WO2023204822A1 - Phenyl phosphine oxide compounds and methods of use thereof - Google Patents

Phenyl phosphine oxide compounds and methods of use thereof Download PDF

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Publication number
WO2023204822A1
WO2023204822A1 PCT/US2022/026028 US2022026028W WO2023204822A1 WO 2023204822 A1 WO2023204822 A1 WO 2023204822A1 US 2022026028 W US2022026028 W US 2022026028W WO 2023204822 A1 WO2023204822 A1 WO 2023204822A1
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substituted
unsubstituted
compound
pharmaceutically acceptable
acceptable salt
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PCT/US2022/026028
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French (fr)
Inventor
Andrei Konradi
Tracy Tzu-Ling Tang Lin
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Vivace Therapeutics, Inc.
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Priority to PCT/US2022/026028 priority Critical patent/WO2023204822A1/en
Publication of WO2023204822A1 publication Critical patent/WO2023204822A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide

Definitions

  • YAP and TAZ are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes and promote cell proliferation.
  • TEAD transcriptional enhancer associate domain
  • Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP/TAZ or inhibitors that modulate the interaction between YAP/TAZ and TEAD.
  • each R z is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetero
  • L 1 is substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C2-Ciocyclolkylene, or substituted or unsubstituted C2- Cioheterocycloalkylene;
  • Y 1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • L 2 is absent, substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C3- Ciocyclolalkylene, or substituted or unsubstituted 3- to 10-membered heterocycloalkylene;
  • Y 2 is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 3 and Y 2 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;
  • R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
  • N N substituted or unsubstituted heteroaryl, or • n is 0, 1, 2, 3, 4, or 5; and each R 4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • each Z 2 is independently -CR Z , -CHR Z -, -C(R Z )2-, -NR Z -, -N-, -O-, or -S-; and each - - is independently a single or double bond.
  • heteroaryl ring containing at least one N atom.
  • a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing at least one N atom is substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing at least one N atom.
  • a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 1 N atom is substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 1 N atom.
  • a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 2 N atoms is substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 2 N atoms.
  • a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 3 N atoms is provided.
  • a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 4 N atoms is provided.
  • the compound has the structure of Formula (la)
  • each Z 2 is independently CR Z , NR Z , N, O, or S; each — is independently a single or double bond; and with the provision that the 5-membered heterocyclic ring contains at least one N atom.
  • the compound has a structure of Formula (Il-a):
  • the compound has a structure of Formula (Il-b):
  • the compound has a structure of Formula (II-c):
  • each R z is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • each R z is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl.
  • each R z is independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl.
  • each R z is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.
  • each R z is independently hydrogen, -F, -Cl, - methyl, ethyl, n- propyl, iso-propyl, or cyclopropyl.
  • each R z is methyl.
  • R z is -l Y 1 .
  • L 1 is substituted or unsubstituted Ci-C4alkylene; and Y 1 is substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R z is -L 2 -L 3 -Y 2 .
  • L 2 is substituted or unsubstituted Ci-Cealkylene;
  • L 2 is absent;
  • each R 3 is independently H or substituted or unsubstituted Ci-Cealkyl; and Y 2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted Cb-Cioheterocycloalkyl,
  • m is 1, 2, or 3.
  • m is 1 or 2.
  • m is 1.
  • m is 1 and R z is methyl.
  • the compound has a structure of Formula (Ill-a):
  • the compound has a structure of Formula (Ill-b):
  • the compound has a structure of Formula (III-c): [0051] In certain embodiments, the compound has a structure of Formula (Ill-d): Formula (Ill-d).
  • R and R’ are each independently substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R and R’ are each independently substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R and R’ are each independently substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl.
  • R and R’ are each independently substituted or unsubstituted Ci- Cealkyl or substituted or unsubstituted Ci-Cealkoxy.
  • R and R’ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, or phenyl.
  • R and R’ are each independently methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, or iso-propoxy.
  • R and R’ are each methyl.
  • R and R’ are each ethyl.
  • R and R’ are each methoxy.
  • R and R’ are each ethoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5- or 6-membered heterocycloalkyl. [0064] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5-membered heterocycloalkyl.
  • R and R’ taken together with the phosphorus atom to which they are attached to form ; wherein R a , R b , R c , and R d are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • R and R’ taken together with the phosphorus atom to which they are attached to form ; wherein R a and R b are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 6-membered heterocycloalkyl.
  • R and R’ taken together with the phosphorus atom to which they are attached to form wherein R a , R b , R c , R d and R e are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci- Cealkoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form [0072] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form ; wherein R a , R b , and R c are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • the compound has the structure of Formula (IV): Formula (IV).
  • the compound has the structure of Formula (IV-a): Formula (IV-a).
  • the compound has the structure of Formula (IV-b): Formula (IV-b).
  • the compound has the structure of Formula (IV-c), or a pharmaceutically acceptable salt thereof:
  • the compound has the structure of Formula (IV-d), or a pharmaceutically acceptable salt thereof:
  • the compound has the structure of Formula (V): Formula (V). [0082] In certain embodiments, In certain embodiments,
  • each R 2 is independently F, Cl, -CN, -OCF3, -CHF2, -SCF3, or - CF 3 .
  • each R 2 is independently F, Cl, -OCF3, -CHF2, -SCF3, or -CF3. [0087] In certain embodiments, each R 2 is independently F, Cl, -SF5, -SCF3, or -CF3.
  • each R 2 is independently F, Cl, -SF5, -OCF3, -SCF3, or -CF3.
  • each R 2 is -CF3.
  • each R 2 is -SF5.
  • each R 2 is -SCF3.
  • each R 2 is -OCF3.
  • n 0, 1, or 2.
  • n is 1 or 2. [0095] In certain embodiments, n is 1.
  • the compound has the structure of Formula (VI):
  • the compound provided herein is a compound from Table 1.
  • compositions comprising the compound or pharmaceutically acceptable salt thereof provided herein, and a pharmaceutically acceptable excipient.
  • TAZ/YAP transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator
  • the subject has cancer, polycystic kidney disease or liver fibrosis.
  • the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof provided herein, or the pharmaceutical composition provided herein.
  • the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
  • kits for treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof provided herein, or the pharmaceutical composition provided herein.
  • ranges and amounts are expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pL” means “about 5 pL” and also “5 pL.” Generally, the term “about” includes an amount that is expected to be within experimental error.
  • the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal.
  • the mammal is a human.
  • the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).
  • a health care worker e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker.
  • Amino refers to the -NH2 radical.
  • Cyano refers to the -CN radical.
  • Niro refers to the -NO2 radical.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., Ci-Ci3 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms e.g., C5-C15 alkyl).
  • an alkyl comprises five to eight carbon atoms e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methylethyl (/.w-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (secbutyl), 2-methylpropyl (/.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (//-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, OR a , -SR a , OC(O)R a , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a ) 2 , N(R a )C(O)OR f , OC(O) NR a R f , N(R a )C(O)R f , N(R a )S(O) t R f (where t is 1 or 2), S(O)tOR a (where t is 1 or 2), S(O)tR f (where t is 1 or 2), and S(O)tN(R a )2 (where t is 1
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-l-enyl i.e., allyl
  • but-l-enyl pent-l-enyl, penta- 1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, OR a , - SR a , OC(O) R a , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a ) 2 , N(R a )C(O)OR f , OC(O) NR a R f , N(R a )C(O)R f , N(R a )S(O)tR f (where t is 1 or 2), S(O)tOR a (where t is 1 or 2), S(O)tR f (where t is 1 or 2), S(O)tR f (where t is 1 or 2), and S(O)tN(R
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl has two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, OR a , -SR a , OC(O) R a , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a ) 2 , N(R a )C(O)OR f , OC(O) NR a R f , N(R a )C(O)R f , N(R a )S(O) t R f (where t is 1 or 2), S(O)tOR a (where t is 1 or 2), S(O)tR f (where t is 1 or 2), and S(O)tN(R a )2 (where t
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -CN, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a ,
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Carbocyclyl or “carbocycle” refers refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclyl from “heterocyclyl” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon.
  • a carbocyclyl is a monocyclic carbocyclyl or a bicyclic carbocyclyl.
  • a carbocyclyl is a monocyclic carbocyclyl.
  • Carbocyclyls are non-aromatic or aromatic.
  • Non-aromatice carbocyclyls are saturated or partially unsaturated.
  • a carbocyclyl is a bicyclic carbocyclyl.
  • at least one of the two rings of a bicyclic carbocyclyl is aromatic.
  • both rings of a bicyclic carbocyclyl are aromatic.
  • Carbocyclyl include aryls and cycloalkyls.
  • Cycloalkyl refers to a monocyclic or polycyclic aliphatic, fully saturated non-aromatic carbocyclyl, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom.
  • 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. In some embodiments, cycloalkyl groups include groups having from 3 to 6 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclefl .1. l]pentyl.
  • a cycloalkyl is a Cs-Cecycloalkyl.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl comprises three to eight carbon atoms (e.g., Cs-Cs cycloalkyl).
  • a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl).
  • a cycloalkyl comprises three to six carbon atoms e.g., C3-C6 cycloalkyl).
  • a cycloalkyl comprises three to five carbon atoms e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms e.g., C3-C4 cycloalkyl).
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • cycloalkyl is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R
  • Carbocycloalkylalkyl refers to a radical of the formula -R c - cycloalkyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the cycloalkyl radical are optionally substituted as defined above.
  • Halo or "halogen” refers to bromo, chloro, fluoro, or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl or “heterocycle” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings 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 heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused, spiro, or bridged ring systems in some embodiments.
  • the heteroatoms in the heterocyclyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • the heterocyclyl radical is partially or fully saturated.
  • the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • Heterocycloalkyl refers to a cycloalkyl group in which one or more skeletal atoms of the cycloalkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxoxo
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C2-Cioheterocycloalkyl.
  • a heterocycloalkyl is a 5- to 10-membered C4-C9heterocycloalkyl.
  • a heterocycloalkyl is a 4- to 7-membered Cs-Ceheterocycloalkyl.
  • 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.
  • heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R
  • 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 Ci-Ceheteroalkyl.
  • the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group.
  • Heterocycloalkylalkyl refers to a radical of the formula -R c -heterocycloalkyl where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocycloalkyl group.
  • Heterocycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c - heterocycloalkyl where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocycloalkylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocycloalkyl part of the heterocycloalkylalkoxy radical is optionally substituted as defined above for a heterocycloalkyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, /. ⁇ ., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 -benzodi oxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothien
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-R a , -R b -
  • A-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroaryloxy refers to radical bonded through an oxygen atom of the formula - O-heteroaryl, where heteroaryl is as defined above.
  • Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or irons'). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to A or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • Optional or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • optional substituents are independently selected from D, halogen, -CN, -NH 2 , -OH, - NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -0CH 3 , and -OCF 3 .
  • substituted groups are substituted with one to six of the preceding groups. In some embodiments, substituted groups are substituted with one to four of the preceding groups. In some embodiments, substituted groups are substituted with one to three of the preceding groups. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups.
  • treatment or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments.
  • the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • each R z is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -l Y 1 , or -L 2 -L 3 -Y
  • L 1 is substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C2-Ciocyclolkylene, or substituted or unsubstituted C2- Cioheterocycloalkylene;
  • Y 1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • L 2 is absent, substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C3- Ciocyclolalkylene, or substituted or unsubstituted 3- to 10-membered heterocycloalkylene;
  • Y 2 is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 3 and Y 2 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;
  • R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
  • N N substituted or unsubstituted heteroaryl, or ; n is 0, 1, 2, 3, 4, or 5; and each R 4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • ring Z is monocyclic 3- to 8-membered heterocycloalkyl ring.
  • ring Z is monocyclic 4- to 7-membered heterocycloalkyl ring.
  • ring Z is monocyclic 4- to 6-membered heterocycloalkyl ring.
  • ring Z is monocyclic 4- to 5-membered heterocycloalkyl ring.
  • ring Z is monocyclic 5- to 6-membered heterocycloalkyl ring.
  • ring Z is monocyclic 5-membered heterocycloalkyl ring.
  • ring Z is monocyclic 6-membered heterocycloalkyl ring.
  • [00161] is a substituted or unsubstituted monocyclic 5-membered heterocycloalkyl ring containing 1-4 N atoms, 0-2 O atoms, and 0-2 S atoms.
  • Z 1 is -N-, -CH-, or -C-; each Z 2 is independently -CR Z , -CHR Z -, -C(R Z )2-, -NR Z -, -N-, -O-, or -S-;
  • each - - is independently a single or double bond
  • ring Z is monocyclic heteroaryl ring.
  • ring Z is monocyclic 5- to 12- membered heteroaryl ring.
  • ring Z is monocyclic 5- to 10- membered heteroaryl ring.
  • ring Z is monocyclic 5- to 8- membered heteroaryl ring.
  • ring Z is monocyclic 5- to 7- membered heteroaryl ring.
  • ring Z is monocyclic 5- to 6- membered heteroaryl ring.
  • ring Z is monocyclic 5-membered heteroaryl ring.
  • ring Z is monocyclic 6-membered heteroaryl ring.
  • ring Z is a 5-, 6-, or 7-membered monocyclic heteroaryl. In some embodiments, ring Z is a 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring Z is a 6- or 7-membered monocyclic heteroaryl. In some embodiments, ring Z is a 6- membered monocyclic heteroaryl.
  • ring Z is a monocyclic heteroaryl having 1-4 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 1-3 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 1-2 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 1 N atom. In some embodiments, ring Z is a monocyclic heteroaryl having 2 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 3 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 4 N atoms.
  • ring Z is a monocyclic 5-membered heteroaryl having 1-4 N atoms.
  • a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 2 N atoms is a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 1 N atom.
  • a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 3 N atoms is a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 3 N atoms.
  • a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 4 N atoms is a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 4 N atoms.
  • each Z 2 is independently CR Z or N; and at least one Z 2 is N.
  • the compound of Formula (I) has the structure of Formula
  • Z 1 is -N-, -CH-, or -C-; each Z 2 is independently CR Z , NR Z , N, O, or S; each - - is independently a single or double bond; and with the provision that the 5-membered heterocyclic ring contains at least one N atom.
  • each Z 2 is independently CR Z or N.
  • the compound of Formula (I) has the structure of Formula
  • the compound of Formula (I) has a structure of Formula (II- b):
  • the compound of Formula (I) has a structure of Formula (II- c):
  • the compound of Formula (I) has a structure of Formula (II- d):
  • the compound of Formula (I) is a compound having a structure selected from Formulas (Il-a), (Il-b), (II-c), and (Il-d).
  • each R z is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • each R z is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • each R z is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cehaloalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl. In some embodiments, each R z is independently hydrogen, halogen, or substituted or unsubstituted Ci- Cealkyl.
  • each R z is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.
  • each R z is independently hydrogen, -F, -Cl, - methyl, ethyl, n- propyl, iso-propyl, or cyclopropyl.
  • each R z is methyl.
  • each R z is -l Y 1 .
  • L 1 is substituted or unsubstituted Ci-C4alkylene; and Y 1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • each R z is -L 2 -L 3 -Y 2 .
  • L 2 is substituted or unsubstituted Ci-Cealkylene;
  • L 2 is absent;
  • m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • m is 1 and R z is methyl.
  • the compound of Formula (I) has a structure of Formula (III- Formula (Ill-a).
  • the compound of Formula (I) has a structure of Formula (HI- Formula (Ill-b).
  • the compound of Formula (I) has a structure of Formula (III- Formula (III-c).
  • the compound of Formula (I) has a structure of Formula (III- Formula (Ill-d).
  • the compound of Formula (I) is a compound having a structure selected from Formulas (Ill-a), (Ill-b), (III-c), and (Ill-d).
  • R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted C3- Ciocycloalkyl, or substituted or unsubstituted aryl. In some embodiments, R and R’ are each independently substituted or unsubstituted Ci-Cealkyl or substituted or unsubstituted Ci-Cealkoxy.
