anti-gitr antibodies and methods of use thereof
WO2015195163A1 (en) 2014-06-20 2015-12-23 R-Pharm Overseas, Inc. Pd-l1 antagonist fully human antibody
WO2015200119A1 (en) 2014-06-26 2015-12-30 Macrogenics, Inc. Covalently bonded diabodies having immunoreactivity with pd-1 and lag-3, and methods of use thereof
US9228016B2 (en) 2014-06-06 2016-01-05 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
WO2016000619A1 (en) 2014-07-03 2016-01-07 Beigene, Ltd. Anti-pd-l1 antibodies and their use as therapeutics and diagnostics
US9244059B2 (en) 2007-04-30 2016-01-26 Immutep Parc Club Orsay Cytotoxic anti-LAG-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2016014576A1 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
WO2016014789A2 (en) 2014-07-24 2016-01-28 Bluebird Bio, Inc. Bcma chimeric antigen receptors
WO2016014535A1 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using a cll-1 chimeric antigen receptor
WO2016014565A2 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using humanized anti-bcma chimeric antigen receptor
WO2016028896A1 (en) 2014-08-19 2016-02-25 Novartis Ag Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment
WO2016028672A1 (en) 2014-08-19 2016-02-25 Merck Sharp & Dohme Corp. Anti-lag3 antibodies and antigen-binding fragments
WO2016054638A1 (en) 2014-10-03 2016-04-07 Dana-Farber Cancer Institute, Inc. Glucocorticoid-induced tumor necrosis factor receptor (gitr) antibodies and methods of use thereof
WO2016057846A1 (en) 2014-10-08 2016-04-14 Novartis Ag Compositions and methods of use for augmented immune response and cancer therapy
US20160108123A1 (en) 2014-10-14 2016-04-21 Novartis Ag Antibody molecules to pd-l1 and uses thereof
US20160129108A1 (en) 2014-11-11 2016-05-12 Medimmune Limited Therapeutic combinations comprising anti-cd73 antibodies and uses thereof
WO2016071448A1 (en) 2014-11-06 2016-05-12 F. Hoffmann-La Roche Ag Anti-tim3 antibodies and methods of use
WO2016092419A1 (en) 2014-12-09 2016-06-16 Rinat Neuroscience Corp. Anti-pd-1 antibodies and methods of use thereof
WO2016111947A2 (en) 2015-01-05 2016-07-14 Jounce Therapeutics, Inc. Antibodies that inhibit tim-3:lilrb2 interactions and uses thereof
WO2016144803A2 (en) 2015-03-06 2016-09-15 Sorrento Therapeutics, Inc. Antibody therapeutics that bind tim3
WO2016161270A1 (en) 2015-04-01 2016-10-06 Anaptysbio, Inc. Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)
US9505839B2 (en) 2012-07-02 2016-11-29 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
WO2016196792A1 (en) 2015-06-03 2016-12-08 Bristol-Myers Squibb Company Anti-gitr antibodies for cancer diagnostics
US20170015758A1 (en) 2014-01-21 2017-01-19 Medimmune, Llc Compositions And Methods For Modulating And Redirecting Immune Responses
WO2017015623A2 (en) 2015-07-23 2017-01-26 Inhibrx Lp Multivalent and multispecific gitr-binding fusion proteins
WO2017027645A1 (en) 2015-08-13 2017-02-16 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
WO2017025918A1 (en) 2015-08-11 2017-02-16 Novartis Ag 5-bromo-2,6-di-(lh-pyrazol-l-yl)pyrimidin-4-amine for use in the treatment of cancer
WO2017025610A1 (en) 2015-08-12 2017-02-16 Medimmune Limited Gitrl fusion proteins and uses thereof
EP3214081A1 (en) * 2014-10-30 2017-09-06 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
WO2018119448A1 (en) * 2016-12-23 2018-06-28 Arvinas, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2019038717A1 (en) * 2017-08-23 2019-02-28 Novartis Ag 3- (1-OXOISOINDOLIN-2-YL) PIPERIDINE-2,6-DIONE DERIVATIVES AND USES THEREOF
WO2019079569A1 (en) * 2017-10-18 2019-04-25 Novartis Ag COMPOSITIONS AND METHODS FOR SELECTIVE DEGRADATION OF A PROTEIN
WO2019191112A1 (en) * 2018-03-26 2019-10-03 C4 Therapeutics, Inc. Cereblon binders for the degradation of ikaros

Family Cites Families (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5221543A (en) * 1986-10-22 1993-06-22 Firma Wilhelm Fette Gmbh Method of making a fast release stabilized aspartame ingredient for chewing gum
US7196170B2 (en) 1992-09-14 2007-03-27 The General Hospital Corporation Aiolos, Helios, Daedalos and Ikaros: genes, polypeptides, regulatory elements and uses thereof
AU2001291195A1 (en) 2000-12-01 2002-06-11 Parker Hughes Institute Nucleotide and protein sequence of helios 3 and methods of use
WO2003014315A2 (en) 2001-08-06 2003-02-20 The Children's Medical Center Corporation Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs
US20040087558A1 (en) 2002-10-24 2004-05-06 Zeldis Jerome B. Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain
US20050203142A1 (en) 2002-10-24 2005-09-15 Zeldis Jerome B. Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain
US7612096B2 (en) 2003-10-23 2009-11-03 Celgene Corporation Methods for treatment, modification and management of radiculopathy using 1-oxo-2-(2,6-dioxopiperidin-3yl)-4-aminoisoindoline
US20070161696A1 (en) 2004-04-23 2007-07-12 Zeldis Jerome B Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain
BRPI0514865A (pt) 2004-09-03 2008-06-24 Celgene Corp processo para preparar um composto
JP4731867B2 (ja) 2004-10-01 2011-07-27 国立大学法人三重大学 Ｃｄ８陽性の細胞傷害性ｔリンパ球の誘導方法
BRPI0518793A2 (pt) 2004-12-01 2008-12-09 Celgene Corp mÉtodos para tratar, controlar ou prevenir uma doenÇa ou distérbio de imunodeficiÊncia, e para melhorar a resposta imune a um imunogene, e, composiÇço farmacÊutica
DE602005023646D1 (de) 2004-12-10 2010-10-28 Siemens Healthcare Diagnostics Für die vorhersage des ansprechens maligner neoplasie auf eine auf taxan beruhende medizinische behandlung geeignete genetische veränderung
KR20080042158A (ko) 2005-08-31 2008-05-14 셀진 코포레이션 이소인돌-이미드 화합물과 이를 포함하는 조성물 및 이를이용한 방법
WO2007067500A2 (en) 2005-12-05 2007-06-14 Genomic Health, Inc. Predictors of patient response to treatment with egfr inhibitors
ZA200804717B (en) 2005-12-29 2010-02-24 Anthrogenesis Corp Improved composition for collecting and preserving a placental stem cells and methods of using the composition
US20070269827A1 (en) 2006-05-18 2007-11-22 Oklahoma Medical Research Foundation Predicting and Diagnosing Patients With Autoimmune Disease
KR101342035B1 (ko) 2006-06-20 2013-12-16 한국과학기술연구원 신장독성 및 부작용 유발 약물 검색용 바이오마커 및 이를이용한 신장독성 및 부작용 유발 약물 검색 방법
US8877780B2 (en) 2006-08-30 2014-11-04 Celgene Corporation 5-substituted isoindoline compounds
JP2009092508A (ja) 2007-10-09 2009-04-30 Norihiro Nishimoto リウマチ治療剤の効果の予測方法
WO2009068621A1 (en) 2007-11-30 2009-06-04 Glaxosmithkline Biologicals S.A. Method for classifying cancer patients as responder or non-responder to immunotherapy
KR100957051B1 (ko) 2007-12-28 2010-05-13 한국과학기술연구원 니트로푸란토인 처리에 따른, 폐독성 유발 약물 검색용마커유전자 및 이를 이용한 검색 방법
GB2456390A (en) 2008-01-15 2009-07-22 Glaxo Group Ltd Bipolar disorder treatments
WO2009094592A2 (en) 2008-01-23 2009-07-30 Perlegen Sciences, Inc. Genetic basis of alzheimer's disease and diagnosis and treatment thereof
US20090307179A1 (en) 2008-03-19 2009-12-10 Brandon Colby Genetic analysis
US20110229498A1 (en) 2008-05-08 2011-09-22 The Johns Hopkins University Compositions and methods for modulating an immune response
EP2177615A1 (en) 2008-10-10 2010-04-21 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Method for a genome wide identification of expression regulatory sequences and use of genes and molecules derived thereof for the diagnosis and therapy of metabolic and/or tumorous diseases
MX2012001504A (es) 2009-08-05 2012-06-01 Versitech Ltd Compuestos antivirales y metodos para elaborarlos y usarlos.
US9212177B2 (en) 2009-08-05 2015-12-15 Versitech Limited Antiviral compounds and methods of making and using thereof
CA2778005A1 (en) 2009-10-26 2011-05-12 Abbott Laboratories Detection of chromosomal abnormalities associated with prognosis of non small cell lung cancer
EP2536706B1 (en) 2010-02-11 2017-06-14 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
CA2799165C (en) 2010-05-12 2022-04-12 Steven E. Schutzer Diagnostic markers for neuropsychiatric disease
US20120142701A1 (en) 2010-05-28 2012-06-07 The University Of Hong Kong Compounds and methods for the treatment of proliferative diseases
WO2011151941A1 (ja) 2010-06-04 2011-12-08 国立大学法人東京大学 制御性ｔ細胞の増殖または集積を誘導する作用を有する組成物
US20130281304A1 (en) 2010-08-13 2013-10-24 Andrew P. Feinberg Comprehensive Methylome Map of Myeloid and Lymphoid Commitment from Hematopoietic Proenitors
CA2815000C (en) 2010-10-22 2024-05-21 Dana-Farber Cancer Institute, Inc. Discovery of regulatory t cells programmed to suppress an immune response
AU2012268036B2 (en) 2011-06-06 2017-04-06 THE UNITED STATES OF AMERICA as represented by THE SECRETARY OF STATE OF THE DEPARTMENT OF VETERANS AFFAIRS Methods of inhibiting muscle atrophy
US20140234342A1 (en) 2011-06-21 2014-08-21 Innate Pharma Nkp46-mediated nk cell tuning
US9910039B2 (en) 2011-07-01 2018-03-06 Beckman Coulter, Inc. Regulatory T cells and methods of identifying, obtaining and using to treat immuno-based disorders
WO2013037118A1 (zh) 2011-09-16 2013-03-21 上海长海医院 前列腺癌的生物学标志物、治疗靶点及其用途
CN116942833A (zh) 2011-12-01 2023-10-27 国立大学法人 东京大学 诱导调节性t细胞的增殖或积累的人源细菌
US9481866B2 (en) 2011-12-16 2016-11-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of producing T cell populations enriched for stable regulatory T-cells
WO2013098797A2 (en) 2011-12-31 2013-07-04 Kuriakose Moni Abraham Diagnostic tests for predicting prognosis, recurrence, resistance or sensitivity to therapy and metastatic status in cancer
WO2013131045A1 (en) 2012-03-02 2013-09-06 The Regents Of The University Of California Expansion of alloantigen-reactive regulatory t cells
GB201207297D0 (en) 2012-04-26 2012-06-06 Senzagen Ab Analytical methods and arrays for use in the same
GB201213571D0 (en) 2012-07-31 2012-09-12 Univ Leuven Kath Growth factor cocktail to enhnce osteogenic differentiayion of mesenchymal
EP2682750A1 (en) 2012-07-02 2014-01-08 Sotio a.s. In vitro method for the diagnosis and surveillance of cancer
AU2013329372B2 (en) 2012-10-08 2018-07-12 St. Jude Children's Research Hospital Therapies based on control of regulatory T cell stability and function via a Neuropilin-1:Semaphorin axis
WO2014122467A1 (en) 2013-02-06 2014-08-14 Loxbridge Research Llp Systems and methods for early disease detection and real-time disease monitoring
EP2970881A4 (en) 2013-03-14 2017-01-25 Children's Medical Center Corporation Compositions and methods for reprogramming hematopoietic stem cell lineages
WO2014151764A2 (en) 2013-03-15 2014-09-25 Veracyte, Inc. Methods and compositions for classification of samples
US20160122821A1 (en) 2013-06-10 2016-05-05 Suregene, Llc Genetic markers of antipsychotic response
GB2532672A (en) 2013-09-09 2016-05-25 Scripps Research Inst Methods and systems for analysis of organ transplantation
WO2015050875A1 (en) 2013-10-01 2015-04-09 The Regents Of The University Of California Endometriosis classifier
UY35790A (es) 2013-10-21 2015-05-29 Teva Pharma Marcadores genéticos que predicen la respuesta al acetato de glatiramer
WO2015109212A1 (en) 2014-01-17 2015-07-23 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
WO2015107196A1 (en) 2014-01-20 2015-07-23 Institut Curie Use of thalidomide or analogs thereof for preventing neurologic disorders induced by brain irradiation
US20180228907A1 (en) 2014-04-14 2018-08-16 Arvinas, Inc. Cereblon ligands and bifunctional compounds comprising the same
AU2015247817C1 (en) 2014-04-14 2022-02-10 Arvinas Operations, Inc. Imide-based modulators of proteolysis and associated methods of use
US20160058872A1 (en) 2014-04-14 2016-03-03 Arvinas, Inc. Imide-based modulators of proteolysis and associated methods of use
EP3227464B1 (en) 2014-12-05 2022-04-20 Foundation Medicine, Inc. Multigene analysis of tumor samples
EP3034620A1 (en) 2014-12-17 2016-06-22 Diaxonhit Compositions and methods for diagnosing thyroid cancer
WO2016103269A1 (en) 2014-12-23 2016-06-30 Ramot At Tel-Aviv University Ltd. Populations of neural progenitor cells and methods of producing and using same
BR112017015273A2 (pt) 2015-01-20 2018-01-09 Merial Inc. compostos e composições antihelmínticos e método de utilizações dos mesmos
EP3050570A1 (en) 2015-01-31 2016-08-03 Neurovision Pharma GmbH Pharmaceutical composition consisting of a combination of G-CSF with GM-CSF
WO2016140974A1 (en) 2015-03-01 2016-09-09 Novena Therapeutics Inc. Process for measuring tumor response to an initial oncology treatment
AU2016266942B2 (en) 2015-05-22 2018-10-18 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
WO2016196580A1 (en) 2015-06-02 2016-12-08 Celgene Corporation Methods for determining drug efficacy for treatment of cancer using ratios of cereblon associated proteins
CA2988119A1 (en) 2015-06-03 2016-12-08 Dana-Farber Cancer Institute, Inc. Methods to induce conversion of regulatory t cells into effector t cells for cancer immunotherapy
HUE054149T2 (hu) 2015-06-04 2021-08-30 Arvinas Operations Inc Proteolízis imid-alapú modulátorai és ezekkel kapcsolatos felhasználási eljárások
WO2016209806A1 (en) 2015-06-22 2016-12-29 President And Fellows Of Harvard College Induction of lamina propria regulatory t cells
WO2017042337A1 (en) 2015-09-09 2017-03-16 Max-Delbrück-Centrum Für Molekulare Medizin In Der Helmhotz-Gemeinschaft Short-chain fatty acids for use in the treatment of cardiovascular disease
WO2017044979A2 (en) 2015-09-11 2017-03-16 Ventria Bioscience Inc. Lactoferrin compositions and methods for modulation of t cell subtypes and treatment of autoimmune diseases
US10954300B2 (en) 2015-09-28 2021-03-23 The Trustees Of Columbia University In The City Of New York Use of pentoxifylline with immune checkpoint-blockade therapies for the treatment of melanoma
US10730835B2 (en) 2015-09-30 2020-08-04 The United States Of America, As Represented By The Secretary, Health And Human Services Thalidomide analogs and methods of use
WO2017075465A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting gata3
WO2017075451A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting pou2af1
WO2017075478A2 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by use of immune cell gene signatures
US11090373B2 (en) 2015-12-04 2021-08-17 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Antigen-specific T cells for inducing immune tolerance
WO2017161001A1 (en) 2016-03-15 2017-09-21 Children's Medical Center Corporation Methods and compositions relating to hematopoietic stem cell expansion
WO2017176958A1 (en) 2016-04-06 2017-10-12 The Regents Of The University Of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
EP3452101A2 (en) 2016-05-04 2019-03-13 CureVac AG Rna encoding a therapeutic protein
WO2017197056A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Bromodomain targeting degronimers for target protein degradation
CN109790143A (zh) 2016-05-10 2019-05-21 C4医药公司 用于靶蛋白降解的胺连接的c3-戊二酰亚胺降解决定子体
WO2018071606A1 (en) 2016-10-11 2018-04-19 Arvinas, Inc. Compounds and methods for the targeted degradation of androgen receptor
IL290809B2 (en) 2016-11-01 2024-01-01 Arvinas Operations Inc Tau-protein targeting protacs and associated methods of use
KR102674902B1 (ko) 2016-12-01 2024-06-14 아비나스 오퍼레이션스, 인코포레이티드 에스트로겐 수용체 분해제로서의 테트라히드로나프탈렌 및 테트라히드로이소퀴놀린 유도체
MX2019007646A (es) 2016-12-23 2019-09-06 Arvinas Operations Inc Moleculas quimericas dirigidas a la proteolisis del egfr y metodos asociados de uso.
US10806737B2 (en) 2016-12-23 2020-10-20 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of fetal liver kinase polypeptides
US11191741B2 (en) 2016-12-24 2021-12-07 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide
AU2018211975B2 (en) 2017-01-26 2022-05-26 Arvinas Operations, Inc. Modulators of estrogen receptor proteolysis and associated methods of use
BR112019015484A2 (pt) 2017-01-31 2020-04-28 Arvinas Operations Inc ligantes de cereblon e compostos bifuncionais compreendendo os mesmos
CN106932576A (zh) 2017-03-22 2017-07-07 山东大学深圳研究院 一种人调节性t细胞的免疫抑制功能的检测方法
DK3820573T3 (da) 2018-07-10 2023-10-23 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidin-2,6-dion-derivativer og anvendelse deraf ved behandling af ikaros family zinc finger 2 (ikzf2)-afhængige sygdomme

