Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
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  • 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
  • A61K31/41—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
• • 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
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

• 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 an N-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, Lck).
• 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
• Src family kinases e.g., Fyn, Lck
• Data from a loss of function in vivo genetic screen using CRISPR/Cas9 genome editing in a mouse B16F10 transplantable tumor model show that deletion of Ptpn2 gene in tumor cells improved response to the immunotherapy regimen of a GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade.
• GVAX GM-CSF secreting vaccine
• PTP1B Protein tyrosine phosphatase non-receptor type 1
• PTP1B protein tyrosine phosphatase-1B
• Ring A is a heterocycloalkyl or heteroaryl
• the compound is of Formula (Ia): Formula (Ia); wherein R 4’ is hydrogen or R 4 .
• R 4’ is hydrogen or R 4 .
• the compound is of Formula (Ib): Formula (Ib); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (Ic): wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (IIa): Formula (IIa); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (IIb): Formula (IIb); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (IIc): wherein R 4’ is hydrogen or R 4 .
• a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
• 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 compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• a method of treating cancer in a subject in need thereof the method comprising administering to the subject a pharmaceutical composition disclosed herein.
• the method further comprises administering an additional therapeutic agent.
• the additional therapeutic agent is an immunotherapeutic agent.
• the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody.
• Also disclosed herein is a method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• a method of treating type-2 diabetes in a subject in need thereof the method comprising administering to the subject a pharmaceutical composition disclosed herein.
• a method of treating and/or controlling obesity in a subject in need thereof the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• Also disclosed herein is a method of treating and/or controlling obesity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.
• a method of treating a metabolic disease in a subject in need thereof the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• a method of treating a metabolic disease in a subject in need thereof the method comprising administering to the subject a pharmaceutical composition disclosed herein.
• 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-pent
• a numerical range such as “C 1 -C 6 alkyl” or “C1-6alkyl”, 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 a C1-10alkyl.
• the alkyl is a C1-6alkyl.
• the alkyl is a C 1 - 5 alkyl.
• the alkyl is a C 1 - 4 alkyl.
• the alkyl is a C1-3alkyl.
• an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
• alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
• 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. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
• a numerical range such as “C 2 -C 6 alkenyl” or “C 2 - 6 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 oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
• the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
• 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.
• a numerical range such as “C 2 -C 6 alkynyl” or “C 2 - 6alkynyl”, 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 oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
• the alkynyl is optionally substituted with halogen, -CN, - OH, or -OMe.
• 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 oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0034] “Alkoxy” refers to a radical of the formula -OR a where R a is an alkyl radical as defined.
• an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
• the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe.
• 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, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
• an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl 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) 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 (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3- C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl).
• the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered 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, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7- dimethyl-bicyclo[2.2.1]heptanyl.
• Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
• the cycloalkyl is optionally substituted with halogen. [0037] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.
• 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, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
• 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 include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [0040] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines.
• the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines.
• Aminoalkyl include, 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.
• the alkyl is substituted with one, two, three, four, five, or six deuteriums.
• Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2.
• the deuteroalkyl is CD3.
• “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 (e.g., -NH-, -N(alkyl)-), 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 (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof 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 , -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)2.
• a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with 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 nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
• the heterocycloalkyl comprises one nitrogen. In some embodiments, 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) 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 (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2- C7 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl or C 2 -C 4 heterocycloalkeny
• heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]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 disaccharides, and the oligosaccharides. Unless otherwise noted, 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). In some embodiments, the heterocycloalkyl is a 3- to 12-membered heterocycloalkyl.
• the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, 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.
• the heterocycloalkyl is a 3- to 12-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 10-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl.
• the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
• a heterocycloalkyl may be optionally substituted as described below, for example, with 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 oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl 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 four 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, oxygen, and sulfur.
• the heteroaryl comprises one to four heteroatoms selected from the group consisting of nitrogen and oxygen.