  • R and R’ are each independently methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, or phenyl.
  • R and R’ are each independently methyl, ethyl, n-propyl, methoxy, ethoxy, n- propoxy, or iso-propoxy.
  • R and R’ are each methyl.
  • R and R’ are each ethyl.
  • R and R’ are each methoxy.
  • R and R’ are each ethoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5- or 6-membered heterocycloalkyl.
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5-membered heterocycloalkyl.
  • R and R’ taken together with the phosphorus atom to which they are attached to form wherein R a , R b , R c , and R d are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci- Cealkoxy.
  • R a , R b , R c , and R d are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl.
  • R a , R b , R c , and R d are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, R a , R b , R c , and R d are each independently hydrogen or halogen. In certain embodiments, R a , R b , R c , and R d are each hydrogen.
  • R a , R b , R c , and R d are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • R and R’ taken together with the phosphorus atom to which they are attached to form ; wherein R a and R b are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, R a and R b are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, R a and R b are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, R a and R b are each independently hydrogen or halogen.
  • R a and R b are each hydrogen. In certain embodiments, R a and R b are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 6-membered heterocycloalkyl. In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form ; wherein R a , R b , R c , R d and R e are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy.
  • R a , R b , R c , R d and R e are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, R a , R b , R c , R d and R e are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, R a , R b , R c , R d and R e are each independently hydrogen or halogen. In certain embodiments, R a , R b , R c , R d and R e are each hydrogen.
  • R a , R b , R c , R d and R e are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • R and R’ taken together with the phosphorus atom to which they are attached to form ; wherein R a , R b , and R c are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, R a , R b , and R c are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, R a , R b , and R c are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy.
  • R a , R b , and R c are each independently hydrogen or halogen. In certain embodiments, R a , R b , and R c are each hydrogen. In certain embodiments, R a , R b , and R c are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
  • R and R’ taken together with the phosphorus atom to which they are attached to form
  • the compound of Formula (I) has a structure of Formula (IV):
  • the compound of Formula (I) has a structure of Formula (IV- a):
  • the compound of Formula (I) has a structure of Formula (IV- b):
  • the compound of Formula (I) has a structure of Formula (IV- c):
  • the compound of Formula (I) has a structure of Formula (IV- d):
  • the compound of Formula (I) is a compound having a structure selected from Formulas (IV), (IV-a), (IV-b), (IV-c), and (IV-d).
  • the compound of Formula (I) is a compound having a structure selected from Formulas (IV-a), (IV-b), (IV-c), and (IV-d). [00245] In some embodiments, the compound of Formula (I) has a structure of Formula (V):
  • each R 2 is independently F, Cl, -CN, -OCF3, -CHF2, -SCF3, or -CF3.
  • each R 2 is independently F, Cl, -OCF3, -CHF2, -SCF3, or -CF3.
  • each R 2 is independently F, Cl, -SF5, -SCF3, or -CF3. In some embodiments, each R 2 is independently F, Cl, -SF5, -OCF3, -SCF3, or -CF3. In one embodiment, each R 2 is -CF3. In another embodiment, each R 2 is -SF5. In yet another embodiment, each R 2 is -SCF3. In yet another embodiment, each R 2 is -OCF3.
  • n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • the compound of Formula (I) has a structure of Formula (VI):
  • the compound of Formula (I) is selected from the group consisting of:
  • the compound disclosed herein has the structure provided in
  • the compounds disclosed herein are prepared as described in the Examples section.
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes e.g., crystalline diastereomeric salts.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3 H and carbon-14, i. e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, /. ⁇ ., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • compositions [00264]
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • the compounds described herein exist as solvates.
  • the disclosure provides for methods of treating diseases by administering such solvates.
  • the disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed 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 the compounds described herein are conveniently prepared or formed during the processes described herein.
  • hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol.
  • the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds described herein exist in prodrug form.
  • the disclosure provides for methods of treating diseases by administering such prodrugs.
  • the disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
  • prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three, or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of the present disclosure.
  • the amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone.
  • prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e. g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure.
  • Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters.
  • compounds having free amino, amido, hydroxy, or carboxylic groups are converted into prodrugs.
  • free carboxyl groups are derivatized as amides or alkyl esters.
  • all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.
  • Hydroxy prodrugs include esters such as, though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in
  • Amine derived prodrugs include, but are not limited to, the following groups and combinations of groups: as well as sulfonamides and phosphonamides.
  • Metabolites [00274]
  • compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.
  • 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.
  • the compound as described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.
  • a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI), or a pharmaceutically acceptable salt thereof.
  • Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable carrier consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI), or a pharmaceutically acceptable salt thereof.
  • the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
  • compositions include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
  • rectal vaginal
  • aerosol administration although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions are formulated as a unit dose, and/or are formulated for oral or subcutaneous administration.
  • exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
  • the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums
  • other pharmaceutical diluents e.g., water
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions also comprise buffering agents in some embodiments.
  • Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-buty
  • Suspensions in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component is optionally mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which are required in some embodiments.
  • the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds disclosed herein are alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers are used because they minimize exposing the agent to shear, which result in degradation of the compounds contained in the subject compositions in some embodiments.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which optionally contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants
  • enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about
  • enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylme
  • the dose of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts.
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • the Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation.
  • the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional coactivator with PDZ-binding motif (TAZ; also known as WWTR1).
  • YAP transcriptional co-activators Yes-associated protein
  • TEZ transcriptional coactivator with PDZ-binding motif
  • the Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control.
  • YAP also known as YAP1 or YAP65
  • TAZ TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis.
  • unregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer.
  • overexpression of YAP/TAZ is associated with cancer.
  • Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (M0BKL1 A and MOBKL1B; homologues of Mats), respectively.
  • MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase.
  • Latsl/2 is also activated by the scaffold protein Mob.
  • the activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ.
  • the phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.
  • Latsl/2 phosphorylates YAP at the [HXRXXS] consensus motifs.
  • YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue.
  • Latsl/2 phosphorylates YAP at one or more of the consensus motifs.
  • Latsl/2 phosphorylates YAP at all five of the consensus motifs.
  • Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
  • Latsl/2 phosphorylates TAZ at the [HXRXXS] consensus motifs.
  • TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues.
  • Latsl/2 phosphorylates TAZ at one or more of the consensus motifs.
  • Latsl/2 phosphorylates TAZ at all four of the consensus motifs.
  • Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
  • phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCF p ' TRCP -mediated ubiquitination and subsequent proteasomal degradation.
  • the Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme.
  • the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, pTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2).
  • the SCF complex e.g. SCF pTrCP1
  • an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate.
  • Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1.
  • Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1.
  • the ubiquitin
  • the Hippo pathway is regulated upstream by several different families of regulators.
  • the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
  • un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus.
  • YAP/TAZ interacts with the TEtOAcD family of transcription factors (e.g., TEtOAcD 1, TEtOAcD2, TEtOAcD3, or TEtOAcD4) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61. and FGF1.
  • TEtOAcD family of transcription factors
  • the compounds disclosed herein modulate the interaction between YAP/TAZ and TEtOAcD. In some embodiments, the compounds disclosed herein bind to TEtOAcD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEtOAcD.
  • the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins.
  • G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs.
  • monomeric small GTPases and heterotrimeric G protein complexes.
  • the latter class of complexes comprise of alpha (Ga), beta (Gp), and gamma (G y ) subunits.
  • G a subunits Gq/ua, Gu/ua, Gi/ O a (G inhibitory, G other), and G s a (G stimulatory).
  • Gia (G inhibitory), G o a (G other), Gq/ua, and Gi2/na coupled GPCRs activate YAP/TAZ and promote nuclear translocation.
  • G s a (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
  • Gia (G inhibitory), G o a (G other), G q /ua, and Gn/na coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities.
  • G s a in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.
  • G q a also known as G q /u protein
  • G q a participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca 2+ ) release from intracellular storage through the activation of phospholipase C (PLC).
  • PLC phospholipase C
  • PLC phospholipase C
  • PIP2 phosphatidylinositol 4,5- bisphosphate
  • DAG diacyl glycerol
  • IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca 2+ channel.
  • the binding triggers the opening of the Ca 2+ channel, and thereby increases the release of Ca 2+ into the cytoplasm.
  • the GPCRs that interact with G q a include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1.
  • 5-HT receptor 5-hydroxytryptamine receptor
  • 5-HT2 and 5-HT3 alpha-1 adrenergic receptor
  • vasopressin type 1 receptors 1A and IB angiotensin II receptor type 1
  • calcitonin receptor histamine Hl receptor
  • metabotropic glutamate receptor group I
  • muscarinic receptors Mi, M3, and M5 and trace amine-associated receptor 1.
  • G q a there are several types of G q a: G q , G q /n, G q /i4, and G q /i5.
  • the G q protein is encoded by GNAQ.
  • G q /n is encoded by GNA11.
  • G q /i4 is encoded by GNA14.
  • G q /i5 is encoded by GNA15.
  • G q a genes have been associated with cancer. Indeed, studies have shown that mutations in G q a promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
  • mutations or modifications of the G q a genes have been associated with congenital diseases.
  • mutations of G q a have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
  • congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
  • Port-Wine Stain and/or Sturge-Weber Syndrome.
  • about 92% of Port-Wine stain cases harbors a mutation in GNAQ.
  • about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ.
  • Gi2/i3a modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs).
  • GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways.
  • small GTPases include the Ras-related GTPase superfamily (e.g. Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
  • the GPCRs that interact with Gi2/na include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g. SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g.
  • purinergic receptors e.g. P2Yi, P2Y2, P2Y4, P2Ye
  • muscarinic acetylcholine receptors Ml and M3 receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]
  • thromboxane TXA2
  • sphingosine 1 -phosphate e.g. S
  • LPAi LPA2, LPA3; angiotensin II (ATI); serotonin (5-HT2 C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; on adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.
  • TSHV-ORF74 thyroid-stimulating hormone
  • G12/1301 is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.
  • Gi/oO G inhibitory, G other
  • Gi/Go G protein
  • cAMP 3’,5’-cyclic AMP
  • the GPCRs that interact with Gia include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as a2A, a2B, and a2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GAB AB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (m
  • 5-HT receptor 5-hydroxy
  • Gial is encoded by GNAI1.
  • Gia2 is encoded by GNAI2.
  • Gia3 is encoded by GNAI3.
  • G o a the a 0 subunit, is encoded by GNAO1.
  • Gt is encoded by GNAT1 and GNAT2.
  • G z is encoded by GNAZ.
  • G s a also known as G stimulatory, G s alpha subunit, or G s protein
  • G s a activates the cAMP-dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate.
  • ATP adenosine triphosphate
  • cAMP cyclic AMP
  • the GPCRs that interact with G s a include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); P-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3
  • G s there are two types of G s a: G s and G o if.
  • G s is encoded by GNAS.
  • Goif is encoded by GN AL.
  • the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex.
  • the Crumbs complex is a key regulator of cell polarity and cell shape.
  • the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity.
  • CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components.
  • AMOT Angiomotin
  • the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family.
  • MST kinases monitor actin cytoskeletal integrity.
  • the regulators include TAO kinases and cell polarity kinase PAR-1.
  • the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction.
  • E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity.
  • E- cad-associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm.
  • Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
  • additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
  • the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP).
  • the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP).
  • the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway.
  • the one or more proteins comprise a protein described above. 1 and/or 2.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein.
  • an inhibitor of the Hippo pathway is an inhibitor of the G q a family proteins such as G q , Gq/n, Gq/u, and Gq/15; the Gn/na family of proteins such as G12 and G13; or the Gia family of proteins such as Gial, Gia2, Gia3, Gia4, G o a, Gt, Ggust, and G z .
  • an inhibitor of the Hippo pathway is an inhibitor of G q .
  • an inhibitor of the Hippo pathway is an inhibitor of G q /u.
  • an inhibitor of the Hippo pathway is an inhibitor of G q /i4.
  • an inhibitor of the Hippo pathway is an inhibitor of G q /i5.
  • an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gial. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G o a. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G z .
  • an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.
  • an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g. 26S proteasome).
  • an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
  • Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.
  • GEFs guanine nucleotide exchange factors
  • an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme.
  • an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease.
  • an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease.
  • USP47 is a member of the ubiquitinspecific protease (USP/UBP) superfamily of cysteine proteases.
  • the compounds disclosed herein are inhibitors of USP47.
  • the present disclosure provides a method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the subject has cancer, polycystic kidney disease, or liver fibrosis.
  • the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
  • the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
  • the present disclosure provides a method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits the activity of one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
  • a compound that inhibits transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator TEZ/YAP
  • a disease or disorder e.g., a disease or disorder conducive to treatment to prevention by inhibiting one or more of proteins encompassed by, or related to, the Hippo
  • a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof, such cancer.
  • a disease or disorder e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)
  • Such a compound is, for example, a compound of Formula (I), (la), (Il-a), (Il-b), (II- c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • compositions comprising a compound Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI) as disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof.
  • a disease or disorder e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo
  • the compounds disclosed herein are useful for treating cancer.
  • a method for treating a cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof.
  • a compound for use in treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof.
  • the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP).
  • the cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD.
  • the cancer is characterized by a mutant Ga-protein.
  • the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs.
  • the mutant Ga-protein is G12.
  • the mutant Ga-protein is G13.
  • the mutant Ga- protein is Gq.
  • the mutant Ga-protein is Gl 1.
  • the mutant Ga-protein is Gi.
  • the mutant Ga-protein is Go.
  • the mutant Ga-protein is Gs.
  • the cancer is a solid tumor.
  • the cancer is a hematologic malignancy.
  • the solid tumor is a sarcoma or carcinoma.
  • the solid tumor is a sarcoma.
  • the solid tumor is a carcinoma.
  • Exemplary sarcoma includes, but is not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor,
  • Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
  • the liver cancer is primary liver cancer.
  • the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
  • the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma.
  • the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer.
  • the cancer is uveal melanoma.
  • the cancer is mesothelioma.
  • the cancer is esophageal cancer.
  • the cancer is liver cancer.
  • the cancer is primary liver cancer.
  • the cancer is a hematologic malignancy.
  • a hematologic malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • a hematologic malignancy is a T-cell malignancy.
  • Exemplary T-cell malignancy includes, but is not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, and treatment-related T-cell lymphomas.
  • PTCL-NOS peripheral T-cell lymphoma not otherwise specified
  • anaplastic large cell lymphoma angioimmunoblastic lymphoma
  • ATLL adult T-cell leukemia/lymphoma
  • blastic NK-cell lymphoma enteropathy -type T-cell lymphoma
  • a hematologic malignancy is a B-cell malignancy.
  • Exemplary B- cell malignancy includes, but is not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, and a non-CLL/SLL lymphoma.
  • the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • FL follicular lymphoma
  • the cancer is a relapsed or refractory cancer.
  • the relapsed or refractory cancer is a relapsed or refractory solid tumor.
  • the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma.
  • the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
  • bile duct cancer i.e., cholangiocarcinoma
  • bladder cancer i.e.,
  • the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
  • the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma.
  • the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the relapsed or refractory cancer is relapsed or refractory mesothelioma. In some cases, the relapsed or refractory cancer is relapsed or refractory esophageal cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory primary liver cancer.
  • the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy.
  • a relapsed or refractory hematologic malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin’s lymphoma, a relapsed or refractory Hodgkin’s lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy.
  • a relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy.
  • a relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • high risk CLL or a non-CLL/SLL lymphoma.
  • the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • FL follicular lymphoma
  • the cancer is a metastasized cancer.
  • the metastasized cancer is a metastasized solid tumor.
  • the metastasized solid tumor is a metastasized sarcoma or a metastasized carcinoma.
  • the metastasized carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
  • CUP Unknown Primary
  • the metastasized cancer is selected from metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
  • the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma.
  • the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, or liver cancer.