Patent Citations (408)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
US2779780A (en) 1955-03-01 1957-01-29 Du Pont 1, 4-diamino-2, 3-dicyano-1, 4-bis (substituted mercapto) butadienes and their preparation
US4261989A (en) 1979-02-19 1981-04-14 Kaken Chemical Co. Ltd. Geldanamycin derivatives and antitumor drug
US4433059A (en) 1981-09-08 1984-02-21 Ortho Diagnostic Systems Inc. Double antibody conjugate
US4444878A (en) 1981-12-21 1984-04-24 Boston Biomedical Research Institute, Inc. Bispecific antibody determinants
US4851332A (en) 1985-04-01 1989-07-25 Sloan-Kettering Institute For Cancer Research Choriocarcinoma monoclonal antibodies and antibody panels
US5869620A (en) 1986-09-02 1999-02-09 Enzon, Inc. Multivalent antigen-binding proteins
US5114946A (en) 1987-06-12 1992-05-19 American Cyanamid Company Transdermal delivery of pharmaceuticals
US4818541A (en) 1987-08-19 1989-04-04 Schering Corporation Transdermal delivery of enantiomers of phenylpropanolamine
EP0346087A2 (en) 1988-06-09 1989-12-13 Snow Brand Milk Products Co., Ltd. Hybrid antibody and process for the production thereof
US5591828A (en) 1989-06-22 1997-01-07 Behringwerke Aktiengesellschaft Bispecific and oligospecific mono-and oligovalent receptors, the preparation and use thereof
WO1991003493A1 (en) 1989-08-29 1991-03-21 The University Of Southampton Bi-or trispecific (fab)3 or (fab)4 conjugates
US5273743A (en) 1990-03-09 1993-12-28 Hybritech Incorporated Trifunctional antibody-like compounds as a combined diagnostic and therapeutic agent
US5864019A (en) 1990-06-11 1999-01-26 Celltech Limited Multivalent antigen-binding proteins
US5582996A (en) 1990-12-04 1996-12-10 The Wistar Institute Of Anatomy & Biology Bifunctional antibodies and method of preparing same
US5959083A (en) 1991-06-03 1999-09-28 Behringwerke Aktiengellschaft Tetravalent bispecific receptors, the preparation and use thereof
US6511663B1 (en) 1991-06-11 2003-01-28 Celltech R&D Limited Tri- and tetra-valent monospecific antigen-binding proteins
EP1013761A2 (en) 1991-09-18 2000-06-28 Kyowa Hakko Kogyo Co., Ltd. Humanized chimeric antibody directed against ganglioside GD3
US6437098B1 (en) 1991-09-18 2002-08-20 Kyowa Hakko Kogyo Co., Ltd. Human chimeric antibody specific for the ganglioside GD3
US5932448A (en) 1991-11-29 1999-08-03 Protein Design Labs., Inc. Bispecific antibody heterodimers
US5910573A (en) 1992-01-23 1999-06-08 Merck Patent Gesellschaft Mit Beschrankter Haftung Monomeric and dimeric antibody-fragment fusion proteins
US5534254A (en) 1992-02-06 1996-07-09 Chiron Corporation Biosynthetic binding proteins for immuno-targeting
WO1993023537A1 (en) 1992-05-08 1993-11-25 Creative Biomolecules Chimeric multivalent protein analogues and methods of use thereof
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
US5844094A (en) 1992-09-25 1998-12-01 Commonwealth Scientific And Industrial Research Organization Target binding polypeptide
WO1994009131A1 (en) 1992-10-15 1994-04-28 Scotgen Limited Recombinant specific binding protein
US5262564A (en) 1992-10-30 1993-11-16 Octamer, Inc. Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents
US5837821A (en) 1992-11-04 1998-11-17 City Of Hope Antibody construct
WO1994012625A2 (en) 1992-11-23 1994-06-09 Zeneca Limited LIGAND BINDING VARIABLE DOMAIN (V-MIN) COMPRISING A FRAMEWORK REGION WITH A CYCLICALLY PERMUTED CENTRAL β-BARREL
US5837242A (en) 1992-12-04 1998-11-17 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US5637481A (en) 1993-02-01 1997-06-10 Bristol-Myers Squibb Company Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
US6476198B1 (en) 1993-07-13 2002-11-05 The Scripps Research Institute Multispecific and multivalent antigen-binding polypeptide molecules
US5635602A (en) 1993-08-13 1997-06-03 The Regents Of The University Of California Design and synthesis of bispecific DNA-antibody conjugates
WO1995009917A1 (en) 1993-10-07 1995-04-13 The Regents Of The University Of California Genetically engineered bispecific tetravalent antibodies
US5843674A (en) 1993-11-16 1998-12-01 Pola Chemical Industries Inc. Anti-human tyrosinase monoclonal antibody
US5952484A (en) 1994-03-08 1999-09-14 Sloan-Kettering Cancer Center Recombinant human anti-LK26 antibodies
EP0754230A1 (en) 1994-04-04 1997-01-22 Genentech, Inc. Agonist antibodies against the flk2/flt3 receptor and uses thereof
US7749719B2 (en) 1994-04-22 2010-07-06 The United States Of America As Represented By The Department Of Health And Human Services Melanoma antigens and their use in diagnostic and therapeutic methods
US5786464A (en) 1994-09-19 1998-07-28 The General Hospital Corporation Overexpression of mammalian and viral proteins
US5786464C1 (en) 1994-09-19 2012-04-24 Gen Hospital Corp Overexpression of mammalian and viral proteins
US6294353B1 (en) 1994-10-20 2001-09-25 Morphosys Ag Targeted hetero-association of recombinant proteins to multi-functional complexes
EP0805871A1 (en) 1995-01-18 1997-11-12 Roche Diagnostics GmbH Anti-cd 30 antibodies preventing proteolytic cleavage and release of membrane-bound cd 30 antigen
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US20070014794A1 (en) 1995-03-01 2007-01-18 Genentech, Inc. Method for making heteromultimeric polypeptides
WO1996037621A2 (en) 1995-05-23 1996-11-28 Morphosys Gesellschaft Für Proteinoptimierung Mbh Multimeric proteins
US5989830A (en) 1995-10-16 1999-11-23 Unilever Patent Holdings Bv Bifunctional or bivalent antibody fragment analogue
WO1997025068A2 (en) 1996-01-05 1997-07-17 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Mesothelin antigen and methods and kits for targeting it
US5777084A (en) 1996-03-07 1998-07-07 Eberhard-Karls-Universitat Tubingen Antibody BV10A4H2 specific for human FLT3/FLK2 receptor and mybridoma
US6239259B1 (en) 1996-04-04 2001-05-29 Unilever Patent Holdings B.V. Multivalent and multispecific antigen-binding protein
US6114148C1 (en) 1996-09-20 2012-05-01 Gen Hospital Corp High level expression of proteins
US6114148A (en) 1996-09-20 2000-09-05 The General Hospital Corporation High level expression of proteins
US6846911B2 (en) 1996-10-25 2005-01-25 The United States Of America As Represented By The Department Of Health And Human Services Methods and compositions for inhibiting inflammation and angiogenesis comprising a mammalian CD97 α subunit
US6743896B2 (en) 1997-04-30 2004-06-01 Enzon, Inc. Single-chain antigen-binding proteins capable of glycosylation, production and uses thereof
US7183076B2 (en) 1997-05-02 2007-02-27 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
US20030207346A1 (en) 1997-05-02 2003-11-06 William R. Arathoon Method for making multispecific antibodies having heteromultimeric and common components
US20070154901A1 (en) 1997-06-11 2007-07-05 Protein Engineering Technology Aps Trimerising module
US6670453B2 (en) 1997-10-27 2003-12-30 Unilever Patent Holdings B.V. Multivalent antigen-binding proteins
WO1999028471A2 (en) 1997-12-01 1999-06-10 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services ANTIBODIES, INCLUDING Fv MOLECULES, AND IMMUNOCONJUGATES HAVING HIGH BINDING AFFINITY FOR MESOTHELIN AND METHODS FOR THEIR USE
US6809185B1 (en) 1998-01-23 2004-10-26 Vlaams Interuniversitair Instituut Voor Biotechnologie Multipurpose antibody derivatives
US20050004352A1 (en) 1998-04-09 2005-01-06 Roland Kontermann Single-chain multiple antigen-binding molecule, its preparation and use
US7129330B1 (en) 1998-05-05 2006-10-31 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Multivalent antibody constructs
WO1999064460A1 (en) 1998-06-10 1999-12-16 Celltech Therapeutics Limited Divalent antibody fragments
US7410640B2 (en) 1998-07-22 2008-08-12 Vanderbilt University GBS toxin receptor antibodies
WO2000006605A2 (en) 1998-07-28 2000-02-10 Micromet Ag Heterominibodies
US6333396B1 (en) 1998-10-20 2001-12-25 Enzon, Inc. Method for targeted delivery of nucleic acids
WO2000035436A2 (en) 1998-12-16 2000-06-22 Warner-Lambert Company Treatment of arthritis with mek inhibitors
US6528481B1 (en) 1999-02-16 2003-03-04 The Burnam Institute NG2/HM proteoglycan-binding peptides that home to angiogenic vasculature and related methods
WO2001012812A2 (en) 1999-08-17 2001-02-22 Biogen, Inc. Baff receptor (bcma), an immunoregulatory agent
US7253263B1 (en) 1999-09-30 2007-08-07 Kyowa Hakko Kogyo Co., Ltd. Complementarity determining region-grafted antibody against ganglioside GD3 and derivative of antibody against ganglioside GD3
WO2001038490A2 (en) 1999-11-29 2001-05-31 The Trustees Of Columbia University In The City Of New York ISOLATION OF FIVE NOVEL GENES CODING FOR NEW Fc RECEPTORS-TYPE MELANOMA INVOLVED IN THE PATHOGENESIS OF LYMPHOMA/MELANOMA
US8460927B2 (en) 1999-11-30 2013-06-11 Mayo Foundation For Medical Education And Research B7-H1 antibodies and method of use
WO2001051056A1 (en) 2000-01-10 2001-07-19 Astrazeneca Ab Fulvestrant formulation
WO2001066139A1 (en) 2000-03-06 2001-09-13 University Of Kentucky Research Foundation Use of a compound that selectively binds to cd123 to impair hematologic cancer progenitor cell
US20020004587A1 (en) 2000-04-11 2002-01-10 Genentech, Inc. Multivalent antibodies and uses therefor
US20020103345A1 (en) 2000-05-24 2002-08-01 Zhenping Zhu Bispecific immunoglobulin-like antigen binding proteins and method of production
US20040220388A1 (en) 2000-06-30 2004-11-04 Nico Mertens Novel heterodimeric fusion proteins
WO2002006213A2 (en) 2000-07-19 2002-01-24 Warner-Lambert Company Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
US20020076406A1 (en) 2000-07-25 2002-06-20 Leung Shui-On Multivalent target binding protein
US7446175B2 (en) 2000-08-22 2008-11-04 Novartis Ag Antibodies to human IL-1β
WO2002016436A2 (en) 2000-08-22 2002-02-28 Novartis Ag ANTIBODIES TO HUMAN IL-1$g(b)
EP1313769A2 (en) 2000-08-22 2003-05-28 Novartis AG Antibodies to human il-1 beta
US20040242847A1 (en) 2000-10-20 2004-12-02 Naoshi Fukushima Degraded agonist antibody
US7090843B1 (en) 2000-11-28 2006-08-15 Seattle Genetics, Inc. Recombinant anti-CD30 antibodies and uses thereof
WO2002066470A1 (en) 2001-01-12 2002-08-29 Amgen Inc. Substituted alkylamine derivatives and methods of use
US20050136049A1 (en) 2001-01-17 2005-06-23 Ledbetter Jeffrey A. Binding constructs and methods for use thereof
WO2002072635A2 (en) 2001-03-13 2002-09-19 University College London Specific binding members
US20050175606A1 (en) 2001-04-11 2005-08-11 Hua-Liang Huang Cyclic single-chain trispecific antibody
US6770622B2 (en) 2001-06-08 2004-08-03 Gary A. Jarvis N-terminally truncated galectin-3 for use in treating cancer
US20040219643A1 (en) 2001-06-28 2004-11-04 Greg Winter Dual-specific ligand
US6833441B2 (en) 2001-08-01 2004-12-21 Abmaxis, Inc. Compositions and methods for generating chimeric heteromultimers
US8309693B2 (en) 2001-08-23 2012-11-13 Rsr Limited Epitope regions of a thyrotrophin (TSH) receptor, uses thereof and antibodies thereto
US20050079170A1 (en) 2001-09-14 2005-04-14 Fabrice Le Gall Dimeric and multimeric antigen binding structure
US20050129701A1 (en) 2001-12-04 2005-06-16 Marasco Wayne A. Antibody to latent membrane proteins and uses thereof
US20030211078A1 (en) 2001-12-07 2003-11-13 Heavner George A. Pseudo-antibody constructs
WO2003062401A2 (en) 2002-01-22 2003-07-31 Corixa Corporation Compositions and methods for the detection, diagnosis and therapy of hematological malignancies
WO2003064383A2 (en) 2002-02-01 2003-08-07 Ariad Gene Therapeutics, Inc. Phosphorus-containing compounds & uses thereof
US20090274649A1 (en) 2002-03-01 2009-11-05 Immunomedics, Inc. Bispecific Antibody Point Mutations for Enhancing Rate of Clearance