• the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
• the heteroaryl comprises one to four nitrogens. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen.
• 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 quaternized.
• the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
• a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
• the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
• the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
• “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above.
• an optionally substituted group may be un-substituted (e.g., - CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) 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 , - CFHCHF2, etc.).
• any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
• the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents.
• the subject 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.
• An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
• “Treatment” of an individual e.g.
• 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.
• 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.
• 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.
• the methods relate to treating or lessening the severity of one or more diseases in which PTPN1, or a mutant thereof, is known to play a role.
• the compound is of Formula (Ia): Formula (Ia); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (Ib): Formula (Ib); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (Ic): wherein R 4’ is hydrogen or R 4 .
• Ring A is heterocycloalkyl.
• Ring A is N-linked heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is C-linked heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5- to 6-membered heterocycloalkyl.
• Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heterocycloalkyl 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 (Ia)-(Ic), Ring A is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N.
• Ring A is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heterocycloalkyl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I) or (Ia)-(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 (Ia)-(Ic), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyrrolidinyl or piperidinyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyrrolidinyl.
• 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 (Ia)-(Ic), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(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 (Ia)-(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 (Ia)-(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 (Ia)- (Ic), Ring A is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heteroaryl comprising 1 heteroatom that is N. [0064] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is , ,
• Ring A is , , some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring . [0066] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is ,
• Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring .
• 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.
• 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 (I) or (Ia)-(Ic), 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 (Ia)-(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 (Ia)-(Ic), each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is hydrogen.
• m is 1-3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 2. [0073] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -CH2-, -CH2CH2-, or - CH2CH2CH2-.
• L is -NR 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 -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.
• each R 4 is independently deuterium or halogen.
• each R 4 is independently halogen.
• each R 4 is independently -OR a or C 1 -C 6 alkyl.
• p is 0 or 1.
• p is 0.
• p is 1.
• W is N.
• W is CR W .
• R W is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R W is hydrogen or C 1 -C 6 alkyl.
• R W is hydrogen.
• 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 1a .
• 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 1a .
• each R 1 is independently 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.
• 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. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R 1a .
• 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 (Ia)-(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 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, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, 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 1a 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 1a is independently halogen, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently -NR c R d , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
• each R 1a is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. [ 0085] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently fluoro, [0086] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-8. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-7. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), n is 0-6.
• n is 0-5. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0.
• n is 1-8. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-7. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-6. In some embodiments of a compound of 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 (Ia)-(Ic), n is 1-3.
• n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 3. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), n is 4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 5. In some embodiments of
• the compound is of Formula (IIa): Formula (IIa); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (IIb): Formula (IIb); wherein R 4’ is hydrogen or R 4 .
• the compound is of Formula (IIc): wherein R 4’ is hydrogen or R 4 .
• Ring B is heterocycloalkyl.
• Ring B is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- to 8- membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5-membered heterocycloalkyl.
• Ring B is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl 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 (IIa)-(IIc), 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. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), 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 (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms that are N.
• Ring B is heterocycloalkyl comprising 1 heteroatom that is N.
• Ring B is cycloalkyl.
• Ring B is 4- to 8-membered cycloalkyl.
• Ring B is 5- to 8-membered cycloalkyl.
• Ring B is 5- to 6-membered cycloalkyl.
• Ring B is heteroaryl.
• Ring B is 5- or 6-membered heteroaryl.
• Ring B is 5-membered heteroaryl.
• 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 (IIa)-(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 (IIa)-(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 (IIa)-(IIc), Ring B is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 heteroatom that is N.
• L is -[C(R 3 )2]m-.
• L is -CH2-, -CH2CH2-, or - CH 2 CH 2 CH 2 -.
• L is -CH 2 -.
• L is -CH 2 CH 2 -.
• L is -CH2CH2CH2-.
• L is -O-.
• L is -NR 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 -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 -.
• 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 (IIa)-(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.
• each R 3 is hydrogen.