  • the metastasized cancer is metastasized uveal melanoma. In some cases, the metastasized cancer is metastasized mesothelioma. In some cases, the metastasized cancer is metastasized esophageal cancer. In some cases, the metastasized cancer is metastasized liver cancer. In some cases, the metastasized cancer is metastasized primary liver cancer.
  • the metastasized cancer is a metastasized hematologic malignancy.
  • the metastasized hematologic malignancy is a metastasized leukemia, a metastasized lymphoma, a metastasized myeloma, a metastasized non-Hodgkin’s lymphoma, a metastasized Hodgkin’s lymphoma, a metastasized T-cell malignancy, or a metastasized B-cell malignancy.
  • a metastasized hematologic malignancy is a metastasized T-cell malignancy.
  • a metastasized hematologic malignancy is a metastasized B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • high risk CLL or a non-CLL/SLL lymphoma.
  • the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • FL follicular lymphoma
  • the compounds disclosed herein are useful for treating a congenital disease.
  • the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP).
  • the congenital disease is characterized by a mutant Ga-protein.
  • the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs.
  • the mutant Ga-protein is G12.
  • the mutant Ga-protein is G13.
  • the mutant Ga-protein is Gq.
  • the mutant Ga- protein is Gl 1.
  • the mutant Ga-protein is Gi.
  • the mutant Ga-protein is Go.
  • the mutant Ga-protein is Gs.
  • the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, epigenetic modifications on a parental germline, or a chromosomal abnormality.
  • exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port-Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich’s ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase defici
  • HEK293T cells stably transfected with 8XTBD luciferase reporter and pRLTK in 384-well plates were treated with the test compounds, starting from 3 pM (final concentration in assay plate), 1 :3 dilution, and 10 points in quadruplicates. Post 24-hr incubation with compounds at 37 °C and 5% CO2, cells were lysed and 8XTBD-driven firefly luciferase and control TK-driven renilla luciferase activities were measured using Promega Dual-Luciferase Reporter Assay System.
  • Reagents The reagents used for this study were: DMEM: Invitrogen# 11960077, Dual-Glo Luciferase Assay System: Promega-E2980, Puromycin Dihydrochloride: Invitrogen- A1113803, 384-well plate: PerkinElmer-6007480, L-GLUTAMINE: Invitrogen-25030164, Hygromycin B: Invitrogen- 10687010 , and Penicillin-Streptomycin: Merk-TMS-AB2-C.
  • the media used for this assay were: Culture Medium: DMEM+ lug/mL puromycin + 200 ug/mL hygromycin (with 10% FBS + ImM L-glutamine); and Assay Medium: DMEM (with 10% FBS + ImM L-glutamine + lx P/S).
  • Cell Plating The appropriate media was warmed at 37 °C by water bath: Culture Medium, Assay Medium, lx D-PBS, 0.05% trypsin-EDTA. The cells were trypsinized after removing all media, then washed with lx sterile D-PBS and then with 2 ml 0.05% trypsin-EDTA. The cells were then incubated at RT for one minute. Then 10 mL/75 cm 2 flask Assay Medium was added to each flask. Using a 10 mL pipette, the cells were then gently resuspended in the media, until the clumps completely disappeared.
  • the cells were then transferred into 50 mL centrifuge tubes and were centrifuged at 800 rpm for 5 mins. The medium was removed, and the cells were resuspended with Assay Medium. An aliquot of cells was used to count the cell density (cells/mL). The cell suspension was then diluted with Assay Medium to a concentration of 6xl0 4 cells/mL. 50 pL cells suspension was then plated to 384-well plate (PerkinElmer-6007480), 3xl0 3 cells/well and the cells were incubated in an incubator at 37 °C, 5% CO2.
  • Biochemical assay IC50 data are designated within the following ranges: A: ⁇ 0.1 pM C: > 0.2 pM to ⁇ 1.0 pM
  • the average tumor diameter (two perpendicular axes of the tumor are measured) are recorded.
  • the data are expressed in tumor volume estimated by ([width]2 x length/2). Paired, two-tailed Student's t-test is performed to access the statistical significance.
  • Cancer cell lines are plated in 384-well plates 24 hrs before drug treatment. Post incubation for various time periods with the test compounds, starting from 3 pM (final concentration in assay plate), 1 :3 dilution, and 10 points in duplicates, the number of viable cells and proliferative cells are determined using CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega) and Click-iT EdU HCS Assay Kit (Invitrogen) according to the manufacturers’ protocols. The IC50 values and maximum % inhibition of the test compounds are calculated using the dose response curves.

Abstract

Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating diseases (e.g., cancers). Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEtOAcD (TEAD).

Description

PHENYL PHOSPHINE OXIDE COMPOUNDS AND METHODS OF USE THEREOF
BACKGROUND OF THE DISCLOSURE
[0001] YAP and TAZ are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP/TAZ or inhibitors that modulate the interaction between YAP/TAZ and TEAD.
SUMMARY OF THE DISCLOSURE
[0002] In one aspect, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000002_0001
wherein,
Figure imgf000002_0002
is a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl ring containing at least one N atom, or a substituted or unsubstituted monocyclic heteroaryl ring containing at least one N atom; each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -L^Y1, or -L2-L3-Y2; m is 0, 1, 2, 3, 4, or 5;
L1 is substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C2-Ciocyclolkylene, or substituted or unsubstituted C2- Cioheterocycloalkylene; Y1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is absent, substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C3- Ciocyclolalkylene, or substituted or unsubstituted 3- to 10-membered heterocycloalkylene;
L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, -(C=O)NR3- O-, -O-NR3(C=O)-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-,-(SO2)NR3-, -(SO2)NR3-(C=O)-, -(C=O)-NR3(SO2)-, -(SO2)NR3-(C=O)O-, -O(C=O)- NR3(SO2)-, -NR3(SO2)NR3-(C=O)-, -(C=O)-NR3(SO2)NR3-, -O(C=O)-NR3(SO2)-NR3-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;
Y2 is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3 and Y2 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;
R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
Figure imgf000003_0001
substituted or unsubstituted phenyl or substituted or unsubstituted cyclohexyl; each R2 is independently hydrogen, halogen, -N3, -CN, -OR4, -SR4, -(SO2)R4, -S(R4)5, -(S=O)R4, -
(SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl,
N=N substituted or unsubstituted heteroaryl, or • n is 0, 1, 2, 3, 4, or 5; and each R4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0003] In certain embodiments,
Figure imgf000004_0001
is a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl ring containing at least one N atom.
[0004] In certain embodiments,
Figure imgf000004_0002
is a substituted or unsubstituted monocyclic 5- membered heterocycloalkyl ring containing 1-4 N atoms, 0-2 O atoms, and 0-2 S atoms.
[0005] In certain embodiments,
Figure imgf000004_0003
each Z2 is independently -CRZ, -CHRZ-, -C(RZ)2-, -NRZ-, -N-, -O-, or -S-; and each - - is independently a single or double bond.
[0006] In certain embodiments,
Figure imgf000004_0004
is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted thiazolidinyl, or substituted or unsubstituted isothiazolidinyl.
Figure imgf000004_0005
Figure imgf000005_0001
heteroaryl ring containing at least one N atom.
[0009] In certain embodiments,
Figure imgf000005_0002
a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing at least one N atom.
[0010] In certain embodiments,
Figure imgf000005_0003
a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 1 N atom.
[0011] In certain embodiments,
Figure imgf000005_0004
a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 2 N atoms.
[0012] In certain embodiments,
Figure imgf000005_0005
a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 3 N atoms.
[0013] In certain embodiments,
Figure imgf000005_0006
a substituted or unsubstituted monocyclic 5- membered heteroaryl ring containing 4 N atoms.
[0014] In certain embodiments,
Figure imgf000005_0007
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazoyl, substituted or unsubstituted tetrazoyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted dithiazolyl. [0015] In certain embodiments,
Figure imgf000006_0001
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted isoxazolyl.
[0016] In certain embodiments,
Figure imgf000006_0002
is substituted or unsubstituted imidazolyl or substituted or unsubstituted pyrazolyl.
[0017] In certain embodiments,
Figure imgf000006_0003
is substituted or unsubstituted imidazolyl.
Figure imgf000006_0004
Figure imgf000007_0001
[0022] In certain embodiments,
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0006
[0023] In certain embodiments, the compound has the structure of Formula (la)
Figure imgf000008_0003
Formula (la) wherein: Z1 is -N-, -CH-, or -C-.
[0024] In certain embodiments,
Figure imgf000008_0004
is a substituted or unsubstituted monocyclic 5- membered heterocyclic ring containing at least one N atom, and the at least one N atom is adjacent to Z1.
[0025] In certain embodiments,
Figure imgf000008_0005
CH-, or -C-; each Z2 is independently CRZ, NRZ, N, O, or S; each — is independently a single or double bond; and with the provision that the 5-membered heterocyclic ring contains at least one N atom. [0026] In certain embodiments,
Figure imgf000009_0001
is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted thiazolidinyl, or substituted or unsubstituted isothiazolidinyl.
Figure imgf000009_0002
[0028] In certain embodiments, wherein:
Figure imgf000009_0003
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazoyl, substituted or unsubstituted tetrazoyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted dithiazolyl.
Figure imgf000009_0004
Figure imgf000010_0001
[0030] In certain embodiments, the compound has a structure of Formula (Il-a):
Figure imgf000010_0002
[0031] In certain embodiments, the compound has a structure of Formula (Il-b):
Figure imgf000010_0003
[0032] In certain embodiments, the compound has a structure of Formula (II-c):
Figure imgf000010_0004
[0033] In certain embodiments, the compound has a structure of Formula (Il-d):
Figure imgf000010_0005
Formula (Il-d). [0034] In certain embodiments, each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0035] In certain embodiments, each Rz is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl.
In certain embodiments, each Rz is independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl.
[0036] In certain embodiments, each Rz is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.
[0037] In certain embodiments, each Rz is independently hydrogen, -F, -Cl, - methyl, ethyl, n- propyl, iso-propyl, or cyclopropyl.
[0038] In certain embodiments, each Rz is methyl.
[0039] In certain embodiments, Rz is -l Y1.
[0040] In certain embodiments, L1 is substituted or unsubstituted Ci-C4alkylene; and Y1 is substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0041] In certain embodiments, Rz is -L2-L3-Y2.
[0042] In certain embodiments, L2 is substituted or unsubstituted Ci-Cealkylene; L3 is -O-, -S-, - (S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, -(C=O)NR3-O-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-, -(SO2)NR3-, - (SO2)NR3-(C=O)-, -(SO2)NR3-(C=O)O-, -NR3(SO2)NR3-(C=O)-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently H or substituted or unsubstituted Ci-Cealkyl; and Y2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, L2 is absent; L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, - O(C=O)-, -(C=O)NR3-, -(C=O)NR3-O-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -
NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-, -(SO2)NR3-, -(SO2)NR3-(C=O)-, -(SO2)NR3-(C=O)O-, -NR3(SO2)NR3-(C=O)-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently H or substituted or unsubstituted Ci-Cealkyl; and Y2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted Cb-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0043] In certain embodiments, m is 1, 2, or 3.
[0044] In certain embodiments, m is 1 or 2.
[0045] In certain embodiments, m is 1.
[0046] In certain embodiments, m is 1 and Rz is methyl.
Figure imgf000012_0001
[0048] In certain embodiments, the compound has a structure of Formula (Ill-a):
Figure imgf000012_0002
[0049] In certain embodiments, the compound has a structure of Formula (Ill-b):
Figure imgf000012_0003
[0050] In certain embodiments, the compound has a structure of Formula (III-c):
Figure imgf000012_0004
[0051] In certain embodiments, the compound has a structure of Formula (Ill-d):
Figure imgf000013_0001
Formula (Ill-d).
[0052] In certain embodiments, R and R’ are each independently substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0053] In certain embodiments, R and R’ are each independently substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0054] In certain embodiments, R and R’ are each independently substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl.
[0055] In certain embodiments, R and R’ are each independently substituted or unsubstituted Ci- Cealkyl or substituted or unsubstituted Ci-Cealkoxy.
[0056] In certain embodiments, R and R’ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, or phenyl.
[0057] In certain embodiments, R and R’ are each independently methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, or iso-propoxy.
[0058] In certain embodiments, R and R’ are each methyl.
[0059] In certain embodiments, R and R’ are each ethyl.
[0060] In certain embodiments, R and R’ are each methoxy.
[0061] In certain embodiments, R and R’ are each ethoxy.
[0062] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
[0063] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5- or 6-membered heterocycloalkyl. [0064] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5-membered heterocycloalkyl.
[0065] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000014_0001
; wherein Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy.
[0066] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000014_0002
[0067] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000014_0003
; wherein Ra and Rb are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy.
[0068] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000014_0004
[0069] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 6-membered heterocycloalkyl.
[0070] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000014_0005
wherein Ra, Rb, Rc, Rd and Re are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci- Cealkoxy.
[0071] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000014_0006
[0072] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000015_0001
; wherein Ra, Rb, and Rc are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl.
[0073] In certain embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000015_0002
[0074] In certain embodiments,
Figure imgf000015_0003
[0075] In certain embodiments, the compound has the structure of Formula (IV):
Figure imgf000015_0004
Formula (IV).
[0076] In certain embodiments, the compound has the structure of Formula (IV-a):
Figure imgf000015_0005
Formula (IV-a).
[0077] In certain embodiments, the compound has the structure of Formula (IV-b):
Figure imgf000015_0006
Formula (IV-b).
[0078] In certain embodiments, the compound has the structure of Formula (IV-c), or a pharmaceutically acceptable salt thereof:
Figure imgf000016_0001
[0079] In certain embodiments, the compound has the structure of Formula (IV-d), or a pharmaceutically acceptable salt thereof:
Figure imgf000016_0002
[0081] In certain embodiments, the compound has the structure of Formula (V):
Figure imgf000016_0003
Formula (V). [0082] In certain embodiments,
Figure imgf000017_0001
In certain embodiments,
Figure imgf000017_0002
[0083] In certain embodiments, each R2 is independently hydrogen, halogen, nitro, -N3, -CN, -OR4, -SR4, -S(R4)5, -(S=O)R4, -(SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, or substituted or unsubstituted Cs-Ciocycloalkyl; each R4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl.
[0084] In certain embodiments, each R2 is independently F, Cl, Br, I, nitro, -CN, -SF5, -SCF3, - 0CH2F, -0CHF2, -0CF3, -C(=O)OCH3 -S(=O)2CH3, - N(CH3)2, -NH(CH3), -CH2F, -CHF2, or - CF3.
[0085] In certain embodiments, each R2 is independently F, Cl, -CN, -OCF3, -CHF2, -SCF3, or - CF3.
[0086] In certain embodiments, each R2 is independently F, Cl, -OCF3, -CHF2, -SCF3, or -CF3. [0087] In certain embodiments, each R2 is independently F, Cl, -SF5, -SCF3, or -CF3.
[0088] In certain embodiments, each R2 is independently F, Cl, -SF5, -OCF3, -SCF3, or -CF3.
[0089] In certain embodiments, each R2 is -CF3.
[0090] In certain embodiments, each R2 is -SF5.
[0091] In certain embodiments, each R2 is -SCF3.
[0092] In certain embodiments, each R2 is -OCF3.
[0093] In certain embodiments, n is 0, 1, or 2.
[0094] In certain embodiments, n is 1 or 2. [0095] In certain embodiments, n is 1.
[0096] In certain embodiments, the compound has the structure of Formula (VI):
Figure imgf000018_0001
[0098] In certain embodiments, the compound provided herein is a compound from Table 1.
[0099] In another aspect, also provided herein are pharmaceutical compositions comprising the compound or pharmaceutically acceptable salt thereof provided herein, and a pharmaceutically acceptable excipient.
[00100] In yet another aspect, also provided herein are methods of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof provided herein or pharmaceutical compositions provided herein. [00101] In yet another aspect, also provided herein are methods of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject the compound or pharmaceutically acceptable salt thereof provided herein, or the pharmaceutical composition provided herein.
[00102] In certain embodiments, the subject has cancer, polycystic kidney disease or liver fibrosis.
