WO2022272060A1 - Ep2 antagonist compounds - Google Patents

Ep2 antagonist compounds Download PDF

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Publication number
WO2022272060A1
WO2022272060A1 PCT/US2022/034901 US2022034901W WO2022272060A1 WO 2022272060 A1 WO2022272060 A1 WO 2022272060A1 US 2022034901 W US2022034901 W US 2022034901W WO 2022272060 A1 WO2022272060 A1 WO 2022272060A1
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alkyl
ring
compound
substituted
unsubstituted
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English (en)
French (fr)
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Matthew Alexander James Duncton
JR. Vladimir V. SENATOROV
Aaron R. FRIEDMAN
Steven Howard Olson
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Reservoir Neuroscience Inc
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Reservoir Neuroscience Inc
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Priority to EP22829383.3A priority Critical patent/EP4359392A4/en
Priority to JP2023579119A priority patent/JP2024524986A/ja
Publication of WO2022272060A1 publication Critical patent/WO2022272060A1/en
Priority to US18/395,334 priority patent/US20240182459A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • EP2 ANTAGONIST COMPOUNDS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/214,645, filed on June 24, 2021, which is incorporated herein by reference in its entirety.
  • FIELD OF THE INVENTION [0002] Described herein are compounds that are inhibitors of prostaglandin E2 receptor 2, also known as EP2, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity.
  • EP2 is a prostaglandin receptor that functions, for example, as a mediator of inflammation.
  • EP2 signaling is implicated in, for example, inflammatory conditions, allergic diseases, ocular diseases, nervous system diseases, bone diseases, fibrotic conditions, cardiovascular diseases, and certain forms of cancer.
  • Compounds described herein are antagonists of EP2.
  • the compounds described herein are used in the treatment or prevention of diseases or conditions in which EP2 activity contributes to the symptomology or progression of the diseases or conditions, such as, for example, inflammatory diseases or conditions.
  • R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl;
  • a 3 is -CR 9 R 10 - or absent;
  • R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl;
  • R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or
  • R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C1-4 alkyl, -C1-4 hal
  • Ring B is C3-6 cycloalkyl, phenyl, or 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; each R B is independently selected from the group consisting of halogen, -CN, -C1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 methoxyalkyl, -(C 1-4 alkyl)O(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , - C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, -NH2, -NH(C1-4
  • each R B is independently selected from the group consisting of halogen, -CN, -C1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 methoxyalkyl, -(C 1-4 alkyl)O(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , - C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, -NH2, -NH(C1-4 alkyl), -NH(C3-6 cycloalkyl), -NH(C 3-6 heterocycloal
  • Ring B is a substituted or unsubstituted heterocycle; wherein if Ring B is substituted, it is substituted with one or more R B groups, and each R B is independently selected from the group consisting of halogen, -CN, -C1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 methoxyalkyl, -(C 1-4 alkyl)O(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , - C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, -NH2, -NH(C1-4 alkyl), -NH(C3-6 cycloalkyl), -NH(C 3-6 heterocycloalkyl), -N(C
  • a compound of Tables I, II, III, III’, VII, VIII, or IX or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, Formula I’, Formula Ia, Formula Ia’, Formula Ib, FormulaIb’ Formula Ic, Formula Ic’, Formula ID, Formula Id’, or Formula Id’’, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a method of modulating the activity of the prostaglandin E2 receptor 2 (EP2) in a mammal comprising administering to the mammal a compound disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • a method of treating a disease or condition that would benefit from the modulation of prostaglandin E2 receptor 2 (EP2) activity comprising administering to the mammal a compound disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • a pharmaceutical composition comprising a compound decribed herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, or nasal administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a dispersion, a solution, or an emulsion.
  • described herein is a method of modulating the activity of the prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • a method of treating a disease or condition that would benefit from the modulation of prostaglandin E2 receptor 2 (EP2) activity comprising administering to the mammal a compound of described herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • Prostaglandins act on prostaglandin receptors such as the prostaglandin DP1 receptor (DP1), prostaglandin DP2 receptor (DP2), prostaglandin EP1 receptor (EP1), prostaglandin EP2 receptor (EP2), prostaglandin EP3 receptor (EP3), prostaglandin EP4 receptor (EP4), prostaglandin F2 ⁇ receptor (FP1), prostacyclin I2 receptor (IP), and thromboxane A2 receptor (TP), or a combination thereof.
  • DP1 receptor DP1 receptor
  • DP2 receptor prostaglandin DP2 receptor
  • EP1 receptor prostaglandin EP1 receptor
  • EP2 receptor prostaglandin EP2 receptor
  • EP3 receptor EP3 receptor
  • prostaglandin EP4 receptor EP4
  • FP1 receptor prostaglandin F2 ⁇ receptor
  • IP prostacyclin I2 receptor
  • TP thromboxane A2 receptor
  • Prostaglandin E2 is a metabolite of arachidonic acid, synthesized by the action of cyclooxygenase and prostaglandin E synthase.
  • PGE2 which is produced in nearly all organs and tissues, has a variety of physiological effects, including mucosal protection, induction of gastric acid secretion in stomach, generation of fever, hyperalgesia, inflammation and immunity.
  • the actions of PGE2 are mediated by four receptors, EP1, EP2, EP3 and EP4.
  • PGE2 has affinity not only for all four EP receptor subtypes but also for other prostanoid receptors, such as the PGE2 DP1 receptor.
  • PGE2 is a downstream product of the cyclooxy-genase 2 (COX-2) pathway and a major modulator of inflammation.
  • EP2 is a G-protein coupled receptor that, when bound to PGE2, mobilizes G s proteins and initiates signaling cascades involving adenylyl cyclase (and thereby elevates cAMP) and protein kinase A (PKA). Coupling of EP2 to Gs proteins stimulates adenylate cyclase and their activation increases intracellular cAMP levels. This signaling pathway has implications on inflammation, pain, immunoregulation, mitogenesis, plasticity, and cell injury.
  • EP2 also interacts with ⁇ -arrestin/JNK pathways, which pathway can affect proliferation and metastasis.
  • Expression of EP2 receptors has been demonstrated in a broad range of cell types and tissues, including lung, gastrointestinal tract, kidney, uterus, myleoid and thymus and has been linked with PGE2-mediated vasodilation and smooth muscle relaxation in pulmonary, gastrointestinal and reproductive tracts.
  • compounds described herein modulate the activity of EP2.
  • compounds described herein inhibit or reduce the magnitude of inflammatory PGE2 signalling through the EP2 receptor.
  • compounds described herein reduce or abolish one or more symptoms associated with an EP2 mediated disease or disorder (e.g., an EP2 mediated inflammatory disease or disorder.)
  • an EP2 mediated disease or disorder e.g., an EP2 mediated inflammatory disease or disorder.
  • Abberrant EP2 expression is observed in several forms of cancers, including cancers of the colon, prostate, liver, and breast.
  • EP2 activity e.g., over-activity
  • disclosed herein are methods of treating cancer with a compound disclosed herein.
  • the term “cancer” as used herein, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • compounds described herein reduce one or more symptoms of an EP2 mediated cancer. In some embodiments, compounds described herein reduce or reverse the progression of an EP2 mediated cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is colon cancer.
  • EP2 signaling i.e., through activation by PGE2
  • PGE2 contributes to inflammation by enhancing edema and leukocyte infiltration from increased vascular permeability, thereby allowing more blood flow into an inflamed area of the body.
  • modulation of EP2 function has effects on B lymphocytes, T lymphocytes, cytotoxic T-cell function, or a combination thereof.
  • disclosed herein are methods of treating inflammation with a compound disclosed herein.
  • the compounds disclosed herein are used in the reduction or suppression of inflammation in a mammal.
  • the compounds disclosed herein are used in the treatement or prevention of inflammation-related conditions (e.g., allergies, pain, and the like).
  • a method of reducing inflammation in a tissue comprising contacting an inflamed cell or tissue with a compound disclosed herein, in an amount sufficient to decrease or inhibit the inflammation.
  • the inflammation includes an inflammatory or allergic condition.
  • the compounds disclosed herein reduce one or more symptoms of a neuroinflammatory disease or disorder comprising reducing the activity of EP2 (e.g., by contacting the inflamed tissue with an EP2 antagonist disclosed herein).
  • disclosed herein is a method of reducing or halting the progression of a neuroinflammatory disease or disorder comprising administering a compound disclosed herein to an individual (e.g., a mammal, a human, etc.) in need thereof.
  • reducing inflammation, or treatment of an inflammatory condition includes reducing or inhibiting the activity of EP2.
  • reducing inflammation, or treatment of an inflammatory condition includes administering an antagonist of EP2 (e.g., an EP2 antagonist disclosed herein).
  • the inflammatory condition is an allergic condition.
  • the inflammatory condition is asthma.
  • the inflammatory condition is anaphylaxis.
  • the inflammatory condition is chronic inflammation.
  • disclosed herein is a method of treating chronic inflammation comprising administering an EP2 antagonist (e.g., a compound disclosed herein) to the individual in need thereof.
  • an EP2 antagonist e.g., a compound disclosed herein
  • a compound of any one of the formulae described herein, or a pharmaceutically acceptable salt thereof is an EP2 antagonist.
  • a 1 is -O-.
  • a 1 is -CR 5 R 6 -.
  • a 1 is -S-.
  • a 1 is absent.
  • a 2 is -CR 7 R 8 -.
  • a 3 is -CR 9 R 10 - or absent.
  • a 2 is -CR 7 R 8 -; and
  • a 3 is -CR 9 R 10 -; or A 1 is -O-;
  • a 3 is -CR 9 R 10 -; or A 1 is absent;
  • a 2 is -CR 7 R 8 -; and A 3 is -CR 9 R 10 -; or A 1 is -O-, -CR 5 R 6 -, or absent;
  • a 2 is -CR 7 R 8 -; and
  • a 3 is absent.
  • a 2 is -CR 7 R 8 -; and
  • a 3 is -CR 9 R 10 -; or A 1 is -O-;
  • a 3 is -CR 9 R 10 -.
  • a 1 is absent;
  • a 2 is -CR 7 R 8 -; and
  • a 3 is absent.
  • a 1 is -CR 5 R 6 -; and R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane.
  • R 5 and R 6 are each independently hydrogen, deuterium, or -CH 3 ; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane.
  • R 5 and R 6 are each independently hydrogen, deuterium, or -CH 3 .
  • R 5 is hydrogen and R 6 is hydrogen, deuterium, or -CH 3 .
  • R 5 and R 6 are each independently hydrogen or deuterium. In some embodiments, R 5 and R 6 are each hydrogen. In some embodiments, R 5 and R 6 are each deuterium. In some embodiments, R 5 and R 6 are each -CH3. In some embodiments, R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane. In some embodiments, R 5 and R 6 are each independently hydrogen or deuterium; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane.
  • a 2 is -CR 7 R 8 -; and R 7 and R 8 are each independently hydrogen, deuterium, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form a cyclopropane or an oxetane.