• m is 1-3. In some embodiments of a compound of Formula (II) or (IIa)-(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), m is 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 (IIa)-(IIc), each R 4 is independently deuterium or halogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 4 is independently halogen. In some embodiments of a compound of Formula (II) or (IIa)-(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 (IIa)-(IIc), p is 0. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), p is 1. [00110] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), W is N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), W is CR W .
• R W is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R W is hydrogen.
• R W is C 1 -C 6 alkyl.
• 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 (IIa)-(IIc), each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 1 on the same atom are taken together to form an oxo.
• 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.
• n is 1-8.
• n is 1-7. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-6. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-5. In some embodiments of a compound of Formula (II) or (IIa)-(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 (IIa)-(IIc), n is 1 or 2.
• n is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 4. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 5. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 6.
• 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 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 b is 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.
• R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl.
• each R is independently halogen, -CN, - OH, -OC 1 -C 3 alkyl, -OC 1 -C 3 haloalkyl, NH 2 , -NHC 1 -C 3 alkyl, -N(C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl.
• each R is independently halogen, -CN, -OH, -OC1-C3alkyl, - OC 1 -C 3 haloalkyl, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, or C 1 -C 3 haloalkyl.
• each R is independently halogen, -CN, -OH, -OC1-C3alkyl, NH2, C1-C3alkyl, or C1-C3haloalkyl.
• each R is independently halogen, C1- C 3 alkyl, or C 1 -C 3 haloalkyl.
• any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
• the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. TABLE 1 * Stereochemistry arbitrarily assigned [00120] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Table 2
• the compounds described herein exist as geometric isomers.
• the compounds described herein possess one or more double bonds.
• the compounds presented herein include all cis, trans, syn, anti,
• E
• Z
• the compounds described herein possess one or more chiral centers and each center 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.
• mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
• 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. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• Labeled compounds [00122] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, 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 chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, 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.
• 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. Further, 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.
• Pharmaceutically acceptable salts [00124] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, 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, 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, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, HEWAMNASE& HEWXME'*&/'DINASE& HX
• 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, 1,2-
• 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 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.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
• the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
• Solvates [00130] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates.
• 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 [00132] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. 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.
• Method of Treatment Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1/ PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• methods of treatment of a disease in which inhibition of PTPN1 is beneficial the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, 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.
• 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, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma,
• 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 carcinoma
• 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, immuno
• 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.
• a symptom comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.
• the 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.
• 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.
• 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, 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.
• Pharmaceutical Compositions/Formulations [00152] 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, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
• the additional therapeutic agent is an anticancer agent.
• 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.
• the additional therapeutic agent is administered after the administration of the compound disclosed herein.
• the additional therapeutic agent is an immunotherapeutic agent.
• the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody.
• Example 1 Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpyrrolidin-3-yl)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Step 1 Synthesis of compound 1-2 [00160] To a solution of 1-1 (100 g, 420.1 mmol, 1 eq) in THF (1.5 L) was added benzyl alcohol (47.7 g, 441.2 mmol, 45.8 mL, 1.05 eq) followed by dropwise addition of 1M t-BuOK (441 mL, 1.05 eq) at -78°C and then allowed to stir for 0.5 h.
• Step 6 Synthesis of compound 1-9A [00165] To a solution of 0.5M 9-BBN (180 mL, 1.5 eq) was added 1-8 (16.5 g, 90.3 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C.
• Step 7 Synthesis of compound 1-10 [00166] A solution of 1-9A (13 g, 25 mmol, 1 eq) in 4M HCl/ethyl acetate (200 mL) was allowed to stir for 2 h at 25 °C. The reaction mixture was then concentrated under reduced pressure to give 1-10 (15.7 g, HCl salt, crude) as a brown solid.