[00103] In certain embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[00104] In yet another aspect, also provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof provided herein, or the pharmaceutical composition provided herein.
[00105] In certain embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[00106] In yet another aspect, also provided herein are methods of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof provided herein, or the pharmaceutical composition provided herein.
INCORPORATION BY REFERENCE
[00107] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE DISCLOSURE
Certain Terminology [00108] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.
[00109] As used herein, in some embodiments, ranges and amounts are expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pL” means “about 5 pL” and also “5 pL.” Generally, the term “about” includes an amount that is expected to be within experimental error.
[00110] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[00111] As used herein, the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).
[00112] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[00113] Amino" refers to the -NH2 radical.
[00114] "Cyano" refers to the -CN radical. [00115] "Nitro" refers to the -NO2 radical. [00116] Oxa" refers to the -O- radical.
[00117] Oxo" refers to the =0 radical.
[00118] Thioxo" refers to the =S radical. [00119] Imino" refers to the =N-H radical. [00120] Oximo" refers to the =N-0H radical. [00121] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., Ci-Ci3 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methylethyl (/.w-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (secbutyl), 2-methylpropyl (/.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (//-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, -SRa, OC(O)Ra, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf (where t is 1 or 2), S(O)tORa (where t is 1 or 2), S(O)tRf (where t is 1 or 2), and S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[00122] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above.
[00123] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, - SRa, OC(O) Ra, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf (where t is 1 or 2), S(O)tORa (where t is 1 or 2), S(O)tRf (where t is 1 or 2), and S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[00124] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, -SRa, OC(O) Ra, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf (where t is 1 or 2), S(O)tORa (where t is 1 or 2), S(O)tRf (where t is 1 or 2), and S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[00125] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -
SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N( Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[00126] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra) C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [00127] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O- aryl, where aryl is as defined above.
[00128] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[00129] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
[00130] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
[00131] "Carbocyclyl" or “carbocycle” refers refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclyl from “heterocyclyl” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, a carbocyclyl is a monocyclic carbocyclyl or a bicyclic carbocyclyl. In some embodiments, a carbocyclyl is a monocyclic carbocyclyl. Carbocyclyls are non-aromatic or aromatic. Non-aromatice carbocyclyls are saturated or partially unsaturated. In some embodiments, a carbocyclyl is a bicyclic carbocyclyl. In some embodiments, at least one of the two rings of a bicyclic carbocyclyl is aromatic. In some embodiments, both rings of a bicyclic carbocyclyl are aromatic. Carbocyclyl include aryls and cycloalkyls.
[00132] “Cycloalkyl” refers to a monocyclic or polycyclic aliphatic, fully saturated non-aromatic carbocyclyl, 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. In some embodiments, 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. In some embodiments, cycloalkyl groups include groups having from 3 to 6 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclefl .1. l]pentyl. In some embodiments, a cycloalkyl is a Cs-Cecycloalkyl.
Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., Cs-Cs cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms e.g., C3-C4 cycloalkyl). An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term " cycloalkyl" is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb -C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O )Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[00133] "Carbocycloalkylalkyl" refers to a radical of the formula -Rc- cycloalkyl where Rc is an alkylene chain as defined above. The alkylene chain and the cycloalkyl radical are optionally substituted as defined above.
[00134] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo substituents.
[00135] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
[00136] "Heterocyclyl" or “heterocycle” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings 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) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused, spiro, or bridged ring systems in some embodiments. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
[00137] “Heterocycloalkyl” refers to a cycloalkyl group in which one or more skeletal atoms of the cycloalkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a 5- to 10-membered C4-C9heterocycloalkyl. In another aspect, a heterocycloalkyl is a 4- to 7-membered Cs-Ceheterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. Unless stated otherwise specifically in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-CN
, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)O Ra, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)t Ra (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[00138] “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. In one aspect, a heteroalkyl is a Ci-Ceheteroalkyl. In some embodiments, the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group.
[00139] "Heterocycloalkylalkyl" refers to a radical of the formula -Rc-heterocycloalkyl where Rc is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocycloalkyl group.
[00140] "Heterocycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc- heterocycloalkyl where Rc is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocycloalkylalkoxy radical is optionally substituted as defined above for a heterocycloalkyl group.
[00141] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, in some embodiments, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, /.< ., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 -benzodi oxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1.6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 177-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O )Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[00142] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[00143] C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[00144] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula - O-heteroaryl, where heteroaryl is as defined above.
[00145] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.
[00146] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
[00147] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or irons'). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to A or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
[00148] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000030_0001
[00149] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
[00150] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). In some other embodiments, optional substituents are individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), - N(alkyl)2, -OH, =0, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, - S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -CH2CO2H, -CH2CO2alkyl, -CH2C(=O)NH2, - CH2C(=O)NH(alkyl), -CH2C(=O)N(alkyl)2, -CH2S(=O)2NH2, - CH2S(=O)2NH(alkyl), - CH2S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CChalkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, - S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, =0, -C02H, - CO2(Ci-C4alkyl), -C(=0)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci- C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci- C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, - CN, -NH2, -OH, =0, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -0CH3, and -OCF3. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -0CH3, and -OCF3. In some embodiments, optional substituents are independently selected from D, F, Cl, -CN, -NH2, -OH, =0, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CF3, -0CH3, and -OCF3. In some embodiments, substituted groups are substituted with one to six of the preceding groups. In some embodiments, substituted groups are substituted with one to four of the preceding groups. In some embodiments, substituted groups are substituted with one to three of the preceding groups. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups.
[00151] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
Compounds
[00152] In one aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000032_0001
Formula (I) wherein,
Figure imgf000032_0002
is a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl ring containing at least one N atom, or a substituted or unsubstituted monocyclic heteroaryl ring containing at least one N atom; each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -l Y1, or -L2-L3-Y2; m is 0, 1, 2, 3, 4, or 5;
L1 is substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C2-Ciocyclolkylene, or substituted or unsubstituted C2- Cioheterocycloalkylene;
Y1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is absent, substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C3- Ciocyclolalkylene, or substituted or unsubstituted 3- to 10-membered heterocycloalkylene;
L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, -(C=O)NR3- O-, -O-NR3(C=O)-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-,-(SO2)NR3-, -(SO2)NR3-(C=O)-, -(C=O)-NR3(SO2)-, -(SO2)NR3-(C=O)O-, -O(C=O)- NR3(SO2)-, -NR3(SO2)NR3-(C=O)-, -(C=O)-NR3(SO2)NR3-, -O(C=O)-NR3(SO2)-NR3-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;
Y2 is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3 and Y2 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;
R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. O>(R2)n is substituted or unsubstituted phenyl or substituted or unsubstituted cyclohexyl; each R2 is independently hydrogen, halogen, -N3, -CN, -OR4, -SR4, -(SO2)R4, -S(R4)5, -(S=O)R4, - (SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl,
N=N substituted or unsubstituted heteroaryl, or
Figure imgf000033_0001
; n is 0, 1, 2, 3, 4, or 5; and each R4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[00153] In some embodiments, ring Z is monocyclic 3- to 8-membered heterocycloalkyl ring.
[00154] In some embodiments, ring Z is monocyclic 4- to 7-membered heterocycloalkyl ring.
[00155] In some embodiments, ring Z is monocyclic 4- to 6-membered heterocycloalkyl ring.
[00156] In some embodiments, ring Z is monocyclic 4- to 5-membered heterocycloalkyl ring. [00157] In some embodiments, ring Z is monocyclic 5- to 6-membered heterocycloalkyl ring.
[00158] In some embodiments, ring Z is monocyclic 5-membered heterocycloalkyl ring.
[00159] In some embodiments, ring Z is monocyclic 6-membered heterocycloalkyl ring.
[00160] In some embodiments,
Figure imgf000034_0001
is a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl ring containing at least one N atom.
[00161] In some embodiments,
Figure imgf000034_0002
is a substituted or unsubstituted monocyclic 5-membered heterocycloalkyl ring containing 1-4 N atoms, 0-2 O atoms, and 0-2 S atoms.
[00162] In some embodiments,
Figure imgf000034_0003
Z1 is -N-, -CH-, or -C-; each Z2 is independently -CRZ, -CHRZ-, -C(RZ)2-, -NRZ-, -N-, -O-, or -S-;
[00163] each - - is independently a single or double bond
[00164] In some embodiments,
Figure imgf000034_0004
is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted thiazolidinyl, or substituted or unsubstituted isothiazolidinyl.
Figure imgf000034_0005
Figure imgf000035_0001
[00166] In some embodiments, ring Z is monocyclic heteroaryl ring.
[00167] In some embodiments, ring Z is monocyclic 5- to 12- membered heteroaryl ring.
[00168] In some embodiments, ring Z is monocyclic 5- to 10- membered heteroaryl ring.
[00169] In some embodiments, ring Z is monocyclic 5- to 8- membered heteroaryl ring.
[00170] In some embodiments, ring Z is monocyclic 5- to 7- membered heteroaryl ring.
[00171] In some embodiments, ring Z is monocyclic 5- to 6- membered heteroaryl ring.
[00172] In some embodiments, ring Z is monocyclic 5-membered heteroaryl ring.
[00173] In some embodiments, ring Z is monocyclic 6-membered heteroaryl ring.
[00174] In some embodiments, ring Z is a 5-, 6-, or 7-membered monocyclic heteroaryl. In some embodiments, ring Z is a 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring Z is a 6- or 7-membered monocyclic heteroaryl. In some embodiments, ring Z is a 6- membered monocyclic heteroaryl.
[00175] In some embodiments, ring Z is a monocyclic heteroaryl having 1-4 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 1-3 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 1-2 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 1 N atom. In some embodiments, ring Z is a monocyclic heteroaryl having 2 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 3 N atoms. In some embodiments, ring Z is a monocyclic heteroaryl having 4 N atoms.
[00176] In some embodiments, ring Z is a monocyclic 5-membered heteroaryl having 1-4 N atoms.
[00177] In some embodiments,
Figure imgf000035_0002
is a substituted or unsubstituted monocyclic heteroaryl ring containing at least one N atom.
[00178] In some embodiments,
Figure imgf000035_0003
is a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 1 N atom. [00179] In some embodiments,
Figure imgf000036_0001
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 2 N atoms.
[00180] In some embodiments,
Figure imgf000036_0002
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 3 N atoms.
[00181] In some embodiments,
Figure imgf000036_0003
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 4 N atoms.
[00182] In some embodiments,
Figure imgf000036_0004
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazoyl, substituted or unsubstituted tetrazoyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted dithiazolyl.
[00183] In some embodiments,
Figure imgf000036_0005
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted isoxazolyl.
[00184] In some embodiments,
Figure imgf000036_0006
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted oxazolyl. In some embodiments,
Figure imgf000036_0007
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted isoxazolyl.
[00185] In some embodiments,
Figure imgf000036_0008
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted pyrazolyl. In some embodiments,
Figure imgf000036_0009
is substituted or unsubstituted imidazolyl or substituted or unsubstituted pyrazolyl. In some embodiments,
Figure imgf000037_0001
is substituted or unsubstituted pyrrolyl or substituted or unsubstituted imidazolyl. In some embodiments,
Figure imgf000037_0002
is substituted or unsubstituted pyrrolyl or substituted or unsubstituted pyrazolyl.
[00186] In some embodiments,
Figure imgf000037_0003
is substituted or unsubstituted pyrrolyl. In some embodiments,
Figure imgf000037_0004
is substituted or unsubstituted imidazolyl. In some embodiments,
Figure imgf000037_0005
is substituted or unsubstituted pyrazolyl.
Figure imgf000037_0006
Figure imgf000038_0001
[00190] In some embodiments,
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000039_0003
yet another embodiment,
Figure imgf000039_0004
[00192] In some embodiments,
Figure imgf000039_0005
each Z2 is independently CRZ or N; and at least one Z2 is N. [00193] In some embodiments,
Figure imgf000040_0001
is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl.
Figure imgf000040_0002
[00195] In some embodiments, the compound of Formula (I) has the structure of Formula
(la):
Figure imgf000040_0003
Formula (la) wherein Z1 is -N-, -CH-, or -C-.
Figure imgf000040_0004
is a substituted or unsubstituted monocyclic 5-membered heterocyclic ring containing at least one N atom, and the at least one N atom is adjacent to Z1.
[00197] In some embodiments,
Figure imgf000040_0005
Z1 is -N-, -CH-, or -C-; each Z2 is independently CRZ, NRZ, N, O, or S; each - - is independently a single or double bond; and with the provision that the 5-membered heterocyclic ring contains at least one N atom.
[00198] In some embodiments,
Figure imgf000041_0001
is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted thiazolidinyl, or substituted or unsubstituted isothiazolidinyl.
Figure imgf000041_0002
[00200] In some embodiments,
Figure imgf000041_0003
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazoyl, substituted or unsubstituted tetrazoyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted dithiazolyl.
Figure imgf000041_0004
Figure imgf000042_0001
[00202] In some embodiments,
Figure imgf000042_0002
is a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one N atom, and wherein the at least one N atom is adjacent to Z1.
[00203] In some embodiments,
Figure imgf000042_0003
each Z2 is independently CRZ or N.
[00204] In some embodiments,
Figure imgf000042_0004
is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl.
Figure imgf000042_0005
[00206] In some embodiments, the compound of Formula (I) has the structure of Formula
(Il-a):
Figure imgf000043_0001
[00207] In some embodiments, the compound of Formula (I) has a structure of Formula (II- b):
Figure imgf000043_0002
[00208] In some embodiments, the compound of Formula (I) has a structure of Formula (II- c):
Figure imgf000043_0003
[00209] In some embodiments, the compound of Formula (I) has a structure of Formula (II- d):
Figure imgf000043_0004
[00210] In some embodiments, the compound of Formula (I) is a compound having a structure selected from Formulas (Il-a), (Il-b), (II-c), and (Il-d).
[00211] In some embodiments, each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, each Rz is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cehaloalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl. In some embodiments, each Rz is independently hydrogen, halogen, or substituted or unsubstituted Ci- Cealkyl. In some embodiments, each Rz is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In some embodiments, each Rz is independently hydrogen, -F, -Cl, - methyl, ethyl, n- propyl, iso-propyl, or cyclopropyl. In some embodiments, each Rz is methyl.
[00212] In some embodiments, each Rz is -l Y1. In some embodiments, L1 is substituted or unsubstituted Ci-C4alkylene; and Y1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[00213] In some embodiments, each Rz is -L2-L3-Y2. In some embodiments, L2 is substituted or unsubstituted Ci-Cealkylene; L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, - O(C=O)-, -(C=O)NR3-, -(C=O)NR3-O-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, - NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-, -(SO2)NR3-, -(SO2)NR3-(C=O)-, -(SO2)NR3-(C=O)O-, -NR3(SO2)NR3-(C=O)-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently H or substituted or unsubstituted Ci-Cealkyl; and Y2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[00214] In some embodiments, L2 is absent; L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, -(C=O)NR3-O-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-, -(SO2)NR3-, -(SO2)NR3-(C=O)-, -(SO2)NR3-(C=O)O- , -NR3(SO2)NR3-(C=O)-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently H or substituted or unsubstituted Ci-Cealkyl; and Y2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [00215] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3.
In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
[00216] In one specific embodiment, m is 1 and Rz is methyl.
Figure imgf000045_0001
,
[00217] In some embodiments, the compound of Formula (I) has a structure of Formula (III-
Figure imgf000045_0002
Formula (Ill-a).
[00218] In some embodiments, the compound of Formula (I) has a structure of Formula (HI-
Figure imgf000046_0001
Formula (Ill-b).
[00219] In some embodiments, the compound of Formula (I) has a structure of Formula (III-
Figure imgf000046_0002
Formula (III-c).
[00220] In some embodiments, the compound of Formula (I) has a structure of Formula (III-
Figure imgf000046_0003
Formula (Ill-d).