  • R 7 and R 8 are each independently hydrogen, deuterium, -CH3, or CF3; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form a cyclopropane or an oxetane.
  • R 7 and R 8 are each independently hydrogen, deuterium, -CH 3 , or -CF 3 . In some embodiments, R 7 and R 8 are each independently hydrogen, deuterium, or -CH3. In some embodiments, R 7 is hydrogen and R 8 is hydrogen, deuterium, -CH 3 , or -CF 3 . In some embodiments, R 7 is hydrogen and R 8 is hydrogen, deuterium, or -CH 3 . In some embodiments, R 7 and R 8 are each independently hydrogen or deuterium. In some embodiments, R 7 and R 8 are each hydrogen. In some embodiments, R 7 and R 8 are each deuterium. In some embodiments, R 7 and R 8 are each -CH 3 .
  • a 1 is -O-;
  • a 3 is -CR 9 R 10 .
  • a 3 is -CR 9 R 10 -; and R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • R 9 and R 10 are each independently hydrogen, deuterium, or -CH 3 ; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • R 9 and R 10 are each independently hydrogen, deuterium, or -CH3. In some embodiments, R 9 is hydrogen and R 10 is hydrogen, deuterium, or -CH 3 . In some embodiments, R 9 and R 10 are each independently hydrogen or deuterium. In some embodiments, R 9 and R 10 are each hydrogen. In some embodiments, R 9 and R 10 are each deuterium. In some embodiments, R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane. In some embodiments, R 9 and R 10 are each independently hydrogen or deuterium; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • R 5 and R 6 are each independently hydrogen, deuterium, or - CH3; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R 7 and R 8 are each independently hydrogen, deuterium, or -CH 3 ; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R 9 and R 10 are each independently hydrogen, deuterium, or -CH3; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • a 3 is -CR 9 R 10 - or absent.
  • R 3 and R 4 are each independently hydrogen or deuterium. In some embodiments, R 3 and R 4 are each independently hydrogen. In some embodiments, R 3 and R 4 are each independently deuterium. [0047] In some embodiments, R A1 is halogen, C 1-4 alkyl, or cyclopropyl. In some embodiments, R A1 is halogen. In some embodiments, R A1 is -F, -Cl, -Br, or -I. In some embodiments, R A1 is -F or -Cl. In some embodiments, R A1 is -F. In some embodiments, R A1 is - Cl. In some embodiments, R A1 is C1-4 alkyl.
  • R A1 is -CH3, -CH2CH3, - CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , or -C(CH 3 ) 3 . In some embodiments, R A1 is -CH 3 , -CH 2 CH 3 , or - CH(CH 3 ) 2 . In some embodiments, R A1 is -CH 3 . In some embodiments, R A1 is cyclopropyl. [0048] In some embodiments, alternatively “ring A,” is selected from the group consisting of: , , , , . [0049] In some embodiments, selected from the group consisting of:
  • a 1 is -O-;
  • a 3 is -CR 9 R 10 -.
  • the compound of Formula (I) is a compound of Formula (Ia) or Formula (Ia’): Formula (Ia) or Formula (Ia’), or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or deuterium;
  • R 7 and R 8 are each hydrogen or deuterium; or
  • R 7 and R 8 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R 9 and R 10 are each hydrogen or deuterium; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R A1 is halogen, C 1-4 alkyl, or cyclopropyl; and Ring C’ is as defined in Formula (I).
  • the compound of Formula (I) is a compound of Formula (Ib) or Formula (Ib’): Formula (Ib), or Formula (Ib’), or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • R A1 is halogen, C1-4 alkyl, or cyclopropyl; R 1 and R 2 are each independently hydrogen or deuterium; and Ring C’ is as defined in Formula (I).
  • the compound of Formula (I) is a compound of Formula (Ic): or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • R A1 is halogen, C1-4 alkyl, or cyclopropyl; R 1 and R 2 are each independently hydrogen or deuterium; and Ring C’ is as defined in Formula (I).
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen or deuterium; or R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 are each independently hydrogen or deuterium; and R 7 and R 8 are taken together with the carbon atom to which they are attached to form an oxetane; or R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are each independently hydrogen or deuterium; and R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane; and R A1 is -F, -Cl, or cyclopropyl.
  • R 3 is H; R 4 is H; R 7 is H; R 8 is H; R 9 is H; R 10 is H; and R A1 is -F; or R 3 is H; R 4 is H; R 7 is H; R 8 is H; R 9 is H; R 10 is H; and R A1 is cyclopropyl; or R 3 is D; R 4 is D; R 7 is H; R 8 is H; R 9 is H; R 10 is H; and R A1 is -Cl; or R 3 is D; R 4 is D; R 7 is D; R 8 is D; R 9 is H; R 10 is H; and R A1 is -Cl; or R 3 is H; R 4 is H; R 7 is D; R 8 is D; R 9 is H; R 10 is H; and R A1 is -Cl; or R 3 is H; R 4 is H; R 7 is D; R 8 is D; R 9 is H; R 10 is H; and R A1 is -Cl; or R 3 is H; R 4
  • the compound of Formula (I) is a compound of Formula (Id), Formula (Id’), or Formula (Id”): or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (Id), Formula (Id’), or Formula (Id”), wherein: R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; R 7 and R 8 are each independently hydrogen, deuterium, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane; R
  • R 1 and R 2 are each independently hydrogen or deuterium; and Ring C’ is selected from the group consisting of: .
  • R 1 and R 2 are each hydrogen.
  • R 1 and R 2 are each deuterium.
  • in another embodiment is a compound of the following formula: or a tautomer, or a pharmaceutically acceptable salt thereof, as disclosed in Table I. Table I. Compounds 1-8.
  • R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl;
  • a 3 is -CR 9 R 10 - or absent;
  • R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl;
  • R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C1-4 alkyl, -C1-4 haloalky
  • Ring B is C 3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is Ring B’.
  • Ring B’ is a Ring B’ disclosed in Table VII.
  • a 1 is -O-.
  • a 1 is -O-;
  • a 2 is -CR 7 R 8 -; and
  • a 3 is -CR 9 R 10 -.
  • a 2 is -CR 7 R 8 -; and R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -OH, -O(C 1-4 alkyl), -O(C 1-4 haloalkyl), - NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, -(C1-4 alkyl)O(C1-4 alkyl), -C(O)OH, -C(O)O(C1-4 alkyl), - C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R 7 and R 8 are taken together with the carbon atom to which they are
  • a 2 is -CR 7 R 8 -; and R 7 and R 8 are each independently hydrogen, deuterium, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form a cyclopropane or an oxetane.
  • a 3 is -CR 9 R 10 -; and R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • a 3 is -CR 9 R 10 -; and R 9 and R 10 are each independently hydrogen, deuterium, or methyl. In some embodiments, R 9 and R 10 are each independently hydrogen. In some embodiments, R 9 and R 10 are each independently deuterium. In some embodiments, R 9 is hydrogen and R 10 is methyl.
  • R 9 is a compound of Formula (IIa): Formula (IIa) or a pharmaceutically acceptable salt thereof.
  • Ring C is a bicyclic heteroaryl having one or more nitrogen atoms. In some embodiments, Ring C is Ring C’. In some embodiments, Ring C is a group of Table III.
  • Rign C is a substituted indole (e.g., haloindole or haloalkyl indole, (e.g., fluoroindole)).
  • Ring B is C 3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6- membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is C3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is C3-6 cycloalkyl.
  • Ring B is a substituted or unsubstituted cyclopropyl. In some embodiments, Ring B is a substituted or unsubstituted cyclobutyl. In some embodiments, Ring B is a substituted or unsubstituted cyclopentyl. In some embodiments, Ring B is a substituted or unsubstituted cyclohexyl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is 5-membered heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl containing two or more nitrogen atoms. In some embodiments, Ring B is a 5-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is a 6-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is a substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazolidinone, substituted or unsubstituted imidazole, substituted or unsubstituted imidazolidinone, or a substituted or unsubstituted triazole.
  • Ring B is a substituted or unsubstituted pyrazole.
  • Ring B is a substituted or unsubstituted pyrazolidinone.
  • Ring B is a substituted or unsubstituted imidazole.
  • Ring B is a substituted or unsubstituted triazole.
  • Ring B is a substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrimidone, substituted or unsubstituted pyridazine, substituted or unsubstituted pyridazinone, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrazinone, substituted or unsubstituted triazine, or a substituted or unsubstituted tetrazine.
  • Ring B is a substituted or unsubstituted pyrimidine, or a substituted or unsubstituted pyrimidone. In some embodiments, Ring B is a substituted pyrimidine. In some embodiments, Ring B is an unsubstituted pyrimidine. In some embodiments, Ring B is a substituted pyrimidone. In some embodiments, Ring B is an unsubstituted pyrimidone. In some embodiments, Ring B is a substituted or unsubstituted pyridazine. In some embodiments, Ring B is a substituted or unsubstituted pyridazinone. [0074] In some embodiments, the compound of Formula (II) is a compound of Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe):
  • Ring C is a bicyclic heteroaryl having one or more nitrogen atoms.
  • Ring C is a substituted or unsubstituted indole, substituted or unsubstituted indazole, substituted or unsubstituted azaindole, substituted or unsubstituted indolizine, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, substituted or unsubstituted pyrazolopyridine, substituted or unsubstituted pyrrolopyrimidine, substituted or unsubstituted imidazopyrimidine, or substituted or unsubstituted pyrazolopyrimidine.
  • Ring C is a substituted or unsubstituted indole. In some embodiments, Ring C is a substituted or unsubstituted haloindole. In some embodiments, Ring C is a substituted or unsubstituted 5-fluoroindole. In some embodiments, Ring C is a 5-fluoroindole. [0076] In some embodiments, Ring C is a bicyclic heterocycloalkyl having one or more nitrogen atoms.
  • Ring C is a substituted or unsubstituted indoline, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted dihydrobenzoxazine, or substituted or unsubstituted dihydrobenzothiazine. In some embodiments, Ring C is a substituted or unsubstituted indoline. In some embodiments, Ring C is a substituted haloindoline. In some embodiments, Ring C is a substituted or unsubstituted 5- fluoroindoline. In some embodiments, Ring C is a 5-fluoroindoline. In some embodiments, Ring C is Ring C’.
  • m is 0.
  • m is 1, and R C is -D, -F, -Cl, -Br, -CH 3 , -CH 2 OCH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OH, -OCH 3 , -SCH 3 , -NH 2 , -N(CH 3 ) 2 , or - NHC(O)O(C1-4 alkyl).
  • m is 1, and R C is fluoro.
  • m is 1, and R C is chloro.
  • m is 1, and R C is methyl.
  • m is 1, and R C is trifluoromethyl. In some embodiments, m is 1, and R C is methoxy. In some embodiments, m is 1, and R C is dimethylamino. [0078] In some embodiments, m is 2, and each R C is independently -D, -F, -Cl, -Br, -CH3, - CF 3 , or -OCH 3 . In some embodiments, m is 2, and each R C is independently -D, -F, -Cl, -Br, or - CH 3 . In some embodiments, m is 2, and each R C is halogen or C 1-4 alkyl.