WO2003076424A1 (en) 2002-03-08 2003-09-18 Eisai Co. Ltd. Macrocyclic compounds useful as pharmaceuticals
WO2003077914A1 (en) 2002-03-13 2003-09-25 Array Biopharma, Inc N3 alkylated benzimidazole derivatives as mek inhibitors
US20070087381A1 (en) 2002-04-15 2007-04-19 Tetsuo Kojima Methods for constructing scdb libraries
US6780996B2 (en) 2002-04-30 2004-08-24 Wyeth Holdings Corporation Process for the preparation of 7-substituted-3 quinolinecarbonitriles
US7446190B2 (en) 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
US8168179B2 (en) 2002-07-03 2012-05-01 Ono Pharmaceutical Co., Ltd. Treatment method using anti-PD-L1 antibody
WO2004005284A1 (en) 2002-07-09 2004-01-15 Astrazeneca Ab Substituted 3-cyanoquinolines as mek inhibitors
WO2004007529A2 (en) 2002-07-15 2004-01-22 The Trustees Of Princeton University Iap binding compounds
WO2004045532A2 (en) 2002-11-15 2004-06-03 Chiron Corporation Methods for preventing and treating cancer metastasis and bone loss associated with cancer metastasis
US8501415B2 (en) 2002-11-26 2013-08-06 B.R.A.H.M.S. Gmbh Identification of TSH receptor autoantibodies using affinity-purified antibodies
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US20100028330A1 (en) 2002-12-23 2010-02-04 Medimmune Limited Methods of upmodulating adaptive immune response using anti-pd1 antibodies
US7612114B2 (en) 2002-12-26 2009-11-03 Eisai R&D Management Co., Ltd. Selective estrogen receptor modulator
US20060083747A1 (en) 2002-12-27 2006-04-20 Domantis Limited Fc fusion
WO2004081051A1 (en) 2003-03-12 2004-09-23 The University Of Birmingham Bispecific antibodies
WO2004087758A2 (en) 2003-03-26 2004-10-14 Neopharm, Inc. Il 13 receptor alpha 2 antibody and methods of use
US20050003403A1 (en) 2003-04-22 2005-01-06 Rossi Edmund A. Polyvalent protein complex
US20080171855A1 (en) 2003-04-22 2008-07-17 Ibc Pharmaceuticals, Inc. Polyvalent protein complex
US20050163782A1 (en) 2003-06-27 2005-07-28 Biogen Idec Ma Inc. Modified binding molecules comprising connecting peptides
US8080650B2 (en) 2003-06-27 2011-12-20 Diadexus, Inc. Pro104 antibody compositions and methods of use
US20050100543A1 (en) 2003-07-01 2005-05-12 Immunomedics, Inc. Multivalent carriers of bi-specific antibodies
US20050069552A1 (en) 2003-07-28 2005-03-31 Bleck Gregory T. Fusion antibodies
WO2005014652A1 (en) 2003-08-05 2005-02-17 Morphotek, Inc. A variant cell surface molecule associated with cancer
WO2005028443A2 (en) 2003-09-15 2005-03-31 Wyeth A Corporation Of The State Of Delaware, Usa Protein tyrosine kinase enzyme inhibitors
WO2005035577A1 (ja) 2003-10-08 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. ガングリオシドｇｄ３に特異的に結合する抗体組成物
US20080241884A1 (en) 2003-10-08 2008-10-02 Kenya Shitara Fused Protein Composition
US8399645B2 (en) 2003-11-05 2013-03-19 St. Jude Children's Research Hospital, Inc. Chimeric receptors with 4-1BB stimulatory signaling domain
US20050136051A1 (en) 2003-12-22 2005-06-23 Bernard Scallon Methods for generating multimeric molecules
US20070128150A1 (en) 2003-12-23 2007-06-07 Norman Timothy J Branched molecular scaffolds for linking polymer residues to biologically active moieties
US20050266425A1 (en) 2003-12-31 2005-12-01 Vaccinex, Inc. Methods for producing and identifying multispecific antibodies
WO2005068503A2 (en) 2004-01-07 2005-07-28 Chiron Corporation M-csf-specific monoclonal antibody and uses thereof
US9079956B2 (en) 2004-01-07 2015-07-14 Novartis Vaccines And Diagnostics Inc. M-CSF specific monoclonal antibody and uses thereof
WO2005069888A2 (en) 2004-01-16 2005-08-04 The Regents Of The University Of Michigan Smac peptidomimetics and the uses thereof
WO2005069894A2 (en) 2004-01-16 2005-08-04 The Regents Of The University Of Michigan Conformationally constrained smac mimetics and the uses thereof
US20060120960A1 (en) 2004-01-30 2006-06-08 Sergey Deyev Multivalent complexes, their production and method of use
US8263746B2 (en) 2004-02-06 2012-09-11 Morphosys Ag Anti-CD38 human antibodies and uses thereof
WO2005094818A1 (en) 2004-03-23 2005-10-13 Genentech, Inc. Azabicyclo-octane inhibitors of iap
WO2005097791A1 (en) 2004-04-07 2005-10-20 Novartis Ag Inhibitors of iap
WO2005117986A2 (en) 2004-06-01 2005-12-15 Genentech, Inc. Antibody drug conjugates and methods
WO2005121142A1 (en) 2004-06-11 2005-12-22 Japan Tobacco Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido’2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer
US20060014700A1 (en) 2004-07-02 2006-01-19 Genentech, Inc. Inhibitors of IAP
WO2006010118A2 (en) 2004-07-09 2006-01-26 The Regents Of The University Of Michigan Conformationally constrained smac mimetics and the uses thereof
WO2006017295A2 (en) 2004-07-12 2006-02-16 Idun Pharmaceuticals, Inc. Tetrapeptide analogs
US20060025347A1 (en) 2004-07-15 2006-02-02 Condon Stephen M IAP binding compounds
WO2006020258A2 (en) 2004-07-17 2006-02-23 Imclone Systems Incorporated Novel tetravalent bispecific antibody
US20060204493A1 (en) 2004-09-02 2006-09-14 Genentech, Inc. Heteromultimeric molecules
WO2006039238A2 (en) 2004-09-30 2006-04-13 The Goverment Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Irta2 antibodies and methods of use
US8207228B2 (en) 2004-10-04 2012-06-26 Regents Of The University Of Minnesota Calixarene-based peptide conformation mimetics, methods of use, and methods of making
WO2006069063A1 (en) 2004-12-20 2006-06-29 Genentech, Inc. Pyrrolidine inhibitors of iap
EP2322550A1 (en) 2004-12-22 2011-05-18 Amgen, Inc Compositions comprising anti-IGF-1R Antibodies and Methods for obtaining said Antibodies
WO2006076691A2 (en) 2005-01-12 2006-07-20 Medarex, Inc. Irta-2 antibodies and their uses
WO2006086469A2 (en) 2005-02-08 2006-08-17 Genzyme Corporation Antibodies to tgfbeta
US8383780B2 (en) 2005-02-08 2013-02-26 Genzyme Corporation Antibodies to TGFβ
US8591901B2 (en) 2005-02-08 2013-11-26 Genzyme Corporation Antibodies to TGF-β
WO2006099141A2 (en) 2005-03-10 2006-09-21 Morphotek, Inc. Anti-mesothelin antibodies
US8388967B2 (en) 2005-03-25 2013-03-05 Gitr, Inc. Methods for inducing or enhancing an immune response by administering agonistic GITR-binding antibodies
WO2006105021A2 (en) 2005-03-25 2006-10-05 Tolerrx, Inc. Gitr binding molecules and uses therefor
US9028823B2 (en) 2005-03-25 2015-05-12 Gitr, Inc. Methods of inducing or enhancing an immune response in a subject by administering agonistic GITR binding antibodies
US7812135B2 (en) 2005-03-25 2010-10-12 Tolerrx, Inc. GITR-binding antibodies
WO2006106905A1 (ja) 2005-03-31 2006-10-12 Chugai Seiyaku Kabushiki Kaisha 会合制御によるポリペプチド製造方法
US7521056B2 (en) 2005-04-06 2009-04-21 Ibc Pharmaceuticals, Inc. Stably tethered structures of defined compositions with multiple functions or binding specificities
US20070004909A1 (en) 2005-04-15 2007-01-04 Macrogenics, Inc. Covalent diabodies and uses thereof
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US20060263367A1 (en) 2005-05-23 2006-11-23 Fey Georg H Bispecific antibody devoid of Fc region and method of treatment using same
WO2006125481A1 (en) 2005-05-27 2006-11-30 Universitätsklinikum Freiburg Monoclonal antibodies and single chain antibody fragments against cell-surface prostate specific membrane antigen
WO2006138315A2 (en) 2005-06-15 2006-12-28 Schering Corporation Anti-igf1r antibody formulations
WO2007004415A1 (ja) 2005-07-01 2007-01-11 Murata Manufacturing Co., Ltd. 多層セラミック基板およびその製造方法ならびに多層セラミック基板作製用複合グリーンシート
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
WO2007004606A1 (ja) 2005-07-04 2007-01-11 Nikon Vision Co., Ltd. 測距装置
WO2007014011A2 (en) 2005-07-21 2007-02-01 Ardea Biosciences, Inc. N-(arylamino)-sulfonamide inhibitors of mek
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
WO2007024715A2 (en) 2005-08-19 2007-03-01 Abbott Laboratories Dual variable domain immunoglobin and uses thereof
US20070141049A1 (en) 2005-08-26 2007-06-21 Reinhard Bredehorst Bivalent IgY antibody constructs for diagnostic and therapeutic applications
WO2007044887A2 (en) 2005-10-11 2007-04-19 Transtarget, Inc. Method for producing a population of homogenous tetravalent bispecific antibodies
US7527787B2 (en) 2005-10-19 2009-05-05 Ibc Pharmaceuticals, Inc. Multivalent immunoglobulin-based bioactive assemblies
US7534866B2 (en) 2005-10-19 2009-05-19 Ibc Pharmaceuticals, Inc. Methods and compositions for generating bioactive assemblies of increased complexity and uses
US20090130106A1 (en) 2005-11-29 2009-05-21 The University Of Sydney Demibodies: dimerization-activated therapeutic agents
WO2007067992A2 (en) 2005-12-08 2007-06-14 Medarex, Inc. Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1
US20100297138A1 (en) 2005-12-08 2010-11-25 Vistica Cynthia A Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1
US20090304718A1 (en) 2006-01-05 2009-12-10 Guenther Adolf Antibody Molecules Specific for Fibroblast Activation Protein and Immunoconjugates Containing Them
WO2007084342A2 (en) 2006-01-13 2007-07-26 The Government Of The United States, As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Codon optimi zed il- 15 and il- 15r-alpha genes for expression in mammalian cells
WO2007095338A2 (en) 2006-02-15 2007-08-23 Imclone Systems Incorporated Functional antibodies
US20080050370A1 (en) 2006-03-17 2008-02-28 Scott Glaser Stabilized polypeptide compositions
US20090311181A1 (en) 2006-03-20 2009-12-17 The Regents Of The University Of California Engineered Anti-Prostate Stem Cell Antigen (PSCA) Antibodies for Cancer Targeting
WO2007110205A2 (en) 2006-03-24 2007-10-04 Merck Patent Gmbh Engineered heterodimeric protein domains
US20090234105A1 (en) 2006-03-24 2009-09-17 The Regents Of The University Of California Construction of a Multivalent SCFV Through Alkyne-Azide 1,3-Dipolar Cycloaddition
US8603466B2 (en) 2006-03-29 2013-12-10 King's College London Agonist antibodies against TSHR
US20090263392A1 (en) 2006-03-31 2009-10-22 Chugai Seiyaku Kabushiki Kaisha Methods of modifying antibodies for purification of bispecific antibodies
US8710048B2 (en) 2006-04-19 2014-04-29 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US8173689B2 (en) 2006-04-19 2012-05-08 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
WO2007121484A2 (en) 2006-04-19 2007-10-25 Novartis Ag 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting csf-1r signaling
US7553854B2 (en) 2006-04-19 2009-06-30 Novartis Vaccines And Diagnostics, Inc. 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US7915391B2 (en) 2006-04-24 2011-03-29 Amgen Inc. Humanized c-Kit antibody
US20090304657A1 (en) 2006-05-03 2009-12-10 The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services Chimeric t cell receptors and related materials and methods of use
US8236780B2 (en) 2006-05-16 2012-08-07 Galectin Therapeutics Galactose—pronged polysaccharides in a formulation for antifibrotic therapies
WO2007137760A2 (en) 2006-05-25 2007-12-06 Bayer Schering Pharma Aktiengesellschaft Dimeric molecular complexes
US20070274985A1 (en) 2006-05-26 2007-11-29 Stefan Dubel Antibody
US20090175867A1 (en) 2006-06-12 2009-07-09 Trubion Pharmaceuticals, Inc. Single-Chain Multivalent Binding Proteins with Effector Function
US20080152645A1 (en) 2006-08-18 2008-06-26 Armagen Technologies, Inc. Genetically Encoded Multifunctional Compositions Bidrectionally Transported Between Peripheral Blood and the CNS
WO2008024725A1 (en) 2006-08-21 2008-02-28 Genentech, Inc. Aza-benzofuranyl compounds and methods of use
US20080069820A1 (en) 2006-08-30 2008-03-20 Genentech, Inc. Multispecific antibodies
US8440798B2 (en) 2006-10-04 2013-05-14 Københavns Universitet Generation of a cancer-specific immune response toward MUC1 and cancer specific MUC1 antibodies
