WO2025030008A1 - Combinaisons d'inhibiteurs de protéine tyrosine phosphatase - Google Patents

Combinaisons d'inhibiteurs de protéine tyrosine phosphatase Download PDF

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WO2025030008A1
WO2025030008A1 PCT/US2024/040524 US2024040524W WO2025030008A1 WO 2025030008 A1 WO2025030008 A1 WO 2025030008A1 US 2024040524 W US2024040524 W US 2024040524W WO 2025030008 A1 WO2025030008 A1 WO 2025030008A1
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alkyl
heterocycloalkyl
cycloalkyl
compound
formula
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Suzanne PAZ
Jason ROLAND
Mark Eben Massari
Christian Perez
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Nerio Therapeutics Inc
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Nerio Therapeutics Inc
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Priority to CN202480050834.5A priority Critical patent/CN121646467A/zh
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
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    • 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
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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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    • A61K33/00—Medicinal preparations containing inorganic active ingredients
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    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • checkpoint blockade e.g., PD-1/PD-L1 and CTLA-4 blocking antibodies
  • PD-1/PD-L1 and CTLA-4 blocking antibodies have been shown to be effective in treating in a variety of cancers, dramatically improving outcomes in some populations refractory to conventional therapies.
  • incomplete clinical responses and the development of intrinsic or acquired resistance continue to limit the patient populations who could benefit from checkpoint blockade.
  • Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phospho-tyrosine specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates.
  • PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells.
  • PTPN2 expression is controlled post-transcriptionally by the existence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form which has a C-terminal ER retention motif.
  • the 45 kDa isoform can passively transfuse into the cytosol under certain cellular stress conditions. Both isoforms share anN-terminal phospho-tyrosine phosphatase catalytic domain.
  • PTPN2 negatively regulates signaling of non- receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a/b), and Src family kinases (e.g., Fyn, Lek).
  • JAK1, JAK3 receptor tyrosine kinases
  • receptor tyrosine kinases e.g., INSR, EGFR, CSF1R, PDGFR
  • transcription factors e.g., STAT1, STAT3, STAT5a/b
  • Src family kinases e.g., Fyn, Lek
  • PTPN2 functions to directly regulate signaling through cytokine receptors, including IFN ⁇ .
  • the PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also
  • Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase- IB (PTP1B), has been shown to play a key role in insulin and leptin signaling and is a primary
  • SUBSTITUTE SHEET (RULE 26) mechanism for down-regulating both the insulin and leptin receptor signaling pathways. Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet. Thus, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (III):
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.
  • SUBSTITUTE SHEET (RULE 26)
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of (a) a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of (a) a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and (b) an additional therapeutic agent.
  • the additional therapeutic agent is an immunotherapeutic agent.
  • the immune checkpoint inhibitor is atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab.
  • the additional therapeutic agent is chemotherapeutic agent.
  • the chemotherapeutic agent is cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or a combination thereof.
  • the additional therapeutic agent is radiation therapy (RT).
  • RT radiation therapy
  • the additional therapeutic agent is a VEGF inhibitor.
  • the VEGF inhibitor is aflibercept, axitinib, bevacizumab, cabozatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ramucirumab, regorafenib, sorafenib, sunitunib, tivozanib, or vandetanib.
  • the additional therapeutic agent is a bi-specific antibody or T cell engager.
  • the T cell engager is bintrafusp alfa, blinatumomab, elranatamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR-1701, tebentafusp, or teclistamab.
  • the additional therapeutic agent is CAR-T cell therapy.
  • the CAR-T cell therapy is axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel.
  • the additional therapeutic agent is a KRAS G12C inhibitor.
  • the cancer vaccine is BCG, sipuleucel-T, or talimogene laherparepvec (T- VEC).
  • the HER2-targeted therapy is lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab emtansine (T-DM1), trastuzumab, tucatinib, or zongertinib.
  • the additional therapeutic agent is a CXCR4 antagonist.
  • the CXCR4 antagonist is plerixafor.
  • Haldroxy refers to -OH
  • Carboxyl refers to -COOH.
  • Alkyl refers to a straight- chain or branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n- butyl, isobutyl, sec- butyl, t-butyl, n-penty
  • alkyl SUBSTITUTE SHEET (RULE 26) hexyl, and longer alkyl groups, such as heptyl, octyl and the like.
  • a numerical range such as “C 1 -C 6 alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is aCi-Cio alkyl.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a Ci- Cs alkyl. In some embodiments, the alkyl is aCi-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • Alkenyl refers to a straight- chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • C2-C6 alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or - NO 2 . In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or - OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like.
  • C2-C6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with one
  • SUBSTITUTE SHEET (RULE 26) or more halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10- membered aryl.
  • the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluor anthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, - COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Arylene refers to a divalent aryl as defined above. Unless stated otherwise specifically in the specification, an arylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the arylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the arylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the arylene is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and/or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g. , C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g.
  • C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl).
  • C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cyclo
  • the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis- decalinyl, trans-decalinyl, bicyclo[2.1.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Cycloalkylene refers to a divalent cycloalkyl as defined above. Unless stated otherwise specifically in the specification, a cycloalkylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the cycloalkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the cycloalkylene is optionally substituted with one or more halogen, -CN, -OH, or - OMe. In some embodiments, the cycloalkylene is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to -O-haloalkyl, with haloalkyl as defined above.
  • Hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Deuteroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 .
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 NHCH 3 , - CH 2 N(CH 3 )2, -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 )2.
  • a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl is C-linked.
  • the heterocycloalkyl is N-linked.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heterocycloalkyl comprises one to three nitrogens.
  • the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen.
  • the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloal
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the di saccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the
  • heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl is optionally substituted, for example, withone or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, - COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heterocycloalkylene refers to a divalent heterocycloalkyl as defined above. Unless stated otherwise specifically in the specification, an heterocycloalkylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the heterocycloalkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the heterocycloalkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the heterocycloalkylene is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl is C-linked.
  • the heteroaryl is N-linked.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5- membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,
  • SUBSTITUTE SHEET (RULE 26) benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, , isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl
  • a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • Heteroarylene refers to a divalent heteroaryl as defined above. Unless stated otherwise specifically in the specification, an heteroarylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroarylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the heteroarylene is optionally substituted with one or more halogen, -CN, -OH, or - OMe. In some embodiments, the heteroarylene is optionally substituted with halogen.
  • an optionally substituted group may be un- substituted (e.g., - CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , - CFHCHF 2 , etc.).
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject
  • SUBSTITUTE SHEET (RULE 26) group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • Treatment of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.
  • the term “PTPN2-mediated” disorder or disease or alternatively “disease or disorder associated with PTPN2” means any disease or other deleterious condition in which PTPN2 or a mutant thereof is known to play a role. Accordingly, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN2, or a mutant thereof, is known to play a role.
  • the term “PTPN1 -mediated” disorder or disease or alternatively “disease or disorder associated with PTPN1” means any disease or other deleterious condition in which PTPN1 or a mutant thereof is known to play a role. Accordingly, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN 1 , or a mutant thereof, is known to play a role.
  • W is CR W or N
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene( cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R
  • the compound is of Formula (la): wherein R 4 ’ is hydrogen or R 4 .
  • the compound is of Formula (lb):
  • the compound is of Formula (Ic): wherein R 4 ’ is hydrogen or R 4 .
  • Ring A is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heterocycloalkyl comprising 1 heteroatom that is N.
  • Ring A is monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is pyrrolidinyl or piperidinyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyrrolidinyl. In some embodiments of a compound of Formula (I) or (la)- (Ic), Ring A is piperidinyl.
  • Ring A is bicyclic heterocycloalkyl.
  • Ring A is 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2- azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, or 2-azaspiro[3.3]heptanyl.
  • Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is 6-membered heteroaryl.
  • Ring A is heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • Ring A is heteroaryl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (la)- (Ic), Ring A is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring A is heteroaryl comprising 1 heteroatom that is N.
  • Ring A is
  • L is -[C(R 3 ) 2 ] m -.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R 3 are taken together to form a cycloalkyl.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 3 is independently
  • SUBSTITUTE SHEET hydrogen, halogen, -OH, or C 1 -C 6 alkyl; or two R 3 are taken together to form a cycloalkyl.
  • two R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 3 are taken together to form a cycloalkyl optionally substituted with one or more R.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 3 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 3 is hydrogen.
  • m is 1-3. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 1 or 2. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 2.
  • L is -CH 2 -, -CH 2 CH 2 -, or - CH 2 CH 2 CH 2 -. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH 2 -. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH 2 CH 2 -. In some embodiments of a compound of Formula (I) or (la)-(Ic), L is -CH 2 CH 2 CH 2 -.
  • L is -O[C(R 3 )2] m -, -NR 2 [C(R 3 )2] m -, -[C(R 3 )2] m O-, or -[C(R 3 ) 2 ]mNR 2 -.
  • L is -O[C(R 3 )2]m- or - NR 2 [C(R 3 ) 2 ]m-.
  • L is -[C(R 3 )2]mO- or - [C(R 3 ) 2 ]mNR 2 -.
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is hydrogen or C 1 -C 6 alkyl.
  • each R 4 is independently deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 4 is independently deuterium or halogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 4 is independently deuterium or halogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 4 is independently deuterium or halogen.
  • each R 4 is independently halogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 4 is independently -OR a or C 1 -C 6 alkyl.
  • p is 0 or 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 0. In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 1.
  • W is N. In some embodiments of a compound of Formula (I) or (la)-(Ic), W is CR W
  • R w is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R w is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R w is hydrogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), R w is C 1 -C 6 alkyl.
  • each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R la .
  • each R 1 is independently deuterium, halogen, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R la .
  • each R 1 is independently halogen, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 heteroalkyl, or cycloalkyl.
  • each R 1 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen or C 1 -C 6 alkyl.
  • each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R la .
  • each R 1 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R 1 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (la)-(Ic), two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • each R la is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, Ci -Cedeuteroalkyl, Ci -Cehydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R.
  • each R la is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloallyl, aryl, and heteroaryl is independently and optionally substituted with one or more R.