• Step 8 Synthesis of compound 1-11A [00167] To a solution of 1-10 (250 mg, 548 ⁇ mol, 1 eq) in MeOH (3 mL) was added formaldehyde (82 mg, 1.1 mmol, 75 ⁇ L, 2 eq) and AcOH (82 mg, 1.3 mmol, 78 ⁇ L, 2.5 eq) and allowed to stir for 0.5 h at 0 °C. To this was then added NaBH4 (130 mg, 3.4 mmol, 6.27 eq) and allowed to stir for an additional 2 h at 0 °C. The resulting reaction mixture was added to H 2 O (50 mL) then extracted with ethyl acetate (5 mL ⁇ 3).
• Example 1 (6 mg, 98% purity).
• LCMS (ESI-): m/z 342.2 (M-H)-.
• Examples 2-30 were prepared according to the procedures described in Example 1 using the appropriate intermediates.
• Example 31 Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpiperidin-3-yl)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Step 1 Synthesis of compound 31-2 [00169] To 31-1 (17.8 g, 90.3 mmol, 1.5 eq) was added to 0.5M 9-BBN (180 mL, 1.5 eq) then heated to 60 °C and allowed to stir for 1 h.
• reaction mixture was then cooled to 20 °C and added to a solution of 1- 7A (1 eq), K2CO3 (12.48 g, 90.31 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (4.92 g, 6.02 mmol, 0.1 eq) in DMF (250 mL) and H2O (25 mL) then heated to 60 °C and allowed to stir for an additional 12 h. To the resulting reaction mixture was then added to H 2 O (200 mL) then extracted with ethyl acetate (100 mL ⁇ 3).
• Step 2 Synthesis of compound 31-3 [00170] A mixture of 31-2 (33 g, 61.84 mmol, 1 eq) in 4M HCl/ethyl acetate (350 mL) was degassed and purged with N2 for 3 times, then allowed to stir for 2 h at 25 °C. The reaction mixture was then concentrated under reduced pressure and purified by HPLC to give 31-3 (11 g, 23.4 mmol, 37% yield) as a white solid.
• Step 3 Synthesis of compound 31-4A [00171] To a solution of formaldehyde (259 mg, 3.2 mmol, 237 ⁇ L, 3 eq) in acetonitrile (5 mL) was added 31-3 (0.5 g, 1.06 mmol, 1 eq) and acetic acid (159 mg, 2.66 mmol, 152 ⁇ L, 2.5 eq) and allowed to stir for 1 h at 15 °C. To this was then added NaBH 3 CN (74 mg, 1.17 mmol, 1.1 eq) and allowed to stir for an additional 1 h. The resulting reaction mixture was concentrated under reduced pressure to give 31-4A (0.5 g, crude) as a yellow solid.
• Example 55 Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Step 1 Synthesis of compound 55-2A [00173] To a solution of 0.5M 9-BBN (3.18 mL, 1.5 eq) was added 55-1 (244 mg, 1.16 mmol, 1.2 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C.
• Example 56 Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Compound 56-1 was prepared according to the procedure described for Example 55.
• the suspension was degassed under vacuum and purged with H2 (15 psi) 3 times then allowed to stir for 2 h at 20 °C.
• Example 61 Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Step 1 Synthesis of compound 61-2 [00177] To a solution of 0.5M 9-BBN (14.4 mL, 1.5 eq) was added 61-1 (1.4 g, 7.2 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C.
• Step 2 Synthesis of compound 61-3 A solution of 61-2 (470 mg, 880 ⁇ mol, 1 eq) in 4M HCl/ethyl acetate (10 mL) was allowed to stir for 0.5 h at 25 °C. The reaction mixture was concentrated under reduced pressure to give 61-3 (400 mg, crude) as a yellow solid.