US20100150910A1 (en) 2006-10-10 2010-06-17 Universite De Nantes Use of monoclonal antibodies specific to the o-acetylated form of gd2 ganglioside for treatment of certain cancers
US20080254512A1 (en) 2006-11-02 2008-10-16 Capon Daniel J Hybrid immunoglobulins with moving parts
US7767675B2 (en) 2006-11-22 2010-08-03 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
US8461330B2 (en) 2006-11-22 2013-06-11 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
WO2008061740A1 (en) 2006-11-23 2008-05-29 Novartis Ag Pyrimidines and their use as cxcr2 receptor antagonists
WO2008061741A1 (en) 2006-11-23 2008-05-29 Novartis Ag 5-sulfanylmethyl-[1,2,4] triazol[1, 5-a] pyrimidin-7-ol derivatives as cxcr2 antagonists
US20100152205A1 (en) 2006-11-23 2010-06-17 Novartis Ag Cxcr2 inhibitors
WO2008062026A1 (en) 2006-11-23 2008-05-29 Novartis Ag 5-sulfanylmethyl-pyrazolo [1,5-a] pyrimidin-7-ol derivatives as cxcr2 antagonists
US20120276046A1 (en) 2007-02-16 2012-11-01 Sloan-Kettering Institute For Cancer Research Anti ganglioside gd3 antibodies and uses thereof
US8207308B2 (en) 2007-02-16 2012-06-26 Sloan-Kettering Institute For Cancer Research Anti ganglioside GD3 antibodies and uses thereof
US7635753B2 (en) 2007-02-19 2009-12-22 Wisconsin Alumni Research Foundation Prostate cancer and melanoma antigens
EP2514766A2 (en) 2007-03-29 2012-10-24 Technion Research & Development Foundation Ltd. Antibodies, methods and kits for diagnosing and treating melanoma
WO2008119353A1 (en) 2007-03-29 2008-10-09 Genmab A/S Bispecific antibodies and methods for production thereof
US20090252742A1 (en) 2007-04-13 2009-10-08 Ivan Bergstein IL3Ralpha antibody conjugates and uses thereof
US20080260738A1 (en) 2007-04-18 2008-10-23 Moore Margaret D Single chain fc, methods of making and methods of treatment
WO2008132601A1 (en) 2007-04-30 2008-11-06 Immutep Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2008134679A1 (en) 2007-04-30 2008-11-06 Genentech, Inc. Inhibitors of iap
US9244059B2 (en) 2007-04-30 2016-01-26 Immutep Parc Club Orsay Cytotoxic anti-LAG-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2008143794A1 (en) 2007-05-11 2008-11-27 Altor Bioscience Corporation Fusion molecules and il-15 variants
WO2008146911A1 (ja) 2007-06-01 2008-12-04 Sapporo Medical University IL13Ra2に対する抗体およびこれを含む診断・治療薬
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
US8344112B2 (en) 2007-07-31 2013-01-01 Merck Sharp & Dohme Limited IGF-1R specific antibodies useful in the detection and diagnosis of cellular proliferative disorders
US20090155275A1 (en) 2007-07-31 2009-06-18 Medimmune, Llc Multispecific epitope binding proteins and uses thereof
WO2009021754A2 (en) 2007-08-15 2009-02-19 Bayer Schering Pharma Aktiengesellschaft Monospecific and multispecific antibodies and method of use
WO2009036082A2 (en) 2007-09-12 2009-03-19 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use
WO2009045957A1 (en) 2007-10-01 2009-04-09 Medarex, Inc. Human antibodies that bind mesothelin, and uses thereof
WO2009044273A2 (en) 2007-10-05 2009-04-09 Immutep Use of recombinant lag-3 or the derivatives thereof for eliciting monocyte immune response
WO2009055730A1 (en) 2007-10-25 2009-04-30 Genentech, Inc. Process for making thienopyrimidine compounds
WO2009068204A1 (en) 2007-11-26 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin antibodies and uses therefor
WO2009068630A1 (en) 2007-11-27 2009-06-04 Ablynx N.V. Immunoglobulin constructs
US20090148905A1 (en) 2007-11-30 2009-06-11 Claire Ashman Antigen-binding constructs
WO2009085983A1 (en) 2007-12-19 2009-07-09 Genentech, Inc. 5-anilinoimidazopyridines and methods of use
US20090162359A1 (en) 2007-12-21 2009-06-25 Christian Klein Bivalent, bispecific antibodies
US20090162360A1 (en) 2007-12-21 2009-06-25 Christian Klein Bivalent, bispecific antibodies
US20090232811A1 (en) 2007-12-21 2009-09-17 Christian Klein Bivalent, bispecific antibodies
US20090175851A1 (en) 2007-12-21 2009-07-09 Christian Klein Bivalent, bispecific antibodies
WO2009089004A1 (en) 2008-01-07 2009-07-16 Amgen Inc. Method for making antibody fc-heterodimeric molecules using electrostatic steering effects
WO2009101611A1 (en) 2008-02-11 2009-08-20 Curetech Ltd. Monoclonal antibodies for tumor treatment
WO2009106539A1 (en) 2008-02-26 2009-09-03 Novartis Ag Heterocyclic compounds as inhibitors of cxcr2
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
US20090297529A1 (en) 2008-05-30 2009-12-03 Yiwen Li Anti-flt3 antibodies
WO2009155386A1 (en) 2008-06-20 2009-12-23 Abbott Laboratories A process for the preparation of the apoptosis promoter abt-263
WO2009156737A1 (en) 2008-06-25 2009-12-30 Vernalis (R&D) Limited Triazolo [4, 5-d] pyramidine derivatives and their use as purine receptor antagonists
US8329754B2 (en) 2008-08-04 2012-12-11 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US8722925B2 (en) 2008-08-04 2014-05-13 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US8288588B2 (en) 2008-08-04 2012-10-16 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US7989497B2 (en) 2008-08-04 2011-08-02 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US9115087B2 (en) 2008-08-04 2015-08-25 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US20110251206A1 (en) 2008-08-04 2011-10-13 Novartis Ag Squaramide derivatives as CXCR2 antagonist
WO2010015613A1 (en) 2008-08-04 2010-02-11 Novartis Ag Organic compounds
US20110251205A1 (en) 2008-08-04 2011-10-13 Novartis Ag Squaramide derivatives as cxcr2 antagonist
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US8415355B2 (en) 2008-08-22 2013-04-09 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8685980B2 (en) 2008-08-22 2014-04-01 Novartis Ag Pyrrolopyrimidine compounds and their uses
WO2010020675A1 (en) 2008-08-22 2010-02-25 Novartis Ag Pyrrolopyrimidine compounds as cdk inhibitors
US20120114649A1 (en) 2008-08-25 2012-05-10 Amplimmune, Inc. Delaware Compositions of pd-1 antagonists and methods of use
US8114845B2 (en) 2008-08-25 2012-02-14 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
WO2010027827A2 (en) 2008-08-25 2010-03-11 Amplimmune, Inc. Targeted costimulatory polypeptides and methods of use to treat cancer
US8609089B2 (en) 2008-08-25 2013-12-17 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
US8927697B2 (en) 2008-09-12 2015-01-06 Isis Innovation Limited PD-1 specific antibodies and uses thereof
US20140004124A1 (en) 2008-09-19 2014-01-02 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Monoclonal antibodies for cspg4 for the diagnosis and treatment of basal breast carcinoma
WO2010033866A2 (en) 2008-09-19 2010-03-25 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Monoclonal antibodies for cspg4 for the diagnosis and treatment of basal breast carcinoma
US9102727B2 (en) 2008-09-26 2015-08-11 Emory University Human anti-PD-1 antibodies and uses therefor
US8552154B2 (en) 2008-09-26 2013-10-08 Emory University Anti-PD-L1 antibodies and uses therefor
WO2010053732A1 (en) * 2008-10-29 2010-05-14 Celgene Corporation Isoindoline compounds for use in the treatment of cancer
WO2010063802A1 (en) 2008-12-05 2010-06-10 Novartis Ag 3, 4-di-substituted cyclobutene- 1, 2 -diones as cxcr2 receptor antagonists
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US9029393B2 (en) 2009-01-26 2015-05-12 Kaldi Pharma, Sas Adenosine receptor ligands and uses thereof
US20120039906A1 (en) 2009-02-09 2012-02-16 INSER (Institut National de la Recherche Medicale) PD-1 Antibodies and PD-L1 Antibodies and Uses Thereof
US9133197B2 (en) 2009-03-20 2015-09-15 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Oxidated derivatives of triazolylpurines useful as ligands of the adenosine A2A receptor and their use as medicaments
WO2010114940A1 (en) 2009-04-01 2010-10-07 Genentech, Inc. Anti-fcrh5 antibodies and immunoconjugates and methods of use
WO2010120561A1 (en) 2009-04-01 2010-10-21 Genentech, Inc. Anti-fcrh5 antibodies and immunoconjugates and methods of use
WO2010129304A2 (en) 2009-04-27 2010-11-11 Oncomed Pharmaceuticals, Inc. Method for making heteromultimeric molecules
WO2010126066A1 (ja) 2009-04-27 2010-11-04 協和発酵キリン株式会社 血液腫瘍治療を目的とした抗IL-3Rα抗体
WO2011049677A1 (en) 2009-09-02 2011-04-28 Irm Llc Compounds and compositions as tlr activity modulators
US8709424B2 (en) 2009-09-03 2014-04-29 Merck Sharp & Dohme Corp. Anti-GITR antibodies
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
US8779108B2 (en) 2009-11-24 2014-07-15 Medimmune, Limited Targeted binding agents against B7-H1
WO2011066342A2 (en) 2009-11-24 2011-06-03 Amplimmune, Inc. Simultaneous inhibition of pd-l1/pd-l2
US20110268656A1 (en) 2009-12-02 2011-11-03 David Ho J591 minibodies and cys-diabodies for targeting human prostate specific membrane antigen (psma) and methods for their use
WO2011076786A1 (en) 2009-12-22 2011-06-30 Novartis Ag Substituted isoquinolinones and quinazolinones
WO2011076922A1 (en) 2009-12-23 2011-06-30 Synimmune Gmbh Anti-flt3 antibodies and methods of using the same
WO2011095625A1 (en) 2010-02-05 2011-08-11 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
US20120009181A1 (en) 2010-02-24 2012-01-12 Ab Olga Folate Receptor 1 Antibodies and Immunoconjugates and Uses Thereof
US8993731B2 (en) 2010-03-11 2015-03-31 Ucb Biopharma Sprl PD-1 antibody
US8796284B2 (en) 2010-03-31 2014-08-05 Palobiofarma, S.L. 4-aminopyrimidine derivatives and their as as adenosine A2a receptor antagonists
WO2011131746A2 (en) 2010-04-20 2011-10-27 Genmab A/S Heterodimeric antibody fc-containing proteins and methods for production thereof
WO2011156518A2 (en) 2010-06-10 2011-12-15 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8552156B2 (en) 2010-06-11 2013-10-08 Kyowa Hakko Kirin Co., Ltd Anti-TIM-3 antibody
US20130101607A1 (en) 2010-06-15 2013-04-25 Thomas J. Kipps Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) Single Chain FV Antibody Fragment Conjugates and Methods of Use Thereof
WO2011159847A2 (en) 2010-06-15 2011-12-22 The Regents Of The University Of California Receptor tyrosine kinase-like orphan receptor 1 (ror1) single chain fv antibody fragment conjugates and methods of use thereof
WO2011159769A2 (en) 2010-06-17 2011-12-22 Aragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
US9163087B2 (en) 2010-06-18 2015-10-20 The Brigham And Women's Hospital, Inc. Bi-specific antibodies against TIM-3 and PD-1 for immunotherapy in chronic immune conditions
WO2011160119A2 (en) 2010-06-19 2011-12-22 Memorial Sloan-Kettering Cancer Center Anti-gd2 antibodies
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
WO2012033885A1 (en) 2010-09-08 2012-03-15 Baylor College Of Medicine Immunotherapy of cancer using genetically engineered gd2-specific t cells
US20120071535A1 (en) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
WO2012037410A2 (en) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
WO2012037411A2 (en) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
WO2012062713A1 (en) 2010-11-08 2012-05-18 Novartis Ag Cxcr2 binding polypeptides
WO2012079000A1 (en) 2010-12-09 2012-06-14 The Trustees Of The University Of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
US8362211B2 (en) 2010-12-30 2013-01-29 Takeda Pharmaceutical Company Limited Anti-CD38 antibodies
WO2012135854A2 (en) 2011-04-01 2012-10-04 Memorial Sloan-Kettering Cancer Center Antibodies to cytosolic peptides
US9205148B2 (en) 2011-04-20 2015-12-08 Medimmune, Llc Antibodies and other molecules that bind B7-H1 and PD-1
WO2012145493A1 (en) 2011-04-20 2012-10-26 Amplimmune, Inc. Antibodies and other molecules that bind b7-h1 and pd-1
US20120288506A1 (en) 2011-05-12 2012-11-15 Imclone Llc C-kit antibodies and uses thereof