  • each R la is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl. C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R la is independently halogen, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R la is independently -NR c R d , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • each R la is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • n is 0-8. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-7. In some embodiments of a compound of Formula (I) or (la)- (Ic), n is 0-6. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-5. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0-4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-3.
  • n is 0-2. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0. In some embodiments of a compound of Formula (I) or (la)- (Ic), n is 1-8. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1-7. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1-6. In some embodiments of a compound of a compound of Formula (I) or (Ia)-(Ic), n is
  • SUBSTITUTE SHEET (RULE 26) Formula (I) or (Ia)-(Ic), n is 1-5. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-4. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1-3. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1 or 2. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 2.
  • n is 3. In some embodiments of a compound of Formula (I) or (la)- (Ic), n is 4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 5. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 6.
  • W is CR W or N
  • SUBSTITUTE SHEET each Ris independently halogen, -CN, -OH, -OC 1 -C 3 alkyl, -OC 1 -C 3 haloalkyl.
  • the compound is of Formula (Ila): wherein R 4 ’ is hydrogen or R 4 .
  • the compound is of Formula (lib) : wherein R 4 ’ is hydrogen or R 4 .
  • the compound is of Formula (lie): wherein R 4 ’ is hydrogen or R 4 .
  • Ring B is heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 5- to 8- membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 5- to 6-membered heterocycloalkyl.
  • Ring B is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B
  • SUBSTITUTE SHEET (RULE 26) is heterocycloalkyl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heterocycloalkyl comprising 1 heteroatom that is N.
  • Ring B is cycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 4- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 5- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 5- to 6-membered cycloalkyl.
  • Ring B is heteroaryl. In some embodiments of a compound of Formula (II) or (na)-(IIc), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is 6-membered heteroaryl.
  • Ring B is heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • Ring B is heteroaryl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), Ring B is heteroaryl comprising 1 heteroatom that is N.
  • L is -[C(R 3 ) 2 ] m -.
  • L is -CH 2 -, -CH 2 CH 2 -, or - CH 2 CH 2 CH 2 -. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH 2 -. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH 2 CH 2 -. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), L is -CH 2 CH 2 CH 2 -.
  • L is -O[C(R 3 )2]m-, - NR 2 [C(R 3 ) 2 ]m-, -[C(R 3 )2]mO-, or -[C(R 3 ) 2 ]mNR 2 -.
  • L is -[C(R 3 ) 2 ]mO- or -[C(R 3 ) 2 ] m NR 2 -.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R 3 are taken together to form a cycloalkyl.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R 3 are taken together to form a cycloalkyl.
  • each R 3 is independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl; or two R 3 are taken together to form a cycloalkyl.
  • two R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 3 are taken together to form a cycloalkyl optionally substituted with one or more R.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R 3 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R 3 is hydrogen.
  • m is 1-3. In some embodiments of a compound of Formula (II) or (na)-(IIc), m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), mis 2.
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is hydrogen or C 1 -C 6 alkyl.
  • each R 4 is independently deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R 4 is independently deuterium or halogen. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R 4 is independently deuterium or halogen.
  • each R 4 is independently halogen. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R 4 is independently -OR a or C 1 -C 6 alkyl.
  • p is 0 or 1. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), p is 0. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), p is 1.
  • W is N. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), W is CRT
  • R w is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), R w is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), R w is hydrogen.
  • each R 1 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (na)-(IIc), two R 1 on the same atom are taken together to form an oxo.
  • n is 1-8.
  • n is 1-7. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1-6. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1-5. In some embodiments of a compound of Formula (II) or (na)-(IIc), n is 1-4. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-3. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 1
  • n is 1. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 2. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 3. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 4. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 5. In some embodiments of a compound of Formula (II) or (Ila)-(IIc), n is 6.
  • Y is CR Y or N
  • Z is CR Z or N
  • W is CR W or N
  • Ring A is a 7- to 10-membered cycloalkyl or 7- to 10-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N.
  • Ring A is a 7- to 8-membered cycloalkyl or 7- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N.
  • Ring A is a 7- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), Ring A is a 7-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O and N.
  • the heterocycloalkyl in Ring A comprises 1 or 2 heteroatoms selected from O and N. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 heteroatom that is O. In some embodiments of a compound of Formula (III), the heterocycloalkyl in Ring A comprises 1 heteroatom that is N.
  • X is N. In some embodiments of a compound of Formula (III), X is CR X .
  • R x is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R x is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • R x is halogen.
  • R x is fluoro.
  • Y is N. In some embodiments of a compound of Formula (III), Y is CR Y .
  • R z is hydrogen, deuterium, halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R z is hydrogen.
  • W is N. In some embodiments of a compound of Formula (III), W is CRT
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a .
  • each R 1 is independently -NR c R d ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d . In some embodiments of a compound of Formula (III), each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a .
  • each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl. C 1 -C 6 hydroxyalkyl. C 1 -C 6 aminoalkyl. cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a .
  • each R 1 is independently -OH, -OR a , -NR c R d ,
  • each R 1 is independently -OH, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, or heterocycloalkyl; wherein each alkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a .
  • each R 1 is independently -OH, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, or heterocycloalkyl; wherein each alkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a .
  • each R 1 is independently C 1 -C 6 alkyl independently and optionally substituted with one or more R 1a . In some embodiments of a compound of Formula (III), each R 1 is independently C 1 -C 6 alkyl.