  • m is 2, and each R C is halogen. In some embodiments, m is 2, and each R C is fluorine or chlorine. In some embodiments, m is 2, and each R C is fluorine. In some embodiments, m is 2, and each R C is deuterium. In some embodiments, m is 3 and each R C is halogen.
  • R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl;
  • a 3 is -CR 9 R 10 - or absent;
  • R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl;
  • R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or
  • R 5 and R 6 are taken together with the carbon atom to which they are attached to form an oxetane;
  • R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C1-4 alkyl, -C1-4 haloalkyl,
  • R A1 is halogen, C 1-4 alkyl, or cyclopropyl. In some embodiments, R A1 is halogen. In some embodiments, R A1 is -F, -Cl, -Br, or -I. In some embodiments, R A1 is -F or -Cl. In some embodiments, R A1 is -F. In some embodiments, R A1 is - Cl. In some embodiments, R A1 is C1-4 alkyl. In some embodiments, R A1 is -CH3, -CH2CH3, - CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , or -C(CH 3 ) 3 .
  • R A1 is -CH 3 , -CH 2 CH 3 , or - CH(CH 3 ) 2 . In some embodiments, R A1 is -CH 3 . In some embodiments, R A1 is cyclopropyl. [0081] In another embodiments, is a compound of the following formula: or a tautomer, or a pharmaceutically acceptable salt thereof, disclosed in Table II. Table II. [0082] In some embodiments, alternatively “ring A,” is selected from the group consisting of: , , , , , , , , ,
  • the compound of Formula (II) is a compound of Formula (IIII): Formula (III) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring B is C3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B’; each R B is independently selected from the group consisting of halogen, -CN, -C 1-4 alkyl, -C1-4 haloalkyl, -C1-4 aminoalkyl, -C1-4 hydroxyalkyl, -C1-4 methoxyalkyl, -(C1-4 alkyl)O(C1-4 alkyl), -C(O)(C1-4 alkyl), -C(O)OH, -C(O)O(C1-4 alkyl), -C(O)NH2, - C(O)NH(C
  • Ring B is C3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6- membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B’.
  • Ring B is C 3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is Ring B’.
  • Ring B’ is a Ring B’ disclosed in Table VII.
  • Ring B’ is selected from the group consisting of: , , , , , , , ,
  • Ring B is a substituted or unsubstituted cyclopropyl.
  • Ring B is a substituted or unsubstituted cyclobutyl.
  • Ring B is a substituted or unsubstituted cyclopentyl.
  • Ring B is a substituted or unsubstituted cyclohexyl.
  • Ring B is phenyl.
  • Ring B is a 5-membered heteroaryl.
  • Ring B is a 5- or 6-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is a 5-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is a 6-membered heteroaryl containing two or more nitrogen atoms.
  • Ring B is a substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazolidinone, substituted or unsubstituted imidazole, substituted or unsubstituted imidazolidinone, or a substituted or unsubstituted triazole.
  • Ring B is a substituted or unsubstituted pyrazole.
  • Ring B is a substituted or unsubstituted pyrazolidinone.
  • Ring B is a substituted or unsubstituted imidazole.
  • Ring B is a substituted or unsubstituted triazole.
  • Ring B is a substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrimidone, substituted or unsubstituted pyridazine, substituted or unsubstituted pyridazinone, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrazinone, substituted or unsubstituted triazine, or a substituted or unsubstituted tetrazine.
  • Ring B is a substituted or unsubstituted pyrimidine, or a substituted or unsubstituted pyrimidone. In some embodiments, Ring B is a substituted pyrimidine. In some embodiments, Ring B is an unsubstituted pyrimidine. In some embodiments, Ring B is a substituted pyrimidone. In some embodiments, Ring B is an unsubstituted pyrimidone. In some embodiments, Ring B is a substituted or unsubstituted pyridazine. In some embodiments, Ring B is a substituted or unsubstituted pyridazinone.
  • the compound of Formula (III) is a compound of Formula (IIIb), Formula (IIIc), Formula (IIId), or Formula (IIIe): o u a e , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: [0090]
  • Ring C is a bicyclic heterocycle having one or more nitrogen atoms. In some embodiments, Ring C is a bicyclic heteroaryl having one or more nitrogen atoms.
  • Ring C is a substituted or unsubstituted indole, substituted or unsubstituted indazole, substituted or unsubstituted azaindole, substituted or unsubstituted indolizine, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, substituted or unsubstituted pyrazolopyridine, substituted or unsubstituted pyrrolopyrimidine, substituted or unsubstituted imidazopyrimidine, or substituted or unsubstituted pyrazolopyrimidine. In some embodiments, Ring C is a substituted or unsubstituted indole.
  • each R C is independently selected from halogen, -CN, -C 1-4 alkyl, -C1-4 haloalkyl, -NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, -OH, -O(C1-4 alkyl), or C3-6 cycloalkyl; or two R B taken together form a carbonyl.
  • each R C is independently selected from halogen, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, ), -NH 2 , -NH(C 1-4 alkyl), -N(C1-4 alkyl)2, -OH, -O(C1-4 alkyl), or C3-6 cycloalkyl; or two R B taken together form a carbonyl.
  • R C is -F, -Cl, -Br, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCH3, - SCH 3 , -NH 2 , -N(CH 3 ) 2 , or -NHC(O)O(C 1-4 alkyl).
  • each R C is independently selected from -F, -Cl, -CN, CH 3 , -CF 3 , -N(CH 3 ) 2 , -OCH 3 , -SCH 3 , and cyclopropyl.
  • Ring C is a substituted or unsubstituted haloindole.
  • Ring C is: [0093] In some embodiments, Ring C is a substituted or unsubstituted 5-fluoroindole. In some embodiments, Ring C is a 5-fluoroindole. In some embodiments, Ring C is: . [0094] In some embodiments, Ring C is a bicyclic heterocycloalkyl having one or more nitrogen atoms. In some embodiments, Ring C is a substituted or unsubstituted indoline, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted dihydrobenzoxazine, or substituted or unsubstituted dihydrobenzothiazine.
  • Ring C is a substituted or unsubstituted indoline. In some embodiments, Ring C is a substituted haloindoline. In some embodiments, Ring C is a substituted or unsubstituted 5- fluoroindoline. In some embodiments, Ring C is a 5-fluoroindoline. In some embodiments, Ring C is Ring C’. [0095] In some embodiments, m is 0.
  • m is 1, and R C is -D, -F, -Cl, -Br, -CH3, -CH2OCH3, -CH2F, -CHF2, -CF3, -OH, -OCH3, -SCH3, -NH2, -N(CH3)2, or - NHC(O)O(C1-4 alkyl).
  • m is 1, and R C is fluoro.
  • m is 1, and R C is chloro.
  • m is 1, and R C is methyl.
  • R C is trifluoromethyl.
  • m is 1, and R C is methoxy.
  • m is 1, and R C is dimethylamino.
  • m is 2, and each R C is independently -D, -F, -Cl, -Br, -CH 3 , - CF 3 , or -OCH 3 .
  • m is 2, and each R C is independently -D, -F, -Cl, -Br, or - CH3.
  • m is 2, and each R C is halogen or C1-4 alkyl.
  • m is 2, and each R C is halogen.
  • m is 2, and each R C is fluorine or chlorine.
  • Ring C is a bicyclic heterocycle having one or more nitrogens, selected from the group consisting of: , [0098] In some embodiments, Ring C’ is selected from the group consisting of: [0099] In some embodiments, Ring B is C3-6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6- membered heteroaryl containing two or more nitrogen atoms. In some embodiments, Ring B is further substituted with 0 to 3 groups R B .
  • each R B is independently selected from the group consisting of halogen, -CN, -C1-4 alkyl, -C1-4 haloalkyl, -C1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 methoxyalkyl, -(C 1-4 alkyl)O(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NH 2 , - NH(C1-4 alkyl), -NH(C3-6 cycloalkyl), -NH(C3-6 heterocycloalkyl), -N(C1-4 alkyl)2, -NHC(O)C1-4 alkyl, -NHC(O)O(C1-4 alkyl, -
  • each R B is independently selected from the group consisting of halogen, -CN, -C1-4 alkyl, -C1-4 haloalkyl, -C1-4 aminoalkyl, -C1-4 hydroxyalkyl, -C(O)(C1-4 alkyl), -C(O)OH, -C(O)O(C1-4 alkyl), -C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, - NH 2 , -NH(C 1-4 alkyl), -NH(C 3-6 heterocycloalkyl), -N(C 1-4 alkyl) 2 , -NHC(O)O(C 1-4 alkyl), -OH, -O(C 1-4 alkyl), -S(O) 2 (C 1-4 alkyl), and substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R
  • each R B is independently selected from the group consisting of -F, -Cl, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , - C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, -OH, -OCH3 is -C(O)OH, -C(O)O(C1-4 alkyl), - C(O)NH2, -C(O)NH(C1-4 alkyl), or -C(O)N(C1-4 alkyl)2, -C(O)(C1-4 alkyl), -C(O)OH, -NH2, - NH(C 1-4 alkyl), -NH(oxetanyl), -N(C 1-4 alkyl) 2 , -
  • each R B is independently selected from the group consisting of - F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, CH2NH2, -CH2NHBoc, -CH2OH, -CH2OCH3, - C(O)NH 2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)OH, -C(O)OCH 3 , -NH 2 , NHCH 3 , -N(CH 3 ) 2 , - NH(oxetanyl), -NHC(O)CH3, -NHS(O2)CH3, -OH, -OCH3, -OCH2CF3, methylpyrazolyl, pyrazolyl, and oxo.
  • Ring B is phenyl, and n is 0. In some embodiments, Ring B is phenyl, and n is 1. In some embodiments, Ring B is phenyl, n is 1, and R B is -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, -OH, or -OCH3. In some embodiments, Ring B is phenyl, n is 1, and R B is - CN. In some embodiments, Ring B is phenyl, n is 1, and R B is -OH. In some embodiments, Ring B is phenyl, n is 1, and R B is -OCH3.
  • Ring B is phenyl, n is 1, and R B is - F. In some embodiments, Ring B is phenyl, n is 1, and R B is -Cl. In some embodiments, Ring B is phenyl, n is 1, and R B is -CF 3. [00104] In some embodiments, Ring B is cyclohexyl, and n is 0. In some embodiments, Ring B is cyclohexyl, and n is 1.
  • Ring B is cyclohexyl, n is 1, and R B is - C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), or -C(O)N(C 1-4 alkyl) 2 .
  • Ring B is cyclohexyl, n is 1, and R B is -C(O)OH.
  • Ring B is cyclohexyl, n is 1, and R B is -C(O)O(C1-4 alkyl).