WO2012163805A1 (en) 2011-05-27 2012-12-06 Glaxo Group Limited Bcma (cd269/tnfrsf17) -binding proteins
WO2012167143A1 (en) 2011-06-03 2012-12-06 Xoma Technology Ltd. Antibodies specific for tgf-beta
WO2012175222A1 (en) 2011-06-24 2012-12-27 Cytune AN IL-15 AND IL-15Rα SUSHI DOMAIN BASED IMMUNOCYTOKINES
US8841418B2 (en) 2011-07-01 2014-09-23 Cellerant Therapeutics, Inc. Antibodies that specifically bind to TIM3
WO2013019906A1 (en) 2011-08-01 2013-02-07 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors
WO2013030803A1 (en) 2011-09-02 2013-03-07 Novartis Ag Choline salt of an anti - inflammatory substituted cyclobutenedione compound
WO2013040557A2 (en) 2011-09-16 2013-03-21 The Trustees Of The University Of Pennsylvania Rna engineered t cells for the treatment of cancer
WO2013040371A2 (en) 2011-09-16 2013-03-21 Baylor College Of Medicine Targeting the tumor microenvironment using manipulated nkt cells
WO2013061273A1 (en) 2011-10-25 2013-05-02 Massimo Dominici A modified effector cell (or chimeric receptor) for treating disialoganglioside gd2 -expressing neoplasia
WO2013060867A2 (en) 2011-10-27 2013-05-02 Genmab A/S Production of heterodimeric proteins
WO2013063419A2 (en) 2011-10-28 2013-05-02 The Trustees Of The University Of Pennsylvania A fully human, anti-mesothelin specific chimeric immune receptor for redirected mesothelin-expressing cell targeting
WO2013074916A1 (en) 2011-11-18 2013-05-23 Board Of Regents, The University Of Texas System Car+ t cells genetically modified to eliminate expression of t- cell receptor and/or hla
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
WO2013085552A1 (en) 2011-12-08 2013-06-13 Cleveland Clinic Foundation Glenoid vault fixation
WO2013111105A1 (en) 2012-01-26 2013-08-01 Novartis Ag Imidazopyrrolidinone compounds
WO2013123061A1 (en) 2012-02-13 2013-08-22 Seattle Children's Hospital D/B/A Seattle Children's Research Institute Bispecific chimeric antigen receptors and therapeutic uses thereof
WO2013126712A1 (en) 2012-02-22 2013-08-29 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer
WO2013142034A1 (en) 2012-03-23 2013-09-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-mesothelin chimeric antigen receptors
WO2013165940A1 (en) 2012-05-01 2013-11-07 Genentech, Inc. Anti-pmel17 antibodies and immunoconjugates
US20130295007A1 (en) 2012-05-01 2013-11-07 Genentech, Inc. Anti-pmel17 antibodies and immunoconjugates
WO2013168108A2 (en) 2012-05-09 2013-11-14 Novartis Ag Chemokine receptor binding polypeptides
WO2013173820A2 (en) 2012-05-18 2013-11-21 Scott & White Healthcare Bispecific scfv immunofusion (bif)
WO2013179174A1 (en) 2012-05-29 2013-12-05 Koninklijke Philips N.V. Lighting arrangement
US9175082B2 (en) 2012-05-31 2015-11-03 Sorrento Therapeutics, Inc. Antigen binding proteins that bind PD-L1
WO2013192294A1 (en) 2012-06-20 2013-12-27 Boston 3T Biotechnologies, Inc. Cellular therapies for treating and preventing cancers and other immune system disorders
US9505839B2 (en) 2012-07-02 2016-11-29 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
WO2014022758A1 (en) 2012-08-03 2014-02-06 Dana-Farber Cancer Institute, Inc. Single agent anti-pd-l1 and pd-l2 dual binding antibodies and methods of use
WO2014031687A1 (en) 2012-08-20 2014-02-27 Jensen, Michael Method and compositions for cellular immunotherapy
WO2014039960A1 (en) * 2012-09-10 2014-03-13 Celgene Corporation Methods for the treatment of locally advanced breast cancer
US20140086932A1 (en) 2012-09-17 2014-03-27 Peter G. Traber Method for enhancing specific immunotherapies in cancer treatment
WO2014055897A2 (en) 2012-10-04 2014-04-10 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-pd-l1 antibodies and methods of use
WO2014066527A2 (en) 2012-10-24 2014-05-01 Admune Therapeutics Llc Il-15r alpha forms, cells expressing il-15r alpha forms, and therapeutic uses of il-15r alpha and il-15/il-15r alpha complexes
WO2014089335A2 (en) 2012-12-07 2014-06-12 Amgen Inc. Bcma antigen binding proteins
WO2014100079A1 (en) 2012-12-21 2014-06-26 Merck Sharp & Dohme Corp. Antibodies that bind to human programmed death ligand 1 (pd-l1)
WO2014122144A1 (en) 2013-02-05 2014-08-14 Engmab Ag BISPECIFIC ANTIBODIES AGAINST CD3ε AND BCMA
WO2014130310A1 (en) 2013-02-19 2014-08-28 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
WO2014130657A1 (en) 2013-02-20 2014-08-28 The Trustees Of The University Of Pennsylvania Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor
WO2014130635A1 (en) 2013-02-20 2014-08-28 Novartis Ag Effective targeting of primary human leukemia using anti-cd123 chimeric antigen receptor engineered t cells
WO2014138819A1 (en) 2013-03-14 2014-09-18 Csl Limited Agents that neutralize il-3 signaling and uses thereof
WO2014138805A1 (en) 2013-03-14 2014-09-18 Csl Limited Anti il-3r alpha agents and uses thereof
WO2014140248A1 (en) 2013-03-15 2014-09-18 Amgen Research (Munich) Gmbh Binding molecules for bcma and cd3
WO2014144622A2 (en) 2013-03-15 2014-09-18 Stephen Forman Cd123-specific chimeric antigen receptor redirected t cells and methods of their use
WO2014140180A1 (en) 2013-03-15 2014-09-18 Glaxosmithkline Intellectual Property Development Limited Anti-lag-3 binding proteins
WO2014153270A1 (en) 2013-03-16 2014-09-25 Novartis Ag Treatment of cancer using humanized anti-cd19 chimeric antigen receptor
WO2014165707A2 (en) 2013-04-03 2014-10-09 Memorial Sloan-Kettering Cancer Center Effective generation of tumor-targeted t-cells derived from pluripotent stem cells
WO2014179664A2 (en) 2013-05-02 2014-11-06 Anaptysbio, Inc. Antibodies directed against programmed death-1 (pd-1)
WO2014194302A2 (en) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-1
WO2014210064A1 (en) 2013-06-24 2014-12-31 Genentech, Inc. Anti-fcrh5 antibodies
WO2014209804A1 (en) 2013-06-24 2014-12-31 Biomed Valley Discoveries, Inc. Bispecific antibodies
WO2015026684A1 (en) 2013-08-20 2015-02-26 Merck Sharp & Dohme Corp. Modulation of tumor immunity
WO2015031667A2 (en) 2013-08-30 2015-03-05 Amgen Inc. Gitr antigen binding proteins
US9464139B2 (en) 2013-08-30 2016-10-11 Amgen Inc. GITR antigen binding proteins and methods of use thereof
US8735553B1 (en) 2013-09-13 2014-05-27 Beigene, Ltd. Anti-PD1 antibodies and their use as therapeutics and diagnostics
WO2015061668A1 (en) 2013-10-25 2015-04-30 Dana-Farber Cancer Institute, Inc. Anti-pd-l1 monoclonal antibodies and fragments thereof
WO2015081158A1 (en) 2013-11-26 2015-06-04 Bristol-Myers Squibb Company Method of treating hiv by disrupting pd-1/pd-l1 signaling
WO2015085847A1 (zh) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Pd-1抗体、其抗原结合片段及其医药用途
WO2015090230A1 (en) 2013-12-19 2015-06-25 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
WO2015109124A2 (en) 2014-01-15 2015-07-23 Kadmon Corporation, Llc Immunomodulatory agents
US20170015758A1 (en) 2014-01-21 2017-01-19 Medimmune, Llc Compositions And Methods For Modulating And Redirecting Immune Responses
WO2015112800A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-1
WO2015112805A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
US20150210769A1 (en) 2014-01-24 2015-07-30 Novartis Ag Antibody molecules to pd-1 and uses thereof
WO2015116539A1 (en) 2014-01-28 2015-08-06 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
US20150218274A1 (en) 2014-01-31 2015-08-06 Novartis Ag Antibody molecules to tim-3 and uses thereof
WO2015136017A1 (en) 2014-03-13 2015-09-17 F. Hoffmann-La Roche Ag Methods and compositions for modulating estrogen receptor mutants
US20150259420A1 (en) 2014-03-14 2015-09-17 Novartis Ag Antibody molecules to lag-3 and uses thereof
WO2015142675A2 (en) 2014-03-15 2015-09-24 Novartis Ag Treatment of cancer using chimeric antigen receptor
US20150368349A1 (en) 2014-05-28 2015-12-24 4-Antibody Ag Anti-GITR Antibodies and Methods of Use Thereof
WO2015184099A1 (en) 2014-05-28 2015-12-03 4-Antibody Ag Anti-gitr antibodies and methods of use thereof
WO2015181342A1 (en) 2014-05-29 2015-12-03 Spring Bioscience Corporation Pd-l1 antibodies and uses thereof
US9228016B2 (en) 2014-06-06 2016-01-05 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
WO2015195163A1 (en) 2014-06-20 2015-12-23 R-Pharm Overseas, Inc. Pd-l1 antagonist fully human antibody
WO2015200119A1 (en) 2014-06-26 2015-12-30 Macrogenics, Inc. Covalently bonded diabodies having immunoreactivity with pd-1 and lag-3, and methods of use thereof
WO2016000619A1 (en) 2014-07-03 2016-01-07 Beigene, Ltd. Anti-pd-l1 antibodies and their use as therapeutics and diagnostics
WO2016014576A1 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
WO2016014535A1 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using a cll-1 chimeric antigen receptor
WO2016014565A2 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using humanized anti-bcma chimeric antigen receptor
WO2016014789A2 (en) 2014-07-24 2016-01-28 Bluebird Bio, Inc. Bcma chimeric antigen receptors
WO2016028672A1 (en) 2014-08-19 2016-02-25 Merck Sharp & Dohme Corp. Anti-lag3 antibodies and antigen-binding fragments
WO2016028896A1 (en) 2014-08-19 2016-02-25 Novartis Ag Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment
WO2016054638A1 (en) 2014-10-03 2016-04-07 Dana-Farber Cancer Institute, Inc. Glucocorticoid-induced tumor necrosis factor receptor (gitr) antibodies and methods of use thereof
WO2016057846A1 (en) 2014-10-08 2016-04-14 Novartis Ag Compositions and methods of use for augmented immune response and cancer therapy
US20160108123A1 (en) 2014-10-14 2016-04-21 Novartis Ag Antibody molecules to pd-l1 and uses thereof
EP3214081A1 (en) * 2014-10-30 2017-09-06 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
WO2016071448A1 (en) 2014-11-06 2016-05-12 F. Hoffmann-La Roche Ag Anti-tim3 antibodies and methods of use
US20160129108A1 (en) 2014-11-11 2016-05-12 Medimmune Limited Therapeutic combinations comprising anti-cd73 antibodies and uses thereof
WO2016092419A1 (en) 2014-12-09 2016-06-16 Rinat Neuroscience Corp. Anti-pd-1 antibodies and methods of use thereof
WO2016111947A2 (en) 2015-01-05 2016-07-14 Jounce Therapeutics, Inc. Antibodies that inhibit tim-3:lilrb2 interactions and uses thereof
WO2016144803A2 (en) 2015-03-06 2016-09-15 Sorrento Therapeutics, Inc. Antibody therapeutics that bind tim3
WO2016161270A1 (en) 2015-04-01 2016-10-06 Anaptysbio, Inc. Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)
WO2016196792A1 (en) 2015-06-03 2016-12-08 Bristol-Myers Squibb Company Anti-gitr antibodies for cancer diagnostics
WO2017015623A2 (en) 2015-07-23 2017-01-26 Inhibrx Lp Multivalent and multispecific gitr-binding fusion proteins
US20170022284A1 (en) 2015-07-23 2017-01-26 Inhibrx Lp Multivalent and multispecific gitr-binding fusion proteins
WO2017025918A1 (en) 2015-08-11 2017-02-16 Novartis Ag 5-bromo-2,6-di-(lh-pyrazol-l-yl)pyrimidin-4-amine for use in the treatment of cancer
US20170073386A1 (en) 2015-08-12 2017-03-16 Medimmune Limited Gitrl fusion proteins and uses thereof
WO2017025610A1 (en) 2015-08-12 2017-02-16 Medimmune Limited Gitrl fusion proteins and uses thereof
WO2017027645A1 (en) 2015-08-13 2017-02-16 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
WO2018119448A1 (en) * 2016-12-23 2018-06-28 Arvinas, Inc. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
WO2019038717A1 (en) * 2017-08-23 2019-02-28 Novartis Ag 3- (1-OXOISOINDOLIN-2-YL) PIPERIDINE-2,6-DIONE DERIVATIVES AND USES THEREOF
WO2019079569A1 (en) * 2017-10-18 2019-04-25 Novartis Ag COMPOSITIONS AND METHODS FOR SELECTIVE DEGRADATION OF A PROTEIN
WO2019191112A1 (en) * 2018-03-26 2019-10-03 C4 Therapeutics, Inc. Cereblon binders for the degradation of ikaros