  • each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R 1a is independently deuterium, halogen or C 1 -C 6 alkyl.
  • each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R 1a is independently deuterium, halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), each R 1a is independently -CN or -NR c R d .
  • n is 1-4. In some embodiments of a compound of Formula (III), n is 1-3. In some embodiments of a compound of Formula (III), n is 1 or 2. In some embodiments of a compound of Formula (III), n is 0 or 1. In some embodiments of a compound of Formula (III), n is 0. In some embodiments of a compound of Formula (III), n is 1. In some embodiments of a compound of Formula (III), n is 2. In some embodiments of a compound of Formula (III), n is 3.
  • X is CR X or N
  • Y is CR Y or N
  • Z is CR Z or N
  • W is CR W or N
  • SUBSTITUTE SHEET (RULE 26) C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(ary
  • Ring A is 6- to 15-membered fused bicyclic cycloalkyl.
  • Ring A is 8- to 10-membered fused bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered bridged bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10- membered bridged bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered spirocyclic bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10-membered spirocyclic bicyclic cycloalkyl.
  • Ring A is 6- to 15-membered fused bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10- membered fused bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered bridged bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N.
  • Ring A is 8- to 10-membered bridged bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 6- to 15-membered spirocyclic bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), Ring A is 8- to 10-membered spirocyclic bicyclic heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N.
  • the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O and N. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 or 2 heteroatoms selected from O andN. In some embodiments of a
  • the heterocycloalkyl in Ring A comprises 1 heteroatom that is O. In some embodiments of a compound of Formula (IV), the heterocycloalkyl in Ring A comprises 1 heteroatom that is N.
  • n’ is 1-5; and R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • n’ is 0 or 1. In some embodiments, n’ is 1 or 2. In some embodiments, n’ is 2 or 3. In some embodiments, n’ is 0. In some embodiments, n’ is 1. In some embodiments, n’ is 2. In some embodiments, n’ is 3.
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 2 is C 1 -C 6 alkyl.
  • the compound is a compound of Formula (IVa): wherein Ring B is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.
  • Ring B is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.
  • the compound is a compound of Formula (IVb):
  • 5UB5TITUTE SHEET (RULE 26) Formula (IVb); wherein Ring C is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.
  • the compound is a compound of Formula (IVc): wherein Ring D is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.
  • the compound is a compound of Formula (IVd): wherein Ring E is a cycloalkyl or heterocycloalkyl comprising 1 to 2 heteroatoms selected from O, S, and N.
  • the compound is a compound of Formula (IVe): wherein Ring F is a cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, S, and N.
  • the compound is a compound of Formula (IVf):
  • Ring G is a cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, S, and N.
  • the compound is a compound of Formula (IV).
  • Ring H is a cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, S, and N.
  • X is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), X is CR X .
  • R x is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R x is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • R x is halogen.
  • Y is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Y is CR Y .
  • R Y is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R Y is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d .
  • R Y is -OH.
  • Z is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), Z is CR Z .
  • R z is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R z is hydrogen.
  • W is N. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), W is CR W .
  • R w is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R w is hydrogen.
  • SUBSTITUTE SHEET (RULE 26) C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R 1a is independently deuterium, halogen or C 1 -C 6 alkyl. [00161]
  • n is 1-4.
  • n is 1-3. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 1 or 2. In some embodiments of a compound of Formula (IV) or (IVa)- (IVg), n is 0. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 1. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 2. In some embodiments of a compound of Formula (IV) or (IVa)-(IVg), n is 3.
  • X is CR X or N
  • Y is CR Y or N
  • W is CR W or N
  • each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocyclo
  • Ring A is a 3- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 5- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 6- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 6-membered cycloalkyl. In some embodiments of a compound of Formula (V), Ring A is a 3- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N.
  • Ring A is a 5- to 8- membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, andN. In some embodiments of a compound of Formula (V), Ring A is a 6- to 8-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (V), Ring A is a 6- membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O, S, and N.
  • the heterocycloalkyl in Ring A comprises 1 to 3 heteroatoms selected from O and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 or 2 heteroatoms selected from O and N. In some embodiments of a compound of Formula (V), the heterocycloalkyl in Ring A comprises 1 heteroatom that is O. In some embodiments of a compound of Formula (V), the heterocycloallyl in Ring A comprises 1 heteroatom that is N.
  • X is N. In some embodiments of a compound of Formula (V), X is CR X .
  • R x is hydrogen, deuterium, halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R x is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • R x is halogen.
  • Y is N. In some embodiments of a compound of Formula (V), Y is CR Y .
  • R Y is hydrogen, deuterium, halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R Y is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d .
  • R Y is -OH.
  • W is N. In some embodiments of a compound of Formula (V), W is CRT
  • R w is hydrogen, deuterium, halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R w is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d .
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a .
  • each R 1 is independently -NR c R d ; or two R 1 on the same atom are taken together
  • each R 1 is independently -NR c R d .
  • each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R 1a is independently deuterium, halogen or C 1 -C 6 alkyl.