  • Ring B is cyclohexyl, n is 1, and R B is -C(O)OCH3. In some embodiments, Ring B is cyclohexyl, n is 1, and R B is - C(O)NH 2 . In some embodiments, Ring B is cyclohexyl, n is 1, and R B is -C(O)NH(C 1-4 alkyl). In some embodiments, Ring B is cyclohexyl, n is 1, and R B is -C(O)NHCH3. In some embodiments, Ring B is cyclohexyl, n is 1, and R B is -C(O)N(C1-4 alkyl)2.
  • Ring B is cyclohexyl, n is 1, and R B is -C(O)N(CH 3 ) 2 .
  • Ring B is cyclohexyl, and n is 2.
  • Ring B is cyclohexyl, n is 2, and each R B is independently halogen, C1-4 alkyl, C1-4 haloalkyl, -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), or -C(O)N(C 1-4 alkyl) 2 .
  • Ring B is pyrimidinyl and n is 0. In some embodiments, Ring B is pyrimidinyl and n is 1. In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -CH3, - C(O)(C1-4 alkyl), -C(O)OH, -NH2, -NH(C1-4 alkyl), -NH(oxetanyl), -N(C1-4 alkyl)2, -OH or - O(C 1-4 alkyl). In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -C(O)OH.
  • Ring B is pyrimidinyl, n is 1, and R B is -C(O)CH 3 . In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -OH or -O(C1-4 alkyl). In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -OH. In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -O(C 1-4 alkyl). In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -OCH 3 . In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -NH2.
  • Ring B is pyrimidinyl, n is 1, and R B is -NH(C1-4 alkyl). In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -NHCH 3 . In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -N(C 1-4 alkyl)2. In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -N(CH3)2. In some embodiments, Ring B is pyrimidinyl, and n is 2. In some embodiments, Ring B is pyrimidinyl, n is 2, and two R B taken together form a carbonyl.
  • Ring B is pyrimidinonyl. In some embodiments, Ring B is pyrimidinyl, and n is 3. In some embodiments, Ring B is pyrimidinyl, n is 3, and two R B taken together form a carbonyl. In some embodiments, Ring B is an unsubstituted pyrimidinonyl. In some embodiments, Ring B is a substituted pyrimidinonyl.
  • Ring B is a methylpyrimidinonyl, aminopyrimidinonyl, hydroxypyrimidinonyl, methoxypyrimidinonyl, methoxyalkylpyrimidinonyl, halopyrimidinonyl, or C1-4 haloalkylpyrimidinonyl. In some embodiments, Ring B is a methylpyrimidinonyl. [00107] In some embodiments, Ring B is Ring B’. In some embodiments, Ring B’ is as described in Table VII. In some embodiments, Ring B is selected from the group consisting of: , each of which is optionally further substituted with one group, R B , as defined above.
  • Ring B is selected from the group consisting of: [00109] In some embodiments, is a compound of the following formula: or a tautomer thereof, or a pharmaceutically acceptable salt thereof, disclosed in Table III. Table III.
  • Ring B is C3-6 cycloalkyl, phenyl, or 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms;
  • R B is halogen, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, - C 1-4 methoxyalkyl, -OH, -O(C 1-4 alkyl), -O(C 1-4 haloalkyl), -NH 2 , -NH(C 1-4 alkyl), - NH(C3-6 cycloalkyl), -NH(C3-6 heterocycloalkyl), -N(C1-4 alkyl)2, -NHC(O)C1-4 alkyl, -NHC(O)O(C1-4 alkyl, -NHC(O)O(C1-4 alkyl
  • each R B is independently selected from -F, -Cl, -CN, -CH3, - CH2F, -CHF2, -CF3, CH2NH2, -CH2NHBoc, -CH2OH, -CH2OCH3, -C(O)NH2, -C(O)NHCH3, - C(O)N(CH3)2, -C(O)OH, -C(O)OCH3, -NH2, NHCH3, -N(CH3)2, -NH(oxetanyl), -NHC(O)CH3, -NHS(O 2 )CH 3 , -OH, -OCH 3 , -OCH 2 CF 3 , methylpyrazolyl, pyrazolyl, and oxo.
  • the compound of Formula (II) is a compound of the following formula: or a tautomer thereof, or a pharmaceutically acceptable salt thereof, disclosed in Table III
  • Ring B is any one of the B rings disclosed in Tables II, III, and/or III’, or a salt thereof.
  • R 7 and R 8 are taken together with the carbon atom to which they are attached to form an oxetane. In some embodiments, each R 7 and R 8 is independently hydrogen or deuterium; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form an oxetane.
  • the compound of Formula (IV) is a compound of Formula (IVa): or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • each R 3 and R 4 is independently hydrogen, deuterium, halogen, or C1-4 alkyl. In some embodiments, each R 3 and R 4 is independently hydrogen, deuterium, or - CH3.
  • each R 3 and R 4 is independently hydrogen or deuterium. In some embodiments, each R 3 and R 4 is hydrogen. In some embodiments, each R 3 and R 4 is deuterium. [00119] In some embodiments, R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane. In some embodiments, R 9 and R 10 are each independently hydrogen or deuterium. In some embodiments, R 9 and R 10 are each hydrogen. In some embodiments, R 9 and R 10 are each deuterium.
  • R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • each R 9 and R 10 is independently hydrogen or deuterium; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • each R 3 and R 4 is hydrogen; and each R 7 and R 8 is hydrogen.
  • each R 3 , R 4 , R 7 , and R 8 is hydrogen; and each R 9 and R 10 is independently hydrogen or deuterium; or R 9 and R 10 are taken together with the carbon atom to which they are attached to form an oxetane.
  • each R 3 and R 4 is hydrogen; and each R 9 and R 10 is hydrogen. In some embodiments, each R 3 , R 4 , R 9 , and R 10 is hydrogen; and each R 7 and R 8 is independently hydrogen or deuterium; or R 7 and R 8 are taken together with the carbon atom to which they are attached to form an oxetane. In some embodiments, each R 7 and R 8 is hydrogen; and each R 9 and R 10 is hydrogen. In some embodiments, each R 7 , R 8 , R 9 , and R 10 is hydrogen; and each R 3 and R 4 is independently hydrogen or deuterium.
  • the compound of Formula (IV) is a compound of Formula (V): or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (IV) is a compound of Formula (VI): or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • Ring C is a substituted or unsubstituted bicyclic heterocycle containing one or more nitrogen atoms. In some embodiments, Ring C is a substituted bicyclic heterocycle containing one or two nitrogen atoms. In some embodiments, Ring C is an unsubstituted bicyclic heterocycle containing one or two nitrogen atoms.
  • Ring C is a substituted bicyclic heteroaryl containing one or two nitrogen atoms. In some embodiments, Ring C is an unsubstituted bicyclic heteroaryl containing one or two nitrogen atoms. In some embodiments, Ring C is a fused bicyclic heterocycle containing a five- membered heterocycle and a 6-membered aryl or heteroaryl. [00124] In some embodiments, the 6-membered aryl or heteroaryl of Ring C is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
  • the 6-membered aryl or heteroaryl of Ring C is phenyl or pyridinyl.
  • the compound of Formula (IV) is a compound of Formula (VIa) or Formula (VIb): or a tautomer, or a pharmaceutically acceptable salt thereof.
  • each X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is independently C, CH, CH2, N, or NH.
  • the compound of Formula (VI) is a compound of Formula (VIc) or Formula (VId): Formula VIc Formula VId, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • X 2 is CH or N.
  • Ring C is selected from the group consisting of substituted or unsubstituted indole, substituted or unsubstituted indoline, substituted or unsubstituted indazole, substituted or unsubstituted indolizine, substituted or unsubstituted azaindole, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, substituted or unsubstituted pyrazolopyridine, substituted or unsubstituted pyrrolopyrimidine, substituted or unsubstituted pyrazolopyrimidine, and substituted or unsubstituted imidazopyrimidine.
  • Ring C is selected from the group consisting of substituted or unsubstituted indole, substituted or unsubstituted indoline, substituted or unsubstituted indazole, substituted or unsubstituted indolizine, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, and substituted or unsubstituted pyrazolopyridine.
  • Ring C is selected from the group consisting of substituted or unsubstituted indole, substituted or unsubstituted 2,3-dihydroindole, substituted or unsubstituted indolizine, substituted or unsubstituted azaindole, and substituted or unsubstituted indazole.
  • Ring C is a substituted indole.
  • Ring C is a 5-fluoroindole.
  • Ring C is a fused bicyclic heterocycle containing a 6-membered heterocycle and a 6-membered aryl or heteroaryl.
  • Ring C is selected from the group consisting of substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisioquinoline, substituted or unsubstituted naphthyridine, substituted or unsubstituted quinone, and substituted or unsubstituted quinolinzine.
  • Ring C is substituted with one or more groups selected from deuterium, halogen, and C 1-4 alkyl. In some embodiments, Ring C is substituted with one or more groups selected from halogen and methyl.
  • Ring C is substituted with -CH 3 .
  • Ring C is substituted with one or more halogen atoms.
  • Ring C is substituted with one or more -F or -Cl.
  • Ring C is substituted with -F.
  • Ring C is substituted with -Cl.
  • Ring C is selected from the group consisting of: , , .
  • Ring C is selected from the group consisting of: .
  • the compound of Formula (IV) is a compound of Formula (VII): or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently hydrogen or deuterium. In some embodiments, R 1 and R 2 are each hydrogen. In some embodiments, R 1 and R 2 are each deuterium. In some embodiments, R 1 and R 2 are each independently hydrogen or deuterium; and Ring B’ is selected from the group consisting of: ,
  • the compound of Formula (VII) is a compound of Formula (VIIa): or a tautomer, or a pharmaceutically acceptable salt thereof.
  • each Y 1 , Y 2 , and Y 3 is independently CH, CH2, N, or NH.
  • Y 1 is CH
  • Y 2 is CH
  • Y 3 is N
  • Y 1 is N
  • Y 2 is CH
  • Y 3 is CH
  • Y 1 is CH
  • Y 2 is N
  • Y 3 is CH.
  • Y 1 is CH
  • Y 2 is N
  • Y 3 is CH.
  • Y 1 is CH
  • Y 2 is N
  • Y 3 is CH.
  • the compound of Formula (VII) is a compound of Formula (VIIb): wherein Y 4 , Y 5 , or Y 6 is N, and the other members are each CH.
  • Y 4 is CH, Y 5 is CH, and Y 6 is N.
  • Y 4 is N, Y 5 is CH, and Y 6 is CH.
  • Y 4 is CH, Y 5 is N, and Y 6 is CH.
  • Y 4 is CH, Y 5 is N, and Y 6 is CH.
  • a compound of Formula (VIII) Formula VIII or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen or deuterium; Ring A’ is selected from the group consisting of: , , , ,
  • Ring A’ is selected from the group consisting of: [00145] In some embodiments, Ring B is a substituted or unsubstituted monocyclic heterocycle. In some embodiments, Ring B is a substituted or unsubstituted bicyclic heterocycle. In some embodiments, Ring B is a substituted or unsubstituted 5- or 6-membered heterocycle. In some embodiments, Ring B is a substituted or unsubstituted 5-membered heterocycle. In some embodiments, Ring B is a substituted 5-membered heterocycle. In some embodiments, Ring B is an unsubstituted 5-membered heterocycle.