• Step 3 Synthesis of compound 61-4A series [00178] To a solution of 61-3 (100 mg, 230 ⁇ mol, 1 eq), formaldehyde (14 mg, 461 ⁇ mol, 13 ⁇ L, 2 eq) in acetonitrile (2 mL) was added acetic acid (34 mg, 576 ⁇ mol, 33 ⁇ L, 2.5 eq) and allowed to stir for 0.5 h at 25 °C. To this was then added NaBH 3 CN (29 mg, 461 ⁇ mol, 2 eq) and allowed to stir for an additional 1 h. To the reaction mixture was added H2O (5 mL) then extracted with ethyl acetate (5 mL ⁇ 3).
• Example 62 - 64 were prepared according to the procedures described in Example 61 using the appropriate intermediates.
• Example 65 Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)phenyl)-1,2,5- Step 1: Synthesis of compound 65-2 [00180] To a solution of 0.5M 9-BBN (3.61 mL, 1.5 eq) was added 65-1 (356 mg, 1.8 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C.
• Step 2 Synthesis of compound 65-3 [00181] A solution of 65-2 (230 mg, 431 ⁇ mol, 1 eq) in 4M HCl/ethyl acetate (10 mL) was allowed to stir for 0.5 h at 25 °C. The reaction mixture was concentrated under reduced pressure to give 65-3 (250 mg, crude) as a white solid.
• Step 3 Synthesis of compound 65-4A [00182] To a solution of 65-3 (100 mg, 213 ⁇ mol, 1 eq), formaldehyde (34 mg, 425 ⁇ mol, 31 ⁇ L, 2 eq) in 1,2-dichloroethane (2 mL) was added diisopropylethylamine (30 mg, 234 ⁇ mol, 40 ⁇ L, 1.1 eq) and allowed to stir for 0.5 h at 25 °C. To this was then added NaBH(OAc)3 (139 mg, 638 ⁇ mol, 3 eq) and allowed to stir for an additional 1 h.
• Example 69 Synthesis of 5-(4-(azetidin-3-ylmethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide
• Step 1 Synthesis of compound 69-2 [00184] To a solution of 0.5M 9-BBN (3.18 mL, 1.65 eq) was added 69-1 (293 mg, 1.4 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C.
• Step 2 Synthesis of compound Example 69 [00185] To a solution of 69-2 (130 mg, 240 ⁇ mol, 1 eq) in THF (10 mL) was added 10% Pd/C (50 mg) under N 2 . The suspension was degassed under vacuum and purged with H 2 (15 psi) 3 times then allowed to stir for 2 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 69 (3.6 mg, 11.4 ⁇ mol, 5% yield).
• Step 1 Synthesis of compound 70-1 [00186] To a solution of 1-7A (2 g, 4.82 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.42 g, 48.17 mmol, 8.17 mL, 10 eq) and K2CO3 (2.0 g, 14.4 mmol, 3 eq) in DMF (20 mL) and H2O (2 mL) was added Pd(dppf)Cl 2 -CH 2 Cl 2 (393 mg, 481 ⁇ mol, 0.1 eq) then heated to 80 °C and allowed to stir for 12 h.
• Step 2 Synthesis of compound 70-2 [00187] To a solution of 70-1 (1.4 g, 3.86 mmol, 1 eq) and 2,6-dimethylpyridine (827 mg, 7.7 mmol, 900 ⁇ L, 2 eq) in 1,4-dioxane (40 mL) and H2O (10 mL) was added NaIO4 (3.31 g, 15.45 mmol, 856 ⁇ L, 4 eq) slowly and allowed to stir for 2 h at 0 °C under N2. To this was then added potassium osmate (VI) dihydrate (71 mg, 193 ⁇ mol, 0.05 eq) and allowed to warm to 20 °C and stirred for an additional 10 h.
• VI potassium osmate
• Step 3 Synthesis of compound 70-4A [00188] To a solution of 70-2 (100 mg, 274 ⁇ mol, 1 eq) in CH 2 Cl 2 (4 mL) was added diisopropylethylamine (35 mg, 274 ⁇ mol, 47 ⁇ L, 1 eq) and 4A MS (100 mg) at 25 °C then was allowed to stir for 0.5 h. To this was then added 70-3 (49 mg, 329 ⁇ mol, 1.2 eq) and allowed to stir for an additional 2 h. To the reaction mixture was then added NaBH(OAc)3 (174 mg, 823 ⁇ mol, 3 eq) and allowed to stir for an additional 12 h.