  • n is 1-4. In some embodiments of a compound of Formula (V), n is 1-3. In some embodiments of a compound of Formula (V), n is 1 or 2. In some embodiments of a compound of Formula (V), n is 0. In some embodiments of a compound of Formula (V), n is 1. In some embodiments of a compound of Formula (V), n is 2. In some embodiments of a compound of Formula (V), n is 3.
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1-3;
  • X is CR X or N
  • Y is CR Y or N
  • Z is CR Z or N
  • W is CR W or N
  • SUBSTITUTE SHEET (RULE 26) heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1-3;
  • X is CR X or N
  • Y is CR Y or N
  • Z is CR Z or N
  • W is CR W or N
  • each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocyclo
  • X is CR X or N
  • Y is CR Y or N
  • Z is CR Z or N
  • SUBSTITUTE SHEET (RULE 26) C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • W is CR W or N
  • X is CR X or N
  • Y is CR Y or N
  • Z is CR Z or N
  • W is CR W or N
  • U is -C(R 2 ) 2 - or -NR 3 -. In some embodiments of a compound of Formula (VI) or (VII), U is -C(R 2 ) 2 -. In some embodiments of a compound of Formula (VI) or (VII), U is -O-. In some embodiments of a compound of Formula (VI) or (VII), U is - NR 3 -. In some embodiments of a compound of Formula (VI) or (VII), U is -NH- or -NCH 3 -. In some embodiments of a compound of Formula (VI) or (VII), U is -NH-. In some embodiments of a compound of Formula (VI) or (VII), U is -NCH 3 -.
  • each R 2 is independently deuterium, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R 2 is independently halogen or C 1 -C 6 alkyl.
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 3a .
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 3a .
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 3 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 3 is hydrogen or C 1 -C 6 alkyl.
  • R 3 is hydrogen
  • R 3 is C 1 -C 6 alkyl.
  • R 3 is C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 3a .
  • R 3 is C 1 -C 6 alkyl(aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 3a .
  • R 3 is C 1 -C 6 alkyl(aryl); wherein each alkyl aryl is independently and optionally substituted with one or more R 3a .
  • R 3 is C 1 -C 6 alkyl(aryl).
  • R 3 is hydrogen, methyl, ethyl
  • R 3 is methyl, ethyl
  • each R 3a is independently deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VI)-(IX), each R 3a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VI)-(IX), each R 3a is independently halogen or C 1 -C 6 alkyl.
  • p is 1 or 2. In some embodiments of a compound of Formula (VI)-(IX), p is 1.
  • X is N. In some embodiments of a compound of Formula (VI)-(IX), X is CR X .
  • R x is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R x is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
  • R x is halogen.
  • ⁇ is N.
  • Y is CR Y .
  • R Y is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R Y is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d .
  • R Y is -OH.
  • Z is N. In some embodiments of a compound of Formula (VI)-(IX), Z is CR Z .
  • R z is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R z is hydrogen.
  • W is N. In some embodiments of a compound of Formula (VI)-(IX), W is CR W .
  • R w is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R w is hydrogen.
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d or C 1 -C 6 alkyl optionally substituted with one or more R 1a .
  • each R 1 is independently -NR c R d ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1 is independently -NR c R d .
  • each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo.
  • each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R 1a is independently deuterium, halogen or C 1 -C 6 alkyl.
  • n is 1-4. In some embodiments of a compound of Formula (VI) or (VII), n is 1-3. In some embodiments of a compound of Formula (VI) or (VII), n is 1 or 2. In some embodiments of a compound of Formula (VI) or (VII), n is 1. In some embodiments of a compound of Formula (VI) or (VII), n is not 2.
  • m is 0-4. In some embodiments of a compound of Formula (VIII) or (IX), m is 0-3. In some embodiments of a compound of Formula (VIII) or (IX), m is 0-2. In some embodiments of a compound of Formula (VIII) or (IX), m is 0 or 1. In some embodiments of a compound of Formula (VIII) or (IX), m is 1 or 2. In some embodiments of a compound of Formula (VIII) or (IX), m is 0. In some embodiments of a compound of Formula (VIII) or (IX), m is 1. In some embodiments of a compound of Formula (VIII) or (IX), m is 2.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more
  • SUBSTITUTE SHEET independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R b is independently hydrogen or C 1 -C 6 alkyl independently and optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
  • each R c and R d are independently hydrogen or C 1 -C 6 alkyl independently and optionally substituted with one or more R.
  • R c is cycloalkyl and R d hydrogen.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl.
  • each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , - NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R on the same atom form an oxo.
  • each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , - NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R on the same atom form an oxo.
  • each R is independently
  • each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two Ron the same atom form an oxo.
  • each R is independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R is independently halogen or C 1 -C 6 alkyl.
  • each R is independently halogen.
  • the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound disclosed herein is a compound selected from Table 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound disclosed herein is a compound selected from Table 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • C 6 rtain isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavy isotopes such as deuterium, i.e., 2 H produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable
  • SUBSTITUTE SHEET (RULE 26) metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (CI-C4 alkyl)4 hydroxide, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and one or more adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • SUBSTITUTE SHEET (RULE 26) solvate, or stereoisomer thereof.
  • the disease in which inhibition of PTPN1 is beneficial is cancer or a metabolic disease.