  • Ring B is a substituted or unsubstituted 6-membered heterocycle. In some embodiments, Ring B is a substituted 6-membered heterocycle. In some embodiments, Ring B is an unsubstituted 6-membered heterocycle. In some embodiments, Ring B is a substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyridazine, or substituted or unsubstituted piperidine.
  • Ring B is a substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, or substituted piperidine. In some embodiments, Ring B is an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyrazine, unsubstituted pyridazine, or unsubstituted piperidine. [00147] In some embodiments, Ring B is a substituted or unsubstituted pyridine. In some embodiments, Ring B is a substituted or unsubstituted pyrimidine. In some embodiments, Ring B is a substituted or unsubstituted pyrazine.
  • Ring B is a substituted or unsubstituted pyridazine. In some embodiments, Ring B is a substituted or unsubstituted piperidine. [00148] In some embodiments, Ring B is a substituted pyridine. In some embodiments, Ring B is a substituted pyrimidine. In some embodiments, Ring B is a substituted pyrazine. [00149] In some embodiments, Ring B is a substituted pyridazine. In some embodiments, Ring B is a substituted piperidine. In some embodiments, Ring B is an unsubstituted pyridine. In some embodiments, Ring B is an unsubstituted pyrimidine.
  • Ring B is an unsubstituted pyrazine. In some embodiments, Ring B is an unsubstituted pyridazine. In some embodiments, Ring B is an unsubstituted piperidine. [00150] In some embodiments, Ring B is substituted with one or more R B groups. In some embodiments, Ring B is a substituted or unsubstituted pyridone. In some embodiments, Ring B is a substituted or unsubstituted pyrimidone. In some embodiments, Ring B is a substituted or unsubstituted pyrazone. In some embodiments, Ring B is a substituted or unsubstituted pyridazone.
  • the compound of Formula (VIII) is a compound of Formula (IX): Formula IX, or a tautomer, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently hydrogen or deuterium; and Ring A’ is selected from the group consisting of: wherein # C denotes a bond to the fluoroindole ring.
  • Ring A’ is selected from the group consisting of: [00158] In some embodiments, Ring A’ is selected from the group consisting of: , , .
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use.
  • salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid.
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D);
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • a compound described herein is prepared as a hydrochloride salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base.
  • the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt. In some embodiments, the compounds provided herein are prepared as a sodium salt.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization 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 compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented 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 the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl.
  • isotopically labeled compounds described herein 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.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • 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/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.
  • stereoisomers are obtained by stereoselective synthesis. [00173]
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. In some instances, a prodrug may pass through membranes (e.g., cell membranes, the intestinal lumen, the blood brain barrier, and the like) whereas the active agent would not. In some instances, a charged or highly polar moiety is masked with a more permeable group which can be cleaved in vivo. The prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug.
  • membranes e.g., cell membranes, the intestinal lumen, the blood brain barrier, and the like
  • the design of a prodrug increases the effective water solubility.
  • a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • the prodrug is enzymatically metabolized to the active form in vivo via an esterase, protease, peptidase, hydrolase, etc.
  • the prodrug transforms into the active form of the compound independent of a metabolizing enzyme (e.g., via hydrolysis or pH-dependent decomposition).
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers (e.g., oxymethyl ethers), carbonates, thiocarbonates, carbamates, anhydrides, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • compounds described herein are prepared as oxymethyl ether or polyoxymethylene dimethyl ether prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • compounds of the present disclosure provide enhanced pharmacokinetic or pharmacodynamic profiles compared to other known EP2 antagonists.
  • a compound described herein may increase the bioavailability, volume of distribution, absorption, half-life, duration of action, receptor occupancy, cellular permeability, blood-brain barrier permeability, plasma stability, metabolic stability, excretion, or toxicity profile compared to the EP2 antagonists currently available.
  • a compound is formulated as a prodrug, wherein the active metabolite is cleaved in vivo after reaching the target cell or tissue. In other embodiments, a compound is not cleaved in vivo.
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 ... C 1 -C x .
  • a group designated as "C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C 1 - C 10 alkyl.
  • an alkyl is a C1-C6alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • alkynyl group include -C ⁇ CH, -C ⁇ CCH3 -C ⁇ CCH2CH3, - CH 2 C ⁇ CH.
  • An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the –N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • carbocyclic or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. [00188] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C 13 aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl.
  • a cycloalkyl is a C 3 - C6cycloalkyl.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is a C1-C6fluoroalkyl.
  • 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, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6heteroalkyl.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C1-C9heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • a “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 - C 10 heterocycloalkyl.
  • a heterocycloalkyl is a C 2 -C 6 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CF3, -OCH3, and -OCF3.
  • substituted groups are substituted with one or two of the preceding groups.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • the terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • the term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • the terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • PHARMACEUTICAL COMPOSITIONS [00210]
  • the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically.
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be performed by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of Formula (I) are used in the preparation of medicaments for the treatment or prevention of diseases or conditions that would benefit from or by the reduction or inhibition of EP2 activity.
  • a method for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound of Formula (I) or Formula (X), or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said mammal.
  • the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • 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 clinical trial. [00219] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • Doses employed for adult human treatment are typically in the range of 0.01mg-5000 mg per day or from about 1mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.
  • a compound of Formula (I) or Formula (X) is co-administered with a second therapeutic agent, wherein the compound of Formula (I) or Formula (X) and the second therapeutic agent modulate different aspects of the disease or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth.
  • the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • Step 2 Synthesis of 4-bromo-2-chloro-6-( ⁇ [2-hydroxy(1,1,2,2- 2H4)ethyl]amino ⁇ (2H2)methyl)phenol [00229] To a stirred mixture of NaBD4 (1.68 g, 40.190 mmol, 10 equiv) in THF (24 mL) at 0 °C under an atmosphere of N 2 was added BF 3 .Et 2 O (5.70 g, 40.2 mmol) dropwise.
  • Step 3 Synthesis of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)(2H2)methyl]-N-[2- hydroxy(1,1,2,2-2H4)ethyl]carbamate
  • 4-bromo-2-chloro-6-( ⁇ [2-hydroxy(1,1,2,2-2H4)ethyl] amino ⁇ (2H2)methyl)phenol 550 mg, 1.9 mmol
  • THF 10 mL
  • saturated aqueous NaHCO 3 5 mL
  • Step 4 Synthesis of Tert-butyl 7-bromo-9-chloro(2,2,3,3,5,5-2H6)-1,4-benzoxazepine-4- carboxylate [00231] To a stirred solution of tert-butyl N-[(5-bromo-3-chloro-2- hydroxyphenyl)(2H2)methyl]-N-[2-hydroxy(1,1,2,2-2H4)ethyl]carbamate (500 mg, 1.29 mmol) and PPh 3 (850 mg, 3.23 mmol) in THF (5 mL) at rt under an atmosphere of N 2 was added DIAD (650 mg, 3.23 mmol) dropwise.
  • DIAD 650 mg, 3.23 mmol
  • Step 5 Synthesis of Tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-1,4- benzoxazepine-4-carboxylate [00232] To a stirred solution of tert-butyl 7-bromo-9-chloro(2,2,3,3,5,5-2H6)-1,4- benzoxazepine-4-carboxylate (300 mg, 0.81 mmol) and 5-fluoro-1H-indole (170 mg, 1.22 mmol) in 1,4-dioxane (10 mL) at rt under an atmosphere of N 2 were added CuI (50 mg, 0.24 mmol), K3PO4 (520 mg, 2.4 mmol) and trans-cyclohexane-1,2-diamine (50 mg, 0.41 mmol).
  • Step 6 Synthesis of 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-4H-1,4-benzoxazepine
  • tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-1,4- benzoxazepine-4-carboxylate 120 mg, 0.28 mmol
  • DCM 5 mL
  • TFA 1 mL
  • the mixture was stirred for 30 min at rt, then neutralized with saturated aqueous NaHCO 3 and extracted with DCM (3 x 5 mL).
  • Step 2 Synthesis of 2-(4-Bromo-2-chlorophenyl)ethanamine [00234] To a stirred solution of LiBH 4 (1.26 g, 57.9 mmol) in THF (30 mL) at rt was added TMSCl (12.58 g, 115.8 mmol) dropwise over 2 minutes. After stirring for 20 min, the mixture was sparged with N2 to remove trmethylsilane that had formed. A solution of 4-bromo-2-chloro- 1-[(E)-2-nitroethenyl]benzene (3.80 g, 14.5 mmol) in THF (20 mL) was added dropwise at rt over 4 min.
  • Step 4 Synthesis of 1-(7-Bromo-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2- trifluoroethanone [00236]
  • Step 5 Synthesis of 5-Chloro-7-(5-fluoroindol-1-yl)-1,2,3,4-tetrahydroisoquinoline [00237] To a stirred solution of 1-(7-bromo-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2- trifluoroethanone (600 mg, 1.75 mmol), 5-fluoro-1H-indole (360 mg, 2.62 mmol) in 1,4-dioxane (10 mL) under an atmosphere of N2 were added K3PO4 (1.1 g, 5.26 mmol), CuI (100 mg, 0.53 mmol) and trans-cyclohexane-1,2-diamine (100 mg, 0.88 mmol).
  • K3PO4 1.1 g, 5.26 mmol
  • CuI 100 mg, 0.53 mmol
  • trans-cyclohexane-1,2-diamine 100 mg, 0.88 m
  • Step 2 Synthesis of Tert-butyl (5-bromo-3-chloro-2-hydroxybenzyl)(1- (hydroxymethyl)cyclopropyl) carbamate
  • 4-bromo-2-chloro-6-( ⁇ [1-(hydroxymethyl)cyclopropyl]amino ⁇ methyl)phenol 2.0 g, 6.5 mmol
  • Boc 2 O 1.71 g, 7.8 mmol
  • Et 3 N 0..99 g, 9.8 mmol
  • Step 3 Synthesis of Tert-butyl 7-bromo-9-chloro-2H-spiro[benzo[f][1,4]oxazepine-3,1'- cyclopropane]-4(5H)-carboxylate [00240] To a stirred solution of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N- [1-(hydroxymethyl) cyclopropyl]carbamate (600 mg, 1.48 mmol) and PPh3 (780 mg, 2.95 mmol) in THF (10 mL) at rt under an atmosphere of N 2 was added DIAD (600 mg, 2.95 mmol) dropwise.