[00221] In some embodiments, the compound of Formula (I) is a compound having a structure selected from Formulas (Ill-a), (Ill-b), (III-c), and (Ill-d).
[00222] In some embodiments, R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[00223] In some embodiments, R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted C3- Ciocycloalkyl, or substituted or unsubstituted aryl. In some embodiments, R and R’ are each independently substituted or unsubstituted Ci-Cealkyl or substituted or unsubstituted Ci-Cealkoxy. In some embodiments, R and R’ are each independently methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, or phenyl. In some embodiments, R and R’ are each independently methyl, ethyl, n-propyl, methoxy, ethoxy, n- propoxy, or iso-propoxy. In one embodiment, R and R’ are each methyl. In another embodiment, R and R’ are each ethyl. In yet another embodiment, R and R’ are each methoxy. In yet another embodiment, R and R’ are each ethoxy.
[00224] In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5- or 6-membered heterocycloalkyl. In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5-membered heterocycloalkyl.
[00225] In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000047_0001
wherein Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci- Cealkoxy. In certain embodiments, Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra, Rb, Rc, and Rd are each independently hydrogen or halogen. In certain embodiments, Ra, Rb, Rc, and Rd are each hydrogen. In certain embodiments, Ra, Rb, Rc, and Rd are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
[00226] In one embodiment, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000047_0002
[00227] In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000047_0003
; wherein Ra and Rb are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra and Rb are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, Ra and Rb are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra and Rb are each independently hydrogen or halogen. In certain embodiments, Ra and Rb are each hydrogen. In certain embodiments, Ra and Rb are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
[00228] In one embodiment, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000048_0001
[00229] In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 6-membered heterocycloalkyl. In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000048_0002
; wherein Ra, Rb, Rc, Rd and Re are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra, Rb, Rc, Rd and Re are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, Ra, Rb, Rc, Rd and Re are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra, Rb, Rc, Rd and Re are each independently hydrogen or halogen. In certain embodiments, Ra, Rb, Rc, Rd and Re are each hydrogen. In certain embodiments, Ra, Rb, Rc, Rd and Re are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
[00230] In one embodiment, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000048_0003
[00231] In some embodiments, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000048_0004
; wherein Ra, Rb, and Rc are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra, Rb, and Rc are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. In certain embodiments, Ra, Rb, and Rc are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkoxy. In certain embodiments, Ra, Rb, and Rc are each independently hydrogen or halogen. In certain embodiments, Ra, Rb, and Rc are each hydrogen. In certain embodiments, Ra, Rb, and Rc are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, or ethoxy.
[00232] In one embodiment, R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000049_0001
[00233] In some embodiments,
Figure imgf000049_0002
[00234] In some embodiments, the compound of Formula (I) has a structure of Formula (IV):
Figure imgf000049_0003
[00235] In some embodiments, the compound of Formula (I) has a structure of Formula (IV- a):
Figure imgf000049_0004
[00236] In some embodiments, the compound of Formula (I) has a structure of Formula (IV- b):
Figure imgf000049_0005
[00237] In some embodiments, the compound of Formula (I) has a structure of Formula (IV- c):
Figure imgf000050_0001
[00238] In some embodiments, the compound of Formula (I) has a structure of Formula (IV- d):
Figure imgf000050_0002
[00239] In some embodiments, the compound of Formula (I) is a compound having a structure selected from Formulas (IV), (IV-a), (IV-b), (IV-c), and (IV-d).
[00240] In some embodiments, the compound of Formula (I) is a compound having a structure selected from Formulas (IV-a), (IV-b), (IV-c), and (IV-d).
Figure imgf000050_0003
[00245] In some embodiments, the compound of Formula (I) has a structure of Formula (V):
Figure imgf000051_0001
[00249] In some embodiments, each R2 is independently hydrogen, halogen, nitro, -N3, -CN, -OR4, -SR4, -S(R4)5, -(S=O)R4, -(SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, or substituted or unsubstituted Cs-Ciocycloalkyl; each R4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl. [00250] In some embodiments, each R2 is independently F, Cl, Br, I, nitro, -CN, -SFs, -SCF3, -0CH2F, -0CHF2, -OCF3, -C(=O)OCH3 -S(=O)2CH3, - N(CH3)2, -NH(CH3), -CH2F, -CHF2, or - CF3. In some embodiments, each R2 is independently F, Cl, -CN, -OCF3, -CHF2, -SCF3, or -CF3. In some embodiments, each R2 is independently F, Cl, -OCF3, -CHF2, -SCF3, or -CF3. In some embodiments, each R2 is independently F, Cl, -SF5, -SCF3, or -CF3. In some embodiments, each R2 is independently F, Cl, -SF5, -OCF3, -SCF3, or -CF3. In one embodiment, each R2 is -CF3. In another embodiment, each R2 is -SF5. In yet another embodiment, each R2 is -SCF3. In yet another embodiment, each R2 is -OCF3.
[00251] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
[00252] In some embodiments, the compound of Formula (I) has a structure of Formula (VI):
Figure imgf000052_0001
[00253] In certain embodiments of compounds of Formula (VI),
Figure imgf000052_0002
Figure imgf000052_0005
compounds of Formula (
Figure imgf000052_0003
certain embodiments of compounds of Formula (
Figure imgf000052_0004
certain embodiments of compounds of Formula (
Figure imgf000053_0001
embodiments of compounds of Formula (
Figure imgf000053_0002
[00254] In some embodiments, the compound of Formula (I) is selected from the group consisting of:
Figure imgf000053_0003
[00255] In some embodiments, the compound disclosed herein has the structure provided in
Table 1.
TABLE 1
Figure imgf000053_0004
Figure imgf000054_0001
[00256] In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate thereof of a compound described in Table 1.
Preparation of the Compounds [00257] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).
[00258] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[00259] In some instances, specific and analogous reactants are identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., is contacted for more details). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
[00260] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section.
Further Forms of Compounds
Isomers
[00261] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (/■/), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, disclosed herein are dissociable complexes (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
Labeled compounds
[00262] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i. e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, /.< ., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.
[00263] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts [00264] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00265] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Solvates
[00266] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00267] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, 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. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Prodrugs
[00268] In some embodiments, the compounds described herein exist in prodrug form. The disclosure provides for methods of treating diseases by administering such prodrugs. The disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
[00269] In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three, or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of the present disclosure. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e. g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure. [00270] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy, or carboxylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.
[00271] Hydroxy prodrugs include esters such as, though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in
Advanced Drug Delivery Reviews 1996, 19, 115.
[00272] Amine derived prodrugs include, but are not limited to, the following groups and combinations of groups:
Figure imgf000059_0001
as well as sulfonamides and phosphonamides.
[00273] In certain instances, sites on any aromatic ring portions are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures reduce, minimize, or eliminate this metabolic pathway.
Metabolites [00274] In some embodiments, compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.
[00275] In additional or further embodiments, 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.
Pharmaceutical Compositions
[00276] In certain embodiments, the compound as described herein is administered as a pure chemical. In other embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.
[00277] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
[00278] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI), or a pharmaceutically acceptable salt thereof.
[00279] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI), or a pharmaceutically acceptable salt thereof.
[00280] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
[00281] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and/or are formulated for oral or subcutaneous administration.
[00282] In some instances, exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
[00283] For preparing solid compositions such as tablets in some instances, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.
[00284] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions also comprise buffering agents in some embodiments. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[00285] In some instances, a tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
[00286] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
[00287] Suspensions, in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[00288] In some embodiments, formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
[00289] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component is optionally mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which are required in some embodiments.
[00290] In some embodiments, the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
[00291] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[00292] Compositions and compounds disclosed herein are alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are used because they minimize exposing the agent to shear, which result in degradation of the compounds contained in the subject compositions in some embodiments. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
[00293] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which optionally contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [00294] Examples of suitable aqueous and non-aqueous carriers employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. In some embodiments, proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants [00295] Also contemplated are enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about
5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about
8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems e.g., Eudragit L30D55, Eudragit FS30D, Eudragit LIOO, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure will recognize that it is not comprehensive and that there are other enteric materials that meet the objectives of the present disclosure.
[00296] In some embodiments, the dose of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.
[00297] In some instances, pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.
[00298] In some embodiments, oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
The Hippo Signaling Network
[00299] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional coactivator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un- phosphorylated/de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer.
[00300] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (M0BKL1 A and MOBKL1B; homologues of Mats), respectively. In general, MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase. Latsl/2 is also activated by the scaffold protein Mob. The activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.
[00301] In some instances, Latsl/2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl/2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates YAP at all five of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
[00302] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK16/s in the degradation motif, which then signals for interaction with the P-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.
[00303] In some instances, Latsl/2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl/2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
[00304] In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCFp'TRCP-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, pTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g. SCFpTrCP1) interacts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.
[00305] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
YAP/TAZ Interaction with TEtOAcD (TEAD)
[00306] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ interacts with the TEtOAcD family of transcription factors (e.g., TEtOAcD 1, TEtOAcD2, TEtOAcD3, or TEtOAcD4) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61. and FGF1.
[00307] In some embodiments, the compounds disclosed herein modulate the interaction between YAP/TAZ and TEtOAcD. In some embodiments, the compounds disclosed herein bind to TEtOAcD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEtOAcD.
YAP/TAZ regulation mediated by G-proteins/GPCRs
[00308] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins. G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of alpha (Ga), beta (Gp), and gamma (Gy) subunits. In some cases, there are several classes of Ga subunits: Gq/ua, Gu/ua, Gi/Oa (G inhibitory, G other), and Gsa (G stimulatory).
[00309] In some instances, Gia (G inhibitory), Goa (G other), Gq/ua, and Gi2/na coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other instances, Gsa (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation. [00310] In some cases, Gia (G inhibitory), Goa (G other), Gq/ua, and Gn/na coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities. In contrast, Gsa, in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.
Gq Family
[00311] Gqa (also known as Gq/u protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca2+) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4,5- bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca2+ channel. In some cases, the binding triggers the opening of the Ca2+ channel, and thereby increases the release of Ca2+ into the cytoplasm.
[00312] In some embodiments, the GPCRs that interact with Gqa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1.
[00313] In some instances, there are several types of Gqa: Gq, Gq/n, Gq/i4, and Gq/i5. The Gq protein is encoded by GNAQ. Gq/n is encoded by GNA11. Gq/i4 is encoded by GNA14. Gq/i5 is encoded by GNA15.
[00314] In some instances, mutations or modifications of the Gqa genes have been associated with cancer. Indeed, studies have shown that mutations in Gqa promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
[00315] In some instances, mutations or modifications of the Gqa genes have been associated with congenital diseases. In some instances, mutations of Gqa have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ.
G 12/13 Family
[00316] Gi2/i3a modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g. Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
[00317] In some embodiments, the GPCRs that interact with Gi2/na include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g. SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g. LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; on adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.
[00318] In some instances, G12/1301 is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.
Gi/o Family
[00319] Gi/oO. (G inhibitory, G other) (also known as Gi/Go or Gi protein) suppresses the production of 3’,5’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
[00320] In some embodiments, the GPCRs that interact with Gia include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as a2A, a2B, and a2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GAB AB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H3 and EU receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as 6, K, p, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sstl, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.
[00321] In some instances, there are several types of Gia: Gial, Gia2, Gia3, Gia4, Goa, Gt, Ggust, and Gz. Gial is encoded by GNAI1. Gia2 is encoded by GNAI2. Gia3 is encoded by GNAI3. Goa, the a0 subunit, is encoded by GNAO1. Gt is encoded by GNAT1 and GNAT2. Ggustis encoded by GNAT3. Gzis encoded by GNAZ.
Gs Family
[00322] Gsa (also known as G stimulatory, Gs alpha subunit, or Gs protein) activates the cAMP-dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with Gsa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); P-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.
[00323] In some instances, there are two types of Gsa: Gs and Goif. Gs is encoded by GNAS. Goif is encoded by GN AL.
Additional Regulators of the Hippo signaling network
[00324] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.
[00325] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.
[00326] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E- cad-associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
[00327] In some embodiments, additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2. [00328] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP).
[00329] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway. In some instances, the one or more proteins comprise a protein described above. 1 and/or 2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the Gqa family proteins such as Gq, Gq/n, Gq/u, and Gq/15; the Gn/na family of proteins such as G12 and G13; or the Gia family of proteins such as Gial, Gia2, Gia3, Gia4, Goa, Gt, Ggust, and Gz. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/u. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/i4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/i5. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gial. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goa. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gz.
[00330] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.
[00331] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g. 26S proteasome).
[00332] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
[00333] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.
[00334] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease. USP47 is a member of the ubiquitinspecific protease (USP/UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.
[00335] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.
[00336] In another aspect, the present disclosure provides a method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00337] In another aspect, the present disclosure provides a method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer, polycystic kidney disease, or liver fibrosis. In some embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[00338] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[00339] In another aspect, the present disclosure provides a method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00340] In yet another aspect, the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits the activity of one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00341] In yet another aspect, the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00342] In yet another aspect, provided herein are uses of a compound of Formula (I), (la), (Il-a), (n-b), (II-c), (D-d), (in-a), (in-b), (III-c), (in-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI) as disclosed herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating a disease or disorder (e.g., a disease or disorder conducive to treatment to prevention by inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof. [00343] In another aspect, a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof, such cancer. Such a compound is, for example, a compound of Formula (I), (la), (Il-a), (Il-b), (II- c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI) as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
[00344] In another aspect, provided herein are pharmaceutical compositions comprising a compound Formula (I), (la), (Il-a), (Il-b), (II-c), (Il-d), (Ill-a), (Ill-b), (III-c), (Ill-d), (IV), (IV-a), (IV-b), (IV-c), (IV-d), (V), or (VI) as disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof.
Diseases
Cancer
[00345] In some embodiments, the compounds disclosed herein are useful for treating cancer. In some embodiments, disclosed herein is a method for treating a cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a compound for use in treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD. In some embodiments, the cancer is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga-protein is G12. In some embodiments, the mutant Ga-protein is G13. In some embodiments, the mutant Ga- protein is Gq. In some embodiments, the mutant Ga-protein is Gl 1. In some embodiments, the mutant Ga-protein is Gi. In some embodiments, the mutant Ga-protein is Go. In some embodiments, the mutant Ga-protein is Gs.
[00346] In some embodiments, the cancer is a solid tumor. In some instances, the cancer is a hematologic malignancy. In some instances, the solid tumor is a sarcoma or carcinoma. In some instances, the solid tumor is a sarcoma. In some instances, the solid tumor is a carcinoma.
[00347] Exemplary sarcoma includes, but is not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epithelioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET/extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma. [00348] Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some instances, the liver cancer is primary liver cancer.
[00349] In some instances, the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the cancer is uveal melanoma. In some cases, the cancer is mesothelioma. In some cases, the cancer is esophageal cancer. In some cases, the cancer is liver cancer. In some cases, the cancer is primary liver cancer.
[00350] In some instances, the cancer is a hematologic malignancy. In some embodiments, a hematologic malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a T-cell malignancy, or a B-cell malignancy. In some instances, a hematologic malignancy is a T-cell malignancy. Exemplary T-cell malignancy includes, but is not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, and treatment-related T-cell lymphomas.
[00351] In some instances, a hematologic malignancy is a B-cell malignancy. Exemplary B- cell malignancy includes, but is not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, and a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
[00352] In some instances, the cancer is a relapsed or refractory cancer. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma. In some embodiments, the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
[00353] In some instances, the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the relapsed or refractory cancer is relapsed or refractory mesothelioma. In some cases, the relapsed or refractory cancer is relapsed or refractory esophageal cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory primary liver cancer.