• Example 71 – 73 were prepared according to the procedures described in Example 70 using the appropriate intermediates.
• Example 74 Synthesis of 5-(2-fluoro-6-hydroxy-3-((1-methylpiperidin-2-yl)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Step 1 Synthesis of compound 74-2 [00190] To a solution of 2-bromopyridine (5 g, 31.6 mmol, 3.01 mL, 1 eq) in THF (50 mL) was added 2.5M n-BuLi (12.6 mL, 1 eq) dropwise at -78 °C under N2 and allowed to stir for 1 h. To this was then added a solution of 74-1 (4.43 g, 31.6 mmol, 1 eq) in THF (5 mL) and allowed to stir for an additional 0.5 h. The resulting reaction mixture was quenched with a mixture of sat. NH 4 Cl (aq) (80 mL) and allowed to stir for 5 minutes at 25 °C.
• Step 2 Synthesis of compound 74-3 [00191] To a solution of 74-2 (2.46 g, 11.22 mmol, 1 eq) in TFA (25 mL) was added Et3SiH (6.52 g, 56.1 mmol, 9 mL, 5 eq) then heated to 60 °C and allowed to stir for 12 h. To the reaction mixture was added sat. NaHCO 3 (aq) (100 mL) then extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers were washed with brine (300 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude.
• Step 3 Synthesis of compound 74-4 [00192] To a solution of 74-3 (1.5 g, 7.38 mmol, 1 eq) in THF (50 mL) was added 1M HCl (1.66 mL) and PtO 2 (300 mg) under N 2 . The suspension was degassed under vacuum and purged with H 2 (200 psi) then allowed to stir for 8 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude.
• Step 4 Synthesis of compound 74-5 [00193] To a solution of 74-4 (820 mg, 3.9 mmol, 1 eq) in THF (8.2 mL) was added triethylamine (594 mg, 5.88 mmol, 818 ⁇ L, 1.5 eq) and Boc 2 O (1.28 g, 5.88 mmol, 1.35 mL, 1.5 eq) at 20 °C and allowed to stir for 1 h. To the reaction mixture was added H2O (15 mL) then extracted with ethyl acetate (15 mL ⁇ 3). The combined organic layers were washed with brine (45 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude.
• Step 5 Synthesis of compound 74-6 [00194] To a solution of 74-5 (800 mg, 2.6 mmol, 1 eq) in DMF (8 mL) was added K 2 CO 3 (1.07 g, 7.76 mmol, 3 eq) and BnBr (884 mg, 5.17 mmol, 614 ⁇ L, 2 eq) at 20 °C and allowed to stir for 1 h. To the reaction mixture was added H2O (15 mL) then extracted with ethyl acetate (15 mL ⁇ 3). The combined organic layers were washed with brine (30 mL ⁇ 5), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude.
• Step 6 Synthesis of compound 74-7 [00195] To a solution of 74-6 (710 mg, 1.78 mmol, 1 eq) in THF (7 mL) was added 2.5M n-BuLi (1.07 mL, 1.5 eq) at -78 °C and allowed to stir for 1 h under N2. To this was added a solution of I2 (676 mg, 2.67 mmol, 537 ⁇ L, 1.5 eq) in THF (7 mL) and allowed to stir for an additional 1 h. The resulting suspension was quenched with a mixture of sat.
• Step 7 Synthesis of compound 74-8 [00196] A solution of 74-7 (650 mg, 1.24 mmol, 1 eq), tert-butyl 2-aminoacetate (243 mg, 1.86 mmol, 1.5 eq) and Cs2CO3 (1.21 g, 3.71 mmol, 3 eq) in 1,4-dioxane (6.5 mL) was degassed and purged with N2 for 3 times.