  • DIAD 600 mg, 2.95 mmol
  • Step 4 Synthesis of Tert-butyl 9-chloro-7-(5-fluoro-1H-indol-1-yl)-2H- spiro[benzo[f][1,4]oxazepine-3,1'-cyclopropane]-4(5H)-carboxylate [00241] A mixture of tert-butyl 7-bromo-9-chloro-2,5-dihydrospiro[1,4-benzoxazepine-3,1'- cyclopropane]-4-carboxylate (450 mg, 1.16 mmol), 5-fluoro-1H-indole (235 mg, 1.74 mmol), K3PO4 (740 mg, 3.47 mmol), CuI (67 mg, 0.35 mmol) and trans-cyclohexane-1,2-diamine (67 mg, 0.58 mmol) in 1,4-dioxane (15 mL) under an atmosphere of N2 was heated to 100 °
  • Step 5 Synthesis of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4,5-dihydro-2H- spiro[benzo[f][1,4]oxazepine-3,1'-cyclopropane] [00242] A mixture of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-2,5-dihydrospiro[1,4- benzoxazepine-3,1'-cyclopropane]-4-carboxylate (300 mg, 0.68 mmol) in DCM (2 mL) was added TFA (0.4 mL).
  • Step 2 Synthesis of 5-[(7-bromo-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-4- yl)methyl]pyrimidin-2-ol
  • 7-bromo-9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-3,5- dihydro-2H-1,4-benzoxazepine 4.4 g, 11.3 mmol
  • DMSO 50 mL
  • K2CO3 7.81 g, 56.6 mmol
  • Step 2 Synthesis of 4-Bromo-2-chloro-6- ⁇ 1-[(2-hydroxyethyl)amino]ethyl ⁇ phenol [00247] To a mixture of 1-(5-bromo-3-chloro-2-hydroxyphenyl)ethanone (1.0 g, 4.0 mmol) in EtOH (10 mL) and THF (10 mL) was added ethanolamine (489 mg, 8.0 mmol).
  • Step 3 Synthesis of Tert-butyl N-[1-(5-bromo-3-chloro-2-hydroxyphenyl)ethyl]-N-(2- hydroxyethyl) carbamate
  • 4-bromo-2-chloro-6- ⁇ 1-[(2-hydroxyethyl)amino]ethyl ⁇ phenol 2.7 g, 9.2 mmol
  • MeOH MeOH
  • Boc2O 2.4 g, 11 mmol
  • Et3N 2.7 g, 27.5 mmol
  • Step 4 Synthesis of Tert-butyl 7-bromo-9-chloro-5-methyl-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate [00249] To a mixture of tert-butyl N-[1-(5-bromo-3-chloro-2-hydroxyphenyl)ethyl]-N-(2- hydroxyethyl)carbamate (240 mg, 0.61 mmol) in toluene (5 mL) under an atmosphere of N 2 was added Bu 3 P (307 mg, 1.52 mmol) and ADDP (380 mg, 1.52 mmol).
  • Step 5 Synthesis of Tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H- 1,4-benzoxazepine-4-carboxylate [00250] To a mixture of tert-butyl 7-bromo-9-chloro-5-methyl-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate (180 mg, 0.48 mmol), 5-fluoro-1H-indole (96 mg, 0.72 mmol), K 3 PO 4 (304 mg, 1.43 mmol) in 1,4-dioxane (5 mL) was added trans-cyclohexane-1,2- diamine (27 mg, 0.24 mmol).
  • Step 6 Synthesis of 9-Chloro-7-(5-fluoroindol-1-yl)-5-methyl-2,3,4,5-tetrahydro-1,4- benzoxazepine [00251] To a mixture of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H- 1,4-benzoxazepine-4-carboxylate (120 mg, 0.28 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixture was stirred at rt for 1 h, then aq.
  • Step 2 Synthesis of Tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[(2S)-1- hydroxypropan-2-yl]carbamate
  • a mixture of 4-bromo-2-chloro-6-( ⁇ [(2S)-1-hydroxypropan-2-yl]amino ⁇ methyl)phenol (4.0 g, 13.6 mmol), Et3N (2.75 g, 27.158 mmol) and Boc2O (4.45 g, 20.4 mmol) in THF (4 mL) and MeOH (1 mL) at rt was stirred overnight.
  • Step 3 Synthesis of Tert-butyl (3R)-7-bromo-9-chloro-3-methyl-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate
  • tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[(2S)-1- hydroxypropan-2-yl]carbamate (3.8 g, 9.6 mmol) and PPh3 (5.05 g, 19.3 mmol) in THF (40 mL) at rt under an atmosphere of N2 was added DIAD (2.86 mL, 14.4 mmol) dropwise.
  • Step 4 Synthesis of Tert-butyl (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro- 2H-1,4-benzoxazepine-4-carboxylate [00254] To a stirred solution of tert-butyl (3R)-7-bromo-9-chloro-3-methyl-3,5-dihydro-2H- 1,4-benzoxazepine-4-carboxylate (3.5 g, 9.3 mmol) and 5-fluoro-1H-indole (1.51 g, 11.2 mmol) in 1,4-dioxane (40 mL) at rt under an atmosphere of N 2 were added trans-cyclohexane- 1,2-diamine (0.53 g, 4.7 mmol), CuI (0.53 g, 2.8 mmol) and K3PO4 (5.92 g, 27.9 mmol).
  • Step 5 Synthesis of (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-2,3,4,5-tetrahydro-1,4- benzoxazepine [00255] To a stirred solution of tert-butyl (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5- dihydro-2H-1,4-benzoxazepine-4-carboxylate (1.5 g, 3.5 mmol) in DCM (20 mL) was added TFA (6.0 mL, 80.8 mmol). The mixture was stirred at rt for 30 min, then neutralized with saturated aq.
  • Step 2 Synthesis of Tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1,3- dihydroxypropan-2-yl)carbamate
  • Boc2O (2.62 g, 12.0 mmol)
  • EtOAc 20 mL x 3
  • Step 3 Synthesis of Tert-butyl 7-bromo-9-chloro-3-(methoxymethyl)-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate [00258] To a mixture of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1- hydroxy-3-methoxypropan-2-yl)carbamate (500 mg, 1.2 mmol) and PPh3 (770 mg, 2.9 mmol) in THF (10 mL) under an atmosphere of N2 was added DIAD (600 mg, 2.9 mmol).
  • Step 4 Synthesis of Tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-3,5- dihydro-2H-1,4-benzoxazepine-4-carboxylate [00259] To a mixture of tert-butyl 7-bromo-9-chloro-3-(methoxymethyl)-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate (230 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 5-fluoro- 1H-indole (115 mg, 0.85 mmol), CuI (32 mg, 0.17 mmol), K3PO4 (360 mg, 1.7 mmol) and trans-cyclohexane-1,2-diamine (32 mg, 0.28 mmol).
  • Step 5 Synthesis of 9-Chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-2,3,4,5-tetrahydro- 1,4-benzoxazepine [00260] To a mixture of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-3,5- dihydro-2H-1,4-benzoxazepine-4-carboxylate (200 mg, 0.43 mmol) in DCM (5 mL) was added TFA (1 mL) . The mixture was stirred at rt for 1 h, then neutralized with saturated aq.
  • Step 2 Synthesis of Tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1- cyclopropyl-2-hydroxyethyl)carbamate
  • 4-bromo-2-chloro-6- ⁇ [(1-cyclopropyl-2- hydroxyethyl)amino]methyl ⁇ phenol 1.1 g, 3.4 mmol
  • THF 20 mL
  • Boc2O 1.1 g, 5.2 mmol
  • Step 3 Synthesis of Tert-butyl 7-bromo-9-chloro-3-cyclopropyl-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate [00263] To a stirred mixture of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N- (1-cyclopropyl-2-hydroxyethyl)carbamate (380 mg, 0.9 mmol) in THF (3 mL) at rt under an atmosphere of N2 were added PPh3 (616 mg, 2.4 mmol) and DIAD (475 mg, 2.4 mmol).
  • Step 4 Synthesis of Tert-butyl 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-3,5-dihydro- 2H-1,4-benzoxazepine-4-carboxylate [00264] To a stirred mixture of tert-butyl 7-bromo-9-chloro-3-cyclopropyl-3,5-dihydro-2H-1,4- benzoxazepine-4-carboxylate (230 mg, 0.57 mmol) and 5-fluoro-1H-indole (125 mg, 0.93 mmol) in 1,4-dioxane (5 mL) were added trans-cyclohexane-1,2-diamine (35 mg, 0.31 mmol), CuI (35 mg, 0.19 mmol) and K 3 PO 4 (450 mg, 2.1 mmol).
  • Step 5 Synthesis of 9-Chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine [00265] To a stirred mixture of tert-butyl 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-3,5- dihydro-2H-1,4-benzoxazepine-4-carboxylate (180 mg, 0.39 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at rt for 30 min, then neutralized with sat.
  • Step 2 Synthesis of 2-bromo-N-[(3-bromo-5-chloro-6-hydroxy-2-methylphenyl)methyl]-N- [(2-methoxypyridin-4-yl)methyl]acetamide
  • 4-bromo-6-chloro-2-( ⁇ [(2-methoxypyridin-4- yl)methyl]amino ⁇ methyl)-3-methylphenol 3.4 g, 9.2 mmol
  • DCM 42 mL
  • bromoacetyl bromide 2.18 g, 10.8 mmol
  • Step 3 Synthesis of 7-Bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-2,5- dihydro-1,4-benzoxazepin-3-one
  • Step 4 Synthesis of 7-Bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-3,5- dihydro-2H-1,4-benzoxazepine [00269] To a stirred mixture of NaBH4 (922 mg, 24.4 mmol) in THF (10 mL) at rt under an atmosphere of N2 was added BF3.Et2O (3 mL, 23.7 mmol) dropwise.
  • EP2 Inhibitors Method A Preparation of 9-chloro-4-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)-7-(5-fluoro- 1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane (Compound 106) [00271] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine (50 mg, 0.16 mmol) and 1,5-dimethylpyrazole-4-carbaldehyde (40 mg, 0.32 mmol) in DCM (1 ml) at rt was added NaBH(OAc)3 (70 mg, 0.32 mmol) and AcOH (40 ⁇ L).
  • Method K Preparation of trans-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -N-methylcyclohexane-1-carboxamide[f][1,4]oxazepane (Compound 127) [00280] The mixture of trans-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ cyclohexane-1-carboxylic acid (50 mg, 0.11 mmol) in DCM (1 mL) was added CH ⁇ 3NH 2 HCl (15 mg, 0.22 mmol), PyBOP (86 mg, 0.16 mmol) and DIPEA (30 mg, 0.22 mmol).
  • Example S3 Preparation of 9-chloro-7- ⁇ imidazo[1,5-a]pyridin-3-yl ⁇ -4-[(2- methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 40) [00287] A mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H- 1,4-benzoxazepine (100 mg, 0.26 mmol) and imidazo[1,5-a]pyridine (31 mg, 0.260 mmol), PPh3 (7 mg, 0.03 mmol), Bu4NOAc (157 mg, 0.52 mmol) in toluene (3 mL) under an atmosphere of N 2 was heated to 100 °C and stirred for 16 h.