  • the disease in which inhibition of PTPN2 is beneficial is cancer.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat cancer.
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers.
  • adenocarcinomas e.g., papillary adenocarcinomas
  • lymphomas e.g., leukemias, melanomas, etc., including solid and lymphoid cancers.
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, erythroleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leuk
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma,
  • SUBSTITUTE SHEET (RULE 26) lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemo
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bile duct carcinoma, bladder carcinoma, breast carcinoma, Brenner carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedo carcinoma, corpus carcinoma, cribriform
  • SUBSTITUTE SHEET (RULE 26) cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or carcinoma villosum.
  • the cancer is acoustic neuroma, adrenal cortical cancer, adrenal gland cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchus cancer, cancer of the hematological tissues, cancer of the hepatic stellate cells, cancer of the oral cavity or pharynx, cancer of the pancreatic stellate cells, carcinoma, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecologic cancers, head and neck cancer, hemangioblastoma, Hodgkin's Disease,
  • the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is used to treat a metabolic disease.
  • the term “metabolic disease” refers to a disease or condition affecting a metabolic process in a subject.
  • exemplary metabolic diseases include non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.
  • a compound disclosed herein is used to treat a metabolic disease (e.g., a metabolic disease described herein) by decreasing or eliminating a symptom of the disease.
  • the method of treatment comprises decreasing or eliminating a symptom comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.
  • compositions containing the compound(s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’ s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular,
  • SUBSTITUTE SHEET subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • compositions/F ormulat ions
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’ s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees,
  • SUBSTITUTE SHEET (RULE 26) effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of (a) a PTPN2/N1 inhibitor disclosed herein; and (b) an additional therapeutic agent.
  • the combination therapy improves patient outcomes.
  • the additional therapeutic agent is an anticancer agent.
  • the additional therapeutic agent is an immunotherapeutic agent.
  • Use of immunotherapeutic agents in combination with other cancer treatment regimens has emerged as a promising approach to address limitations such as suboptimal efficacy, dose- dependent toxicity and acquired resistance while generating long-lasting anti-tumor immune responses and improving patient outcomes.
  • combining a PTPN2/N 1 inhibitor with a checkpoint inhibitor enhances therapeutic efficacy and improves tumor clearance in an in vivo tumor model.
  • a PTPN2/N1 inhibitor disclosed herein with a clinically approved immune checkpoint inhibitor such as, but not limited to, atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab.
  • a clinically approved immune checkpoint inhibitor such as, but not limited to, atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab.
  • checkpoint inhibitors are AMG-404, camrelizumab, ezabenlimab, pidilizumab, or spartalizumab.
  • PTPN2 has emerged as a validated immunotherapy target as multiple published studies have demonstrated that PTPN2 deletion in either the tumor or in the immune compartment significantly enhanced anti-tumor immunity and sensitivity to other immunotherapies such as checkpoint inhibitors (Manguso et al. 2017; LaFleur et al. 2019; Weide et al. 2020). Emerging data have also shown that PTPN1 functions as an intracellular checkpoint and that PTPN1 deletion in T cells enhanced tumor clearance (Weide et al. 2022). Recently, it was shown that a small molecule PTPN2/N1 inhibitor enhanced T cell activation and proliferation and inhibited tumor growth in a murine syngeneic model (Liang et al. 2023).
  • the additional therapeutic agent is chemotherapeutic agent.
  • Chemotherapy induces cytotoxic effects on tumor cells but is also recognized for reinstating cancer cell immune surveillance and acting as an adjuvant for anti-tumor immunity (Liu et al. 2020).
  • chemotherapeutic agent includes, but is not limited to, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or a combination thereof.
  • the additional therapeutic agent is radiation therapy (RT).
  • Radiation therapy can induce tumor cells to release antigens and trigger local or systemic anti-tumor immunity (Demaria et al. 2016).
  • the additional therapeutic agent is a VEGF inhibitor.
  • SUBSTITUTE SHEET (RULE 26) had synergistic effects and several of these combinations have recently been approved for the treatment of advanced renal cell carcinoma (Motzer et al. 2021; Makker et al. 2019; Jonasch et al. 2022).
  • the VEGF inhibitor includes, but is not limited to, aflibercept, axitinib, bevacizumab, cabozatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ramucirumab, regorafenib, sorafenib, sunitunib, tivozanib, and vandetanib, to potentially improve the clinical efficacy of these agents.
  • the additional therapeutic agent is a bi-specific antibody or T cell engager.
  • the bi-specific antibodies or T cell engagers is, but is not limited to, bintrafusp alfa, blinatumomab, elranatamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR- 1701, tebentafusp, or teclistamab.
  • the combination disclosed herein enhances T cell mediated tumor immunity as most of these bi-specific antibodies are designed to redirect T cells.
  • the additional therapeutic agent is CAR-T cell therapy.
  • Wiede et al. recently demonstrated that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of CAR-T therapy by augmenting both CAR-T cell activation and homing to CXCL9/CXCL 10- expressing tumors via STAT5 signaling (Wiede et al. 2020).
  • the CAR-T cell therapy is, but is not limited to, axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel.
  • the combination disclosed herein enhances the clinical efficacy of human CAR-T cells.