[00354] In some instances, the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy. In some embodiments, a relapsed or refractory hematologic malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin’s lymphoma, a relapsed or refractory Hodgkin’s lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
[00355] In some instances, the cancer is a metastasized cancer. In some instances, the metastasized cancer is a metastasized solid tumor. In some instances, the metastasized solid tumor is a metastasized sarcoma or a metastasized carcinoma. In some embodiments, the metastasized carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
[00356] In some instances, the metastasized cancer is selected from metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the metastasized cancer is metastasized uveal melanoma. In some cases, the metastasized cancer is metastasized mesothelioma. In some cases, the metastasized cancer is metastasized esophageal cancer. In some cases, the metastasized cancer is metastasized liver cancer. In some cases, the metastasized cancer is metastasized primary liver cancer.
[00357] In some instances, the metastasized cancer is a metastasized hematologic malignancy. In some embodiments, the metastasized hematologic malignancy is a metastasized leukemia, a metastasized lymphoma, a metastasized myeloma, a metastasized non-Hodgkin’s lymphoma, a metastasized Hodgkin’s lymphoma, a metastasized T-cell malignancy, or a metastasized B-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized T-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
Congenital Diseases
[00358] In some embodiments, the compounds disclosed herein are useful for treating a congenital disease. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the congenital disease is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga-protein is G12. In some embodiments, the mutant Ga-protein is G13. In some embodiments, the mutant Ga-protein is Gq. In some embodiments, the mutant Ga- protein is Gl 1. In some embodiments, the mutant Ga-protein is Gi. In some embodiments, the mutant Ga-protein is Go. In some embodiments, the mutant Ga-protein is Gs.
[00359] In some embodiments, the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, epigenetic modifications on a parental germline, or a chromosomal abnormality. Exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port-Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich’s ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase deficiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunodeficiency (SCID), Stickler syndrome (or hereditary progressive arthro- ophthalmopathy), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disease is Sturge-Weber Syndrome or Port-Wine stain. In some embodiments, the congenital disease is Sturge-Weber Syndrome. In some embodiments, the congenital disease is Port-Wine stain.
EXAMPLES
[00360] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
List of abbreviations
[00361] As used above, and throughout the disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile
Ac acetyl
Bn benzyl
BOC or Boc tert-butyl carbamate
Z-Bu tert-butyl
Cy cyclohexyl
°C degrees Celsius
DBA or dba dib enzy li deneacetone
DCE di chloroethane (CICH2CH2CI)
DCM dichloromethane (CH2Q2)
DIAD diisopropyl azodicarboxylate
DIPEA or DIEA diisopropylethylamine
DMAP 4-(7V,7V-dimethylamino)pyridine
DMF dimethylformamide DMA M -di methyl acetamide
DMSO dimethylsulfoxide
Dppf or dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
EA or EtO Ac ethyl acetate eq equivalent(s)
Et ethyl
Et2O diethyl ether
EtOH ethanol g gram(s) h hour(s)
HPLC high performance liquid chromatography
Hz hertz
LAH lithium aluminum anhydride
LCMS liquid chromatography mass spectrometry m/z mass-to-charge ratio
M molar
Me methyl
Mel methyl iodide
MeOH methanol mg milligram(s)
MHz megahertz umol micromole(s) uL microliter(s) mL milliliter(s) mmol millimole(s)
MS mass spectroscopy
MsCl methanesulfonyl chloride
MW micro wave radiation
NCS 7V-chlorosuccinimide
NMM M-methyl-morpholine
NMP M-methyl-pyrrolidin-2-one
NMR nuclear magnetic resonance
PE petroleum ether
Ph phenyl prep-HPLC preparative high pressure liquid chromatography prep-TLC preparative thin layer chromatography Py pyridine RP-HPLC reverse phase-high pressure liquid chromatography RT retention time
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMSC1 trimethyl silyl chloride
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
XPhos 2 -di cy clohexylphosphino-2 ',4 ', 6 ' -tri i sopropylbiphenyl
XPhos Pd G II chi oro(2-dicy clohexylphosphino-2', 4', 6'-triisopropyl-l, 1 biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II)
I. Chemical Synthesis
[00362] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times were approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted.
Example 1: Dimethyl(3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)phenyl)amino)phenyl)phosphine oxide (Compound 1)
Figure imgf000083_0001
Figure imgf000083_0002
2-Bromo-4-iodo-A-[4-(trifluoromethyl)phenyl]aniline (1C)
[00363] To a solution of 2-bromo-4-iodo-aniline (1A, 200 mg, 0.67 mmol, 1 eq), [4- (trifhioromethyl)phenyl]boronic acid (IB, 153.0 mg, 0.80 mmol, 1.2 eq) and Cu(OAc)2 (146.3 mg, 0.80 mmol, 1.2 eq) in DCM (4 mL) was added DIPEA (173.5 mg, 1.34 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 hours under O2. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and the resultant mixture was extracted with EA (30 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 :0 to 10: 1) to give intermediate 1C (60 mg, 98% purity) as red oil. 'H NMR (400MHz, CDCh) 8 7.88 (d, J= 2.0 Hz, 1H), 7.55 (d, J= 8.5 Hz, 2H), 7.51 (dd, J= 1.9, 8.6 Hz, 1H), 7.15 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.6 Hz, 1H), 6.19 (s, 1H).
2-Bromo-4-dimethylphosphoryl-7V-[4-(trifluoromethyl)phenyl]aniline (IE)
[00364] A solution of Pd2(dba)3 (10.3 mg, 11.3 umol, 0.05 eq) and Xantphos (13.0 mg, 22.6 umol, 0.1 eq) in dioxane (0.5 mL) was stirred at 25 °C for 20 min. A solution of intermediate 1C (100 mg, 0.22 mmol, 1 eq), methylphosphonoylmethane (ID, 17.6 mg, 0.22 mmol, 1 eq) and TEA (34.3 mg, 0.33 mmol, 1.5 eq) in dioxane (0.5 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EA (20 mL x 3). The combined organic layers were dried over ISfeSCU, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate : methol = 1 :0 to 5: 1) to give intermediate IE (45 mg, 46.6% yield, 92% purity) as a light yellow solid. LCMS (ESI): RT = 0.863 min, mass calcd for Ci5Hi4BrF3NOP 390.99 m/z, found 392.1 [M+H]+,
4-Dimethylphosphoryl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7V-[4- (trifluoromethyl)phenyl] aniline (IF)
[00365] To a solution of intermediate IE (45 mg, 0.11 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (43.7 mg, 0.17 mmol, 1.5 eq) and KOAc (22.5 mg, 0.22 mmol, 2 eq in dioxane (2 mL) was added Pd(dppf)C12 (4.2 mg, 5.7 umol, 0.05 eq), and then the reaction mixture was stirred at 90 °C for 1 hour under N2. The crude product intermediate IF (50 mg, 113.84 umol) was used in the next step without further purification.
4-Dimethylphosphoryl-2-(l-methylimidazol-4-yl)-A-[4-(trifluoromethyl)phenyl]aniline (Compound 1)
[00366] To a solution of intermediate IF (50 mg, 0.11 mmol, 1 eq), 4-bromo-l -methylimidazole (1G, 21.9 mg, 0.13 mmol, 1.2 eq) and NajCOs (24.1 mg, 0.22 mmol, 2 eq) in dioxane (2 mL) and H2O (0.4 mL) was added Pd(dppf)C12 (4.1 mg, 5.6 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The reaction mixture was stirred at 90°C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure, and was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by /vc -TLC (Petroleum ether: Ethyl acetate=10: l) to give a crude product, which was purified by /c -HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(0.05%NH3H20)-ACN]; B%: 34%-64%, 9.5min) to afford Compound 1 (2.08 mg, 4.4% yield, 96% purity) as a light yellow solid. LCMS (ESI): RT = 0.756 min, mass calcd for C19H19F3N3OP 393.12 m/z, found 394.2 [M+H]+,
XH NMR (400MHz, CDCh) 8 10.72 (s, 1H), 7.97 (dd, J= 1.8, 12.3 Hz, 1H), 7.58 - 7.48 (m, 4H), 7.36 (d, J= 1.0 Hz, 1H), 7.34 - 7.28 (m, 3H), 3.78 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H).
Example 2: Diethyl (3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)phenyl)amino)phenyl)phosphonate (Compound 2)
Figure imgf000085_0001
Dioxane Dioxane / H2O
2E
Figure imgf000085_0002
Diethyl (4-amino-3-bromophenyl)phosphonate (2B)
[00367] To a solution of Pd(OAc)2 (75.3 mg, 0.33 mmol, 0.05 eq), dppf (372.1 mg, 0.67 mmol, 0.1 eq) and KOAc (131.7 mg, 1.34 mmol, 0.2 eq) in dioxane (20 mL) was added TEA (1.36 g, 13.43 mmol, 1.87 mL, 2 eq) under N2, and then the reaction mixture was stirred at 65 °C for 15 min. After 2-bromo-4-iodo-aniline (1A, 2 g, 6.71 mmol, 543.48 uL, 1 eq) and 1- ethoxyphosphonoyl oxy ethane (2A, 1.11 g, 8.06 mmol, 1.04 mL, 1.2 eq) in dioxane (5 mL ) were added dropwise, the reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and the resultant mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 :0 to 1 :2) to give intermediate 2B (520 mg, 17% yield, 69 % purity) as brown oil.
Diethyl (3-bromo-4-((4-(trifluoromethyl)phenyl)amino)phenyl)phosphonate (2D) [00368] To a solution of intermediate 2B (400 mg, 1.30 mmol, 1 eq), l-iodo-4- (trifluoromethyl)benzene (2C, 423.7 mg, 1.56 mmol, 1.2 eq), Xantphos (75.1 mg, 0.12 mmol, 0.1 eq) and CS2CO3 (634.4 mg, 1.95 mmol, 1.5 eq) in Dioxane (5 mL) was added Pd2(dba)3 (59.4 mg, 64.9 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (15 mL) and the resultant mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = l :0to 1 : 1) to give intermediate 2D (450 mg, 74% yield, 97% purity) as a light yellow solid. LCMS (ESI): RT = 0.977 min, mass calcd for CnHisBrFsNOsP 451.02 m/z, found 454.1 [M+H]+.
Diethyl (3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl) amino)phenyl)phosphonate (2E)
[00369] To a solution of intermediate 2D (250 mg, 0.55 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (210.5 mg, 0.82 mmol, 1.5 eq) and KO Ac (108.5 mg, 1.11 mmol, 2 eq) in dioxane (5 mL) was added Pd(dppf)C12 (20.2 mg, 27.6 umol, 0.05 eq), and then the reaction mixture was stirred at 90 °C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (15 mL) and the resultant mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1 :0 to 2: 1) to give intermediate 2E as a brown solid. LCMS (ESI): RT = 1.080 min, mass calcd for C23H30BF3NO5P 499.19 m/z, found 500.3 [M+H]+.
Diethyl (3-( 1 -met hyl-1 //-ini idazol-4-yl)-4-((4-( trifl uoromethyl)phenyl)amino)phenyl) Phosphonate (Compound 2)
[00370] To a solution of intermediate 2E (100 mg, 0.20 mmol, 1 eq), 4-bromo-l -methylimidazole (1G, 32.2 mg, 0.20 mmol, 1 eq) and ISfeCCL (42.4 mg, 0.40 mmol, 2 eq) in Dioxane (2 mL) and H2O (0.4 mL) was added Pd(dppf)C12 (7.3 mg, 10.0 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 90°C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (DCM: MeOH = 1 :0 to 10: 1) to give a crude product, which was purified by /c -HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (0.05%NH3H20+10mM NH4HCO3)-ACN]; B%: 56%-86%, 7.8min) to afford Compound 2 (7.90 mg, 8.6% yield, 99% purity) as a white solid. LCMS (ESI): RT = 0.823 min, mass calcd for C21H23F3N3O3P 453.14 m/z, found 454.3 [M+H]+. 'H NMR (400 MHz, CDCh) 8 10.80 (br s, 1H), 8.01 - 7.91 (m, 1H), 7.57 - 7.47 (m, 5H), 7.37 - 7.30 (m, 3H), 4.23 - 4.00 (m, 4H), 3.82 - 3.75 (m, 3H), 1.34 (t, ./=7,0 Hz, 6H). Example 3: Diethyl(3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)phenyl)amino)phenyl)phosphine oxide (Compound 3)
Figure imgf000087_0001
2-Bromo-4-diethylphosphoryl-7V-[4-(trifluoromethyl)phenyl]aniline (3B)
[00371] A solution of Pd2(dba)3 (31.0 mg, 33.9 umol, 0.05 eq and Xantphos (39.2 mg, 67.8 umol, 0.1 eq) in dioxane (2.5 mL) was stirred at 25 °C for 20 min. A solution of intermediate 1C (300 mg, 0.67 mmol, 1 eq), 1-ethylphosphonoylethane (3A, 72.0 mg, 0.67 mumol, 1 eq) and TEA (103.0 mg, 1.02 mmol, 1.5 eq) in dioxane (2.5 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over ISfeSCU, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate: methol = 1 :0 to 10: 1) to give intermediate 3B (150 mg, 46.8% yield, 89% purity) as a brown solid. LCMS (ESI): RT = 0.897 min, mass calcd for CnHisBrFsNOP 419.03 m/z, found 420.2 [M+H]+.
4-Diethylphosphoryl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7V-[4- (trifluoromethyl)phenyl] aniline (3C)
[00372] To a solution of intermediate 3B (140 mg, 0.33 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (126.9 mg, 0.50 mmol, 1.5 eq) and KO Ac (65.4 mg, 0.66 mmol, 2 eq) in dioxane (2 mL) was added Pd(dppf)C12 (12.1 mg, 16.6 umol, 0.05 eq), and then the reaction mixture was stirred at 90 °C for 4 hours under N2. Intermediate 3C (150 mg, crude) was obtained as black solution, which was used in the next step without further purification. 4-Diethylphosphoryl-2-(l-methylimidazol-4-yl)-A-[4-(trifluoromethyl)phenyl]aniline (Compound 3)
[00373] To a solution of intermediate 3C (150 mg, 0.32 mmol, 1 eq), 4-bromo-l -methylimidazole (1G, 77.5 mg, 0.48 mmol, 1.5 eq) and lSfeCCL (68.0 mg, 0.64 mmol, 2 eq) in dioxane (2.5 mL) and H2O (0.5 mL) was added Pd(dppf)C12 (11.7 mg, 16.0 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 90°C for 4 hours under N2. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by /v -TLC (DCM: MeOH = 10: 1) to give a residue as a crude product, which was purified by p/c -HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [water (0.05% HC1)-ACN]; B%: 15%- 45%, 6.5min) to afford Compound 3 (3.62 mg, 2.4% yield, 99% purity, HC1) as a whtie solid. LCMS (ESI): RT = 0.710 min, mass calcd for C21H23F3N3OP 421.15 m/z, found 422.1 [M+H]+. 'H NMR (400 MHz, CD3OD) 8 8.99 (s, 1H), 7.88 - 7.80 (m, 2H), 7.78 - 7.71 (m, 1H), 7.61 (dd, J = 2.1, 8.4 Hz, 1H), 7.56 (d, J= 8.8 Hz, 2H), 7.21 (d, J= 8.5 Hz, 2H), 3.98 (s, 3H), 2.22 - 1.98 (m, 4H), 1.14 (td, J= 7.7, 17.2 Hz, 6H).
Example 4: l-(3-(l-Methyl-lH-imidazol-4-yl)-4-((4-
(trifluoromethyl)phenyl)amino)phenyl)phospholane 1-oxide (Compound 4)
Figure imgf000088_0001
1 phospholane 1-oxide (4A)
[00374] A solution of 1-ethoxyphosphonoyloxy ethane (2A, 1 g, 7.24 mmol, 0 .93 mL, 1 eq) in THF (10 mL) was added to a solution of bromo-[4-(bromomagnesio)butyl]magnesium (0.57 M, 18.92 mL, 1.5 eq) at 0 °C, and then the reaction mixture was allowed to warm up to 65 °C for 2 hours. The reaction mixture was quenched with MeOH (300 mL) at 0 °C, and then the suspension was filtered. The filtrate was concentrated under reduce pressure. The residue was purified by column chromatography on silica gel (DCM: MeOH = 1 :0 to 10: 1) to give intermediate 4A (132 mg, 1.27 mmol, 17.5% yield) as a colorless oil. XH NMR (400 MHz, CDCh) 6 8.04 (br s, 1H), 6.90 (br s, 1H), 2.09 - 1.97 (m, 4H), 1.86 - 1.74 (m, 4H).