  • Example S4 Preparation of 9-chloro-7- ⁇ 7-chloroimidazo[1,5-a]pyridin-3-yl ⁇ -4-[(2- methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 41) [00288] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro- 2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 7-chloroimidazo[1,5-a]pyridine (20 mg, 0.13 mmol) in toluene (1 mL) under an atmosphere of N 2 were added Pd(OAc) 2 (2 mg, 0.007 mmol), PPh3 (4 mg, 0.013 mmol) and Bu4NOAc (78 mg, 0.26 mmol).
  • Example S6 Preparation of 9-chloro-7-(5-fluoro-2,3-dihydroindol-1-yl)-4-[(2- methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 45) [00290] A mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H- 1,4-benzoxazepine (50 mg, 0.13 mmol) in toluene (1 mL) under an atmosphere of N 2 was added 5-fluoro-1H,2H,3H-pyrrolo[2,3-b]pyridine (27 mg, 0.2 mmol), Pd2(dba)3 (6 mg, 0.007 mmol), Ruphos (6 mg, 0.013 mmol) and Cs 2 CO 3 (127 mg, 0.39 mmol) were heated to 110 °
  • Example S9 Preparation of 9-chloro-7-(6-fluoro-4-methyl-2,3-dihydroquinoxalin-1-yl)-4- [(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 50) [00293] To a stirred mixture of 7-fluoro-1-methyl-3,4-dihydro-2H-quinoxaline [CAS No: 1354953-50-6] (36 mg, 0.22 mmol) and 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5- yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.26 mmol) in 1,4-dioxane (2 mL) under an atmosphere of N 2 was added Cphos pd G 3 (18 mg, 0.02 mmol), Cphos (10 mg, 0.02 mmol) and
  • Example S11 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3-thiazol-4-ylmethyl)-3,5- dihydro-2H-1,4-benzoxazepine (Compound 100) [00295] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine (50 mg, 0.16 mmol) in THF (1 mL) was added 4-(bromomethyl)-1,3-thiazole (61 mg) and Et3N (32 mg, 0.32 mmol).
  • Ethyl 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carboxylate [00297] To a stirred mixture of ethyl 1-(tert-butyldimethylsilyl)-3-hydroxypyrazole-4- carboxylate (300 mg, 1.1 mmol) and K2CO3 (300 mg, 2.22 mmol) in MeCN (2 mL) was added MeI (0.21 mL, 3.37 mmol).
  • Example S14 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(4H-1,2,4-triazol-3- ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 109)
  • 2-Chloro-N'-formylacetimidohydrazide [00304] MeONa (0.03 g, 0.6 mmol) was added to an ice-cold solution of chloroacetonitrile (1.5 g, 19.9 mmol) in MeOH (15 mL).
  • Example S15 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3,4-oxadiazol-2- ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 111) Ethyl 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetate [00306] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine (200 mg, 0.63 mmol) in THF (2 mL) were added ethyl bromoacetate (210 mg, 1.3 mmol) and Et3N (127 mg, 1.3 mmol).
  • Example S19 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3,4-tetrazol-5- ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 118) 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetonitrile [00312] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine (100 mg, 0.32 mmol) in THF (1 mL) was added 2-bromoacetonitrile (57 mg, 0.47 mmol) and Et 3 N (64 mg, 0.63 mmol).
  • Example S21 Preparation of trans-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl] methylcyclohexane-1-carboxylic acid (Compound 131) Trans-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl] methylcyclohexane-1-carboxylic acid [00316] A solution of methyl trans-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ cyclohexane-1-carboxylate (50 mg, 0.11 mmol) in 6M HCl (5 mL) was stirred at 80 °C for 2 h
  • Example S22 Preparation of cis-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ cyclohexane-1-carboxylic acid (Compound 132) [00317] A mixture of methyl cis-4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ cyclohexane-1-carboxylate (50 mg, 0.11 mmol) in aq.
  • Example S24 Preparation of (5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-yl)methanol (Compound 141) [00321] To a stirred mixture of methyl 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidine-2-carboxylate (90 mg, 0.19 mmol) in THF (2 mL) was added LiBH 4 (8 mg, 0.39 mmol).
  • Example S25 Preparation of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidine-2-carboxamide (Compound 143) [00322] To an 8 mL vial containing NaCN (25 mg, 0.51 mmol), 1,4-diazabicyclo[2.2.2]octane (2 mg, 0.02 mmol) and DMSO (2 mL) was added 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]- 7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (150 mg, 0.34 mmol) in DMSO (1 mL) dropwise over 5 min at rt.
  • Example S27 Preparation of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -N-(oxetan-3-yl)pyrimidin-2-amine (Compound 149) [00326] To a stirred mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol- 1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (10 mg, 0.023 mmol) and in 1,4-dioxane (1 mL) was added oxetan-3-amine (3 mg, 0.05 mmol) and DIPEA (6 mg, 0.05 mmol).
  • Example S28 Preparation of N-(5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-yl)acetamide (Compound 150) [00327] A solution of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4- yl]methyl ⁇ pyrimidin-2-amine (50 mg, 0.12 mmol) in Ac 2 O (1 mL) was heated to 140 °C and stirred for overnight, then concentrated under reduced pressure. Aq.
  • Example S29 Preparation of N-(5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-yl)methanesulfonamide (Compound 151) [00328] To a stirred solution of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-amine (50 mg, 0.118 mmol) in DCM (1 mL) at 0 °C was added MsCl (20 uL, 0.24 mmol) and Et3N (33 uL, 0.24 mmol).
  • Example S30 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4- ⁇ [2-(1-methylpyrazol-4- yl)pyrimidin-5-yl]methyl ⁇ -3,5-dihydro-2H-1,4-benzoxazepine (Compound 153) [00329] To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)- 3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and 1-methylpyrazol-4-ylboronic acid (28 mg, 0.23 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) under an atmosphere of N2 was added K 2 CO 3 (31 mg, 0.23 mmol) and Pd(PPh 3 ) 4 (13 mg, 0.011 mmol).
  • Example S31 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4- ⁇ [2-(pyrazol-1-yl)pyrimidin- 5-yl]methyl ⁇ -3,5-dihydro-2H-1,4-benzoxazepine (Compound 154) [00330] To a stirred mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol- 1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and pyrazole (15 mg, 0.23 mmol) in DMF was added K2CO3 (31 mg, 0.23 mmol).
  • Example S33 Preparation of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -4-fluoro-3H-pyrimidin-2-one (Compound 155) and 4-chloro-5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ -3H- pyrimidin-2-one & (Compound 158) 9-chloro-4-[(2,4-dichloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepine [00331] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,
  • Example S33 Preparation of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -4-hydroxy-3H-pyrimidin-2-one (Compound 157) [00333] To a mixture of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin- 4-yl]methyl ⁇ -4-fluoro-3H-pyrimidin-2-one (30 mg, 0.07 mmol) in 1,4-dioxane (1 mL) was added NaOH (4 mg, 0.1 mmol) in H 2 O (0.5 mL).
  • Example S35 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-amine (Compound 163) [00335] A stirred mixture of 9-chloro-4-[(2-chloropyrimidin-4-yl)methyl]-7-(5-fluoroindol-1- yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.23 mmol) in 7M NH 3 in MeOH (3 mL) was heated to 70 o C and stirred for 12 h.
  • Example S36 Preparation of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -2H-pyridazin-3-one (Compound 169) [00336] To a stirred mixture of 5-iodo-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (700 mg, 2.1 mmol) in methylbenzene (1 mL) under an atmosphere of N 2 were added tributyl(ethenyl)stannane (649 mg, 2.1 mmol) and Pd(dppf)Cl2 (72 mg, 0.1 mmol).
  • Example S37 Preparation of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyridine-2-carboxylic acid (Compound 177) [00341] To a stirred solution of methyl 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H- 1,4-benzoxazepin-4-yl]methyl ⁇ pyridine-2-carboxylate (50 mg, 0.11 mmol) in THF (1 mL) at rt was added 1M aq LiOH (0.5 mL, 0.5 mmol).
  • Example S38 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl] methyl ⁇ pyridin-2-amine (Compound 179) [00342] To a stirred solution of tert-butyl N-(4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro- 2H-1,4-benzoxazepin-4-yl]methyl ⁇ pyridin-2-yl)carbamate (60 mg, 0.12 mmol) in toluene (2 mL) was added silica gel (70 mg, 1.2 mmol).
  • Example S39 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -N-methylpyridin-2-amine (Compound 180) 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepine [00343] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine (100 mg, 0.32 mmol) and 2-chloropyridine-4-carbaldehyde (90 mg, 0.63 mmol) in DCM were added NaBH(OAc)3 (134 mg, 0.63 mmol) and AcOH (2 mg, cat
  • Example 40 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -N,N-dimethylpyridin-2-amine) (Compound 181) [00345] A mixture of 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5- dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and Me2NH (15 mg, 0.34 mmol) in n- butanol (2 mL) was heated to 140 °C under microwave radiation and stirred for 30 min, then concentrated under reduced pressure and the residue was purified by reparative-HPLC (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.05%
  • Example S41 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -N-(oxetan-3-yl)pyridin-2-amine (Compound 182) [00346] To a stirred mixture of 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1- yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and oxetan-3-amine (25 mg, 0.34 mmol) in 1,4-dioxane were added t-BuBrettPhos Pd G3 (20 mg, 0.023 mmol), t-BuBrettPhos (11 mg, 0.023 mmol) and t-BuOK (25 mg
  • Example S42 Preparation of 1-(4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyridin-2-yl)methanamine (Compound 184) (4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ pyridin- 2-yl)methyl methanesulfonate [00347] To a mixture of (4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyridin-2-yl)methanol (40 mg, 0.09 mmol) in DCM (4 mL) at 0 °C was added MsCl (20 mg,
  • Example S43 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyridine-2-carboxylic acid (Compound 185) [00349] To a mixture of methyl 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyridine-2-carboxylate (40 mg, 0.09 mmol) in THF (0.2 mL) and MeOH (0.8 mL) was added LiOH.H2O (12 mg, 0.29 mmol) in H2O (0.1 mL).
  • Example S44 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4- ⁇ [2-(oxetan-3-yl)pyridin-4- yl]methyl ⁇ -3,5-dihydro-2H-1,4-benzoxazepine (Compound 187) 9-chloro-7-(5-fluoroindol-1-yl)-4-(pyridin-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine [00350] To a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (300 mg, 0.95 mmol) and 4-formylpyridine (131 mg, 1.23 mmol) in DCM (5 mL) was added NaBH(OAc) 3 (400 mg, 1.9 mmol) and AcOH (0.2 mL).