Non-Patent Citations (133)

* Cited by examiner, † Cited by third party
Title
"4507 Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies", ABSTRACTS OF 56TH ASH ANNUAL MEETING AND EXPOSITION, 6 December 2014 (2014-12-06)
"A Textbook of Drug Design and Development", 1991, GORDON & BREACH, article "Design and Applications of Prodrugs"
"Pro-Drugs as Novel Delivery Systems", 1975, AM. CHEM. SOC.
16TH ANNU MEET AM SOC GEN CELL THER (ASGCT, 15 May 2013 (2013-05-15)
ABENGOZAR ET AL., BLOOD, vol. 119, no. 19, 2012, pages 4565 - 4576
ACHYUT ET AL., GASTROENTEROLOGY, vol. 141, no. 4, 2011, pages 1167 - 78
AGGEN ET AL., GENE THER., vol. 19, no. 4, 2012, pages 365 - 74
AIGNER ET AL., LEUKEMIA, vol. 27, no. 5, 2013, pages 1107 - 1115
APTE ET AL., ADV. EXP. MED. BIOL., 2000, pages 277 - 88
APTE ET AL., CANCER METASTASIS REV., 2006, pages 387 - 408
ASANUMA, S. ET AL., CANCER SCI., vol. 104, 2013, pages 1097 - 1106
BEJCEK, CANCER RESEARCH, vol. 55, 1995, pages 2346 - 178,949-982
BIN DHUBAN, K. ET AL., J. IMMUNOL., vol. 194, 2015, pages 3687 - 96
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
BLOBE ET AL., N ENGL J MED., vol. 342, no. 18, 2000, pages 1350 - 8
BOER K. ET AL., THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, vol. 9, no. 7, 2017, pages 465 - 479
BRASS ET AL., CLIN CANCER RES, vol. 7, no. 6, 2001, pages 1490 - 1496
BREMER E-G ET AL., J BIOL CHEM, vol. 259, 1984, pages 14773 - 14777
BRENTJENS ET AL., BLOOD, vol. 118, no. 18, 2011, pages 4817 - 4828
BROOKS ET AL., PNAS, vol. 107, no. 22, 2010, pages 10056 - 10061
CARON ET AL., CANCER RES, vol. 52, no. 24, 1992, pages 6761 - 6767
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1204531-25-80
CHEUNG ET AL., CANCER RES, vol. 45, no. 6, 1985, pages 2642 - 2649
CHEUNG ET AL., J CLIN ONCOL, vol. 16, no. 9, 1998, pages 3053 - 3060
CHEUNG ET AL., J CLIN ONCOL, vol. 5, no. 9, 1987, pages 1430 - 1440
CHINNASAMY ET AL., J CLIN INVEST, vol. 120, no. 11, 2010, pages 3953 - 3968
CHMIELEWSKI ET AL., GASTOENTEROLOGY, vol. 143, no. 4, 2012, pages 1095 - 1107
DAO ET AL., SCI TRANSL MED, vol. 5, no. 176, 2013, pages 176ra33
DE GROOT ET AL., J IMMUNOL, vol. 183, no. 6, 2009, pages 4127 - 4134
DEMBIC ET AL., NATURE, vol. 320, 1986, pages 232 - 238
DINARELLO, EUR. J. IMMUNOL., 2010, pages 599 - 606
DOLEZAL ET AL., PROTEIN ENGINEERING, vol. 16, no. l, 2003, pages 47 - 56
DORNAN ET AL.: "Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma", BLOOD, vol. 114, no. 13, 24 September 2009 (2009-09-24), pages 2721 - 9, XP055075268, doi:10.1182/blood-2009-02-205500
DUTOUR ET AL., ADV HEMATOL, vol. 2012, 2012, pages 683065
E.L. ELIELS.H. WILENL.N. MANDER: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
ELKINS ET AL.: "FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma", MOL CANCER THER., vol. ll, no. 10, October 2012 (2012-10-01), pages 2222 - 32, XP055141107, doi:10.1158/1535-7163.MCT-12-0087
ENGELS ET AL., HUM. GENE THER., vol. 16, 2005, pages 799 - 810
FENG ET AL.: "Glypican-3 antibodies: a new therapeutic target for liver cancer", FEBS LETT., vol. 588, no. 2, 21 January 2014 (2014-01-21), pages 377 - 82, XP028669969, doi:10.1016/j.febslet.2013.10.002
FINN ET AL., BREAST CANCER RESEARCH, vol. 11, no. 5, 2009, pages R77
FRIGERIO ET AL., EUROPEAN J CANCER, vol. 49, no. 9, 2013, pages 2223 - 2232
GARNER F ET AL., ANTICANCER DRUGS, vol. 26, no. 9, 2015, pages 948 - 56
GETNET, D. ET AL., MOL. IMMUNOL., vol. 47, 2010, pages 1595 - 1600
GHODS ET AL., BIOTECHNOL APPL BIOCHEM, 2013
HAMID, O. ET AL., NEW ENGLAND JOURNAL OF MEDICINE, vol. 369, no. 2, 2013, pages 134 - 44
HANDGRETINGER ET AL., CANCER IMMUNOL IMMUNOTHER, vol. 35, no. 3, pages 199 - 204
HOFHEINZ ET AL., ONCOLOGY RESEARCH AND TREATMENT, vol. 26, no. 1, 2003
HOLLINGER ET AL., PROC NATL ACAD. SCI. U.S.A., vol. 90, 1993, pages 6444 - 6448
HOMBACH ET AL., GASTROENTEROLOGY, vol. 113, no. 4, 1997, pages 1163 - 1170
HONG ET AL., J IMMUNOTHER, vol. 37, no. 2, 2014, pages 93 - 104
HUANG ET AL., CANCER RES, vol. 72, no. 1, 2012, pages 271 - 281
HUDECEK ET AL., CLIN CANCER RES, vol. 19, no. 12, 2013, pages 3153 - 3164
HUSTON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883
JAGER ET AL., APPL IMMUNOHISTOCHEM MOL MORPHOL, vol. 15, no. 1, 2007, pages 77 - 83
JOHN, L.B. ET AL., MOL. IMMUNOL., vol. 48, 2011, pages 1272 - 1278
JUNE ET AL., NATURE REVIEWS IMMUNOLOGY, vol. 9.10, 2009, pages 704 - 716
KATAOKA, D. ET AL., NATURE GENETICS, vol. 47, 2015, pages 1304 - 1315
KATO ET AL., LEUK RES, vol. 37, no. 1, 2013, pages 83 - 88
KELLY ET AL., CANCER BIOTHER RADIOPHARM, vol. 23, no. 4, 2008, pages 411 - 423
KERSHAW ET AL., NAT. REV. IMMUNOL., vol. 5, 2005, pages 928 - 940
KIM, H-J. ET AL., SCIENCE, vol. 350, 2015, pages 334 - 339
KMIECIK ET AL., ONCOIMMUNOLOGY, vol. 3, no. l, 2014, pages e27185
KOCHENDERFER ET AL., BLOOD, vol. 122, no. 25, 2013, pages 4129 - 2973
KOCHENDERFER, J.N. ET AL., BLOOD, vol. 116, no. 20, 2010, pages 4099 - 1262
KOCHENDERFER, J.N. ET AL., J. IMMUNOTHER., vol. 32, no. 7, 2009, pages 689 - 702
KUDRYASHOV V ET AL., GLYCOCONJ J., vol. 15, no. 3, 1998, pages 243 - 9
LANZAVECCHIA ET AL., EUR. J. IMMUNOL., vol. 17, 1987, pages 105
LAPUSAN ET AL., INVEST NEW DRUGS, vol. 30, no. 3, 2012, pages 1121 - 1131
LEWITT, ANNALS OF NEUROLOGY, vol. 63, no. 3, 2008, pages 295 - 302
LOU ET AL., PROC NATL ACAD SCI USA, vol. 111, no. 7, 2014, pages 2482 - 2487
LUO ET AL., EMBO MOL. MED., vol. 4, no. 6, 2012, pages 453 - 461
MAECKER ET AL., BLOOD, vol. 102, no. 9, 2003, pages 3287 - 3294
MAHNE ET AL., CANCER RES., vol. 77, no. 5, 2017, pages 1108 - 1118
MALIAR ET AL., GASTROENTEROLOGY, vol. 143, no. 5, 2012, pages 1375 - 1384
MARTY ET AL., CANCER LETT, vol. 235, no. 2, 2006, pages 298 - 308
MCDONELL ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 12, 2015, pages 4883 - 4887
MILLER ET AL., BMC PHARMACOLOGY AND TOXICOLOGY, vol. 16, 2015, pages 18
MILLER ET AL., EUR J DRUG METAB PHARMACOKINET, vol. 39, 2014, pages 173 - 181
MILLER ET AL., J. IMMUNOL., 2007, pages 6933 - 42
MINO-KENUDSON ET AL., CLIN CANCER RES, vol. 16, no. 5, 2010, pages 1561 - 1571
MORGAN ET AL., J. IMMUNOL., vol. 171, 2003, pages 3287 - 3295
MORGENROTH ET AL., PROSTATE, vol. 67, no. 10, 2007, pages 1121 - 1131
MUJOO ET AL., CANCER RES., vol. 47, no. 4, 1987, pages 1098 - 1104
MURPHY ET AL., IMMUNITY, vol. 22, 2005, pages 403 - 414
MYERSUCKUN: "An anti-CD72 immunotoxin against therapy-refractory B-lineage acute lymphoblastic leukemia", LEUK LYMPHOMA., vol. 18, no. 1-2, June 1995 (1995-06-01), pages 119 - 22, XP002964114
NAGAE ET AL., J BIOL CHEM, vol. 288, no. 47, 2013, pages 33784 - 33796
NAKANO KISHIGURO TKONISHI H ET AL.: "Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization", ANTICANCER DRUGS, vol. 21, no. 10, November 2010 (2010-11-01), pages 907 - 916, XP008177208, doi:10.1097/CAD.0b013e32833f5d68
NAKAWAGA, H. ET AL., PNAS, vol. 113, 2016, pages 6248 - 6253
NEESON ET AL., J IMMUNOL, vol. 190, May 2013 (2013-05-01), pages 177.10
NEJATOLLAHI ET AL., J OF ONCOLOGY, 2013
NING ET AL., MOL CANCER THER., vol. 11, no. 6, 2012, pages 1353 - 64
NOORDHUIS ET AL.: "Targeting of CLEC12A In Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-lxCD3 BiTE Antibody", 53RD ASH ANNUAL MEETING AND EXPOSITION, 10 December 2011 (2011-12-10)
OSTERMANN ET AL., CLINICAL CANCER RESEARCH, vol. 14, 2008, pages 4584 - 4592
PARKER ET AL., PROTEIN EXPR PURIF, vol. 89, no. 2, 2013, pages 136 - 145
PERDOMO, J. ET AL., J. BIOL. CHEM., vol. 275, 2000, pages 38347 - 38354
PIZZITOLA ET AL., LEUKEMIA, 2014
POISON ET AL.: "Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker-Drug Selection", CANCER RES, vol. 69, 15 March 2009 (2009-03-15), pages 2358, XP055076856, doi:10.1158/0008-5472.CAN-08-2250
PONTE J, CLINICAL IMMUNOLOGY, vol. 135, 2010, pages S96
ROSS ET AL., CANCER RES, vol. 76, no. 14, 2016
ROSSIG ET AL., MOL. THER., vol. 10, 2004, pages 5 - 18
ROSZKOWSKI ET AL., CANCER RES., vol. 65, 2005, pages 1570 - 1576
S.M. BIRGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
SALOMONSSON E ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 286, no. 16, 2011, pages 13801 - 13804
SCHUMACHER, NAT. REV. IMMUNOL., vol. 2, 2002, pages 512 - 519
SCOTT AM ET AL., CANCER RES, vol. 60, 2000, pages 3254 - 61
SMITH ET AL.: "Ex vivo expansion of human T cells for adoptive immunotherapy using the novel Xeno-free CTS Immune Cell Serum Replacement", CLINICAL & TRANSLATIONAL IMMUNOLOGY, vol. 4, 2015, pages e31, XP055549892, doi:10.1038/cti.2014.31
SONG ET AL., MED ONCOL, vol. 29, no. 4, 2012, pages 2923 - 2931
SONG ET AL., TARGET ONCOL, 14 August 2013 (2013-08-14)
STONE ET AL., ONCOLMMUNOLOGY, vol. 1, no. 6, 2012, pages 863 - 873
T. W. GREENP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS
TAI ET AL., BLOOD, vol. 112, no. 4, 2008, pages 1329 - 37
THEMELI M. ET AL., NAT. BIOTECHNOL., vol. 31, 2013, pages 928 - 933
TIAN ET AL., CELL SIGNAL, vol. 23, no. 6, 2011, pages 951 - 62
TOBIAS MAETZIG ET AL.: "Gammaretroviral Vectors: Biology, Technology and Application", VIRUSES, vol. 3, no. 6, June 2011 (2011-06-01), pages 677 - 713
TORRES-GUZMAN R ET AL., ONCOTARGET, 2017
TRAN ET AL., J EXP MED, vol. 210, no. 6, 2013, pages 1125 - 1135
TRUTYURMTIA, PANEREATOLOGY, vol. 7, no. 5-6, 2007, pages 423 - 35
VORONOV ET AL., FRONT PHYSIOL., 2014, pages 114
VORONOV ET AL., PROC. NATL. ACAD. SCI. U.S.A., 2003, pages 2645 - 50
WAKEFIELDHILL, NAT REV CANCER, vol. 13, no. 5, 2013, pages 328 - 41
WANG ET AL., J EXP MED., vol. 184, no. 6, 1996, pages 2207 - 16
WILLEMSEN ET AL., J IMMUNOL, vol. 174, no. 12, 2005, pages 7853 - 7858
WILLEMSEN RA ET AL., GENE THERAPY, vol. 7, 2000, pages 1369 - 1377
WOJTOWICZ-PRAGA INVEST NEW DRUGS, vol. 21, no. l, 2003, pages 21 - 32
XU ET AL., LEUK LYMPHOMA., vol. 54, no. 2, 2012, pages 255 - 260
XUE ET AL., CLIN. EXP. IMMUNOL., vol. 139, 2005, pages 167 - 172
YANG ET AL., TRENDS IMMUNOL., vol. 31, no. 6, 2010, pages 220 - 7
YEE, JNCI, vol. 104, 2012, pages 975
YU ET AL., MOL THER, vol. 22, no. 1, 2014, pages 102 - 111
ZARBOCK ET AL., BR J PHARMACOL., vol. 155, no. 3, 2008, pages 357 - 64
ZHANG T ET AL., CANCER GENE THER, vol. 11, 2004, pages 487 - 496
ZHANG, Z. ET AL., BLOOD, vol. 110, no. 5, 2007, pages 1656 - 2197
ZHAO ET AL., J IMMUNOL METHODS, vol. 363, no. 2, 2011, pages 221 - 232
ZHAO ET AL., J. IMMUNOL., vol. 174, 2005, pages 4415 - 4423