2-Bromo-4-(l-oxo-lphospholan-l-yl)-7V-[4-(trifluoromethyl)phenyl]aniline (4B)
[00375] A solution of Pd2(dba)3 (31.0 mg, 33.9 umol, 0.05 eq) and Xantphos (39.2 mg, 67.8 umol, 0.1 eq) in dioxane (2 mL) was stirred at 25 °C for 20 min. A solution of intermediate 1C (300 mg, 0.67 mmol, 1 eq), intermediate 4A (70.6 mg, 0.67 mmol, 1 eq) and TEA (103.0 mg, 1.02 mmol, 0.14 mL, 1.5 eq) in dioxane (3 mL) was added dropwise, and then the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (15 mL) and the resultant mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over TsfeSCU, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate: methol = 1 :0 to 10: 1) to give intermediate 4B (205 mg, 475.50 umol, 70.06% yield, 97% purity) as a brown solid.
4-(l-Oxo-lphospholan-l-yl)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7V-[4- (trifluoromethyl)phenyl] aniline (4C)
[00376] To a solution of intermediate 4B (80 mg, 0.19 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (242.8 mg, 0.95 mmol, 5 eq) and KO Ac (37.5 mg, 0.38 mmol, 2 eq) in dioxane (1.5 mL) was added Pd(dppf)C12 (14.0 mg, 19.1 umol, 0.1 eq), and then the reaction mixture was stirred at 90 °C for 6 hours under N2. The crude product of intermediate 4C (89 mg, crude) was obtained as a black solution, which was used in the next step without further purification.
2-(l-Methylimidazol-4-yl)-4-(l-oxo-lphospholan-l-yl)-7V-[4-(trifluoromethyl)phenyl]aniline (Compound 4)
[00377] To a solution of intermediate 4C (89 mg, 0.19 mmol, 1 eq), 4-bromo-l -methylimidazole (1G, 46.2 mg, 0.28 mmol, 1.5 eq) and lSfeCCL (40.5 mg, 0.38 mmol, 2 eq) in dioxane (2.5 mL) and H2O (0.5 mL) was added Pd(dppf)C12 (7.0 mg, 9.5 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 90°C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and the resultant mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (DCM: MeOH = 1 :0 to 20: 1) to give a crude product, which was purified by /c -HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [water (0.05%HCl)-ACN]; B%: 15%-45%, 6.5min) to afford Compound 4 (4.90 mg, 10.5 umol, 5.51% yield, 98% purity, HC1) as a white solid. LCMS (ESI): RT = 0.780 min, mass calcd for C21H21F3N3OP 419.14 m/z, found 420.3 [M+H]+. 'H NMR (400 MHz, CD3CD) 8 9.00 (s, 1H), 7.93 - 7.83 (m, 2H), 7.78 (br t, J= 9.3 Hz, 1H), 7.62 (br d, J= 7.8 Hz, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.22 (br d, J= 8.0 Hz, 2H), 3.99 (s, 3H), 2.20 (br d, J= 8.3 Hz, 4H), 2.05 (br s, 4H).
Example 5: Dimethyl(3-(l-methyl-lH-imidazol-4-yl)-4-((4-(pentafluoro-k6- sulfaneyl)phenyl)amino)phenyl)phosphine oxide (Compound 5)
Figure imgf000090_0002
TE
Figure imgf000090_0004
, oxane
Figure imgf000090_0001
Cs2CO3
Dioxane
Figure imgf000090_0005
Figure imgf000090_0003
2-bromo-4-dimethylphosphoryl-aniline
[00378] A solution of Pd2(dba)3 (122.9 mg, 0.13 mmol, 0.05 eq) and Xantphos (155.3 mg, 0.26 mmol, 0.1 eq) in dioxane (1 mL) was stirred at 25 °C for 20 min. A solution of 2-bromo-4- iodo-aniline (1A, 800 mg, 2.69 mmol, 1 eq , methylphosphonoylmethane (ID, 419.1 mg, 5.37 mmol, 2 eq) and TEA (407.5 mg, 4.03 mmol, 0.56 mL, 1.5 eq) in Dioxane (1 mL) was added dropwise, and then the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and the resultant mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA: MeOH = 1 :0 to 10: 1) to give intermediate 5A (553 mg, 2.23 mmol, 83.0% yield) as yellow oil.
2-bromo-4-dimethylphosphoryl-7V-[4-(pentafluoro-sulfanyl)phenyl]aniline
[00379] To a solution of intermediate 5A (230 mg, 0.92 mmol, 1 eq), [4-(pentafluoro- sulfanyl)phenyl] trifluoromethanesulfonate (5B, 326.5 mg, 0.92 mmol, 1 eq), Xantphos (53.6 mg, 92.7 umol, 0.1 eq) and CS2CO3 (453.1 mg, 1.39 mmol, 1.5 eq) in dioxane (2 mL) was added Pd2(dba)3 (42.4 mg, 46.3 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by /v -TLC (DCM: MeOH = 10:1) to give intermediate 5C (260 mg, 0.46 mmol, 49.8% yield, 80% purity) as a light yellow solid.
4-dimethylphosphoryl-A-[4-(pentafluoro-k6-sulfanyl)phenyl]-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline
[00380] To a solution of intermediate 5C (150 mg, 0.33 mmol, 1 eq) and 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (126.9 mg, 0.49 mmol, 1.5 eq) in dioxane (1 mL) was added Pd(dppf)C12 (24.3 mg, 33.3 umol, 0.1 eq) and KOAc (65.40 mg, 0.66 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH = 100/1 to 101) to give intermediate 5D (120 mg, 0.24 mmol, 72% yield) as a black solid, which was used in the next step without further purification.
4-dimethylphosphoryl-2-(l-methylimidazol-4-yl)-A-[4-(pentafluoro-k6-sulfanyl)phenyl]aniline (Compound 5)
[00381] To a solution of intermediate 5D (60 mg, 0.12 mmol, 1 eq) and 1G (48.5 mg, 030 mmol, 2.5 eq) in H2O (0.1 mL) and dioxane (1 mL) was added ISfeCCL (25.5 mg, 0.24 mmol, 2.0 eq) and Pd(dppf)C12 (8.8 mg, 12.0 umol, 0.1 eq). The mixture was stirred at 90 °C for 16 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by /c -HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 15%-45%, 6.5 min) to afford Compound 5 (6.96 mg, 14.1 umol, 11.7% yield, 99% purity, HC1) as a white solid. LCMS (ESI): RT = 0.768 min, mass calcd for: C18H19F5N3OPS 451.09 m/z found 452.0 [M+H]+. 'H NMR (400 MHz, DMSO ) 69.26 (s, 1H), 8.88 (s, 1H), 8.16 - 7.96 (m, 2H), 7.79 (t, J = 9.0 Hz, 1H), 7.71 (d, = 9.0 Hz, 2H), 7.64 - 7.51 (m, 1H), 7.11 (d, J= 8.8 Hz, 2H), 3.87 (s, 3H), 1.71 (d, J= 13.6 Hz, 6H).
Example 6: Diethyl(3-(l-methyl-lH-imidazol-4-yl)-4-((4-(pentafluoro-k6- sulfaneyl)phenyl)amino)phenyl)phosphine oxide (Compound 6)
Figure imgf000092_0004
, Cs2CO3
Dioxane
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000092_0005
Figure imgf000092_0003
(4-Amino-3-bromophenyl)diethylphosphine oxide (6A)
[00382] Intermediate 6A was prepared using the procedure for intermediate 5A using 3A in lieu of ID.
2-Bromo-4-diethylphosphoryl-7V- [4-(pentafluoro-sulfanyl)phenyl] aniline (6B)
[00383] To a solution of intermediate 6A (50 mg, 0.18 mmol, 1 eq}, [4-(pentafluoro- sulfanyl)phenyl] trifluoromethanesulfonate (5B, 63.7 mg, 0.18 mmol, 1 eq}, Xantphos (10.4 mg, 18.1 umol, 0.1 eq} and CS2CO3 (88.5 mg, 0.27 mmol, 1.5 eq in dioxane (1 mL) was added Pd2(dba)3 (8.2 mg, 9.0 umol, 0.05 eq} under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (DCM: MeOH = 1 :0 to 10: 1) to give intermediate 6B (45 mg, 80.9 umol, 44.6% yield, 86% purity) as a light yellow oil. LCMS (ESI): RT = 0.911 min, mass calcd for: Ci6Hi8BrF5NOPS 477.00 m/z found 478.0 [M+H]+;
4-Diethylphosphoryl-7V-[4-(pentafluoro-sulfanyl)phenyl]-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline
[00384] To a solution of intermediate 6B (45 mg, 94.0 umol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (35.8 mg, 0.14 mmol, 1.5 eq) and KOAc (18.4 mg, 0.18 mmol, 2 eq) in dioxane (2 mL) was added Pd(dppf)C12 (3.4 mg, 4.7 umol, 0.05 eq), and then the reaction mixture was stirred at 90 °C for 2 hours under N2. Intermediate 6C (49 mg, 93.2 umol, 99.1% yield) was obtained as black solution, which was used in the next step without further purification.
2-[4-methoxy-3-(2-methyltetrazol-5-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]sulfanyl-pyrazine [00385] To a solution of intermediate 6C (49 mg, 93.2 umol, 1 eq), 4-bromo-l -methylimidazole (1G, 22.5 mg, 0.14 mmol, 1.5 eq) and lSfeCCL (19.7 mg, 0.18 mmol, 2 eq) in dioxane (2 mL) and H2O (0.4 mL) was added Pd(dppf)C12 (3.4 mg, 4.6 umol, 0.05 eq) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 90 °C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [water(0.05%HCl)-ACN]; B%: 20%- 50%, 6.5 min) to afford Compound 6 (2.42 mg, 4.55 umol, 4.88% yield, 97% purity, HC1) as a white solid. LCMS (ESI): RT = 0.799 min, mass calcd for: C20H23F5N3OPS 479.12 m/z found 480.1 [M+H]+. 'H NMR (400 MHz, CD3OD) 8 9.00 (s, 1H), 7.91 - 7.62 (m, 6H), 7.15 (br d, J= 8.3 Hz, 2H), 3.98 (s, 3H), 2.09 (br s, 4H), 1.14 (br s, 6H).
II. Biological Evaluation
Example Al: YAP Reporter Assay
[00386] HEK293T cells stably transfected with 8XTBD luciferase reporter and pRLTK in 384-well plates were treated with the test compounds, starting from 3 pM (final concentration in assay plate), 1 :3 dilution, and 10 points in quadruplicates. Post 24-hr incubation with compounds at 37 °C and 5% CO2, cells were lysed and 8XTBD-driven firefly luciferase and control TK-driven renilla luciferase activities were measured using Promega Dual-Luciferase Reporter Assay System. [00387] Reagents: The reagents used for this study were: DMEM: Invitrogen# 11960077, Dual-Glo Luciferase Assay System: Promega-E2980, Puromycin Dihydrochloride: Invitrogen- A1113803, 384-well plate: PerkinElmer-6007480, L-GLUTAMINE: Invitrogen-25030164, Hygromycin B: Invitrogen- 10687010 , and Penicillin-Streptomycin: Merk-TMS-AB2-C.
[00388] Media: The media used for this assay were: Culture Medium: DMEM+ lug/mL puromycin + 200 ug/mL hygromycin (with 10% FBS + ImM L-glutamine); and Assay Medium: DMEM (with 10% FBS + ImM L-glutamine + lx P/S).
[00389] Cell Plating: The appropriate media was warmed at 37 °C by water bath: Culture Medium, Assay Medium, lx D-PBS, 0.05% trypsin-EDTA. The cells were trypsinized after removing all media, then washed with lx sterile D-PBS and then with 2 ml 0.05% trypsin-EDTA. The cells were then incubated at RT for one minute. Then 10 mL/75 cm2 flask Assay Medium was added to each flask. Using a 10 mL pipette, the cells were then gently resuspended in the media, until the clumps completely disappeared. The cells were then transferred into 50 mL centrifuge tubes and were centrifuged at 800 rpm for 5 mins. The medium was removed, and the cells were resuspended with Assay Medium. An aliquot of cells was used to count the cell density (cells/mL). The cell suspension was then diluted with Assay Medium to a concentration of 6xl04 cells/mL. 50 pL cells suspension was then plated to 384-well plate (PerkinElmer-6007480), 3xl03 cells/well and the cells were incubated in an incubator at 37 °C, 5% CO2.
[00390] Compound Treatment: In the afternoon (incubation of the plate with 3-4 hrs), the test compounds were added by Echo, starting from 3 pM (final concentration in the assay plate), 1 :3 dilution, 10 points, quadruplicates. The plate was placed at 37°C, 5% CO2 incubator for 24hrs. [00391] Detection: The Dual-Glo Luciferase Reagent was prepared by transferring the contents of one bottle of Dual-Glo Luciferase Buffer to one bottle of Dual-Glo Luciferase Substrate to create the Dual-Glo Luciferase Reagent. Mixing was performed by inversion until the substrate was thoroughly dissolved. After mixing, the reagent was aliquoted into 15 mL tubes. In the afternoon (24 hrs post-compound treatment), the DMEM+ medium in the 384 well plates were aspirated by Microplate Washer.
[00392] Measuring firefly luciferase activity: 20 pL Dual-Glo Luciferase Reagent was added to the 384-well plates. The plates were protected from light to prevent interference with the assay. The plates were shaken for 1 min followed centrifuging plates at 1000 rpm for 30 seconds. After waiting at least 10 minutes, the firefly luminescence was measured by Envision. [00393] Measuring renilla luciferase activity: 20 pL Stop-Gio Reagent was added to the 384- well plates. The plates were shaken for 1 min and then centrifuged at lOOOrpm for 30 seconds.
After waiting at least 10 minutes, the renilla luminescence was measured by Envision.
[00394] Compounds’ IC50 and maximum inhibition on the firefly luciferase and renilla luciferase activities were reported separately. ICso’s for firefly luciferase activity of the tested compounds are shown in Table 2.
TABLE 2
Figure imgf000095_0001
Note: Biochemical assay IC50 data are designated within the following ranges: A: < 0.1 pM C: > 0.2 pM to < 1.0 pM
B: > 0.1 pM to < 0.2 pM D: > 1.0 pM < 10 pM
N.D.: Not determined Example A2: Tumor Suppression Assay
[00395] The procedures described herein for the tumor suppression assay is as described in PCT/US2013/043752 (WO 2013/188138). Mouse procedures are performed according to the guidelines of approved animal protocol and based on the methods. After the cells are grown to 90%> confluence, these cells are harvested by trypsinization, washed in phosphate-buffered saline (PBS), and resuspended in PBS supplemented with 50% Matrigel (BD Biosciences). An appropriate amount of cells is prepared for administration, such as 200 pL per injection site. Immuno-compromised mice are injected on the dorsolateral sites subcutaneously. Any one of the compounds described herein is formulated accordingly and is then administered at a suitable dose. Control mice received vehicle alone. The average tumor diameter (two perpendicular axes of the tumor are measured) are recorded. The data are expressed in tumor volume estimated by ([width]2 x length/2). Paired, two-tailed Student's t-test is performed to access the statistical significance.
Example A3: Cell Proliferation Assay
[00396] Cancer cell lines are plated in 384-well plates 24 hrs before drug treatment. Post incubation for various time periods with the test compounds, starting from 3 pM (final concentration in assay plate), 1 :3 dilution, and 10 points in duplicates, the number of viable cells and proliferative cells are determined using CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega) and Click-iT EdU HCS Assay Kit (Invitrogen) according to the manufacturers’ protocols. The IC50 values and maximum % inhibition of the test compounds are calculated using the dose response curves.