• Step 8 Synthesis of compound 74-9 [00197] To a solution of N-(oxomethylene)sulfamoyl chloride (225 mg, 1.6 mmol, 138 ⁇ L, 1.5 eq) in CH 2 Cl 2 (6 mL) was added prop-2-en-1-ol (100 mg, 1.7 mmol, 117 ⁇ L, 1.63 eq) at 0 °C under N 2 and allowed to stir for 0.5 h.
• Step 9 Synthesis of compound 74-10 [00198] To a solution of 74-9 (776 mg, 1.12 mmol, 1 eq) in MeOH (8 mL) was added NaOMe (606 mg, 3.37 mmol, 3 eq) and Pd(PPh3)4 (26 mg, 22 ⁇ mol, 0.02 eq) under N2 then heated to 60 °C for 0.5 h. To the reaction mixture was added 1M HCl (15 mL) then extracted with ethyl acetate (15 mL ⁇ 3). The combined organic layers were washed with brine (45 mL), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give 74-10 (540 mg, crude) as yellow oil.
• Step 10 Synthesis of compound 74-11 [00199] To 74-10 (540 mg, 1.01 mmol, 1 eq) was added 4M HCl/ethyl acetate (10 mL) at 20 °C and allowed to stir for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give 1-11 (472 mg, crude) as a yellow solid.
• Step 11 Synthesis of compound 74-12A [00200] To a solution of 74-11 (200 mg, 425 ⁇ mol, 1 eq), formaldehyde (107 mg, 1.3 mmol, 98 ⁇ L, 3.1 eq) in acetonitrile (2 mL) was added acetic acid (64 mg, 1.06 mmol, 61 ⁇ L, 2.5 eq) at 20 °C and allowed to stir for 0.5 h. To this was then added NaBH 3 CN (29 mg, 468 ⁇ mol, 1.1 eq) and allowed to stir for an additional 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 74- 12A (190 mg, crude) as colorless oil.
• Example 83 (2.16 mg, 100% purity).
• LCMS (ESI-): m/z 342.2 (M-H)-.
• Example 84 Synthesis of 5-(4-(2-(2-ethylpyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
• Compound 83-5C was prepared according to the procedure described for 83-5A. To a solution of 83-5C (0.02 g, 46.14 ⁇ mol, 1 eq) in MeOH (1 mL) was added Pd/C (0.02 g, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times. This was then allowed to stir for 1 h at 40 °C.
• Example 85 – 128 were prepared according to the procedures described in Example 83 using the appropriate intermediates.
• Example A Enzymatic Assay used to determine potency of PTPN2 Inhibitors
• Compound activity was determined in an in vitro enzymatic assay using untagged, full-length human PTPN2 (TC45) (1-387) protein.
• TC45 human PTPN2
• 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 (50mM HEPES pH7.5, 0.2mM EDTA, 1mM DTT, 0.02% Brij- 35, 0.02% BSA) to a final 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. Following a 10 min incubation at room temperature, 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.
• assay buffer 50mM HEPES pH7.5, 0.2mM EDTA, 1mM DTT, 0.02% Brij- 35, 0.02% BSA
• Example B B16F10 Cellular Growth Inhibition Assay [00207] 4NLONTMD ACSIUISX VAR DESEQLIMED TRIMG AM IMSEQFEQNM GALLA $86; ⁇ %'IMDTCED CEKKTKAQ GQNVSH inhibition assay with the murine B16F10 melanoma cell line on an Agilent xCELLigence Real-Time Cell Analysis platform (RTCA).
• RTCA Real-Time Cell Analysis platform
• RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibrated with 50 ⁇ L of assay media (DMEM+10% FBS, Gibco 10566-024, Gibco 10082-147) at 37°C in a humidified incubator before taking an initial measurement of impedance (sweep).
• 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.

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