  • the additional therapeutic agent is a KRAS G12C inhibitor.
  • KRAS G12C inhibitor adagrasib sensitizes tumors to immunotherapy altering immune cell populations in the tumor microenvironment.
  • the KRAS G12C inhibitor is, but is not limited to, adagrasib or sotorasib. Further examples of KRAS G12C inhibitors are disclosed in WO2021/245051, WO2021/245055 and WO2023/099612, which are herein incorporated by reference in their entireties.
  • KRAS G12C inhibitors that can be used according to the present invention are represented by compounds Ib-1 to Ib-16, Ic-1 to Ic-9, Id-1 to Id-9 and Ie-1 of WO2021/245051, compounds la- 1 to la-170 of WO2021/245055 and compounds la-1 to la-4andlb- 1 to Ib-9 of WO2023/099612.
  • KRAS G12C inhibitors are compounds known as: divarasib (GDC-6036), opnurasib (also known as JDQ443), garsorasib (D-1553), glecirasib (JAC-21822), GFH925/GF105/ IBI351, RMC-6291, LY3537982, JNJ-74699157 and LY3499446.
  • the combination disclosed herein potentiates anti -tumor immunity and potentially improve patient outcomes.
  • the additional therapeutic agent is a cancer vaccine.
  • Cancer vaccines such as, but not limited to, BCG, sipuleucel-T, and talimogene laherparepvec (T-VEC), where T-VEC is the oncolytic virus approved by the FDA, activate the immune response both locally and systemically ensuring better induction of tumor-specific effector T cell function (Vafaei at al., 2021, Ferrucci et al., 2021).
  • Current clinical trials utilize the combination of DC-based mRNA vaccines in combination with ipilimumab to stimulate a strong T cell response (De Keersmaecker et al., 2020).
  • a combination disclosed herein promotes an additive or synergistic effect on anti-tumor immunity, thus potentially improves clinical outcomes.
  • the additional therapeutic agent is aHER2-targeted therapy.
  • HER2-targeted therapies can enhance anti-tumor immunity by enhancing expression of dendritic (DC) markers, boosting MHC I expression on cancer cells for ease of recognition by the immune system and enhancing recruitment of tumor-infiltrating CD4+ and CD8+ T cells (Iwata et al., 2018 & 2019).
  • DC dendritic
  • HER2-targeted therapies such as, but not limited to, lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab emtansine (T-DM1), trastuzumab, tucatinib, and zongertinib could also be combined with a PTPN2/N1 inhibitor to achieve more robust anti-tumor immune responses (Vafaei et al., 2022).
  • the additional therapeutic agent is a CXCR4 antagonist.
  • CXCR4 antagonists have been developed to impair pathological procedures and disrupt cancer cell adhesion to the stromal cells, facilitating cancer cell release into circulation (Otsuka et al., 2008; Schrader et al., 2002).
  • the combination disclosed herein confers a strong immune response and attacks the circulating cancer cells to delay tumor development and enable tumor regression.
  • the CXCR4 antagonist is, but not limited to, plerixafor.
  • the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
  • Example A Enzymatic Assay used to determine potency of PTPN2 Inhibitors
  • PTPN2 was produced in E. coli as a GST-TEV fusion and the GST was removed by TEV digestion, followed by additional purification to yield full-length PTPN2 (SEQ ID 1).
  • PTPN2 enzyme was diluted in assay buffer (50mMHEPES pH7.5, 0.2mM EDTA, ImM DTT, 0.02% Brij- 35, 0.02% BSA) to afinal concentration of 0.5 nM and added to black 384- well non- binding plates (Greiner, 781900). Compounds were subsequently added using a Tecan D300e dispenser.
  • DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 100 ⁇ M. Plates were transferred to a SpectraMax plate reader (Molecular Devices) and fluorescence intensity was measured (ex 358, em 455) after a 30 min incubation at room temperature. Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO) from which %
  • SUBSTITUTE SHEET (RULE 26) inhibition for test compounds was calculated.
  • a four-parameter curve fit was used to determine ICso values from % inhibition data.
  • RTCA Real-Time Cell Analysis platform
  • B16F10 cells cultured in assay media were dissociated with TrypLE Express (Gibco 12605-010) for five minutes at 37°C, diluted in 3 volumes of assay buffer, centrifuged for 5 minutes at 500xg at room temperature before diluting cells to 7,700 cells/mL in assay media, plating 130 ⁇ L/well (1,000 cells/well) in the inner 60 wells of the assay plate, and adding 150 ⁇ L of assay media to the outer wells of the plate. Cells were incubated at room temperature for 20 min to allow cells to settle before placing them in the xCELLigence reader and incubating overnight at 37°C, sweeping wells every 15 minutes.
  • Example A The data from Example A and Example B is shown in table 5, 6, 7, and 8.
  • Example C In Vivo Efficacy of PTPN2/N1 Inhibitors in Combination with an Immune Checkpoint Inhibitor in an MC38 Murine Tumor Model
  • C57BL/6 female mice (5-9 weeks of age) were obtained from GemPharmatech Co. Ltd and grouped up to 5 mice per cage and provided food and water ad libitum. Animals were acclimated to the facilities for a period of at least a week prior to cancer cell inoculation.