[00397] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000097_0001
Formula (I) wherein,
Figure imgf000097_0002
is a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl ring containing at least one N atom, or a substituted or unsubstituted monocyclic heteroaryl ring containing at least one N atom; each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -L^Y1, or -L2-L3-Y2; m is 0, 1, 2, 3, 4, or 5;
L1 is substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C2-Ciocyclolkylene, or substituted or unsubstituted C2- Cioheterocycloalkylene;
Y1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is absent, substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C3- Ciocyclolalkylene, or substituted or unsubstituted 3- to 10-membered heterocycloalkylene;
L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, -(C=O)NR3- O-, -O-NR3(C=O)-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-,-(SO2)NR3-, -(SO2)NR3-(C=O)-, -(C=O)-NR3(SO2)-, -(SO2)NR3-(C=O)O-, -O(C=O)- NR3(SO2)-, -NR3(SO2)NR3-(C=O)-, -(C=O)-NR3(SO2)NR3-, -O(C=O)-NR3(SO2)-NR3-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;
Y2 is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3 and Y2 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;
R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
Figure imgf000098_0001
substituted or unsubstituted phenyl or substituted or unsubstituted cyclohexyl; each R2 is independently hydrogen, halogen, -N3, -CN, -OR4, -SR4, -(SO2)R4, -S(R4)5, -(S=O)R4, - (SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl,
N=N substituted or unsubstituted heteroaryl, or
Figure imgf000098_0002
• n is 0, 1, 2, 3, 4, or 5; and each R4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
2. The compound or pharmaceutically acceptable salt of claim 1, wherein:
Figure imgf000098_0003
is a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl ring containing at least one N atom.
3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein:
Figure imgf000099_0001
is a substituted or unsubstituted monocyclic 5-membered heterocycloalkyl ring containing 1-4 N atoms, 0-2 O atoms, and 0-2 S atoms.
4. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein:
Figure imgf000099_0002
Z1 is -N-, -CH-, or -C-; each Z2 is independently -CRZ, -CHRZ-, -C(RZ)2-, -NRZ-, -N-, -O-, or -S-; each - - is independently a single or double bond.
5. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein:
Figure imgf000099_0003
is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted thiazolidinyl, or substituted or unsubstituted isothiazolidinyl.
6. The compound or pharmaceutically acceptable salt of claim 5, wherein:
Figure imgf000099_0004
7. The compound or pharmaceutically acceptable salt of claim 1, wherein:
Figure imgf000100_0001
is a substituted or unsubstituted monocyclic heteroaryl ring containing at least one N atom.
8. The compound or pharmaceutically acceptable salt of claim 7, wherein:
Figure imgf000100_0002
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing at least one N atom.
9. The compound or pharmaceutically acceptable salt of claim 8, wherein:
Figure imgf000100_0003
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 1 N atom.
10. The compound or pharmaceutically acceptable salt of claim 8, wherein:
Figure imgf000100_0004
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 2 N atoms.
11. The compound or pharmaceutically acceptable salt of claim 8, wherein:
Figure imgf000100_0005
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 3 N atoms.
12. The compound or pharmaceutically acceptable salt of claim 8, wherein:
Figure imgf000100_0006
a substituted or unsubstituted monocyclic 5-membered heteroaryl ring containing 4 N atoms.
13. The compound or pharmaceutically acceptable salt of claim 7, wherein:
Figure imgf000100_0007
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazoyl, substituted or unsubstituted tetrazoyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted dithiazolyl.
14. The compound or pharmaceutically acceptable salt of claim 13, wherein: (RZ)m— ( Z J is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted isoxazolyl.
15. The compound or pharmaceutically acceptable salt of claim 13 or 14, wherein:
Figure imgf000101_0001
is substituted or unsubstituted imidazolyl or substituted or unsubstituted pyrazolyl.
16. The compound or pharmaceutically acceptable salt of any one of claims 13-15, wherein:
Figure imgf000101_0002
. K J j j , , is substituted or unsubstituted imidazolyl.
17. The compound or pharmaceutically acceptable salt of claim 13, wherein:
Figure imgf000101_0003
Figure imgf000102_0001
19. The compound or pharmaceutically acceptable salt of claim 17 or 18, wherein:
Figure imgf000102_0002
20. The compound or pharmaceutically acceptable salt of any one of claims 17-19, wherein:
Figure imgf000102_0003
21. The compound or pharmaceutically acceptable salt of any one of claims 17-20, wherein:
Figure imgf000102_0004
22. The compound or pharmaceutically acceptable salt of claim 21, wherein:
Figure imgf000103_0003
24. The compound or pharmaceutically acceptable salt of any one of claims 17-20, wherein:
Figure imgf000103_0004
26. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has the structure of Formula (la)
Figure imgf000103_0001
Formula (la) wherein: Z1 is -N-, -CH-, or -C-.
27. The compound or pharmaceutically acceptable salt of claim 26, wherein:
Figure imgf000103_0002
is a substituted or unsubstituted monocyclic 5-membered heterocyclic ring containing at least one N atom, and the at least one N atom is adjacent to Z1.
28. The compound or pharmaceutically acceptable salt of claim 26 or 27, wherein:
Figure imgf000104_0001
Z1 is -N-, -CH-, or -C-; each Z2 is independently CRZ, NRZ, N, O, or S; each — is independently a single or double bond; and with the provision that the 5-membered heterocyclic ring contains at least one N atom.
29. The compound or pharmaceutically acceptable salt of claim 26 or 27, wherein:
Figure imgf000104_0002
is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted thiazolidinyl, or substituted or unsubstituted isothiazolidinyl.
30. The compound or pharmaceutically acceptable salt of claim 29, wherein:
Figure imgf000104_0003
31. The compound or pharmaceutically acceptable salt of claim 26, wherein:
Figure imgf000104_0004
is substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazoyl, substituted or unsubstituted tetrazoyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted dithiazolyl.
32. The compound or pharmaceutically acceptable salt of claim 26, wherein:
Figure imgf000105_0001
The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (Il-a):
Figure imgf000105_0002
Formula (Il-a). The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (Il-b):
Figure imgf000105_0003
Formula (Il-b).
35. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (II-c):
Figure imgf000106_0001
Formula (II-c).
36. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (Il-d):
Figure imgf000106_0002
Formula (Il-d).
37. The compound or pharmaceutically acceptable salt of any one of claims 1-36, wherein: each Rz is independently hydrogen, halogen, -CN, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
38. The compound or pharmaceutically acceptable salt of claim 37, wherein: each Rz is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl.
39. The compound or pharmaceutically acceptable salt of claim 37 or 38, wherein: each Rz is independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl.
40. The compound or pharmaceutically acceptable salt of claim 37 or 38, wherein: each Rz is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.
41. The compound or pharmaceutically acceptable salt of claim 40, wherein: each Rz is independently hydrogen, -F, -Cl, - methyl, ethyl, n-propyl, iso-propyl, or cyclopropyl.
42. The compound or pharmaceutically acceptable salt of claim 40, wherein: each Rz is methyl.
43. The compound or pharmaceutically acceptable salt of any one of claims 1-36, wherein Rz is
-IAY1.
44. The compound or pharmaceutically acceptable salt of claim 43, wherein:
L1 is substituted or unsubstituted Ci-C4alkylene; and
Y1 is substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
45. The compound or pharmaceutically acceptable salt of any one of claims 1-36, wherein Rz is -L2-L3-Y2.
46. The compound or pharmaceutically acceptable salt of claim 45, wherein:
L2 is substituted or unsubstituted Ci-Cealkylene;
L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, - (C=O)NR3-O-, -NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, - NR3(SO2)NR3-, -NR3(SO2)-, -(SO2)NR3-, -(SO2)NR3-(C=O)-, -(SO2)NR3-(C=O)O-, - NR3(SO2)NR3-(C=O)-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently H or substituted or unsubstituted Ci-Cealkyl; and
Y2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
47. The compound or pharmaceutically acceptable salt of claim 45, wherein:
L2 is absent;
L3 is -O-, -S-, -(S=O)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, - (C=O)NR3-O-,
-NR3(C=O)-, -NR3(C=O)NR3-, -O(C=O)NR3-, -NR3(C=O)O-, -NR3(SO2)NR3-, - NR3(SO2)-,
-(SO2)NR3-, -(SO2)NR3-(C=O)-, -(SO2)NR3-(C=O)O-, -NR3(SO2)NR3-(C=O)-, or -NR3(SO2)NR3-(C=O)O-; each R3 is independently H or substituted or unsubstituted Ci-Cealkyl; and
Y2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-
Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The compound or pharmaceutically acceptable salt of any one of claims 1-47, wherein m is 1, 2, or 3. The compound or pharmaceutically acceptable salt of claim 48, wherein m is 1 or 2. The compound or pharmaceutically acceptable salt of claim 48, wherein m is 1. The compound or pharmaceutically acceptable salt of any one of claims 1-42, wherein m is
1 and Rz is methyl. The compound or pharmaceutically acceptable salt of any one of claims 1-51, wherein:
Figure imgf000108_0001
The compound or pharmaceutically acceptable salt of claim 52, wherein:
Figure imgf000108_0002
The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (III- a):
Figure imgf000108_0003
Formula (Ill-a). The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (ITI-b):
Figure imgf000108_0004
Formula (Ill-b). The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (III-c):
Figure imgf000109_0001
Formula (III-c). The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of Formula (Ill-d):
Figure imgf000109_0002
Formula (Ill-d). The compound or pharmaceutically acceptable salt of any one of claims 1-57, wherein: R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The compound or pharmaceutically acceptable salt of claim 58, wherein:
R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The compound or pharmaceutically acceptable salt of claim 58, wherein:
R and R’ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted aryl. The compound or pharmaceutically acceptable salt of claim 58, wherein:
R and R’ are each independently substituted or unsubstituted Ci-Cealkyl or substituted or unsubstituted Ci-Cealkoxy. The compound or pharmaceutically acceptable salt of claim 58, wherein:
R and R’ are each independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, or phenyl. The compound or pharmaceutically acceptable salt of claim 58, wherein: R and R’ are each independently methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, or iso-propoxy. The compound or pharmaceutically acceptable salt of claim 63, wherein: R and R’ are each methyl. The compound or pharmaceutically acceptable salt of claim 63, wherein: R and R’ are each ethyl. The compound or pharmaceutically acceptable salt of claim 58, wherein: R and R’ are each methoxy. The compound or pharmaceutically acceptable salt of claim 58, wherein: R and R’ are each ethoxy. The compound or pharmaceutically acceptable salt of any one of claims 1-57, wherein: R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. The compound or pharmaceutically acceptable salt of claim 68, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5- or 6-membered heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim 68 or 69, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 5-membered heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim 70, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000110_0001
wherein Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. The compound or pharmaceutically acceptable salt of claim 71, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000110_0002
The compound or pharmaceutically acceptable salt of claim 70, wherein: R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000111_0001
; wherein Ra and Rb are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. The compound or pharmaceutically acceptable salt of claim 73, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000111_0002
The compound or pharmaceutically acceptable salt of claim 68 or 69, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form a substituted or unsubstituted P-containing 6-membered heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim 70, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000111_0003
wherein Ra, Rb, Rc, Rd and Re are each independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Cealkoxy. The compound or pharmaceutically acceptable salt of claim 76, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000111_0004
The compound or pharmaceutically acceptable salt of claim 70, wherein:
R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000111_0005
wherein Ra, Rb, and Rc are each independently hydrogen, halogen, or substituted or unsubstituted Ci-Cealkyl. The compound or pharmaceutically acceptable salt of claim 78, wherein: R and R’ taken together with the phosphorus atom to which they are attached to form
Figure imgf000112_0001
80. The compound or pharmaceutically acceptable salt of any one of claims 1-79, wherein:
Figure imgf000112_0002
81. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has the structure of Formula (IV):
Figure imgf000112_0003
82. The compound or pharmaceutically acceptable salt of claim 81, wherein the compound has the structure of Formula (IV-a):
Figure imgf000112_0004
83. The compound or pharmaceutically acceptable salt of claim 81, wherein the compound has the structure of Formula (IV-b):
Figure imgf000112_0005
84. The compound or pharmaceutically acceptable salt of claim 81, wherein the compound has the structure of Formula (IV-c), or a pharmaceutically acceptable salt thereof:
Figure imgf000113_0001
Formula (IV-c).
85. The compound or pharmaceutically acceptable salt of claim 81, wherein the compound has the structure of Formula (IV-d), or a pharmaceutically acceptable salt thereof:
Figure imgf000113_0002
ormul a (IV -d) .
86. The compound or pharmaceutically acceptable salt of any one of claims 80-85, wherein:
Figure imgf000113_0003
87. The compound or pharmaceutically acceptable salt of any one of claims 80-85, wherein:
Figure imgf000113_0004
88. The compound or pharmaceutically acceptable salt of claim 87, wherein:
Figure imgf000113_0005
Figure imgf000113_0006
89. The compound or pharmaceutically acceptable salt of any one of claims 80-85, wherein:
Figure imgf000113_0007
90. The compound or pharmaceutically acceptable salt of any one of claims 1-79, wherein:
Figure imgf000114_0001
91. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has the structure of Formula (V):
Figure imgf000114_0002
92. The compound or pharmaceutically acceptable salt of claim 90 or 91, wherein:
Figure imgf000114_0003
93. The compound or pharmaceutically acceptable salt of claim 90 or 91, wherein:
Figure imgf000114_0004
94. The compound or pharmaceutically acceptable salt of claim 90 or 91, wherein:
Figure imgf000114_0005
95. The compound or pharmaceutically acceptable salt of any one of claims 1-94, wherein: each R2 is independently hydrogen, halogen, nitro, -N3, -CN, -OR4, -SR4, -S(R4)5, -(S=O)R4, - (SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, or substituted or unsubstituted Cs-Ciocycloalkyl; each R4 is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cehaloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl.
96. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is independently F, Cl, Br, I, nitro, -CN, -SF5, -SCF3, -OCH2F, -OCHF2, -OCF3, -C(=O)OCH3 - S(=O)2CH3, - N(CH3)2, -NH(CH3), -CH2F, -CHF2, or -CF3.
97. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is independently F, Cl, -CN, -OCF3, -CHF2, -SCF3, or -CF3.
98. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is independently F, Cl, -OCF3, -CHF2, -SCF3, or -CF3.
99. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is independently F, Cl, -SFs, -SCF3, or -CF3.
100. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is independently F, Cl, -SFs, -OCF3, -SCF3, or -CF3.
101. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is -CF3.
102. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is -SFs.
103. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is -SCF3.
104. The compound or pharmaceutically acceptable salt of claim 95, wherein each R2 is -OCF3.
105. The compound or pharmaceutically acceptable salt of any one of claims 1-104, wherein n is
0, 1, or 2.
106. The compound or pharmaceutically acceptable salt of claim 105, wherein n is 1 or 2.
107. The compound or pharmaceutically acceptable salt of claim 105, wherein n is 1.
108. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound has the structure of Formula (VI):
Figure imgf000115_0001
109. The compound or pharmaceutically acceptable salt of claim 108, wherein
Figure imgf000115_0002
Figure imgf000115_0003
110. The compound or pharmaceutically acceptable salt of claim 109, wherein:
Figure imgf000116_0001
111. The compound or pharmaceutically acceptable salt of claim 110, wherein:
Figure imgf000116_0002
113. The compound or pharmaceutically acceptable salt of claim 109, wherein:
Figure imgf000116_0003
115. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound from Table 1.
116. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1-115, and a pharmaceutically acceptable excipient.
117. A method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject the compound or pharmaceutically acceptable salt of any one of claims 1-115, or a pharmaceutical composition of claim 116.
118. A method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject the compound or pharmaceutically acceptable salt of any one of claims 1-115, or a pharmaceutical composition of claim 116. The method of claim 117 or claim 118, wherein the subject has cancer, polycystic kidney disease or liver fibrosis. The method of claim 119, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer. A method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-115, or a pharmaceutical composition of claim 116. The method of claim 121, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer. A method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-115, or a pharmaceutical composition of claim 116.
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