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020128972A1 (en) * 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
JP2023520759A (ja) * 2020-03-23 2023-05-19 ブリストル－マイヤーズ スクイブ カンパニー がん治療のための置換オキソイソインドリン化合物
US12570671B2 (en) 2020-03-23 2026-03-10 Bristol-Myers Squibb Company Substituted oxoisoindoline compounds for the treatment of cancer
JP7698658B2 (ja) 2020-03-23 2025-06-25 ブリストル－マイヤーズ スクイブ カンパニー がん治療のための置換オキソイソインドリン化合物
WO2021194914A1 (en) * 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Substituted oxoisoindoline compounds for the treatment of cancer
CN115605466A (zh) * 2020-03-23 2023-01-13 百时美施贵宝公司（Us） 用于治疗癌症的经取代的氧代异吲哚啉化合物
WO2021260528A1 (en) * 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
EP4228624A4 (en) * 2020-10-14 2025-04-23 C4 Therapeutics, Inc. Tricyclic compounds for the degradation of neosubstrates for medical therapy
JP2023545508A (ja) * 2020-10-14 2023-10-30 シーフォー セラピューティクス， インコーポレイテッド Ｉｋｚｆ２又はｉｋｚｆ４を分解する三環式リガンド
CN116783180A (zh) * 2020-10-14 2023-09-19 C4医药公司 用于降解ikzf2或ikzf4的三环配体
JP2023545509A (ja) * 2020-10-14 2023-10-30 シーフォー セラピューティクス， インコーポレイテッド 医学的療法のための、ネオ基質を分解する三環式化合物
EP4228639A4 (en) * 2020-10-14 2025-01-22 C4 Therapeutics, Inc. TRICYCLIC LIGANDS TO IMPROVE IKZF2 OR IKZF4
US11718601B2 (en) 2021-04-06 2023-08-08 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds
EP4329744A4 (en) * 2021-04-29 2025-03-26 Neomorph, Inc. SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-5-(1-PIPERIDIN-4-YL)ISOINDOLINE-1,3-DIONE DERIVATIVES AND THEIR USES
EP4329746A4 (en) * 2021-04-29 2025-03-19 Dana-Farber Cancer Institute, Inc. Phthalimido cereblon complex binders and transcription factor degraders and methods of use
JP2024517772A (ja) * 2021-04-29 2024-04-23 ネオモルフ インコーポレイテッド 置換された２－（２，６－ジオキソピペリジン－３－イル）－５－（１－ピペリジン－４－イル）イソインドリン－１，３－ジオン誘導体及びその使用
US12161722B2 (en) 2021-06-25 2024-12-10 Korea Research Institute Of Chemical Technology Bifunctional heterocyclic compound having BTK degradation function via ubiquitin proteasome pathway, and use thereof
WO2022270994A1 (ko) 2021-06-25 2022-12-29 한국화학연구원 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도
JP2024529298A (ja) * 2021-07-09 2024-08-06 プレキシウム インコーポレイテッド Ｉｋｚｆ２を調節するアリール化合物及び医薬組成物
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2
WO2023283428A1 (en) * 2021-07-09 2023-01-12 Plexium, Inc. Heterocycloalkyl and heteroaryl compounds and pharmaceutical compositions that modulate ikzf2
WO2023283425A1 (en) * 2021-07-09 2023-01-12 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate ikzf2
WO2023283430A1 (en) * 2021-07-09 2023-01-12 Plexium, Inc. Cycloalkyl compounds and pharmaceutical compositions that modulate ikzf2
US12122764B2 (en) 2021-12-22 2024-10-22 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof
US11897862B2 (en) 2022-03-17 2024-02-13 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof
US12358887B2 (en) 2022-03-17 2025-07-15 Gilead Sciences, Inc. IKAROS Zinc Finger Family degraders and uses thereof