  • the MC-38 (murine colon carcinoma) tumor cells were maintained in vitro with DMEM medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5%CO 2 . The cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation into the right flank.
  • each mouse was inoculated subcutaneously to the right lower flank region with MC-38 tumor cells (1 x 10 6 ) in 0.1 ml of PBS for tumor development. After tumor cells inoculation, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain/loss, eye/hair matting and any
  • Dosing was conducted either orally (p.o.) for herein disclosed PTPN2/N1 inhibitor exemplary compound 1 or intraperitoneally (i.p.) for anti -PD1 antibody (Biocell (#BP0146)) or isotype Rat IgG2a control (Biocell (#BE0089)) or both for the combination groups.
  • Dosing of exemplary compound 1 was conducted once per day (q.d.) during the light cycle phase at 15 mg/kg.
  • For anti-PD-1 or isotype control compounds were dosed bi-weekly at 10 mg/kg.
  • Exemplary compound 1 was formulated in 10% ethanol, 30% PEG-400, 60% Phosal-50 PG and was dosed at 10 ⁇ L/g.
  • Anti-PD-1 antibody or isotype control were formulated in PBS.
  • the individual mouse was euthanized if its tumor volume exceeds 3,000 mm 3 or if they lost over 20% of their BW recorded on the day of randomization. In the event of tumor ulceration and to deter cannibalization, such animals were separated immediately and singly housed and monitored daily.
  • Exemplary compound 1 was well tolerated either alone or in combination with anti-PD-1 antibody or isotype control.
  • Mean percentage (%) inhibition of TVs was calculated using (mean(C)- mean(T))/mean(C) * 100%), where mean(C) is the vehicle TV mean and mean(T) is the treatment group TV.
  • TGI Tumor Growth Inhibition
  • Exemplary compound 1 led to significant tumor growth inhibition (TGI) as a single agent or in combination with isotype control by day 9.
  • TGI tumor growth inhibition
  • exemplary compound 2 Dosing of exemplary compound 2 was conducted once per day (q.d.) during the light cycle phase at 1, 2.5, 5 or 7.5 for single agent activity and 1, 2.5 or 5 mg/kg for combo activity.
  • anti-PD- 1 compounds were dosed bi-weekly at 10 mg/kg.
  • Exemplary compound 2 was formulated in 10% ethanol, 30% PEG-400, 60% Phosal-50 PG and was dosed at 10 ⁇ L/g.
  • Anti-PD-1 antibody was formulated in PBS. The individual mouse was euthanized if its tumor volume exceeds 3,000 mm3 or if they lost over 20% of their BW recorded on the day of randomization. In the event of tumor ulceration and to deter cannibalization, such animals were separated immediately and singly housed and monitored daily.
  • Exemplary compound 2 was well tolerated either alone or in combination with anti-PD-1 antibody or isotype control.
  • Mean percentage (%) inhibition of TVs was calculated using (mean(C)- mean(T))/mean(C) * 100%), where mean(C) is the vehicle TV mean and mean(T) is the treatment group TV.
  • TGI Tumor Growth Inhibition
  • Exemplary compound 2 led to significant tumor growth inhibition (TGI) as a single agent by day 8. By day 19, exemplary compound 2 showed 37%, 81% and 94% TGI for 1, 2.5 and 7.5 mg/kg groups respectively Table 10. Tumor regression was observed in the 5 (4 out of 10 animals) and 7.5 (8 out of 10 animals) mg/kg dosing groups.
  • TGI tumor growth inhibition
  • the anti-PD-1 antibody alone only reached about 57% TGI by Day 19, whereas in combination with exemplary compound 2, significant TGI was observed as early as Day 5 for group 09 (exemplary compound 2 at 5 mg/kg + anti-PD1 antibody) (30% TGI, Table 10) and reached 99% TGI by Day 19 with over 80% of animals cured of their tumors.
  • combination with exemplary compound 2 at lower doses of 1 mg/kg and 2.5 mg/kg combination reached 68% and 75% TGI, which is greater than anti-PD-1 alone (57%) Table 10, with greater number of regressions and cured observed in the single agent groups, clearly indicating that the combination of both compounds led to greater efficacy than when each was administered as a single agent.
  • PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity. Cancer Discov. 2022 Mar l;12(3):752-773. doi: 10.1158/2159-8290. CD-21-0694. PMID: 34794959; PMCID: PMC8904293.
  • trastuzumab deruxtecan (DS-820 la)- induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model.
  • PLoS ONE trastuzumab deruxtecan

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Abstract

L'invention concerne des procédés utilisant une combinaison comprenant un non-récepteur de protéine tyrosine phosphatase de type 2 (PTPN2) et/ou un non-récepteur de protéine tyrosine phosphatase de type 1 (PTPN1), et un agent thérapeutique supplémentaire pour traiter des maladies favorablement sensibles au traitement par inhibiteur de PTPN1 ou PTPN2, par exemple, un cancer ou une maladie métabolique.
PCT/US2024/040524 2023-08-02 2024-08-01 Combinaisons d'inhibiteurs de protéine tyrosine phosphatase Pending WO2025030008A1 (fr)

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