  • Example S45 Preparation of 4- ⁇ [2-(azetidin-3-yl)pyridin-4-yl]methyl ⁇ -9-chloro-7-(5- fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine; trifluoroacetic acid (Compound 188) Tert-butyl 3-(4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4- yl]methyl ⁇ pyridin-2-yl)azetidine-1-carboxylate [00352] H2O2, 30% in H2O (50 uL, 1.5 mmol) was added to a stirred mixture of 9-chloro-7-(5- fluoroindol-1-yl)-4-(pyridin-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxa
  • Example S46 Preparation of 4- ⁇ [9-chloro-7-(5–fluoroindol-1-yl)-3,5-di hydro-2H-1,4- benzox azepin-4-yl] methyl ⁇ -1H-pyridine-2-thione (Compound 189) 5-Bromo-3-chloro-2-hydroxy-N-[2-hydroxy(1,1,2,2-2H4) ethyl]benzamide [00354] A solution of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4- yl]methyl ⁇ -1H-pyridin- 2-one (20 mg, 0.05 mmol) in toluene (1 mL) at 80 °C was treated with Lawesson’s Reagent (11.0 mg, 0.03 mmol).
  • Example S47 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -3-methyl-1H-pyridin-2-one (Compound 194) [00355] To a stirred mixture of 9-chloro-4-[(2-chloro-3-methylpyridin-4-yl)methyl]-7-(5- fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (40 mg, 0.09 mmol) in HCOOH (1 mL) was added CH 3 COONH 4 (67 mg, 0.9 mmol).
  • Example S48 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -1,3-dihydropyridine-2,6-dione (Compound 204 & 4- ⁇ [9-chloro- 7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ -6-methoxy-1H- pyridin-2-one (Compound 196) [00356] To a 10 cc glass sealed tube was added 9-chloro-4-[(2,6-dimethoxypyridin-4- yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.21 mmol), HCl (1 m
  • Example S50 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ piperidin-2-one (Compound 200) 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ piperidin-2-one [00361] (2-Oxopiperidin-4-yl)methyl 4-methylbenzenesulfonate (CAS No: 2629362-45-2) (100 mg, 0.35 mmol) was added to a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro- 1,4-benzoxazepine (67 mg, 0.21 mmol) and Et 3 N (48 mg, 0.48 mmol) in DMF (10
  • Example S51 Preparation of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyran-2-one (Compound 203) 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4- benzoxazepine [00362] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4- benzoxazepine (100 mg, 0.32 mmol) in THF (2 mL) at 0 °C was added NaH, 60% in oil (65 mg, 1.58 mmol).
  • Example S52 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-[1-(2-methoxypyridin-4- yl)ethyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 217) 9-chloro-7-(5-fluoroindol-1-yl)-4-[1-(2-methoxypyridin-4-yl)ethyl]-3,5-dihydro-2H-1,4- benzoxazepine [00364] A mixture of 1-(2-methoxypyridin-4-yl)ethanone (143 mg, 0.95 mmol), 9-chloro-7-(5- fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (200 mg, 0.63 mmol) and titanium(IV) isopropoxide (500 uL) were heated to 45
  • Example S53 Preparation of 4- ⁇ [(5S)-9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5- dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ -1H-pyridin-2-one (Compound 236 and 237) [00365] The racemates of 4- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ -1H-pyridin-2-one (20 mg, 0.046 mmol) were separated by preparative-chiral-HPLC (Column:(R, R)-WHELK-O1-Kromasil, 2.11*25 cm, 5 ⁇ m; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate; 20 mL/
  • Example P2 (second eluting isomer): 4- ⁇ [(5S)-9-chloro-7-(5-fluoroindol-1-yl)-5- methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ -1H-pyridin-2-one (4.6 mg, 23%) as a solid.
  • LC/MS mass calcd.
  • Example S53 Preparation of 2-(5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-yl)acetonitrile (Compound 252) [00368] To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)- 3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.23 mmol) in DMF (2 mL) under an atmosphere of N2 was added 2-(trimethylsilyl)acetonitrile (38 mg, 0.34 mmol), Xantphos (5 mg, 0.009 mmol), Pd 2 (dba) 3 (4 mg, 0.005 mmol) and ZnF 2 (14 mg, 0.14 mmol).
  • Example S54 Preparation of (5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidin-2-yl)(imino)methyl-lambda6-sulfanone (Compound 254) 9-chloro-7-(5-fluoroindol-1-yl)-4- ⁇ [2-(methylsulfanyl)pyrimidin-5-yl]methyl ⁇ -3,5-dihydro- 2H-1,4-benzoxazepine [00369] To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)- 3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.23 mmol) in DMF (3 mL) was added (methylsulfany
  • Example S55 Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4- ⁇ [2-(1H-1,2,3,4-tetrazol-5- yl)pyrimidin-5-yl]methyl ⁇ -3,5-dihydro-2H-1,4-benzoxazepine (Compound 255) [00371] To a stirred mixture of 5- ⁇ [9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4- benzoxazepin-4-yl]methyl ⁇ pyrimidine-2-carbonitrile (50 mg, 0.12 mmol) and NaN3 (22 mg, 0.35 mmol) in H 2 O (2 mL) at rt was added ZnCl 2 (47 mg, 0.35 mmol) and 2- (trimethylazaniumyl)acetate (2 mg, 0.012 mmol).
  • Example S56 Preparation of 9-chloro-4-[(2-chloro-4-methylpyrimidin-5-yl)methyl]-7-(5- fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 256) (2-chloro-4-methylpyrimidin-5-yl)methyl methanesulfonate [00372] To a stirred mixture of (2-chloro-4-methylpyrimidin-5-yl)methanol (30 mg, 0.19 mmol) in DCM (1 mL) was added MsCl (43 mg, 0.38 mmol) and Et3N (38 mg, 0.38 mmol).
  • Example S58 Preparation of tert-butyl N-(tert-butoxycarbonyl)-N-(5- ⁇ [9-chloro-7-(5- fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl ⁇ pyridazin-3-yl)carbamate (Compound 259) Tert-butyl N-(tert-butoxycarbonyl)-N-(5-chloropyridazin-3-yl)carbamate [00375] To a stirred mixture of 5-chloropyridazin-3-amine (500 mg, 3.9 mmol) and Boc2O (1.26 g, 5.8 mmol) in DCM (10 mL) was added Et 3 N (590 mg, 5.8 mmol) and DMAP (47 mg, 0.39 mmol).
  • EP2 Potency Assay Compounds of the present disclosure are EP2 antagonists with half-max inhibitory concentration (IC 50 ) values below 25 ⁇ M. Compound potency was measured using a cAMP TR- FRET assay.
  • CHO-K1 cells ATCC
  • Opti-Mem I reduced serum media Gibco
  • transfected with a plasmid for expression of the EP2 receptor the target receptor of interest
  • FuGENE 6 Transfection reagent Promega
  • EP2 Potency (Compound ID No.9-182) 19 D 60 C 100 D 20 B 61 D 101 D 21 D 62 A 102 D 22 D 64 AA 103 C 24 C 65 B 104 D 2 5 A 66 C 105 D 26 B 67 A 106 B 27 B 68 B 107 D 28 D 69 D 108 C 29 D 70 C 109 D 30 C 71 D 110 D 31 B 72 D 111 C 32 C 73 D 112 C 33 C 74 C 113 C 34 D 75 B 115 D 35 D 76 D 117 D 36 D 77 D 118 D 3 7 B 78 A 119 D 38 C 79 A 120 D 39 C 80 C 121 D 40 C 81 C 122 D 41 B 82 C 123 D 42 D 83 D 124 D 43 D 84 A 125 C 44 C 85 D 126 B 45 B 86 D 127 B 46 B 87 D 128 C 47 C 88 D 129 C 48 D 89 D 130 C Table B1 cont’d.
  • Example B2 Human Liver Microsome Stability
  • the tested compound was incubated in duplicate with human liver microsomes (0.5 mg/mL) at 37 °C. These incubations were carried out at a final test article concentration of 2 ⁇ M over a total incubation period of 60 minutes. Samples were taken at 0, 15, 30, 45 and 60 min and the reaction terminated by addition of 4 volumes of acetonitrile containing internal standard (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 ⁇ M ketoprofen). Diclofenac was used as a positive control in this study.
  • T 1/2 Half-life
  • T 1/2 microsomal
  • A 100+
  • B 50 to 100
  • C 20 to 50
  • D 20.
  • CL int In vitro clearance
  • the reference compound (“Ref”) of Tables B2 and B3 is 4-((9-chloro-7-(5-fluoro-1H-indol-1- yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyridin-2(1H)-one, which has the structure: .
  • Chromatographic analyses were performed on a Shimadzu UPLC apparatus (Kyoto, Japan) consisting of a gradient pump (model LC-30AD), an automatic injector (model HTC PAL System) and an on-line degasser (model DGU-20A5R). Detection was a triple quadrupole tandem mass spectrometer equipped with a turbo ion spray interface (API 4000/Triple Quad 4500/Triple Quad 5500/ Triple Quad 6500). Data acquisition and integration were carried out with LC-MS software (Analyst 1.6) linked directly to the LC-MS/MS system. Chromatographic separations were achieved on a XSelect Hss T32.5 ⁇ (2.1x30 mm) Column.
  • Example C-1 Parenteral Pharmaceutical Composition
  • a parenteral pharmaceutical composition suitable for administration by injection subcutaneous, intravenous, and the like
  • 100 mg of a water-soluble salt of a compound of Formula (I) or Formula (X), or a pharmaceutically acceptable salt or solvate thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline.
  • Example C-2 Oral Pharmaceutical Composition
  • 100 mg of a compound of Formula (I) or Formula (X), or a pharmaceutically acceptable salt or solvate thereof is mixed with 750 mg of starch.
  • the mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
  • Example C-3 Topical Gel Pharmaceutical Composition
  • 100 mg of a compound of Formula (I) or Formula (X), or a pharmaceutically acceptable salt or solvate thereof is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP.
  • the resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • Example C-4 Ophthalmic Solution
  • 100 mg of a compound of Formula (I) or Formula (X), or a pharmaceutically acceptable salt or solvate thereof is mixed with 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2 micron filter.
  • the resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • ophthalmic delivery units such as eye drop containers

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PCT/US2022/034901 2021-06-24 2022-06-24 Ep2 antagonist compounds Ceased WO2022272060A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2024145259A3 (en) * 2022-12-28 2024-08-29 Reservoir Neuroscience, Inc. Ep2 antagonist compounds

Citations (2)

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Publication number Priority date Publication date Assignee Title
US20200289517A1 (en) * 2017-10-27 2020-09-17 Zhejiang DTRM Biopharma Co. Ltd. Methods for Treating Lymphoid Malignancies
WO2020249527A1 (en) * 2019-06-10 2020-12-17 Adc Therapeutics Sa Combination therapy comprising an anti-cd25 antibody drug conjugate and a further agent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200289517A1 (en) * 2017-10-27 2020-09-17 Zhejiang DTRM Biopharma Co. Ltd. Methods for Treating Lymphoid Malignancies
WO2020249527A1 (en) * 2019-06-10 2020-12-17 Adc Therapeutics Sa Combination therapy comprising an anti-cd25 antibody drug conjugate and a further agent

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Title
DATABASE PUBCHEM 30 November 2016 (2016-11-30), Database accession no. 318473298 *
See also references of EP4359392A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024145259A3 (en) * 2022-12-28 2024-08-29 Reservoir Neuroscience, Inc. Ep2 antagonist compounds

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