Also Published As

Publication number Publication date
EP3820574B1 (en) 2023-08-09
US11833142B2 (en) 2023-12-05
JP7462606B2 (ja) 2024-04-05
CN112334194B (zh) 2024-12-06
UY38296A (es) 2020-02-28
ES2963695T3 (es) 2024-04-01
BR112021000049B1 (pt) 2023-01-17
US20230037639A1 (en) 2023-02-09
CN112334194A (zh) 2021-02-05
PY1954554A (es) 2020-02-11
AU2019301947B2 (en) 2021-07-22
KR20210031923A (ko) 2021-03-23
BR112021000049A2 (pt) 2021-04-06
AU2019301947A1 (en) 2020-12-24
TWI830747B (zh) 2024-02-01
US11185537B2 (en) 2021-11-30
BR122022012745B1 (pt) 2023-01-10
EP3820574A1 (en) 2021-05-19
AR116109A1 (es) 2021-03-31
MX2021000310A (es) 2021-04-12
TW202012386A (zh) 2020-04-01
CA3103674A1 (en) 2020-01-16
JP2021529812A (ja) 2021-11-04
US20200016143A1 (en) 2020-01-16

Similar Documents

Publication Publication Date Title
JP7462606B2 (ja) ３－（５－アミノ－１－オキソイソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びＩｋａｒｏｓファミリージンクフィンガー２（ＩＫＺＦ２）依存性疾患の治療におけるその使用
US12479817B2 (en) Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
JP7483732B2 (ja) ３－（１－オキソ－５－（ピペリジン－４－イル）イソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びその使用
JP7819176B2 (ja) ヘテロアリール置換３－（１－オキソイソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びその使用
AU2019301944A1 (en) 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of Ikaros family zinc finger 2 (IKZF2)-dependent diseases
CA3123511A1 (en) Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19782692

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3103674

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2019301947

Country of ref document: AU

Date of ref document: 20190708

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 122022012745

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2021500409

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021000049

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20217003431

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112021000049

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210104